Neurotransmitters

and Intro to Neuropeptides

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Contents
Articles
Neurotransmitter Neuropeptide Amino acid Alanine Aspartic acid Climbing fiber Cycloserine Dimethylglycine Gamma-Aminobutyric acid Globus pallidus Glutamic acid Somatostatin Cholecystokinin Thalamus Subthalamic nucleus Glycine Renshaw cell Hypotaurine Kynurenic acid N-Acetylaspartylglutamic acid Sarcosine Serine Taurine Trimethylglycine Cannabinoid 2-Arachidonoylglycerol 2-Arachidonyl glyceryl ether Anandamide N-Arachidonoyl dopamine Virodhamine Oleamide Palmitoylethanolamide RVD-Hp Hemopressin 1 7 10 24 28 32 34 36 38 44 49 55 62 66 73 78 83 86 87 89 92 95 99 104 108 119 122 124 127 128 130 132 136 137

Gasotransmitter Carbon monoxide Hydrogen sulfide Nitric oxide Nitrous oxide Biogenic amine Monoamine neurotransmitter Dopamine Dopaminergic pathways Mesocortical pathway Mesolimbic pathway Ventral tegmental area Frontal lobe Nucleus accumbens Nigrostriatal pathway Substantia nigra pars compacta Striatum Tuberoinfundibular pathway Hypothalamus Pituitary gland Epinephrine Neurotensin Melatonin N-Acetylserotonin Norepinephrine Neuropeptide Y Arcuate nucleus Locus coeruleus Solitary nucleus Galanin Enkephalin Serotonin Serotonin pathways Raphe nuclei Anterior raphespinal tract Lateral raphespinal tract Thyrotropin-releasing hormone Purine

138 140 152 162 172 185 186 188 205 206 207 209 215 222 226 228 230 234 235 246 251 259 264 275 277 287 293 295 300 302 309 311 321 322 325 326 326 330

Adenosine Adenosine diphosphate Adenosine monophosphate Adenosine triphosphate Trace amine 3-Iodothyronamine 5-MeO-DMT Bufotenin Dimethyltryptamine Norfenefrine Octopamine Meta-Tyramine Tyramine N-Methyltryptamine Phenethylamine Synephrine Thyronamine Tryptamine 1,4-Butanediol Acetylcholine Nucleus basalis of Meynert Neocortex Septal nuclei Medial septal nucleus Fornix of the brain Vasoactive intestinal peptide Substance P Hippocampus Gamma-Butyrolactone Gamma-Hydroxybutyric acid Histamine Vasopressin Dynorphin Supraoptic nucleus CRF Paraventricular nucleus of hypothalamus Oxytocin Cocaine and amphetamine regulated transcript

335 341 345 348 357 359 360 365 370 382 384 387 388 391 393 397 411 413 417 422 431 434 436 438 439 442 447 451 472 479 489 495 506 511 514 515 517 529

Capsaicin

532

References
Article Sources and Contributors Image Sources, Licenses and Contributors 542 554

Article Licenses
License 561

Neurotransmitter

Neurotransmitter
Structure of a typical chemical synapse

Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse.[1] Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane in the axon terminal, on the presynaptic side of a synapse. They are released into and diffuse across the synaptic cleft, where they bind to specific receptors in the membrane on the postsynaptic side of the synapse.[2] Release of neurotransmitters usually follows arrival of an action potential at the synapse, but may also follow graded electrical potentials. Low level "baseline" release also occurs without electrical stimulation. Many neurotransmitters are synthesized from plentiful and simple precursors, such as amino acids, which are readily available from the diet and which require only a small number of biosynthetic steps to convert.[]

Discovery
Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. However, through the careful histological examinations of Ramn y Cajal (18521934), a 20 to 40nm gap between neurons, known today as the synaptic cleft, was discovered. The presence of such a gap suggested communication via chemical messengers traversing the synaptic cleft, and in 1921 German pharmacologist Otto Loewi (18731961) confirmed that neurons can communicate by releasing chemicals. Through a series of experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate of frogs by controlling the amount of saline solution present around the vagus nerve. Upon completion of this experiment, Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical concentrations. Furthermore, Otto Loewi is accredited with discovering acetylcholine (ACh)the first known neurotransmitter.[3] Some neurons do, however, communicate via electrical synapses through the use of gap junctions, which allow specific ions to pass directly from one cell to another.[]

Identifying neurotransmitters
The chemical identity of neurotransmitters is often difficult to determine experimentally. For example, it is easy using an electron microscope to recognize vesicles on the presynaptic side of a synapse, but it may not be easy to determine directly what chemical is packed into them. The difficulties led to many historical controversies over whether a given chemical was or was not clearly established as a transmitter. In an effort to give some structure to the arguments, neurochemists worked out a set of experimentally tractable rules. According to the prevailing beliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets the following conditions:

Neurotransmitter There are precursors and/or synthesis enzymes located in the presynaptic side of the synapse. The chemical is present in the presynaptic element. It is available in sufficient quantity in the presynaptic neuron to affect the postsynaptic neuron. There are postsynaptic receptors and the chemical is able to bind to them. A biochemical mechanism for inactivation is present.

Modern advances in pharmacology, genetics, and chemical neuroanatomy have greatly reduced the importance of these rules. A series of experiments that may have taken several years in the 1960s can now be done, with much better precision, in a few months. Thus, it is unusual nowadays for the identification of a chemical as a neurotransmitter to remain controversial for very long periods of time.

Types of neurotransmitters
There are many different ways to classify neurotransmitters. Dividing them into amino acids, peptides, and monoamines is sufficient for some classification purposes. Major neurotransmitters: Amino acids: glutamate,[] aspartate, D-serine, -aminobutyric acid (GABA), glycine Monoamines and other biogenic amines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine (adrenaline), histamine, serotonin (SE, 5-HT) Peptides: somatostatin, substance P, opioid peptides[4] Others: acetylcholine (ACh), adenosine, anandamide, nitric oxide, etc. In addition, over 50 neuroactive peptides have been found, and new ones are discovered regularly. Many of these are "co-released" along with a small-molecule transmitter, but in some cases a peptide is the primary transmitter at a synapse. -endorphin is a relatively well known example of a peptide neurotransmitter; it engages in highly specific interactions with opioid receptors in the central nervous system. Single ions, such as synaptically released zinc, are also considered neurotransmitters by some,[5] as are some gaseous molecules such as nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO).[6] Because they are not packaged into vesicles they are not classical neurotransmitters by the strictest definition, however they have all been shown experimentally to be released by presynaptic terminals in an activity-dependent way. By far the most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain.[] The next most prevalent is GABA, which is inhibitory at more than 90% of the synapses that do not use glutamate. Even though other transmitters are used in far fewer synapses, they may be very important functionallythe great majority of psychoactive drugs exert their effects by altering the actions of some neurotransmitter systems, often acting through transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamine exert their effects primarily on the dopamine system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid peptides, which, in turn, regulate dopamine levels.

Excitatory and inhibitory

Some neurotransmitters are commonly described as "excitatory" or "inhibitory". The only direct effect of a neurotransmitter is to activate one or more types of receptors. The effect on the postsynaptic cell depends, therefore, entirely on the properties of those receptors. It happens that for some neurotransmitters (for example, glutamate), the most important receptors all have excitatory effects: that is, they increase the probability that the target cell will fire an action potential. For other neurotransmitters, such as GABA, the most important receptors all have inhibitory effects (although there is evidence that GABA is excitatory during early brain development). There are, however, other neurotransmitters, such as acetylcholine, for which both excitatory and inhibitory receptors exist; and there are some types of receptors that activate complex metabolic pathways in the postsynaptic cell to produce effects that cannot appropriately be called either excitatory or inhibitory. Thus, it is an oversimplification to call a

Neurotransmitter neurotransmitter excitatory or inhibitorynevertheless it is convenient to call glutamate excitatory and GABA inhibitory so this usage is seen frequently.

Actions
As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore, the effects of a neurotransmitter system depend on the connections of the neurons that use the transmitter, and the chemical properties of the receptors that the transmitter binds to. Here are a few examples of important neurotransmitter actions: Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Excess glutamate can overstimulate the brain and causes seizures.[citation needed] Modifiable synapses are thought to be the main memory-storage elements in the brain. Excessive glutamate release can lead to excitotoxicity causing cell death. GABA is used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA. Correspondingly glycine is the inhibitory transmitter in the spinal cord. Acetylcholine is distinguished as the transmitter at the neuromuscular junction connecting motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses. Acetylcholine also operates in many regions of the brain, but using different types of receptors, including nicotinic and muscarinic receptors.[7] Dopamine has a number of important functions in the brain; this includes regulation of motor behavior, pleasures related to motivation and also emotional arousal. It plays a critical role in the reward system; people with Parkinson's disease have been linked to low levels of dopamine and people with schizophrenia have been linked to high levels of dopamine.[8] Serotonin is a monoamine neurotransmitter. Most is produced by and found in the intestine (approximately 90%), and the remainder in central nervous system neurons. It functions to regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle contraction, and function of the cardiovascular system and endocrine system. It is speculated to have a role in depression, as some depressed patients are seen to have lower concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.[] Substance P is an undecapeptide responsible for transmission of pain from certain sensory neurons to the central nervous system. It also aids in controlling relaxation of the vasculature and lowering blood pressure through the release of nitric oxide.[9] Opioid peptides are neurotransmitters that act within pain pathways and the emotional centers of the brain; some of them are analgesics and elicit pleasure or euphoria.[10] Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where activation of the system affects large volumes of the brain, called volume transmission. Major neurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system and the cholinergic system. Drugs targeting the neurotransmitter of such systems affect the whole system; this fact explains the complexity of action of some drugs. Cocaine, for example, blocks the reuptake of dopamine back into the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap longer. Since the dopamine remains in the synapse longer, the neurotransmitter continues to bind to the receptors on the postsynaptic neuron, eliciting a pleasurable emotional response. Physical addiction to cocaine may result from prolonged exposure to excess dopamine in the synapses, which leads to the downregulation of some postsynaptic receptors. After the effects of the drug wear off, one might feel depressed because of the decreased probability of the neurotransmitter binding to a receptor. Prozac is a selective serotonin reuptake inhibitor (SSRI), which blocks re-uptake of serotonin by the presynaptic cell. This increases the amount of serotonin present at the synapse and allows it to remain there longer, hence potentiating the effect of naturally released serotonin.[] AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to

Neurotransmitter dopamine; reserpine prevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels. Diseases may affect specific neurotransmitter systems. For example, Parkinson's disease is at least in part related to failure of dopaminergic cells in deep-brain nuclei, for example the substantia nigra. Levodopa is a precursor of dopamine, and is the most widely used drug to treat Parkinson's disease. A brief comparison of the major neurotransmitter systems follows:

Neurotransmitter systems
System Noradrenaline system Dopamine system Origin locus coeruleus Lateral tegmental field dopamine pathways: Serotonin system mesocortical pathway mesolimbic pathway nigrostriatal pathway tuberoinfundibular pathway Increase (introversion), mood, satiety, body temperature and sleep, while decreasing nociception. learning short-term memory arousal reward [] arousal reward [] Effects

motor system, reward, cognition, endocrine, nausea

caudal dorsal raphe nucleus rostral dorsal raphe nucleus

Cholinergic system

pontomesencephalotegmental complex basal optic nucleus of Meynert medial septal nucleus

Common neurotransmitters
Category Small: Amino acids Neuropeptides Name Aspartate N-Acetylaspartylglutamate NAAG Abbreviation Metabotropic Metabotropic glutamate receptors; selective agonist of mGluR3 Metabotropic glutamate receptor Ionotropic -

Small: Amino acids

Glutamate (glutamic acid)

Glu

NMDA receptor, Kainate receptor, AMPA receptor GABAA, GABAA- receptor Glycine receptor Nicotinic acetylcholine receptor -

Small: Amino acids Small: Amino acids Small: Acetylcholine

Gamma-aminobutyric acid Glycine Acetylcholine

GABA Gly Ach

GABAB receptor Muscarinic acetylcholine receptor

Small: Monoamine (Phe/Tyr) Small: Monoamine (Phe/Tyr) Small: Monoamine (Phe/Tyr) Small: Monoamine (Phe/Tyr)

Dopamine

DA

Dopamine receptor

Norepinephrine (noradrenaline)

NE

Adrenergic receptor

Epinephrine (adrenaline)

Epi

Adrenergic receptor

Octopamine

Neurotransmitter

5
Tyramine -

Small: Monoamine (Phe/Tyr) Small: Monoamine (Trp) Small: Monoamine (Trp) Small: Diamine (His) PP: Gastrins PP: Gastrins

Serotonin (5-hydroxytryptamine)

5-HT

Serotonin receptor, all but 5-HT3 Melatonin receptor

5-HT3 -

Melatonin

Mel

Histamine Gastrin Cholecystokinin

Histamine receptor -

CCK AVP OT

Cholecystokinin receptor Vasopressin receptor Oxytocin receptor -

PP: Neurohypophyseals Vasopressin PP: Neurohypophyseals Oxytocin PP: Neurohypophyseals Neurophysin I PP: Neurohypophyseals Neurophysin II PP: Neuropeptide Y PP: Neuropeptide Y PP: Neuropeptide Y PP: Opioids Neuropeptide Y Pancreatic polypeptide Peptide YY

NY PP PYY

Neuropeptide Y receptor Corticotropin receptor

Corticotropin (adrenocorticotropic ACTH hormone) Dynorphin Endorphin Enkephaline Secretin Motilin Glucagon Vasoactive intestinal peptide VIP

PP: Opioids PP: Opioids PP: Opioids PP: Secretins PP: Secretins PP: Secretins PP: Secretins

Secretin receptor Motilin receptor Glucagon receptor Vasoactive intestinal peptide receptor Somatostatin receptor GRP NO CO Soluble guanylyl cyclase -

PP: Secretins PP: Somatostatins SS: Tachykinins SS: Tachykinins SS: Tachykinins PP: Other PP: Other Gas Gas

Growth hormone-releasing factor Somatostatin Neurokinin A Neurokinin B Substance P Bombesin Gastrin releasing peptide Nitric oxide Carbon monoxide

GRF

Heme bound to potassium channels P2X receptor

Other Other

Anandamide Adenosine triphosphate

AEA ATP

Cannabinoid receptor P2Y12

Neurotransmitter

Precursors of neurotransmitters
While intake of neurotransmitter precursors does increase neurotransmitter synthesis, evidence is mixed as to whether neurotransmitter release (firing) is increased. Even with increased neurotransmitter release, it is unclear whether this will result in a long-term increase in neurotransmitter signal strength, since the nervous system can adapt to changes such as increased neurotransmitter synthesis and may therefore maintain constant firing.[] Some neurotransmitters may have a role in depression, and there is some evidence to suggest that intake of precursors of these neurotransmitters may be useful in the treatment of mild and moderate depression.[][]

Dopamine precursors
L-DOPA,

a precursor of dopamine that crosses the bloodbrain barrier, is used in the treatment of Parkinson's

disease.

Norepinephrine precursors
For depressed patients where low activity of the neurotransmitter norepinephrine is implicated, there is only little evidence for benefit of neurotransmitter precursor administration. L-phenylalanine and L-tyrosine are both precursors for dopamine, norepinephrine, and epinephrine. These conversions require vitamin B6, vitamin C, and S-adenosylmethionine. A few studies suggest potential antidepressant effects of L-phenylalanine and L-tyrosine, but there is much room for further research in this area.[]

Serotonin precursors
Administration of L-tryptophan, a precursor for serotonin, is seen to double the production of serotonin in the brain. It is significantly more effective than a placebo in the treatment of mild and moderate depression.[] This conversion requires vitamin C.[] 5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is also more effective than a placebo.[]

Degradation and elimination

A neurotransmitter must be broken down once it reaches the post-synaptic cell to prevent further excitatory or inhibitory signal transduction. For example, acetylcholine (ACh), an excitatory neurotransmitter, is broken down by acetylcholinesterase (AChE). Choline is taken up and recycled by the pre-synaptic neuron to synthesize more ACh. Other neurotransmitters such as dopamine are able to diffuse away from their targeted synaptic junctions and are eliminated from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very specific degradation pathways at regulatory points, which may be the target of the body's own regulatory system or recreational drugs.

References
[2] [3] [4] [5] Elias, L. J, & Saucier, D. M. (2005). Neuropsychology: Clinical and Experimental Foundations. Boston: Pearson Saladin, Kenneth S. Anatomy and Physiology: The Unity of Form and Function. McGraw Hill. 2009 ISBN 0-07-727620-5 http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 38738 Kodirov,Sodikdjon A., Shuichi Takizawa, Jamie Joseph, Eric R. Kandel, Gleb P. Shumyatsky, and Vadim Y. Bolshakov. Synaptically released zinc gates long-term potentiation in fear conditioning pathways. PNAS, October 10, 2006. 103(41): 15218-23. [6] Nitric oxide and other gaseous neurotransmitters (http:/ / www. marsdd. com/ events/ details/ international-symposium-on-nitric-oxide-and-other-gaseous-neurotransmitters/ ) [7] http:/ / www. ebi. ac. uk/ interpro/ potm/ 2005_11/ Page2. htm [8] Schacter, Gilbert and Weger. Psychology.United States of America.2009.Print. [9] http:/ / www. wellnessresources. com/ health_topics/ sleep/ substance_p. php [10] Schacter, Gilbert and Weger. Psychology. 2009.Print.

Neurotransmitter

External links
Molecular Expressions Photo Gallery: The Neurotransmitter Collection (http://micro.magnet.fsu.edu/micro/ gallery/neurotrans/neurotrans.html) Brain Neurotransmitters (http://www.benbest.com/science/anatmind/anatmd10.html) Endogenous Neuroactive Extracellular Signal Transducers (http://www.neurotransmitter.net/neurosignaling. html) Neurotransmitter (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Neurotransmitter) at the US National Library of Medicine Medical Subject Headings (MeSH) neuroscience for kids website (http://faculty.washington.edu/chudler/chnt1.html) brain explorer website (http://www.brainexplorer.org/neurological_control/Neurological_Neurotransmitters. shtml) wikibooks cellular neurobiology (http://en.wikibooks.org/wiki/Neuroscience/Cellular_Neurobiology/ Neurotransmitters)

Neuropeptide
Neuropeptides are small protein-like molecules (peptides) used by neurons to communicate with each other. They are neuronal signaling molecules that influence the activity of the brain in specific ways. Different neuropeptides are involved in a wide range of brain functions, including analgesia, reward, food intake, metabolism, reproduction, social behaviors, learning and memory. Neuropeptides are related to peptide hormones, and in some cases peptides that function in the periphery as hormones also have neuronal functions as neuropeptides. The distinction between neuropeptide and peptide hormone has to do with the cell types that release and respond to the molecule; neuropeptides are secreted from neuronal cells (primarily neurons but also glia for some peptides) and signal to neighboring cells (primarily neurons). In contrast, peptide hormones are secreted from neuroendocrine cells and travel through the blood to distant tissues where they evoke a response. Both neuropeptides and peptide hormones are synthesized by the same sets of enzymes, which include prohormone convertases and carboxypeptidases that selectively cleave the peptide precursor at specific processing sites to generate the bioactive peptides. [1]

Neuropeptide Y

Neuropeptides modulate neuronal communication by acting on cell surface receptors. Many neuropeptides are co-released with other small-molecule neurotransmitters. The human genome contains about 90 genes that encode precursors of neuropeptides. At present about 100 different peptides are known to be released by different populations of neurons in the mammalian brain.[2] Neurons use many different chemical signals to communicate information, including neurotransmitters, peptides, cannabinoids, and even some gases, like nitric oxide. Peptides are unique among these cell-cell signaling molecules in several respects. One major difference is that peptides are not recycled back into the cell once secreted, unlike many conventional neurotransmitters (glutamate, dopamine, serotonin). Another difference is that after secretion, peptides are modified by extracellular peptidases; in some cases, these extracellular cleavages inactivate the biological activity, but in other cases the extracellular cleavages increase the affinity of a peptide for a particular receptor while decreasing its affinity for another receptor. These extracellular processing events add to the complexity of neuropeptides as cell-cell signaling molecules.

Neuropeptide Many populations of neurons have distinctive biochemical phenotypes. For example, in one subpopulation of about 3000 neurons in the arcuate nucleus of the hypothalamus, three anorectic peptides are co-expressed: -melanocyte-stimulating hormone (-MSH), galanin-like peptide, and cocaine-and-amphetamine-regulated transcript (CART), and in another subpopulation two orexigenic peptides are co-expressed, neuropeptide Y and agouti-related peptide (AGRP). These are not the only peptides in the arcuate nucleus; -endorphin, dynorphin, enkephalin, galanin, ghrelin, growth-hormone releasing hormone, neurotensin, neuromedin U, and somatostatin are also expressed in subpopulations of arcuate neurons. These peptides are all released centrally and act on other neurons at specific receptors. The neuropeptide Y neurons also make the classical inhibitory neurotransmitter GABA. Invertebrates also have many neuropeptides. CCAP has several functions including regulating heart rate, allatostatin and proctolin regulate food intake and growth, bursicon controls tanning of the cuticle and corazonin has a role in cuticle pigmentation and moulting. Peptide signals play a role in information processing that is different from that of conventional neurotransmitters, and many appear to be particularly associated with specific behaviours. For example, oxytocin and vasopressin have striking and specific effects on social behaviours, including maternal behaviour and pair bonding.

Function
Generally, peptides act at metabotropic or G-protein-coupled receptors expressed by selective populations of neurons. In essence they act as specific signals between one population of neurons and another. Neurotransmitters generally affect the excitability of other neurons, by depolarising them or by hyperpolarising them. Peptides have much more diverse effects; amongst other things, they can affect gene expression, local blood flow, synaptogenesis, and glial cell morphology. Peptides tend to have prolonged actions, and some have striking effects on behaviour. Neurons very often make both a conventional neurotransmitter (such as glutamate, GABA or dopamine) and one or more neuropeptides. Peptides are generally packaged in large dense-core vesicles, and the co-existing neurotransmitters in small synaptic vesicles. The large dense-core vesicles are often found in all parts of a neuron, including the soma, dendrites, axonal swellings (vericosities) and nerve endings, whereas the small synaptic vesicles are mainly found in clusters at presynaptic locations. Release of the large vesicles and the small vesicles is regulated differentially.

Examples
The following is a list of neuroactive peptides coexisting with other neurotransmitters. Transmitter names are shown in bold. Norepinephrine (noradrenaline). In neurons of the A2 cell group in the nucleus of the solitary tract), norepinephrine co-exists with: Galanin Enkephalin Neuropeptide Y GABA Somatostatin (in the hippocampus) Cholecystokinin Neuropeptide Y (in the arcuate nucleus) Acetylcholine VIP Substance P

Neuropeptide Dopamine Cholecystokinin Neurotensin Epinephrine (adrenaline) Neuropeptide Y Neurotensin Serotonin (5-HT) Substance P TRH Enkephalin Some neurons make several different peptides. For instance, Vasopressin co-exists with dynorphin and galanin in magnocellular neurons of the supraoptic nucleus and paraventricular nucleus, and with CRF (in parvocellular neurons of the paraventricular nucleus) Oxytocin in the supraoptic nucleus co-exists with enkephalin, dynorphin, cocaine-and amphetamine regulated transcript (CART) and cholecystokinin.

Diabetes link
A 2006 discovery might have important implications for treatment of diabetes,.[3][4] Researchers at the Toronto Hospital for Sick Children injected capsaicin into NOD mice (Non-obese diabetic mice, a strain that is genetically predisposed to develop the equivalent of Type 1 diabetes) to kill the pancreatic sensory nerves. This treatment reduced the development of diabetes in these mice by 80%, suggesting a link between neuropeptides and the development of Type 1 diabetes. When the researchers injected the pancreas of the diabetic mice with substance P, they were cured of the diabetes for as long as 4 months. Also, insulin resistance (characteristic of type 2 diabetes) was reduced. These research results are in the process of being confirmed, and their applicability in humans will have to be established in the future. Any treatment that could result from this research is probably years away.

Depression link
There are studies investigating the relation of neuropeptides and CNS disorders including depression.

References
[1] Neuropeptides and Other Bioactive Peptides: From Discovery to Function, L.D.Fricker, Morgan & Claypool Publishers, 2012, ISBN 978-1-61504-521-1, DOI 10.4199/C00056ED1V01Y201204NPE002 (http:/ / www. morganclaypool. com/ doi/ abs/ 10. 4199/ C00058ED1V01Y201205NPE003) [2] database of all neuropetides (http:/ / www. neuropeptides. nl) [3] T1DM, diabetes and trpv1 / capsaicin (http:/ / www. capsicum-capsaicin. com/ T1DM-diabetes-trpv1-capsaicin. html) [4] TRPV1+ Sensory Neurons Control Cell Stress and Islet Inflammation in Autoimmune Diabetes (http:/ / www. cell. com/ abstract/ S0092-8674(06)01465-6)

Neuropeptide

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External links
Neuropeptides Journal (http://www.intl.elsevierhealth.com/journals/npep/) Neuropeptides reference website (http://www.neuropeptides.nl/) Neuropeptides eBook series (http://www.morganclaypool.com/toc/npe/1/1)

Amino acid
Amino acids (/mino/, /mano/, or /mno/) are biologically important organic compounds made from amine (-NH2) and carboxylic acid (-COOH) functional groups, along with a side-chain specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen, though other elements are found in the side-chains of certain amino acids. About 500 amino acids are known[1] and can be classified in many ways. Structurally they can be classified according to the functional groups' locations as alpha- (-), beta- (-), gamma- (-) or delta- (-) amino acids; other categories relate to polarity, pH level, and side chain group type (aliphatic, acyclic, aromatic, containing hydroxyl or sulfur, etc.) In the form of proteins, amino acids comprise the second largest component (after water) of human muscles, cells and other tissues.[2] Outside proteins, amino acids perform critical roles in processes such as neurotransmitter transport and biosynthesis. Amino acids having both the amine and carboxylic acid groups attached to the first (alpha-) carbon atom have particular importance in biochemistry. They are known as 2-, alpha-, or -amino acids (generic formula H2NCHRCOOH in most cases[3] where R is an organic substituent known as a "side-chain");[4] often the term "amino acid" is used to refer specifically to these. They include the 23 proteinogenic ("protein-building") amino acids which combine into peptide chains ("polypeptides") to form the building blocks of a vast array of proteins.[] These are all L-stereoisomers ("left-handed" isomers)

The generic structure of an alpha amino acid in its un-ionized form

The 21 amino acids found in eukaryotes, grouped according to their side-chains' pKa values and charges carried at physiological pH 7.4

Amino acid although a few D-amino acids ("right-handed") occur in bacterial envelopes and some antibiotics.[5][6] 20 of the 23 proteinogenic amino acids are encoded directly by triplet codons in the genetic code and are known as "standard" amino acids. The other three ("non-standard" or "non-canonical") are pyrrolysine (found in methanogenic organisms and other eukaryotes), selenocysteine (present in many noneukaryotes as well as most eukaryotes), and N-Formylmethionine. For example, 25 human proteins include selenocysteine (Sec) in their primary structure,[7] and the structurally characterized enzymes (selenoenzymes) employ Sec as the catalytic moiety in their active sites.[8] Pyrollysine and selenocysteine are encoded via variant codons; for example, selenocysteine is encoded by stop codon and SECIS element.[9][10][] CodontRNA combinations not found in nature can also be used to "expand" the genetic code and create novel proteins known as alloproteins incorporating non-proteinogenic amino acids.[][][] Many important proteinogenic and non-proteinogenic amino acids also play critical non-protein roles within the body. For example: in the human brain, glutamate (standard glutamic acid) and gamma-amino-butyric acid ("GABA", non-standard gamma-amino acid) are respectively the main excitatory and inhibitory neurotransmitters;[] hydroxyproline (a major component of the connective tissue collagen) is synthesised from proline; the standard amino acid glycine is used to synthesise porphyrins used in red blood cells; and the non-standard carnitine is used in lipid transport. 9 of the 20 standard amino acids are called "essential" for humans because they cannot be created from other compounds by the human body, and so must be taken in as food. Others may be conditionally essential for certain ages or medical conditions. Essential amino acids may also differ between species.[11] Because of their biological significance, amino acids are important in nutrition and are commonly used in nutritional supplements, fertilizers, and food technology. Industrial uses include the production of drugs, biodegradable plastics and chiral catalysts.

11

History
The first few amino acids were discovered in the early 19th century. In 1806, French chemists Louis-Nicolas Vauquelin and Pierre Jean Robiquet isolated a compound in asparagus that was subsequently named asparagine, the first amino acid to be discovered.[12][] Cystine was discovered in 1810,[13] although its monomer, cysteine, remained undiscovered until 1884.[][14] Glycine and leucine were discovered in 1820.[15] Usage of the term amino acid in the English language is from 1898.[16] Proteins were found to yield amino acids after enzymatic digestion or acid hydrolysis. In 1902, Emil Fischer and Franz Hofmeister proposed that proteins are the result of the formation of bonds between the amino group of one amino acid with the carboxyl group of another, in a linear structure which Fischer termed peptide.[17]

Amino acid

12

General structure
In the structure shown at the top of the page, R represents a side-chain specific to each amino acid. The carbon atom next to the carboxyl group is called the carbon and amino acids with a side-chain bonded to this carbon are referred to as alpha amino acids. These are the most common form found in nature. In the alpha amino acids, the carbon is a chiral carbon atom, with the exception of glycine.[] In amino acids that have a carbon chain attached to the carbon (such as lysine, shown to the right) the carbons are labeled in order as , , , , and so on.[18] In some amino acids, the amine group is attached to the or -carbon, and these are therefore referred to as beta or gamma amino acids. Amino acids are usually classified by the properties Lysine with the carbon atoms in the side-chain labeled of their side-chain into four groups. The side-chain can make an amino acid a weak acid or a weak base, and a hydrophile if the side-chain is polar or a hydrophobe if it is nonpolar.[] The chemical structures of the 22 standard amino acids, along with their chemical properties, are described more fully in the article on these proteinogenic amino acids. The phrase "branched-chain amino acids" or BCAA refers to the amino acids having aliphatic side-chains that are non-linear; these are leucine, isoleucine, and valine. Proline is the only proteinogenic amino acid whose side-group links to the -amino group and, thus, is also the only proteinogenic amino acid containing a secondary amine at this position.[] In chemical terms, proline is, therefore, an imino acid, since it lacks a primary amino group,[19] although it is still classed as an amino acid in the current biochemical nomenclature,[20] and may also be called an "N-alkylated alpha-amino acid".[21]

Isomerism
Of the standard -amino acids, all but glycine can exist in either of two enantiomers, called L or D amino acids, which are mirror images of each other (see also Chirality). While L-amino acids represent all of the amino acids found in proteins during translation in the ribosome, D-amino acids are found in some proteins produced by enzyme posttranslational modifications after translation and translocation to the endoplasmic reticulum, as in exotic sea-dwelling organisms such as The two enantiomers of alanine, D-Alanine and cone snails.[22] They are also abundant components of the L-Alanine peptidoglycan cell walls of bacteria,[23] and D-serine may act as a neurotransmitter in the brain.[24] The L and D convention for amino acid configuration refers not to the optical activity of the amino acid itself, but rather to the optical activity of the isomer of glyceraldehyde from which that amino acid can, in theory, be synthesized (D-glyceraldehyde is dextrorotary; L-glyceraldehyde is levorotatory). In alternative fashion, the (S) and (R) designators are used to indicate the absolute stereochemistry. Almost all of the amino acids in proteins are (S) at the carbon, with cysteine being (R) and glycine non-chiral.[25] Cysteine is unusual since it has a sulfur atom at the second position in its side-chain, which has a larger atomic mass than the groups attached to the first carbon, which is attached to the -carbon in the other standard amino acids, thus the (R) instead of (S).

Amino acid

13

Zwitterions
The amine and carboxylic acid functional groups found in amino acids allow them to have amphiprotic properties.[] Carboxylic acid groups (CO2H) can be deprotonated to become negative carboxylates (CO2 ), and -amino groups (NH2) can be protonated to become positive + -ammonium groups ( NH3). At pH An amino acid in its (1) un-ionized and (2) zwitterionic forms values greater than the pKa of the carboxylic acid group (mean for the 20 common amino acids is about 2.2, see the table of amino acid structures above), the negative carboxylate ion predominates. At pH values lower than the pKa of the -ammonium group (mean for the 20 common -amino acids is about 9.4), the nitrogen is predominantly protonated as a positively charged -ammonium group. Thus, at pH between 2.2 and 9.4, the predominant form adopted by -amino acids contains a negative carboxylate and a positive -ammonium group, as shown in structure (2) on the right, so has net zero charge. This molecular state is known as a zwitterion, from the German Zwitter meaning hermaphrodite or hybrid.[26] Below pH 2.2, the predominant form will have a neutral carboxylic acid group and a positive -ammonium ion (net charge +1), and above pH 9.4, a negative carboxylate and neutral -amino group (net charge 1). The fully neutral form (structure (1) on the right) is a very minor species in aqueous solution throughout the pH range (less than 1 part in 107). Amino acids also exist as zwitterions in the solid phase, and crystallize with salt-like properties unlike typical organic acids or amines.

Isoelectric point
At pH values between the two pKa values, the zwitterion predominates, but coexists in dynamic equilibrium with small amounts of net negative and net positive ions. At the exact midpoint between the two pKa values, the trace amount of net negative and trace of net positive ions exactly balance, so that average net charge of all forms present is zero.[27] This pH is known as the isoelectric point pI, so pI = (pKa1 + pKa2). The individual amino acids all have slightly different pKa values, so have different isoelectric points. For amino acids with charged side-chains, the pKa of the side-chain is involved. Thus for Asp, Glu with negative side-chains, pI = (pKa1 + pKaR), where pKaR is the side-chain pKa. Cysteine also has potentially negative side-chain with pKaR = 8.14, so pI should be calculated as for Asp and Glu, even though the side-chain is not significantly charged at neutral pH. For His, Lys, and Arg with positive side-chains, pI = (pKaR + pKa2). Amino acids have zero mobility in electrophoresis at their isoelectric point, although this behaviour is more usually exploited for peptides and proteins than single amino acids. Zwitterions have minimum solubility at their isolectric point and some amino acids (in particular, with non-polar side-chains) can be isolated by precipitation from water by adjusting the pH to the required isoelectric point.

Amino acid

14

Occurrence and functions in biochemistry

Standard amino acids
Amino acids are the structural units (monomers) that make up proteins. They join together to form short polymer chains called peptides or longer chains called either polypeptides or proteins. These polymers are linear and unbranched, with each amino acid within the chain attached to two neighboring amino acids. The process of making proteins is called translation and involves the step-by-step addition of amino A polypeptide is an unbranched chain of amino acids. acids to a growing protein chain by a [28] ribozyme that is called a ribosome. The order in which the amino acids are added is read through the genetic code from an mRNA template, which is a RNA copy of one of the organism's genes. Twenty-two amino acids are naturally incorporated into polypeptides and are called proteinogenic or natural amino acids.[] Of these, 20 are encoded by the universal genetic code. The remaining 2, selenocysteine and pyrrolysine, are incorporated into proteins by unique synthetic mechanisms. Selenocysteine is incorporated when the mRNA being translated includes a SECIS element, which causes the UGA codon to encode selenocysteine instead of a stop codon.[29] Pyrrolysine is used by some methanogenic archaea in enzymes that they use to produce methane. It is coded for with the codon UAG, which is normally a stop codon in other organisms.[30] This UAG codon is followed by a PYLIS downstream sequence.[]

Amino acid

15

Non-standard amino acids

Aside from the 22 standard amino acids, there are many other amino acids that are called non-proteinogenic or non-standard. Those either are not found in proteins (for example carnitine, GABA), or are not produced directly and in isolation by standard cellular machinery (for example, hydroxyproline and selenomethionine). Non-standard amino acids that are found in proteins are formed by post-translational modification, which is modification after translation during protein synthesis. These modifications are often essential for the function or regulation of a protein; for example, the carboxylation of glutamate allows for better binding of calcium cations,[31] and the hydroxylation of proline is critical for maintaining connective tissues.[32] Another example is the formation of hypusine in the translation initiation factor EIF5A, through modification of a lysine residue.[33] Such modifications can also determine the localization of the protein, e.g., the addition of long hydrophobic groups can cause a protein to bind to a phospholipid membrane.[34]
The amino acid selenocysteine

Some nonstandard amino acids are not found in proteins. Examples include lanthionine, 2-aminoisobutyric acid, dehydroalanine, and the neurotransmitter gamma-aminobutyric acid. Nonstandard amino acids often occur as intermediates in the metabolic pathways for standard amino acids for example, ornithine and citrulline occur in the urea cycle, part of amino acid catabolism (see below).[35] A -alanine and its -alanine isomer rare exception to the dominance of -amino acids in biology is the -amino acid beta alanine (3-aminopropanoic acid), which is used in plants and microorganisms in the synthesis of pantothenic acid (vitamin B5), a component of coenzyme A.[36]

In human nutrition
When taken up into the human body from the diet, the 22 standard amino acids either are used to synthesize proteins and other biomolecules or are oxidized to urea and carbon dioxide as a source of energy.[37] The oxidation pathway starts with the removal of the amino group by a transaminase, the amino group is then fed into the urea cycle. The other product of transamidation is a keto acid that enters the citric acid cycle.[38] Glucogenic amino acids can also be converted into glucose, through gluconeogenesis.[39]

Amino acid Pyrrolysine trait is restricted to several microbes, and only one organism has both Pyl and Sec. Of the 22 standard amino acids, 9 are called essential amino acids because the human body cannot synthesize them from other compounds at the level needed for normal growth, so they must be obtained from food.[40] In addition, cysteine, taurine, tyrosine, and arginine are considered semiessential amino-acids in children (though taurine is not technically an amino acid), because the metabolic pathways that synthesize these amino acids are not fully developed.[41][42] The amounts required also depend on the age and health of the individual, so it is hard to make general statements about the dietary requirement for some amino acids.
Essential Histidine Isoleucine Leucine Lysine Methionine Nonessential Alanine Arginine* Asparagine Aspartic acid Cysteine*

16

Phenylalanine Glutamic acid Threonine Tryptophan Valine Glutamine* Glycine Ornithine* Proline* Serine* Tyrosine*

(*) Essential only in certain cases.[43][44]

Classification of Amino Acids

Although there are many ways to classify amino acids, these molecules can be assorted into six main groups, on the basis of their structure and the general chemical characteristics of their R groups.
Class Aliphatic Name of the amino acids Glycine, Alanine, Valine, Leucine, Isoleucine

Hydroxyl or Sulfur-containing Serine, Cysteine, Threonine, Methionine Cyclic Aromatic Basic Acidic and their Amide Proline Phenylalanine, Tyrosine, Tryptophan Histidine, Lysine, Arginine Aspartate, Glutamate, Asparagine, Glutamine

Amino acid

17

Non-protein functions
In humans, non-protein amino acids also have important roles as metabolic intermediates, such as in the biosynthesis of the neurotransmitter gamma-aminobutyric acid. Many amino acids are used to synthesize other molecules, for example: Tryptophan is a precursor of the neurotransmitter serotonin.[45] Tyrosine (and its precursor phenylalanine) are precursors of the catecholamine neurotransmitters dopamine, epinephrine and norepinephrine. Glycine is a precursor of porphyrins such as heme.[46] Arginine is a precursor of nitric oxide.[47] Ornithine and S-adenosylmethionine are precursors of polyamines.[48] Aspartate, glycine, and glutamine are precursors of nucleotides.[49] Phenylalanine is a precursor of various phenylpropanoids, which are important in plant metabolism. However, not all of the functions of other abundant non-standard amino acids are known. Some non-standard amino acids are used as defenses against herbivores in plants.[] For example canavanine is an analogue of arginine that is found in many legumes,[] and in particularly large amounts in Canavalia gladiata (sword bean).[50] This amino acid protects the plants from predators such as insects and can cause illness in people if some types of legumes are eaten without processing.[51] The non-protein amino acid mimosine is found in other species of legume, particularly Leucaena leucocephala.[52] This compound is an analogue of tyrosine and can poison animals that graze on these plants.

Uses in industry
Amino acids are used for a variety of applications in industry, but their main use is as additives to animal feed. This is necessary, since many of the bulk components of these feeds, such as soybeans, either have low levels or lack some of the essential amino acids: Lysine, methionine, threonine, and tryptophan are most important in the production of these feeds.[] In this industry, amino acids are also used to chelate metal cations in order to improve the absorption of minerals from supplements, which may be required to improve the health or production of these animals.[53] The food industry is also a major consumer of amino acids, in particular, glutamic acid, which is used as a flavor enhancer,[] and Aspartame (aspartyl-phenylalanine-1-methyl ester) as a low-calorie artificial sweetener.[54] Similar technology to that used for animal nutrition is employed in the human nutrition industry to alleviate symptoms of mineral deficiencies, such as anemia, by improving mineral absorption and reducing negative side effects from inorganic mineral supplementation.[55] The chelating ability of amino acids has been used in fertilizers for agriculture to facilitate the delivery of minerals to plants in order to correct mineral deficiencies, such as iron chlorosis. These fertilizers are also used to prevent deficiencies from occurring and improving the overall health of the plants.[56] The remaining production of amino acids is used in the synthesis of drugs and cosmetics.[]

Amino acid

18

Amino acid derivative 5-HTP (5-hydroxytryptophan) L-DOPA (L-dihydroxyphenylalanine) Eflornithine

Pharmaceutical application Experimental treatment for depression. Treatment for Parkinsonism. [58] [59] [57]

Drug that inhibits ornithine decarboxylase and is used in the treatment of sleeping sickness.

Expanded genetic code

Since 2001, 40 non-natural amino acids have been added into protein by creating a unique codon (recoding) and a corresponding transfer-RNA:aminoacyl tRNA-synthetase pair to encode it with diverse physicochemical and biological properties in order to be used as a tool to exploring protein structure and function or to create novel or enhanced proteins.[][]

Nullomers
Nullomers are codons which in theory code for an amino acid, however in nature there is a selective bias against using this codon in favor of another, for example bacteria prefer to use CGA instead of AGA to code for arginine.[60] This creates some sequences which do not appear in the genome, this characteristic can be taken advantage of and used to create new selective cancer fighting drugs[61] and to prevent cross contamination of DNA samples from crime scene investigations.[62]

Chemical building blocks

Amino acids are important as low-cost feedstocks. These compounds are used in chiral pool synthesis as enantiomerically pure building blocks.[] Amino acids have been investigated as precursors chiral catalysts, e.g., for asymmetric hydrogenation reactions, although no commercial applications exist.[]

Biodegradable plastics
Amino acids are under development as components of a range of biodegradable polymers. These materials have applications as environmentally friendly packaging and in medicine in drug delivery and the construction of prosthetic implants. These polymers include polypeptides, polyamides, polyesters, polysulfides, and polyurethanes with amino acids either forming part of their main chains or bonded as side-chains. These modifications alter the physical properties and reactivities of the polymers.[] An interesting example of such materials is polyaspartate, a water-soluble biodegradable polymer that may have applications in disposable diapers and agriculture.[] Due to its solubility and ability to chelate metal ions, polyaspartate is also being used as a biodegradeable anti-scaling agent and a corrosion inhibitor.[63][] In addition, the aromatic amino acid tyrosine is being developed as a possible replacement for toxic phenols such as bisphenol A in the manufacture of polycarbonates.[]

Reactions
As amino acids have both a primary amine group and a primary carboxyl group, these chemicals can undergo most of the reactions associated with these functional groups. These include nucleophilic addition, amide bond formation and imine formation for the amine group and esterification, amide bond formation and decarboxylation for the carboxylic acid group.[64] The combination of these functional groups allow amino acids to be effective polydentate ligands for metal-amino acid chelates.[65] The multiple side-chains of amino acids can also undergo chemical reactions.[66] The types of these reactions are determined by the groups on these side-chains and are, therefore, different between the various types of amino acid.

Amino acid

19

Chemical synthesis
Several methods exist to synthesize amino acids. One of the oldest methods begins with the bromination at the -carbon of a carboxylic acid. The Strecker amino acid synthesis Nucleophilic substitution with ammonia then converts the alkyl bromide to the amino acid.[67] In alternative fashion, the Strecker amino acid synthesis involves the treatment of an aldehyde with potassium cyanide and ammonia, this produces an -amino nitrile as an intermediate. Hydrolysis of the nitrile in acid then yields a -amino acid.[68] Using ammonia or ammonium salts in this reaction gives unsubstituted amino acids, while substituting primary and secondary amines will yield substituted amino acids.[69] Likewise, using ketones, instead of aldehydes, gives ,-disubstituted amino [70] acids. The classical synthesis gives racemic mixtures of -amino acids as products, but several alternative procedures using asymmetric auxiliaries [71] or asymmetric catalysts [72][73] have been developed.[74] At the current time, the most-adopted method is an automated synthesis on a solid support (e.g., polystyrene beads), using protecting groups (e.g., Fmoc and t-Boc) and activating groups (e.g., DCC and DIC).

Peptide bond formation

As both the amine and carboxylic acid groups of amino acids can react to form amide bonds, one amino acid molecule can react with another and become joined through an amide linkage. This polymerization of amino acids is what creates proteins. This condensation reaction yields the newly formed peptide bond and a molecule of water. In cells, this reaction does not occur directly; instead the amino acid is first activated by attachment to a transfer RNA molecule through an ester bond. This aminoacyl-tRNA is produced in an ATP-dependent reaction carried out by an aminoacyl tRNA synthetase.[75] This The condensation of two amino acids to form a dipeptide through a peptide bond aminoacyl-tRNA is then a substrate for the ribosome, which catalyzes the attack of the amino group of the elongating protein chain on the ester bond.[76] As a result of this mechanism, all proteins made by ribosomes are synthesized starting at their N-terminus and moving towards their C-terminus. However, not all peptide bonds are formed in this way. In a few cases, peptides are synthesized by specific enzymes. For example, the tripeptide glutathione is an essential part of the defenses of cells against oxidative stress. This peptide is synthesized in two steps from free amino acids.[77] In the first step gamma-glutamylcysteine synthetase condenses cysteine and glutamic acid through a peptide bond formed between the side-chain carboxyl of the glutamate (the gamma carbon of this side-chain) and the amino group of the cysteine. This dipeptide is then condensed with glycine by glutathione synthetase to form glutathione.[78]

Amino acid In chemistry, peptides are synthesized by a variety of reactions. One of the most-used in solid-phase peptide synthesis uses the aromatic oxime derivatives of amino acids as activated units. These are added in sequence onto the growing peptide chain, which is attached to a solid resin support.[79] The ability to easily synthesize vast numbers of different peptides by varying the types and order of amino acids (using combinatorial chemistry) has made peptide synthesis particularly important in creating libraries of peptides for use in drug discovery through high-throughput screening.[80]

20

Biosynthesis
In plants, nitrogen is first assimilated into organic compounds in the form of glutamate, formed from alpha-ketoglutarate and ammonia in the mitochondrion. In order to form other amino acids, the plant uses transaminases to move the amino group to another alpha-keto carboxylic acid. For example, aspartate aminotransferase converts glutamate and oxaloacetate to alpha-ketoglutarate and aspartate.[81] Other organisms use transaminases for amino acid synthesis, too. Nonstandard amino acids are usually formed through modifications to standard amino acids. For example, homocysteine is formed through the transsulfuration pathway or by the demethylation of methionine via the intermediate metabolite S-adenosyl methionine,[] while hydroxyproline is made by a posttranslational modification of proline.[82] Microorganisms and plants can synthesize many uncommon amino acids. For example, some microbes make 2-aminoisobutyric acid and lanthionine, which is a sulfide-bridged derivative of alanine. Both of these amino acids are found in peptidic lantibiotics such as alamethicin.[83] While in plants, 1-aminocyclopropane-1-carboxylic acid is a small disubstituted cyclic amino acid that is a key intermediate in the production of the plant hormone ethylene.[84]

Catabolism
Degradation of an amino acid often involves deamination by moving its amino group to alpha-ketoglutarate, forming glutamate. This process involves transaminases, often the same as those used in amination during synthesis. In many vertebrates, the amino group is then removed through the urea cycle and is excreted in the form of urea. However, amino acid degradation can produce uric acid or ammonia instead. For example, serine dehydratase converts serine to pyruvate and ammonia.[86] After removal of one or more amino groups, the remainder of the molecule can sometimes be used to synthesize new amino acids, or it can be used for energy by entering glycolysis or the citric acid cycle, as detailed in image at right.

Catabolism of proteinogenic amino acids. Amino acids can be classified according [85] to the properties of their main products as either of the following: * Glucogenic, with the products having the ability to form glucose by gluconeogenesis* Ketogenic, with the products not having the ability to form glucose. These products may still be used for ketogenesis or lipid synthesis.* Amino acids catabolized into both glucogenic and ketogenic products.

Physicochemical properties of amino acids

Amino acid The 20 amino acids encoded directly by the genetic code can be divided into several groups based on their properties. Important factors are charge, hydrophilicity or hydrophobicity, size, and functional groups.[] These properties are important for protein structure and proteinprotein interactions. The water-soluble proteins tend to have their hydrophobic residues (Leu, Ile, Val, Phe, and Trp) buried in the middle of the protein, whereas hydrophilic side-chains are exposed to the aqueous solvent. The integral membrane proteins tend to have outer rings of exposed hydrophobic amino acids that anchor them into the lipid bilayer. In the case part-way between these two extremes, some peripheral membrane proteins have a patch of hydrophobic amino acids on their surface that locks onto the membrane. In similar fashion, proteins that have to bind to positively charged molecules have surfaces rich with negatively charged amino acids like glutamate and aspartate, while proteins binding to negatively charged molecules have surfaces rich with positively charged chains like lysine and arginine. There are different hydrophobicity scales of amino acid residues.[87] Some amino acids have special properties such as cysteine, that can form covalent disulfide bonds to other cysteine residues, proline that forms a cycle to the polypeptide backbone, and glycine that is more flexible than other amino acids. Many proteins undergo a range of posttranslational modifications, when additional chemical groups are attached to the amino acids in proteins. Some modifications can produce hydrophobic lipoproteins,[88] or hydrophilic glycoproteins.[89] These type of modification allow the reversible targeting of a protein to a membrane. For example, the addition and removal of the fatty acid palmitic acid to cysteine residues in some signaling proteins causes the proteins to attach and then detach from cell membranes.[90]

21

Table of standard amino acid abbreviations and properties

Amino Acid 3-Letter [] 1-Letter [] Side-chain [] polarity nonpolar Basic polar polar acidic polar nonpolar acidic polar polar nonpolar Basic polar Side-chain charge [] (pH 7.4) neutral positive neutral negative neutral negative neutral neutral positive(10%) neutral(90%) neutral neutral positive neutral neutral neutral neutral neutral neutral Hydropathy [91] index 1.8 4.5 3.5 3.5 2.5 3.5 3.5 0.4 3.2 211 5.9 250 0.3 Absorbance [] max(nm) at max (x103 [] M1 cm1)

Alanine Arginine Asparagine Aspartic acid Cysteine Glutamic acid Glutamine Glycine Histidine

Ala Arg Asn Asp Cys Glu Gln Gly His

A R N D C E Q G H

Isoleucine Leucine Lysine Methionine Phenylalanine Proline Serine Threonine Tryptophan

Ile Leu Lys Met Phe Pro Ser Thr Trp

I L K M F P S T W

nonpolar nonpolar Basic polar nonpolar nonpolar nonpolar polar polar nonpolar

4.5 3.8 3.9 1.9 2.8 1.6 0.8 0.7 0.9 280, 219 5.6, 47.0 257, 206, 188 0.2, 9.3, 60.0

Amino acid

22
Tyr Val Y V polar nonpolar neutral neutral 1.3 4.2 274, 222, 193 1.4, 8.0, 48.0

Tyrosine Valine

Two additional amino acids are in some species coded for by codons that are usually interpreted as stop codons:
21st and 22nd amino acids 3-Letter 1-Letter Selenocysteine Pyrrolysine Sec Pyl U O

In addition to the specific amino acid codes, placeholders are used in cases where chemical or crystallographic analysis of a peptide or protein cannot conclusively determine the identity of a residue.
Ambiguous Amino Acids Asparagine or aspartic acid Glutamine or glutamic acid Leucine or Isoleucine Unspecified or unknown amino acid 3-Letter 1-Letter Asx Glx Xle Xaa B Z J X

Unk is sometimes used instead of Xaa, but is less standard. In addition, many non-standard amino acids have a specific code. For example, several peptide drugs, such as Bortezomib and MG132, are artificially synthesized and retain their protecting groups, which have specific codes. Bortezomib is Pyz-Phe-boroLeu, and MG132 is Z-Leu-Leu-Leu-al. To aid in the analysis of protein structure, photocrosslinking amino acid analogues are available. These include photoleucine (pLeu) and photomethionine (pMet).[92]

References and notes

[2] Human nutrition in the developing world (http:/ / www. fao. org/ docrep/ W0073E/ w0073e04. htm#P1625_217364) United Nations Food and Agriculture Organization, ch.8 [3] Proline is an exception to this general formula. It lacks the NH2 group because of the cyclization of the side-chain and is known as an imino acid; it falls under the category of special structured amino acids. [4] INTRODUCING AMINO ACIDS (http:/ / www. chemguide. co. uk/ organicprops/ aminoacids/ background. html) [5] "Biochemical pathways: an atlas of biochemistry and molecular biology" Michal, p.5 [7] Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigo R, et al. Characterization of mammalian selenoproteomes. Science. 2003;300:14391443. [8] Gromer, S., Urig, S., Becker, K. (2004) The Thioredoxin System - From Science to Clinic. Medicinal Research Reviews. 24(1):40-89. [9] Modeling Electrostatic Contributions to Protein Folding and Binding (http:/ / books. google. com/ books?id=BDn-AI_YBlMC& pg=PA1& lpg=PA1& ots=WSsFhHJwDy& sig=jkSLFr7AK8iu6OhdX7KOc10eKRY& hl=en& sa=X& ei=gshLUOWZLIin0AXRm4GoBg) Tjong, p.1 footnote [10] Frontiers in Drug Design and Discovery (http:/ / books. google. com/ books?id=VoJw6fIISSkC& pg=PA299& lpg=PA299& ots=C20L115r05& sig=4cix7yKNlod3xbzy2TWiOzEe6As& hl=en& sa=X& ei=H81LUL6MOfC10QX4wYG4Cw& ved=0CIcBEOgBMA8) ed. Atta-Ur-Rahman & others, p.299 [11] For example, ruminants such as cows obtain a number of amino acids via microbes in the first two stomach chambers. [85] Stipanuk, M. H. (2006). Biochemical, physiological, & molecular aspects of human nutrition (2 ed.): Saunders Elsevier.

Amino acid

23

Further reading
Tymoczko, John L. (2012). "Protein Composition and Structure". Biochemistry. New York: W. H. Freeman and company. pp.2831. ISBN9781429229364. Doolittle, Russell F. (1989). "Redundancies in protein sequences". In Fasman, G.D.. Predictions of Protein Structure and the Principles of Protein Conformation. New York: Plenum Press. pp.599623. ISBN978-0-306-43131-9. LCCN 89008555 (http://lccn.loc.gov/89008555). Nelson, David L.; Cox, Michael M. (2000). Lehninger Principles of Biochemistry (3rd ed.). Worth Publishers. ISBN978-1-57259-153-0. LCCN 99049137 (http://lccn.loc.gov/99049137). Meierhenrich, Uwe (2008). Amino acids and the asymmetry of life (http://rogov.zwz.ru/Macroevolution/ amino.pdf) (PDF, 11.2 MB). Berlin: Springer Verlag. ISBN978-3-540-76885-2. LCCN 2008930865 (http:// lccn.loc.gov/2008930865). Morelli, Robert J. (1952). Studies of amino acid absorption from the small intestine. San Francisco.

External links
The origin of the single-letter code for the amino acids (http://www.biology.arizona.edu/biochemistry/ problem_sets/aa/Dayhoff.html)

Alanine

24

Alanine
Alanine

Identifiers CAS number PubChem ChemSpider UNII EC-number KEGG ChEBI ChEMBL IUPHAR ligand Jmol-3D images 338-69-2 5950
[4] [5] [1]

(D-isomer) , 56-41-7

[2]

(L-isomer), 302-72-7

[3]

(racemic)

64234

(D-isomer) , 5735
[8]

[6]

(L-isomer), 582

[7]

(Racemic)

1FU7983T0U 206-126-4 C01401

[9]

[10]

CHEBI:57416

[11]

CHEMBL66693 720
[13] [14]

[12]

Image 1 [15] Image 2 Properties

Molecular formula Molar mass Appearance Density Melting point Solubility in water Acidity (pK )
a

C H NO
3 7

89.09 g mol1 white powder 1.424 g/cm3 258C, 531K, 496F (subl.) 167.2 g/L (25 C) 2.35 (carboxyl), 9.69 (amino) Supplementary data page
[16]

Alanine

25
Structure and properties Thermodynamic data Spectral data n, r, etc. Phase behaviour Solid, liquid, gas UV, IR, NMR, MS
(verify) [17]

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Alanine (abbreviated as Ala or A)[18] is an -amino acid with the chemical formula CH3CH(NH2)COOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid. L-Alanine is second only to leucine in rate of occurrence, accounting for 7.8% of the primary structure in a sample of 1,150 proteins.[19] D-Alanine occurs in bacterial cell walls and in some peptide antibiotics.

Structure
The -carbon atom of alanine is bound with a methyl group (-CH3), making it one of the simplest -amino acids with respect to molecular structure and also resulting in alanine's being classified as an aliphatic amino acid. The methyl group of alanine is non-reactive and is thus almost never directly involved in protein function.

Sources
Dietary sources
Alanine is a nonessential amino acid, meaning it can be manufactured by the human body, and does not need to be obtained directly through the diet. Alanine is found in a wide variety of foods, but is particularly concentrated in meats. Good sources of alanine include Animal sources: meat, seafood, caseinate, dairy products, eggs, fish, gelatin, lactalbumin Vegetarian sources: beans, nuts, seeds, soy, whey, brewer's yeast, brown rice, bran, corn, legumes, whole grains.

Biosynthesis
Alanine can be manufactured in the body from pyruvate and branched chain amino acids such as valine, leucine, and isoleucine. Alanine is most commonly produced by reductive amination of pyruvate. Because transamination reactions are readily reversible and pyruvate pervasive, alanine can be easily formed and thus has close links to metabolic pathways such as glycolysis, gluconeogenesis, and the citric acid cycle. It also arises together with lactate and generates glucose from protein via the alanine cycle.

Alanine

26

Chemical synthesis
Racemic alanine can be prepared by the condensation of acetaldehyde with ammonium chloride in the presence of sodium cyanide by the Strecker reaction, or by the ammonolysis of 2-bromopropanoic acid:[20]

Physiological function
Glucosealanine cycle
Alanine plays a key role in glucosealanine cycle between tissues and liver. In muscle and other tissues that degrade amino acids for fuel, amino groups are collected in the form of glutamate by transamination. Glutamate can then transfer its amino group through the action of alanine aminotransferase to pyruvate, a product of muscle glycolysis, forming alanine and -ketoglutarate. The alanine formed is passed into the blood and transported to the liver. A reverse of the alanine aminotransferase reaction takes place in liver. Pyruvate regenerated forms glucose through gluconeogenesis, which returns to muscle through the circulation system. Glutamate in the liver enters mitochondria and degrades into ammonium ion through the action of glutamate dehydrogenase, which in turn participate in the urea cycle to form urea.[21] The glucosealanine cycle enables pyruvate and glutamate to be removed from the muscle and find their way to the liver. Glucose is regenerated from pyruvate and then returned to muscle: the energetic burden of gluconeogenesis is thus imposed on the liver instead of the muscle. All available ATP in muscle is devoted to muscle contraction.[21]

Link to hypertension
An international study led by Imperial College London found a correlation between high levels of alanine and higher blood pressure, energy intake, cholesterol levels, and body mass index.[22]

Link to diabetes
Alterations in the alanine cycle that increase the levels of serum alanine aminotransferase (ALT) is linked to the development of type II diabetes. With an elevated level of ALT the risk of developing type II diabetes increases.[23]

(S)-Alanine (left) and (R)-alanine (right) in zwitterionic form at neutral pH

Alanine

27

Chemical properties
Free radical stability
The deamination of an alanine molecule produces a stable alkyl free radical, CH3CHCOO. Deamination can be induced in solid or aqueous alanine by radiation.[24] This property of alanine is used in dosimetric measurements in radiotherapy. When normal alanine is irradiated, the radiation causes certain alanine molecules to become free radicals, and, as these radicals are stable, the free radical content[citation needed] can later be measured by nuclear magnetic resonance in order to find out how much radiation the alanine was exposed to. Radiotherapy treatment plans can be delivered in test mode to alanine pellets, which can then be measured to check that the intended pattern of radiation dose is correctly delivered by the treatment system.

References
[1] [2] [3] [4] [5] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=338-69-2 http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=56-41-7 http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=302-72-7 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5950 http:/ / www. chemspider. com/ 64234

[6] http:/ / www. chemspider. com/ 5735 [7] http:/ / www. chemspider. com/ 582 [8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=1FU7983T0U [9] http:/ / ecb. jrc. ec. europa. eu/ esis/ index. php?GENRE=ECNO& ENTREE=206-126-4 [10] http:/ / www. kegg. jp/ entry/ C01401 [11] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=57416 [12] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL66693 [13] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=720 [14] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DC%28O%29C%28N%29C [15] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DC%28O%29%5BC%40H%5D%28N%29C [16] Dawson, R.M.C., et al., Data for Biochemical Research, Oxford, Clarendon Press, 1959. [17] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477316311& page2=Alanine [18] . [19] . [20] . [21] . [22] . [24] .

Aspartic acid

28

Aspartic acid
Aspartic acid

Identifiers CAS number 617-45-8 , 56-84-8 (L-isomer) 1783-96-6 (D-isomer) 424 411
[2] [3] [4] [1]

PubChem ChemSpider UNII EC-number KEGG ChEBI ChEMBL Jmol-3D images

28XF4669EP 200-291-6 C16433

[5]

[6]

CHEBI:22660

[7]

[8]

CHEMBL139661 Image 1 [10] Image 2 Properties

[9]

Molecular formula Molar mass Appearance Density Melting point Boiling point Solubility in water Acidity (pK )
a

C H NO
4 7

133.10 g mol1 colourless crystals 1.7 g/cm3 270C 324C (decomposes) 4.5 g/L 3.9 Hazards
[11]

Aspartic acid

29
MSDS EU Index NFPA 704 External MSDS not listed

Supplementary data page Structure and properties Thermodynamic data Spectral data
(verify) [12]

n, r, etc. Phase behaviour Solid, liquid, gas UV, IR, NMR, MS

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Aspartic acid (abbreviated as Asp or D)[13] is an -amino acid with the chemical formula HOOCCH(NH2)CH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins. Its codons are GAU and GAC. Aspartic acid is, together with glutamic acid, classified as an acidic amino acid with a pKa of 3.9, however in a peptide the pKa is highly dependent on the local environment. A pKa as high as 14 is not at all uncommon. Aspartate is pervasive in biosynthesis. As with all amino acids, the presence of acid protons depends on the residue's local chemical environment and the pH of the solution.

Discovery
Aspartic acid was first discovered in 1827 by Plisson, derived from asparagine, which had been isolated from asparagus juice in 1806, by boiling with a base.[14]

Forms and nomenclature

There are two forms or enantiomers of aspartic acid. The name "aspartic acid" can refer to either enantiomer or a mixture of two.[13] Of these two forms, only one, "L-aspartic acid", is directly incorporated into proteins. The biological roles of its counterpart, "D-aspartic acid" are more limited. Where enzymatic synthesis will produce one or the other, most chemical syntheses will produce both forms, "DL-aspartic acid," known as a racemic mixture.

Role in biosynthesis of amino acids

Aspartate is non-essential in mammals, being produced from oxaloacetate by transamination. It can also be generated from ornithine and citrulline in the urea cycle. In plants and microorganisms, aspartate is the precursor to several amino acids, including four that are essential for humans: methionine, threonine, isoleucine, and lysine. The conversion of aspartate to these other amino acids begins with reduction of aspartate to its "semialdehyde," O2CCH(NH2)CH2CHO.[15] Asparagine is derived from aspartate via transamidation: -O2CCH(NH2)CH2CO2- + GC(O)NH3+ O2CCH(NH2)CH2CONH3+ + GC(O)O (where GC(O)NH2 and GC(O)OH are glutamine and glutamic acid, respectively)

Aspartic acid

30

Other biochemical roles

Aspartate is also a metabolite in the urea cycle and participates in gluconeogenesis. It carries reducing equivalents in the malate-aspartate shuttle, which utilizes the ready interconversion of aspartate and oxaloacetate, which is the oxidized (dehydrogenated) derivative of malic acid. Aspartate donates one nitrogen atom in the biosynthesis of inosine, the precursor to the purine bases. In addition, aspartic acid acts as hydrogen acceptor in a chain of ATP synthase.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [16]

Glycolysis and Gluconeogenesis edit [17]

[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=617-45-8 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=424 [3] http:/ / www. chemspider. com/ 411 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=28XF4669EP [5] http:/ / ecb. jrc. ec. europa. eu/ esis/ index. php?GENRE=ECNO& ENTREE=200-291-6 [6] http:/ / www. kegg. jp/ entry/ C16433 [7] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=22660 [8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL139661 [9] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DC%28O%29CC%28N%29C%28%3DO%29O [10] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=C%28C%28C%28%3DO%29O%29N%29C%28%3DO%29O [11] http:/ / www. inchem. org/ documents/ icsc/ icsc/ eics1439. htm [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=464371725& page2=Aspartic+ acid [13] . [15] . [16] The interactive pathway map can be edited at WikiPathways: [17] http:/ / www. wikipathways. org/ index. php/ Pathway:WP534

Aspartic acid

31

Neurotransmitter
Aspartate (the conjugate base of aspartic acid) stimulates NMDA receptors, though not as strongly as the amino acid neurotransmitter glutamate does.[1]

Sources
Dietary sources
Aspartic acid is not an essential amino acid, which means that it can be synthesized from central metabolic pathway intermediates in humans. Aspartic acid is found in: Animal sources: luncheon meats, sausage meat, wild game Vegetable sources: sprouting seeds, oat flakes, avocado, asparagus[citation needed], young sugarcane, and molasses from sugar beets.[] Dietary supplements, either as aspartic acid itself or salts (such as magnesium aspartate) The sweetener aspartame (NutraSweet, Equal, Canderel, etc.)

Chemical synthesis
Racemic aspartic acid can be synthesized from diethyl sodium phthalimidomalonate, (C6H4(CO)2NC(CO2Et)2).[2] The major disadvantage of the above technique is that equimolar amounts of each enantiomer are made, but the body only utilizes L-amino acids. Using biotechnology it is now possible to use immobilised enzymes to create just one type of enantiomer owing to their stereospecificity. Aspartic acid is made synthetically using ammonium fumarate and aspartase from E.coli, E.coli usually breaks down the aspartic acid as a nitrogen source but using excess amounts of ammonium fumarate a reversal of the enzyme's job is possible, and so aspartic acid is made to very high yields, 98.7 mM from 1 M.

References
[2] .

External links
American Chemical Society (21 April 2010). "Ancestral Eve' Crystal May Explain Origin of Life's Left-Handedness" (http://www.sciencedaily.com/releases/2010/04/100421121501.htm). ScienceDaily. Archived (http://web.archive.org/web/20100423002752/http://www.sciencedaily.com/releases/2010/04/ 100421121501.htm) from the original on 23 April 2010. Retrieved 2010-04-21.

Climbing fiber

32

Climbing fiber
Neuron: Climbing fiber

Microcircuitry of the cerebellum. Excitatory synapses are denoted by (+) and inhibitory synapses by (-). Climbing fiber is shown originating from the inferior olive (green). Location Function Morphology Presynaptic connections Postsynaptic connections Gray's Inferior Olive and Cerebellum Unique excitatory function (see text) Unique projection neuron (see text) Inferior olive Purkinje cells subject #187 796 [1]

Climbing fibers are the name given to a series of neuronal projections from the inferior olivary nucleus located in the medulla oblongata.[][2] These axons pass through the pons and enter the cerebellum via the inferior cerebellar peduncle where they form synapses with the deep cerebellar nuclei and Purkinje cells. Each climbing fiber will form synapses with 1-10 Purkinje cells. Early in development, Purkinje cells are innervated by multiple climbing fibers, but as the cerebellum matures, these inputs gradually become eliminated resulting in a single climbing fiber input per Purkinje cell. These fibers provide very powerful, excitatory input to the cerebellum which results in the generation of complex spike excitatory postsynaptic potential (EPSP) in Purkinje cells.[] In this way climbing fibers (CFs) perform a central role in motor behaviors.[3] The climbing fibers carry information from various sources such as the spinal cord, vestibular system, red nucleus, superior colliculus, reticular formation and sensory and motor cortices. Climbing fiber activation is thought to serve as a motor error signal sent to the cerebellum, and is an important signal for motor timing. In addition to the control and coordination of movements,[] the climbing fiber afferent system contributes to sensory processing and cognitive tasks likely by encoding the timing of sensory input independently of attention or awareness .[4][5] [6] In the central nervous system, these fibers are able to undergo to remarkable regenerative modifications in response to injuries, being able to generate new branches by sprouting to innervate surrounding Purkinje cells if these lose their CF innervation.[] This kind of injury-induced sprouting has been shown to need the growth associated protein GAP-43.[] []

Climbing fiber

33

References
[1] [2] [4] [5] [6] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=187#p796 Image of Parallel fiber Xu D, Liu T, Ashe J, Bushara KO. Role of the olivo-cerebellar system in timing. J Neurosci 2006; 26: 5990-5. Liu T, Xu D, Ashe J, Bushara K. Specificity of inferior olive response to stimulus timing. J Neurophysiol 2008; 100: 1557-61. Wu X, Ashe J, Bushara KO. Role of olivocerebellar system in timing without awareness. Proc Natl Acad Sci U S A 2011.

External links
Climbing Fiber Discharge Regulates Cerebellar Functions by Controlling the intrinsic Characteristics of Purkinje Cell Output (http://www.ucalgary.ca/~rwturner/files/purkinje_trimodal_cf_07.pdf) Spatiotemporal Tuning of Optic Flow Inputs to the Vestibulocerebellum in Pigeons: Differences Between Mossy and Climbing Fiber Pathways (http://www.psych.ualberta.ca/~phurd/papers/Winship_etal05.pdf)

Cycloserine

34

Cycloserine
Cycloserine

Systematic (IUPAC) name

(R)-4-amino-1,2-oxazolidin-3-one
Clinical data Trade names AHFS/Drugs.com Pregnancy cat. Legal status Seromycin monograph C ? [1]

Pharmacokinetic data Bioavailability Metabolism Half-life Excretion ~70% to 90% Hepatic 10 hrs (normal renal function) Renal Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL NIAID ChemDB 68-41-7 [2]

J04AB01 CID 6234 DB00260 5998 [6]

[3] [4] [5]

95IK5KI84Z D00877 [8]

[7]

CHEBI:40009 CHEMBL771 007654 [11]

[9]

[10]

Chemical data

Cycloserine

35
Formula Mol. mass C3H6N2O2 102.092 g/mol

(what is this?) (verify)

[12]

Cycloserine is an antibiotic effective against Mycobacterium tuberculosis. For the treatment of tuberculosis, it is classified as a second line drug, i.e. its use is only considered if one or more first line drugs cannot be used. Although in principle active against other bacteria as well, cycloserine is not commonly used in the treatment of infections other than tuberculosis.

Mode of action
The terminal two amino acid residues of the murein precursor lipid II consist of D-alanine, which is produced by the enzyme alanine racemase; the two residues are joined by D-alanine ligase. Both enzymes are competitively inhibited by cycloserine.[]

Applications and side effects unrelated to antibiotic activity

It is also being trialed as an adjuvant to exposure therapy for anxiety disorders (e.g. phobias[]), depression, obsessive-compulsive disorder and schizophrenia. It has been experimentally used for treatment of Gaucher's disease. Recent research suggests that pain.[13]
D-cycloserine

(d-4-amino-3-isoxazolidinone) may be effective in treating chronic

The side effects are mainly central nervous system (CNS) manifestations, i.e. headache, irritability, depression, psychosis convulsions. Co-administration of pyridoxine can reduce the incidence of some of the CNS side effects (e.g. convulsions). These psychotropic responses are related to D-cycloserine's action as a partial agonist of the neuronal NMDA receptor for glutamate and have been examined in implications with sensory-related fear extinction in the amygdala,[] and extinction of cocaine seeking in the nucleus accumbens.[14]
D-cycloserine

is a partial agonist at the glycine receptor, and has been shown to have cognition-enhancing properties for models of Parkinsons disease in primates.[15]

References
[1] http:/ / www. drugs. com/ monograph/ cycloserine. html [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=68-41-7& rn=1 [3] http:/ / www. whocc. no/ atc_ddd_index/ ?code=J04AB01 [4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=6234 [5] http:/ / www. drugbank. ca/ drugs/ DB00260 [6] http:/ / www. chemspider. com/ Chemical-Structure. 5998 [7] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=95IK5KI84Z [8] http:/ / www. kegg. jp/ entry/ D00877 [9] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:40009 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL771 [11] http:/ / chemdb. niaid. nih. gov/ CompoundDetails. aspx?AIDSNO=007654 [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=460111047& page2=Cycloserine

Dimethylglycine

36

Dimethylglycine
Dimethylglycine

Identifiers CAS number PubChem ChemSpider EC number DrugBank KEGG MeSH ChEBI RTECS number Beilstein Reference Gmelin Reference 3DMet Jmol-3D images 1118-68-9 673 653
[2] [3] [4] [1]

214-267-8 DB02083 C01026

[5] [7]

[6]

dimethylglycine CHEBI:17724 MB9865000 1700261 82215 B00224

[9] [10]

[8]

Image 1 [11] Image 2 Properties

Molecular formula Molar mass Appearance Odor Density Melting point Boiling point

C H NO
4 9

103.12 g mol1 White crystals Odourless 1.069 g/mL 178-182C, 451-455K, 352-360F 175.2C, 448K, 347F Hazards

GHS pictograms

GHS signal word GHS hazard statements LD

50

WARNING H302 >650 mg kg1 (oral, rat) Related compounds

Dimethylglycine

37
Related alkanoic acids

Sarcosine Glycocyamine Creatine N-Methyl-D-aspartic acid beta-Methylamino-L-alanine Guanidinopropionic acid

Related compounds
(verify) [12]

Dimethylacetamide

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Dimethylglycine (DMG) is a derivative of the amino acid glycine with the structural formula (CH3)2NCH2COOH. It can be found in beans and liver. It can be formed from trimethylglycine upon the loss of one of its methyl groups. It is also a byproduct of the metabolism of choline. When DMG was first discovered, it was referred to as vitamin B16, but, unlike true B vitamins, deficiency of DMG in the diet does not lead to any ill-effects meaning it does not meet the definition of a vitamin.

Uses
Dimethylglycine has been suggested for use as an athletic performance enhancer, immunostimulant, and a treatment for autism, epilepsy, or mitochondrial disease.[13][] Published studies on the subject have shown little to no difference between DMG treatment and placebo in autism spectrum disorders.[14][15]

Preparation
This compound is commercially available as the free form amino acid, and as the hydrochloride salt [2491-06-7 [16] ]. DMG may be prepared by the alkylation of glycine via the EschweilerClarke reaction. In this reaction, glycine is treated with aqueous formaldehyde in formic acid that serves as both solvent and reductant. Hydrochloric acid is added thereafter to give the hydrochloride salt. The free amino acid may been obtained by neutralization of the acid salt, which has been performed with silver oxide.[17] H2NCH2COOH + 2 CH2O + 2 HCOOH (CH3)2NCH2COOH + 2 CO2 + 2 H2O

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=1118-68-9 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=673 [3] http:/ / www. chemspider. com/ 653 [4] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=214-267-8 [5] http:/ / www. drugbank. ca/ drugs/ DB02083 [6] http:/ / www. kegg. jp/ entry/ C01026 [7] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=dimethylglycine [8] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=17724 [9] http:/ / www. 3dmet. dna. affrc. go. jp/ html/ B00224. html [10] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CN%28C%29Cc%28%3A%5Bo%5D%29%3A%5BoH%5D [11] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CN%28C%29CC%28O%29%3DO [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=443693225& page2=Dimethylglycine [16] http:/ / toolserver. org/ ~magnus/ cas. php?language=en& cas=2491-06-7& title=

Gamma-Aminobutyric acid

38

Gamma-Aminobutyric acid
gamma-Aminobutyric acid

Identifiers CAS number PubChem ChemSpider UNII EC number DrugBank KEGG MeSH ChEBI ChEMBL IUPHAR ligand RTECS number Jmol-3D images 56-12-2 119 116
[2] [3] [4] [1]

2ACZ6IPC6I 200-258-6 DB02530 D00058

[5]

[6] [8]

[7]

gamma-Aminobutyric+Acid CHEBI:16865 CHEMBL96 1067

[11] [9]

[10]

ES6300000 Image 1 Properties

[12]

Molecular formula Molar mass Appearance Density Melting point Boiling point Solubility in water log P Acidity (pK )
a

C H NO
4 9

103.120 g/mol white microcrystalline powder 1.11 g/mL 203.7C, 477K, 399F 247.9C, 521K, 478F 130 g/100 mL -3.17 4.23 (carboxyl), 10.43 (amino)
[13]

Gamma-Aminobutyric acid

39
Hazards

Main hazards LD50

(verify) [14]

Irritant, Harmful 12,680 mg/kg (mouse, oral)

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

-Aminobutyric acid (/mHelp:IPA for English#KeyminobjutrkHelp:IPA for English#Keysd/ (GAMuh a-MEE-noh-byuu-TEER-ik asid); or GABA /b/) is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.[] Although chemically it is an amino acid, GABA is rarely referred to as such in the scientific or medical communities, because the term "amino acid," used without a qualifier, conventionally refers to the alpha amino acids, which GABA is not, nor is it ever incorporated into a protein. In spastic diplegia in humans, GABA absorption becomes impaired by nerves damaged from the condition's upper motor neuron lesion, which leads to hypertonia of the muscles signaled by those nerves that can no longer absorb GABA.

Function
Neurotransmitter
In vertebrates, GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane of both pre- and postsynaptic neuronal processes. This binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization. Two general classes of GABA receptor are known: GABAA in which the receptor is part of a ligand-gated ion channel complex, and GABAB metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins).

Gamma-Aminobutyric acid

40 Neurons that produce GABA as their output are called GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate. Medium Spiny Cells are a typical example of inhibitory CNS GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions in insects, mediating muscle activation at synapses between nerves and muscle cells, and also the stimulation of certain glands.[] In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic [] counterparts.

GABAA receptors are ligand-activated chloride channels; that is, when activated by GABA, they allow the The production, release, action, and degradation of GABA at a stereotyped GABAergic flow of chloride ions across the synapse membrane of the cell. Whether this chloride flow is excitatory/depolarizing (makes the voltage across the cell's membrane less negative), shunting (has no effect on the cell's membrane) or inhibitory/hyperpolarizing (makes the cell's membrane more negative) depends on the direction of the flow of chloride. When net chloride flows out of the cell, GABA is excitatory or depolarizing; when the net chloride flows into the cell, GABA is inhibitory or hyperpolarizing. When the net flow of chloride is close to zero, the action of GABA is shunting. Shunting inhibition has no direct effect on the membrane potential of the cell; however, it minimizes the effect of any coincident synaptic input essentially by reducing the electrical resistance of the cell's membrane (in essence, equivalent to Ohm's law). A developmental switch in the molecular machinery controlling concentration of chloride inside the cell and, hence, the direction of this ion flow is responsible for the changes in the functional role of GABA between the neonatal and adult stages. That is to say, GABA's role changes from excitatory to inhibitory as the brain develops into adulthood.[]

Brain development
While GABA is an inhibitory transmitter in the mature brain, its actions are primarily excitatory in the developing brain.[][] The gradient of chloride is reversed in immature neurons, and its reversal potential is higher than the resting membrane potential of the cell; activation of a GABA-A receptor thus leads to efflux of Cl- ions from the cell, i.e. a depolarizing current. The differential gradient of chloride in immature neurons is primarily due to the higher concentration of NKCC1 co-transporters relative to KCC2 co-transporters in immature cells. GABA itself is partially responsible for orchestrating the maturation of ion pumps.[] GABA-ergic interneurons mature faster in the hippocampus and the GABA signalling machinery appears earlier than glutamatergic transmission. Thus, GABA is the major excitatory neurotransmitter in many regions of the brain before the maturation of glutamatergic synapses. However, this theory has been questioned based on results showing that in brain slices of immature mice incubated in artificial cerebrospinal fluid (ACSF) (modified in a way that takes into account the normal composition of the neuronal milieu in sucklings by adding an energy substrate alternative to glucose, beta-hydroxybutyrate) GABA action shifts from excitatory to inhibitory mode.[]

Gamma-Aminobutyric acid This effect has been later repeated when other energy substrates, pyruvate and lactate, supplemented glucose in the slices' media.[] Later investigations of pyruvate[] and lactate[] metabolism found that the original results were not due to energy source issues but to changes in pH resulting from the substrates acting as "weak acids". These arguments were later rebutted by further findings[][] showing that changes in pH even greater than that caused by energy substrates do not affect the GABA-shift described in the presence of energy substrate-fortified ACSF and that the mode of action of beta-hydroxybutyrate, pyruvate and lactate (assessed by measurement NAD(P)H and oxygen utilization) was energy metabolism-related.[] In the developmental stages preceding the formation of synaptic contacts, GABA is synthesized by neurons and acts both as an autocrine (acting on the same cell) and paracrine (acting on nearby cells) signalling mediator.[][] The ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.[] GABA regulates the proliferation of neural progenitor cells[][] the migration[] and differentiation[][] the elongation of neurites[] and the formation of synapses.[] GABA also regulates the growth of embryonic and neural stem cells. GABA can inuence the development of neural progenitor cells via brain-derived neurotrophic factor (BDNF) expression.[] GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth.[]

41

Beyond the nervous system

GABAergic mechanisms have been demonstrated in various peripheral tissues and organs including, but not restricted to the intestine, stomach, pancreas, Fallopian tube, uterus, ovary, testis, kidney, urinary bladder, lung, and liver.[] In 2007, an excitatory GABAergic system was described in the airway epithelium. The system activates following exposure to allergens and may participate in the mechanisms of asthma.[] GABAergic systems have also been found in the testis[] and in the eye lens.[]

GABA-producing GAD67 enzyme in the brain slice at 1st postnatal day, with the highest expression in subventricular zone [] (svz). From Popp et al., 2009.

Structure and conformation

GABA is found mostly as a zwitterion, that is, with the carboxy group deprotonated and the amino group protonated. Its conformation depends on its environment. In the gas phase, a highly folded conformation is strongly favored because of the electrostatic attraction between the two functional groups. The stabilization is about 50 kcal/mol, according to quantum chemistry calculations. In the solid state, a more extended conformation is found, with a trans conformation at the amino end and a gauche conformation at the carboxyl end. This is due to the packing interactions with the neighboring molecules. In solution, five different conformations, some folded and some extended, are found as a result of solvation effects. The conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations. Many GABA analogues with pharmaceutical applications have more rigid structures in order to control the binding better.[][15]

Gamma-Aminobutyric acid

42

History
Gamma-aminobutyric acid was first synthesized in 1883, and was first known only as a plant and microbe metabolic product. In 1950, however, GABA was discovered to be an integral part of the mammalian central nervous system.[]

Bio-synthesis
GABA does not penetrate the bloodbrain barrier; it is synthesized in the brain. It is synthesized from glutamate using the enzyme L-glutamic acid decarboxylase and pyridoxal phosphate (which is the active form of vitamin B6) as a cofactor via a metabolic pathway called the GABA shunt. This process converts glutamate, the principal excitatory neurotransmitter, into the principal inhibitory neurotransmitter (GABA).[][]

Catabolism
GABA transaminase enzyme catalyzes the conversion of 4-aminobutanoic acid and 2-oxoglutarate into succinic semialdehyde and glutamate. Succinic semialdehyde is then oxidized into succinic acid by succinic semialdehyde dehydrogenase and as such enters the citric acid cycle as a usable source of energy.[]

Pharmacology
Drugs that act as allosteric modulators of GABA receptors (known as GABA analogues or GABAergic drugs) or increase the available amount of GABA typically have relaxing, anti-anxiety, and anti-convulsive effects.[][] Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.[] In general, GABA does not cross the bloodbrain barrier,[] although certain areas of the brain that have no effective bloodbrain barrier, such as the periventricular nucleus, can be reached by drugs such as systematically injected GABA.[] At least one study suggests that orally administered GABA increases the amount of Human Growth Hormone.[] GABA directly injected to the brain has been reported to have both stimulatory and inhibitory effects on the production of growth hormone, depending on the physiology of the individual.[]

GABAergic drugs
GABAA receptor ligands Agonists/Positive allosteric modulators: ethanol,[][][] barbiturates, benzodiazepines, carisoprodol, chloral hydrate, etaqualone, etomidate, glutethimide, kava, methaqualone, muscimol, neuroactive steroids, z-drugs, propofol, scullcap, valerian, volatile/inhaled anaesthetics. Antagonists/Negative allosteric modulators: bicuculline, cicutoxin, flumazenil, furosemide, gabazine, oenanthotoxin, picrotoxin, Ro15-4513, thujone. GABAB receptor ligands Agonists: baclofen, GBL, propofol, GHB,[] phenibut. Antagonists: phaclofen, saclofen. GABA reuptake inhibitors: deramciclane, hyperforin, tiagabine. GABA-transaminase inhibitors: gabaculine, phenelzine, valproate, vigabatrin, Lemon balm (Melissa officinalis).[] GABA analogues: pregabalin, gabapentin. Others: GABA (itself), L-glutamine, picamilon, progabide, tetanospasmin.

Gamma-Aminobutyric acid

43

GABA as a supplement
A number of commercial sources sell formulations of GABA for use as a dietary supplement, sometimes for sublingual administration. These sources typically claim that the supplement has a calming effect. These claims are not yet scientifically proven. For example, there is evidence stating that the calming effects of GABA can be seen observably in the human brain after administration of GABA as an oral supplement.[] However, there is also evidence that GABA does not cross the bloodbrain barrier at significant levels.[] There are some over-the-counter supplements such as phenylated GABA itself directly, or Phenibut; and Picamilon (both Soviet cosmonaut products) Picamilon combines niacin and phenylated GABA and crosses the bloodbrain barrier as a prodrug that later hydrolyzes into GABA and niacin.[]

In plants
GABA is also found in plants, where it is the most abundant amino acid in the apoplast of tomatoes.[16] It may also have a role in cell signalling in plants.[][]

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=56-12-2 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=119 [3] http:/ / www. chemspider. com/ 116 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=2ACZ6IPC6I [5] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=200-258-6 [6] http:/ / www. drugbank. ca/ drugs/ DB02530 [7] http:/ / www. kegg. jp/ entry/ D00058 [8] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=gamma-Aminobutyric+ Acid [9] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=16865 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL96 [11] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=1067 [12] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=C%28CC%28%3DO%29O%29CN [14] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=476992474& page2=Gamma-Aminobutyric+ acid

External links
Lydiard B, Pollack MH, Ketter TA, Kisch E, Hettema JM (2001-10-26). "GABA" (http://www.vcu-cme.org/ gaba/overview.html). Continuing Medical Education. School of Medicine, Virginia Commonwealth University, Medical College of Virginia Campus (VCU), Richmond, VA. Retrieved 2008-06-20. "The role of GABA in the pathogenesis and treatment of anxiety and other neuropsychiatric disorders" Scholarpedia article on GABA (http://www.scholarpedia.org/article/Gamma-aminobutyric_acid) List of GABA neurons on NeuroLex.org (http://neurolex.org/wiki/GABAergic_Neurons)

Globus pallidus

44

Globus pallidus
Brain: Globus pallidus

Globus pallidus labeled at bottom right.

DA-loops in PD Latin Globus pallidus

NeuroNames hier-213 [1] MeSH Globus+Pallidus

[2]

NeuroLex ID birnlex_1234 [3]

The globus pallidus (Latin for "pale globe") also known as paleostriatum, is a sub-cortical structure of the brain. It is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system.[4] The globus pallidus is a major component of the basal ganglia core along with the striatum and its direct target, the substantia nigra. The latter are made up of similar neuronal elements, have similar afferents from the dorsal striatum and have a similar synaptology; neither receives cortical afferents.

Function
The globus pallidus is a structure in the brain which is involved in the regulation of voluntary movement. It is part of the basal ganglia, which, among many other things, regulate movements which occur on the subconscious level. If the globus pallidus is damaged, it can cause movement disorders, as its regulatory function will be impaired. There may be cases in which damage is deliberately induced, as in a procedure known as a pallidotomy, in which a lesion is created to reduce involuntary muscle tremors. When it comes to regulation of movement, the globus pallidus has a primarily inhibitory action which balances the excitatory action of the cerebellum. These two systems are designed to work in harmony with each other to allow people to move smoothly, with even, controlled movements. Imbalances can result in tremors, jerks, and other movement problems, as seen in some people with progressive neurological disorders characterized by symptoms like tremors. The basal ganglia act on a subconscious level, requiring no conscious effort to function. When someone makes a decision to engage in an activity such as petting a cat, for example, these structures help to regulate the movement to make it as smooth as possible, and to respond to sensory feedback. Likewise, the globus pallidus is involved in the constant subtle regulation of movement which allows people to walk, talk, and engage in a wide variety of other activities with a minimal level of disruption.

Globus pallidus

45

Pathway
This area of the basal ganglia receives input from another area, called the striatum, which has two parts, the caudate nucleus and the putamen. This data is routed to the thalamus, either directly or indirectly. In the case of the interna, one area of the globus pallidus, the structure can feed directly to the thalamus. The externa, which lies, as one might imagine, on the outside of this structure, feeds information to the interna, where it can be passed on to the thalamus.

Parts
In primates, the dorsal pallidum, or globus pallidus, is divided into two parts by the medial medullary lamina. These are often termed "internal" and "external" (the internal globus pallidus [GPi] and the external globus pallidus [GPe]); both are composed of closed nuclei surrounded by myelinic walls. The ventral pallidum lies within the substantia innominata (Latin for unnamed substance) and receives efferent connections from the ventral striatum (the nucleus accumbens and the olfactory tubercle). It projects Microscopic image of the external globus pallidus to the dorsomedial nucleus of the dorsal thalamus, which, in turn, (lower left of image) and putamen (upper right of projects to the prefrontal cortex; it also projects to the image). H&E-LFB stain. pedunculopontine nucleus and tegmental motor areas. Its function is to serve as a limbic-somatic motor interface, and it is involved in the planning and inhibition of movements from the dorsal striatopallidal complex.

Structure
Pallidal nuclei are made up of the same neuronal components. In primates, almost all pallidal neurons are very large, parvalbumin-positive, with very large dendritic arborizations. These have the peculiarity of having the three-dimensional shape of flat discs, parallel to one another, parallel to the border of the pallidum[5] and perpendicular to the afferent striatopallidal axons.[6] There are only a few small local circuitry neurons. The globus pallidus is traversed by the numerous myelinated axons of the striato-pallidonigral bundle that give it the pale appearance from which it is named. The ultrastructure is very peculiar, as the long dendrites are everywhere, without discontinuity, covered by synapses.[7][8]

Pallidonigral pacemaker
The two pallidal nuclei and the two nigral (pars compacta and pars reticulata) parts constitute a high-frequency autonomous pacemaker[9] (see primate basal ganglia system#Pallido-nigral_set_and_pacemaker)
Transverse section of the Globus Pallidus from a structural MR image.

Globus pallidus

46

Common afferents
The two parts receive successively a large quantity of GABAergic axonal terminal arborisations from the striatum through the dense striato-pallidonigral bundle. The synaptology is very peculiar (see primate basal ganglia system).[7][8] The striatal afference contribute for more than 90% of synapses.[citation needed] The two pallidal nuclei receives dopaminergic axons from the pars compacta of the substantia nigra.

History of name
The origin of the name is not established. It was known by Dejerine (1906) but not by Santiago Ramn y Cajal (19091911). As the elements in no way have the shape of a globe, Foix and Nicolesco (1925), the Vogts (1941), Crosby et al. (1962) followed by the Terminologia anatomica Coronal slices of human brain showing the basal ganglia. proposed the simpler term (neuter ROSTRAL: striatum, globus pallidus (GPe and GPi) CAUDAL: subthalamic nucleus (STN), substantia nigra (SN) adjective) of pallidum ("pale"). For a long time the globus pallidus was linked to the putamen and termed the lentiform nucleus (nucleus lenticularis or lentiformis), a heterogeneous anatomical entity that is part of the striatum rather than the pallidum. The link with the substantia nigra pars reticulata was stressed very early on due to the similarities in dendritic arborisation (and they are sometimes known as the pallidonigral set) but, in spite of strong evidence, this association remains controversial.

Globus pallidus

47

Overview of the main circuits of the basal ganglia. Globus pallidus externa and interna are shown in green. Picture shows 2 coronal slices that have been superimposed to include the involved basal ganglia structures, with + and - signs at the point of the arrows indicating, respectively, whether the pathway is excitatory or inhibitory in effect. Green arrows refer to excitatory glutamatergic pathways, red arrows refer to inhibitory GABAergic pathways and turquoise arrows refer to dopaminergic pathways that are excitatory on the direct pathway and inhibitory on the indirect pathway.

Additional images

Coronal section of brain through intermediate mass of third ventricle.

Coronal section of brain through anterior commissure.

Horizontal section of right cerebral hemisphere.

Connectivity Diagram showing glutamatergic pathways as red, dopaminergic as magenta and GABA pathways as blue.

Globus pallidus

48

Horizontal slice of MRI-image showing the globus pallidus.

Globus pallidus

References
[1] [2] [3] [5] [6] [7] [8] [9] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=213 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Globus+ Pallidus http:/ / www. neurolex. org/ wiki/ birnlex_1234 Yelnik, J., Percheron, G., and Franois, C. (1984) A Golgi analysis of the primate globus pallidus. II- Quantitative morphology and spatial orientation of dendritic arborisations. J. Comp. Neurol. 227:200-213 Percheron, G.,Yelnik, J. and Franois. C. (1984) A Golgi analysis of the primate globus pallidus. III-Spatial organization of the striato-pallidal complex. J. Comp. Neurol. 227: 214-227 Fox, C.A., Andrade, A.N. Du Qui, I.J., Rafols, J.A. (1974) The primate globus pallidus. A Golgi and electron microscopic study. J. Hirnforsch. 15: 75-93 di Figlia, M., Pasik, P., Pasik, T. (1982) A Golgi and ultrastructural study of the monkey globus pallidus. J. Comp. Neurol. 212: 53-75 Surmeier, D.J., Mercer, J.N. and Savio Chan, C. (2005) Autonomous pacemakers in the basal ganglia: who needs excitatory synapses anyway? Cur. Opin.Neurobiol. 15:312-318.

External links
BrainMaps at UCDavis Globus pallidus (http://brainmaps.org/index.php?q=Globus pallidus) Globus+pallidus (http://www.emedicinehealth.com/script/main/srchcont_dict.asp?src=Globus+pallidus) at eMedicine Dictionary Paleostriatum (http://www.emedicinehealth.com/script/main/srchcont_dict.asp?src=Paleostriatum) at eMedicine Dictionary Diagram at uni-tuebingen.de (http://www.prometheus.uni-tuebingen.de/sec/vl/documents/42/bgana_normal. gif) NIF Search - Globus Pallidus (https://www.neuinfo.org/mynif/search.php?q=Globus pallidus&t=data& s=cover&b=0&r=20) via the Neuroscience Information Framework What Is the Globus Pallidus? (http://www.wisegeek.com/what-is-the-globus-pallidus.htm)

Glutamic acid

49

Glutamic acid
Glutamic acid

Identifiers CAS number ChemSpider UNII KEGG ChEBI ChEMBL Jmol-3D images 617-65-2 591
[2] [3] [1]

61LJO5I15S D04341
[4]

CHEBI:18237

[5]

[6]

CHEMBL276389 Image 1 Properties

[7]

Molecular formula Molar mass Appearance Density Melting point Solubility in water Solubility Acidity (pK )
a

C5H9NO4 147.13 g mol1 white crystalline powder 1.4601 (20 C) 199 C decomp. 8.64 g/l (25 C)
[8] [9]

0.00035g/100g ethanol 25 degC 2.1, 4.07, 9.47 Hazards

[10]

MSDS NFPA 704

External MSDS

Supplementary data page

Glutamic acid

50
Structure and properties Thermodynamic data Spectral data
(verify) [11]

n, r, etc. Phase behaviour Solid, liquid, gas UV, IR, NMR, MS

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Glutamic acid (abbreviated as Glu or E) is one of the 20-22 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates. In neuroscience, glutamate is an important neurotransmitter that plays a key role in long-term potentiation and is important for learning and memory.[]

Chemistry
The side chain carboxylic acid functional group has a pKa of 4.1 and therefore exists almost entirely in its negatively charged deprotonated carboxylate form at pH values greater than 4.1; therefore, it is negatively charged at physiological pH ranging from 7.35 to 7.45.

History
Although they occur naturally in many foods, the flavour contributions made by glutamic acid and other amino acids were only scientifically identified early in the twentieth century. The substance was discovered and identified in the year 1866, by the German chemist Karl Heinrich Leopold Ritthausen who treated wheat gluten (for which it was named) with sulfuric acid.[12] In 1908 Japanese researcher Kikunae Ikeda of the Tokyo Imperial University identified brown crystals left behind after the evaporation of a large amount of kombu broth as glutamic acid. These crystals, when tasted, reproduced the ineffable but undeniable flavour he detected in many foods, most especially in seaweed. Professor Ikeda termed this flavour umami. He then patented a method of mass-producing a crystalline salt of glutamic acid, monosodium glutamate.[][13]

Biosynthesis
Reactants Glutamine + H2O NAcGlu + H2O -ketoglutarate + NADPH + NH4+ -ketoglutarate + -amino acid Products Glu + NH3 Glu + Acetate Glu + NADP+ + H2O Glu + -keto acid Enzymes GLS, GLS2 (unknown) GLUD1, GLUD2 transaminase ALDH4A1 []

1-Pyrroline-5-carboxylate + NAD+ + H2O Glu + NADH N-formimino-L-glutamate + FH4 NAAG

Glu + 5-formimino-FH4 FTCD Glu + NAA GCPII

Glutamic acid

51

Function and uses

Metabolism
Glutamate is a key compound in cellular metabolism. In humans, dietary proteins are broken down by digestion into amino acids, which serve as metabolic fuel for other functional roles in the body. A key process in amino acid degradation is transamination, in which the amino group of an amino acid is transferred to an -ketoacid, typically catalysed by a transaminase. The reaction can be generalised as such: R1-amino acid + R2--ketoacid R1--ketoacid + R2-amino acid A very common -keto acid is -ketoglutarate, an intermediate in the citric acid cycle. Transamination of -ketoglutarate gives glutamate. The resulting -ketoacid product is often a useful one as well, which can contribute as fuel or as a substrate for further metabolism processes. Examples are as follows: Alanine + -ketoglutarate pyruvate + glutamate Aspartate + -ketoglutarate oxaloacetate + glutamate Both pyruvate and oxaloacetate are key components of cellular metabolism, contributing as substrates or intermediates in fundamental processes such as glycolysis, gluconeogenesis, and the citric acid cycle. Glutamate also plays an important role in the body's disposal of excess or waste nitrogen. Glutamate undergoes deamination, an oxidative reaction catalysed by glutamate dehydrogenase,[] as follows: glutamate + H2O + NADP+ -ketoglutarate + NADPH + NH3 + H+ Ammonia (as ammonium) is then excreted predominantly as urea, synthesised in the liver. Transamination can, thus, be linked to deamination, effectively allowing nitrogen from the amine groups of amino acids to be removed, via glutamate as an intermediate, and finally excreted from the body in the form of urea.

Neurotransmitter
Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system.[] At chemical synapses, glutamate is stored in vesicles. Nerve impulses trigger release of glutamate from the pre-synaptic cell. In the opposing post-synaptic cell, glutamate receptors, such as the NMDA receptor, bind glutamate and are activated. Because of its role in synaptic plasticity, glutamate is involved in cognitive functions like learning and memory in the brain.[14] The form of plasticity known as long-term potentiation takes place at glutamatergic synapses in the hippocampus, neocortex, and other parts of the brain. Glutamate works not only as a point-to-point transmitter but also through spill-over synaptic crosstalk between synapses in which summation of glutamate released from a neighboring synapse creates extrasynaptic signaling/volume transmission.[15] Glutamate transporters[16] are found in neuronal and glial membranes. They rapidly remove glutamate from the extracellular space. In brain injury or disease, they can work in reverse, and excess glutamate can accumulate outside cells. This process causes calcium ions to enter cells via NMDA receptor channels, leading to neuronal damage and eventual cell death, and is called excitotoxicity. The mechanisms of cell death include Damage to mitochondria from excessively high intracellular Ca2+[17] Glu/Ca2+-mediated promotion of transcription factors for pro-apoptotic genes, or downregulation of transcription factors for anti-apoptotic genes Excitotoxicity due to excessive glutamate release and impaired uptake occurs as part of the ischemic cascade and is associated with stroke[] and diseases like amyotrophic lateral sclerosis, lathyrism, autism, some forms of mental retardation, and Alzheimer's disease.[][18] In contrast, decreased glutamate release is observed under conditions of classical phenylketonuria[19] leading to developmental disruption of glutamate receptor expression.[20] Glutamic acid has been implicated in epileptic seizures. Microinjection of glutamic acid into neurons produces spontaneous depolarisations around one second apart, and this firing pattern is similar to what is known as

Glutamic acid paroxysmal depolarizing shift in epileptic attacks. This change in the resting membrane potential at seizure foci could cause spontaneous opening of voltage-activated calcium channels, leading to glutamic acid release and further depolarization [citation needed]. Experimental techniques to detect glutamate in intact cells include using a genetically engineered nanosensor.[21] The sensor is a fusion of a glutamate-binding protein and two fluorescent proteins. When glutamate binds, the fluorescence of the sensor under ultraviolet light changes by resonance between the two fluorophores. Introduction of the nanosensor into cells enables optical detection of the glutamate concentration. Synthetic analogs of glutamic acid that can be activated by ultraviolet light and two-photon excitation microscopy have also been described.[22] This method of rapidly uncaging by photostimulation is useful for mapping the connections between neurons, and understanding synapse function. Evolution of glutamate receptors is entirely the opposite in invertebrates, in particular, arthropods and nematodes, where glutamate stimulates glutamate-gated chloride channels.[citation needed] The beta subunits of the receptor respond with very high affinity to glutamate and glycine.[23] Targeting these receptors has been the therapeutic goal of anthelmintic therapy using avermectins. Avermectins target the alpha-subunit of glutamate-gated chloride channels with high affinity.[24] These receptors have also been described in arthropods, such as Drosophila melanogaster[25] and Lepeophtheirus salmonis.[26] Irreversible activation of these receptors with avermectins results in hyperpolarization at synapses and neuromuscular junctions resulting in flaccid paralysis and death of nematodes and arthropods.

52

Brain nonsynaptic glutamatergic signaling circuits

Extracellular glutamate in Drosophila brains has been found to regulate postsynaptic glutamate receptor clustering, via a process involving receptor desensitization.[] A gene expressed in glial cells actively transports glutamate into the extracellular space,[] while, in the nucleus accumbens-stimulating L-Glutamate at physiological conditions group II metabotropic glutamate receptors, this gene was found to reduce extracellular glutamate levels.[27] This raises the possibility that this extracellular glutamate plays an "endocrine-like" role as part of a larger homeostatic system. GABA precursor Glutamate also serves as the precursor for the synthesis of the inhibitory GABA in GABA-ergic neurons. This reaction is catalyzed by glutamate decarboxylase (GAD), which is most abundant in the cerebellum and pancreas. Stiff-man syndrome is a neurologic disorder caused by anti-GAD antibodies, leading to a decrease in GABA synthesis and, therefore, impaired motor function such as muscle stiffness and spasm. Since the pancreas is also abundant for the enzyme GAD, a direct immunological destruction occurs in the pancreas and the patients will have diabetes mellitus.

Glutamic acid

53

Flavor enhancer
Glutamic acid, being a constituent of protein, is present in every food that contains protein, but it can only be tasted when it is present in an unbound form. Significant amounts of free glutamic acid are present in a wide variety of foods, including cheese and soy sauce, and is responsible for umami, one of the five basic tastes of the human sense of taste. Glutamic acid is often used as a food additive and flavour enhancer in the form of its salt, known as monosodium glutamate (MSG).

Nutrient
All meats, poultry, fish, eggs, dairy products, and kombu are excellent sources of glutamic acid. Some protein-rich plant foods also serve as sources. Thirty to 35% of the protein in wheat is glutamic acid. Ninety-five percent of the dietary glutamate is metabolized by intestinal cells in a first pass.[28]

Plant growth
Auxigro is a plant growth preparation that contains 30% glutamic acid.

NMR spectroscopy
In recent years, there has been much research into the use of RDCs in NMR spectroscopy. A glutamic acid derivative, poly--benzyl-L-glutamate (PBLG), is often used as an alignment medium to control the scale of the dipolar interactions observed.[29]

Production
China-based Fufeng Group Limited is the largest producer of glutamic acid in the world, with capacity increasing to 300,000 tons at the end of 2006 from 180,000 tons during 2006, putting them at 25%30% of the Chinese market. Meihua is the second-largest Chinese producer. Together, the top-five producers have roughly 50% share in China. Chinese demand is roughly 1.1 million tons per year, while global demand, including China, is 1.7 million tons per year.

Pharmacology
The drug phencyclidine (more commonly known as PCP) antagonizes glutamic acid non-competitively at the NMDA receptor. For the same reasons, dextromethorphan and ketamine also have strong dissociative and hallucinogenic effects. Acute infusion of the drug LY354740 (also known as Eglumegad, an agonist of the metabotropic glutamate receptors 2 and 3) resulted in a marked diminution of yohimbine-induced stress response in bonnet macaques (Macaca radiata); chronic oral administration of LY354740 in those animals led to markedly reduced baseline cortisol levels (approximately 50 percent) in comparison to untreated control subjects.[30]. Glutamate does not easily pass the blood brain barrier, but, instead, is transported by a high-affinity transport system.[31] It can also be converted into glutamine.

Glutamic acid

54

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=617-65-2 [2] http:/ / www. chemspider. com/ 591 [3] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=61LJO5I15S [4] http:/ / www. kegg. jp/ entry/ D04341 [5] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=18237 [6] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL276389 [7] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=C%28CC%28%3DO%29O%29C%28C%28%3DO%29O%29N [8] http:/ / hazard. com/ msds/ mf/ baker/ baker/ files/ g3970. htm [10] http:/ / www. cem. msu. edu/ ~cem252/ sp97/ ch24/ ch24aa. html [11] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=476993405& page2=Glutamic+ acid [25] Cully, D.F., Paress, P.S., Liu, K.K., Schaeffer, J.M. and Arena, J.P. 1996. "Identification of a Drosophila melanogaster glutamate-gated chloride channel sensitive to the antiparasitic agent avermectin". J. Biol. Chem. '271, 20187-20191' [29] C. M. Thiele, Concepts Magn. Reson. A, 2007, 30A, 65-80

Further reading
Nelson, David L.; Cox, Michael M. (2005), Principles of Biochemistry (4th ed.), New York: W.H. Freeman, ISBN0-7167-4339-6

Somatostatin

55

Somatostatin
Somatostatin

Available structures PDB Ortholog search: PDBe [1], RCSB [2] List of PDB id codes 1P2W
[3]

Identifiers Symbols External IDs SST

[4]

; SMST
[5]

OMIM: 182450

MGI: 98326

[6]

HomoloGene: 819

[7]

ChEMBL: 1795130

[8]

GeneCards: SST Gene

[9]

Gene Ontology Molecular function hormone activity [10] Cellular component extracellular region [11] [12] extracellular space [13] neuronal cell body Biological process hyperosmotic response [15] cell surface receptor signaling pathway [16] G-protein coupled receptor signaling pathway [17] cell-cell signaling [18] synaptic transmission [19] response to nutrient [20] digestion [21] negative regulation of cell proliferation hormone-mediated apoptotic signaling pathway
[22] [14]

response to heat [24] regulation of cell migration [25] response to drug [26] response to amino acid stimulus [27] response to steroid hormone stimulus Sources: Amigo
[28]

[23]

/ QuickGO

[29]

RNA expression pattern

Somatostatin

56

More reference expression data Orthologs Species Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Human 6750
[31] [33]

[30]

Mouse 20604
[32] [34]

ENSG00000157005 P61278
[35] [37]

ENSMUSG00000004366 P60041
[36] [38]

NM_001048 NP_001039

NM_009215 NP_033241

[39]

[40]

Location (UCSC) Chr 3: [41] 187.39 187.39 Mb PubMed search

[43]

Chr 16: [42] 23.89 23.89 Mb

[44]

Somatostatin (also known as growth hormone-inhibiting hormone (GHIH) or somatotropin release-inhibiting factor (SRIF)) or somatotropin release-inhibiting hormone[citation needed] is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin has two active forms produced by alternative cleavage of a single preproprotein: one of 14 amino acids, the other of 28 amino acids.[] In all vertebrates, there exists six different somatostatin genes that have been named SS1, SS2, SS3, SS4, SS5, and SS6.[] The six different genes along with the five different somatostatin receptors allows somatostatin to possess a large range of functions.[] Humans have only one somatostatin gene, SST.[][][]

Production
Digestive system
Somatostatin is secreted in several locations in the digestive system: stomach intestine delta cells of the pancreas[] Somatostatin will travel through the portal blood system, to the heart, then to systemic circulation, where it will exert its digestive system effects. In the stomach, somatostatin acts on the acid-producing parietal cells via G-coupled receptor to reduce secretion. Somatostatin also indirectly decreases stomach acid production by preventing the release of other hormones, including gastrin and histamine.

Somatostatin

57

Brain

[45] Sst is expressed in interneurons in the telencephalon of the embryonic day 15.5 mouse. Allen Brain Atlases Sst [46] expression in the adult mouse. Allen Brain Atlases

Somatostatin is produced by neuroendocrine neurons of the periventricular nucleus of the hypothalamus. These neurons project to the median eminence, where somatostatin is released from neurosecretory nerve endings into the hypothalamo-hypophysial system through neuron axons. Somatostatin is then carried to the anterior pituitary gland, where it inhibits the secretion of growth hormone from somatotrope cells. The somatostatin neurons in the periventricular nucleus mediate negative feedback effects of growth hormone on its own release; the somatostatin neurons respond to high circulating concentrations of growth hormone and somatomedins by increasing the release of somatostatin, so reducing the rate of secretion of growth hormone. Somatostatin is also produced by several other populations that project centrally, i.e., to other areas of the brain, and somatostatin receptors are expressed at many different sites in the brain. In particular, there are populations of somatostatin neurons in the arcuate nucleus,[citation needed] the hippocampus,[citation needed] and the brainstem nucleus of the solitary tract.[citation needed]

Somatostatin

58

Actions
Somatostatin is classified as an inhibitory hormone,[] whose actions are spread to different parts of the body:

Anterior pituitary
In the anterior pituitary gland, the effects of somatostatin are: Inhibit the release of growth hormone (GH)[] (thus opposing the effects of Growth Hormone-Releasing Hormone (GHRH)) Inhibit the release of thyroid-stimulating hormone (TSH)[47] It is induced by low pH. Inhibit adenylyl cyclase in parietal cells.

Gastrointestinal system
Somatostatin is homologous with cortistatin (see somatostatin family) and suppresses the release of gastrointestinal hormones Gastrin Cholecystokinin (CCK) Secretin Motilin Vasoactive intestinal peptide (VIP) Gastric inhibitory polypeptide (GIP) Enteroglucagon Decrease rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine[] Suppresses the release of pancreatic hormones Inhibits insulin release when somatostatin is released from delta cells of pancreas[] Inhibits the release of glucagon[] Suppresses the exocrine secretory action of pancreas.
D cell is visible at upper-right, and somatostatin is represented by middle arrow pointing left

Synthetic substitutes
Octreotide (brand name Sandostatin, Novartis Pharmaceuticals) is an octapeptide that mimics natural somatostatin pharmacologically, though is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone and has a much longer half-life (approximately 90 minutes, compared to 23 minutes for somatostatin). Since it is absorbed poorly from the gut, it is administered parenterally (subcutaneously, intramuscularly, or intravenously). It is indicated for symptomatic treatment of carcinoid syndrome and acromegaly. It is also finding increased use in polycystic diseases of the liver and kidney. Lanreotide (INN) is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analogue of somatostatin, like octreotide.

Somatostatin Lanreotide (as lanreotide acetate) is manufactured by Ipsen and marketed under the trade name Somatuline. It is available in several countries, including the United Kingdom, Australia, and Canada, and was approved for sale in the United States by the Food and Drug Administration (FDA) on August 30, 2007.

59

Evolutionary history
There are six somatostatin genes that have been discovered in vertebrates. The current proposed history as to how these six genes arose is based on the three whole-genome duplication events that took place in vertebrate evolution along with local duplications in teleost fish. An ancestral somatostatin gene was duplicated during the first whole-genome duplication event (1R) to create SS1 and SS2. These two genes were duplicated during the second whole-genome duplication event (2R) to create four new somatostatin genes: SS1, SS2, SS3, and one gene that was lost during the evolution of vertebrates. Tetrapods retained SS1 (also known as SS-14 and SS-28) and SS2 (also known as cortistatin) after the split in the sarcopterygii and actinopterygii lineage split. In teleost fish, SS1, SS2, and SS3 were duplicated during the third whole-genome duplication event (3R) to create SS1, SS2, SS4, SS5, and two genes that were lost during the evolution of teleost fish. SS1 and SS2 went through local duplications to give rise to SS6 and SS3.[]

References

[1] http:/ / www. ebi. ac. uk/ pdbe/ searchResults. html?display=both& term=P61278%20or%20P49670%20or%20P26917%20or%20Q545V6%20or%20P60041%20or%20P60042%20or%20P33094%20or%20A5YW27%20or%20Q8 [2] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=UpAccessionIdQuery& accessionIdList=P61278,P49670,P26917,Q545V6,P60041,P60042,P33094,A5YW27,Q8JHX5 [3] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1P2W [4] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=11329 [5] http:/ / omim. org/ entry/ 182450 [6] http:/ / www. informatics. jax. org/ searches/ accession_report. cgi?id=MGI:98326 [7] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=819 [8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ target/ inspect/ CHEMBL1795130 [9] http:/ / www. genecards. org/ cgi-bin/ carddisp. pl?id_type=entrezgene& id=6750 [10] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005179 [11] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005576 [12] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005615 [13] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043025 [14] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006972 [15] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007166 [16] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007186 [17] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007267 [18] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007268 [19] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007584 [20] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007586 [21] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0008285 [22] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0008628 [23] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0009408 [24] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030334 [25] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042493 [26] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043200 [27] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0048545 [28] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ gp-assoc. cgi?gp=UniProtKB:P61278 [29] http:/ / www. ebi. ac. uk/ QuickGO/ GProtein?ac=P61278 [30] http:/ / biogps. org/ gene/ 6750/ [31] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=6750& rn=1 [32] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=20604& rn=1 [33] http:/ / www. ensembl. org/ Homo_sapiens/ geneview?gene=ENSG00000157005;db=core [34] http:/ / www. ensembl. org/ Mus_musculus/ geneview?gene=ENSMUSG00000004366;db=core [35] http:/ / www. uniprot. org/ uniprot/ P61278

Somatostatin
[36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] http:/ / www. uniprot. org/ uniprot/ P60041 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_001048 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_009215 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_001039 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_033241 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Human& db=hg19& position=chr3:187386694-187388187 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Mouse& db=mm9& position=chr16:23889581-23890844 http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=6750 http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=20604 http:/ / developingmouse. brain-map. org/ data/ Sst/ 100053205. html?ispopup=true http:/ / mouse. brain-map. org/ experiment/ show/ 1001 First Aid for the USMLE Step 1, 2010. Page 286.

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Further reading
Florio T, Schettini G (2002). "[Somatostatin and its receptors. Role in the control of cell proliferation]". Minerva Endocrinol. 26 (3): 91102. PMID 11753230 (http://www.ncbi.nlm.nih.gov/pubmed/11753230). Yamada Y, Reisine T, Law SF, et al. (1993). "Somatostatin receptors, an expanding gene family: cloning and functional characterization of human SSTR3, a protein coupled to adenylyl cyclase". Mol. Endocrinol. 6 (12): 213642. doi: 10.1210/me.6.12.2136 (http://dx.doi.org/10.1210/me.6.12.2136). PMID 1337145 (http:// www.ncbi.nlm.nih.gov/pubmed/1337145). Yamada Y, Post SR, Wang K, et al. (1992). "Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney" (http://www.ncbi.nlm.nih. gov/pmc/articles/PMC48214). Proc. Natl. Acad. Sci. U.S.A. 89 (1): 2515. doi: 10.1073/pnas.89.1.251 (http:// dx.doi.org/10.1073/pnas.89.1.251). PMC 48214 (http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC48214). PMID 1346068 (http://www.ncbi.nlm.nih.gov/pubmed/1346068). Brazeau P, Vale W, Burgus R, et al. (1973). "Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone". Science 179 (4068): 779. doi: 10.1126/science.179.4068.77 (http:// dx.doi.org/10.1126/science.179.4068.77). PMID 4682131 (http://www.ncbi.nlm.nih.gov/pubmed/ 4682131). Shen LP, Pictet RL, Rutter WJ (1982). "Human somatostatin I: sequence of the cDNA" (http://www.ncbi.nlm. nih.gov/pmc/articles/PMC346717). Proc. Natl. Acad. Sci. U.S.A. 79 (15): 45759. doi: 10.1073/pnas.79.15.4575 (http://dx.doi.org/10.1073/pnas.79.15.4575). PMC 346717 (http://www.ncbi. nlm.nih.gov/pmc/articles/PMC346717). PMID 6126875 (http://www.ncbi.nlm.nih.gov/pubmed/ 6126875). Shen LP, Rutter WJ (1984). "Sequence of the human somatostatin I gene". Science 224 (4645): 16871. doi: 10.1126/science.6142531 (http://dx.doi.org/10.1126/science.6142531). PMID 6142531 (http://www.ncbi. nlm.nih.gov/pubmed/6142531). Montminy MR, Goodman RH, Horovitch SJ, Habener JF (1984). "Primary structure of the gene encoding rat preprosomatostatin" (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC345502). Proc. Natl. Acad. Sci. U.S.A. 81 (11): 333740. doi: 10.1073/pnas.81.11.3337 (http://dx.doi.org/10.1073/pnas.81.11.3337). PMC 345502 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC345502). PMID 6145156 (http://www.ncbi.nlm. nih.gov/pubmed/6145156). Zabel BU, Naylor SL, Sakaguchi AY, et al. (1984). "High-resolution chromosomal localization of human genes for amylase, proopiomelanocortin, somatostatin, and a DNA fragment (D3S1) by in situ hybridization" (http:// www.ncbi.nlm.nih.gov/pmc/articles/PMC390100). Proc. Natl. Acad. Sci. U.S.A. 80 (22): 69326. doi: 10.1073/pnas.80.22.6932 (http://dx.doi.org/10.1073/pnas.80.22.6932). PMC 390100 (http://www.ncbi. nlm.nih.gov/pmc/articles/PMC390100). PMID 6196780 (http://www.ncbi.nlm.nih.gov/pubmed/ 6196780).

Somatostatin Panetta R, Greenwood MT, Warszynska A, et al. (1994). "Molecular cloning, functional characterization, and chromosomal localization of a human somatostatin receptor (somatostatin receptor type 5) with preferential affinity for somatostatin-28". Mol. Pharmacol. 45 (3): 41727. PMID 7908405 (http://www.ncbi.nlm.nih. gov/pubmed/7908405). Demchyshyn LL, Srikant CB, Sunahara RK, et al. (1993). "Cloning and expression of a human somatostatin-14-selective receptor variant (somatostatin receptor 4) located on chromosome 20". Mol. Pharmacol. 43 (6): 894901. PMID 8100352 (http://www.ncbi.nlm.nih.gov/pubmed/8100352). Kaupmann K, Bruns C, Hoyer D, et al. (1993). "Distribution and second messenger coupling of four somatostatin receptor subtypes expressed in brain". FEBS Lett. 331 (12): 539. doi: 10.1016/0014-5793(93)80296-7 (http:// dx.doi.org/10.1016/0014-5793(93)80296-7). PMID 8405411 (http://www.ncbi.nlm.nih.gov/pubmed/ 8405411). Aguila MC, Rodriguez AM, Aguila-Mansilla HN, Lee WT (1996). "Somatostatin antisense oligodeoxynucleotide-mediated stimulation of lymphocyte proliferation in culture". Endocrinology 137 (5): 158590. doi: 10.1210/en.137.5.1585 (http://dx.doi.org/10.1210/en.137.5.1585). PMID 8612489 (http:// www.ncbi.nlm.nih.gov/pubmed/8612489). Sharma K, Patel YC, Srikant CB (1997). "Subtype-selective induction of wild-type p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3". Mol. Endocrinol. 10 (12): 168896. doi: 10.1210/me.10.12.1688 (http://dx.doi.org/10.1210/me.10.12.1688). PMID 8961277 (http://www.ncbi.nlm.nih.gov/pubmed/ 8961277). Dournaud P, Boudin H, Schonbrunn A, et al. (1998). "Interrelationships between somatostatin sst2A receptors and somatostatin-containing axons in rat brain: evidence for regulation of cell surface receptors by endogenous somatostatin". J. Neurosci. 18 (3): 105671. PMID 9437026 (http://www.ncbi.nlm.nih.gov/pubmed/ 9437026). Barnea A, Roberts J, Ho RH (1999). "Evidence for a synergistic effect of the HIV-1 envelope protein gp120 and brain-derived neurotrophic factor (BDNF) leading to enhanced expression of somatostatin neurons in aggregate cultures derived from the human fetal cortex". Brain Res. 815 (2): 34957. doi: 10.1016/S0006-8993(98)01098-1 (http://dx.doi.org/10.1016/S0006-8993(98)01098-1). PMID 9878821 (http://www.ncbi.nlm.nih.gov/ pubmed/9878821). Ferone D, van Hagen PM, van Koetsveld PM, et al. (1999). "In vitro characterization of somatostatin receptors in the human thymus and effects of somatostatin and octreotide on cultured thymic epithelial cells". Endocrinology 140 (1): 37380. doi: 10.1210/en.140.1.373 (http://dx.doi.org/10.1210/en.140.1.373). PMID 9886848 (http://www.ncbi.nlm.nih.gov/pubmed/9886848). Brakch N, Lazar N, Panchal M, et al. (2002). "The somatostatin-28(1-12)-NPAMAP sequence: an essential helical-promoting motif governing prosomatostatin processing at mono- and dibasic sites". Biochemistry 41 (5): 16309. doi: 10.1021/bi011928m (http://dx.doi.org/10.1021/bi011928m). PMID 11814357 (http://www. ncbi.nlm.nih.gov/pubmed/11814357). Oomen SP, van Hennik PB, Antonissen C, et al. (2002). "Somatostatin is a selective chemoattractant for primitive (CD34(+)) hematopoietic progenitor cells". Exp. Hematol. 30 (2): 11625. doi: 10.1016/S0301-472X(01)00772-X (http://dx.doi.org/10.1016/S0301-472X(01)00772-X). PMID 11823046 (http://www.ncbi.nlm.nih.gov/ pubmed/11823046). Simonetti M, Di BC (2002). "Structural motifs in the maturation process of peptide hormones. The somatostatin precursor. I. A CD conformational study". J. Pept. Sci. 8 (2): 6679. doi: 10.1002/psc.370 (http://dx.doi.org/ 10.1002/psc.370). PMID 11860030 (http://www.ncbi.nlm.nih.gov/pubmed/11860030).

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Cholecystokinin

62

Cholecystokinin
Cholecystokinin
Identifiers Symbols External IDs CCK
[1]

; MGC117187
[2]

OMIM: 118440

MGI: 88297

[3]

HomoloGene: 583

[4]

ChEMBL: 1649050

[5]

GeneCards: CCK Gene

[6]

Gene Ontology Molecular function hormone activity [10] [7] neuropeptide hormone activity Cellular component extracellular region [11] [12] extracellular space [8] axon [9] dendrite [10] axon initial segment [11] terminal bouton [12] axon hillock [13] perikaryon Biological process behavioral fear response [15] neuron migration [16] release of cytochrome c from mitochondria activation of cysteine-type endopeptidase activity involved in apoptotic process
[17] [14]

signal transduction [19] protein kinase C-activating G-protein coupled receptor signaling pathway [20] axonogenesis [21] positive regulation of cell proliferation [22] negative regulation of appetite [23] positive regulation of protein oligomerization [24] eating behavior [25] positive regulation of apoptotic process [26] positive regulation of peptidyl-tyrosine phosphorylation [27] positive regulation of mitochondrial depolarization [28] regulation of sensory perception of pain Sources: Amigo
[29]

[18]

/ QuickGO

[30]

RNA expression pattern

More reference expression data Orthologs Species Entrez Human 885

[32]

[31]

Mouse 12424
[33]

Cholecystokinin
[34] [35]

63

Ensembl UniProt RefSeq (mRNA) RefSeq (protein)

ENSG00000187094 P06307
[36] [38]

ENSMUSG00000032532 P09240
[37] [39]

NM_000729 NP_000720

NM_031161 NP_112438

[40]

[41]

Location (UCSC) Chr 3: [42] 42.3 42.31 Mb PubMed search

[44]

Chr 9: [43] 121.49 121.5 Mb

[45]

Cholecystokinin (CCK or CCK-PZ; from Greek chole, "bile"; cysto, "sac"; kinin, "move"; hence, move the bile-sac (gallbladder)) is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. Cholecystokinin, previously called pancreozymin, is synthesized by I-cells in the mucosal epithelium of the small intestine and secreted in the duodenum, the first segment of the small intestine, and causes the release of digestive enzymes and bile from the pancreas and gallbladder, respectively. It also acts as a hunger suppressant. Recent evidence has suggested that it also plays a major role in inducing drug tolerance to opioids like morphine and heroin, and is partly implicated in experiences of pain hypersensitivity during opioid withdrawal.[][]

Structure

CCK identified at bottom right.

CCK is composed of varying numbers of amino acids depending on post-translational modification of the CCK gene product, preprocholecystokinin. Thus CCK is actually a family of hormones identified by number of amino acids, e.g., CCK58, CCK33, and CCK8. CCK58 assumes a helix-turn-helix configuration.[] Its existence was first suggested in 1905 by the British physiologist Joy Simcha Cohen. CCK is very similar in structure to gastrin, another of the gastrointestinal hormones. CCK and gastrin share the same five amino acids at their C-termini.

Functions
CCK mediates a number of physiological processes, including digestion and satiety. It is released by I cells located in the mucosal epithelium of the small intestine (mostly in the duodenum and jejunum), neurons of the enteric nervous system and neurons in the brain. Release of CCK is stimulated by monitor peptide released by pancreatic acinar cells as well as CCK-releasing protein, a paracrine factor secreted by enterocytes in the gastrointestinal mucosa. In addition, release of acetylcholine by the parasympathetic nerve fibers of the vagus nerve also stimulate its secretion. The presence of fatty acids and/or certain amino acids in the chyme entering the duodenum is the greatest stimulator of CCK release. CCK mediates digestion in the small intestine by inhibiting gastric emptying and gastric acid secretion. It stimulates the acinar cells of the pancreas to release digestive enzymes and stimulates the secretion of a juice rich in pancreatic digestive enzymes, hence the old name pancreozymin. Together these enzymes catalyze the digestion of fat, protein, and carbohydrates. Thus, as the levels of the substances that stimulated the release of CCK drop, the concentration of the hormone drops as well. The release of CCK is also inhibited by somatostatin. Trypsin, a protease released by pancreatic acinar cells hydrolyzes CCK-releasing peptide and monitor peptide effectively turning off the additional

Cholecystokinin signals to secrete CCK. CCK also causes the increased production of hepatic bile, and stimulates the contraction of the gall bladder and the relaxation of the Sphincter of Oddi (Glisson's sphincter), resulting in the delivery of bile into the duodenal part of the small intestine. Bile salts form amphipathic micelles that emulsify fats, aiding in their digestion and absorption.

64

Neurobiology
As a neuropeptide, CCK mediates satiety by acting on the CCK receptors distributed widely throughout the central nervous system. In humans, it has been suggested that CCK administration causes nausea and anxiety, and induces a satiating effect. CCK-4 is routinely used to induce anxiety in humans though certainly different forms of CCK are being shown to have highly variable effects.[] The mechanism for this hunger suppression is thought to be a decrease in the rate of gastric emptying.[] CCK also has stimulatory effects on the vagus nerve, effects that can be inhibited by capsaicin.[] The stimulatory effects of CCK oppose those of ghrelin, which has been shown to inhibit the vagus nerve.[] The CCK tetrapeptide fragment CCK-4 (Trp-Met-Asp-Phe-NH2) reliably causes anxiety when administered to humans, and is commonly used in scientific research to induce panic attacks for the purpose of testing new anxiolytic drugs.[] The effects of CCK vary between individuals. For example, in rats, CCK administration significantly reduces hunger in young males, but is slightly less effective in older subjects, and even slightly less effective in females. The hunger-suppressive effects of CCK also are reduced in obese rats.[]

Interactions
Cholecystokinin has been shown to interact with the Cholecystokinin A receptor located mainly on pancreatic acinar cells and Cholecystokinin B receptor mostly in the brain and stomach. CCKB receptor also binds gastrin, a gastrointestinal hormone involved in stimulating gastric acid release and growth of the gastric mucosa.[][][] CCK has also been shown to interact with calcineurin in the pancreas. Calcineurin will go on to activate the transcription factors NFAT 13, which will stimulate hypertrophy and growth of the pancreas. CCK can be stimulated by a diet high in protein, or by protease inhibitors.[] Cholecystokinin has been shown to interact with orexin neurons which control appetite and wakefulness (sleep).[] Cholecystokinin can have indirect effects on sleep regulation.[46] Cholecystokinin in the body cannot cross the blood brain barrier, but certain parts of the hypothalamus and brainstem aren't protected by the barrier. In the hypothalamus, CCK8 injection excites CRF neurosecretory neurons in par ventricular nucleus that is different cell responsive to pain stimulation:They show slow a 1 sec-hyperpolarizaiton with subsequent long (30min) depolarization to CCK8 injection (psychological stress), whereas tail pinch (physical stress), transient excitation. Consistently, in the cerebellum, Golgi cells express c-fos mRNA to CCK8 injection, whereas granule cells express junD mRNA to capsaicin injection to the limb skin. Thus, psychological and physical stress excite different neural path.

Cholecystokinin

65

References
[1] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=1569 [2] http:/ / omim. org/ entry/ 118440 [3] http:/ / www. informatics. jax. org/ searches/ accession_report. cgi?id=MGI:88297 [4] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=583 [5] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ target/ inspect/ CHEMBL1649050 [6] http:/ / www. genecards. org/ cgi-bin/ carddisp. pl?id_type=entrezgene& id=885 [7] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005184 [8] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030424 [9] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030425 [10] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043194 [11] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043195 [12] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043203 [13] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043204 [14] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0001662 [15] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0001764 [16] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0001836 [17] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006919 [18] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007165 [19] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007205 [20] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007409 [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0008284 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032099 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032461 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042755 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043065 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0050731 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0051901 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0051930 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ gp-assoc. cgi?gp=UniProtKB:P06307 http:/ / www. ebi. ac. uk/ QuickGO/ GProtein?ac=P06307 http:/ / biogps. org/ gene/ 885/ http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=885& rn=1 http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=12424& rn=1 http:/ / www. ensembl. org/ Homo_sapiens/ geneview?gene=ENSG00000187094;db=core http:/ / www. ensembl. org/ Mus_musculus/ geneview?gene=ENSMUSG00000032532;db=core http:/ / www. uniprot. org/ uniprot/ P06307 http:/ / www. uniprot. org/ uniprot/ P09240 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_000729 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_031161 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_000720 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_112438 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Human& db=hg19& position=chr3:42299317-42307699 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Mouse& db=mm9& position=chr9:121489825-121495689 http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=885 http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=12424

External links
Cholecystokinin (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Cholecystokinin) at the US National Library of Medicine Medical Subject Headings (MeSH)

Thalamus

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Thalamus
Brain: Thalamus

thalamus marked (MRI cross-section)

anterolateral view Latin Gray's Part of thalamus dorsalis subject #189 808 Diencephalon
[1]

Components See List of thalamic nuclei Artery Posterior cerebral artery and branches

NeuroNames hier-283 [2] MeSH Thalamus

[3]

NeuroLex ID birnlex_954 [4]

The thalamus (from Greek , "inner chamber")[5] is a midline symmetrical structure within the brains of vertebrates including humans, situated between the cerebral cortex and midbrain. Its function includes relaying sensory and motor signals to the cerebral cortex,[][6] along with the regulation of consciousness, sleep, and alertness. The thalamus surrounds the third ventricle. It is the main product of the embryonic diencephalon.

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Anatomy
The thalamus is perched on top of the brainstem, near the center of the brain, with nerve fibers projecting out to the cerebral cortex in all directions. The medial surface of the thalamus constitutes the upper part of the lateral wall of the third ventricle, and is connected to the corresponding surface of the opposite thalamus by a flattened gray band, the Interthalamic adhesion.

Morphology
Both parts of this structure of the brain in the human are each about the size and shape of a walnut.[] These are about three centimetres in length, at the widest part 2.5 centimetres across and about 2 centimetres in height (comparable to an unshelled walnut, with the nut-shell joining in the horizontal plane).

The two thalami in a 360o rotation

The two halves of the thalamus are prominent bulb-shaped masses, about 5.7cm in length, located obliquely (about 30) and symmetrically on each side of the third ventricle.

Blood supply
The thalamus derives its blood supply from four arteries including the polar artery (posterior communicating artery), paramedian thalamic-subthalamic arteries, inferolateral (thalamogeniculate) arteries, and posterior (medial and lateral) choroidal arteries.[7] These are all derived from the vertebrobasilar arterial system except the polar artery. Some people have the artery of Percheron, which is a rare anatomic variation in which a single arterial trunk arises from the posterior cerebral artery to supply both thalami.

Thalamic nuclei
The thalamus is part of a nuclear complex structured of four parts, the hypothalamus, epithalamus, ventral thalamus, and dorsal thalamus.[8] Derivatives of the diencephalon also include the dorsally-located epithalamus (essentially the habenula and annexes) and the perithalamus (prethalamus formerly described as ventral thalamus) containing the zona incerta and the "reticulate nucleus" (not the reticular, term of confusion). Due to their different ontogenetic origins, the epithalamus and the perithalamus are formally distinguished from the thalamus proper.
Nuclei of the thalamus The thalamus comprises a system of lamellae (made up of myelinated fibers) separating different thalamic subparts. Other areas are defined by distinct clusters of neurons, such as the periventricular gray, the intralaminar elements, the "nucleus limitans", and others.[9] These latter structures, different in structure from the major part of the thalamus, have been grouped together into the allothalamus as opposed to the isothalamus.[10] This distinction simplifies the global description of the thalamus.

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68

Connections
The thalamus is manifoldly connected to the hippocampus via the mammillo-thalamic tract, this tract comprises the mammilary body and fornix.[] The spinothalamic tract is a sensory pathway originating in the spinal cord. It transmits information to the thalamus about pain, temperature, itch and crude touch. There are two main parts: the lateral spinothalamic tract, which transmits pain and temperature, and the anterior (or ventral) spinothalamic tract, which transmits crude touch and pressure.

The thalamus is connected to the spinal cord via the spinothalamic tract.

Function
The thalamus has multiple functions. It may be thought of as a kind of switchboard of information. It is generally believed to act as a relay between a variety of subcortical areas and the cerebral cortex. In particular, every sensory system (with the exception of the olfactory system) includes a thalamic nucleus that receives sensory signals and sends them to the associated primary cortical area. For the visual system, for example, inputs from the retina are sent to the lateral geniculate nucleus of the thalamus, which in turn projects to the primary visual cortex (area V1) in the occipital lobe. The thalamus is believed to both process sensory information as well as relay iteach of the primary sensory relay areas receives strong "back projections" from the cerebral cortex. Similarly the medial geniculate nucleus acts as a key auditory relay between the inferior colliculus of the midbrain and the primary auditory cortex, and the ventral posterior nucleus is a key somatosensory relay, which sends touch and proprioceptive information to the primary somatosensory cortex. The thalamus also plays an important role in regulating states of sleep and wakefulness.[11] Thalamic nuclei have strong reciprocal connections with the cerebral cortex, forming thalamo-cortico-thalamic circuits that are believed to be involved with consciousness. The thalamus plays a major role in regulating arousal, the level of awareness, and activity. Damage to the thalamus can lead to permanent coma. The role of the thalamus in the more anterior pallidal and nigral territories in the basal ganglia system disturbances is recognized but still poorly understood. The contribution of the thalamus to vestibular or to tectal functions is almost ignored. The thalamus has been thought of as a "relay" that simply forwards signals to the cerebral cortex. Newer research suggests that thalamic function is more selective.[12] Many different functions are linked to various regions of the thalamus. This is the case for many of the sensory systems (except for the olfactory system), such as the auditory, somatic, visceral, gustatory and visual systems where localized lesions provoke specific sensory deficits. A major role of the thalamus is devoted to "motor" systems. The thalamus is functionally connected to the hippocampus[13] as part of the extended hippocampal system at the thalamic anterior nuclei[14] with respect to spatial memory and spatial sensory datum they are crucial for human episodic memory and rodent event memory.[15][16] There is support for the hypothesis that thalamic regions connection to particular parts of the mesio-temporal lobe provide differentiation of the functioning of recollective and familiarity memory.[] The neuronal information processes necessary for motor control were proposed as a network involving the thalamus as a subcortical motor centre.[17] Through investigations of the anatomy of the brains of primates[18] the nature of the interconnected tissues of the cerebellum to the multiple motor cortices suggested that the thalamus fulfills a key function in providing the specific channels from the basal ganglia and cerebellum to the cortical motor areas.[19][20] In an investigation of the saccade and antisaccade[21] motor response in three monkeys, the thalamic regions were found to be involved in the generation of antisaccade eye-movement.[22]

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69

Human brain frontal (coronal) section

Development
The thalamic complex is composed of the perithalamus (or prethalamus, previously also known as ventral thalamus), the mid-diencephalic organiser (which forms later the zona limitans intrathalamica (ZLI) ) and the thalamus (dorsal thalamus).[23][24] The development of the thalamus can be subdivide into three steps[] The thalamus is the largest structure deriving from the embryonic diencephalon, the posterior part of the forebrain situated between the midbrain and the cerebrum.

Early brain development

After neurulation the anlage of the prethalamus and the thalamus is induced within the neural tube. Data from different vertebrate model organisms support a model in which the interaction between two transcription factors, Fez and Otx, are of decisive importance. Fez is expressed in the prethalamus, and functional experiments show that Fez is required for prethalamus formation.[25][26] Posteriorly, Otx1 and Otx2 abut the expression domain of Fez and are required for proper development of the thalamus.[27][28]

The formation of the mid-diencephalic organiser (MDO)

At the interface between the expression domains of Fez and Otx, the mid-diencephalic organizer (MDO, also called the ZLI organiser) is induced within the thalamic anlage. The MDO is the central signalling organizer in the thalamus. A lack of the organizer leads to the absence of the thalamus. The MDO matures from ventral to dorsal during development. Members of the SHH family and of the Wnt family are the main principal signals emitted by the MDO. Besides its importance as signalling center, the organizer matures into the morphological structure of the zona limitans intrathalamica (ZLI).

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Maturation and parcellation of the thalamus

After its induction, the MDO starts to orchestrate the development of the thalamic anlage by release of signalling molecules such as Shh.[29] In mice, the function of signaling at the MDO has not been addressed directly due to a complete absence of the diencephalon in Shh mutants.[30] Studies in chicks have shown that Shh is both necessary and sufficient for thalamic gene induction.[31] In zebrafish, it was shown that the expression of two Shh genes, shh-a and shh-b (formerly described as twhh) mark the MDO territory, and that Shh signaling is sufficient for the molecular differentiation of both the prethalamus and the thalamus but is not required for their maintenance and Shh signaling from the MDO/alar plate is sufficient for the maturation of prethalamic and thalamic territory while ventral Shh signals are dispensable.[32] The exposure to Shh leads to differentiation of thalamic neurons. SHH signaling from the MDO induces a posterior-to-anterior wave of expression the proneural gene Neurogenin1 in the major (caudal) part of the thalamus, and Ascl1 (formerly Mash1) in the remaining narrow stripe of rostral thalamic cells immediately adjacent to the MDO, and in the prethalamus.[33][34] This zonation of proneural gene expression leads to the differentiation of glutamatergic relay neurons from the Neurogenin1+ precursors and of GABAergic inhibitory neurons from the Ascl1+ precursors. In fish, selection of these alternative neurotransmitter fates is controlled by the dynamic expression of Her6 the homolog of HES1. Expression of this hairy-like bHLH transcription factor, which represses Neurogenin but is required for Ascl1, is progressively lost from the caudal thalamus but maintained in the prethalamus and in the stripe of rostral thalamic cells. In addition, studies on chick and mice have shown that blocking the Shh pathway leads to absence of the rostral thalamus and substantial decrease of the caudal thalamus. The rostral thalamus will give rise to the reticular nucleus mainly whereby the caudal thalamus will form the relay thalamus and will be further subdivided in the thalamic nuclei.[] In humans, a common genetic variation in the promotor region of the serotonin transporter (the SERT-long and -short allele: 5-HTTLPR) has been shown to affect the development of several regions of the thalamus in adults. People who inherit two short alleles (SERT-ss) have more neurons and a larger volume in the pulvinar and possibly the limbic regions of the thalamus. Enlargement of the thalamus provides an anatomical basis for why people who inherit two SERT-ss alleles are more vulnerable to major depression, posttraumatic stress disorder, and suicide.[35]

Pathology
A cerebrovascular accident (stroke) can lead to the thalamic syndrome,[36] which involves a one-sided burning or aching sensation often accompanied by mood swings. Bilateral ischemia of the area supplied by the paramedian artery can cause serious problems including akinetic mutism, and be accompanied by oculomotor problems. A related concept is thalamocortical dysrhythmia. The occlusion of the artery of Percheron can lead to a bilateral thalamus infarction. Korsakoff's syndrome stems from damage to the mammillary body, the mammillothalamic fasciculus or the thalamus. Fatal familial insomnia is a hereditary prion disease in which degeneration of the thalamus occurs, causing the patient to gradually lose his ability to sleep and progressing to a state of total insomnia, which invariably leads to death.

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Gallery
Images are circa 1858.[37]

The left optic nerve and the optic tracts.

Coronal section of lateral and third ventricles.

Dissection showing the ventricles of the brain.

Section of brain showing upper surface of temporal lobe.

Horizontal section of right cerebral hemisphere.

Mesal aspect of a brain sectioned in the median sagittal plane.

Schematic representation of the chief ganglionic categories (I to V).

Scheme showing the course of the fibers of the lemniscus; medial lemniscus in blue, lateral in red.

Deep dissection of brain-stem. Lateral view.

Deep dissection of brain-stem. Ventral view.

Coronal section of brain immediately in front of pons.

Coronal section of brain through intermediate mass of third ventricle.

Thalamus

Thalamus

72

References
[1] [2] [3] [4] [5] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=189#p808 http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=283 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Thalamus http:/ / www. neurolex. org/ wiki/ birnlex_954 Harper - index (http:/ / www. etymonline. com/ index. php?allowed_in_frame=0& search=thalamus& searchmode=none) & University of Washington Faculty Web Server (http:/ / faculty. washington. edu/ chudler/ neuroroot. html) & Search engine search page (http:/ / www. google. co. uk/ #hl=en& cp=18& gs_id=1y& xhr=t& q=etymology+ thalamus& pf=p& sclient=psy-ab& rlz=1W1GPCK_enGB446& source=hp& pbx=1& oq=etymology+ thalamus& aq=0v& aqi=g-v1& aql=& gs_sm=& gs_upl=& bav=on. 2,or. r_gc. r_pw. r_cp. ,cf. osb& fp=c5c3f35eb03724& biw=1600& bih=694) + Perseus Project tufts.edu (http:/ / www. perseus. tufts. edu/ hopper/ searchresults?q=thalamus) Retrieved 2012-02-09 [6] S. M. Sherman & Ray Guillery -ISBN 0-12-305460-5 Elsevier B.V (http:/ / www. elsevier. com/ wps/ find/ bookdescription. cws_home/ 673351/ description#description) [Retrieved 2012-02-10] [9] Jones Edward G.(2007) "The Thalamus" Cambridge Uni. Press [19] Asanuma et al. 1983; et al [21] http:/ / www. optomotorik. de/ blicken/ anti-rev. htm [37] Gray, H. & Carter, H. V. (1858), Anatomy Descriptive and Surgical, London: John W. Parker and Son, Retrieved (16 October 2011) [2012-02-10] (http:/ / www. archive. org/ stream/ anatomydescript09graygoog#page/ n7/ mode/ 2up)

External links
BrainMaps at UCDavis thalamus (http://brainmaps.org/index.php?q=thalamus)

Subthalamic nucleus

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Subthalamic nucleus
Brain: Subthalamic nucleus

Coronal slices of human brain showing the basal ganglia, subthalamic nucleus (STN) and substantia nigra (SN).

DA-loops in Parkinson's disease Latin Part of NeuroNames MeSH nucleus subthalamicus Basal ganglia hier-418
[1] [2]

Subthalamic+Nucleus

The subthalamic nucleus is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. In terms of anatomy, it is the major part of subthalamus. As suggested by its name, the subthalamic nucleus is located ventral to the thalamus. It is also dorsal to the substantia nigra and medial to the internal capsule. It was first described by Jules Bernard Luys in 1865,[3] and the term corpus Luysi or Luys' body is still sometimes used.

Anatomy
Structure
The principal type of neuron found in the subthalamic nucleus has rather long sparsely spiny dendrites.[][4] The dendritic arborizations are ellipsoid, replicating in smaller dimension the shape of the nucleus.[5] The dimensions of these arborizations (1200,600 and 300 m) are similar across many speciesincluding rat, cat, monkey and manwhich is unusual. However, the number of neurons increases with brain size as well as the external dimensions of the nucleus. The principal neurons are glutamatergic, which give them a particular functional position in the basal ganglia system. In humans there are also a small number (about 7.5%) of GABAergic interneurons that participate in the local circuitry; however, the dendritic arborizations of subthalamic neurons shy away from the border and majorly interact with one another.[6]

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Afferent axons
The subthalamic nucleus receives its main input from the globus pallidus,[] not so much through the ansa lenticularis as often said but by radiating fibers crossing the medial pallidum first and the internal capsule (see figure). These afferents are GABAergic, inhibiting neurons in the subthalamic nucleus. Excitatory, glutamatergic inputs come from the cerebral cortex (particularly the motor cortex), and from the pars parafascicularis of the central complex. The subthalamic nucleus also receives neuromodulatory inputs, notably dopaminergic axons from the substantia nigra pars compacta.[7] It also receives inputs from the pedunculopontine nucleus.

Efferent targets
The axons of subthalamic nucleus neurons leave the nucleus dorsally. The efferent axons are glutamatergic (excitatory). Except for the connection to the striatum (17.3% in macaques), most of the subthalamic principal neurons are multitargets and directed to the other elements of the core of the basal ganglia.[] Some send axons to the substantia nigra medially and to the medial and lateral nuclei of the pallidum laterally (3-target, 21.3%). Some are 2-target with the lateral pallidum and the substantia nigra (2.7%) or the lateral pallidum and the medial (48%). Less are single target for the lateral pallidum. In the pallidum, subthalamic terminals end in bands parallel to the pallidal border.[8][] When all axons reaching this target are added, the main afference of the subthalamic nucleus is, in 82.7% of the cases, clearly the medial pallidum (internal segment of the globus pallidus). Some researchers have reported internal axon collaterals.[9] However, there is little functional evidence for this.

Subthalamic nucleus

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Physiology
Subthalamic nucleus
The first intracellular electrical recordings of subthalamic neurons were performed using sharp electrodes in a rat slice preparation.[citation needed] In these recordings three key observations were made, all three of which have dominated subsequent reports of subthalamic firing properties. The first observation was that, in the absence of current injection or synaptic stimulation, the majority of cells were spontaneously firing. The second observation is that these cells are capable of transiently firing at very high frequencies. The third observation concerns non-linear behaviors when cells are transiently depolarized after being hyperpolarized below 65mV. They are then able to engage voltage-gated calcium and sodium currents to fire bursts of action potentials. Several recent studies have focused on the autonomous pacemaking ability of subthalamic neurons. These cells are often referred to as "fast-spiking pacemakers",[10] since they can generate spontaneous action potentials at rates of 80 to 90Hz in primates.

Lateropallido-subthalamic system
Strong reciprocal connections link the subthalamic nucleus and the external segment of the globus pallidus. Both are fast-spiking pacemakers. Together, they are thought to constitute the "central pacemaker of the basal ganglia"[11] with synchronous bursts.

Anatomical overview of the main circuits of the basal ganglia. Subthalamic nucleus is shown in red. Picture shows 2 coronal slices that have been superimposed to include the involved basal ganglia structures. + and - signs at the point of the arrows indicate respectively whether the pathway is excitatory or inhibitory in effect. Green arrows refer to excitatory glutamatergic pathways, red arrows refer to inhibitory GABAergic pathways and turquoise arrows refer to dopaminergic pathways that are excitatory on the direct pathway and inhibitory on the indirect pathway.

The connection of the lateral pallidum with the subthalamic nucleus is also the one in the basal ganglia system where the reduction between emitter/receiving elements is likely the strongest. In terms of volume, in humans, the lateral pallidum measures 808mm, the subthalamic nucleus only 158mm.[12] This translated in numbers of neurons represents a strong compression with loss of map precision. Some axons from the lateral pallidum go to the striatum.[13] The activity of the medial pallidum is influenced by afferences from the lateral pallidum and from the subthalamic nucleus.[14] The same for the nigra reticulata.[] The subthalamic nucleus sends axons to another regulator: the pedunculo-pontine complex (id). The lateropallido-subthalamic system is thought to play a key role in the generation of the patterns of activity seen in Parkinson's disease.[15]

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Pathophysiology
Chronic stimulation of the STN, called deep brain stimulation (DBS), is used to treat patients with Parkinson disease. The first to be stimulated are the terminal arborisations of afferent axons, which modify the activity of subthalamic neurons. However, it has been shown in thalamic slices from mice,[16] that the stimulus also causes nearby astrocytes to release Adenosine Triphosphate (ATP), a precursor to adenosine (through a catabolic process). In turn, adenosine A1 receptor activation depresses excitatory transmission in the thalamus, thus mimicking ablation of the subthalamic nucleus. Unilateral destruction or disruption of the subthalamic nucleus which can commonly occur via a small vessel stroke in patients with diabetes, hypertension, or a history of smoking produces hemiballismus. As one of the STN's suspected functions is in impulse control, dysfunction in this region has been implicated in Obsessivecompulsive disorder.[17] Artificially stimulating the STN has shown some promise in correcting severe implusive behavior and may later be used as an alternative treatment for the disorder.[18]

Function
The function of the STN is unknown, but current theories place it as a component of the basal ganglia control system that may perform action selection. STN dysfunction has also been shown to increase impulsivity in individuals presented with two equally rewarding stimuli.[19]

Additional images

Coronal section of brain immediately in front of pons. Subthalamic nucleus labeled as "Nucleus of Luys".

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References
[1] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=418 [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Subthalamic+ Nucleus

External links
http://isc.temple.edu/neuroanatomy/lab/atlas/pdhn/

Glycine

78

Glycine
Glycine[1]

Identifiers Abbreviations CAS number PubChem ChemSpider UNII EC-number DrugBank KEGG ChEBI ChEMBL IUPHAR ligand ATC code Jmol-3D images Gly, G 56-40-6 750 730
[3] [4] [5] [2]

TE7660XO1C 200-272-2 DB00145 D00011

[6]

[7] [9]

[8]

CHEBI:15428 CHEMBL773 727

[11]

[10]

B05 CX03 Image 1 Properties

[12]

[13]

Molecular formula Molar mass Appearance Density Melting point Solubility in water Solubility Acidity (pK )
a

C H NO
2 5

75.07 g mol1 white solid 1.607 g/cm3 233 C (decomposition) 24.99 g/100 mL (25 C)
[14]

soluble in ethanol, pyridine insoluble in ether 2.34 (carboxyl), 9.6 (amino)

[15]

Glycine

79
Hazards MSDS LD50 External MSDS 2600 mg/kg (mouse, oral) Supplementary data page Structure and properties Thermodynamic data Spectral data
(verify) [16]

n, r, etc. Phase behaviour Solid, liquid, gas UV, IR, NMR, MS

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Glycine (abbreviated as Gly or G)[17] is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its side-chain, glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG of the genetic code. Glycine is a colourless, sweet-tasting crystalline solid. It is unique among the proteinogenic amino acids in that it is not chiral. It can fit into hydrophilic or hydrophobic environments, due to its minimal side chain of only one hydrogen atom. Glycine is also the genus name of the Soybean plant (species name = Glycine max).

Production and key properties

Glycine was discovered in 1820, by Henri Braconnot who boiled gelatin with sulfuric acid.[18] Glycine is manufactured industrially by treating chloroacetic acid with ammonia:[19] About 15 million kg are produced annually in this way.[20] In the USA (by GEO Specialty Chemicals, Inc.) and in Japan (by Shoadenko), glycine is produced via the Strecker amino acid synthesis.[21][22] There are two producers of glycine in the United States: Chattem Chemicals, Inc., a subsidiary of Mumbai-based Sun Pharmaceutical, and GEO Specialty Chemicals, Inc., which purchased the glycine and naphthalene sulfonate production facilities of Hampshire Chemical Corp, a subsidiary of Dow Chemical.[21][23] Chattem's manufacturing process ("MCA" process) occurs in batches and results in a finished product with some residual chloride but no sulfate, while GEOs manufacturing process is considered a semi-batch process and results in a finished product with some residual sulfate but no chloride. Its pKA values are 2.35 and 9.78, so above pH 9.78, most of the glycine exists as the anionic amine, H2NCH2CO2-. Below pH 2.35, its solutions contain mostly the cationic carboxylic acid H3N+CH2CO2H. Its isoelectric point (pI) is 6.06. Glycine exists in zwitterionic form in solution. In this form, the partial charges on different atoms as determined using Gasteiger charge method are given as follows: N (+0.2358), H (attached to N) (+0.1964), alpha-C (+0.001853), H (attached to alpha-C) (+0.08799), carbonyl C (+0.085) and carbonyl O (-0.5445). ClCH2COOH + 2 NH3 H2NCH2COOH + NH4Cl

Glycine

80

Biosynthesis
Glycine is not essential to the human diet, as it is biosynthesized in the body from the amino acid serine, which is in turn derived from 3-phosphoglycerate. In most organisms, the enzyme Serine hydroxymethyltransferase catalyses this transformation via the cofactor pyridoxal phosphate:[24] serine + tetrahydrofolate glycine + N5,N10-Methylene tetrahydrofolate + H2O In the liver of vertebrates, glycine synthesis is catalyzed by glycine synthase (also called glycine cleavage enzyme). This conversion is readily reversible:[24] CO2 + NH4+ + N5,N10-Methylene tetrahydrofolate + NADH + H+ Glycine + tetrahydrofolate + NAD+ Glycine is coded by codons GGU, GGC, GGA and GGG. Most proteins incorporate only small quantities of glycine. A notable exception is collagen, which contains about 35% glycine.[24][]

Degradation
Glycine is degraded via three pathways. The predominant pathway in animals and plants involves the glycine cleavage enzyme[24] Glycine + tetrahydrofolate + NAD+ CO2 + NH4+ + N5,N10-Methylene tetrahydrofolate + NADH + H+ In the second pathway, glycine is degraded in two steps. The first step is the reverse of glycine biosynthesis from serine with serine hydroxymethyl transferase. Serine is then converted to pyruvate by serine dehydratase.[24] In the third pathway of glycine degradation, glycine is converted to glyoxylate by D-amino acid oxidase. Glyoxylate is then oxidized by hepatic lactate dehydrogenase to oxalate in an NAD+-dependent reaction.[24] The half-life of glycine and its elimination from the body varies significantly based on dose. In one study, the half-life was between 0.5 and 4.0 hours. [25]

Physiological function
The principal function of glycine is as a precursor to proteins. It is also a building block to numerous natural products.

As a biosynthetic intermediate
In higher eukaryotes, D-Aminolevulinic acid, the key precursor to porphyrins, is biosynthesized from glycine and succinyl-CoA. Glycine provides the central C2N subunit of all purines.[24]

As a neurotransmitter
Glycine is an inhibitory neurotransmitter in the central nervous system, especially in the spinal cord, brainstem, and retina. When glycine receptors are activated, chloride enters the neuron via ionotropic receptors, causing an Inhibitory postsynaptic potential (IPSP). Strychnine is a strong antagonist at ionotropic glycine receptors, whereas bicuculline is a weak one. Glycine is a required co-agonist along with glutamate for NMDA receptors. In contrast to the inhibitory role of glycine in the spinal cord, this behaviour is facilitated at the (NMDA) glutaminergic receptors which are excitatory.[26] The LD50 of glycine is 7930mg/kg in rats (oral),[27] and it usually causes death by hyperexcitability. There is some evidence showing that 3000 milligrams of glycine before bedtime improves sleep quality.[28]Wikipedia:No original research#Primary, secondary and tertiary sources

Glycine

81

Commercial uses
In the US, glycine is typically sold in two grades: United States Pharmacopeia (USP), and technical grade. Most glycine is manufactured as USP grade material for diverse uses. USP grade sales account for approximately 80 to 85 percent of the U.S. market for glycine. Pharmaceutical grade glycine is produced for some pharmaceutical applications, such as intravenous injections, where the customers purity requirements often exceed the minimum required under the USP grade designation. Pharmaceutical grade glycine is often produced to proprietary specifications and is typically sold at a premium over USP grade glycine. Technical grade glycine, which may or may not meet USP grade standards, is sold for use in industrial applications; e.g., as an agent in metal complexing and finishing. Technical grade glycine is typically sold at a discount to USP grade glycine.[29]

Animal and human foods

Other markets for USP grade glycine include its use an additive in pet food and animal feed. For humans, glycine is sold as a sweetener/taste enhancer. Certain food supplements and protein drinks contain glycine.[citation needed] Certain drug formulations include glycine to improve gastric absorption of the drug.[citation needed]

Cosmetics and miscellaneous applications

Glycine serves as a buffering agent in antacids, analgesics, antiperspirants, cosmetics, and toiletries. Many miscellaneous products use glycine or its derivatives, such as the production of rubber sponge products, fertilizers, metal complexants.[30]

Chemical feedstock
Glycine is an intermediate in the synthesis of a variety of chemical products. It is used in the manufacture of the herbicide glyphosate. Glyphosate is a non-selective Zwitterionic salt (right) of glycine at neutral pH systemic herbicide used to kill weeds, especially perennials and broadcast or used in the cut-stump treatment as a forestry herbicide. Initially, glyphosate was sold only by Monsanto under the tradename Roundup, but is no longer under patent.

Presence in space
The detection of glycine in the interstellar medium has been debated.[] In 2008, the glycine-like molecule aminoacetonitrile was discovered in the Large Molecule Heimat, a giant gas cloud near the galactic center in the constellation Sagittarius by the Max Planck Institute for Radio Astronomy.[31] In 2009, glycine sampled in 2004 from comet Wild 2 by the NASA spacecraft Stardust was confirmed, the first discovery of extraterrestrial glycine. That mission's results bolstered the theory of panspermia, which claims that the "seeds" of life are widespread throughout the universe.[32]

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References
[1] . [2] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=56-40-6 [3] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=750 [4] http:/ / www. chemspider. com/ 730 [5] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=TE7660XO1C [6] http:/ / ecb. jrc. ec. europa. eu/ esis/ index. php?GENRE=ECNO& ENTREE=200-272-2 [7] http:/ / www. drugbank. ca/ drugs/ DB00145 [8] http:/ / www. kegg. jp/ entry/ D00011 [9] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=15428 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL773 [11] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=727 [12] http:/ / www. whocc. no/ atc_ddd_index/ ?code=B05CX03 [13] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=C%28C%28%3DO%29O%29N [14] http:/ / prowl. rockefeller. edu/ aainfo/ solub. htm [15] Dawson, R.M.C., et al., Data for Biochemical Research, Oxford, Clarendon Press, 1959. [16] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=464190930& page2=Glycine [17] . [19] . [20] Karlheinz Drauz, Ian Grayson, Axel Kleemann, Hans-Peter Krimmer, Wolfgang Leuchtenberger, Christoph Weckbecker Amino Acids in Ullmann's Encyclopedia of Industrial Chemistry 2007, Wiley-VCH, Weinheim. [21] http:/ / www. usitc. gov/ trade_remedy/ 731_ad_701_cvd/ investigations/ 2007/ glycine_from_india_japan_korea/ preliminary/ DOC/ Glycine%20Conference%20(prelim). wpd [22] http:/ / www. geosc. com/ consumeradditives/ default. aspx [23] U.S. International Trade Commission, "Glycine From China." Investigation No. 731-TA-718 (Second Review), Publication No. 3810, October 2005 [24] . [29] http:/ / www. usitc. gov/ publications/ 701_731/ pub3980. pdf [30] "Notice of Preliminary Determination of Sales at Less Than Fair Value: Glycine From India" Federal Register 72 (7 November 2007): 62827.

Further reading
On attempts to detect glycine in interstellar medium Kuan YJ, Charnley SB, Huang HC, et al. (2003). "Interstellar glycine". Astrophys J 593 (2): 848867. Bibcode: 2003ApJ...593..848K (http://adsabs.harvard.edu/abs/2003ApJ...593..848K). doi: 10.1086/375637 (http:// dx.doi.org/10.1086/375637). Rachel Nowak. "Amino acid found in deep space - 18 July 2002 - New Scientist" (http://www.newscientist. com/news/news.jsp?id=ns99992558). Retrieved 2007-07-01.

External links
Glycine (http://www.pdrhealth.com/drugs/altmed/altmed-mono.aspx?contentFileName=ame0084.xml& contentName=Glycine&contentId=247) at PDRHealth.com Glycine cleavage system (http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/AminoAcid/GlyCleave. html) Glycine Therapy - A New Direction for Schizophrenia Treatment? (http://www.schizophrenia.com/ glycinetreat.htm) "Organic Molecule, Amino Acid-Like, Found In Constellation Sagittarius" (http://www.sciencedaily.com/ releases/2008/03/080326161658.htm). ScienceDaily. 27 March 2008. Guochuan E. Tsai (1 December 2008). "A New Class of Antipsychotic Drugs: Enhancing Neurotransmission Mediated by NMDA Receptors" (http://www.psychiatrictimes.com/display/article/10168/1357569). Psychiatric Times 25 (14).

Glycine ChemSub Online (Glycine) (http://chemsub.online.fr/name/glycine.html). NASA scientists have discovered glycine, a fundamental building block of life, in samples of comet Wild 2 returned by NASA's Stardust spacecraft. (http://www.jpl.nasa.gov/news/news.cfm?release=2009-126)

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Renshaw cell
Neuron: Renshaw Cell
Neurotransmitter Glycine NeuroLex ID nifext_113 [1]

Renshaw cells are inhibitory interneurons found in the gray matter of the spinal cord, and are associated in two ways with an alpha motor neuron. They receive an excitatory collateral from the alpha neuron's axon as they emerge from the motor root, and are thus "kept informed" of how vigorously that neuron is firing. They send an inhibitory axon to synapse with the cell body of the initial alpha neuron and/or an alpha motor neuron of the same motor pool. In this way, Renshaw cell inhibition represents a negative feedback mechanism. A Renshaw cell may be supplied by more than one alpha motor neuron collateral and it may synapse on multiple motor neurons.

Discovery
The concept of the Renshaw cells was postulated by B. Renshaw,[2] when it was discovered that with antidromic signals from a motor neuron running collaterally back via the ventral horn into the spinal cord, there were interneurons firing with a high frequency, resulting in inhibition. Later work by Eccles et al.,[3] provided evidence that these interneurones, which they called Renshaw Cells, are stimulated by acetylcholine from motor neurons. Previous work by Renshaw[4] and Lloyd[5][6] had shown that this antidromic inhibition resembled direct inhibition from spinal nerves but resulted in relatively longer inhibition of 40-50ms (compared to 15ms). The stimulation of the antidromic nerve fiber also resulted in action potentials of the central part of the motoneurones that would generate the original impulse, along with hyperpolarization of other groups of motor neurons. In the event where the initial stimulation of the motoneuron originated in the spinal track, these impulses occurred after the initial stimulation, and where the Renshaw cell spike occurred during the declining phase of the initial motoneuron soma spike had thus giving an indication of the source and sequence of stimulation of the Renshaw cell.

Physiology
Although during embryonic development the Renshaw cells lack synapses from the dorsal root, prenatal and postnatal stages show the development of dorsal root originating synapses, which are functional and stimulate action potentials. But these decrease during development while acetylcholine motor axons begin to synapse and proliferate with Renshaw cells, ultimately being primarily stimulated by the motor neurons.[7] The Renshaw cells are ultimately excited by multiple antidromic motor neuron axons, where the majority of axons originate from synergist motor neurons, and in turn the Renshaw cell synapses with multiple neurons, eliciting IPSP in alpha motor, 1a inhibitory interneurons and gamma motor neurons. The antidromic collateral circuit back to the triggering motor neuron is known as recurrent inhibition. This homonymous inhibition is not universal. Whereas most initial experiments have been done on cats, it has been found that in man that proximal muscles of the hand and foot do not have homonymous inhibition. Heteronymous inhibition has been found to be dominant in the leg

Renshaw cell compared to the arm, where antagonist muscles work simultaneously. (It must also be noted that Renshaw cells are activated by gamma motor neurons, but to a lesser extent). The Renshaw cells not only synapse with homonymous and heteronymous nerves, but also with the Ia interneurones, which are stimulated by the Ia afferents from the same muscle group activated by the motor neurons, which have an inhibitory effect on the antagonist muscle group. This recurrent facilitation causes reduced inhibition of the reciprocal inhibition of the Ia interneuron of the antagonist group (Baret et al.; 2003), which may in turn also be inhibited by signals from the corticospinal tract.[8] It has been shown that:[9][10][11] Recurrent inhibition is depressed during strong voluntary contractions (presumably due to inhibition of the Reshaw cell by descending input). Renshaw cells are more inhibited at the same level during a dynamic contraction compared with sustained contraction. Renshaw cells are facilitated during weak voluntary contractions. Renshaw cells are facilitated during co-activation of antagonists. The Renshaw cells may also be inhibited by both proprioceptive dorsal root afferents],[12][13] antidromic ventral axons[14] as well as descending inhibition.[15][16] The hyperpolarization of Renshaw cells by afferent and descending neurons have been shown to be caused by the release of glycine, but GABA may also hyperpolarize the Renshaw cell- for a prolonged time relative to glycine. It has also be show that glycine is the inhibitory transmitter released by the Renshaw cells.[17][18] In essence the Renshaw cells regulate the firing of the alpha motor neuron leaving the ventral horn. Conceptually they remove noise by dampening the firing frequency of over-excited neurons with a negative feedback loop, which prevents weakly excited alpha motor neurons from firing. Descending spinal cord nerves in turn regulate the Renshaw cells. The rate of discharge of the Renshaw cell is broadly proportional to the rate of discharge of the associated motor neuron(s), and the rate of discharge of the motor neuron(s) is broadly inversely proportional to the rate of discharge of the Renshaw cell(s). Renshaw cells thus act as "limiters," or "governors," on the alpha motor neuron system, thus helping to prevent muscular damage from tetanus. Renshaw cells utilize the neurotransmitter glycine as an inhibitory substance that synapses on the alpha motor neurons. Strychnine specifically acts on these cell's ability to control alpha motor neuron firing by binding to the glycine receptors on the motor neuron. This antagonistic poison will predispose someone to tetanic contractions, and can prove fatal if the diaphragm becomes involved.

84

Target of neurotoxins
Renshaw cells are also the target of the toxin of Clostridium tetani, a spore-forming anaerobic bacterium that lives in the soil. When wounds are contaminated with C. tetani, the toxin travels to the spinal cord where it inhibits the release of glycine from Renshaw cells. As a result, alpha motor neurons become hyperactive, and muscles constantly contract.

References
[1] http:/ / www. neurolex. org/ wiki/ nifext_113 [2] Renshaw B. Central effects of centripetal impulses in axons of spinal ventral roots. J Neurophysiol 1946 9:191204 [3] Eccles JC, Fatt P, Koketsu K. Cholinergic and inhibitory synapses in a pathway from motor-axon collaterals to motoneurones. J Physiol. 1954;126:524562. [4] Renshaw B. Influence of discharge of motoneurons upon excitation of neighboring motoneurons. J Neurophysiol 1941 4:167 [5] Lloyd, D. P. C.. Facilitation and inhibition of spinal motoneurons, J.Neurophysiol.,1946, 9,421. [6] Lloyd, D. P. C., After-currents, after-potentials, excitability, and ventral root electrotonus in spinal motoneurons, J.gen. Physiol..,1951,35 ,289

Renshaw cell
[7] George Z. Mentis, Valerie C. Siembab, Ricardo Zerda, Michael J. O'Donovan, and Francisco J. Alvarez, Primary Afferent Synapses on Developing and Adult Renshaw Cells. The J.of Neuroscience, 2006, 26(51):13297-13310 [8] Mazzocchio R, Rossi A, Rothwell JC. Depression of Renshaw recurrent inhibition by activation of corticospinal fibres in human upper and lower limb. J Physiol (Lond) 1994; 481: 4879 [9] H. Hultborn, E. Pierrot-Deseilligny.Changes in recurrent inhibition during voluntary soleus contractions in man studied by an H-Reflex Technique. J. Phyeiol. 1979, 297, pp.229251. [10] Iles JF, Pardoe J. Changes in transmission in the pathway of heteronymous spinal recurrent inhibition from soleus to quadriceps motor neurons during movement in man. Brain 1999; 122: 175764 [11] Nielsen J, Pierrot-Deseilligny E. Evidence of facilitation of soleus-coupled Renshaw cells during voluntary co-contraction of antagonistic ankle muscles in man. J Physiol (Lond) 1996; 493: 60311 [12] Wilson VJ, Talbot WH, Kato M Inhibitory convergence upon Renshaw cells. Journal of neurophysiology. 1964;27:1063-1079. [13] R. W. Ryall, M. F. Piercey, and C. Polosa. Intersegmental and intrasegmental distribution of mutual inhibition of Renshaw cells. J Neurophysiol 34: 700-, 1971 [14] RYALL, R. W. Renshaw cell mediated inhibition of Renshaw cells: patterns of excitation and inhibition from impulses in motor axon collaterals. J.Neurophysiol. 1970, 33, 257-270 [15] R. Granit, J. Haase, and L. T. Rutledge. Recurrent inhibition in relation to frequency of firing and limitation of discharge rate of extensor motoneurones. J.Physiol. 1960 December; 154(2): 308328. [16] J Haase, J van der Meulen. Effects of supraspinal stimulation on Renshaw cells belonging to extensor motoneurones. Journal of neurophysiology. 10/1961; 24:510-20 [17] D R Curtis, C J Game, D Lodge, and R M McCulloch. A pharmacological study of Renshaw cell inhibition.J Physiol. 1976 June; 258(1): 227242 [18] Victor J. Wilson & William H. Talbot. Integration at an Inhibitory Interneurone: Inhibition of Renshaw Cells. Nature 1963 200, 13251327

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External links
Diagram at pediatricneuro.com (http://www.pediatricneuro.com/alfonso/pg129.htm) NIF Search - Renshaw Cell (https://www.neuinfo.org/mynif/search.php?q=Renshaw Cell&t=data& s=cover&b=0&r=20) via the Neuroscience Information Framework

Hypotaurine

86

Hypotaurine
Hypotaurine

Identifiers CAS number PubChem ChemSpider UNII KEGG ChEBI Jmol-3D images 300-84-5 107812 96959
[1]

[2] [4]

[3]

5L08GE4332 C00519
[5]

CHEBI:57853 Image 1 Properties

[7]

[6]

Molecular formula Molar mass

(verify) [8]

C2H7NO2S 109.15 g/mol

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Hypotaurine is a sulfinic acid that is an intermediate in the biosynthesis of taurine. Like taurine, it also acts as an endogenous neurotransmitter via action on the glycine receptors.

References
[1] [2] [3] [4] [5] [6] [7] [8] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=300-84-5 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=107812 http:/ / www. chemspider. com/ 96959 http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=5L08GE4332 http:/ / www. kegg. jp/ entry/ C00519 https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=57853 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DS%28O%29CCN http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=443865475& page2=Hypotaurine

Kynurenic acid

87

Kynurenic acid
Kynurenic acid

Identifiers CAS number PubChem ChemSpider KEGG ChEBI ChEMBL Jmol-3D images 492-27-3 3845 3712
[2] [3] [4] [5] [6] [1]

C01717

CHEBI:18344

CHEMBL299155 Image 1 Properties

[7]

Molecular formula Molar mass Melting point

(verify) [8]

C10H7NO3 189.168 g/mol 282.5C

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Kynurenic acid (KYNA or KYN) is a product of the normal metabolism of amino acid L-tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an antagonist at excitatory amino acid receptors. Because of this activity, it may influence important neurophysiological and neuropathological processes. As a result, kynurenic acid has been considered for use in therapy in certain neurobiological disorders. Conversely, increased levels of kynurenic acid have also been linked to certain pathological conditions. Kynurenic acid was discovered in 1853 by the German chemist Justus von Liebig in dog urine, which it was apparently named after.[9] It is formed from L-kynurenine in a reaction catalyzed by the enzyme kynurenineoxoglutarate transaminase.

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Mechanism of action
KYNA has been proposed to act on four targets: As an antagonist at ionotropic AMPA, NMDA and Kainate glutamate receptors in the concentration range of 0.1-2.5 mM[10] As a noncompetitive antagonist at the glycine site of the NMDA receptor. As an antagonist of the 7 nicotinic acetylcholine receptor.[11] However, recently (2011) direct recording of 7 nicotinic acetylcholine receptor currents in adult (noncultured) hippocampal interneurons by the Cooper laboratory [12] [13] validated a 2009 study [14] that failed to find any blocking effect of kynurenic acid across a wide range of concentrations, thus suggesting that in noncultured, intact preparations from adult animals there is no effect of kynurenic acid on 7 nicotinic acetylcholine receptor currents [13] [14] As a ligand for the orphan G protein-coupled receptor GPR35.[] Another tryptophan metabolite, 5-hydroxyindoleacetic acid exerts its effects via the orphan G protein-coupled receptor GPR35 []

Role in disease
High levels of kynurenic acid have been identified in patients suffering from tick-borne encephalitis, schizophrenia and HIV-related illnesses. In all these situations increased levels were associated with confusion and psychotic symptoms. Kynurenic acid acts in the brain as a glycine-site NMDAr antagonist, key in glutamatergic neurotransmission system, which is thought to be involved in the pathophysiology and pathogenesis of schizophrenia. A kynurenic acid hypothesis of schizophrenia has been proposed in 2007,[][] based on its action on midbrain dopamine activity and NMDArs, thus linking dopamine hypothesis of schizophrenia with the glutamate hypothesis of the disease. High levels of kynurenic acid have been identified in human urine in certain metabolic disorders, such as marked pyridoxine deficiency and deficiency/absence of kynureninase. When researchers decreased the levels of kynurenic acid in the brains of mice, the cognition was shown to improve markedly. []

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=492-27-3 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=3845 [3] http:/ / www. chemspider. com/ 3712 [4] http:/ / www. kegg. jp/ entry/ C01717 [5] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=18344 [6] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL299155 [7] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DC%5C2c1c%28cccc1%29NC%28%3DC%2F2%29%2FC%28%3DO%29O [8] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=476994638& page2=Kynurenic+ acid [9] Liebig, J., Uber Kynurensure, Justus Liebigs Ann. Chem., 86: 125-126, 1853. [10] Elmslie KS, Yoshikami D. (1985) Effects of kynurenate on root potentials evoked by synaptic activity and amino acids in the frog spinal cord. Brain Res. Mar 25;330(2):265-72. [11] Hilmas, C., Pereira, EFR., Alkondon,M., Rassoulpour,A. Schwarcz,R., Albuquerque E.X.,(2001) The Brain Metabolite Kynurenic Acid Inhibits 7 Nicotinic Receptor Activity and Increases Non-7 Nicotinic Receptor Expression: Physiopathological Implications. J. Neurosci 21(19):74637473. [12] http:/ / neurocloud. org [13] Dobelis P., Varnell A., and Donald C. Cooper. Nicotinic 7 acetylcholine receptor-mediated currents are not modulated by the tryptophan metabolite kynurenic acid in adult hippocampal interneurons. (2011) Nature Precedings doi=10.1038/npre.2011.6277.1, http:/ / www. neuro-cloud. net/ nature-precedings/ dobelis/ [14] Mok MH, Fricker AC, Weil A, Kew JN (2009) Electrophysiological characterisation of the actions of kynurenic acid at ligand-gated ion channels. Neuropharmacology 57: 242-249.

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External links
Link found between TBE and schizophrenia (http://www.thelocal.se/9013/20071106/) - TheLocal.se, Sweden's news in English, 6 November 2007.

N-Acetylaspartylglutamic acid
N-Acetylaspartylglutamic acid

Identifiers Abbreviations PubChem ChemSpider MeSH Jmol-3D images Properties Molecular formula Molar mass
(verify) [5]

NAAG 188803 164080

[2] [3] [4]

N-acetyl-1-aspartylglutamic+acid

C11H16N2O8 304.25 g mol

1

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

N-Acetylaspartylglutamic acid (N-acetylaspartylglutamate or NAAG) is a neuropeptide that is the third-most-prevalent neurotransmitter in the mammalian nervous system. NAAG consists of N-acetylaspartic acid (NAA) and glutamic acid coupled via a peptide bond. NAAG was discovered as a nervous system-specific peptide in 1965 by Curatolo and colleagues[6] but was not extensively studied. It meets the criteria for a neurotransmitter, including being concentrated in neurons, packed in synaptic vesicles, released in a calcium-dependent manner, and hydrolyzed in the synaptic space by enzymatic activity. NAAG activates a specific receptor, the metabotropic glutamate receptor type 3. It is synthesized enzymatically from its two precursors and catabolized by NAAG peptidases in the synapse. The inhibition of the latter enzymes has potentially important therapeutic effects in animal models of several neurologic conditions and disorders. Under the INN spaglumic acid,[1] NAAG is used as an antiallergic medication in eye drops and nasal preparations.

N-Acetylaspartylglutamic acid

90

Research history
After its discovery in 1965, NAAG was disregarded as a neurotransmitter for several reasons. First, neuropeptides were not considered neurotransmitters until years later. Second, it did not seem to directly affect membrane potential, so it was classified as a metabolic intermediate. The importance of brain peptides became clearer with the discovery of endogenous opioids. Whereas the ability of NAAG to interact with NMDA receptors in a manner relevant to physiology is controversial, its primary receptor was long believed to be the mGluR3. Its interaction with the mGluR3 causes an activation of G proteins that reduce the concentration of the second messengers cAMP and cGMP in the both nerve cells and glia. This can lead to several changes in the cellular activity, including regulation of gene expression, reduction in the release of transmitter, and inhibition of long-term potentiation.[7][8] Stimulation of the mGluR3 by NAAG has been, however, questioned, finding relevant glutamate contamination in commercially available NAAG.[9][10] According to one publication, NAAG can be differentiated from NAA in vivo by MR spectroscopy at 3 Tesla.[11]

Biosynthesis
NAAG synthetase activity mediates the biosynthesis of NAAG from glutamate and NAA, but little is known about the mechanism or regulation of this enzyme, and no NAAG synthetase activity has been isolated in cell-free preparations. Since other neuropeptides and nearly all vertebrate peptides are synthesized by post-translational processing, NAAG synthtase activity is relatively unique. As with NAA, the synthesis of NAAG is primarily restricted to neurons, although glial cells also contain and synthesize this peptide. In vitro, NAAG synthesis appears to be regulated by the availability of its precursor, NAA. In addition, during differentiation of neuroblastoma cells, it has been shown that a protein kinase A (PKA) activator will increase the quantity of NAAG, while a protein kinase C (PKC) activator will decrease its concentration. This finding suggests that PKA and PKC have opposing regulatory effects on the NAAG synthetase enzyme.[12][13]

Catabolism
NAAG is catabolized via NAAG peptidase activity. Two enzymes with NAAG peptidase activity have been cloned, glutamate carboxypeptidase II and glutamate carboxypeptidase III. These enzymes mediate the hydrolysis of NAAG to NAA and glutamate. Their inhibition can produce therapeutic benefits. Two main types of inhibitors of this enzyme are known: compounds related to 2-(phosphonomethyl)pentanedioic acid (2-PMPA) and urea-based analogs of NAAG, including ZJ43, ZJ17, and ZJ11. In rat models, ZJ43 and 2-PMPA reduce perception of inflammatory and neuropathic pain when administered systemically, intracerebrally, or locally, suggesting that NAAG modulates neurotrasmission in pain circuits via mGlu3 receptors. The inhibition of NAAG hydrolysis increases the concentration of NAAG in the synaptic space analogous to the effects of SSRIs in increasing the concentration of serotonin. This elevated NAAG gives greater activation of presynaptic mGluR3 receptors, which decrease release of transmitter (glutamate) in the pain signaling pathways of the spinal cord and brain. In the case of traumatic brain injury, the injection of a NAAG peptidase inhibitor reduces neuron and astrocyte death in the hippocampus nearest the site of the injury. In a mouse model of amyotrophic lateral sclerosis (ALS), the chronic inhibition of NAAG peptidase activity delayed the onset of ALS symptoms and slowed the progress of the neuronal death. To model schizophrenia, animals were injected with phencyclidine (PCP) and, therefore, exhibited symptoms of the disorder, such as social withdrawal and motor responses. Upon injection with ZJ43, these behaviors were decreased, suggesting that an increase in NAAG in the synapse and its subsequent activation of mGluR3 receptors has potential as a co-therapy for schizophernia. In these cases, NAAG peptidase inhibition reduces the adverse effects in these disorders. Future research focuses on the role of NAAG in pain perception, brain injury, and schizophrenia while developing NAAG peptidase inhibitors with even greater ability to cross the bloodbrain barrier.[14][15][16][17][18]

N-Acetylaspartylglutamic acid

91

References
[1] [2] [3] [4] [5] Spaglumic Acid (http:/ / www. drugs. com/ international/ spaglumic-acid. html), drugs.com http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=188803 http:/ / www. chemspider. com/ 164080 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=N-acetyl-1-aspartylglutamic+ acid http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=453508811& page2=N-Acetylaspartylglutamic+ acid

Sarcosine

92

Sarcosine
Sarcosine

Identifiers CAS number PubChem ChemSpider UNII EC number KEGG ChEBI ChEMBL Beilstein Reference Gmelin Reference 3DMet Jmol-3D images 107-97-1 1088 1057
[2] [3] [4] [1]

Z711V88R5F 203-538-6 C00213

[5]

[6]

CHEBI:15611

[7]

[8]

CHEMBL304383 1699442 2018 B01190

[9] [10]

Image 1 [11] Image 2 Properties

Molecular formula Molar mass Appearance Odor Density Melting point Boiling point Solubility in water log P Acidity (pK )
a

C3H7NO2 89.09 g mol1 White crystalline powder Odourless 1.093 g/mL 208-212C, 481-485K, 406-414F 195.1C, 468K, 383F 89.09 g L1 (at 20 C) 0.599 2.36 11.64 260 nm 0.05 Thermochemistry

Basicity (pK )
b

max

Absorbance

Sarcosine

93

Std enthalpy of formation fHo298 Std enthalpy of combustion cHo298 Specific heat capacity, C

513.50512.98 kJ mol1

1667.841667.54 kJ mol1

128.9 J K1 mol1 Related compounds

Related alkanoic acids

Dimethylglycine Glycocyamine Creatine N-Methyl-D-aspartic acid beta-Methylamino-L-alanine Guanidinopropionic acid

Related compounds
(verify) [12]

Dimethylacetamide

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Sarcosine, also known as N-methylglycine, is an intermediate and byproduct in glycine synthesis and degradation. Sarcosine is metabolized to glycine by the enzyme sarcosine dehydrogenase, while glycine-N-methyl transferase generates sarcosine from glycine. Sarcosine is a natural amino acid found in muscles and other body tissues. In the laboratory, it may be synthesized from chloroacetic acid and methylamine. Sarcosine is found naturally as an intermediate in the metabolism of choline to glycine. Sarcosine is sweet to the taste and dissolves in water. It is used in manufacturing biodegradable surfactants and toothpastes as well as in other applications. Sarcosine is ubiquitous in biological materials and is present in such foods as egg yolks, turkey, ham, vegetables, legumes, etc. Sarcosine is formed from dietary intake of choline and from the metabolism of methionine, and is rapidly degraded to glycine, which, in addition to its importance as a constituent of protein, plays a significant role in various physiological processes as a prime metabolic source of components of living cells such as glutathione, creatine, purines and serine. The concentration of sarcosine in blood serum of normal human subjects is 1.59 1.08 nanomolar.[13]

Clinical significance
Sarcosine has no known toxicity, as evidenced by the lack of phenotypic manifestations of sarcosinemia, an inborn error of sarcosine metabolism. Sarcosinemia can result from severe folate deficiency because of the folate requirement for the conversion of sarcosine to glycine.

Schizophrenia
Recently, sarcosine has been investigated in relation to the mental illness schizophrenia. Early evidence suggests that intake of 2g/day sarcosine as add-on therapy to certain antipsychotics (not clozapine[14]) in schizophrenia gives significant additional reductions in both positive and negative symptomatology as well as the neurocognitive and general psychopathological symptoms that are common to the illness. Sarcosine had been tolerated well.[15] It is also under investigation for the possible prevention of schizophrenic illness during the prodromal stage of the disease. It acts as a type1 glycine transporter inhibitor and a glycine agonist. It increases glycine concentrations in the brain thus causing increased NMDA receptor activation and a reduction in symptoms. As such, it might be an interesting treatment option and a possible new direction in the treatment of the mental illness in the future.

Sarcosine

94

Depression
Major depressive disorder is a complex disease and most currently available antidepressants aiming at monoamine neurotransmission exhibit limited efficacy and cognitive effects. N-methyl-D-aspartate (NMDA), one subtype of glutamate receptors, plays an important role in learning and memory. N-methyl-D-aspartic acid (NMDA) enhancing agents, such as Sarcosine (N-methylglycine), have been used as adjunctive therapy of schizophrenia. Preliminary clinic trials indicated that intake of Sarcosine improved not only psychotic but also depressive symptoms in patients with schizophrenia.[16]

Prostate cancer marker

In a paper published in the journal Nature in 2009, sarcosine was reported to activate prostate cancer cells and to indicate the malignancy of prostate cancer cells when measured in urine.[] Sarcosine was identified as a differential metabolite that was greatly increased during prostate cancer progression to metastasis and could be detected in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells.[17] Sarcosine levels seemed to control the invasiveness of the cancer.[] However, this conclusion has been disputed. A German research team reported a different result in 2010.[18] After measuring sarcosine levels in urine samples from prostate cancer patients, they concluded that measuring sarcosine in urine fails as a marker in prostate cancer detection and identification of aggressive tumors. In addition, another report concluded that serum sarcosine is not a marker for prostate cancer.[19] A review of the literature reached a similar conclusion.[20]

History
Sarcosine was first isolated and named by the German chemist Justus von Liebig in 1847, while Jacob Volhard first synthesized it in 1862. Volhard successfully synthesized the compound while working the lab of Hermann Kolbe. Prior to the synthesis of sarcosine, it had long been known to be hydrolysis product of creatine, a compound found in meat extract. Under this assumption, Volhard proposed that sarcosine was N-methylglycine, and proved so by preparing the compound with methylamine and monochloroacetic acid.[21]

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=107-97-1 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=1088 [3] http:/ / www. chemspider. com/ 1057 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=Z711V88R5F [5] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=203-538-6 [6] http:/ / www. kegg. jp/ entry/ C00213 [7] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=15611 [8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL304383 [9] http:/ / www. 3dmet. dna. affrc. go. jp/ html/ B01190. html [10] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CNCc%28%3A%5Bo%5D%29%3A%5BoH%5D [11] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CNCC%28O%29%3DO [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=464387230& page2=Sarcosine [16] http:/ / clinicaltrials. gov/ ct2/ show/ NCT00977353 Clinicaltrials.gov "N-methylglycine (Sarcosine) Treatment for Depression" [17] A Urine Test for Prostate Cancer? (http:/ / sciencenow. sciencemag. org/ cgi/ content/ full/ 2009/ 211/ 1?etoc), Jennifer Couzin, Science NOW, 11 February 2009 [21] http:/ / publishing. cdlib. org/ ucpressebooks/ view?docId=ft5g500723& chunk. id=d0e7179& toc. depth=1& toc. id=d0e7179& brand=eschol University of California Press "The Quiet Revolution"

Serine

95

Serine
Serine

Identifiers CAS number PubChem ChemSpider UNII EC-number DrugBank ChEBI ChEMBL IUPHAR ligand Jmol-3D images 56-45-1 617
[4] [5] [1]

, 302-84-1

[2]

, 312-84-5

[3]

(D-isomer)

5736

(L-form) , 597
[7]

[6]

452VLY9402 206-130-6 DB00133

[8]

[9] [10]

CHEBI:17115

CHEMBL11298 726
[12] [13]

[11]

Image 1

Properties Molecular formula Molar mass Appearance Density Melting point Solubility in water Acidity (pK )
a

[14]

C3H7NO3 105.09 g mol1 white crystals or powder 1.603 g/cm3 (22C) 246C decomp. soluble 2.21 (carboxyl), 9.15 (amino) Supplementary data page
[15]

Structure and properties Thermodynamic data Spectral data

(verify)

n, , etc.
r

Phase behaviour Solid, liquid, gas UV, IR, NMR, MS

[16]

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Serine

96
Infobox references

Serine (abbreviated as Ser or S)[17] is an amino acid with the formula HO2CCH(NH2)CH2OH. It is one of the proteinogenic amino acids. Its codons in the genetic code are UCU, UCC, UCA, UCG, AGU and AGC. By virtue of the hydroxyl group, serine is classified as a polar amino acid.

Occurrence and biosynthesis

This compound is one of the naturally occurring proteinogenic amino acids. Only the L-stereoisomer appears naturally in proteins. It is not essential to the human diet, since it is synthesized in the body from other metabolites, including glycine. Serine was first obtained from silk protein, a particularly rich source, in 1865. Its name is derived from the Latin for silk, sericum. Serine's structure was established in 1902.[18]

(S)-Serine (left) and (R)-serine (right) in zwitterionic form at neutral pH

The biosynthesis of serine starts with the oxidation of 3-phosphoglycerate to 3-phosphohydroxypyruvate and NADH. Reductive amination of this ketone followed by hydrolysis gives serine. Serine hydroxymethyltransferase catalyzes the reversible, simultaneous conversions of L-serine to glycine (retro-aldol cleavage) and 5,6,7,8-tetrahydrofolate to 5,10-methylenetetrahydrofolate (hydrolysis).[19] This compound may also be naturally produced when UV light illuminates simple ices such as a combination of water, methanol, hydrogen cyanide, and ammonia, suggesting that it may be easily produced in cold regions of space.[20]

Production
Industrially, L-serine is produced by fermentation, with an estimated 100-1000 tonnes per year produced.[] In the laboratory, racemic serine can be prepared from methyl acrylate via several steps:[21]

Serine

97

Biological function
Metabolic
Serine is important in metabolism in that it participates in the biosynthesis of purines and pyrimidines. It is the precursor to several amino acids including glycine and cysteine, and tryptophan in bacteria. It is also the precursor to numerous other metabolites, including sphingolipids and folate, which is the principal donor of one-carbon fragments in biosynthesis.

Structural role
Serine plays an important role in the catalytic function of many enzymes. It has been shown to occur in the active sites of chymotrypsin, trypsin, and many other enzymes. The so-called nerve gases and many substances used in insecticides have been shown to act by combining with a residue of serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. As a constituent (residue) of proteins, its side chain can undergo O-linked glycosylation, which may be functionally related toWikipedia:Please clarify diabetes. It is one of three amino acid residues that are commonly phosphorylated by kinases during cell signaling in eukaryotes. Phosphorylated serine residues are often referred to as phosphoserine. Serine proteases are a common type of protease.
Cysteine synthesis from serine. Cystathionine beta synthase catalyzes the upper reaction and cystathionine gamma-lyase catalyzes the lower reaction.

Signaling
D-Serine,

synthesized in the brain by serine racemase from L-serine (its enantiomer), serves as both a neurotransmitter and a gliotransmitter by coactivating NMDA receptors, making them able to open if they then also bind glutamate. D-serine is a potent agonist at the glycine site of the NMDA-type glutamate receptor. For the receptor to open, glutamate and either glycine or D-serine must bind to it. In fact, D-serine is a more potent agonist at the glycine site on the NMDAR than glycine itself. D-serine was only thought to exist in bacteria until relatively recently; it was the second D amino acid discovered to naturally exist in humans, present as a signalling molecule in the brain, soon after the discovery of D-aspartate. Had D amino acids been discovered in humans sooner, the glycine site on the NMDA receptor might instead be named the D-serine site.[22]

Gustatory sensation
Pure D-Serine is an off-white crystalline powder with a very faint funky or dirty aroma. L-Serine is sweet with minor umami and sour tastes at high concentration. D-Serine is sweet with an additional minor sour taste at medium and high concentrations.[23]

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=56-45-1 [2] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=302-84-1 [3] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=312-84-5 [4] [5] [6] [7] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=617 http:/ / www. chemspider. com/ 5736 http:/ / www. chemspider. com/ 597 http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=452VLY9402

Serine
[8] http:/ / ecb. jrc. ec. europa. eu/ esis/ index. php?GENRE=ECNO& ENTREE=206-130-6 [9] http:/ / www. drugbank. ca/ drugs/ DB00133 [10] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=17115 [11] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL11298 [12] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=726 [13] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=C%28%5BC%40%40H%5D%28C%28%3DO%29O%29N%29O [14] . [15] Dawson, R.M.C., et al., Data for Biochemical Research, Oxford, Clarendon Press, 1959. [16] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=464389254& page2=Serine [17] . [19] . [21] . [22] . [23] http:/ / www. springerlink. com/ content/ 27074j4t2n508r7t/ fulltext. html [Amino Acids. 2012 May 16. [Epub ahead of print] Gustatory sensation of L: - and D: -amino acids in humans. Kawai M, Sekine-Hayakawa Y, Okiyama A, Ninomiya Y.

98

Taurine

99

Taurine
Taurine

Identifiers CAS number PubChem ChemSpider UNII DrugBank ChEBI ChEMBL IUPHAR ligand Jmol-3D images 107-35-7 1123 1091
[2] [3] [4] [1]

1EQV5MLY3D DB01956
[5]

CHEBI:15891

[6]

[7]

CHEMBL239243 2379
[8] [9]

Image 1 Properties

Molecular formula Molar mass Density Melting point Acidity (pK )

a

C2H7NO3S 125.15 g mol1 1.734g/cm3 (at 173.15C) 305.11C <0, 9.06

(verify) [10]

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Taurine, or 2-aminoethanesulfonic acid, is an organic acid widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine and accounts for approximately 0.1% of total human body weight.[11] Taurine has many fundamental biological roles such as conjugation of bile acids, antioxidation, osmoregulation, membrane stabilization and modulation of calcium signaling. It is essential for cardiovascular function, and development and function of skeletal muscle, the retina and the central nervous system. Taurine is unusual among biological molecules in being a sulfonic acid, while the vast majority of biologically occurring acids contain the more weakly acidic carboxyl group. While taurine is sometimes called an amino acid, and indeed is an acid containing an amino group, it is not an amino acid in the usual biochemical meaning of the term, which refers to

Taurine compounds containing both an amino and a carboxyl group.

100

Discovery and etymology

Taurine is named after the Latin taurus (a cognate of the Greek ) which means bull or ox, as it was first isolated from ox bile in 1827 by German scientists Friedrich Tiedemann and Leopold Gmelin.[12]

Structure
Taurine is a derivative of cysteine, an amino acid which contains a thiol group. Taurine is one of the few known naturally occurring sulfonic acids. In the strict sense, it is not an amino acid, as it lacks a carboxyl group,[13] but it is often called one, even in scientific literature.[14][15][16] It does contain a sulfonate group and may be called an amino sulfonic acid. Small polypeptides have been identified which contain taurine, but to date no aminoacyl tRNA synthetase has been identified as specifically recognizing taurine and capable of incorporating it into a tRNA.[17]

Sources
Dietary intake
Taurine occurs naturally in food, especially in seafood and meat. The mean daily intake from omnivore diets was determined to be around 58mg (range from 9 to 372mg) and to be low or negligible from a strict vegan diet. In another study, taurine intake was estimated to be generally less than 200mg/day, even in individuals eating a high-meat diet. According to another study, taurine consumption was estimated to vary between 40 and 400mg/day.
[]

Biosynthesis
Taurine is a major constituent of bile and can be found in the large intestine and in the tissues of many animals, including humans.[][] Mammalian taurine synthesis occurs in the pancreas via the cysteine sulfinic acid pathway. In this pathway, the thiol group of cysteine is first oxidized to cysteine sulfinic acid by the enzyme cysteine dioxygenase. Cysteine sulfinic acid, in turn, is decarboxylated by sulfinoalanine decarboxylase to form hypotaurine. It is unclear whether hypotaurine is then spontaneously or enzymatically oxidized to yield taurine.

Nutritional significance
A study of mice hereditarily unable to transport taurine suggests that it is needed for proper maintenance and functioning of skeletal muscles.[] In addition, it has been shown to be effective in removing fatty liver deposits in rats, preventing liver disease, and reducing cirrhosis in tested animals.[18][19] There is also evidence that taurine is beneficial for adult human blood pressure and possibly, the alleviation of other cardiovascular ailments (in humans suffering essential hypertension, taurine supplementation resulted in measurable decreases in blood pressure).[citation
needed]

Taurine is regularly used as an ingredient in energy drinks, with many containing 1000mg per serving,[20] and some as much as 2000mg.[21] A 2003 study by the European Food Safety Authority found no adverse effects for up to 1,000mg of taurine per kilogram of body weight per day.[22] A review published in 2008 found no documented reports of negative or positive health effects associated with the amount of taurine used in energy drinks, concluding that "The amounts of guarana, taurine, and ginseng found in popular energy drinks are far below the amounts expected to deliver either therapeutic benefits or adverse events".[23]

Taurine

101

Chemical synthesis and commercial production

Synthetic taurine is obtained from isethionic acid (2-hydroxyethanesulfonic acid), which in turn is obtained from the reaction of ethylene oxide with aqueous sodium bisulfite. Another approach is the reaction of aziridine with sulfurous acid. This leads directly to taurine.[24] In 1993, approximately 5,0006,000tons of taurine were produced for commercial purposes; 50% for pet food manufacture, 50% in pharmaceutical applications.[] As of 2010, China alone has more than 40 manufacturers of taurine. Most of these enterprises employ the ethanolamine method to produce a total annual production of about 3,000tons.[]

Physiological functions
Taurine is essential for cardiovascular function, and development and function of skeletal muscle, the retina and the central nervous system.[] Taurine is conjugated via its amino terminal group with chenodeoxycholic acid and cholic acid to form the bile salts sodium taurochenodeoxycholate and sodium taurocholate. The low pKa[25] of taurine's sulfonic acid group ensures this moiety is negatively charged in the pH ranges normally found in the intestinal tract and, thus, improves the surfactant properties of the cholic acid conjugate. Taurine crosses the bloodbrain barrier[26][27][28] and has been implicated in a wide array of physiological phenomena including inhibitory neurotransmission,[29] long-term potentiation in the striatum/hippocampus,[30] membrane stabilization,[31] feedback inhibition of neutrophil/macrophage respiratory burst, adipose tissue regulation and possible prevention of obesity,[32][33] calcium homeostasis,[34] recovery from osmotic shock,[35] protection against glutamate excitotoxicity[36] and prevention of epileptic seizures.[37] It also acts as an antioxidant and protects against toxicity of various substances (such as lead and cadmium).[38][39][40][41] Additionally, supplementation with taurine has been shown to prevent oxidative stress induced by exercise.[42] In a 2008 study, taurine has been shown to reduce the secretion of apolipoprotein B100 and lipids in HepG2 cells.[43] High concentrations of serum lipids and apolipoprotein B100 (essential structural component of VLDL and LDL) are major risk factors of atherosclerosis and coronary heart disease. Hence, taurine supplementation is possibly beneficial for the prevention of these diseases. In a 2003 study, Zhang et al. have demonstrated the hypocholesterolemic (blood cholesterol-lowering) effect of dietary taurine in young overweight adults. Furthermore, they reported body weight also decreased significantly in the taurine supplemented group.[44] These findings are consistent with animal studies.[45] Taurine has also been shown to help people with congestive heart failure by increasing the force and effectiveness of heart-muscle contractions.[46] Taurine levels were found to be significantly lower in vegans than in a control group on a standard American diet. Plasma taurine was 78% of control values, and urinary taurine was 29%.[47] In the cell, taurine keeps potassium and magnesium inside the cell, while keeping excessive sodium out. In this sense, it works like a diuretic. Because it aids the movement of potassium, sodium, and calcium in and out of the cell, taurine has been used as a dietary supplement for epileptics, as well as for people who have uncontrollable facial twitches.[48] According to animal studies, taurine produces an anxiolytic effect and may act as a modulator or antianxiety agent in the central nervous system by activating the glycine receptor.[49][50][51] Taurine is necessary for normal skeletal muscle functioning. This was shown by a 2004 study[] using mice with a genetic taurine deficiency. They had a nearly complete depletion of skeletal and cardiac muscle taurine levels. These mice had a reduction of more than 80% of exercise capacity compared to control mice. The authors expressed

Taurine themselves as "surprised" their cardiac function showed as largely normal (given various other studies about effects of taurine on the heart). Studies have shown taurine can influence (and possibly reverse) defects in nerve blood flow, motor nerve conduction velocity, and nerve sensory thresholds in experimental diabetic neuropathic rats.[][] In another study on diabetic rats, taurine significantly decreased weight and decreased blood sugar in these animal models.[] Likewise, a 2008 study demonstrated taurine administration to diabetic rabbits resulted in 30% decrease in serum glucose levels.[52] According to the single study on human subjects, daily administration of 1.5g taurine had no significant effect on insulin secretion or insulin sensitivity.[53] There is evidence that taurine may exert a beneficial effect in preventing diabetes-associated microangiopathy and tubulointerstitial injury in diabetic nephropathy.[54][55] Taurine acts as a glycation inhibitor. Studies have shown taurine-treated diabetic rats had a decrease in the formation of advanced glycation end products (AGEs) and AGEs content.[56][57] The United States Department of Agriculture has found a link between cataract development and lower levels of vitamin B6, folate, and taurine in the diets of the elderly.[58] Taurine has been investigated in animal studies as an alternative to glucose as osmotic agent for use in peritoneal dialysis solutions.[59]

102

Toxicity
Taurine is involved in a number of crucial physiological processes. However, the role of taurine in these processes is not clearly understood and the influence of high taurine doses on these processes is uncertain. A substantial increase in the plasma concentration of growth hormone was reported in some epileptic patients during taurine tolerance testing (oral dose of 50mg/kg bw/day), suggesting a potential to stimulate the hypothalamus and to modify neuroendocrine function. There is an indication that taurine (2 g/day) has some function in the maintenance and possibly in the induction of psoriasis. It may also be necessary to take into consideration that absorption of taurine from beverages may be more rapid than from foods.[]

In animal nutrition
Taurine is an essential dietary requirement for feline health, since cats cannot synthesize the compound. The absence of taurine causes a cat's retina to slowly degenerate, causing eye problems and (eventually) irreversible blindness a condition known as central retinal degeneration (CRD),[60][61] as well as hair loss and tooth decay. Decreased plasma taurine concentration has been demonstrated to be associated with feline dilated cardiomyopathy.[62] Unlike CRD, the condition is reversible with supplementation. Taurine is now a requirement of the Association of American Feed Control Officials (AAFCO) and any dry or wet food product labeled approved by the AAFCO should have a minimum of 0.1% taurine in dry food and 0.2% in wet food.[63] Research suggests taurine is essential to the normal development of passerine birds. Many passerines seek out taurine-rich spiders to feed their young, particularly just after hatching. Researchers compared the behaviors and development of birds fed a taurine-supplemented diet to a control diet and found the juveniles fed taurine-rich diets as neonates were much larger risk takers and more adept at spatial learning tasks.[]

Taurine

103

Other uses
Lately, cosmetic compositions containing taurine have been introduced, possibly due to its antifibrotic properties. It has been shown to prevent the damaging effects of TGFB1 to hair follicles.[] It also helps to maintain skin hydration.[64] Prematurely born infants are believed to lack the enzymes needed to convert cystathionine to cysteine, and may, therefore, become deficient in taurine. Taurine is present in breast milk, and has been added to many infant formulas, as a measure of prudence, since the early 1980s. However, this practice has never been rigorously studied, and as such it has yet to be proven to be necessary, or even beneficial.[65] Taurine is also used in some contact lens solutions.[66]

References
[1] [2] [3] [4] [5] [6] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=107-35-7 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=1123 http:/ / www. chemspider. com/ 1091 http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=1EQV5MLY3D http:/ / www. drugbank. ca/ drugs/ DB01956 https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=15891

[7] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL239243 [8] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=2379 [9] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DS%28%3DO%29%28O%29CCN [10] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=413848354& page2=Taurine [20] rockstar69.com Original Rockstar Ingredients (http:/ / www. rockstar69. com/ productIngredients. php?pdt=1) [22] EFSA adopts opinion on two ingredients commonly used in some energy drinks (http:/ / www. efsa. europa. eu/ EFSA/ efsa_locale-1178620753812_1211902328128. htm) efsa.europa.eu/ [32] Ide T, Kushiro M, Takahashi Y, Shinohara K, Cha S. "mRNA expression of enzymes involved in taurine biosynthesis in rat adipose tissues. Metabolism: Clinical and Experimental 2002 Sep;51(9):1191-7. [46] Congestive Heart Failure (http:/ / www. peacehealth. org/ KBASE/ cam/ hn-1193009. htm), Healthnotes, Inc, PeaceHealth, January 19, 2007 [48] Kirk J and Kirk K. Inhibition of volume-activated I- and taurine efflux from HeLa cells by P-glycoprotein blockers correlates with calmodulin inhibition. J. Biol. Chem., Nov 1994;269:2938929394. [53] C. Brns, C. Spohr, H. Storgaard, J. Dyerberg, A. Vaag. "Effect of taurine treatment on insulin secretion and action, and on serum lipid levels in overweight men with a genetic predisposition for type II diabetes mellitus. European Journal of Clinical Nutrition (2004) 58, 12391247. [56] Effects of taurine on advanced glycosylation end products and expression of TGF- in renal cortex of, TsingHua, 2005, http:/ / www. shvoong. com/ medicine-and-health/ 1599878-effects-taurine-advanced-glycosylation-end/ [62] Myocardial failure in cats associated with low plasma taurine: a reversible cardiomyopathy (http:/ / www. sciencemag. org/ cgi/ content/ abstract/ sci;237/ 4816/ 764?maxtoshow=& HITS=10& hits=10& RESULTFORMAT=& fulltext=Pion+ Taurine& searchid=1& FIRSTINDEX=0& resourcetype=HWCIT) [63] AAFCO (http:/ / maxshouse. com/ nutrition/ aafco_cat_food_nutrient_profiles. htm) [65] Heird W.C. Taurine in neonatal nutritionrevisited. Arch Dis Child Fetal Neonatal. Ed 89. F473-F474 2004

External links
Taurine bound to proteins (http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=TAU) in the PDB

Trimethylglycine

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Trimethylglycine
Trimethylglycine

Identifiers CAS number PubChem ChemSpider UNII MeSH ChEBI ChEMBL ATC code Jmol-3D images 107-43-7 247 242
[2] [3] [4] [1]

3SCV180C9W Betaine
[5]

CHEBI:17750

[6]

CHEMBL1182 A16 AA06 Image 1 Properties

[9] [8]

[7]

Molecular formula Molar mass

C H NO
5 11

117.146 Related compounds

Related amino acids

Glycine Methylglycine Dimethylglycine

(verify) [10]

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Trimethylglycine (TMG) is an organic compound that occurs in plants. Trimethylglycine was the first betaine discovered by science; originally it was simply called betaine because, in the 19th century, it was discovered in sugar beets.[11] Since then, many other betaines have been discovered, and the more specific name glycine betaine distinguishes this one.

Trimethylglycine

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Structure and reactions

Trimethylglycine is an N-trimethylated amino acid. This quaternary ammonium exists as the zwitterion at neutral pH. Strong acids such as hydrochloric acid converts TMG to various salts, HCl yielding betaine hydrochloride: (CH3)3N+CH2CO2- + HCl [(CH3)3N+CH2CO2H]ClDemethylation of TMG gives dimethylglycine. Degradation of TMG yields trimethylamine, the scent of putrifying fish.

Production and biochemical processes

Processing sucrose from sugar beets yields glycine betaine as a byproduct. The value of the TMG rivals that of the sugar content in sugar beets.[12] Glycine betaine production involves chromatographic separation.

Biosynthesis
In most organisms, glycine betaine is biosynthesized by oxidation of choline in two steps. The intermediate, betaine aldehyde, is generated by the action of the enzyme mitochondrial choline oxidase (choline dehydrogenase, EC 1.1.99.1). Betaine aldehyde is further oxidised in the mitochondria or cytoplasm to betaine by the enzyme called betaine aldehyde dehydrogenase (EC 1.1.1.8).[13]

Biological function
TMG is an organic osmolyte that occurs in high concentrations (10s of millimolar) in many marine invertebrates, such as crustaceans and molluscs. It serves as a potent appetitive attractant to generalist carnivores such as the predatory sea-slug Pleurobranchaea californica.[14] TMG is an important cofactor in methylation, a process that occurs in every cell of mammals to synthesize and donate methyl groups (CH3) for other processes in the body. These processes include the synthesis of neurotransmitters such as dopamine, serotonin. Methylation is also required for the biosynthesis of melatonin and the electron transport chain constituent coenzyme Q10. The major step in the methylation cycle is the remethylation of homocysteine, which can occur via either of two pathways. The major pathway involves the enzyme methionine synthase, which requires vitamin B12 as a cofactor, and also depends indirectly on folate and various other B vitamins. The minor pathway involves betaine-homocysteine methyltransferase and requires TMG as a cofactor. Betaine is thus involved in the synthesis of many biologically important molecules, and may be even more important in situations where the major pathway for the regeneration of methionine from homocysteine has been compromised by genetic polymorphisms.

TMG in agriculture and aquaculture

Factory farms supplement fodder with TMG and lysine to increase livestocks' muscle mass (and, therefore, "carcass yield", the amount of usable meat). Salmon farms apply TMG to relieve the osmotic pressure on salmons' cells when workers transfer the fish from freshwater to saltwater.[12][15] TMG supplementation decreases the amount of adipose tissue in pigs; however, research in human subjects has shown no effect on body weight, body composition, or resting energy expenditure,[] but only on muscle strength (2,5 gr/die).

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TMG in the human diet

TMG in foods
Food Quinoa Spinach Wheat bran TMG per 100g 630mg 577mg 360mg

Lamb's quarters 332mg Beet 256mg

Nutritional supplement
Although TMG supplementation decreases the amount of adipose tissue in pigs, research on human subjects has shown no effect on body weight, body composition, or resting energy expenditure when used in conjunction with a hypoenergetic diet.[] The Food and Drug Administration of the United States approved anhydrous trimethylglycine (also known by the brand name Cystadane) for the treatment of homocystinuria, a disease caused by abnormally high homocysteine levels at birth.[] TMG supplementation may cause diarrhea, stomach upset, or nausea. Obese persons or those with kidney disease supplementing with TMG, folic acid, and vitamin B6 can experience an increase in total cholesterol levels.[16]

Other uses: PCR

Trimethylglycine can act as an adjuvant of the polymerase chain reaction (PCR) process, and other DNA polymerase-based assays such as DNA sequencing. By an unknown mechanism, it aids in the prevention of secondary structures in the DNA molecules, and prevents problems associated with the amplification and sequencing of GC-rich regions. Trimethylglycine makes guanosine and cytidine (strong binders) behave with thermodynamics similar to those of thymidine and adenosine (weak binders). It has been determined under experiment that it is best used at a final concentration of 1M.[]

Speculative uses
Laboratory studies and two clinical trials have indicated that TMG is a potential treatment of non-alcoholic steatohepatitis.[17][18][19] TMG is sometimes used as a treatment for depression, as it can increase S-adenosylmethionine (SAMe) by remethylating homocysteine. SAMe has been shown to work as a nonspecific antidepressant in several studies.[20][21][22]

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IEX Ion Exchange Chromatography

In the book from Amersham Biosciences/GE Healthcare, Ion Exchange Chromatography & Chromatofocusing Principles and Methods, page48. "Zwitterionic additives such as betaine can prevent precipitation and can be used at high concentrations without interfering with the gradient elution"

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=107-43-7 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=247 [3] http:/ / www. chemspider. com/ 242 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=3SCV180C9W [5] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Betaine [6] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=17750 [7] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL1182 [8] http:/ / www. whocc. no/ atc_ddd_index/ ?code=A16AA06 [9] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=C%5BN%2B%5D%28C%29%28C%29CC%28%3DO%29%5BO-%5D [10] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=419118341& page2=Trimethylglycine [11] Hubert Schiweck, Margaret Clarke, Gnter Pollach "Sugar in Ullmanns Encyclopedia of Industrial Chemistry 2007, Wiley-VCH, Weinheim. [12] P. Mkel "Agro-industrial uses of glycinebetaine" Sugar Tech 2004 Volume 6, 207-212. [13] Kempf, B.; Bremer, E."Uptake and synthesis of compatible solutes as microbial stress responses to high-osmolality environments" Arch Microbiol. 1998, volume 170, pp. 319-30. [15] Xue, M. Xie, S. & Cui Y. (2004). Effect of a feeding stimulant on feeding adaptation of gibel carp Carassius auratus gibelio (Bloch), fed diets with replacement of fish meal by meat and bone meal. Aquaculture Research, 35: 473-482. [16] http:/ / www. umm. edu/ altmed/ articles/ betaine-000287. htm

External links
USDA Database for the Choline Content of Common Foods (http://www.nal.usda.gov/fnic/foodcomp/Data/ Choline/Choline.html) - including the data on choline metabolites, such as betaine, in 434 food items.

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Cannabinoid
Cannabinoids are a class of diverse chemical compounds that activate cannabinoid receptors on cells that repress neurotransmitter release in the brain. These receptor proteins include the endocannabinoids (produced naturally in the body by humans and animals),[] the phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (produced chemically by humans). The most notable cannabinoid is the phytocannabinoid 9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis.[][1] Cannabidiol (CBD) is another major constituent of the plant, representing up to 40% in its extracts.[2] There are at least 85 different cannabinoids isolated from cannabis, exhibiting varied effects.[3] Synthetic cannabinoids encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids (cannabimimetics) including the aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, and arylsulphonamides, as well as eicosanoids related to the endocannabinoids.[]

Cannabinoid receptors
Before the 1980s, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate. These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles. At present, there are two known types of cannabinoid receptors, termed CB1 and CB2,[] with mounting evidence of more.[] The human brain has more cannabinoid receptors than any other G protein-coupled receptor (GPCR) type.[]

Cannabinoid receptor type 1

CB1 receptors are found primarily in the brain, to be specific in the basal ganglia and in the limbic system, including the hippocampus.[] They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. Thus, there is not the risk of respiratory or cardiovascular failure that can be produced by some drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.

Cannabinoid receptor type 2

CB2 receptors are predominantly found in the immune system, or immune-derived cells[] with the greatest density in the spleen. While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum .[] CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.[]

Phytocannabinoids

Cannabinoid

109

Type Cannabigerol-type CBG

Skeleton

Cyclization

Cannabichromene-type CBC

Cannabidiol-type CBD

Tetrahydrocannabinoland Cannabinol-type THC, CBN Cannabielsoin-type CBE

isoTetrahydrocannabinoltype iso-THC Cannabicyclol-type CBL

Cannabicitran-type CBT

Main classes of natural cannabinoids

Phytocannabinoids (also called natural cannabinoids, herbal cannabinoids, and classical cannabinoids) are known to occur in several different plant species. These include Cannabis sativa, Cannabis indica, Cannabis ruderalis, Echinacea purpurea, Echinacea angustifolia, Echinacea pallida, Acmella oleracea, Helichrysum umbraculigerum, and Radula marginata.[] The best known herbal cannabinoids are 9-tetrahydrocannabinol (THC) from Cannabis and the lipophilic alkamides (alkylamides) from Echinacea species.[] At least 85 different cannabinoids have been isolated from the Cannabis plant[4] and 25 different cannabinoids from Echinacea species.[] In Cannabis, these cannabinoids are concentrated in a The bracts surrounding a cluster of Cannabis sativa flowers are coated with cannabinoid-laden viscous resin produced in structures known as glandular trichomes. In trichomes Echinacea species, cannabinoids are found throughout the plant [] structure, but are most concentrated in the roots and stems. Tea (Camellia sinensis) catechins have an affinity for human cannabinoid receptors.[]

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110

Phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohols, and other non-polar organic solvents. However, as phenols, they form more water-soluble phenolate salts under strongly alkaline conditions. All-natural cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat, light, or alkaline conditions).

Cannabis-derived cannabinoids
Types To the right, the main classes of cannabinoids from Cannabis are shown. All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized.
Cannabis indica plant

Tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN) (derived from Cannabis); and dodeca-2E,4E,8Z,10E/Z-tetraenoic-acid-isobutylamides (the main bioactive constituents from Echinacea species) are the most prevalent natural cannabinoids and have received the most study. CBG (Cannabigerol) CBC (Cannabichromene) CBL (Cannabicyclol) CBV (Cannabivarin) THCV (Tetrahydrocannabivarin) CBDV (Cannabidivarin) CBCV (Cannabichromevarin) CBGV (Cannabigerovarin) CBGM (Cannabigerol Monomethyl Ether)

Tetrahydrocannabinol Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. Delta-9-tetrahydrocannabinol (9-THC, THC) and delta-8-tetrahydrocannabinol (8-THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body. These two THC's produce the effects associated with cannabis by binding to the CB1 cannabinoid receptors in the brain. THC appears to ease moderate pain (analgesic) and to be neuroprotective. Studies show THC reduces neuroinflammation and stimulates neurogenesis.[5][6][7] THC has approximately equal affinity for the CB1 and CB2 receptors.[8] Cannabidiol Cannabidiol (CBD) is not psychoactive, and was thought not to affect the psychoactivity of THC.[] However, recent evidence shows that smokers of cannabis with a higher CBD/THC ratio were less likely to experience schizophrenia-like symptoms.[] This is supported by psychological tests, in which participants experience less intense psychotic-like effects when intravenous THC was co-administered with CBD (as measured with a PANSS test).[] Cannabidiol has little affinity for CB1 and CB2 receptors but acts as an indirect antagonist of cannabinoid agonists.[] Recently it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.[9] Cannabidiol has also been shown to act as a 5-HT1A receptor agonist,[] an action that is involved in its antidepressant,[][] anxiolytic,[][] and neuroprotective[][] effects.

Cannabinoid It appears to relieve convulsion, inflammation, anxiety, and nausea.[] CBD has a greater affinity for the CB2 receptor than for the CB1 receptor.[] CBD shares a precursor with THC and is the main cannabinoid in low-THC Cannabis strains. CBD apparently plays a role in preventing the short-term memory loss associated with THC in mammals. Some research suggests that the antipsychotic effects of cannabidiol potentially represent a novel mechanism in the treatment of schizophrenia.[10] Researchers at California Pacific Medical Center discovered CBD's ability to "turn off" the activity of ID1, the gene responsible for metastasis in breast and other types of cancers, including the particularly aggressive triple negative breast cancer.[11][12][13] The researchers hope to start human trials soon.[14] Cannabinol Cannabinol (CBN) is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive. Its affinity to the CB2 receptor is higher than for the CB1 receptor.[] Cannabigerol Cannabigerol (CBG) is non-psychotomimetic but still affects the overall effects of Cannabis. It acts as an 2-adrenergic receptor agonist, 5-HT1A receptor antagonist, and CB1 receptor antagonist.[] It also binds to the CB2 receptor.[] Tetrahydrocannabivarin Tetrahydrocannabivarin (THCV) is prevalent in certain central Asian and southern African strains of Cannabis.[15][] It is an antagonist of THC at CB1 receptors and attenuates the psychoactive effects of THC.[16] Cannabidivarin Although cannabidivarin (CBDV) is usually a minor constituent of the cannabinoid profile, enhanced levels of CBDV have been reported in feral cannabis plants from the northwest Himalayas, and in hashish from Nepal.[17][] Cannabichromene Cannabichromene (CBC) is non-psychoactive and does not affect the psychoactivity of THC .[] Double bond position In addition, each of the compounds above may be in different forms depending on the position of the double bond in the alicyclic carbon ring. There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called 9-THC, while the minor form is called 8-THC. Under the alternate terpene numbering system, these same compounds are called 1-THC and 6-THC, respectively. Length Most herbal cannabinoid compounds are 21-carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the side-chain attached to the aromatic ring. In THC, CBD, and CBN, this side-chain is a pentyl (5-carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3-carbon) chain. Cannabinoids with the propyl side-chain are named using the suffix varin, and are designated, for example, THCV, CBDV, or CBNV.

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Cannabinoid Cannabis plant profile Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant is known as the plant's cannabinoid profile. Selective breeding has been used to control the genetics of plants and modify the cannabinoid profile. For example, strains that are used as fiber (commonly called hemp) are bred such that they are low in psychoactive chemicals like THC. Strains used in medicine are often bred for high CBD content, and strains used for recreational purposes are usually bred for high THC content or for a specific chemical balance. Quantitative analysis of a plant's cannabinoid profile is often determined by gas chromatography (GC), or more reliably by gas chromatography combined with mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible, and, unlike GC methods, can differentiate between the acid and neutral forms of the cannabinoids. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries.

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Pharmacology
Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the liver, especially by cytochrome P450 mixed-function oxidases, mainly CYP 2C9. Thus supplementing with CYP 2C9 inhibitors leads to extended intoxication. Some is also stored in fat in addition to being metabolized in liver. 9-THC is metabolized to 11-hydroxy-9-THC, which is then metabolized to 9-carboxy-THC. Some cannabis metabolites can be detected in the body several weeks after administration. These metabolites are the chemicals recognized by common antibody-based "drug tests"; in the case of THC et al., these loads do not represent intoxication (compare to ethanol breath tests that measure instantaneous blood alcohol levels) but an integration of past consumption over an approximately month-long window. Plant synthesis Cannabinoid production starts when an enzyme causes geranyl pyrophosphate and olivetolic acid to combine and form CBG. Next, CBG is independently converted to either CBD or CBC by two separate synthase enzymes. CBD is then enzymatically cyclized to THC. For the propyl homologues (THCV, CBDV and CBNV), there is a similar pathway that is based on CBGV. Recent studiesWikipedia:Avoid weasel words show that THC is not cyclized from CBD but rather directly from CBG. No experiment thus far has turned up an enzyme that converts CBD into THC, although it is still hypothesizedWikipedia:Avoid weasel words. Separation Cannabinoids can be separated from the plant by extraction with organic solvents. Hydrocarbons and alcohols are often used as solvents. However, these solvents are flammable and many are toxic. Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction with carbon dioxide is an alternative technique. Although this process requires high pressures (73 atmospheres or more), there is minimal risk of fire or toxicity, solvent removal is simple and efficient, and extract quality can be well controlled. Once extracted, cannabinoid blends can be separated into individual components using wiped film vacuum distillation or other distillation techniques. However, to produce high-purity cannabinoids, chemical synthesis or semisynthesis is generally required.

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Natural occurrence
Cannabis indica may have a CBD:THC ratio 45 times that of Cannabis sativa.

History
Cannabinoids were first discovered in the 1940s, when CBD and CBN were identified. The structure of THC was first determined in 1964. Due to molecular similarity and ease of synthetic conversion, CBD was originally believed to be a natural precursor to THC. However, it is now known that CBD and THC are produced independently in the cannabis plant from the precursor CBG.

Endocannabinoids
Endocannabinoids are substances produced from within the body that activate cannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, scientists began searching for an endogenous ligand for the receptor.

Types of endocannabinoid ligands

Arachidonoylethanolamine (Anandamide or AEA)
CB2 In 1992, in Raphael Mechoulam's lab, the first such compound was identified as arachidonoyl ethanolamine and named anandamide, a name derived from the Sanskrit word for bliss and -amide. Anandamide is derived from the essential fatty acid arachidonic acid. It has a pharmacology similar to THC, although its chemical structure is different. Anandamide binds to the central (CB1) and, to a lesser extent, peripheral (CB2) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB1 receptor.[] Anandamide is found in nearly all tissues in a wide range of animals.[] Anandamide has also been found in plants, including small amounts in chocolate.[] Anandamide, an endogenous ligand of CB1 and

Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and homo--linolenoylethanolamine, have similar pharmacology. All of these are members of a family of signalling lipids called N-acylethanolamines, which also includes the noncannabimimetic palmitoylethanolamide and oleoylethanolamide, which possess anti-inflammatory and orexigenic effects, respectively. Many N-acylethanolamines have also been identified in plant seeds[18] and in molluscs.[19] 2-arachidonoyl glycerol (2-AG) Another endocannabinoid, 2-arachidonoyl glycerol, binds to both the CB1 and CB2 receptors with similar affinity, acting as a full agonist at both.[] 2-AG is present at significantly higher concentrations in the brain than anandamide,[] and there is some controversy over whether 2-AG rather than anandamide is chiefly responsible for endocannabinoid signalling in vivo.[] In particular, one in vitro study suggests that 2-AG is capable of stimulating higher G-protein activation than anandamide, although the physiological implications of this finding are not yet known.[20]

Cannabinoid 2-arachidonyl glyceryl ether (noladin ether) In 2001, a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), was isolated from porcine brain.[21] Prior to this discovery, it had been synthesized as a stable analog of 2-AG; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at "any appreciable amount" in the brains of several different mammalian species.[] It binds to the CB1 cannabinoid receptor (Ki = 21.2 nmol/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB1 receptor, and only weakly to the CB2 receptor.[] N-arachidonoyl-dopamine (NADA) Discovered in 2000, NADA preferentially binds to the CB1 receptor.[22] Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.[][23] Virodhamine (OAE) A fifth endocannabinoid, virodhamine, or O-arachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full agonist at CB2 and a partial agonist at CB1, it behaves as a CB1 antagonist in vivo. In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2- to 9-fold higher concentrations peripherally.[24] Lysophosphatidylinositol (LPI) Recent evidence has highlighted LPI as the endogenous ligand to novel endocannabinoid receptor GPR55, making it a strong contender as the sixth endocannabinoid. [25]

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Function
Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activating the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine and dopamine, endocannabinoids differ in numerous ways from them. For instance, they are used in retrograde signaling between neurons. Furthermore, endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research. The endocannabinoid 2-AG has been found in bovine and human maternal milk.[26] Retrograde signal Conventional neurotransmitters are released from a presynaptic cell and activate appropriate receptors on a postsynaptic cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids, on the other hand, are described as retrograde transmitters because they most commonly travel backward against the usual synaptic transmitter flow. They are, in effect, released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For instance, when the release of the inhibitory transmitter GABA is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. On the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.

Cannabinoid Range Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.

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Synthetic cannabinoids
Historically, laboratory synthesis of cannabinoids were often based on the structure of herbal cannabinoids, and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam. Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids. Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules. Medications containing natural or synthetic cannabinoids or cannabinoid analogs: Dronabinol (Marinol), is 9-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic, and analgesic Nabilone (Cesamet), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol, which is Schedule III Sativex, a cannabinoid extract oral spray containing THC, CBD, and other cannabinoids used for neuropathic pain and spasticity in 22 countries including England, Canada and Spain. Sativex develops whole-plant cannabinoid medicines Rimonabant (SR141716), a selective cannabinoid (CB1) receptor inverse agonist once used as an anti-obesity drug under the proprietary name Acomplia. It was also used for smoking cessation Other notable Wikipedia:Please clarify synthetic cannabinoids include: JWH-018, a potent synthetic cannabinoid agonist discovered by Dr. John W. Huffman at Clemson University. It is being increasingly sold in legal smoke blends collectively known as "spice". Several countries and states have moved to ban it legally. JWH-073 CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC. Dimethylheptylpyran HU-210, about 100 times as potent as THC[27] HU-331 a potential anti-cancer drug derived from cannabidiol that specifically inhibits topoisomerase II. SR144528, a CB2 receptor antagonist WIN 55,212-2, a potent cannabinoid receptor agonist JWH-133, a potent selective CB2 receptor agonist Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine AM-2201, a potent cannabinoid receptor agonist.

Cannabinoid

116

References
[2] http:/ / www. unodc. org/ unodc/ en/ data-and-analysis/ bulletin/ bulletin_1962-01-01_3_page005. html [5] Alzheimer's disease; taking the edge off with cannabinoids? - Campbell - 2009 - British Journal of Pharmacology - Wiley Online Library (http:/ / onlinelibrary. wiley. com/ doi/ 10. 1038/ sj. bjp. 0707446/ abstract;jsessionid=712767FDF8D8B874186CF7249CA87D59. d01t03) [6] A Molecular Link between the Active Component of Marijuana and Alzheimer's Disease Pathology - Molecular Pharmaceutics (ACS Publications) (http:/ / pubs. acs. org/ doi/ abs/ 10. 1021/ mp060066m) [7] JCI - Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects (http:/ / www. jci. org/ articles/ view/ 25509) [10] Translational Psychiatry - Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia (http:/ / www. nature. com/ tp/ journal/ v2/ n3/ full/ tp201215a. html) [11] Pot compound seen as tool against cancer - SFGate (http:/ / www. sfgate. com/ health/ article/ Pot-compound-seen-as-tool-against-cancer-3875562. php#ixzz2GZmg5kGr) [12] Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells (http:/ / mct. aacrjournals. org/ content/ 6/ 11/ 2921. abstract) [13] Antitumor activity of plant cannabinoid... [J Pharmacol Exp Ther. 2006] - PubMed - NCBI (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 16728591) [14] Marijuana Compound Fights Cancer; Human Trials Next | NBC Bay Area (http:/ / www. nbcbayarea. com/ news/ local/ Marijuana-Compound-Fights-Cancer-Human-Trials-Next-170406116. html) [15] Baker, P.B., T.A. Gough and B.J. Taylor. 1980. Illicitly imported Cannabis products: some physical and chemical features indicative of their origin. Bulletin on Narcotics 32(2): 31-40. [22] Bisogno, T., D. Melck, M. Bobrov, N. M. Gretskaya, V. V. Bezuglov, L. De Petrocellis, V. Di Marzo. "N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo." The Biochemical Journal. 2000 Nov 1;351 Pt 3:817-24. PMID 11042139 [27] http:/ / www. marijuana. org/ mydna10-12-05. htm

Further reading
De Meijer, E. P.; Bagatta, M.; Carboni, A.; Crucitti, P.; Moliterni, V. M.; Ranalli, P.; Mandolino, G. (2003). "The inheritance of chemical phenotype in Cannabis sativa L" (http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC1462421). Genetics 163 (1): 335346. PMC 1462421 (http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC1462421). PMID 12586720 (http://www.ncbi.nlm.nih.gov/pubmed/12586720). Devane WA, Hanu L, Breuer A, et al. (1992). "Isolation and structure of a brain constituent that binds to the cannabinoid receptor". Science 258 (5090): 19469. doi: 10.1126/science.1470919 (http://dx.doi.org/10.1126/ science.1470919). PMID 1470919 (http://www.ncbi.nlm.nih.gov/pubmed/1470919). Elsohly MA, Slade D (2005). "Chemical constituents of marijuana: the complex mixture of natural cannabinoids". Life Sci. 78 (5): 53948. doi: 10.1016/j.lfs.2005.09.011 (http://dx.doi.org/10.1016/j.lfs.2005.09.011). PMID 16199061 (http://www.ncbi.nlm.nih.gov/pubmed/16199061). Hanu L, Gopher A, Almog S, Mechoulam R (1993). "Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor". J. Med. Chem. 36 (20): 30324. doi: 10.1021/jm00072a026 (http://dx.doi. org/10.1021/jm00072a026). PMID 8411021 (http://www.ncbi.nlm.nih.gov/pubmed/8411021). Hanu L (1987). "Biogenesis of cannabinoid substances in the plant". Acta Universitatis Palackianae Olomucensis Facultatis Medicae 116: 4753. PMID 2962461 (http://www.ncbi.nlm.nih.gov/pubmed/ 2962461). Hanu, L., Krej, Z. (1975). "Isolation of two new cannabinoid acids from Cannabis sativa L. of Czechoslovak origin". Acta Univ. Olomuc., Fac. Med 74: 161166. Hanu, L., Krej, Z., Hruban, L. (1975). "Isolation of cannabidiolic acid from Turkish variety of cannabis cultivated for fibre". Acta Univ. Olomuc., Fac. Med 74: 167172. Kfalvi, A. (2008). Kfalvi, Attila, ed. Cannabinoids and the Brain. doi: 10.1007/978-0-387-74349-3 (http://dx. doi.org/10.1007/978-0-387-74349-3). ISBN978-0-387-74348-6.

Cannabinoid Mechoulam R, Ben-Shabat S, Hanu L, et al. (1995). "Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors". Biochem. Pharmacol. 50 (1): 8390. doi: 10.1016/0006-2952(95)00109-D (http://dx.doi.org/10.1016/0006-2952(95)00109-D). PMID 7605349 (http:/ /www.ncbi.nlm.nih.gov/pubmed/7605349). Nicoll RA, Alger BE (2004). "The brain's own marijuana". Sci. Am. 291 (6): 6875. doi: 10.1038/scientificamerican1204-68 (http://dx.doi.org/10.1038/scientificamerican1204-68). PMID 15597982 (http://www.ncbi.nlm.nih.gov/pubmed/15597982). Racz, I.; Nadal, X.; Alferink, J.; Baos, J.; Rehnelt, J.; Martn, M.; Pintado, B.; Gutierrez-Adan, A. et al. (2008). "Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain". Journal of Neuroscience 28 (46): 1213612145. doi: 10.1523/JNEUROSCI.3402-08.2008 (http://dx.doi.org/ 10.1523/JNEUROSCI.3402-08.2008). PMID 19005078 (http://www.ncbi.nlm.nih.gov/pubmed/ 19005078). Racz, I.; Nadal, X.; Alferink, J.; Baos, J.; Rehnelt, J.; Martn, M.; Pintado, B.; Gutierrez-Adan, A. et al. (2008). "Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain". Journal of Neuroscience 28 (46): 1212512135. doi: 10.1523/JNEUROSCI.3400-08.2008 (http://dx.doi. org/10.1523/JNEUROSCI.3400-08.2008). PMID 19005077 (http://www.ncbi.nlm.nih.gov/pubmed/ 19005077). Turner, C. E., Mole, M. L., Hanu, L., ElSohly, H. N. (1981). "Constituents of Cannabis sativa L. XIX. Isolation and structure elucidation of cannabiglendol. A novel cannabinoid from an Indian variant" (http://pubs.acs.org/ cgi-bin/archive.cgi/jnprdf/1981/44/i01/pdf/np50013a005.pdf). J. Nat. Prod. 44 (1): 2733. doi: 10.1021/np50013a005 (http://dx.doi.org/10.1021/np50013a005).

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External links
Cannabinoid information
Bela Szabo: Pharmacology of Cannabinoid Receptors (http://www.biotrend.com/download/ BT-Review_0208_Cannabinoids.pdf) BIOTREND Reviews No. 02, February 2008 Marijuana and Medicine - Assessing the Science Base (Institute of Medicine) - 1999 (http://books.nap.edu/ html/marimed/) at National Academies Press House of Lords Report - Cannabis (United Kingdom) - 1998 (http://www.parliament.the-stationery-office.co. uk/pa/ld199798/ldselect/ldsctech/151/15101.htm) at Parliament of the United Kingdom Cannabis: A Health Perspective and Research Agenda - 1997 (http://whqlibdoc.who.int/hq/1997/ WHO_MSA_PSA_97.4.pdf) at World Health Organization Chemical Ecology of Cannabis (J. Intl. Hemp Assn. - 1994) (http://www.hempfood.com/IHA/iha01201.html) THC (tetrahydrocannabinol) accumulation in glands of Cannabis (Cannabaceae) (http://www.hempreport.com/ issues/17/malbody17.html) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb (PDF) (http://www. onlinepot.org/medical/Izzo Plant Cannabinoids Therapeutic Opportunities TIPS 2009.pdf)

Cannabinoid

118

Cannabinoid research organizations

International Cannabinoid Research Society (http://www.cannabinoidsociety.org) The Canadian Consortium for the Investigation of Cannabinoids (http://www.ccic.net) Therapeutic Potential in Spotlight at Cannabinoid Researchers' Meeting (http://www.ccrmg.org/journal/04spr/ potential.html) at California Cannabis Research Medical Group

2-Arachidonoylglycerol

119

2-Arachidonoylglycerol
2-Arachidonoylglycerol

Identifiers CAS number PubChem ChemSpider ChEBI ChEMBL IUPHAR ligand Jmol-3D images 53847-30-6 5282280 4445451
[2] [3] [4] [5] [1]

CHEBI:52392

CHEMBL122972 729
[6] [7]

Image 1 Properties

Molecular formula Molar mass

(verify) [8]

C23H38O4 378.3 g/mol

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor.[][] It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. The chemical was first described in 1994-1995, although had been discovered some time before that. The activities of Phospholipase C (PLC) and diacylglycerol lipase (DAGL) mediate its formation. 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).

2-Arachidonoylglycerol

120

Occurrence
2-AG, unlike anandamide (another endocannabinoid), is present at relatively high levels in the central nervous system; it is the most abundant molecular species of monoacylglycerol found in mouse and rat brain (~5-10 nmol/g tissue).[][] Detection of 2-AG in brain tissue is complicated by the relative ease of its isomerization to 1-AG during standard lipid extraction conditions. It has been found in maternal bovine and human milk.[9]

Discovery
Shimon Ben-Shabat, of Ben-Gurion University, discovered the chemical.[10] 2-AG was a known chemical compound but its occurrence in mammals and its affinity for the cannabinoid receptors were first described in 1994-1995. A research group at Teikyo University reported the affinity of 2-AG for the cannabinoid receptors in 1994-1995,[11][] but the isolation of 2-AG in the canine gut was first reported in 1995 by the research group of Raphael Mechoulam at the Hebrew University of Jerusalem, which additionally characterized its pharmacological properties in vivo.[] 2-Arachidonoylglycerol, next with Anandamide, was the second endocannabinoid discovered. The cannabinoid established the existence of a cannabinoid neuromodulatory system in the nervous system.[12]

Pharmacology
Unlike anandamide, formation of 2-AG is calcium-dependent and is mediated by the activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL).[] 2-AG acts as a full agonist at the CB1 receptor.[] At a concentration of 0.3nM, 2-AG induces a rapid, transient increase in intracellular free calcium in NG108-15 neuroblastoma X glioma cells through a CB1 receptor-dependent mechanism.[] 2-AG is hydrolyzed in vitro by monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH), and the uncharacterized serine hydrolase enzymes ABHD6 and ABHD12.[] The exact contribution of each of these enzymes to the termination of 2-AG signaling in vivo is unknown, though it is estimated that MAGL is responsible for ~85% of this activity.[13]

Biosynthesis
2-Arachidonoylglycerol is synthesized from arachidonic acid-containing diacylglycerol (DAG), which is derived from the increase of inositol phospholipid metabolism by the action of diacylglycerol lipase. The molecule can also be formed from pathways like the hydrolysis derived (by diglyceride) from both phosphatidylcholine (PC) and phosphatidic acid (PAs) by the action of DAG lipase and the hydrolysis of arachidonic acid-containing lysophosphatidic acid by the action of a phosphatase.[14]

References
Notes
[1] [2] [3] [4] [5] [6] [7] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=53847-30-6 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5282280 http:/ / www. chemspider. com/ 4445451 https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=52392 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL122972 http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=729 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DC%28OC%28CO%29CO%29CCC%5CC%3DC%2FC%5CC%3DC%2FC%5CC%3DC%2FC%5CC%3DC%2FCCCCC [8] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=443313506& page2=2-Arachidonoylglycerol [10] Pizzorno, Lara; MDiv; MA; LMT. "New Developments in Cannabinoid-Based Medicine: An Interview with Dr. Raphael Mechoulam" (http:/ / www. lmreview. com/ articles/ print/ new-developments-in-cannabinoid-based-medicine-an-interview-with-dr-raphael-mechoulam/ ). Longevity Medicine Review. Retrieved 2011-05-26. [11] Sugiura T, Itoh K, Waku K, Hanahan DJ (1994) Proceedings of Japanese conference on the Biochemistry of Lipids, 36, 71-74 (in Japanese)

2-Arachidonoylglycerol
[13] Savinainen, JR; Saario, SM; Laitinen, JT (2011-03-18). "The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors." (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 21418147) Acta Physiol. National Center for Biotechnology Information. PubMed.gov.

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General references
Dinh TP, Carpenter D, Leslie FM, et al. (August 2002). "Brain monoglyceride lipase participating in endocannabinoid inactivation" (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC125056). Proceedings of the National Academy of Sciences of the United States of America 99 (16): 1081924. doi: 10.1073/pnas.152334899 (http://dx.doi.org/10.1073/pnas.152334899). PMC 125056 (http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC125056). PMID 12136125 (http://www.ncbi.nlm.nih.gov/pubmed/12136125).

2-Arachidonyl glyceryl ether

122

2-Arachidonyl glyceryl ether

2-Arachidonyl glyceryl ether

Identifiers CAS number PubChem ChemSpider ChEMBL Jmol-3D images 222723-55-9 6483057 4983515
[2] [3] [4] [1]

CHEMBL146346 Image 1 Properties

[5]

Molecular formula Molar mass

(verify) [6]

C23H40O3 364.56 g/mol

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

2-Arachidonyl glyceryl ether (2-AGE, Noladin ether) is a putative endocannabinoid discovered by Lumr Hanu and colleagues at the Hebrew University of Jerusalem, Israel. Its isolation from porcine brain and its structural elucidation and synthesis were described in 2001.[]

Discovery
Lumr Hanu, Saleh Abu-Lafi, Ester Fride, Aviva Breuer, Zvi Vogel, Deborah E. Shalev, Irina Kustanovich, and Raphael Mechoulam found the endogenous agonist of the cannabinoid receptor type 1 (CB1) in 2000. The discovery was 100 gram of porcine brain, (approximately a single brain) was added to a mixture of 200 mL of chloroform and 200 mL of methanol and mixed in a laboratory blender for 2 minutes. 100 mL of Water was then added, and the mixing process continued for another minute. After this, the mixture was filtered. Two layers then formed and the layer of water-methanol was separated and evaporated when pressure was reduced. Synaptosomal membranes were prepared from 250g of the brains of Sabra male rats. A Hewlett Packard G 1800B GCD system that has a HP-5971 GC with electron ionization detector was used.[]

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Production
The production of in the endocannabinoid is enhanced in normal, but not in endothelium-denuded rat aorta on reacting with carbachol, an parasympathomimetic drug. It potently reduces blood pressure in rats and may represent an endothelium-derived hypotension factor.[] 2-Arachidonyl glyceryl ether's structure can be determined by mass spectrometry and Rutherford backscattering spectrometry. It was confirmed by comparison with a synthetic sample of the endocannabinoid. It binds to the Cannabinoid receptor type 1 (Ki = 21.2 0.5 nM), which causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice.[] The endocannabinoid exhibits Ki values of 21.2 nM and >3 M at the Cannabinoid receptor type 1 and the peripheral cannabinoid receptors.[7] The presence of 2-AGE in body tissue is disputed. Although a research group from Teikyo University, Kanagawa, Japan could not detect it in the brains of mice, hamsters, guinea-pigs or pigs,[] two other research groups successfully detected it in animal tissues.[][]

Pharmacology
2-AGE binds with a Ki of 21 nM to the CB1 receptor[] and 480 nM to the CB2 receptor.[] It shows agonistic behaviour on both receptors and is a partial agonist for the TRPV1 channel.[] After binding to CB2 receptors it inhibits adenylate cyclase and stimulates ERK-MAPK and regulates calcium transients.[] In comparison to 2-arachidonoyl glycerol, noladin is metabolically more stable resulting in a longer half-life.[] It lowers Intraocular pressure,[] increases the uptake of GABA in the globus pallidus of rats[] and is neuroprotective by binding to and activation of PPAR.[]

References
[1] [2] [3] [4] [5] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=222723-55-9 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=6483057 http:/ / www. chemspider. com/ 4983515 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL146346 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=OCC%28OCCCC%5CC%3DC%2FC%2FC%3DC%5CC%5CC%3DC%2FC%5CC%3DC%2FCCCCC%29CO [6] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=413108402& page2=2-Arachidonyl+ glyceryl+ ether [7] "2-Arachidonyl Glycerol ether Noladin; 2-AG ether (CAS 222723-55-9) || Cayman Chemical" (http:/ / www. caymanchem. com/ app/ template/ Product. vm/ catalog/ 62165). Cayman Chemical. Retrieved 2011-05-29.

External links
Commercial supplier of Noladin ether (http://www.caymanchem.com/app/template/Product.vm/catalog/ 62165/a/z)

Anandamide

124

Anandamide
Anandamide

Identifiers CAS number PubChem ChemSpider UNII MeSH ChEBI ChEMBL IUPHAR ligand Jmol-3D images 94421-68-8 5281969 4445241
[2] [3] [4] [1]

UR5G69TJKH Anandamide CHEBI:2700

[5] [6] [7]

CHEMBL15848 737
[8] [9]

Image 1 [10] Image 2 Properties

Molecular formula Molar mass

(verify) [11]

C22H37NO2 347.53 g/mol

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Anandamide, also known as N-arachidonoylethanolamine or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide.[][] It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways.[] It is degraded primarily by the fatty acid amide hydrolase (FAAH) enzyme, which converts anandamide into ethanolamine and arachidonic acid. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for therapeutic use.[12][13]

Anandamide

125

History
It was isolated and its structure first described in 1992 by WA Devane, Lumir Hanus et al. who were working in a team led by Raphael Mechoulam at the Hebrew University.[14]

Physiological functions
Anandamide's effects can be either central, in the brain, or peripheral, in other parts of the body. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery.[] The latter are mainly involved in functions of the immune system. Cannabinoid receptors were originally discovered as being sensitive to 9-tetrahydrocannabinol (9-THC, commonly called THC), which is the primary psychoactive cannabinoid found in cannabis. The discovery of anandamide came from research into CB1 and CB2, as it was inevitable that a naturally occurring (endogenous) chemical would be found to affect these receptors. Anandamide has been shown to impair working memory in rats.[15] Studies are under way to explore what role anandamide plays in human behavior, such as eating and sleep patterns, and pain relief. Anandamide is also important for implantation of the early stage embryo in its blastocyst form into the uterus. Therefore cannabinoids such as 9-THC might influence processes during the earliest stages of human pregnancy.[] Peak plasma anandamide occurs at ovulation and positively correlates with peak estradiol and gonadotrophin levels, suggesting that these may be involved in the regulation of AEA levels.[16] Anandamide plays a role in the regulation of feeding behavior, and the neural generation of motivation and pleasure. In addition, anandamide injected directly into the forebrain reward-related brain structure nucleus accumbens enhances the pleasurable responses of rats to a rewarding sucrose taste, and enhances food intake as well.[][] A study published in 1998 shows that anandamide inhibits human breast cancer cell proliferation.[] Some studies have linked anandamide release as a mechanism of analgesic effects induced by exercise, particularly by running.[17] In 1996, researchers discovered anandamide in chocolate. They also detected the presence of two substances that might mimic the effects of anandamide, N-oleoylethanolamine and N-linoleoylethanolamine.[]

Synthesis and degradation

The human body synthesizes anandamide from N-arachidonoyl phosphatidylethanolamine (NAPE), which is itself made by transferring arachidonic acid from lecithin to the free amine of cephalin through an N-acyltransferase enzyme.[][] Anandamide synthesis from NAPE occurs via multiple pathways and includes enzymes such as phospholipase A2, phospholipase C and NAPE-PLD.[] Endogenous anandamide is present at very low levels and has a very short half-life due to the action of the enzyme fatty acid amide hydrolase (FAAH), which breaks it down into free arachidonic acid and ethanolamine. Studies of piglets show that dietary levels of arachidonic acid and other essential fatty acids affect the levels of anandamide and other endocannabinoids in the brain.[] High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis.[] This suggests that anandamide may play a role in the development of obesity, at least in rodents. Paracetamol (or acetaminophen in the U.S.A.) is metabolically combined with arachidonic acid by FAAH to form AM404.[] This metabolite of paracetamol is a potent agonist at the TRPV1 vanilloid receptor, a weak agonist at both CB1 and CB2 receptors, and an inhibitor of anandamide reuptake. As a result, anandamide levels in the body and brain are elevated. In this fashion, paracetamol acts as a pro-drug for a cannabimimetic metabolite. This action may be partially or fully responsible for the analgesic effects of paracetamol.[][]

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126

References
[1] [2] [3] [4] [5] [6] [7] [8] [9] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=94421-68-8 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5281969 http:/ / www. chemspider. com/ 4445241 http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=UR5G69TJKH http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Anandamide https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=2700 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL15848 http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=737 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DC%28NCCO%29CCC%5CC%3DC%2FC%5CC%3DC%2FC%5CC%3DC%2FC%5CC%3DC%2FCCCCC [10] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CCCCC%2FC%3DC%5CC%2FC%3DC%5CC%2FC%3DC%5CC%2FC%3DC%5CCCCC%28%3DO%29NCCO [11] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=464364547& page2=Anandamide [17] http:/ / www. harford. de/ arne/ articles/ NeuroReport. pdf

External links
Could anandamide be the missing link to "runner's high"? (http://www.runnersworld.com/article/ 0,7120,s6-243-297--1102-0,00.html) Accessed 2008-10-18

N-Arachidonoyl dopamine

127

N-Arachidonoyl dopamine
N-Arachidonoyl dopamine

Identifiers CAS number PubChem ChemSpider ChEMBL Jmol-3D images 199875-69-9 5282105 4445314
[2] [3] [4] [1]

CHEMBL138921 Image 1 Properties

[5]

Molecular formula Molar mass

(verify) [6]

C28H41NO3 439.63 g/mol

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

N-Arachidonoyl dopamine (NADA) is an endocannabinoid which acts as an agonist of the CB1 receptor[] and the transient receptor potential V1 (TRPV1) ion channel. Its discovery was described in 2002 by an academic research group from Italy and the USA. It was found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum and striatum. It activates the TRPV1 channel with an EC50 of approximately of 50nM. The high potency makes it the putative endogenous TRPV1 agonist.[]

References
[1] [2] [3] [4] [5]

http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=199875-69-9 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5282105 http:/ / www. chemspider. com/ 4445314 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL138921 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CCCCC%5CC%3DC%2FC%5CC%3DC%2FC%5CC%3DC%2FC%5CC%3DC%2FCCCC%28%3DO%29NCCC1%3DCC%28%3DC%28C%3DC1 [6] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477503651& page2=N-Arachidonoyl+ dopamine

N-Arachidonoyl dopamine

128

External links
General information (http://www.caymanchem.com/app/template/Product.vm/catalog/90057/tab/data/a/ z) about NADA.

Virodhamine
Virodhamine

Identifiers CAS number PubChem ChemSpider ChEMBL Jmol-3D images 443129-35-9 5712057 4650158
[2] [3] [4] [1]

CHEMBL187349 Image 1 Properties

[5]

Molecular formula Molar mass

(verify) [6]

C22H37NO2 347.53468

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Virodhamine (O-arachidonoyl ethanolamine) is an endocannabinoid and a nonclassic eicosanoid, derived from arachidonic acid. O-Arachidonoyl ethanolamine is arachidonic acid and ethanolamine joined by an ester linkage, the opposite of the amide linkage found in anandamide. Based on this opposite orientation, the molecule was named virodhamine from the Sanskrit word virodha, which means opposition. It acts as an antagonist of the CB1 receptor and agonist of the CB2 receptor. Concentrations of virodhamine in the human hippocampus are similar to those of anandamide, but they are 2- to 9-fold higher in peripheral tissues that express CB2. Virodhamine lowers body temperature in mice, demonstrating cannabinoid activity in vivo.[]

Virodhamine

129

References
[1] [2] [3] [4] [5] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=443129-35-9 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5712057 http:/ / www. chemspider. com/ 4650158 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL187349 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DC%28OCCN%29CCC%5CC%3DC%2FC%5CC%3DC%2FC%5CC%3DC%2FC%5CC%3DC%2FCCCCC [6] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=412704647& page2=Virodhamine

Oleamide

130

Oleamide
Oleamide

Identifiers CAS number PubChem ChemSpider UNII EC number ChEBI ChEMBL IUPHAR ligand Jmol-3D images 301-02-0 5283387 4446508
[1] [2] [3] [4]

7L25QK8BWO 206-103-9
[5]

CHEBI:116314

[6]

CHEMBL15927 284
[8] [9]

[7]

Image 1 Properties

Molecular formula Molar mass Appearance Density Melting point Boiling point Solubility in water

C18H35NO 281.48 g mol

1

Creamy solid 0.879 g/cm3 102-104 C >200 C

[10]

[10]

[10] [10]

Insoluble Hazards

NFPA 704

Flash point
(verify) [11]

>200 C

[10]

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Oleamide Oleamide is an amide of the fatty acid oleic acid. It is an endogenous substance: it occurs naturally in the body of animals. It accumulates in the cerebrospinal fluid during sleep deprivation and induces sleep in animals.[12] It is being studied as a potential medical treatment for mood and sleep disorders, and cannabinoid-regulated depression.[13][14] The mechanism of action of oleamide's sleep inducing effects is an area of current research. It is likely that oleamide interacts with multiple neurotransmitter systems.[15] Oleamide is structurally related to the endogenous cannabinoid anandamide, and has the ability to bind to the CB1 receptor as a full agonist. Synthetically produced oleamide has a variety of industrial uses including as a slip agent, a lubricant, and a corrosion inhibitor.[16] Oleamide was originally characterized as an endogenous bioactive substance, isolated from the cerebrospinal fluid of sleep deprived cats. It was characterised in 1995 by Benjamin Cravatt III and Richard Lerner at The Scripps Research Institute in La Jolla, CA.[] Oleamide was found by researchers to be leaking out of polypropylene plastics used in laboratory experiments, affecting experimental results.[17] Since polypropylene is used in a wide number of food containers such as those for yogurt, the problem is being studied.[18] A chemical analysis of 44 products containing synthetic cannabinoid drugs marketed as "herbal incense" revealed oleamide in 7 of the products tested.[19]

131

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=301-02-0 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5283387 [3] http:/ / www. chemspider. com/ 4446508 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=7L25QK8BWO [5] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=206-103-9 [6] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=116314 [7] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL15927 [8] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=284 [9] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DC%28N%29CCCCCCC%5CC%3DC%2FCCCCCCCC [10] Oleamide (http:/ / www. chemicalland21. com/ arokorhi/ specialtychem/ perchem/ OLEAMIDE. htm#) at chemicalland21.com [11] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=415879332& page2=Oleamide [13] Methods of treating anxiety and mood disorders with oleamide - US Patent 6359010 (http:/ / www. patentstorm. us/ patents/ 6359010/ claims. html) [16] Surfactants : Westco Oleamide a Slip Agent In Polyethylene Films (http:/ / www. wrchem. com/ Products/ OLEAMIDE. htm)

Palmitoylethanolamide

132

Palmitoylethanolamide
Palmitoylethanolamide

Identifiers Abbreviations CAS number PubChem ChemSpider UNII EC number KEGG MeSH ChEMBL Jmol-3D images Palmitamide MEA[citation needed] 544-31-0 4671 4509
[2] [3] [4] [1]

6R8T1UDM3V 208-867-9 D08328

[5]

[6]

palmidrol

[7] [8]

CHEMBL417675 Image 1 [10] Image 2 Properties

[9]

Molecular formula Molar mass Appearance Density Melting point Boiling point log P

C18H37NO2 299.49 g mol

1

White crystals 910 mg mL1 59-60C, 332-333K, 138-140F 461.5C, 735K, 863F 5.796 Hazards

Flash point

323.9 C (615.0F) Related compounds

Related compounds

(verify) [11]

Hypusine Saccharopine

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, belonging to the class of nuclear factor agonists. PEA has been demonstrated to bind to a receptor in the cell-nucleus (a nuclear receptor) and exerts a great variety of biological functions related to chronic pain and inflammation. The main target is thought to be the peroxisome

Palmitoylethanolamide proliferator-activated receptor alpha (PPAR-).[][] PEA also has affinity to cannabinoid-like G-coupled receptors GPR55 and GPR119.[] PEA cannot strictly be considered a classic endocannabinoid because it lacks affinity for the cannabinoid receptors CB1 and CB2.[] However, the presence of PEA (and other structurally related N-acylethanolamines) have been know to enhance anandamide activity by a so-called "entourage effect".[12][13] Quite interesting is the fact that several papers have demonstrated that an imbalance of the endocannabinoid system (ECS) and alterations in the levels of PEA occur in acute and chronic inflammation.[14] For instance during -amyloid-induced neuroinflammation the deregulation of cannabinoid receptors and its endogenous ligands accompanies the development and progression of disease.[] PEA has been shown to have anti-inflammatory,[] anti-nociceptive,[] neuroprotective,[] and anticonvulsant properties
[]

133

Early studies
The early history of PEA is quite interesting. Indications as anti-inflammation and analgesia stem from before 1980, and the birth of the molecule was in 1954. In that year 5 researchers from MSD described N-(2-hydroxyethyl)-palmitamide, as they called the molecule at that time, as a natural anti-inflammatory agent. They stated: " We have succeeded in isolating a crystalline anti-inflammatory factor from soybean lecithin and identifying it as (S)-(2-hydroxyethyl)-palmitamide. The compound also was isolated from a phospholipid fraction of egg yolk and from hexane-extracted peanut meal." In 1975 Czech physicians described the result of a clinical trial in joint pain in The Lancet.[citation needed] The analgesic action of 3 grams of aspirin during the day was compared to PEA 1.8 gram/day. Both drugs were reported to enhance joint movements and decrease pain. In the 1990s, the relation between anandamide and PEA was described, and the expression of receptors sensitive for those two molecules on mast cells was first demonstrated by the group of Nobel price winner Levi-Montalcini.[] In this period more insight into the function of the endogenous fatty acid derivatives emerged, and compounds such as oleamide, palmitoylethanolamide, 2-lineoylglycerol, 2-palmitoylglycerol were explored for their capacity to modulate pain sensitivity and inflammation via what one at that tinme thought, the endocannabinoid signalling pathway.[][] One group demonstrated that PEA could alleviate, in a dose-dependent manner, pain behaviors elicited in mice-pain models and could downregulate hyperactive mast cells.[][] PEA and related compounds such as anandamide also seem to have synergistic effects in models of pain and analgesia.[]

Animal models
In a variety of animal models PEA seems promising, and researchers could demonstrate relevant clinical activity in a variety of disorders, from multiple sclerosis to neuropathic pain.[][] In the mouse forced swimming test palmitoylethanolamide was comparable to fluoxetine in anti-depressant effects.[] An Italian study published in 2011 found that micronized-PEA reduced the raised intraocular pressure in glaucoma.[] In a spinal trauma model, PEA could reduce neurological deficit through the reduction of mast cell infiltration and activation. PEA in this model also reduced the activation of microglia and astrocytes.[] Its activity as an inhibitor of inflammation could counteracts reactive astrogliosis induced by beta-amyloid peptide, in a model relevant for neurodegeneration, probably via the PPAR- mechanism of action.[] In models of stroke and other traumata of the central nervous system, PEA exerted neuroprotective properties.[][][][][] For pet animals PEA has been used successfully to treat painstates and chronic inflammation.

Palmitoylethanolamide

134

Animal models of chronic pain and inflammation

Chronic pain and neuropathic pain are indications for which there is high unmet need in the clinic. PEA has been tested in a variety of animal models for chronic and neuropathic pain. As cannabinoids, such as THC, have been proven to be effective in neuropathic pain states,.[] The analgesic and antihyperalgesic effects of PEA in two models of acute and persistent pain seemed to be explained at least partly via the de novo neurosteroid synthesis.[][] In chronic granulomatous pain and inflammation model, PEA could prevent nerve formation and sprouting, mechanical allodynia, and PEA inhibited dorsal root ganglia activation, which is a hallmark for winding up in neuropathic pain.[] The mechanism of action of PEA as an analgesic and anti-inflammatory molecule is probably based on different aspects. PEA inhibits the release of both preformed and newly synthesised mast cell mediators, such as histamine and TNF-alpha.[] PEA, as well as its analogue adelmidrol (di-amide derivative of azelaic acid), can both down-regulate mast cells.[] PEA reduces the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and prevents IkB-alpha degradation and p65 NF-kappaB nuclear translocation, the latter related to PEA as an endogenous PPAR-alpha agonist. In 2012 it became clear that PEA can also reduce reperfusion injury and the negative impact of shock on various outcome parameters, such as renal dysfunction, ischemic injury and inflammation, most probably via the PPAR-alpha pathway. Among the reperfusion and inflammation markers measured PEA could reduce the increase in creatinine, GT, AST, nuclear translocation of NF-Bp65; kidney MPO activity and MDA levels, nitrotyrosine, PAR and adhesion molecules expression, the infiltration and activation of mastcells and apoptosis.[] PEA seems to be produced in human as well as in animals as a biological response and a repair mechanism in chronic inflammation and chronic pain.[] In a model of visceral pain (inflammation of the urinary bladder) PEA was able to attenuate the viscero-visceral hyper-reflexia induced by inflammation of the urinary bladder, one of the reasons why PEA is currently explored in the painful bladdersyndrome.[] In a different model for bladder pain, the turpentine-induced urinary bladder inflammation in the rat, PEA also attenuated a referred hyperalgesia in a dose-dependent way.[] Chronic pelvic pain in patients seem to respond favourably to a treatment with PEA.[][]

PEA's mechanism on non-neuronal cells

PEA, as an N-acylethanolamine, has physico-chemical properties comparable to anandamide, and while it is not strictly an endocannabinoid, it is often studied in conjunction with anandamide because of their overlapping synthetic and metabolic pathways. N-acylethanolamines like PEA often act as signaling molecules, activating intracellular and membrane-associated receptors to regulate a variety of physiological functions. The signaling lipid PEA is known to activate intracellular, nuclear and membrane-associated receptors and regulate many physiological functions related to the inflammatory cascade and chronic pain states. Endocannabinoid lipids like PEA are widely distributed in nature, in a variety of plant, invertebrate, and mammalian tissues.[] PEA's mechanism of action sometimes is described as Autacoid Local Injury Antagonism (acronym ALIA),[] and PEA under this nomenclature is an ALIAmide. It was the group of the Nobel prize laureate Rita Levi-Montalcini who in 1993 first presented evidence supporting that lipid amides of the N-acylethanolamine type (such as PEA) are potential prototypes of naturally occurring molecules capable of modulating mast cell activation, and her group coined the acronym ALIA in that paper.[] An autocoid is a regulating molecule, locally produced. An ALIAmide is an autocoid synthesized on-demand in response to injury, and acts locally to counteract such pathology. The mast cell soon after the breakthrough paper of Levi-Montalcini appeared to be an important target for the anti-inflammatory activity of PEA, and since 1993, at least 25 papers have been published on the various effects of PEA on the mast cell. Mast cells are often found in proximity to sensory nerve endings and their degranulation can enhance the nociceptive signal, the reason why peripheral mast cells are considered to be pro-inflammatory and pro-nociceptive.[] PEA's activity is currently seen as a new inroad in the treatment of neuropathic pain. Microglia plays a key role in the winding up phenomena and central sensitization.[][]

Palmitoylethanolamide

135

Clinical relevance
PEA has been explored in man in various clinical trials in a variety of pain states, for inflammatory and pain syndromes.[][][][][][] Its positive influence in atopic eczema for instance seems to originate from PPAR alpha activation.[][] PEA is available for human use as food for medical purposes. In a 2012 review, all clinical trials to date were summarized.[15] Its positive influence in chronic pain, and inflammatory states such as atopic eczema, seems to originate mainly from PPAR alpha activation.[][] From a clinical perspective the most important and promising indications for PEA are linked to neuropathic and chronic pain states, such as diabetic neuropathic pain, sciatic pain, pelvic pain and entrapment neuropathic painstates.[][][][][] In a blind pilot trial in 25 patients affected by temporomandibular joint's (TMJ) osteoarthritis or synovitis pain, patients were randomly to ultramicronized PEA or ibuprofen 600mg three times a day for two weeks.[16] Pain decrease after two weeks of treatment was significantly higher in PEA treated patients than in patients receiving the NSAID (p=0.0001). Masticatory function also improves more on PEA compared to the NSAID. In 2012, 20 patients suffering from thalidomide and bortezomib induced neuropathy were reported to have improved nerve functions and less pain after a two months treatment with PEA 600mg daily.[] The authors pointed out that although a placebo effect might play a role in the reported pain relief, the changes in neurophysiological measures clearly indicated that PEA exerted a positive action on the myelinated fibre groups. 30 patients suffering from neuropathic pain, which were refractory to treatment with analgesics, included pregabalin, were responding well in 45 days, with a decrease of painscores > 50% when pregabalin was tapered in again, up to 600mg/day in combination with PEA, without signs of drug-drug interaction.[17]

Metabolism
PEA is metabolized by cellular enzymes, fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA), the latter of which has more specificity toward PEA over other fatty acid amides.[] To date, no drug interactions have been reported in literature, neither any clinical relevant or dose-limiting side effect.

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=544-31-0 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=4671 [3] http:/ / www. chemspider. com/ 4509 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=6R8T1UDM3V [5] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=208-867-9 [6] http:/ / www. kegg. jp/ entry/ D08328 [7] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=palmidrol [8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL417675 [9] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CCCCCCCCCCCCCCCc%28%3A%5Bo%5D%29%3A%5BnH%5DCCO [10] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CCCCCCCCCCCCCCCC%28%3DO%29NCCO [11] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=451970750& page2=Palmitoylethanolamide [16] Palmitoylethanolamide Vs NSAID In The Treatment Of TMJD Pain (http:/ / iadr. confex. com/ iadr/ 2010barce/ webprogramcd/ Paper137174. html)

RVD-Hp

136

RVD-Hp
RVD-Hp fragment of hemoglobin, alpha 1
Identifiers Symbol Entrez HUGO OMIM RefSeq UniProt HBA1 3039 4823 [1] [2] [3] [4]

141800

NM_000558 P69905 Other data [5]

Locus

Chr. 16 p13.3

[6]

RVD-Hp is an endogenous neuropeptide found in human and mammalian brain, which acts as a selective agonist for the CB1 cannabinoid receptor. It is a 12-amino acid polypeptide having the amino acid sequence Arg-Val-Asp-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal extended form of hemopressin, a 9-AA polypeptide derived from the 1 subunit of hemoglobin which has previously been shown to act as a CB1 inverse agonist.[7] The shorter 11-AA polypeptide VD-Hp was found to be an agonist at both CB1 and CB2 receptors. All three polypeptides have been isolated from various mammalian species, with RVD-Hp being one of the more abundant neuropeptides expressed in mouse brain, and these neuropeptides represent a new avenue for cannabinoid research distinct from the previously known endogenous lipid-derived cannabinoid agonists such as anandamide.[8]
species human mouse rat consensus RVD-Hp sequence RVDPVNFKLLSH RVDPVNFKLLSH RVDPVNFKfLSH RVDPVNFKxLSH

References
[1] [2] [3] [4] [5] [6] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& amp;cmd=retrieve& amp;dopt=default& amp;list_uids=3039& rn=1 http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=4823 http:/ / www. omim. org/ 141800 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?Submit=Submit& position=NM_000558& rn=1 http:/ / www. uniprot. org/ uniprot/ P69905 http:/ / omim. org/ search?index=geneMap& search=16p13. 3

Hemopressin

137

Hemopressin
Hemopressin

Identifiers PubChem ChemSpider Jmol-3D images 44560117 23327737 Image 1 Properties Molecular formula Molar mass
(verify) [4] [1] [2]

[3]

C53H77N13O12 1088.25838

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Hemopressin (Hp) is an alpha hemoglobin fragment with the sequence PVNFKFLSH, originally identified in extracts of rat brain using an enzyme capture technique.[] It binds cannabinoid receptors, acting as an inverse agonist at CB1 receptors.[] Longer forms of hemopressin containing 2-3 additional amino acids on the N-terminus have been identified in extracts of mouse brain. These longer hemopressin peptides, named RVD-Hp and VD-Hp, bind to CB1 receptors and are agonists.[] In addition to the Hp peptides from alpha hemoglobin, a related peptide from beta hemoglobin has been found in mouse brain extracts; this peptide, named VD-Hp, is also an agonist at CB1 cannabinoid receptors.[] The original Hp peptide reduces sensitivity to painful stimuli in an experimental model of hyperalgesia.[] Hp also reduces food intake in mice.[] However, it remains to be shown if Hp is an endogenous brain peptide. The original purification used boiling acid to extract the peptide from rat brain, and hot acid can specifically cleave D-P bonds. The N-terminally-extended forms RVD-Hp and VD-Hp may represent the true endogenous forms.[]

Role in diet
Scientists at the University of Manchester have discovered that hemopressin could be used as an appetite suppressant without having the side effects of many other drugs that are used for this purpose. In laboratory tests hemopressin was administrated to mice and rats, which significantly reduced food intake. Hemopressin works by affecting the reward centres of the brain which make us feel happy when we eat too much. A further research should be carried out in order to confirm these effects and the safety on people.[5]

Hemopressin

138

References

[1] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=44560117 [2] http:/ / www. chemspider. com/ 23327737 [3] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CC%28C%29C%5BC%40%40H%5D%28C%28%3DO%29N%5BC%40%40H%5D%28CO%29C%28%3DO%29N%5BC%40%40H%5D%28Cc1c [4] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=413151472& page2=Hemopressin [5] http:/ / uk. health. lifestyle. yahoo. net/ hemopressin-naturally-supresses-appetite. htm

Gasotransmitter
Gasotransmitters are gaseous molecules synthesized in the body. They include nitric oxide, hydrogen sulfide, carbon monoxide, and possibly nitrous oxide.

Overview
Gasotransmitters is a family of endogenous molecules of gases or gaseous signaling molecules, including NO, CO, H2S, and others. These particular gases share many common features in their production and function but carry on their tasks in unique ways, which differ from classical signaling molecules, in the human body. The first suggestion that a gas had a direct action at pharmacological receptors and thereby acting as a neurotransmitter was first suggested in 1981 from clinical work with nitrous oxide (1,2,3). In vitro experiments confirmed these observations (4) which were replicated at NIDA later(5). The terminology and characterization criteria of gasotransmitter were firstly introduced in 2002 (see ref. 14). For one gas molecule to be categorized as a gasotransmitters, all of the following criteria should be met (see ref. 13 &14). (i) It is a small molecule of gas; (ii) It is freely permeable to membranes. As such, its effects do not rely on the cognate membrane receptors. It can have endocrine, paracrine, and autocrine effects. In their endocrine mode of action, for example, gasotransmitters can enter the blood stream; be carried to remote targets by scavengers and released there, and modulate functions of remote target cells; (iii) It is endogenously and enzymatically generated and its production is regulated; (iv) It has well defined and specific functions at physiologically relevant concentrations. Thus, manipulating the endogenous levels of this gas evokes specific physiological changes; (v) Functions of this endogenous gas can be mimicked by its exogenously applied counterpart; (vi) Its cellular effects may or may not be mediated by second messengers, but should have specific cellular and molecular targets. In 2011, a European Network on Gasotransmitters (ENOG) [1] was formed. The aim of the network is to promote research on NO, CO and H2S in order to better understand the biology of gasotransmitters and to unravel the role of each mediator in health and disease. Moreover, the network aims to contribute to the translation of basic science knowledge in this area of research into therapeutic or diagnostic tools.

References
1. Gillman MA, Lichtigfeld FJ (January 1981). "A comparison of the effects of morphine sulphate and nitrous oxide analgesia on chronic pain states in man". J. Neurol. Sci. 49 (1): 415. doi:10.1016/0022-510X(81)90186-6 [2]. PMID7205318 [3]. 2. Gillman MA, Lichtigfeld FJ (February 1981). "The similarity of the action of nitrous oxide and morphine". Pain 10 (1): 110. PMID7232008 [4]. 3. Gillman MA, Lichtigfeld FJ (May 1983). "Nitrous oxide interacts with opioid receptors: more evidence". Anesthesiology 58 (5): 4834. PMID6301312 [5]. 4. Daras C, Cantrill R, Gillman MA. (3H)Naloxone displacement: evidence for nitrous oxide as opioid receptor agonist. Eur J Pharmacol 89:177-178.

Gasotransmitter 5. Ori C., Ford-Rice F and London E.D. Effects of nitrous oxide and halothane on mu and kappa opioid receptors in guinea-pig brain. Anesthesiology 70: 541-544,1989. 6. Allen A. US science journal ignores S.A. find. The Star 13 May 1992: 8. 7. Gillman MA. Nitrous oxide as neurotransmitter. Lancet 339 : 307;1992. 8. Gillman MA. Nitrous oxide, Nitric oxide and neurotransmission. Brit Med J 305: 1368,1992. 9. Gillman MA, Lichtigfeld FJ. NO comments. Nature 367: 28;1994. 10. Gillman MA. (2004). Discovery of gasotransmission. The Scientist 18: 11. Hyun J., Chaudhuri G. and Fakuto JM. The reductive metabolism of nitric oxide in hepatocytes: possible interaction with thiols. Dru. Metab Dispos 27: 1005-09, 1999. 12. Einarsdottir O, Caughey WS. Interactions of the anesthetic N2O with bovine heart cytochrome c oxidase. JBiol Chem 263: 9199-9205, 1988. 13. Wang R (ed) (2004) Signal Transduction and the Gasotransmitters: NO, CO and H2S in Biology and Medicine. Humana Press, New Jersey, USA. 14. Wang R. Two's company, three's a crowd - Can H2S be the third endogenous gaseous transmitter? FASEB Journal 16: 1792-1798,2002. 15. Cooke JP. The 1998 Nobel prize in Medicine: clinical implications for 1999 and beyond. Vascular Medicine 4:57-60, 1999. 16. Garthwaite J. (2008). Concepts of neural nitric oxide-mediated transmission. European Journal of Neuroscience 27: 2783-2802. 17. Papapetropoulos A, Pyriochou A, Altaany Z, Yang G, Marazioti A, Zhou Z, Jeschke MG, Branski LK, Herndon DN, Wang R, Szab C . Hydrogen sulfide is an endogenous stimulator of angiogenesis. PNAS 2009.

139

References
[1] [2] [3] [4] [5] http:/ / www. gasotransmitters. eu http:/ / dx. doi. org/ 10. 1016%2F0022-510X%2881%2990186-6 http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 7205318 http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 7232008 http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 6301312

Carbon monoxide

140

Carbon monoxide
Carbon monoxide

Identifiers CAS number PubChem ChemSpider UNII EC number UN number KEGG MeSH ChEBI RTECS number Beilstein Reference Gmelin Reference Jmol-3D images 630-08-0 281 275
[2] [3] [4] [1]

7U1EE4V452 211-128-3 1016 D09706

[6] [5]

Carbon+monoxide CHEBI:17245 FG3500000 3587264 421 Image 1

[9] [8]

[7]

Properties Molecular formula Molar mass Appearance Odor Density CO 28.010 g/mol colourless gas odorless 789kg/m3, liquid 1.250kg/m3 at 0C, 1atm 1.145kg/m3 at 25C, 1atm 205.02C, 68K, -337F 191.5C, 82K, -313F 27.6mg/1 L (25C) soluble in chloroform, acetic acid, ethyl acetate, ethanol, ammonium hydroxide, benzene

Melting point Boiling point Solubility in water Solubility

Carbon monoxide

141
1.0003364 0.122 D Thermochemistry

Refractive index (nD) Dipole moment

Std enthalpy of formation fHo298 Std enthalpy of combustion cHo298 Standard molar entropy So298

110.5kJmol1 283.4 kJ/mol

197.7Jmol1K1

Specific heat capacity, C 29.1 J/K mol Hazards MSDS EU Index EU classification F R-phrases S-phrases NFPA 704 T+ External MSDS 006-001-00-2

R61 R12 R26 R48/23 S53 S45

Flash point Autoignition temperature Explosive limits

191 C (82K; 311.8F) 609 C (882K; 1,128F) 12.5-74.2% Related compounds

Related carbon oxides

Carbon dioxide Carbon suboxide Oxocarbons Supplementary data page

Structure and properties Thermodynamic data Spectral data

n, , etc.
r

Phase behaviour Solid, liquid, gas UV, IR, NMR, MS

(verify) [10]

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Carbon monoxide (CO) is a colorless, odorless, and tasteless gas that is slightly lighter than air. It is toxic to humans and animals when encountered in higher concentrations, although it is also produced in normal animal metabolism in low quantities, and is thought to have some normal biological functions. In the atmosphere it is spatially variable, short lived, having a role in the formation of ground-level ozone.

Carbon monoxide Carbon monoxide consists of one carbon atom and one oxygen atom, connected by a triple bond that consists of two covalent bonds as well as one dative covalent bond. It is the simplest oxocarbon, and isoelectronic with the cyanide ion and molecular nitrogen. In coordination complexes the carbon monoxide ligand is called carbonyl. Carbon monoxide is produced from the partial oxidation of carbon-containing compounds; it forms when there is not enough oxygen to produce carbon dioxide (CO2), such as when operating a stove or an internal combustion engine in an enclosed space. In the presence of oxygen, carbon monoxide burns with a blue flame, producing carbon dioxide.[11] Coal gas, which was widely used before the 1960s for domestic lighting, cooking, and heating, had carbon monoxide as a significant constituent. Some processes in modern technology, such as iron smelting, still produce carbon monoxide as a byproduct.[12] Worldwide, the largest source of carbon monoxide is natural in origin, due to photochemical reactions in the troposphere that generate about 5 x 1012 kilograms per year.[13] Other natural sources of CO include volcanoes, forest fires, and other forms of combustion. In biology, carbon monoxide is naturally produced by the action of heme oxygenase 1 and 2 on the heme from hemoglobin breakdown. This process produces a certain amount of carboxyhemoglobin in normal persons, even if they do not breathe any carbon monoxide. Following the first report that carbon monoxide is a normal neurotransmitter in 1993,[][] as well as one of three gases that naturally modulate inflammatory responses in the body (the other two being nitric oxide and hydrogen sulfide), carbon monoxide has received a great deal of clinical attention as a biological regulator. In many tissues, all three gases are known to act as anti-inflammatories, vasodilators, and promoters of neovascular growth.[] Clinical trials of small amounts of carbon monoxide as a drug are ongoing.

142

History
Aristotle (384322 BC) first recorded that burning coals emanated toxic fumes. An ancient method of execution was to shut the criminal in a bathing room with smouldering coals. What was not known was the mechanism of death. Galen (129199 AD) speculated that there was a change in the composition of the air that caused harm when inhaled.[14] In 1776, the French chemist de Lassone produced CO by heating zinc oxide with coke, but mistakenly concluded that the gaseous product was hydrogen, as it burned with a blue flame. The gas was identified as a compound containing carbon and oxygen by the Scottish chemist William Cumberland Cruikshank in the year 1800. Its toxic properties on dogs were thoroughly investigated by Claude Bernard around 1846.[15] During World War II, a gas mixture including carbon monoxide was used to keep motor vehicles running in parts of the world where gasoline and diesel fuel were scarce. External (with a few exceptions) charcoal or wood gas generators were fitted, and the mixture of atmospheric nitrogen, carbon monoxide, and small amounts of other gases produced by gasification was piped to a gas mixer. The gas mixture produced by this process is known as wood gas. Carbon monoxide was also used on a small scale during the Holocaust at some Nazi extermination camps, the most notable by gas vans in Chelmno, and in the Action T4 "euthanasia" program.[16]

Molecular properties
Carbon monoxide has a molar mass of 28.0, which makes it slightly lighter than air, whose average molar mass is 28.8. According to the ideal gas law, CO is therefore less dense than air. Neither gas is "ideal", however, so neither exactly has the densities predicted by the ideal gas law. The bond length between the carbon atom and the oxygen atom is 112.8 pm.[][17] This bond length is consistent with a triple bond, as in molecular nitrogen (N2), which has a similar bond length and nearly the same molecular mass. Carbonoxygen double bonds are significantly longer, 120.8 pm in formaldehyde, for example.[18] The boiling point (82 K) and melting point (68 K) are very similar to those of N2 (77 K and 63 K, respectively). The bond dissociation energy of 1072 kJ/mol is stronger than that of N2 (942 kJ/mol) and represents the strongest chemical bond known.[19]

Carbon monoxide The ground electronic state of carbon monoxide is a singlet state[20] since there are no unpaired electrons.

143

Bonding and dipole moment

Carbon and oxygen together have a total of 10 valence electrons in carbon monoxide. To satisfy the octet rule for the carbon, the two atoms form a triple bond, with six shared electrons in three bonding molecular orbitals, rather than the usual double bond found in organic carbonyl compounds. Since four of the shared electrons come from the oxygen atom and only two from carbon, one bonding orbital is occupied by two electrons from oxygen, forming a dative or dipolar bond. This causes a C O polarization of the molecule, with a small negative charge on carbon and a small positive charge on oxygen. The other two bonding orbitals are each occupied by one electron from carbon and one from oxygen, forming (polar) covalent bonds with a reverse C O polarization, since oxygen is more electronegative than carbon. In the free carbon monoxide, a net negative charge - remains at the carbon end and the molecule has a small dipole moment of 0.122 D.[21] The molecule is therefore asymmetric: oxygen has more electron density than carbon, and is also slightly positively charged compared to carbon being negative. By contrast, the isoelectronic dinitrogen molecule has no dipole moment. If carbon monoxide acts as a ligand, the polarity of the dipole may reverse with a net negative charge on the oxygen end, depending on the structure of the coordination complex.[22] See also the section "Coordination chemistry" below.

Bond polarity and oxidation state

Theoretical and experimental studies show that, despite the greater electronegativity of oxygen, the dipole moment points from the more-negative carbon end to the more-positive oxygen end.[23][24] The three bonds are in fact polar covalent bonds that are strongly polarized. The calculated polarization toward the oxygen atom is 71% for the -bond and 77% for both -bonds.[] The oxidation state of carbon in carbon monoxide is +2 in each of these structures. It is calculated by counting all the bonding electrons as belonging to the more electronegative oxygen. Only the two non-bonding electrons on carbon are assigned to carbon. In this count, carbon then has only two valence electrons in the molecule compared to four in the free atom.

Biological and physiological properties

Toxicity
Carbon monoxide poisoning is the most common type of fatal air poisoning in many countries.[] Carbon monoxide is colourless, odorless, and tasteless, but highly toxic. It combines with hemoglobin to produce carboxyhemoglobin, which usurps the space in hemoglobin that normally carries oxygen, but is ineffective for delivering oxygen to bodily tissues. Concentrations as low as 667 ppm may cause up to 50% of the body's hemoglobin to convert to carboxyhemoglobin.[25] A level of 50% carboxyhemoglobin may result in seizure, coma, and fatality. In the United States, the OSHA limits long-term workplace exposure levels above 50 ppm.[26] Within short time scales, carbon monoxide absorption is cumulative, since the half-life is about 5 h in fresh air (see main article). The most common symptoms of carbon monoxide poisoning may resemble other types of poisonings and infections, including symptoms such as headache, nausea, vomiting, dizziness, fatigue, and a feeling of weakness. Affected families often believe they are victims of food poisoning. Infants may be irritable and feed poorly. Neurological signs include confusion, disorientation, visual disturbance, syncope and seizures.[] Some descriptions of carbon monoxide poisoning include retinal hemorrhages, and an abnormal cherry-red blood hue.[27] In most clinical diagnoses these signs are seldom noticed.[] One difficulty with the usefulness of this

Carbon monoxide cherry-red effect is that it corrects, or masks, what would otherwise be an unhealthy appearance, since the chief effect of removing deoxygenated hemoglobin is to make an asphyxiated person appear more normal, or a dead person appear more lifelike, similar to the effect of red colorants in embalming fluid. The "false" or unphysiologic red-coloring effect in anoxic CO-poisoned tissue is related to the meat-coloring commercial use of carbon monoxide, discussed below. Carbon monoxide also binds to other molecules such as myoglobin and mitochondrial cytochrome oxidase. Exposures to carbon monoxide may cause significant damage to the heart and central nervous system, especially to the globus pallidus,[28] often with long-term sequelae. Carbon monoxide may have severe adverse effects on the fetus of a pregnant woman.[29]

144

Normal human physiology

Carbon monoxide is produced naturally by the human body as a signaling molecule. Thus, carbon monoxide may have a physiological role in the body, such as a neurotransmitter or a blood vessel relaxant.[] Because of carbon monoxide's role in the body, abnormalities in its metabolism have been linked to a variety of diseases, including neurodegenerations, hypertension, heart failure, and inflammation.[]

Microbiology
Carbon monoxide is a nutrient for methanogenic bacteria,[30] a building-block for acetylcoenzyme A. This is the theme for the emerging field of bioorganometallic chemistry. Extremophile micro-organisms can, thus, metabolise carbon monoxide in such locations as the thermal vents of volcanoes.[31] In bacteria, carbon monoxide is produced via the reduction of carbon dioxide by the enzyme carbon monoxide dehydrogenase, an Fe-Ni-S-containing protein.[32] CooA is a carbon monoxide sensor protein.[33] The scope of its biological role is still unknown; it may be part of a signaling pathway in bacteria and archaea. Its occurrence in mammals is not established.

Occurrence
Carbon monoxide occurs in various natural and artificial environments. Typical concentrations in parts per million are as follows:

Composition of dry atmosphere, by volume[34]

ppmv: parts per million by volume (note: volume fraction is equal to mole fraction for ideal gas only, see volume (thermodynamics))
Concentration 0.1 ppmv 0.55 ppmv 515 ppmv 17 ppmv 100200 ppmv 700 ppmv 5,000 ppmv 7,000 ppmv Source Natural atmosphere level (MOPITT) [] Average level in homes Near-properly adjusted gas stoves in homes, modern vehicle exhaust emissions Atmosphere of Venus [36] Exhaust from automobiles in the Mexico City central area Atmosphere of Mars Exhaust from a home wood fire [] [] [] [35]

Undiluted warm car exhaust without a catalytic converter

Carbon monoxide

145

Atmospheric presence
Carbon monoxide is present in small amounts in the atmosphere, chiefly as a product of volcanic activity but also from natural and man-made fires (such as forest and bushfires, burning of crop residues, and sugarcane fire-cleaning). The burning of fossil fuels also contributes to carbon monoxide production. Carbon monoxide occurs dissolved in molten volcanic rock at high pressures in the Earth's mantle.[37] Because natural sources of carbon monoxide are so variable from year to year, it is extremely difficult to accurately measure natural emissions of the gas. Carbon monoxide has an indirect radiative forcing effect by elevating concentrations of methane and tropospheric ozone through chemical reactions with other atmospheric constituents (e.g., the hydroxyl radical, OH.) that would otherwise destroy them.[38] Through natural processes in the atmosphere, it is eventually oxidized to carbon dioxide. Carbon monoxide concentrations are both short-lived in the atmosphere and spatially variable.

The streak of red, orange, and yellow across South America, Africa, and the Atlantic Ocean in this animation points to high levels of carbon monoxide on September 30, 2005.

Carbon Monoxide concentrations in Northern Hemisphere spring as measured with the MOPITT instrument.

In the atmosphere of Venus carbon monoxide occurs as a result of the photodissociation of carbon dioxide by electromagnetic radiation of wavelengths shorter than 169 nm.

Urban pollution
Carbon monoxide is a temporary atmospheric pollutant in some urban areas, chiefly from the exhaust of internal combustion engines (including vehicles, portable and back-up generators, lawn mowers, power washers, etc.), but also from incomplete combustion of various other fuels (including wood, coal, charcoal, oil, paraffin, propane, natural gas, and trash). Role in ground-level ozone formation Carbon monoxide is, along with aldehydes, part of the series of cycles of chemical reactions that form photochemical smog. It reacts with hydroxyl radical (OH) to produce a radical intermediate HOCO, which transfers rapidly its radical hydrogen to O2 to form peroxy radical (HO2) and carbon dioxide (CO2).[39] Peroxy radical subsequently reacts with nitrogen oxide (NO) to form nitrogen dioxide (NO2) and hydroxyl radical. NO2 gives O(3P) via photolysis, thereby forming O3 following reaction with O2. Since hydroxyl radical is formed during the formation of NO2, the balance of the sequence of chemical reactions starting with carbon monoxide and leading to the formation of ozone is: CO + 2O2 + h CO2 + O3 (where h refers to the photon of light absorbed by the NO2 molecule in the sequence)

Carbon monoxide Although the creation of NO2 is the critical step leading to low level ozone formation, it also increases this ozone in another, somewhat mutually exclusive way, by reducing the quantity of NO that is available to react with ozone.[]

146

Indoor pollution
In closed environments, the concentration of carbon monoxide can easily rise to lethal levels. On average, 170 people in the United States die every year from carbon monoxide produced by non-automotive consumer products.[40] However, according to the Florida Department of Health, "every year more than 500 Americans die from accidental exposure to carbon monoxide and thousands more across the U.S. require emergency medical care for non-fatal carbon monoxide poisoning"[] These products include malfunctioning fuel-burning appliances such as furnaces, ranges, water heaters, and gas and kerosene room heaters; engine-powered equipment such as portable generators; fireplaces; and charcoal that is burned in homes and other enclosed areas. The American Association of Poison Control Centers (AAPCC) reported 15,769 cases of carbon monoxide poisoning resulting in 39 deaths in 2007.[41] In 2005, the CPSC reported 94 generator-related carbon monoxide poisoning deaths.[40] Forty-seven of these deaths were known to have occurred during power outages due to severe weather, including Hurricane Katrina.[40] Still others die from carbon monoxide produced by non-consumer products, such as cars left running in attached garages. The Centers for Disease Control and Prevention estimates that several thousand people go to hospital emergency rooms every year to be treated for carbon monoxide poisoning.[42]

Blood presence
Carbon monoxide is absorbed through breathing and enters the blood stream through gas exchange in the lungs. Normal circulating levels in the blood are 0% to 3%, and are higher in smokers. Carbon monoxide levels cannot be assessed through a physical exam. Laboratory testing requires a blood sample (arterial or venous) and laboratory analysis on a CO-Oximeter. Additionally, a noninvasive carboxyhemoglobin (SpCO) test method from Pulse CO-Oximetry exists and has been validated compared to invasive methods.[43]

Astrophysics
Outside of Earth, carbon monoxide is the second-most common molecule in the interstellar medium, after molecular hydrogen. Because of its asymmetry, the carbon monoxide molecule produces far brighter spectral lines than the hydrogen molecule, making CO much easier to detect. Interstellar CO was first detected with radio telescopes in 1970. It is now the most commonly used tracer of molecular gas in general in the interstellar medium of galaxies, as molecular hydrogen can only be detected using ultraviolet light, which requires space telescopes. Carbon monoxide observations provide much of the information about the molecular clouds in which most stars form.[44]

Production
Many methods have been developed for carbon monoxide's production.[45]

Industrial production
A major industrial source of CO is producer gas, a mixture containing mostly carbon monoxide and nitrogen, formed by combustion of carbon in air at high temperature when there is an excess of carbon. In an oven, air is passed through a bed of coke. The initially produced CO2 equilibrates with the remaining hot carbon to give CO. The reaction of CO2 with carbon to give CO is described as the Boudouard reaction.[46] Above 800 C, CO is the predominant product: CO2 + C 2 CO (H = 221 kJ/mol) Another source is "water gas", a mixture of hydrogen and carbon monoxide produced via the endothermic reaction of steam and carbon:

Carbon monoxide H2O + C H2 + CO (H = +131 kJ/mol) Other similar "synthesis gases" can be obtained from natural gas and other fuels. Carbon monoxide is also a byproduct of the reduction of metal oxide ores with carbon, shown in a simplified form as follows: MO + C M + CO Since CO is a gas, the reduction process can be driven by heating, exploiting the positive (favorable) entropy of reaction. The Ellingham diagram shows that CO formation is favored over CO2 in high temperatures.

147

Laboratory preparation
Carbon monoxide is conveniently produced in the laboratory by the dehydration of formic acid, for example with sulfuric acid.[][] Another method is heating an intimate mixture of powdered zinc metal and calcium carbonate, which releases CO and leaves behind zinc oxide and calcium oxide: Zn + CaCO3 ZnO + CaO + CO

Coordination chemistry
Most metals form coordination complexes containing covalently attached carbon monoxide. Only metals in lower oxidation states will complex with carbon monoxide ligands. This is because there must be sufficient electron density to facilitate back-donation from the metal dxz-orbital, to the *molecular orbital from CO. The lone pair on the carbon atom in CO, also donates electron density to the dxy on the metal to form a sigma bond. This electron donation is also exhibited with the cis effect, or the labilization of CO ligands in the cis position. In nickel carbonyl, Ni(CO)4 forms by the direct combination of carbon monoxide and nickel metal at room temperature. For this reason, nickel in any tubing or part must not come into prolonged contact with carbon monoxide (corrosion). Nickel carbonyl decomposes readily back to Ni and CO upon contact with hot surfaces, and this method is used for the industrial purification of nickel in the Mond process.[47] In nickel carbonyl and other carbonyls, the electron pair on the carbon interacts with the metal; the carbon monoxide donates the electron pair to the metal. In these situations, carbon monoxide is called the carbonyl ligand. One of the most important metal carbonyls is iron pentacarbonyl, Fe(CO)5:

The HOMO of CO is a MO.

The LUMO of CO is a *antibonding MO.

Many metal-CO complexes are prepared by decarbonylation of organic solvents, not from CO. For instance, iridium trichloride and triphenylphosphine react in boiling 2-methoxyethanol or DMF to afford IrCl(CO)(PPh3)2. Metal carbonyls in coordination chemistry are usually studied using infrared spectroscopy.

Carbon monoxide

148

Organic and main group chemistry

In the presence of strong acids and water, carbon monoxide reacts with alkenes to form carboxylic acids in a process known as the KochHaaf reaction.[] In the Gattermann-Koch reaction, arenes are converted to benzaldehyde derivatives in the presence of AlCl3 and HCl.[] Organolithium compounds (e.g. butyl lithium) react with carbon monoxide, but these reactions have little scientific use. Although CO reacts with carbocations and carbanions, it is relatively nonreactive toward organic compounds without the intervention of metal catalysts.[48] With main group reagents, CO undergoes several noteworthy reactions. Chlorination of CO is the industrial route to the important compound phosgene. With borane CO forms an adduct, H3BCO, which is isoelectronic with the acylium cation [H3CCO]+. CO reacts with sodium to give products resulting from C-C coupling such as sodium acetylenediolate 2Na+ C 2O2 2. It reacts with molten potassium to give a mixture of an organometallic compound, potassium acetylenediolate 2K+ C 2O2 2, potassium benzenehexolate 6K+ C 6O6 [49] 6, and potassium rhodizonate 2K+ C 6O2 [50] 6. The compounds cyclohexanehexone or triquinoyl (C6O6) and cyclopentanepentone or leuconic acid (C5O5), which so far have been obtained only in trace amounts, can be regarded as polymers of carbon monoxide. At pressures of over 5 gigapascals, carbon monoxide converts into a solid polymer of carbon and oxygen. This is metastable at atmospheric pressure but is a powerful explosive.[51][52]

Uses
Chemical industry
Carbon monoxide is an industrial gas that has many applications in bulk chemicals manufacturing.[53] Large quantities of aldehydes are produced by the hydroformylation reaction of alkenes, carbon monoxide, and H2. Hydroformylation is coupled to the Shell Higher Olefin Process to give precursors to detergents. Phosgene, useful for preparing isocyanates, polycarbonates, and polyurethanes, is produced by passing purified carbon monoxide and chlorine gas through a bed of porous activated carbon, which serves as a catalyst. World production of this compound was estimated to be 2.74 million tonnes in 1989.[11] CO + Cl2 COCl2 Methanol is produced by the hydrogenation of carbon monoxide. In a related reaction, the hydrogenation of carbon monoxide is coupled to C-C bond formation, as in the Fischer-Tropsch process where carbon monoxide is hydrogenated to liquid hydrocarbon fuels. This technology allows coal or biomass to be converted to diesel. In the Monsanto process, carbon monoxide and methanol react in the presence of a homogeneous rhodium catalyst and hydroiodic acid to give acetic acid. This process is responsible for most of the industrial production of acetic acid. An industrial scale use for pure carbon monoxide is purifying nickel in the Mond process.

Carbon monoxide

149

Meat coloring
Carbon monoxide is used in modified atmosphere packaging systems in the US, mainly with fresh meat products such as beef, pork, and fish to keep them looking fresh. The carbon monoxide combines with myoglobin to form carboxymyoglobin, a bright-cherry-red pigment. Carboxymyoglobin is more stable than the oxygenated form of myoglobin, oxymyoglobin, which can become oxidized to the brown pigment metmyoglobin. This stable red color can persist much longer than in normally packaged meat.[] Typical levels of carbon monoxide used in the facilities that use this process are between 0.4% to 0.5%. The technology was first given "generally recognized as safe" (GRAS) status by the U.S. Food and Drug Administration (FDA) in 2002 for use as a secondary packaging system, and does not require labeling. In 2004 the FDA approved CO as primary packaging method, declaring that CO does not mask spoilage odor.[] Despite this ruling, the process remains controversial for fears that it masks spoilage.[54] In 2007 a bill[55] was introduced to the United States House of Representatives to label modified atmosphere carbon monoxide packaging as a color additive, but the bill died in subcommittee. The process is banned in many other countries, including Japan, Singapore, and the European Union.[56][57][58]

Medicine
In biology, carbon monoxide is naturally produced by the action of heme oxygenase 1 and 2 on the heme from hemoglobin breakdown. This process produces a certain amount of carboxyhemoglobin in normal persons, even if they do not breathe any carbon monoxide. Following the first report that carbon monoxide is a normal neurotransmitter in 1993,[][] as well as one of three gases that naturally modulate inflammatory responses in the body (the other two being nitric oxide and hydrogen sulfide), carbon monoxide has received a great deal of clinical attention as a biological regulator. In many tissues, all three gases are known to act as anti-inflammatories, vasodilators, and encouragers of neovascular growth.[] However, the issues are complex, as neovascular growth is not always beneficial, since it plays a role in tumor growth, and also the damage from wet macular degeneration, a disease for which smoking (a major source of carbon monoxide in the blood, several times more than natural production) increases the risk from 4 to 6 times. There is a theory that, in some nerve cell synapses, when long-term memories are being laid down, the receiving cell makes carbon monoxide, which back-transmits to the transmitting cell, telling it to transmit more readily in future. Some such nerve cells have been shown to contain guanylate cyclase, an enzyme that is activated by carbon monoxide.[] Studies involving carbon monoxide have been conducted in many laboratories throughout the world for its anti-inflammatory and cytoprotective properties. These properties have potential to be used to prevent the development of a series of pathological conditions including ischemia reperfusion injury, transplant rejection, atherosclerosis, severe sepsis, severe malaria, or autoimmunity. Clinical tests involving humans have been performed, however the results have not yet been released.[59]

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References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=630-08-0 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=281 [3] http:/ / www. chemspider. com/ 275 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=7U1EE4V452 [5] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=211-128-3 [6] http:/ / www. kegg. jp/ entry/ D09706 [7] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Carbon+ monoxide [8] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=17245 [9] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=%5BC-%5D%23%5BO%2B%5D [10] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477004453& page2=Carbon+ monoxide [11] Thompson, Mike. Carbon Monoxide Molecule of the Month (http:/ / www. chm. bris. ac. uk/ motm/ co/ coh. htm), Winchester College, UK. [14] David G. Penney, Carbon Monoxide Toxicity (http:/ / books. google. co. uk/ books?id=XsnPIfP0oBcC& pg=PA5#v=onepage& q& f=true), p.5, CRC Press, 2000 ISBN 0-8493-2065-8. [19] Common Bond Energies (D) and Bond Lengths (r) (http:/ / www. wiredchemist. com/ chemistry/ data/ bond_energies_lengths. html). wiredchemist.com [31] C.Michael Hogan. 2010. Extremophile (http:/ / www. eoearth. org/ article/ Extremophile?topic=49540). eds. E. Monosson and C. Cleveland. Encyclopedia of Earth. National Council for Science and the Environment, Washington, DC [34] Source for figures: Carbon dioxide, NOAA Earth System Research Laboratory (http:/ / www. esrl. noaa. gov/ gmd/ ccgg/ trends/ #mlo), (updated 2010.06). Methane, IPCC TAR table 6.1 (http:/ / www. grida. no/ climate/ ipcc_tar/ wg1/ 221. htm#tab61), (updated to 1998). The NASA total was 17 ppmv over 100%, and CO2 was increased here by 15 ppmv. To normalize, N2 should be reduced by about 25 ppmv and O2 by about 7 ppmv. [40] U.S Consumer Product Safety Commission, Carbon Monoxide Questions and Answers (http:/ / www. cpsc. gov/ cpscpub/ pubs/ 466. html), accessed 2009-12-04 [41] "AAPCC Annual Data Reports 2007" (http:/ / www. aapcc. org/ dnn/ NPDSPoisonData/ AnnualReports/ tabid/ 125/ Default. aspx). American Association of Poison Control Centers. [42] Centers for Disease Control and Prevention, National Environmental Public Health Tracking Network, Carbon Monoxide Poisoning (http:/ / ephtracking. cdc. gov/ showCarbonMonoxideLanding. action), accessed 2009-12-04 [43] Roth D., Herkner H., Schreiber W., Hubmann N., Gamper G., Laggner A.N., Havel C. "Accuracy of Noninvasive Multiwave Pulse Oximetry Compared With Carboxyhemoglobin From Blood Gas Analysis in Unselected Emergency Department Patients" Ann Emerg Med. 2011 Jul;58(1):749. [45] Holleman, A. F.; Wiberg, E. "Inorganic Chemistry" Academic Press: San Diego, 200. ISBN 0-12-352651-5. [48] Chatani, N.; Murai, S. "Carbon Monoxide" in Encyclopedia of Reagents for Organic Synthesis (Ed: L. Paquette) 2004, J. Wiley & Sons, New York.

External links
Explanation of the structure (http://courses.chem.psu.edu/chem210/mol-gallery/co/co.html) Carbon Monoxide Safety Association (http://www.cosafety.org) International Chemical Safety Card 0023 (http://www.inchem.org/documents/icsc/icsc/eics0023.htm) National Pollutant Inventory Carbon Monoxide (http://www.npi.gov.au/database/substance-info/profiles/ 19.html) NIOSH Pocket Guide to Chemical Hazards (http://www.cdc.gov/niosh/npg/npgd0105.html) CDC Carbon Monoxide NIOSH Workplace Safety and Health Topic (http://www.cdc.gov/niosh/topics/ co-comp/) CID 281 (http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=281) from PubChem External MSDS data sheet (http://physchem.ox.ac.uk/MSDS/CA/carbon_monoxide.html) Carbon Monoxide Detector Placement (http://www.homesafe.com/coalert/detect.htm) Carbon Monoxide Kills Awareness Campaign Site (http://www.carbonmonoxidekills.com) Carbon Monoxide Purification Process (http://www.rccostello.com/copure.html) Carbon Monoxide Hazards with Backpacking Stoves (http://zenstoves.net/COHazard.htm)

USFDA IMPORT BULLETIN 16B-95, May 1999 (http://seafood.ucdavis.edu/Guidelines/fdabulletin16b. htm)

Carbon monoxide FDA Agency Response Letter GRAS Notice No. GRN 000083 (http://www.cfsan.fda.gov/~rdb/opa-g083. html) Microscale Gas Chemistry Experiments with Carbon Monoxide (http://mattson.creighton.edu/CO/index.html) Instant insight (http://www.rsc.org/Publishing/Journals/cb/Volume/2007/11/Dont_blame_the_messenger. asp) outlining the physiology of carbon monoxide from the Royal Society of Chemistry Pictures of CO Poisoning (http://rad.usuhs.mil/medpix/medpix_cow.html?mode=quiz&pt_id=10478& quiz=yes#top) Radiology and Pathology Images from MedPix.

151

Hydrogen sulfide

152

Hydrogen sulfide
Hydrogen sulfide

Identifiers CAS number PubChem ChemSpider UNII EC number UN number KEGG MeSH ChEBI ChEMBL RTECS number Beilstein Reference Gmelin Reference 3DMet Jmol-3D images 7783-06-4 402 391
[2] [3] [4] [1]

YY9FVM7NSN 231-977-3 1053 C00283

[6] [5]

Hydrogen+sulfide CHEBI:16136
[8]

[7]

CHEMBL1200739 MX1225000 3535004 303 B01206 Image 1 Properties

[10] [11]

[9]

Molecular formula Molar mass Appearance Odor Density Melting point

HS
2

34.08 g mol1 Colorless gas faint rotten egg 1.363 g dm-3 -82C, 191K, -116F

Hydrogen sulfide

153
Boiling point Solubility in water Vapor pressure Acidity (pKa) Basicity (pKb) Refractive index (nD) -60C, 213K, -76F 4 g dm-3 (at 20 C) 1740 kPa (at 21 C) 7.0
[12]

6.95 1.000644 (0 C) Structure

[13]

Molecular shape Dipole moment

Bent 0.97 D Thermochemistry

Std enthalpy of o formation fH 298 Standard molar o entropy S 298 Specific heat capacity, C

21kJmol

1[]

206Jmol K

1[]

1.003 J K g Hazards

-1 -1

EU Index EU classification

016-001-00-4

F+ R-phrases S-phrases NFPA 704 R12, R26, R50

T+

(S1/2), S9, S16, S36, S38, S45, S61

Flash point Autoignition temperature Explosive limits

-82.4 C. 232 C 4.346%

[14]

Related compounds Related hydrogen chalcogenides Water Hydrogen selenide Hydrogen telluride Hydrogen polonide Hydrogen disulfide Sulfanyl Phosphine
(verify) [15]

Related compounds

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Hydrogen sulfide Hydrogen sulfide (British English: hydrogen sulphide, but this spelling is not recommended by the International Union of Pure and Applied Chemistry nor the Royal Society of Chemistry) is the chemical compound with the formula H 2S. It is a colorless gas with the characteristic foul odor of rotten eggs; it is heavier than air, very poisonous, corrosive, flammable and explosive. Hydrogen sulfide often results from the bacterial breakdown of organic matter in the absence of oxygen, such as in swamps and sewers; this process is commonly known as anaerobic digestion. H 2S also occurs in volcanic gases, natural gas, and some well waters. The human body produces small amounts of H 2S and uses it as a signaling molecule. Dissolved in water, hydrogen sulfide is known as hydrosulfuric acid or sulfhydric acid, a weak acid.

154

Properties
Hydrogen sulfide is slightly heavier than air; a mixture of H 2S and air is explosive. Hydrogen sulfide and oxygen burn with a blue flame to form sulfur dioxide (SO 2) and water. In general, hydrogen sulfide acts as a reducing agent. At high temperature or in the presence of catalysts, sulfur dioxide can be made to react with hydrogen sulfide to form elemental sulfur and water. This is exploited in the Claus process, the main way to convert hydrogen sulfide into elemental sulfur. Hydrogen sulfide is slightly soluble in water and acts as a weak acid, giving the hydrosulfide ion HS (pKa = 6.9 in 0.01-0.1mol/litre solutions at 18 C). A solution of hydrogen sulfide in water, known as sulfhydric acid or hydrosulfuric acid, is initially clear but over time turns cloudy. This is due to the slow reaction of hydrogen sulfide with the oxygen dissolved in water, yielding elemental sulfur, which precipitates out. The sulfide dianion S2 exists only in strongly alkaline aqueous solutions; it is exceptionally basic with a pKa > 14. Hydrogen sulfide reacts with metal ions to form metal sulfides, which may be considered the salts of hydrogen sulfide. Some ores are sulfides. Metal sulfides often have a dark color. Lead(II) acetate paper is used to detect hydrogen sulfide because it turns grey in the presence of the gas as lead(II) sulfide is produced. Reacting metal sulfides with strong acid liberates hydrogen sulfide. If gaseous hydrogen sulfide is put into contact with concentrated nitric acid, it explodes. Hydrogen sulfide reacts with alcohols to form thiols, an important class of organosulfur compounds.

Production
Hydrogen sulfide is most commonly obtained by its separation from sour gas, which is natural gas with high content of H 2S. It can also be produced by reacting hydrogen gas with molten elemental sulfur at about 450 C. Hydrocarbons can replace hydrogen in this process.[16] Sulfate-reducing (resp. sulfur-reducing) bacteria generate usable energy under low-oxygen conditions by using sulfates (resp. elemental sulfur) to oxidize organic compounds or hydrogen; this produces hydrogen sulfide as a waste product. The standard lab preparation is to react ferrous sulfide (FeS) with a strong acid in a Kipp generator: FeS + 2 HCl FeCl2 + H2S A less well-known and more convenient alternative is to react aluminium sulfide with water: 6 H2O + Al2S3 3 H2S + 2 Al(OH)3 This gas is also produced by heating sulfur with solid organic compounds and by reducing sulfurated organic compounds with hydrogen.

Hydrogen sulfide Hydrogen sulfide is also a byproduct of some reactions and caution should be taken when production is likely as exposure can be fatal. Hydrogen sulfide production can be costly because of the dangers involved in production.

155

Occurrence
Small amounts of hydrogen sulfide occur in crude petroleum, but natural gas can contain up to 90%. Volcanoes and some hot springs (as well as cold springs) emit some H 2S, where it probably arises via the hydrolysis of sulfide minerals, i.e. MS + H 2O MO + H [citation needed] 2S. Hydrogen sulfide can be present naturally in well water, often as a result of the action of sulfate-reducing bacteria. About 10% of total global emissions of H Deposit of sulfur on a rock, caused by volcanic [citation needed] 2S is due to human activity. By far the largest industrial gases route to H 2S occurs in petroleum refineries: The hydrodesulfurization process liberates sulfur from petroleum by the action of hydrogen. The resulting H 2S is converted to elemental sulfur by partial combustion via the Claus process, which is a major source of elemental sulfur. Other anthropogenic sources of hydrogen sulfide include coke ovens, paper mills (using the sulfate method), and tanneries. H 2S arises from virtually anywhere where elemental sulfur comes in contact with organic material, especially at high temperatures.

Uses
Production of thioorganic compounds
Several organosulfur compounds are produced using hydrogen sulfide. These include methanethiol, ethanethiol, and thioglycolic acid.

Alkali metal sulfides

Upon combining with alkali metal bases, hydrogen sulfide converts to alkali hydrosulfides such as sodium hydrosulfide and sodium sulfide, which are used in the degradation of biopolymers. The depilation of hides and the delignification of pulp by the Kraft process both are effected by alkali sulfides.

Analytical chemistry
For well over a century, hydrogen sulfide was important in analytical chemistry, in the qualitative inorganic analysis of metal ions. In these analyses, heavy metal (and nonmetal) ions (e.g., Pb(II), Cu(II), Hg(II), As(III)) are precipitated from solution upon exposure to H 2S. The components of the resulting precipitate redissolve with some selectivity. For small-scale laboratory use in analytic chemistry, the use of thioacetamide has superseded H 2S as a source of sulfide ions.

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156

Precursor to metal sulfides

As indicated above, many metal ions react with hydrogen sulfide to give the corresponding metal sulfides. This conversion is widely exploited. For example, gases or waters contaminated by hydrogen sulfide can be cleaned with metal sulfides. In the purification of metal ores by flotation, mineral powders are often treated with hydrogen sulfide to enhance the separation. Metal parts are sometimes passivated with hydrogen sulfide. Catalysts used in hydrodesulfurization are routinely activated with hydrogen sulfide, and the behavior of metallic catalysts used in other parts of a refinery is also modified using hydrogen sulfide.

Miscellaneous applications
Hydrogen sulfide is used to separate deuterium oxide, or heavy water, from normal water via the Girdler Sulfide process.

Removal from fuel gases

Hydrogen sulfide is commonly found in natural gas, biogas, and LPG. It can be removed in a number of ways. Reaction with iron oxide Gas is pumped through a container of hydrated iron(III) oxide, which combines with hydrogen sulfide. Fe 2O 3(s) + H 2O(l) + 3 H 2S(g) Fe 2S 3(s) + 4 H 2O(l) In order to regenerate iron(III) oxide, the container must be taken out of service, flooded with water and aerated. 2 Fe 2S 3(s) + 3 O 2(g) + 2 H 2O(l) 2 Fe 2O 3(s) + 2 H 2O(l) + 6 S(s) On completion of the regeneration reaction the container is drained of water and can be returned to service. The advantage of this system is that it is completely passive during the extraction phase.[17] Hydrodesulfurization Hydrodesulfurization is a more complex method of removing sulfur from fuels. Filtration through impregnated activated carbon A gas stream containing hydrogen sulfide can be purified by passing it through a suitably designed filter containing an impregnated activated carbon. This method is typically used for odor abatement at municipal sewage works and for the purification of landfill biogas, prior to its use in combined heat and power (CHP) engines, or injection into the gas grid.

Hydrogen sulfide

157

Safety
Hydrogen sulfide is a highly toxic and flammable gas (flammable range: 4.346%). Being heavier than air, it tends to accumulate at the bottom of poorly ventilated spaces. Although very pungent at first, it quickly deadens the sense of smell, so potential victims may be unaware of its presence until it is too late. For safe handling procedures, a hydrogen sulfide material safety data sheet (MSDS) should be consulted.[18]

Toxicity
Hydrogen sulfide is considered a broad-spectrum poison, meaning that it can poison several different systems in the body, although the nervous system is most affected. The toxicity of H [] 2S is comparable with that of hydrogen cyanide or carbon monoxide. It forms a complex bond with iron in the mitochondrial cytochrome enzymes, thus preventing cellular respiration. Since hydrogen sulfide occurs naturally in the body, the environment and the gut, enzymes exist in the body capable of detoxifying it by oxidation to (harmless) sulfate.[19] Hence, low levels of hydrogen sulfide may be tolerated indefinitely. At some threshold level, believed to average around 300350 ppm, the oxidative enzymes become overwhelmed. Many personal safety gas detectors, such as those used by utility, sewage and petrochemical workers, are set to alarm at as low as 5 to 10 ppm and to go into high alarm at 15 ppm. A diagnostic clue of extreme poisoning by H 2S is the discoloration of copper coins in the pockets of the victim. Treatment involves immediate inhalation of amyl nitrite, injections of sodium nitrite or administration of 4-dimethylaminophenol in combination with inhalation of pure oxygen, administration of bronchodilators to overcome eventual bronchospasm, and in some cases hyperbaric oxygen therapy (HBO).[] HBO therapy has anecdotal support and remains controversial.[20][21][22] Exposure to lower concentrations can result in eye irritation, a sore throat and cough, nausea, shortness of breath, and fluid in the lungs (pulmonary edema).[] These effects are believed to be due to the fact that hydrogen sulfide combines with alkali present in moist surface tissues to form sodium sulfide, a caustic.[23] These symptoms usually go away in a few weeks. Long-term, low-level exposure may result in fatigue, loss of appetite, headaches, irritability, poor memory, and dizziness. Chronic exposure to low level H 2S (around 2 ppm) has been implicated in increased miscarriage and reproductive health issues among Russian and Finnish wood pulp workers,[24] but the reports have not (as of circa 1995) been replicated. 0.00047 ppm or 0.47 ppb is the odor threshold, the point at which 50% of a human panel can detect the presence of the compound.[] 0.0047 ppm is the recognition threshold, the concentration at which 50% of humans can detect the characteristic odor of hydrogen sulfide,[] normally described as resembling "a rotten egg". OSHA has established a permissible exposure limit (PEL) (8 hour time-weighted average (TWA)) of 10 ppm.[] 1020 ppm is the borderline concentration for eye irritation. 20 ppm is the acceptable ceiling concentration established by OSHA.[] 50 ppm is the acceptable maximum peak above the ceiling concentration for an 8 hour shift, with a maximum duration of 10 minutes.[] 50100 ppm leads to eye damage. At 100150 ppm the olfactory nerve is paralyzed after a few inhalations, and the sense of smell disappears, often together with awareness of danger.[25][26] 320530 ppm leads to pulmonary edema with the possibility of death.[] 5301000 ppm causes strong stimulation of the central nervous system and rapid breathing, leading to loss of breathing.

Hydrogen sulfide 800 ppm is the lethal concentration for 50% of humans for 5 minutes exposure (LC50). Concentrations over 1000 ppm cause immediate collapse with loss of breathing, even after inhalation of a single breath.[] Although respiratory paralysis may be immediate, it can also be delayed up to 72 hours.[27]

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Incidents
Hydrogen sulfide was used by the British Army as a chemical weapon during World War I. It was not considered to be an ideal war gas, but, while other gases were in short supply, it was used on two occasions in 1916.[28] In 1975, a hydrogen sulfide release from an oil drilling operation in Denver City, Texas killed nine people and caused the state legislature to focus on the deadly hazards of the gas. State Representative E L Short took the lead in endorsing an investigation by the Texas Railroad Commission and urged that residents be warned "by knocking on doors if necessary" of the imminent danger stemming from the gas. One may die from the second inhalation of the gas, and a warning itself may be too late.[29] A dump of toxic waste containing hydrogen sulfide is believed to have caused 17 deaths and thousands of illnesses in Abidjan, on the West Africa coast, in the 2006 Cte d'Ivoire toxic waste dump. Three members of one family were killed in a slurry tank in Northern Ireland in September 2012 after one member entered the tank in an attempt to rescue a dog. He was quickly rendered unconscious by the gas (and other toxic gasses), at which point his younger brother entered the tank in an effort to rescue him. He too succumbed to the fumes, and in an attempt to save both sons, the father then entered the tank, and also perished.[30]

Suicides
The gas, produced by mixing certain household ingredients, was used in a suicide wave in 2008 in Japan.[31] The wave prompted staff at Tokyo's suicide prevention center to set up a special hot line during "Golden Week", as they received an increase in calls from people wanting to kill themselves during the annual May holiday.[32] As of 2010, this phenomenon has occurred in a number of US cities, prompting warnings to those arriving at the site of the suicide.[33] These first responders, such as emergency services workers or family members are at risk of death from inhaling lethal quantities of the gas, or by fire.[34][35] Local governments have also initiated campaigns to prevent such suicides.

Function in the body

Hydrogen sulfide is produced in small amounts by some cells of the mammalian body and has a number of biological signaling functions. (Only two other such gases are currently known: nitric oxide (NO) and carbon monoxide (CO).) The gas is produced from cysteine by the enzymes cystathionine beta-synthase and cystathionine gamma-lyase. It acts as a relaxant of smooth muscle and as a vasodilator[] and is also active in the brain, where it increases the response of the NMDA receptor and facilitates long term potentiation,[36] which is involved in the formation of memory. Eventually the gas is converted to sulfite in the mitochondria by thiosulfate reductase, and the sulfite is further oxidized to thiosulfate and sulfate by sulfite oxidase. The sulfates are excreted in the urine.[] Due to its effects similar to nitric oxide (without its potential to form peroxides by interacting with superoxide), hydrogen sulfide is now recognized as potentially protecting against cardiovascular disease.[] The cardioprotective role effect of garlic is caused by catabolism of the polysulfide group in allicin to H [37] 2S, a reaction that could depend on reduction mediated by glutathione.

Hydrogen sulfide Though both nitric oxide (NO) and hydrogen sulfide have been shown to relax blood vessels, their mechanisms of action are different: while NO activates the enzyme guanylyl cyclase, H 2S activates ATP-sensitive potassium channels in smooth muscle cells. Researchers are not clear how the vessel-relaxing responsibilities are shared between nitric oxide and hydrogen sulfide. However there exists some evidence to suggest that nitric oxide does most of the vessel-relaxing work in large vessels and hydrogen sulfide is responsible for similar action in smaller blood vessels.[38] Recent findings suggest strong cellular crosstalk of NO and H2S,[39] demonstrating that the vasodilatatory effects of these two gases are mutually dependent. Additionally, H2S reacts with intracellular S-nitrosothiols to form the smallest S-nitrosothiol (HSNO), and a role of hydrogen sulfide in controlling the intracellular S-nitrosothiol pool has been suggested.[40] Like nitric oxide, hydrogen sulfide is involved in the relaxation of smooth muscle that causes erection of the penis, presenting possible new therapy opportunities for erectile dysfunction.[41][42] In Alzheimer's disease the brain's hydrogen sulfide concentration is severely decreased.[43] In a certain rat model of Parkinson's disease, the brain's hydrogen sulfide concentration was found to be reduced, and administering hydrogen sulfide alleviated the condition.[44] In trisomy 21 (Down syndrome) the body produces an excess of hydrogen sulfide.[] Hydrogen sulfide is also involved in the disease process of type 1 diabetes. The beta cells of the pancreas in type 1 diabetes produce an excess of the gas, leading to the death of these cells and to a reduced production of insulin by those that remain.[38]

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Induced hypothermia and suspended animation

In 2005, it was shown that mice can be put into a state of suspended animation-like hypothermia by applying a low dosage of hydrogen sulfide (81 ppm H 2S) in the air. The breathing rate of the animals sank from 120 to 10 breaths per minute and their temperature fell from 37 C to just 2 C above ambient temperature (in effect, they had become cold-blooded). The mice survived this procedure for 6 hours and afterwards showed no negative health consequences.[45] In 2006 it was shown that the blood pressure of mice treated in this fashion with hydrogen sulfide did not significantly decrease.[46] A similar process known as hibernation occurs naturally in many mammals and also in toads, but not in mice. (Mice can fall into a state called clinical torpor when food shortage occurs). If the H 2S-induced hibernation can be made to work in humans, it could be useful in the emergency management of severely injured patients, and in the conservation of donated organs. In 2008, hypothermia induced by hydrogen sulfide for 48 hours was shown to reduce the extent of brain damage caused by experimental stroke in rats.[] As mentioned above, hydrogen sulfide binds to cytochrome oxidase and thereby prevents oxygen from binding, which leads to the dramatic slowdown of metabolism. Animals and humans naturally produce some hydrogen sulfide in their body; researchers have proposed that the gas is used to regulate metabolic activity and body temperature, which would explain the above findings.[47] Two recent studies cast doubt that the effect can be achieved in larger mammals. A 2008 study failed to reproduce the effect in pigs, concluding that the effects seen in mice were not present in larger mammals.[48] Likewise a paper by Haouzi et al. noted that there is no induction of hypometabolism in sheep, either.[] At the February 2010 TED conference, Mark Roth announced that hydrogen sulfide induced hypothermia had completed Phase I clinical trials.[49] The clinical trials commissioned by the company he helped found, Ikaria, were however withdrawn or terminated by August 2011.[50][51]

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Participant in the sulfur cycle

Hydrogen sulfide is a central participant in the sulfur cycle, the biogeochemical cycle of sulfur on Earth. In the absence of oxygen, sulfur-reducing and sulfate-reducing bacteria derive energy from oxidizing hydrogen or organic molecules by reducing elemental sulfur or sulfate to hydrogen sulfide. Other bacteria liberate hydrogen sulfide from sulfur-containing amino acids; this gives rise to the odor of rotten eggs and contributes to the odor of flatulence. As organic matter decays under low-oxygen (or hypoxic) conditions (such as in swamps, eutrophic lakes or dead zones of oceans), sulfate-reducing bacteria will use the sulfates present in the water to oxidize the organic matter, producing hydrogen sulfide as waste. Some of the hydrogen sulfide will react with metal ions in the water to produce metal sulfides, which are not water soluble. These metal sulfides, such as ferrous sulfide FeS, are often black or brown, leading to the dark color of sludge. Several groups of bacteria can use hydrogen sulfide as fuel, oxidizing it to elemental sulfur or to sulfate by using dissolved oxygen, metal oxides (e.g., Fe oxyhydroxides and Mn oxides) or nitrate as oxidant.[52]
Sludge from a pond; the black color is due to metal sulfides

The purple sulfur bacteria and the green sulfur bacteria use hydrogen sulfide as electron donor in photosynthesis, thereby producing elemental sulfur. (In fact, this mode of photosynthesis is older than the mode of cyanobacteria, algae, and plants, which uses water as electron donor and liberates oxygen.)

Mass extinctions
Hydrogen sulfide has been implicated in several mass extinctions that have occurred in the Earth's past. In particular, a buildup of hydrogen sulfide in the atmosphere may have caused the Permian-Triassic extinction event 252 million years ago.[53] Organic residues from these extinction boundaries indicate that the oceans were anoxic (oxygen-depleted) and had species of shallow plankton that metabolized H 2S. The formation of H A hydrogen sulfide bloom (green) stretching for 2S may have been initiated by massive volcanic eruptions, which about 150km along the coast of Namibia. As emitted carbon dioxide and methane into the atmosphere, which oxygen-poor water reaches the coast, bacteria in the organic-matter rich sediment produce warmed the oceans, lowering their capacity to absorb oxygen that hydrogen sulfide which is toxic to fish. (The would otherwise oxidize H image is taken from a bird's eye view) 2S. The increased levels of hydrogen sulfide could have killed oxygen-generating plants as well as depleted the ozone layer, causing further stress. Small H 2S blooms have been detected in modern times in the Dead Sea and in the Atlantic ocean off the coast of Namibia.[53]

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References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=7783-06-4 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=402 [3] http:/ / www. chemspider. com/ 391 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=YY9FVM7NSN [5] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=231-977-3 [6] http:/ / www. kegg. jp/ entry/ C00283 [7] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Hydrogen+ sulfide [8] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=16136 [9] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL1200739 [10] http:/ / www. 3dmet. dna. affrc. go. jp/ html/ B01206. html [11] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=S [12] Perrin, D.D., Ionisation Constants of Inorganic Acids and Bases in Aqueous Solution, 2nd Ed., Pergamon Press: Oxford, 1982. [13] Pradyot Patnaik. Handbook of Inorganic Chemicals. McGraw-Hill, 2002, ISBN 0-07-049439-8 [14] Hydrogen sulfide: Overview (http:/ / www. npi. gov. au/ substances/ hydrogen-sulfide/ index. html), National Pollutant Inventory, Australia [15] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477313464& page2=Hydrogen+ sulfide [16] Jacques Tournier-Lasserve "Hydrogen Sulfide" in Ullmann's Encyclopedia of Chemical Industry [17] http:/ / www. marcabcoinc. com/ page2. html [23] Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996 [24] Hemminki K., Niemi M.L. (1982) Int. Arch. Occup. Environ. Health 51 (1): 55-63. [25] USEPA; Health and Environmental Effects Profile for Hydrogen Sulfide p.118-8 (1980) ECAO-CIN-026A [26] Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994, p.886 [27] http:/ / www. firerescue1. com/ fire-products/ hazmat-equipment/ articles/ 968922-The-chemical-suicide-phenomenon/ [32] http:/ / abcnews. go. com/ Health/ story?id=4908320& page=1 [33] See e.g. http:/ / info. publicintelligence. net/ LARTTAChydrogensulfide. pdf , http:/ / info. publicintelligence. net/ MAchemicalsuicide. pdf , http:/ / info. publicintelligence. net/ illinoisH2Ssuicide. pdf , http:/ / info. publicintelligence. net/ NYhydrogensulfide. pdf , http:/ / info. publicintelligence. net/ KCTEWhydrogensulfide. pdf [34] http:/ / www. dhmh. maryland. gov/ suicideprevention/ safety%20alert. pdf [35] http:/ / www. policemag. com/ Channel/ Patrol/ Articles/ Print/ Story/ 2011/ 04/ Duty-Dangers-Chemical-Suicides. aspx [38] " Toxic Gas, Lifesaver (http:/ / www. scientificamerican. com/ article. cfm?id=toxic-gas-lifesaver)", Scientific American, March 2010 [45] Mice put in 'suspended animation' (http:/ / news. bbc. co. uk/ go/ pr/ fr/ -/ 2/ hi/ science/ nature/ 4469793. stm), BBC News, 21 April 2005 [46] Gas induces 'suspended animation' (http:/ / news. bbc. co. uk/ 2/ hi/ science/ nature/ 4469793. stm), BBC News, 9 October 2006 [47] Mark B. Roth and Todd Nystul. Buying Time in Suspended Animation. Scientific American, 1 June 2005 [52] Jrgensen, B. B. & D. C. Nelson (2004) Sulfide oxidation in marine sediments: Geochemistry meets microbiology, pp. 3681. In J. P. Amend, K. J. Edwards, and T. W. Lyons (eds.) Sulfur Biogeochemistry - Past and Present. Geological Society of America. [53] "Impact From the Deep" (http:/ / www. sciam. com/ article. cfm?articleID=00037A5D-A938-150E-A93883414B7F0000& sc=I100322) in the October 2006 issue of Scientific American.

Additional resources
"Hydrogen Sulfide", Committee on Medical and Biological Effects of Environmental Pollutants, University Park Press, 1979, Baltimore. ISBN 0-8391-0127-9 Siefers, Andrea (2010). A novel and cost-effective hydrogen sulfide removal technology using tire derived rubber particles (http://lib.dr.iastate.edu/etd/11281/) (MS thesis). Iowa State University. Retrieved 8 February 2013.

External links
International Chemical Safety Card 0165 (http://www.inchem.org/documents/icsc/icsc/eics0165.htm) Concise International Chemical Assessment Document 53 (http://www.inchem.org/documents/cicads/cicads/ cicad53.htm) National Pollutant Inventory - Hydrogen sulfide fact sheet (http://www.npi.gov.au/database/substance-info/ profiles/49.html) NIOSH Pocket Guide to Chemical Hazards (http://www.cdc.gov/niosh/npg/npgd0337.html) NACE (National Association of Corrosion Epal) (http://www.nace.org/)

Nitric oxide

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Nitric oxide
Nitric oxide

Identifiers CAS number PubChem ChemSpider UNII EC number UN number DrugBank KEGG ChEBI ChEMBL RTECS number ATC code Gmelin Reference 3DMet Jmol-3D images 10102-43-9 145068 127983
[2] [3] [4] [1]

31C4KY9ESH 233-271-0 1660 DB00435 D00074

[6] [5]

[7]

CHEBI:16480

[8]

[9]

CHEMBL1200689 QX0525000 R07 AX01 451 B00122 Image 1 Properties

[11] [12] [10]

Molecular formula Molar mass Appearance Density Melting point Boiling point Solubility in water

NO 30.01 g mol1 Colourless gas 1.3402 g dm3 164C, 109K, -263F 152C, 121K, -242F 74 cm3 dm3

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Refractive index (nD) 1.0002697 Structure Molecular shape linear (point group Cv) Thermochemistry Std enthalpy of formation fHo298 Standard molar entropy So298 90.29 kJ mol1

210.76 J K1 mol1 Pharmacology

Bioavailability Routes of administration Metabolism Elimination half-life

good Inhalation via pulmonary capillary bed 26 seconds Hazards

MSDS EU classification

External MSDS

[13]

O R-phrases S-phrases NFPA 704

R8, R23, R34, R44 (S1), S17, S23, S36/37/39, S45

Related compounds Related nitrogen oxides Dinitrogen pentoxide Dinitrogen tetroxide Dinitrogen trioxide Nitrogen dioxide Nitrous oxide
(verify) [14]

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Nitric oxide, or nitrogen oxide,[15] also known as nitrogen monoxide, is a molecule with chemical formula NO. It is a free radical[16] and is an important intermediate in the chemical industry. Nitric oxide is a by-product of combustion of substances in the air, as in automobile engines, fossil fuel power plants, and is produced naturally during the electrical discharges of lightning in thunderstorms. In mammals including humans, NO is an important cellular signaling molecule involved in many physiological and pathological processes.[17] It is a powerful vasodilator with a short half-life of a few seconds in the blood. Long-known pharmaceuticals such as nitroglycerine and amyl nitrite were discovered, more than a century after their first use in medicine, to be active through the mechanism of being precursors to nitric oxide.

Nitric oxide Low levels of nitric oxide production are important in protecting organs such as the liver from ischemic damage. Nitric oxide should not be confused with nitrous oxide (N2O), an anaesthetic and greenhouse gas, or with nitrogen dioxide (NO2), a brown toxic gas and a major air pollutant, however, nitric oxide is rapidly oxidised in air to nitrogen dioxide. Humphry Davy discovered this to his discomfort, when he inhaled the gas early in his career. Despite being a simple molecule, NO is an important biological regulator and is a fundamental component in the fields of neuroscience, physiology, and immunology, with discovery of its key roles leading to Nobel Prize winning research in these areas. It was proclaimed Molecule of the Year in 1992.[]

164

Reactions
When exposed to oxygen, NO is converted into nitrogen dioxide. 2 NO + O2 2 NO2 This conversion has been speculated as occurring via the ONOONO intermediate. In water, NO reacts with oxygen and water to form HNO2 or nitrous acid. The reaction is thought to proceed via the following stoichiometry: 4 NO + O2 + 2 H2O 4 HNO2 NO will react with fluorine, chlorine, and bromine to form the XNO species, known as the nitrosyl halides, such as nitrosyl chloride. Nitrosyl iodide can form but is an extremely short-lived species and tends to reform I2. 2 NO + Cl2 2 NOCl Nitroxyl (HNO) is the reduced form of nitric oxide. Nitric oxide reacts with acetone and an alkoxide to a diazeniumdiolate or nitrosohydroxylamine and methyl acetate:[18]

This is a very old reaction (1898) but of interest today in NO prodrug research. Nitric oxide can also react directly with sodium methoxide, forming sodium formate and nitrous oxide.[19]

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Preparation
Commercially, NO is produced by the oxidation of ammonia at 750 C to 900 C (normally at 850 C) with platinum as catalyst: 4 NH3 + 5 O2 4 NO + 6 H2O The uncatalyzed endothermic reaction of O2 and N2, which is performed at high temperature (>2000 C) by lightning has not been developed into a practical commercial synthesis (see BirkelandEyde process): N2 + O2 2 NO In the laboratory, nitric oxide is conveniently generated by reduction of dilute nitric acid with copper: 8 HNO3 + 3 Cu 3 Cu(NO3)2 + 4 H2O + 2 NO or by the reduction of nitrous acid in the form of sodium nitrite or potassium nitrite: 2 NaNO2 + 2 NaI + 2 H2SO4 I2 + 4 NaHSO4 + 2 NO 2 NaNO2 + 2 FeSO4 + 3 H2SO4 Fe2(SO4)3 + 2 NaHSO4 + 2 H2O + 2 NO 3 KNO2 (l) + KNO3 (l) + Cr2O3(s) 2 K2CrO4(s) + 4 NO (g) The iron(II) sulfate route is simple and has been used in undergraduate laboratory experiments. So-called NONOate compounds are also used for NO generation.
Nitric oxide production.

Coordination chemistry
NO reacts with all transition metals to give complexes called metal nitrosyls. The most common bonding mode of NO is the terminal linear type (M-NO). The angle of the M-N-O group varies from 160 to 180 but is still termed "linear". In this case, the NO group is considered a 3-electron donor under the covalent (neutral) method of electron counting, or a 2-electron donor under the ionic method.[20] In the case of a bent M-N-O conformation, the NO group can be considered a one-electron donor using neutral counting, or a 2-electron donor using ionic counting.[21] One can view such complexes as derived from NO+, which is isoelectronic with CO. Nitric oxide can serve as a one-electron pseudohalide. In such complexes, the M-N-O group is characterized by an angle between 120 and140. The NO group can also bridge between metal centers through the nitrogen atom in a variety of geometries.

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Measurement of nitric oxide concentration

Nitric oxide concentration can be determined using a simple chemiluminescent reaction involving ozone:[22] A sample containing nitric oxide is mixed with a large quantity of ozone. The nitric oxide reacts with the ozone to produce oxygen and nitrogen dioxide. This reaction also produces light (chemiluminescence), which can be measured with a photodetector. The amount of light produced is proportional to the amount of nitric oxide in the sample. NO + O3 NO2 + O2 + light
Nitric oxide (white) in conifer cells, visualized using DAF-2 DA

Other methods of testing include electroanalysis (diaminofluorescein diacetate) (amperometric approach), where NO reacts with an electrode to induce a current or voltage change. The detection of NO radicals in biological tissues is particularly difficult due to the short lifetime and concentration of these radicals in tissues. One of the few practical methods is spin trapping of nitric oxide with iron-dithiocarbamate complexes and subsequent detection of the mono-nitrosyl-iron complex with electron paramagnetic resonance (EPR).[23][24] A group of fluorescent dye indicators that are also available in acetylated form for intracellular measurements exist. The most common compound is 4,5-diaminofluorescein (DAF-2).[]

Production
From a thermodynamic perspective, NO is unstable with respect to O2 and N2, although this conversion is very slow at ambient temperatures in the absence of a catalyst. Because the heat of formation of NO is endothermic, its synthesis from molecular nitrogen and oxygen requires elevated temperatures above 1000 C. A major natural source is lightning. The use of internal combustion engines has drastically increased the presence of nitric oxide in the environment. One purpose of catalytic converters in cars is to minimize NO emission by catalytic reversion to O2 and N2.

Environmental effects
Nitric oxide in the air may convert to nitric acid, which has been implicated in acid rain, however, it is an important source of nutrition for plant life in the form of nitrates. Furthermore, both NO and NO2 participate in ozone layer depletion. Nitric oxide is a small highly diffusible gas and a ubiquitous bioactive molecule.

Technical applications
Although NO has relatively few direct uses, it is produced on a massive scale as an intermediate in the Ostwald process for the synthesis of nitric acid from ammonia. In 2005, the US alone produced 6 million metric tons of nitric acid.[25] It finds use in the semiconductor industry for various processes. In one of its applications it is used along with nitrous oxide to form oxynitride gates in CMOS devices.

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Miscellaneous applications
Nitric oxide can be used for detecting surface radicals on polymers. Quenching of surface radicals with nitric oxide results in incorporation of nitrogen, which can be quantified by means of X-ray photoelectron spectroscopy.

Biological functions
NO is one of the few gaseous signaling molecules known and is additionally exceptional due to the fact that it is a radical gas. It is a key vertebrate biological messenger, playing a role in a variety of biological processes.[26] It is a known bioproduct in almost all types of organisms, ranging from bacteria to plants, fungi, and animal cells.[27] Nitric oxide, known as the 'endothelium-derived relaxing factor', or 'EDRF', is biosynthesized endogenously from L-arginine, oxygen, and NADPH by various nitric oxide synthase (NOS) enzymes. Reduction of inorganic nitrate may also serve to make nitric oxide. The endothelium (inner lining) of blood vessels uses nitric oxide to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow. Nitric oxide is highly reactive (having a lifetime of a few seconds), yet diffuses freely across membranes. These attributes make nitric oxide ideal for a transient paracrine (between adjacent cells) and autocrine (within a single cell) signaling molecule.[] The production of nitric oxide is elevated in populations living at high altitudes, which helps these people avoid hypoxia by aiding in pulmonary vasculature vasodilation. Effects include vasodilatation, neurotransmission (see gasotransmitters), modulation of the hair cycle,[28] production of reactive nitrogen intermediates and penile erections (through its ability to vasodilate). Nitroglycerin and amyl nitrite serve as vasodilators because they are converted to nitric oxide in the body. The vasodilating antihypertensive drug minoxidil contains an NO moiety and may act as an NO agonist. Similarly, Sildenafil citrate, popularly known by the trade name Viagra, stimulates erections primarily by enhancing signaling through the nitric oxide pathway in the penis. Nitric oxide (NO) contributes to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. Humans with atherosclerosis, diabetes, or hypertension often show impaired NO pathways.[29] A high salt intake was demonstrated to attenuate NO production in patients with essential hypertension, although bioavailability remains unregulated.[30] Nitric oxide is also generated by phagocytes (monocytes, macrophages, and neutrophils) as part of the human immune response. Phagocytes are armed with inducible nitric oxide synthase (iNOS), which is activated by interferon-gamma (IFN-) as a single signal or by tumor necrosis factor (TNF) along with a second signal.[31] On the other hand, transforming growth factor-beta (TGF-) provides a strong inhibitory signal to iNOS, whereas interleukin-4 (IL-4) and IL-10 provide weak inhibitory signals. In this way the immune system may regulate the armamentarium of phagocytes that play a role in inflammation and immune responses. Nitric oxide secreted as an immune response is as free radicals and is toxic to bacteria; the mechanism for this includes DNA damage[32][33][34] and degradation of iron sulfur centers into iron ions and iron-nitrosyl compounds.[35] In response, many bacterial pathogens have evolved mechanisms for nitric oxide resistance.[36] Because nitric oxide might serve as an inflammometer in conditions like asthma, there has been increasing interest in the use of exhaled nitric oxide as a breath test in diseases with airway inflammation. Reduced levels of exhaled NO have been associated with exposure to air pollution.[] Nitric oxide can contribute to reperfusion injury when an excessive amount produced during reperfusion (following a period of ischemia) reacts with superoxide to produce the damaging oxidant peroxynitrite. In contrast, inhaled nitric oxide has been shown to help survival and recovery from paraquat poisoning, which produces lung tissuedamaging superoxide and hinders NOS metabolism. In plants, nitric oxide can be produced by any of four routes: (i) L-arginine-dependent nitric oxide synthase,[37][38][39] (although the existence of animal NOS homologs in plants is debated),[40] (ii) by plasma membrane-bound nitrate reductase, (iii) by mitochondrial electron transport chain, or (iv) by non-enzymatic reactions. It is a signaling molecule, acts mainly against oxidative stress and also plays a role in plant pathogen

Nitric oxide interactions. Treating cut flowers and other plants with nitric oxide has been shown to lengthen the time before wilting.[41] Two important biological reaction mechanisms of nitric oxide are S-nitrosation of thiols, and nitrosylation of transition metal ions. S-nitrosation involves the (reversible) conversion of thiol groups, including cysteine residues in proteins, to form S-nitrosothiols (RSNOs). S-Nitrosation is a mechanism for dynamic, post-translational regulation of most or all major classes of protein.[42] The second mechanism, nitrosylation, involves the binding of NO to a transition metal ion like iron or copper. In this function, NO is referred to as a nitrosyl ligand. Typical cases involve the nitrosylation of heme proteins like cytochromes, thereby disabling the normal enzymatic activity of the enzyme. Nitrosylated ferrous iron is particularly stable as the binding of the nitrosyl ligand to ferrous iron (Fe(II)) is very strong. Hemoglobin is a prominent example of a heme protein that may be modified by NO by both pathways: NO may attach directly to the heme in the nitrosylation reaction, and independently form S-nitrosothiols by S-nitrosation of the thiol moieties.[43]

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Mechanism of action
There are several mechanisms by which NO has been demonstrated to affect the biology of living cells. These include oxidation of iron-containing proteins such as ribonucleotide reductase and aconitase, activation of the soluble guanylate cyclase, ADP ribosylation of proteins, protein sulfhydryl group nitrosylation, and iron regulatory factor activation.[44] NO has been demonstrated to activate NF-B in peripheral blood mononuclear cells, an important transcription factor in iNOS gene expression in response to inflammation.[45] It was found that NO acts through the stimulation of the soluble guanylate cyclase, which is a heterodimeric enzyme with subsequent formation of cyclic GMP. Cyclic GMP activates protein kinase G, which causes reuptake of Ca2+ and the opening of calcium-activated potassium channels. The fall in concentration of Ca2+ ensures that the myosin light chain kinase (MLCK) can no longer phosphorylate the myosin molecule and thereby stopping the crossbridge cycle leading to relaxation of the smooth muscle cell.[46]

Medical use
Neonatal use
Nitric oxide/oxygen blends are used in critical care to promote capillary and pulmonary dilation to treat primary pulmonary hypertension in neonatal patients[47][48] post-meconium aspiration and related to birth defects. These are often a last-resort gas mixture before the use of extracorporeal membrane oxygenation (ECMO). Nitric oxide therapy has the potential to significantly increase the quality of life and, in some cases, save the lives of infants at risk for pulmonary vascular disease.[49]

Pediatric and adult use

Currently in the United States nitric oxide use is not approved for any population other than neonates.

Dosage and strength

Currently in the United States nitric oxide is a gas available only in 100 ppm and 800 ppm concentrations. Overdosage with inhaled nitric oxide will be seen by elevations in methemoglobin and pulmonary toxicities associated with inspired NO2. Elevated NO2 may cause acute lung injury.

Contraindications
Inhaled nitric oxide is contraindicated in the treatment of neonates known to be dependent on right-to-left shunting of blood.

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Pulmonary embolism
Nitric oxide is also administered as salvage therapy in patients with acute right ventricular failure secondary to pulmonary embolism.[]

Pharmacology
Nitric oxide is considered an antianginal drug: it causes vasodilation, which can help with ischemic pain, known as angina, by decreasing the cardiac workload. By dilating (expanding) the veins, nitric oxide drugs lower arterial pressure and left ventricular filling pressure.[] This vasodilation does not decrease the volume of blood the heart pumps, but rather it decreases the force the heart muscle must exert to pump the same volume of blood. Nitroglycerin pills, taken sublingually (under the tongue), are used to prevent or treat acute chest pain. The nitroglycerin reacts with a sulfhydryl group (SH) to produce nitric oxide, which eases the pain by causing vasodilation. Recent evidence suggests that nitrates may be beneficial for treatment of angina due to reduced myocardial oxygen consumption both by decreasing preload and afterload and by some direct vasodilation of coronary vessels.[]

Associated problems
There are some associated complaints with utilization of nitric oxide in neonatal patients. Some of them include dose errors associated with the delivery system; headaches associated with environmental exposure of nitric oxide in hospital staff; hypotension associated with acute withdrawal of the drug; hypoxemia associated with acute withdrawal of the drug; pulmonary edema in patients with CREST syndrome.

Mechanism of action
Nitric oxide is a compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3,5-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide dilates the pulmonary vasculature, and because of efficient scavenging by hemoglobin, has minimal effect on the vasculature of the entire body.[] Inhaled nitric oxide appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, moving pulmonary blood flow away from lung segments with low ventilation/perfusion (V/Q) ratios toward segments with normal or better ratios.[] Pharmacokinetics Nitric oxide is absorbed systemically after inhalation. Most of it moves across the pulmonary capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated. Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration.

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References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=10102-43-9 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=145068 [3] http:/ / www. chemspider. com/ 127983 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=31C4KY9ESH [5] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=233-271-0 [6] http:/ / www. drugbank. ca/ drugs/ DB00435 [7] http:/ / www. kegg. jp/ entry/ D00074 [8] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=16480 [9] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL1200689 [10] http:/ / www. whocc. no/ atc_ddd_index/ ?code=R07AX01 [11] http:/ / www. 3dmet. dna. affrc. go. jp/ html/ B00122. html [12] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=%5BN%5D%3DO [13] http:/ / avogadro. chem. iastate. edu/ MSDS/ nitric_oxide. pdf [14] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477001381& page2=Nitric+ oxide [15] {New Oxford Dictionary for Scientific Writers and Editors; http:/ / old. iupac. org/ publications/ books/ rbook/ Red_Book_2005. pdf} [16] Principles and Applications of ESR Spectroscopy , Anders Lund,Masaru Shiotani,Shigetaka Shimada 2010 [20] Robert H. Crabtree: "The Organometallic Chemistry of the Transition Metals" (http:/ / books. google. com/ books?id=0bXMwefSs-kC& pg=PA32), John Wiley and Sons, 2005, ISBN 0-471-66256-9, p. 32. [21] Robert H. Crabtree: "The Organometallic Chemistry of the Transition Metals" (http:/ / books. google. com/ books?id=0bXMwefSs-kC& pg=PA96), John Wiley and Sons, 2005, ISBN 0-471-66256-9, pp. 9698. [25] Production: Growth is the Norm Chemical and Engineering News, July 10, 2006, p. 59. [26] Weller, Richard, Could the sun be good for your heart? (http:/ / www. ted. com/ talks/ richard_weller_could_the_sun_be_good_for_your_heart. html) TedxGlasgow March 2012, posted January 2013 [27] Roszer, T (2012) The Biology of Subcellular Nitric Oxide. ISBN 978-94-007-2818-9 [28] Alopecia & Free Radical " Redox " Signaling-Nitric Oxide and Superoxide (http:/ / www. drproctor. com/ Archd. htm) [31] Gorczyniski and Stanely, Clinical Immunology. Landes Bioscience; Austin, TX. ISBN 1-57059-625-5 [32] About killing of salmonella bacteria. [33] Free text. [34] free text. [41] Judy Siegel-Itzkovich. Viagra makes flowers stand up straight (http:/ / www. studentbmj. com/ issues/ 99/ 09/ news/ 313. php). Student BMJ, September 1999. [42] E. van Faassen and A. Vanin,eds. Radicals for life: The various forms of nitric oxide. Elsevier, Amsterdam 2007, ISBN 978-0-444-52236-8 [43] E. van Faassen and A. Vanin, Nitric Oxide, in Encyclopedia fo Analytical Science, 2nd ed., Elsevier 2004.

Further reading
Butler A. and Nicholson R.; "Life, death and NO." (http://books.google.com/books?id=0d1Z0m76YeYC& printsec=frontcover) Cambridge 2003. ISBN 978-0-85404-686-7. van Faassen, E. E.; Vanin, A. F. (eds); "Radicals for life: The various forms of Nitric Oxide." (http://books. google.com/books?id=UJ4glFNEcn0C&printsec=frontcover) Elsevier, Amsterdam 2007. ISBN 978-0-444-52236-8. Ignarro, L. J. (ed.); "Nitric oxide:biology and pathobiology." (http://books.google.com/ books?id=h5FugARr4bgC&printsec=frontcover) Academic Press, San Diego 2000. ISBN 0-12-370420-0.

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External links
International Chemical Safety Card 1311 (http://www.inchem.org/documents/icsc/icsc/eics1311.htm) National Pollutant Inventory Oxides of nitrogen Fact Sheet (http://www.npi.gov.au/database/ substance-info/profiles/67.html) 1998 Nobel Prize in Physiology/Medicine for discovery of NO's role in cardiovascular regulation (http://www. nobel.se/medicine/laureates/1998/index.html) Nitric Oxide and its Role in Diabetes, Wound Healing and Peripheral Neuropathy (http://www. diabetesincontrol.com/annodyne/burkeseries.php) Microscale Gas Chemistry: Experiments with Nitrogen Oxides (http://mattson.creighton.edu/NOx/index. html) Your Brain Boots Up Like a Computer (http://www.livescience.com/980-brain-boots-computer.html) new insights about the biological role of nitric oxide. Assessing The Potential of Nitric Oxide in the Diabetic Foot (http://www.podiatrytoday.com/article/5164) New Discoveries About Nitric Oxide Can Provide Drugs For Schizophrenia (http://www.sciencedaily.com/ releases/2007/11/071121213845.htm) Nitric Oxide at the Chemical Database (http://ull.chemistry.uakron.edu/erd/Chemicals/8000/6828.html)

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Nitrous oxide
Nitrous oxide

Identifiers CAS number PubChem ChemSpider UNII UN number KEGG ChEBI ChEMBL RTECS number ATC code Jmol-3D images 10024-97-2 948 923
[2] [3] [4] [1]

K50XQU1029

1070 (compressed) 2201 (liquid) D00102

[5] [6] [7]

CHEBI:17045

CHEMBL1234579 QX1350000 N01 AX13 Image 1 Properties

[9] [8]

Molecular formula Molar mass Appearance Density Melting point Boiling point Solubility in water Solubility log P Vapor pressure

NO
2

44.013 g/mol colourless gas 1.977 g/L (gas) 90.86 C (182.29 K) 88.48 C (184.67 K) 0.15 g/100 ml (15 C) soluble in alcohol, ether, sulfuric acid 0.35 5150 kPa (20 C)

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Refractive index (nD) 1.330 Structure Molecular shape Dipole moment linear, Cv 0.166 D Thermochemistry Std enthalpy of formation fHo298 Standard molar entropy So298 +82.05 kJ/mol

219.96 J K1 mol1 Pharmacology

Routes of administration Metabolism Elimination half-life Excretion Pregnancy category

Inhalation 0.004% 5 minutes Respiratory C(US) Hazards

MSDS EU Index NFPA 704

Ilo.org

[10]

, ICSC 0067

Oxidant [O]

Flash point

Non-flammable Related compounds

Related nitrogen oxides

Nitric oxide Dinitrogen trioxide Nitrogen dioxide Dinitrogen tetroxide Dinitrogen pentoxide Ammonium nitrate Azide
(verify) [11]

Related compounds

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Nitrous oxide, commonly known as laughing gas,[12] is a chemical compound with the formula N 2O. It is an oxide of nitrogen. At room temperature, it is a colourless, non-flammable gas, with a slightly sweet odour and taste. It is used in surgery and dentistry for its anaesthetic and analgesic effects. It is known as "laughing gas" due to the euphoric effects of inhaling it, a property that has led to its recreational use as a dissociative anaesthetic. It is also used as an oxidizer in rocketry and in motor racing to increase the power output of engines. At elevated temperatures, nitrous oxide is a powerful oxidiser similar to molecular oxygen.

Nitrous oxide Nitrous oxide gives rise to NO (nitric oxide) on reaction with oxygen atoms, and this NO in turn reacts with ozone. As a result, it is the main naturally occurring regulator of stratospheric ozone. It is also a major greenhouse gas and air pollutant. Considered over a 100-year period, it has 310[13] times more impact 'per unit weight' (Global warming potential) than carbon dioxide according to the Environmental Protection Agency (EPA).

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Occurrence
Nitrous oxide is emitted by bacteria in soils and oceans, and thus has been a part of Earth's atmosphere for aeons. Agriculture is the main source of human-produced nitrous oxide: cultivating soil, the use of nitrogen fertilisers, and animal waste handling can all stimulate naturally occurring bacteria to produce more nitrous oxide. The livestock sector (primarily cows, chickens, and pigs) produces 65% of human-related nitrous oxide.[14] Industrial sources make up only about 20% of all anthropogenic sources, and include the production of nylon, and the burning of fossil fuel in internal combustion engines. Human activity is thought to account for 30%; tropical soils and oceanic

Greenhouse gas trends.

release account for 70%.[15] Nitrous oxide reacts with ozone in the stratosphere. Nitrous oxide is the main naturally occurring regulator of stratospheric ozone. Nitrous oxide is a major greenhouse gas. Considered over a 100-year period, it has 298[citation needed] times more impact per unit weight than carbon dioxide. Thus, despite its low concentration, nitrous oxide is the fourth largest contributor to these greenhouse gases. It ranks behind water vapour, carbon dioxide, and methane. Control of nitrous oxide is part of efforts to curb greenhouse gas emissions.[16]

History
The gas was first synthesised by English natural philosopher and chemist Joseph Priestley in 1772, who called it phlogisticated nitrous air (see phlogiston).[] Priestley published his discovery in the book Experiments and Observations on Different Kinds of Air (1775), where he described how to produce the preparation of "nitrous air diminished", by heating iron filings dampened with nitric acid.[]

Early use
The first important use of nitrous oxide was made possible by Thomas Beddoes and James Watt, who worked together to publish the book Considerations on the Medical Use and on the Production of Factitious Airs (1794). This book was important for two reasons. First, James Watt had invented a novel machine to produce "Factitious Airs" (i.e. nitrous oxide) and a novel "breathing apparatus" to inhale the gas. Second, the book also presented the new medical theories by Thomas Beddoes, that tuberculosis and other lung diseases could be treated by inhalation of "Factitious Airs".[] The machine to produce "Factitious Airs" had three parts: A furnace to burn the needed material, a vessel with water where the produced gas passed through in a spiral pipe (for impurities to be "washed off"), and finally the gas cylinder with a gasometer where the gas produced, 'air,' could be tapped into portable air bags (made of airtight oily silk). The breathing apparatus consisted of one of the portable air bags connected with a tube to a mouthpiece. With this new equipment being engineered and produced by 1794, the way was paved for clinical trials,Wikipedia:Please clarify which began when Thomas Beddoes in 1798 established the "Pneumatic Institution for Relieving Diseases by Medical Airs" in Hotwells (Bristol). In the basement of the building, a large-scale machine was producing the gases under the supervision of a young Humphry Davy, who was encouraged to experiment with new gases for patients to inhale.[] The first important work of Davy was examination of the nitrous oxide, and the publication of his results in

Nitrous oxide the book: Researches, Chemical and Philosophical (1800). In that publication, Davy notes the analgesic effect of nitrous oxide at page 465 and its potential to be used for surgical operations at page 556.[] Despite Davy's discovery that inhalation of nitrous oxide could relieve a conscious person from pain, another 44 years elapsed before doctors attempted to use it for anaesthesia. The use of nitrous oxide as a recreational drug at "laughing gas parties", primarily arranged for the British upper class, became an immediate success beginning in 1799. While the effects of the gas generally make the user appear stuporous, dreamy and sedated, some people also "get the giggles" in a state of euphoria, and frequently, erupt in laughter.[]

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Anaesthetic use
The first time nitrous oxide was used as an anaesthetic drug in the treatment of a patient was when dentist Horace Wells, with assistance by Gardner Quincy Colton and John Mankey Riggs, demonstrated insensitivity to pain from a dental extraction on 11 December 1844.[] In the following weeks, Wells treated the first 1215 patients with nitrous oxide in Hartford, and according to his own record only failed in two cases.[] In spite of these convincing results being reported by Wells to the medical society in Boston already in December 1844, this new method was not immediately adopted by other dentists. The reason for this was most likely that Wells, in January 1845 at his first public demonstration towards the medical faculty in Boston, had been partly unsuccessful, leaving his colleagues doubtful regarding its efficacy and safety.[] The method did not come into general use until 1863, when Gardner Quincy Colton successfully started to use it in all his "Colton Dental Association" clinics, that he had just established in New Haven and New York City.[] Over the following three years, Colton and his associates successfully administered nitrous oxide to more than 25,000 patients.[] Today, nitrous oxide is used in dentistry as an anxiolytic, as an adjunct to local anaesthetic. However, nitrous oxide was not found to be a strong enough anaesthetic for use in major surgery in hospital settings. Being a stronger and more potent anaesthetic, sulfuric ether was instead demonstrated and accepted for use in October 1846, along with chloroform in 1847.[] When Joseph Thomas Clover invented the "gas-ether inhaler" in 1876, it however became a common practice at hospitals to initiate all anaesthetic treatments with a mild flow of nitrous oxide, and then gradually increase the anaesthesia with the stronger ether/chloroform. Clover's gas-ether inhaler was designed to supply the patient with nitrous oxide and ether at the same time, with the exact mixture being controlled by the operator of the device. It remained in use by many hospitals until the 1930s.[] Although hospitals today are using a more advanced anaesthetic machine, these machines still use the same principle launched with Clover's gas-ether inhaler, to initiate the anaesthesia with nitrous oxide, before the administration of a more powerful anaesthetic.

Production
Nitrous oxide is most commonly prepared by careful heating of ammonium nitrate, which decomposes into nitrous oxide and water vapour.[17] The addition of various phosphates favours formation of a purer gas at slightly lower temperatures. One of the earliest commercial producers was George Poe in Trenton, New Jersey.[] NH4NO3 (s) 2 H2O (g) + N2O (g) This reaction occurs between 170 and 240 C, temperatures where ammonium nitrate is a moderately sensitive explosive and a very powerful oxidizer. Above 240C the exothermic reaction may accelerate to the point of detonation, so the mixture must be cooled to avoid such a disaster. Superheated steam is used to reach reaction temperature in some turnkey production plants.[18]

Nitrous oxide production

Nitrous oxide Downstream, the hot, corrosive mixture of gases must be cooled to condense the steam, and filtered to remove higher oxides of nitrogen. Ammonium nitrate smoke, as an extremely persistent colloid, will also have to be removed. The cleanup is often done in a train of three gas washes; namely base, acid and base again. Any significant amounts of nitric oxide (NO) may not necessarily be absorbed directly by the base (sodium hydroxide) washes. The nitric oxide impurity is sometimes chelated out with ferrous sulfate, reduced with iron metal, or oxidised and absorbed in base as a higher oxide. The first base wash may (or may not) react out much of the ammonium nitrate smoke. However, this reaction generates ammonia gas, which may have to be absorbed in the acid wash.

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Other routes
The direct oxidation of ammonia may someday rival the ammonium nitrate pyrolysis synthesis of nitrous oxide mentioned above. This capital-intensive process, which originates in Japan, uses a manganese dioxide-bismuth oxide catalyst:[19] 2 NH3 + 2 O2 N2O + 3 H2O Higher oxides of nitrogen are formed as impurities. In comparison, uncatalysed ammonia oxidation (i.e. combustion or explosion) goes primarily to N2 and H2O. Nitrous oxide can be made by heating a solution of sulfamic acid and nitric acid. Many gases are made this way in Bulgaria.[citation needed] HNO3 + NH2SO3H N2O + H2SO4 + H2O There is no explosive hazard in this reaction if the mixing rate is controlled. However, as usual, toxic higher oxides of nitrogen are formed. Nitrous oxide is produced in large volumes as a by-product in the synthesis of adipic acid; one of the two reactants used in nylon manufacture.[20][21] This might become a major commercial source, but will require the removal of higher oxides of nitrogen and organic impurities. Currently much of the gas is decomposed before release for environmental protection. Hydroxylammonium chloride can react with sodium nitrite to produce N2O as well: NH3OH+Cl + NaNO2 N2O + NaCl + 2 H2O If the nitrite is added to the hydroxylamine solution, the only remaining by-product is salt water. However, if the hydroxylamine solution is added to the nitrite solution (nitrite is in excess), then toxic higher oxides of nitrogen are also formed. Also, HNO3 can be reduced to N2O by SnCl2 and HCl mixture: 2 HNO3 + 8 HCl + 4 SnCl2 5 H2O + 4 SnCl4 + N2O Natural production of N2O occurs through the process of denitrification in oxygen-poor soils and marine environments, in which denitrifying bacteria respire NO3-.

Soil
Of the entire anthropogenic N2O emission (5.7 Tg N2O-N yr1), agricultural soils provide 3.5 Tg N2ON yr1.[22] Nitrous oxide is produced naturally in the soil during the microbial processes of nitrification, denitrification, nitrifier denitrification and others: aerobic autotrophic nitrification, the stepwise oxidation of ammonia (NH3) to nitrite (NO2) and to nitrate (NO3) (e.g., Kowalchuk and Stephen, 2001), anaerobic heterotrophic denitrification, the stepwise reduction of NO3 to NO2, nitric oxide (NO), N2O and ultimately N2, where facultative anaerobe bacteria use NO3 as an electron acceptor in the respiration of organic material in the condition of insufficient oxygen (O2) (e.g. Knowles, 1982), and nitrifier denitrification, which is carried out by autotrophic NH3oxidizing bacteria and the pathway whereby ammonia (NH3) is oxidised to nitrite (NO2), followed by the reduction of NO2 to nitric oxide (NO), N2O and

Nitrous oxide molecular nitrogen (N2) (e.g., Webster and Hopkins, 1996; Wrage et al., 2001). Other N2O production mechanisms include heterotrophic nitrification (Robertson and Kuenen, 1990), aerobic denitrification by the same heterotrophic nitrifiers (Robertson and Kuenen, 1990), fungal denitrification (Laughlin and Stevens, 2002), and non-biological process chemodenitrification (e.g. Chalk and Smith, 1983; Van Cleemput and Baert, 1984; Martikainen and De Boer, 1993; Daum and Schenk, 1998; Mrkved et al., 2007). Soil N2O emissions are reported to be controlled by soil chemical and physical properties such as the availability of mineral N, soil pH, organic matter availability, and soil type, and climate related soil properties such as soil temperature and soil water content (e.g., Mosier, 1994; Bouwman, 1996; Beauchamp, 1997; Yamulki et al. 1997; Dobbie and Smith, 2003; Smith et al. 2003; Dalal et al. 2003).

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Properties and reactions

Nitrous oxide is a colourless, non-toxic gas with a faint, sweet odour. It dissolves in water to give a neutral solution. The equilibrium that exists when nitrous oxide is dissolved in water lies far to the left: N2O + H2O H2N2O2 Nitrous oxide supports combustion by releasing the dative-bonded oxygen radical, thus it can relight a glowing splint. N2O is inert at room temperature and has few reactions. At elevated temperatures, its reactivity increases. For example, nitrous oxide reacts with NaNH2 at 460K to give NaN3 2 NaNH2 + N2O NaN3 + NaOH + NH3 The above reaction is actually the route adopted by commercial chemical industry to produce azide salts, which is used as a detonator.[23]

Applications
Rocket motors
Nitrous oxide can be used as an oxidizer in a rocket motor. This has the advantages over other oxidisers in that it is not only non-toxic, but also, due to its stability at room temperature, easy to store and relatively safe to carry on a flight. As a secondary benefit it can be readily decomposed to form breathing air. Its high density and low storage pressure enable it to be highly competitive with stored high-pressure gas systems. In a 1914 patent, American rocket pioneer Robert Goddard suggested nitrous oxide and gasoline as possible propellants for a liquid-fuelled rocket. Nitrous oxide has been the oxidiser of choice in several hybrid rocket designs (using solid fuel with a liquid or gaseous oxidizer). The combination of nitrous oxide with hydroxyl-terminated polybutadiene fuel has been used by SpaceShipOne and others. It is also notably used in amateur and high power rocketry with various plastics as the fuel. Nitrous oxide can also be used in a monopropellant rocket. In the presence of a heated catalyst, N2O will decompose exothermically into nitrogen and oxygen, at a temperature of approximately 1300C[citation needed]. Because of the large heat release, the catalytic action rapidly becomes secondary as thermal autodecomposition becomes dominant. In a vacuum thruster, this can provide a monopropellant specific impulse (Isp) of as much as 180 s. While noticeably less than the Isp available from hydrazine thrusters (monopropellant or bipropellant with nitrogen tetroxide), the decreased toxicity makes nitrous oxide an option worth investigating. Nitrous oxide is said to deflagrate somewhere around 600 C (1,112F) at a pressure of 21atm. It can also easily be ignited using a combination of the two. At 600psi for example, the required ignition energy is only 6J, whereas N2O at 130psi would not react even with a 2500J ignition energy input.[24][25][26][27] Specific impulse (Isp) can be improved by blending a hydrocarbon fuel with the nitrous oxide inside the same storage tank, becoming a nitrous oxide fuel blend (NOFB) monopropellant. This storage mixture does not incur the danger of spontaneous ignition, since N2O is chemically stable. When the nitrous oxide decomposes by a heated catalyst,

Nitrous oxide high temperature oxygen is released and rapidly ignites the hydrocarbon fuel-blend. NOFB monopropellants are capable of I [28][29] sp greater than 300 seconds, while avoiding the toxicity associated with hypergolic propulsion systems. The low freezing point of NOFB eases thermal management compared to hydrazine and dinitrogen tetroxidea valuable property for space storable propellants.

178

Internal combustion engine

In vehicle racing, nitrous oxide (often referred to as just "nitrous") allows the engine to burn more fuel by providing more oxygen than air alone, resulting in a more powerful combustion. The gas itself is not flammable at a low pressure/temperature, but it delivers more oxygen than atmospheric air by breaking down at elevated temperatures. Therefore, it is often mixed with another fuel that is easier to deflagrate. Nitrous oxide is stored as a compressed liquid; the evaporation and expansion of liquid nitrous oxide in the intake manifold causes a large drop in intake charge temperature, resulting in a denser charge, further allowing more air/fuel mixture to enter the cylinder. Nitrous oxide is sometimes injected into (or prior to) the intake manifold, whereas other systems directly inject right before the cylinder (direct port injection) to increase power. The technique was used during World War II by Luftwaffe aircraft with the GM-1 system to boost the power output of aircraft engines. Originally meant to provide the Luftwaffe standard aircraft with superior high-altitude performance, technological considerations limited its use to extremely high altitudes. Accordingly, it was only used by specialised planes like high-altitude reconnaissance aircraft, high-speed bombers, and high-altitude interceptor aircraft. One of the major problems of using nitrous oxide in a reciprocating engine is that it can produce enough power to damage or destroy the engine. Very large power increases are possible, and if the mechanical structure of the engine is not properly reinforced, the engine may be severely damaged or destroyed during this kind of operation. It is very important with nitrous oxide augmentation of internal combustion engines to maintain proper operating temperatures and fuel levels to prevent "preignition", or "detonation" (sometimes referred to as "knock"). Most problems that are associated with nitrous do not come from mechanical failure due to the power increases. Since nitrous allows a much denser charge into the cylinder it dramatically increases cylinder pressures. The increased pressure and temperature can cause problems such as melting the piston or valves. It may also crack or warp the piston or head and cause preignition due to uneven heating. Automotive-grade liquid nitrous oxide differs slightly from medical-grade nitrous oxide. A small amount of sulfur dioxide (SO2) is added to prevent substance abuse.[] Multiple washes through a base (such as sodium hydroxide) can remove this, decreasing the corrosive properties observed when SO2 is further oxidised during combustion into sulfuric acid, making emissions cleaner.[citation needed]

Aerosol propellant
The gas is approved for use as a food additive (also known as E942), specifically as an aerosol spray propellant. Its most common uses in this context are in aerosol whipped cream canisters, cooking sprays, and as an inert gas used to displace oxygen, to inhibit bacterial growth, when filling packages of potato chips and other similar snack foods. The gas is extremely soluble in fatty compounds. In aerosol whipped cream, it is dissolved in the fatty cream until it leaves the can, when it becomes gaseous and thus creates foam. Used in this way, it produces whipped cream four times the volume of the liquid, whereas whipping air into cream only produces twice the volume. If air were used as a propellant, oxygen would accelerate rancidification of the butterfat; nitrous oxide inhibits such degradation. Carbon dioxide cannot be used for whipped cream because it is acidic in water, which would curdle the cream and give it a seltzer-like 'sparkling' sensation. However, the whipped cream produced with nitrous oxide is unstable and will return to a more liquid state within half an hour to one hour. Thus, the method is not suitable for decorating food that will not be immediately served.

Nitrous oxide Similarly, cooking spray, which is made from various types of oils combined with lecithin (an emulsifier), may use nitrous oxide as a propellant; other propellants used in cooking spray include food-grade alcohol and propane. Users of nitrous oxide often obtain it from whipped cream dispensers that use nitrous oxide as a propellant (see above section), for recreational use as a euphoria-inducing inhalant drug. It is not harmful in small doses, but risks due to lack of oxygen do exist (see Recreational use below).

179

Medicine
Nitrous oxide has been used for anaesthesia in dentistry since December 1844, where Horace Wells made the first 1215 dental operations with the gas in Hartford. Its debut as a generally accepted method, however, came in 1863, when Gardner Quincy Colton introduced it more broadly at all the Colton Dental Association clinics, that he founded in New Haven and New York City.[] The first devices used in dentistry to administer the gas, known as Nitrous Oxide inhalers, were designed in a very simple way with the gas stored and breathed through a breathing bag made of rubber cloth, without a scavenger system and flowmeter, and with no addition of oxygen/air.[] Today these simple and somewhat unreliable inhalers have been replaced by the more modern relative analgesia machine, which is an automated machine designed to deliver a precisely dosed and breath-actuated flow of nitrous oxide mixed with oxygen, for the patient to inhale safely. The machine used in dentistry is designed as a simplified version of the larger anaesthetic machine used by hospitals, as it doesn't feature the additional anaesthetic vaporiser and medical ventilator. The purpose of the machine allows for a simpler design, as it only delivers a mixture of nitrous oxide and oxygen for the patient to inhale, in order to depress the feeling of pain while keeping the patient in a conscious state. Relative analgesia machines typically feature a constant-supply flowmeter, which allow the proportion of nitrous oxide and the combined gas flow rate to be individually adjusted. The gas is administered by dentists through a demand-valve inhaler over the Medical grade N2O tanks nose, which will only release gas when the patient inhales through the nose. Because used in dentistry. nitrous oxide is minimally metabolised in humans (with a rate of 0.004%), it retains its potency when exhaled into the room by the patient, and can pose an intoxicating and prolonged exposure hazard to the clinic staff if the room is poorly ventilated. Where nitrous oxide is administered, a continuous-flow fresh-air ventilation system or nitrous scavenger system is used to prevent a waste-gas buildup. Hospitals administer nitrous oxide as one of the anaesthetic drugs delivered by anaesthetic machines. Nitrous oxide is a weak general anaesthetic, and so is generally not used alone in general anaesthesia. In general anaesthesia it is used as a carrier gas in a 2:1 ratio with oxygen for more powerful general anaesthetic drugs such as sevoflurane or desflurane. It has a minimum alveolar concentration of 105% and a blood/gas partition coefficient of 0.46. The medical grade gas tanks, with the tradename Entonox and Nitronox contain a mixture with 50%, but this will normally be diluted to a lower percentage upon the operational delivery to the patient. Inhalation of nitrous oxide is frequently used to relieve pain associated with childbirth, trauma, oral surgery, and acute coronary syndrome (includes heart attacks). Its use during labour has been shown to be a safe and effective aid for women wanting to give birth without an epidural.[30] Its use for acute coronary syndrome is of unknown benefit.[] In Britain and Canada, Entonox and Nitronox are commonly used by ambulance crews (including unregistered practitioners) as a rapid and highly effective analgesic gas. Nitrous oxide has been shown to be effective in treating a number of addictions, including alcohol withdrawal.[31] Nitrous oxide is also gaining interest as a substitute gas for carbon dioxide in laparoscopic surgery. It has been found to be as safe as carbon dioxide with better pain relief.[32][33]

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Recreational use

Food grade N2O whippets (above) and cracker (below) can be used for recreational purposes Nitrous oxide can cause analgesia, depersonalisation, derealisation, dizziness, euphoria, and some sound distortion.[34] Research has also found that it increases suggestibility and imagination.[35] Inhalation of nitrous oxide for recreational use, with the purpose of causing euphoria and/or slight hallucinations, began as a phenomenon for the British upper class in 1799, known as "laughing gas parties". Until at least 1863, a low availability of equipment to produce the gas, combined with a low usage of the gas for medical purposes, meant it was a relatively rare phenomenon that mainly happened among students at medical universities. When equipment became more widely available for dentistry and hospitals, most countries also restricted the legal access to buy pure nitrous oxide gas cylinders to those sectors. As only medical staff and dentists today are legally allowed to buy the pure gas, the recreational use is also believed to be somewhat limited. A Consumers Union report from 1972, however found that the use of the gas for recreational purpose was [then] still taking place, based upon reports of its use in Maryland 1971, Vancouver 1972, and a survey made by Dr. Edward J. Lynn of its non-medical use in Michigan 1970.[][] It was not uncommon [in the interviews] to hear from individuals who had been to parties where a professional (doctor, nurse, scientist, inhalation therapist, researcher) had provided nitrous oxide. There also were those who work in restaurants who used the N2O stored in tanks for the preparation of whip cream. Reports were received from people who used the gas contained in aerosol cans both of food and non-food products. At a recent rock festival nitrous oxide was widely sold for 25 cents a balloon. Contact was made with a "mystical-religious" group that used the gas to accelerate arriving at their transcendental-meditative state of choice. Although a few, more sophisticated users employed nitrous oxide-oxygen mixes with elaborate equipment, most users used balloons or plastic bags. They either held a breath of N2O or rebreathed the gas. There were no adverse effects reported in the more than one hundred individuals surveyed.[] In Australia, nitrous oxide bulbs are known as nangs, possibly derived from the sound distortion perceived by consumers.[36]

Neuropharmacology
The pharmacological mechanism of action of N2O in medicine is not fully known. However, it has been shown to directly modulate a broad range of ligand-gated ion channels, and this likely plays a major role in many of its effects. It moderately blocks NMDA and 2-subunit-containing nACh channels, weakly inhibits AMPA, kainate, GABAC, and 5-HT3 receptors, and slightly potentiates GABAA and glycine receptors.[][] It has also been shown to activate two-pore-domain K+ channels.[] While N2O affects quite a few ion channels, its anaesthetic, hallucinogenic, and euphoriant effects are likely caused predominantly or fully via inhibition of NMDAR-mediated currents.[][] In addition to its effects on ion channels, N2O may act to imitate nitric oxide (NO) in the central nervous system as well, and this may be related to its analgesic and anxiolytic properties.[]

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Anxiolytic effect
In behavioural tests of anxiety, a low dose of N2O is an effective anxiolytic, and this anti-anxiety effect is associated with enhanced activity of GABAA receptors, as it is partially reversed by benzodiazepine receptor antagonists. Mirroring this, animals which have developed tolerance to the anxiolytic effects of benzodiazepines are partially tolerant to N2O.[] Indeed, in humans given 30% N2O, benzodiazepine receptor antagonists reduced the subjective reports of feeling "high", but did not alter psycho-motor performance, in human clinical studies.[]

Analgesic effect
The analgesic effects of N2O are linked to the interaction between the endogenous opioid system and the descending noradrenergic system. When animals are given morphine chronically they develop tolerance to its pain-killing effects, and this also renders the animals tolerant to the analgesic effects of N2O.[37] Administration of antibodies which bind and block the activity of some endogenous opioids (not -endorphin) also block the antinociceptive effects of N2O.[] Drugs which inhibit the breakdown of endogenous opioids also potentiate the antinociceptive effects of N2O.[] Several experiments have shown that opioid receptor antagonists applied directly to the brain block the antinociceptive effects of N2O, but these drugs have no effect when injected into the spinal cord. Conversely, 2-adrenoceptor antagonists block the antinociceptive effects of N2O when given directly to the spinal cord, but not when applied directly to the brain.[] Indeed, 2B-adrenoceptor knockout mice or animals depleted in norepinephrine are nearly completely resistant to the antinociceptive effects of N2O.[38] Apparently N2O-induced release of endogenous opioids causes disinhibition of brain stem noradrenergic neurons, which release norepinephrine into the spinal cord and inhibit pain signalling.[] Exactly how N2O causes the release of endogenous opioid peptides is still uncertain.

Euphoric effect
In rats, N2O stimulates the mesolimbic reward pathway via inducing dopamine release and activating dopaminergic neurons in the ventral tegmental area and nucleus accumbens, presumably through antagonisation of NMDA receptors localised in the system.[][][][] This action has been implicated in its euphoric effects, and notably, appears to augment its analgesic properties as well.[][][][] However, it is remarkable that in mice, N2O blocks amphetamine-induced carrier-mediated dopamine release in the nucleus accumbens and behavioural sensitisation, abolishes the conditioned place preference (CPP) of cocaine and morphine, and does not produce reinforcing (or aversive) effects of its own.[][] Studies on CPP of N2O in rats is mixed, consisting of reinforcement, aversion, and no change.[] In contrast, it is a positive reinforcer in squirrel monkeys,[] and is well known as a drug of abuse in humans.[] These discrepancies in response to N2O may reflect species variation or methodological differences.[] Though, it is noteworthy that in human clinical studies, N2O was found to produce mixed responses similarly to rats, reflecting high subjective individual variability.[][]

Neurotoxicity
Similarly to some other NMDA antagonists, N2O has been demonstrated to produce neurotoxicity in the form of Olney's lesions (damage to the posterior cingulate and retrosplenial cortices of the brain) in rodents upon prolonged (e.g., several hour) exposure.[][][][] However, it also simultaneously exerts widespread neuroprotective effects via inhibiting glutamate-induced excitotoxicity, and it has been argued that on account of its very short duration under normal circumstances, N2O may not share the neurotoxicity of other NMDA antagonists.[] Indeed, in rodents, short-term exposure results in only mild injury that is rapidly reversible, and permanent neuronal death only occurs after constant and sustained exposure.[] Moreover, Olney's lesions have never been observed in primates (including humans). However, Olney's lesions must be observed within a few hours of death, which may explain why they have not been observed in primates. After a few hours, depending on dose, the vacuoles that have appeared in the neurons resolve. If the dose is large enough to kill neurons, glial cells fill in any spaces left by the dead neurons within a short

Nitrous oxide time, making it impossible to tell that neurons were even there.[39][40]

182

Safety
The major safety hazards of nitrous oxide come from the fact that it is a compressed liquefied gas, an asphyxiation risk, and a dissociative anaesthetic. Exposure to nitrous oxide causes short-term decreases in mental performance, audiovisual ability, and manual dexterity.[41] Long-term exposure can cause vitamin B12 deficiency, numbness, reproductive side effects (in pregnant females), and other problems (see Recreational use and Biological factors in this article). The National Institute for Occupational Safety and Health recommends that workers' exposure to nitrous oxide should be controlled during the administration of anaesthetic gas in medical, dental, and veterinary operators.[42]

Chemical/physical
At room temperature (20C) the saturated vapour pressure is 58.5 bar, rising up to 72.45 bar at 36.4C the critical temperature. The pressure curve is thus unusually sensitive to temperature.[43] Liquid nitrous oxide acts as a good solvent for many organic compounds; liquid mixtures may form shock sensitive explosives.[citation needed] As with many strong oxidisers, contamination of parts with fuels have been implicated in rocketry accidents, where small quantities of nitrous/fuel mixtures explode due to 'water hammer' like effects (sometimes called 'dieseling' heating due to adiabatic compression of gases can reach decomposition temperatures).[44] Some common building materials such as stainless steel and aluminium can act as fuels with strong oxidisers such as nitrous oxide, as can contaminants, which can ignite due to adiabatic compression.[45] There have also been accidents where nitrous oxide decomposition in plumbing has led to the explosion of large tanks.[27]

Biological
Nitrous oxide inactivates the cobalamin form of vitamin B12 by oxidation. Symptoms of vitamin B12 deficiency, including sensory neuropathy, myelopathy, and encephalopathy, can occur within days or weeks of exposure to nitrous oxide anaesthesia in people with subclinical vitamin B12 deficiency.[citation needed] Symptoms are treated with high doses of vitamin B12, but recovery can be slow and incomplete.[46] People with normal vitamin B12 levels have stores to make the effects of nitrous oxide insignificant, unless exposure is repeated and prolonged (nitrous oxide abuse).[citation needed] Vitamin B12 levels should be checked in people with risk factors for vitamin B12 deficiency prior to using nitrous oxide anaesthesia. A study of workers[47] and several experimental animal studies[][][48][49] indicate that adverse reproductive effects for pregnant females may also result from chronic exposure to nitrous oxide.

Environmental
N2O is a greenhouse gas with tremendous global warming potential (GWP). When compared to carbon dioxide (CO2), N2O has 310 times the ability per molecule of gas to trap heat in the atmosphere.[50] N2O is produced naturally in the soil during the microbial processes of nitrification and denitrification.[] The United States of America signed and ratified the United Nations Framework Convention on Climate Change (UNFCCC [51]) in 1992, agreeing to inventory and assess the various sources of greenhouse gases that contribute to climate change.[52] The agreement requires parties to "develop, periodically update, publish and make availablenational inventories of anthropogenic emissions by sources and removals by sinks of all greenhouse gases not controlled by the Montreal Protocol, using comparable methodologies".[53] In response to this agreement, the U.S. is obligated to inventory anthropogenic emissions by sources and sinks, of which agriculture is a key contributor. In 2008, agriculture contributed 6.1% of the total U.S. greenhouse gas emissions and cropland

Nitrous oxide contributed nearly 69% of total direct nitrous oxide (N2O) emissions. Additionally, estimated emissions from agricultural soils were 6% higher in 2008 than 1990.[52] According to 2006 data from the United States Environmental Protection Agency, industrial sources make up only about 20% of all anthropogenic sources, and include the production of nylon, and the burning of fossil fuel in internal combustion engines. Human activity is thought to account for 30%; tropical soils and oceanic release account for 70%.[54] However, a 2008 study by Nobel Laureate Paul Crutzen suggests that the amount of nitrous oxide release attributable to agricultural nitrate fertilizers has been seriously underestimated, most of which would presumably come under soil and oceanic release in the Environmental Protection Agency data.[55] Atmospheric levels have risen by more than 15% since 1750.[56] Nitrous oxide also causes ozone depletion. A new study suggests that N2O emission currently is the single most important ozone-depleting substance (ODS) emission and is expected to remain the largest throughout the 21st century.[57][58]

183

Legality
In the United States, possession of nitrous oxide is legal under federal law and is not subject to DEA purview.[59] It is, however, regulated by the Food and Drug Administration under the Food Drug and Cosmetics Act; prosecution is possible under its "misbranding" clauses, prohibiting the sale or distribution of nitrous oxide for the purpose of human consumption. Many states have laws regulating the possession, sale, and distribution of nitrous oxide. Such laws usually ban distribution to minors or limit the amount of nitrous oxide that may be sold without special license.[citation needed] For example, in the state of California, possession for recreational use is prohibited and qualifies as a misdemeanour.[60] In New Zealand, the Ministry of Health has warned that nitrous oxide is a prescription medicine, and its sale or possession without a prescription is an offence under the Medicines Act.[61] This statement would seemingly prohibit all non-medicinal uses of the chemical, though it is implied that only recreational use will be legally targeted. In India, for general anaesthesia purposes, nitrous oxide is available as Nitrous Oxide IP. India's gas cylinder rules (1985) permit the transfer of gas from one cylinder to another for breathing purposes. This law benefits remote hospitals, which would otherwise suffer as a result of India's geographic immensity. Nitrous Oxide IP is transferred from bulk cylinders (17,000 litres capacity gas) to smaller pin-indexed valve cylinders (1,800 litres of gas), which are then connected to the yoke assembly of Boyle's machines. Because India's Food & Drug Authority (FDA-India) rules state that transferring a drug from one container to another (refilling) is equivalent to manufacturing, anyone found doing so must possess a drug manufacturing license.

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=10024-97-2 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=948 [3] http:/ / www. chemspider. com/ 923 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=K50XQU1029 [5] http:/ / www. kegg. jp/ entry/ D00102 [6] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=17045 [7] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL1234579 [8] http:/ / www. whocc. no/ atc_ddd_index/ ?code=N01AX13 [9] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=N%23%5BN%2B%5D%5BO-%5D [10] http:/ / www. inchem. org/ documents/ icsc/ icsc/ eics0067. htm [11] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477162830& page2=Nitrous+ oxide [19] Suwa T, Matsushima A, Suziki Y and Namina Y (1961) "Synthesis of Nitrous Oxide by Oxidation of Ammonia", Kohyo Kagaku Zasshi, Showa Denka Ltd. [22] IPCC, 2006 [23] . [24] Scaled Composites Safety Guidelines for N2O (http:/ / www. scaled. com/ images/ uploads/ news/ N2OSafetyGuidelines. pdf). Scaled Composites, LLC. 17 June 2009.

Nitrous oxide
[25] Berger, Bruno (5 October 2007). Is nitrous oxide safe? (http:/ / www. spl. ch/ publication/ SPL_Papers/ N2O_safety_e. pdf) Swiss Propulsion Laboratory [26] FR-5904 (http:/ / hobbyspace. com/ AAdmin/ archive/ SpecialTopics/ Misc/ pratt-explosion. pdf). Pratt & Whitney Aircraft. [27] Munke, Konrad (2 July 2001) Nitrous Oxide Trailer Rupture (http:/ / hobbyspace. com/ AAdmin/ archive/ SpecialTopics/ Misc/ eindhoven. pdf), Report at CGA Seminar Safety and Reliability of Industrial Gases, Equipment and Facilities, October 1517, 2001, St. Louis, Missouri [30] Copeland, Claudia. Nitrous Oxide Analgesia for Childbirth (http:/ / www. pregnancy. org/ article/ nitrous-oxide-analgesia-child-birth). pregnancy.org [34] Giannini, A. J. (1991). "Volatiles", p. 396 in N. S. Miller (Ed.). Comprehensive Handbook of Drug and Alcohol Addiction (http:/ / books. google. com/ books?doi=VgetLfJBQv0C& pg=PA396). NY, Marcel Dekker, ISBN 0-8247-8474-X. [36] nang (http:/ / nang. urbanup. com/ 503608) at Urban Dictionary, retrieved 2011-08-29 [41] Criteria for a recommended standard: occupational exposure to waste anesthetic gases and vapors (http:/ / www. cdc. gov/ niosh/ docs/ 1970/ 77-140. html). Cincinnati, OH: U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, DHEW (NIOSH) Publication No. 77B140. [42] CDC.gov NIOSH Alert: Controlling Exposures to Nitrous Oxide During Anesthetic Administration (http:/ / www. cdc. gov/ niosh/ noxidalr. html). Cincinnati, OH: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 94-100 [43] Nitrous oxide (http:/ / encyclopedia. airliquide. com/ encyclopedia. asp?LanguageID=11& CountryID=19& Formula=& GasID=55& UNNumber=). Air Liquide Gas Encyclopedia. [44] Vaseline triggered explosion of hybrid rocket (http:/ / www. ukrocketman. com/ rocketry/ hybridukhistory. shtml). ukrocketman.com [45] Safetygram 20: Nitrous Oxide (http:/ / web. archive. org/ web/ 20060901093045/ http:/ / www. airproducts. com/ nr/ rdonlyres/ 8c46596e-2f7d-4895-b12a-e54cd63e1996/ 0/ safetygram20. pdf). airproducts.com [46] Giannini, AJ (1999) Drug Abuse. Los Angeles, Health Information Press, ISBN 1-885987-11-0. [50] Science | Nitrous Oxide | Climate Change | U.S. EPA (http:/ / www. epa. gov/ nitrousoxide/ scientific. html). Epa.gov (2006-06-28). Retrieved on 2011-04-11. [51] http:/ / unfccc. int/ 2860. php [52] 2011 U.S. Greenhouse Gas Inventory Report | Climate Change Greenhouse Gas Emissions | U.S. EPA (http:/ / www. epa. gov/ climatechange/ emissions/ usinventoryreport. html). Epa.gov. Retrieved on 2011-04-11. [53] FULL TEXT OF THE CONVENTION, ARTICLE 4(1) (a) (http:/ / unfccc. int/ essential_background/ convention/ background/ items/ 1362. php). Unfccc.int (1998-12-31). Retrieved on 2011-04-11. [58] Grossman, Lisa (28 August 2009) Laughing gas is biggest threat to ozone layer (http:/ / www. newscientist. com/ article/ dn17698-laughing-gas-is-biggest-threat-to-ozone-layer. html). NewScientist. [59] US Nitrous Oxide Laws (alphabetically) Based on a search of online free legal databases. Conducted May 2002 (http:/ / www. cognitiveliberty. org/ dll/ N20_state_laws. htm). Center for Cognitive Liberty and Ethics. [60] CAL. PEN. CODE 381b : California Code Section 381b (http:/ / codes. lp. findlaw. com/ cacode/ PEN/ 3/ 1/ 10/ s381b). lp.findlaw.com [61] Anderton, Jim (26 June 2005). Time's up for sham sales of laughing gas (http:/ / www. beehive. govt. nz/ release/ time039s-sham-sales-laughing-gas), Beehive.govt.nz.

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External links
Occupational Safety and Health Guideline for Nitrous Oxide (http://www.osha.gov/SLTC/healthguidelines/ nitrousoxide/recognition.html) Paul Crutzen Interview (http://www.vega.org.uk/video/programme/111) Freeview video of Paul Crutzen Nobel Laureate for his work on decomposition of ozone talking to Harry Kroto Nobel Laureate by the Vega Science Trust. National Pollutant Inventory Oxide of nitrogen fact sheet (http://www.npi.gov.au/database/substance-info/ profiles/67.html) National Institute for Occupational Safety and Health Nitrous Oxide (http://www.cdc.gov/niosh/topics/ nitrousoxide/) CDC NIOSH Pocket Guide to Chemical Hazards Nitrous Oxide (http://www.cdc.gov/niosh/npg/ npgd0465.html) Nitrous Oxide FAQ (http://www.justsayn2o.com) Erowid article on Nitrous Oxide (http://www.erowid.org/chemicals/nitrous/nitrous.shtml) Nitrous oxide fingered as monster ozone slayer (http://www.sciencenews.org/view/generic/id/46776/title/ Nitrous_oxide_fingered_as_monster_ozone_slayer), Science News

Nitrous oxide Dental Fear Central article on the use of nitrous oxide in dentistry (http://www.dentalfearcentral.org/help/ sedation-dentistry/laughing-gas/)

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Biogenic amine
A biogenic amine is a biogenic substance with one or more amine groups.

Examples
Some prominent examples of biogenic amines include: Histamine - a substance derived from the amino acid histidine that acts as a neurotransmitter mediating arousal and attention, as well as a pro-inflammatory signal released from mast cells in response to allergic reactions or tissue damage. Histamine is also an important stimulant of HCl secretion by the stomach through histamine H2 receptors. Serotonin - a central nervous system neurotransmitter derived from the amino acid tryptophan involved in regulating mood, sleep, appetite, and sexuality. The three catecholamine neurotransmitters: Norepinephrine (noradrenaline) - a neurotransmitter involved in sleep and wakefulness, attention, and feeding behavior, as well as a stress hormone released by the adrenal glands that regulates the sympathetic nervous system. Epinephrine (adrenaline) - an adrenal stress hormone, as well as a neurotransmitter present at lower levels in the brain. Dopamine - a neurotransmitter involved in motivation, reward, addiction, behavioral reinforcement, and coordination of bodily movement. The trace amines: 3-Iodothyronamine - a metabolite of the thyroid hormones, and has been hypothesized to be the primary endogenous ligand for the trace amine-associated receptor 1 (TAAR1). Tryptamine - a monoamine alkaloid found in trace amounts in the brains of mammals, and believed to play a role as a neuromodulator or neurotransmitter. Tyramine - a substance that is found in many common foods, and is associated with increased blood pressure and headaches. As well as others such as dimethyltryptamine (DMT), phenethylamine, and octopamine and the meta-substituted positional isomers of octopamine and tyramine.

Physiological importance
There is a distinction between endogenous and exogenous biogenic amines. Endogenous amines are produced in many different tissues (for example: adrenaline in adrenal medulla or histamine in mast cells and liver). The amines are transmitted locally or via the blood system. The exogenous amines are directly absorbed from food in the intestine. Alcohol can increase the absorption rate. Monoamine oxidase (MAO) breaks down biogenic amines and prevents excessive resorption. MAO inhibitors (MAOIs) are also used as medications for the treatment of depression to prevent MAO from breaking down amines important for positive mood.

Biogenic amine

186

References External links

The Biogenic Amines (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.405) Neuroscience 2nd edition, Dale Purves et al.

Monoamine neurotransmitter
Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain (-CH2-CH2-). All monoamines are derived from aromatic amino acids like phenylalanine, tyrosine, tryptophan, and the thyroid hormones by the action of aromatic amino acid decarboxylase enzymes. The function of monoamine is not clear but it is thought to trigger crucial components such as emotion, arousal, and cognition. It has however been found that monoamine neurotransmitters play an important role in the secretion and production of neurotriphin-3 by astrocytes, a chemical which maintains neuron integrity and provides neurons with trophic support.[1] Drugs used to increase the effect of monoamine may be used to treat patients with psychiatric disorders, including depression, anxiety, and schizophrenia.[]

Norepinephrine is a monoamine neurotransmitter

A phylogenetic tree showing how a number of monoamine receptors are related to each other.

Examples
Histamine (His/H is Diamine) Catecholamines: Dopamine (DA) Noradrenaline (NA, NAd) (Norepinephrine, NE) Adrenaline (Ad) (Epinephrine, Epi) Tryptamines: Serotonin (5-HT) Melatonin Trace amines:

Monoamine neurotransmitter -Phenylethylamine (PEA, -PEA) Tyramine Tryptamine Octopamine 3-Iodothyronamine Thyronamines, a new group of compounds derived from thyroid hormones

187

Specific transporter proteins called monoamine transporters that transport monoamines in or out of a cell exist. These are the dopamine transporter (DAT), serotonin transporter (SERT), and the norepinephrine transporter (NET) in the outer cell membrane and the vesicular monoamine transporter (VMAT1 and VMAT2) in the membrane of intracellular vesicles.[citation needed] After release into the synaptic cleft, monoamine neurotransmitter action is ended by reuptake into the presynaptic terminal. There, they can be repackaged into synaptic vesicles or degraded by the enzyme monoamine oxidase (MAO), which is a target of monoamine oxidase inhibitors, a class of antidepressants.[citation needed]

Evolution
As demonstrated by the wide existence of monoamine transmitters, an organism's ability to modify its behavior is advantageous to its survival. This system is found in various species such as nematodes, lobsters, desert locusts, hens, mice and zebra finches.[2]

Disorders
Disorders of monoamine neurotransmitters exist, part of a growing number of neurotransmitter disorders identified. Such disorders are responsible for biosynthesis degradation and difficulty in transporting neurotransmitters such as dopamine, norepinephrine, epinephrine, or serotonin. Monoamine neurotransmitter disorders mimic the symptoms of other more prevalent neurological disorders (e.g. cerebral palsy) and thus are frequently misdiagnosed.[]

References External links

Biogenic monoamines (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Biogenic+ monoamines) at the US National Library of Medicine Medical Subject Headings (MeSH)

Dopamine

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Dopamine
Dopamine

Identifiers CAS number PubChem ChemSpider UNII DrugBank KEGG ChEBI ChEMBL ATC code Jmol-3D images 51-61-6 681 661
[3] [4] [5] [1]

, 62-31-7

[2]

(hydrochloride)

VTD58H1Z2X DB00988 D07870

[6]

[7]

CHEBI:18243 CHEMBL59 C01 CA04 Image 1 Properties

[8]

[9]

[10]

[11]

Molecular formula Molar mass Appearance Density Melting point Boiling point Solubility in water
(verify) [12]

C H NO
8 11

153.18 g/mol colorless solid 1.26 g/cm3 128C, 401K, 262F decomposes 60.0 g/100 ml

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Dopamine is a simple organic chemical in the catecholamine and phenethylamine families that plays a number of important roles in the brains and bodies of animals. Its name derives from its chemical structure: it is an amine that is

Dopamine formed by removing a carboxyl group from a molecule of L-DOPA. In the brain, dopamine functions as a neurotransmittera chemical released by nerve cells to send signals to other nerve cells. The brain includes several distinct dopamine systems, one of which plays a major role in reward-motivated behavior. Every type of reward that has been studied increases the level of dopamine in the brain, and a variety of addictive drugs, including stimulants such as cocaine, amphetamine, and methamphetamine, act by amplifying the effects of dopamine. Other brain dopamine systems are involved in motor control and in controlling the release of several important hormones. Several important diseases of the nervous system are associated with dysfunctions of the dopamine system. Parkinson's disease, a degenerative condition causing tremor and motor impairment, is caused by loss of dopamine-secreting neurons in the midbrain area called the substantia nigra. There is evidence that schizophrenia involves altered levels of dopamine activity, and the antipsychotic drugs that are frequently used to treat it have a primary effect of attenuating dopamine activity. Attention deficit hyperactivity disorder (ADHD) and restless legs syndrome (RLS) are also believed to be associated with decreased dopamine activity. Outside the nervous system, dopamine functions in several parts of the body as a local chemical messenger. In the blood vessels it inhibits norepinephrine release and acts as a vasodilator; in the kidneys it increases sodium excretion and urine output; in the pancreas it reduces insulin production; in the digestive system it reduces gastrointestinal motility and protects intestinal mucosa; and in the immune system it reduces the activity of lymphocytes. With the exception of the blood vessels, dopamine in each of these peripheral systems has a "paracrine" function: it is synthesized locally and exerts its effects on cells that are located near the cells that release it. A variety of important drugs work by altering the way the body makes or uses dopamine. Dopamine itself is available for intravenous injection: although it cannot reach the brain from the bloodstream, its peripheral effects make it useful in the treatment of heart failure or shock, especially in newborn babies. L-DOPA, the metabolic precursor of dopamine, does reach the brain and is the most widely used treatment for Parkinson's disease. Dopamine-activating stimulants such as cocaine, amphetamine, and Ritalin are addictive in high doses, but are used at lower doses to treat ADHD. Conversely, many antipsychotic drugs act by suppressing the effects of dopamine. Drugs that act against dopamine by a different mechanism are also some of the most effective anti-nausea agents.

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Dopaminergic systems of the body

In the brain

Dopamine

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Inside the brain, dopamine plays important roles in motor control, motivation, arousal, cognition, and reward, as well as a number of lower-level functions including lactation, sexual gratification, and nausea. Dopaminergic neurons (i.e., neurons whose primary neurotransmitter is dopamine) are comparatively few in number a total of around 400,000 in the human brain[] and their cell bodies are confined to a few relatively small brain areas, but they send projections to many other brain areas and exert powerful effects on their targets. These dopaminergic cell groups were first mapped in 1964 by Annica Dahlstrm and Kjell Fuxe, who assigned them labels starting with the letter "A" (for "aminergic").[13] In their scheme, areas A1 through A7 contain the neurotransmitter norepinephrine, whereas A8 through A14 contain dopamine. Here is a list of the dopaminergic areas they identified:

Major dopamine pathways. As part of the reward pathway, dopamine is manufactured in nerve cell bodies located within the ventral tegmental area (VTA) and is released in the nucleus accumbens and the prefrontal cortex. The motor functions of dopamine are linked to a separate pathway, with cell bodies in the substantia nigra that manufacture and release dopamine into the striatum.

The substantia nigra, a small midbrain area that forms a component of the basal ganglia. The dopamine neurons are found mainly in a part of this structure called the pars compacta (cell group A8) and nearby (group A9).[] In rodents, their most important projections go to the striatum, globus pallidus, and subthalamic nucleus, all of which also belong to the basal ganglia, and play important roles in motor control. The name substantia nigra is Latin for "dark substance", and refers to the fact that the dopaminergic neurons there are darkly pigmented. These neurons are especially vulnerable to damage. When a large fraction of them die, the result is a Parkinsonian syndrome.[14] The ventral tegmental area (VTA), another midbrain area. This cell group (A10) is the largest group of dopaminergic cells in the human brain, though still quite small in absolute terms. Projections from these dopaminergic neurons go to the nucleus accumbens and the prefrontal cortex as well as several other areas.[] These neurons play a central role in reward and other aspects of motivation. The nucleus accumbens is often considered to be the "limbic" part of the striatum. As such, it is the part of the striatum involved in the highest level aspects of motor control, which include motivation and decision-making. Thus, the role of the VTA in motivation and decision-making is structurally analogous to the role of the substantia nigra in low-level motor control.[] In primates (i.e. monkeys and humans), the dopamine neurons from the regions of the substantia nigra and VTA project throughout most of the cortical mantle, with particularly dense innervation of the motor and premotor cortices. Thus, there are major species differences in cortical dopamine projections.[15] The posterior hypothalamus. These dopaminergic cells (group A11) project to the spinal cord, and their function is not well established. There is some evidence that pathology in this area plays a role in restless legs syndrome, a condition in which people have difficulty sleeping due to an overwhelming compulsion to constantly move parts of the body, especially the legs.[16] The arcuate nucleus (cell group A12) and periventricular nucleus (cell group A14) of the hypothalamus. An important projection from these dopaminergic neurons goes to the pituitary gland, where it influences the section of the hormone prolactin. Dopamine is the primary neuroendocrine inhibitor of the secretion of prolactin from the anterior pituitary gland. Dopamine produced by neurons in the arcuate nucleus is secreted into the hypothalamo-hypophysial blood vessels of the median eminence, which supply the pituitary gland. The lactotrope cells that produce prolactin, in the absence of dopamine, secrete prolactin continuously; dopamine inhibits this secretion. Thus, in the context of regulating prolactin secretion, dopamine is occasionally called prolactin-inhibiting factor (PIF), prolactin-inhibiting hormone (PIH), or prolactostatin.[]

Dopamine The zona incerta. These cells (group A13) project to several areas of the hypothalamus, and participate in the control of gonadotropin-releasing hormone, which is necessary to activate the development of reproductive systems that occurs following puberty, both in males and females.[] An additional group of dopamine-secreting neurons are located in the retina of the eye. These neurons are amacrine cells, meaning that they have no axons. They release dopamine into the extracellular medium, and are specifically active during daylight hours, becoming silent at night. This retinal dopamine acts to enhance the activity of cone cells in the retina while suppressing rod cells the result is to increase sensitivity to color and contrast during bright light conditions, at the cost of reduced sensitivity when the light is dim.[17]

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Outside the nervous system

Dopamine does not cross the bloodbrain barrier, so its synthesis and functions in peripheral areas are to a large degree independent of its synthesis and functions in the brain. A substantial amount of dopamine circulates in the bloodstream, but its functions there are not entirely clear. Dopamine is found in blood plasma at levels comparable to those of epinephrine, but in humans, over 95% of the dopamine in the plasma is in the form of dopamine sulphate, a conjugate produced by the enzyme Sulfotransferase 1A3/1A4 acting on free dopamine. The bulk of this dopamine sulphate is produced in the mesentric organs that surround parts of the digestive system. The production of dopamine sulphate is thought to be a mechanism for detoxifying dopamine that is ingested as food or produced by the digestive process plasma levels typically rise more than fifty-fold after a meal. Dopamine sulphate has no known biological functions and is excreted in urine.[] The relatively small quantity of unconjugated dopamine in the bloodstream may be produced by the sympathetic nervous system, the digestive system, or possibly other organs. It may act on dopamine receptors in peripheral tissues, or be metabolized, or be converted to norepinephrine by the enzyme dopamine beta hydroxylase, which is released into the bloodstream by the adrenal medulla.[] Some dopamine receptors are located in the walls of arteries, where they act as a vasodilator and an inhibitor of norepinephrine release.[] These responses might be activated by dopamine released from the carotid body under conditions of low oxygen, but whether arterial dopamine receptors perform other biologically useful functions is not known. Beyond its role in modulating blood flow, there are several peripheral systems in which dopamine circulates within a limited area and performs an exocrine or paracrine function.[] The peripheral systems in which dopamine plays an important role include: The immune system. Dopamine acts upon receptors present on immune cells, especially lymphocytes.[] Dopamine can also affect immune cells in the spleen, bone marrow, and circulatory system.[18] In addition, dopamine can be synthesized and released by immune cells themselves.[] The main effect of dopamine on lymphocytes is to reduce their activation level. The functional significance of this system is unclear, but it afford a possible route for interactions between the nervous system and immune system, and may be relevant to some autoimmune disorders.[19] The kidneys. Multiple types of dopamine receptors are present in cells of the kidneys. Dopamine is also synthesized there, by tubule cells, and discharged into the tubular fluid. Its actions include increasing the blood supply to the kidneys, increasing filtration by the glomeruli, and increasing excretion of sodium in the urine. Defects in renal dopamine function can be produced by high blood pressure or by genetic problems, and can lead to reduced sodium excretion as well as hypertension.[20] The pancreas. The role of dopamine here is somewhat complex. The pancreas consists of two parts, known as exocrine and endocrine. The exocrine part synthesizes enzymes and other substances, and secretes them into the small intestine, where food is digested. One of the substances synthesized and secreted by the exocrine pancreas is dopamine. The function of this secreted dopamine after it enters the small intestine is not clearly established the possibilities include protecting the intestinal mucosa from damage and reducing gastrointestinal mobility (the rate at which food moves through the intestines).[]

Dopamine The endocrine part of the pancreas, also known as the islets of Langerhans, synthesizes a number of hormones, including insulin, and secretes them into the bloodstream. There is evidence that the beta cells that synthesize insulin contain dopamine receptors, and that dopamine acts to reduce the amount of insulin they release. The source of their dopamine input is not clearly established it may come from dopamine that circulates in the bloodstream and derives from the sympathetic nervous system, or it may be synthesized locally by other types of pancreatic cells.[]

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Cellular effects
Dopamine receptors in the mammal brain
Family Receptor D1-like D1 D5 D2-like D2 D3 D4 Gene DRD1 DRD5 DRD2 DRD3 DRD4 [21] [22] [23] G /G -coupled. i o [24] [25] Decrease intracellular levels of cAMP by inhibiting adenylate cyclase. Type Gs-coupled. Mechanism Increase intracellular levels of cAMP by activating adenylate cyclase.

Like many other biologically active substances, dopamine exerts its effects by binding to and activating receptors located on the surface of cells. In mammals, five subtypes of dopamine receptors have been identified, labeled D1 through D5. All of them function as G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system. Glossing over the details, dopamine receptors in mammals can be divided into two families, known as D1-like and D2-like. The ultimate effect of D1-like receptors (D1 and D5) can be excitation (via opening of sodium channels) or inhibition (via opening of potassium channels); the ultimate effect of D2-like receptors (D2, D3, and D4) is usually inhibition of the target neuron. Consequently, it is incorrect to describe dopamine itself as either excitatory or inhibitory. Its effect on a target neuron depends on which types of receptors are present on the membrane of that neuron and on the internal responses of that neuron to cyclic AMP. D1 receptors are the most numerous dopamine receptors in the central nervous system; D2 receptors are next; D3, D4, and D5 receptors are present at significantly lower levels. The level of extracellular dopamine is modulated by two mechanisms: tonic and phasic dopamine transmission. Tonic dopamine transmission occurs when small amounts of dopamine are released independently of neuronal activity, and is regulated by the activity of other neurons and neurotransmitter reuptake.[26] Phasic dopamine release results from the activity of the dopamine-containing cells themselves. This activity is characterized by irregular pacemaking activity of single spikes, and rapid bursts of typically 2-6 spikes in quick succession.[27][28]

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193

The substantia nigra dopamine system and motor control

The substantia nigra is a component of the basal ganglia, a group of interconnected structures in the forebrain and midbrain that play a central role in motor control. The precise nature of that role has been difficult to work out, but one popular line of thought describes it as "response selection". The response selection theory proposes that when a person or animal is in a situation where several behaviors are possible, activity in the basal ganglia determines which of them is executed, by releasing that response from inhibition. Thus the basal ganglia are responsible for initiating behaviors but not for determining the details of how they are carried out. Dopamine is thought to modulate the response selection process in at least two important ways. First, dopamine sets the "effort threshold" for initiating behaviors. The higher the level of dopamine activity, the lower the impetus required to evoke a given behavior. As a consequence, high levels of dopamine lead to high levels of motor activity and "impulsive" behavior; low levels of dopamine lead to torpor and slowed reactions. Parkinson's disease, in which Main circuits of the basal ganglia. The dopaminergic pathway from the dopamine levels in the substantia nigra circuit are substantia nigra pars compacta to the striatum is shown in light blue. greatly reduced, is characterized by stiffness and greatly reduced movementhowever, when people with the disease are confronted with strong stimuli such as a serious threat, their reactions can be as vigorous as those of a healthy person. In the opposite direction, drugs that increase the effects of dopamine, such as cocaine or amphetamine, produce heightened levels of activity, including at the highest levels psychomotor agitation and stereotyped movements. The second important effect of dopamine is as a "teaching" signal. When a motor response is followed by an increase in dopamine activity, the basal ganglia circuit is altered in a way that makes the same response easier to evoke when similar situations arise in the future. This is a form of operant conditioning, in which dopamine plays the role of a reward signal.

Anatomy and physiology

The anatomy of the basal ganglia is extraordinarily complex, and the role of dopamine there is correspondingly complex. On a macroscopic scale there is only one major dopamine projection, from the substantia nigra pars compacta to the striatum, but the dopamine inputs contact multiple types of neurons and have several distinct effects on their targets, activating some via D1 receptors while inhibiting others via D2 receptors. A substantial number of dopamine inputs are delivered to the necks of dendritic spines, where they are well-placed to exert a gating effect on specific synaptic connections, often arising from the cerebral cortex. There are two distinct pathways of signal flow arising from the striatum, known as the direct pathway and indirect pathway. Dopamine is thought to promote action by upregulating the direct pathway while suppressing the indirect pathway.

Dopamine Many theoreticians believe that the mechanism underlying motor learning in the basal ganglia involves a form of long-term potentiation that occurs in the striatum and is strongly modulated by dopaminein other words, a mechanism by which dopamine activity induces strengthening or weakening of synaptic connections inside the striatum.[29]

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The ventral tegmental area, reward, and cognition

The ventral tegmental area (VTA) contains the largest group of dopamine neurons in the human brain. They project to numerous brain areas, but the two largest projections are the mesolimbic pathway, which targets the nucleus accumbens and other limbic structures, and the mesocortical pathway, which targets the prefrontal and insular parts of the cerebral cortex. There is a strong functional analogy between the VTA dopamine system and the substantia nigra dopamine system. The basal ganglia consist of a set of parallel circuits, which all have similar architecture but control different aspects of behavior. Most of these circuits run through the striatum, which receives dopamine from the substantia nigra. The striatal circuits control low-level forms of response selection, that is, behaviors that use particular muscle groups or specific action patterns. The "limbic" circuit, however, runs through the nucleus accumbens (also known as the "limbic striatum"), which receives dopamine from the VTA. The limbic circuit controls the highest-level aspects of response selection, such as planning and decision-making. The low-level striatal circuits are connected to the primary motor and premotor parts of the cerebral cortex; the limbic circuit is connected to the prefrontal cortex. Thus, the effect of VTA dopamine on high-level decision-making is functionally analogous to the effect of substantia nigra dopamine on the execution of simple movements.

Reinforcement and reward-seeking behavior

Dopamine is strongly associated with the reward system of the brain. Dopamine is released in areas such as the nucleus accumbens and prefrontal cortex as a result of rewarding experiences such as food, sex, and neutral stimuli that become associated with them.[] The source of this dopamine is primarily the VTA, although the substantia nigra may also contribute. Electrical stimulation of the VTA or its output pathways can itself serve as a potent reward: animals will quickly learn to press a lever if it results in stimulation of dopamine release, and often will continue pressing the lever for a long time, at steadily increasing rates.[] A variety of drugs that increase dopamine levels are intrinsically rewarding and increase the effects of other types of reward.[] In spite of the overwhelming evidence showing a strong association between dopamine and reward, there has been a great deal of dispute about whether the function of dopamine should be described as reward per se, or as some more complex construct that relates strongly to reward. The difficulty arises mainly from two observations: (1) in addition to being rewarding, dopamine is also arousing it produces a general increase in movement of all sorts; (2) dopamine release can be caused by events that do not seem to have anything to do with reward, most notably pain. One of the most popular alternatives to the reward theory is the "incentive salience" theory, which argues that the function of dopamine is to increase the effects of motivators of all sorts, both positive and negative.[] A substantial body of evidence suggests that dopamine encodes not reward itself, but rather reward prediction error, that is, the degree to which reward is surprising. According to this hypothesis, which derives initially from recordings made by Wolfram Schultz, rewards that are expected do not produce any activation of dopamine cells, but rewards that are greater than expected produce a short-lasting increase in dopamine, whereas the omission of an expected reward actually causes dopamine release to drop below its ordinary background level. The "prediction error" hypothesis has drawn particular interest from computational neuroscientists, because an influential computational-learning method known as temporal difference learning makes heavy use of a signal that encodes prediction error. This confluence of theory and data has led to a fertile interaction between theoretical and empirical neuroscientists.[]

Dopamine Recent research finds that while some dopaminergic neurons react in the way expected of reward neurons, others do not and seem to respond in regard to salience, including aversive stimuli.[] This research finds the reward neurons predominate in the ventromedial region in the substantia nigra pars compacta as well as the ventral tegmental area. Neurons in these areas project mainly to the ventral striatum and thus might transmit value-related information in regard to reward values.[] The salience neurons are predominate in the dorsolateral area of the substantia nigra pars compacta which projects to the dorsal striatum and may relate to orienting behaviour.[] It has been suggested that the difference between these two types of dopaminergic neurons arises from their input: reward-linked ones have input from the basal forebrain, while the salience-related ones from the lateral habenula.[] In primates, neurons from the regions of both the substantia nigra and VTA project to the prefrontal cortex;[] the origins of the dopamine innervation of other cortical areas in primate have not been studied. It has been appreciated for many years that exposure to even mild, uncontrollable stress increases dopamine release in the rodent prefrontal cortex, e.g. reviewed in,[] suggesting that dopamine salience cells have a large influence on this cortical region. Animal studies Clues to dopamine's role in motivation, desire, and pleasure, as well as in higher cognition, have come from studies performed on animals. In one such study, rats were depleted of dopamine by up to 99 percent in the nucleus accumbens and neostriatum using 6-hydroxydopamine.[] With this large reduction in dopamine, the rats would no longer eat of their own volition. The researchers then force-fed the rats food and noted whether they had the proper facial expressions indicating whether they liked or disliked it. The researchers of this study concluded that the reduction in dopamine did not reduce the rat's consummatory pleasure, only the desire to eat. In another study, mutant hyperdopaminergic (increased dopamine) mice show higher "wanting" but not "liking" of sweet rewards.[] Mice who cannot synthesize dopamine are unable to feed sufficiently to survive more than a few weeks after birth, but will feed normally and survive if administered L-DOPA.[] Dopamine modulates foraging behavior in animals, by activating brain systems registering reward when food sources are found.[30] When monkeys are given a highly palatable food, dopamine levels rise, but levels then decline when the palatable food is available for prolonged periods of time and is no longer novel.[31] Dopamine's effects on higher cognitive function have been studied in monkeys and rodents. This work began with the landmark study of Brozoski et al., 1979 showing that depletion of catecholamines from the dorsolateral prefrontal cortex in monkeys impaired spatial working memory to the same degree as removing the cortex itself.[] It is now known that both dopamine and norepinephrine have essential actions on prefrontal cortical function, and help coordinate cognitive state with arousal state.[] Dopamine has an "inverted U" influence on prefrontal function through its actions on D1 receptors, where either too little or too much impairs working memory function.[] In the primate prefrontal cortex, dopamine D1 receptor stimulation selectively influences the firing of "Delay" cells (also called "Memory" cells), while dopamine D2 receptors selectively alter the firing of "Response cells".[] The role of dopamine in primate cortex beyond the frontal lobe has not been

195

Diseases and disorders

The dopamine system plays a central role in a number of important medical conditions, including Parkinson's disease, attention deficit hyperactivity disorder, schizophrenia, and drug addiction.

Parkinson's disease
Parkinson's disease is a disorder characterized by stiffness of the body, slowing of movement, and trembling of limbs when they are not in use. In advanced stages it progresses to dementia and eventually death. The main symptoms are caused by massive loss of dopamine-secreting cells in the substantia nigra. These dopamine cells are especially vulnerable to damage, and a variety of insults, including encephalitis (as depicted in the book and movie "Awakenings"), repeated sports-related concussions, and some forms of chemical poisoning, can lead to substantial

Dopamine cell loss, producing a Parkinsonian syndrome that is similar in its main features to Parkinson's disease. Most cases of Parkinson's disease, however, are "idiopathic", meaning that the cause of cell death cannot be identified. The most widely used treatment for Parkinsonism is administration of L-DOPA, the metabolic precursor for dopamine. This treatment cannot restore the dopamine cells that have been lost, but it causes the remaining cells to produce more dopamine, thereby compensating for the loss to at least some degree. In advanced stages the treatment begins to fail because the cell loss is so severe that the remaining ones cannot produce enough dopamine regardless of L-DOPA levels. As this stage is approached, the metabolic regulatory mechanisms in the dopamine cells, operating far above their normal level, become erratic, producing dopamine dysregulation syndrome, in which patients fluctuate unpredictably between states of hyperactivity and paralysis.[]

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Attention deficit hyperactivity disorder

Altered dopamine neurotransmission is implicated in attention deficit hyperactivity disorder (ADHD), a condition associated with impaired ability to regulate attention, behavior, and/or impulses. There are some genetic links between dopamine receptors, the dopamine transporter and ADHD,[32], in addition to links to other neurotransmitter receptors and transporters. The most important relationship between dopamine and ADHD involves the drugs that are used to treat ADHD. Some of the most effective therapeutic agents for ADHD are psychostimulants such as Ritalin and amphetamine, drugs that increase both dopamine and norepinephrine levels in brain.[33]

Drug addiction
A variety of addictive drugs produce an increase in reward-related dopamine activity. For some addictive drugs such as alcohol or heroin, activation of the reward system may play only a minor role in addiction, with suppression of suffering being the dominant mechanism, but for other drugs, including nicotine and psychomotor stimulants such as cocaine and methamphetamine, enhancement of dopamine activity appears to be the primary factor. When people addicted to stimulants go through withdrawal, they do not experience the physical suffering associated with withdrawal from alcohol or opiates; instead they experience apathy, boredom, restlessness, and most importantly an overwhelming urge to consume more of the drug. When dopamine levels are increased for a period of time, the sensitivity of the receptors is down-regulated the consequence is that steadily increasing doses of a drug are required to produce the same effect, and that the brain's reward system becomes less active than usual in the absence of the drug. This mechanism causes people who abuse stimulants to feel an urge to steadily escalate their consumption. If consumption levels become very high, the ability of the body to regulate dopamine may be compromised, producing erratic behavior as well as cardiac side-effects that in some cases can be fatal. The addiction potential for stimulants is strongly dependent on the level of dopamine increase they produce, and particularly on the speed with which they act. The most addictive drugs, such as cocaine in the form of "crack", raise dopamine levels in the brain within seconds of consumption. For drugs such as these, even a few exposures can be enough to produce symptoms of addiction in some people. Treatment of stimulant addiction is very difficult, because even if consumption ceases, the urge to consume takes a long time to decrease, and even when apparently gone can reappear unexpectedly if a person is placed in a situation that is mentally associated with drug use. The brain mechanisms underlying these cravings have been a topic of extensive research. There is evidence that they are associated with long-lasting changes in the density of dopamine receptors in parts of the brain.

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Pain
Dopamine has been demonstrated to play a role in pain processing in multiple levels of the central nervous system including the spinal cord, periaqueductal gray (PAG), thalamus, basal ganglia, and cingulate cortex. Accordingly, decreased levels of dopamine have been associated with painful symptoms that frequently occur in Parkinson's disease. Abnormalities in dopaminergic neurotransmission have also been demonstrated in painful clinical conditions, including burning mouth syndrome,[34] fibromyalgia, and restless legs syndrome. In general, the analgesic capacity of dopamine occurs as a result of dopamine D2 receptor activation; however, exceptions to this exist in the PAG, in which dopamine D1 receptor activation attenuates pain presumably via activation of neurons involved in descending inhibition.[35] In addition, D1 receptor activation in the insular cortex appears to attenuate subsequent pain-related behavior.

Nausea
Nausea and vomiting are largely determined by activity in a brainstem area known as the chemoreceptor trigger zone. This area contains a large population of type D2 dopamine receptors. Consequently, drugs that activate D2 receptors have a high potential to cause nausea. This group includes some medications that are administered for Parkinson's disease, as well as other dopamine agonists such as apomorphine. In many cases, D2-receptor antagonists such as metoclopramide are useful as anti-nausea drugs.

Psychosis
Abnormally high dopaminergic transmission has been linked to psychosis and schizophrenia.[36] However, clinical studies relating schizophrenia to brain dopamine metabolism have ranged from controversial to negative, with HVA levels in the CSF the same for schizophrenics and controls.[37] Increased dopaminergic functional activity, specifically in the mesolimbic pathway, is found in schizophrenic individuals. However, decreased activity in another dopaminergic pathway, the mesocortical pathway, may also be involved. The two pathways are thought to be responsible for differing sets of symptoms seen in schizophrenia.[citation needed] Antipsychotic medications act largely as dopamine antagonists, inhibiting dopamine at the receptor level, and thereby blocking the effects of the neurochemical in a dose-dependent manner. The older, so-called typical antipsychotics most commonly act on D2 receptors,[38] while the atypical drugs also act on D1, D3 and D4 receptors, though they have a lower affinity for dopamine receptors in general.[39][40] The finding that drugs such as amphetamines, methamphetamine and cocaine, which can increase dopamine levels by more than tenfold,[41] can temporarily cause psychosis, provides further evidence for this link.[42] However, many non-dopaminergic drugs can induce acute and chronic psychosis.[43] The NMDA antagonists Ketamine and PCP both are used in research to reproduce the positive and negative symptoms commonly associated with schizophrenia.[44][45] Dopaminergic dysregulation has also been linked to depressive disorders.[46] Early research in humans used various methods of analyzing dopamine levels and function in depressed patients. Studies have reported that there is decreased concentration of tyrosine, a precursor to dopamine, in the blood plasma, ventricular spinal fluid, and lumbar spinal fluid of depressed patients compared to control subjects.[47][48] One study measured the amount of homovanillic acid, the major metabolite of dopamine in the CSF, as a marker for the dopamine pathway turnover rate, and found decreased concentrations of homovanillic acid in the CSF of depressed patients.[49] Postmordem real time reverse transcriptase-polymerase chain reaction (RT-PCR) has also been used to find that gene expression of a specific subtype of dopamine receptor was elevated in the amygdale of people suffering from depression as compared to control subjects.[50] The action of commonly used antidepressant drugs also has yielded information about possible alterations of the dopaminergic pathway in treating depression. It has been reported that many antidepressant drugs increase extracellular dopamine concentrations in the rat prefrontal cortex,[51] but vary greatly in their affects on the striatum and nucleus accumbens.[52][53] This can be compared to electro convulsive shock treatment (ECT), which has been

Dopamine shown to have a multiple fold increase in striatal dopamine levels in rats.[54] More recent research studies with rodents have found that depression-related behaviors are associated with dopaminergic system dysregulation.[] In rodents exposed to chronic mild stress, decreased escape behavior and decreased forced swimming is reversed with activation of the dopaminergic mesolimbic pathway.[] Also, rodents that are susceptible to depression-related behavior after social defeat can have their behavior reversed with dopamine pathway activation.[55] Depletion of dopamine in the caudate nucleus and nucleus accumbens has also been reported in cases of learned helplessness in animals. These symptoms can be reversed with dopamine agonists and antidepressant administration prior to the learned helplessness protocol.[56]

198

Comparative biology and evolution

Microorganisms
There are no reports of dopamine in archaea, but it has been detected in some types of bacteria and in a type of protozoan called Tetrahymena.[57] Perhaps more importantly, there are types of bacteria that contain homologs of all the enzymes that animals use to synthesize dopamine. It has even been proposed that animals derived their dopamine-synthesizing machinery from horizontal gene transfer that may have occurred relatively late in evolutionary time, perhaps as a result of the symbiotic incorporation of bacteria into eukaryotic cells that gave rise to mitochondria.[58]

Animals
Dopamine is used as an intercellular messenger in virtually all multicellular animals. In sponges only a single report exists of the presence of dopamine, with no indication of its function;[59] however, dopamine has been reported in the nervous systems of numerous radially symmetric species, including cnidaria (jellyfish, hydra, corals, etc.).[60] This dates the emergence of dopamine as a neurotransmitter back to the earliest appearance of the nervous system, over 500 million years ago in the Cambrian era. Among existing species, dopamine functions as a neurotransmitter in vertebrates, echinoderms, arthropods, molluscs, and several types of worms.[61][62] In every type of animal that has been examined, dopamine acts to modify motor behavior.[] In the much-studied nematode worm Caenorhabditis elegans, it reduces locomotion and increases food-exploratory movements; in planarian worms it produces "screw-like" movements; in leeches it inhibits swimming and promotes crawling; etc. Across a wide range of vertebrates, dopamine has an "activating" effect on behavior-switching and response selection, comparable to its effect in mammals.[] Dopamine also consistently plays a role in reward learning, in all animal groups that have been examined except arthropods. In nematodes, planarians, molluscs, and vertebrates, animals can be trained to repeat an action if it is consistently followed by an increase in dopamine levels.[] Arthropods are an exception, though. In these species insects, crustaceans, etc. dopamine has an aversive effect, and reward is instead mediated by octopamine, a neurotransmitter that is not found in vertebrates but is thought to be closely related to norepinephrine. In insects, dopamine increases aversion learning for olfactory stimuli as well as visual stimuli, and reduces approach learning for stimuli that are followed by rewards. It also improves recall for aversive memories and reduces recall for positive memories.[] The origin of the striking reversal between dopamine's effects in arthropods versus all other types of animals has not been explained.

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Plants
Many plants synthesize dopamine to varying degrees, including a variety of food plants. The highest concentrations have been observed in bananas the fruit pulp of red and yellow bananas contains dopamine at levels of 40 to 50 parts per million by weight. Potatoes, avocados, broccoli, and Brussels sprouts may also contain dopamine at levels of 1 part per million or more; oranges, tomatoes, spinach, beans, and other plants contain measurable concentrations less than 1 part per million.[] The dopamine in plants is synthesized from the amino acid Dopamine can be found in the peel and fruit pulp tyrosine, by biochemical mechanisms similar to those that animals use. of bananas It can be metabolized in a number of ways, producing melanin and a variety of alkaloids as byproducts.[] The functions of plant catecholamines have not been clearly established, but there is evidence that they play a role in the response to stressors such as bacterial infection, act as growth-promoting factors in some situations, and modify the way that sugars are metabolized. The receptors that mediate these actions have not yet been identified, nor have the intracellular mechanisms that they activate.[] Dopamine consumed in food cannot act on the brain, because it cannot cross the bloodbrain barrier. However, there are also a variety of plants that contain L-DOPA, the metabolic precursor of dopamine.[] The highest concentrations are found in the leaves and bean pods of plants of the genus Mucuna, especially in Mucuna pruriens (velvet beans), which have been used as a source for L-DOPA as a drug.[63] Another plant containing substantial amounts of L-DOPA is Vicia faba, the plant that produces fava beans (also known as "broad beans"). The level of L-DOPA in the beans, however, is much lower than in the pod shells and other parts of the plant.[64] The seeds of Cassia and Bauhinia trees also contain substantial amounts of L-DOPA.[] In the marine green alga Ulvaria obscura, which is a major component of some algal blooms, dopamine is present in very high concentrations, estimated at 4.4% of dry weight. There is evidence that this dopamine functions as an anti-herbivore defense, reducing consumption by snails and isopods.[65]

As a precursor for melanin

Melanins are a family of dark-pigmented substances that are found in a wide range of organisms. Their physical properties make them difficult to work with experimentally, and consequently a number of aspects of their biochemistry are not well understood. Chemically they are closely related to dopamine, and there is a type of melanin, known as "dopamine-melanin", that can be synthesized by oxidation of dopamine via the enzyme tyrosinase.[66] The melanin that darkens human skin is not of this type: it is synthesized by a pathway that uses L-DOPA as a precursor but not dopamine. However, there is substantial evidence that the "neuromelanin" that gives a dark color to the brain's substantia nigra is at least in part dopamine-melanin.[67] Dopamine-derived melanin probably appears in at least some other biological systems as well. Some of the dopamine in plants is likely to be used as a precursor for dopamine-melanin.[68] The complex patterns that appear on butterfly wings, as well as black-and-white stripes on the bodies of insect larvae, are also thought to be caused by spatially structured accumulations of dopamine-melanin.[69]

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Pharmacology
Dopamine as an injectable drug
Under the trade names Intropin, Dopastat, Revimine, or other names, dopamine can be used as a drug in injectable form. It is most commonly used in the treatment of severe hypotension, bradycardia (slow heart rate), circulatory shock, or cardiac arrest, especially in newborn infants. Its effects, depending on dosage, include an increase in sodium excretion by the kidneys, an increase in urine output, an increase in heart rate, and an increase in blood pressure. At a "cardiac dose" of 5 to 10 g/kg/min, dopamine acts through the sympathetic nervous system to increase heart muscle contraction force and heart rate, thereby increasing cardiac output and blood pressure. At a "pressor dose" of 10 to 20 g/kg/min, dopamine also causes vasoconstriction that further increases blood pressure, but can produce negative side effects such as an impairment of kidney function.[] Older literature also describes a so-called "renal dose" of 2 to 5 g/kg/min thought to improve kidney function without other consequences, but recent reviews have concluded that doses at this low level are not clinically effective and may sometimes be harmful.[70]

L-DOPA
Levodopa is a dopamine precursor used in various forms to treat Parkinson's disease and dopa-responsive dystonia. It is typically co-administered with an inhibitor of peripheral decarboxylation (DDC, dopa decarboxylase), such as carbidopa or benserazide. Inhibitors of alternative metabolic route for dopamine by catechol-O-methyl transferase are also used. These include entacapone and tolcapone.

Psychomotor stimulants
Cocaine and amphetamines inhibit the re-uptake of dopamine; however, they influence separate mechanisms of action. Cocaine is a dopamine transporter and norepinephrine transporter blocker that competitively inhibits dopamine uptake to increase the lifetime of dopamine and augments an overabundance of dopamine (an increase of up to 150 percent) within the parameters of the dopamine neurotransmitters. Like cocaine, amphetamines increase the concentration of dopamine in the synaptic gap, but by a different mechanism. Amphetamines and methamphetamine are similar in structure to dopamine, and so can enter the terminal bouton of the presynaptic neuron via its dopamine transporters as well as by diffusing through the neural membrane directly.[citation needed] By entering the presynaptic neuron, amphetamines force dopamine molecules out of their storage vesicles and expel them into the synaptic gap by making the dopamine transporters work in reverse.

Antipsychotic drugs
A range of drugs that reduce dopamine activity have been found useful in the treatment of schizophrenia and other disorders that produce psychosis. These antipsychotic drugs are also sometimes known as neuroleptics or "major tranquilizers", in contrast to "minor tranquilizers" such as Valium that are used to treat anxiety or sleep disorders. These drugs have a broadly suppressive effect on most types of active behavior, and particularly reduce the delusional and agitated behavior characteristic of overt psychosis. The introduction of the first widely used antipsychotic drug, chlorpromazine (Thorazine), in the 1950s, led to the release of many schizophrenia patients from institutions in the years that followed. Even so, the widespread use of antipsychotic drugs has long been controversial. There are several reasons for this. First, these drugs are perceived as very aversive by people who have to take them, because they produce a general dullness of thought and suppress the ability to experience pleasure.[] Second, it is difficult to show that they act specifically against psychotic behaviors rather than merely suppressing all types of active behavior. Third, they can produce a range of serious side effects, including weight gain, diabetes, fatigue, sexual dysfunction, hormonal changes, and a type of movement disorder known as tardive dyskinesia. Some of these side effects may continue

Dopamine long after the cessation of drug use, or even permanently. The first drugs introduced specifically for the treatment of psychosis all had strong direct effects on multiple aspects of dopamine function. Drugs of this type are known as "typical antipsychotics". Because of the problems they cause, there has been wide interest in newer types of drugs known as "atypical antipsychotics" or "second-generation antipsychotics", which aim to target the specific types of dopamine receptors involved in psychosis, and thereby reduce psychotic symptoms without producing as many undesirable side effects. There remains substantial dispute, however, about how much of an improvement in the patient experience these drugs produce.

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Toxicity
The LD50, or dose which is expected to be lethal in 50% of the population, has been found to be: 59mg/kg (mouse; administered i.v.); 950mg/kg (mouse; administered i.p.); 163mg/kg (rat; administered i.p.); 79mg/kg (dog; administered i.v.)[71]Wikipedia:Please clarify

Biochemical mechanisms
Structurally, dopamine belongs to the catecholamine and phenethylamine classes. In biological systems, dopamine is synthesized in brain cells and adrenal cells from the precursor L-DOPA. In brain cells, it is transported to synaptic sites and packaged into vesicles for release, which occurs during synaptic transmission. After release, free dopamine is either reabsorbed into the presynaptic terminal for reuse, or broken down by the enzymes monoamine oxidase or COMT, producing a variety of degradation metabolites.

Biosynthesis
Dopamine is synthesized in a restricted set of cell types, mainly neurons and cells in the medulla of the adrenal glands. This is the metabolic pathway:
L-Phenylalanine

L-Tyrosine L-DOPA Dopamine

Thus the direct precursor of dopamine is L-DOPA, but this itself can be synthesized from the essential amino acid phenylalanine or the non-essential amino acid tyrosine. These amino acids are found in nearly every protein and as such are provided from ingestion of protein-containing food, with tyrosine being the most common. Although dopamine itself is also found in many types of food, it is incapable of crossing the bloodbrain barrier that surrounds and protects the brain. It must therefore be synthesized inside the brain in order to perform its neural actions.
L-Phenylalanine

is converted into L-tyrosine by the enzyme phenylalanine hydroxylase (PAH), with molecular oxygen (O2) and tetrahydrobiopterin (THB) as cofactors. L-Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase (TH), with tetrahydrobiopterin (THB), O2, and ferrous iron (Fe2+) as cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (AAAD; also known as DOPA decarboxylase (DDC)), with pyridoxal phosphate (PLP) as the cofactor. Dopamine itself is also used as precursor in the synthesis of the neurotransmitters norepinephrine and epinephrine. Dopamine is converted

Catecholamine biosynthesis

Dopamine into norepinephrine by the enzyme dopamine -hydroxylase (DBH), with O2 and L-ascorbic acid as cofactors. Norepinephrine is converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT) with S-adenosyl-L-methionine (SAMe) as the cofactor. It should be noted that some of the cofactors also require their own synthesis. Deficiency in any required amino acid or cofactor will result in subsequent dopamine, norepinephrine, and epinephrine biosynthesis impairment and deficiency.

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Storage, release, and reuptake

Inside the brain dopamine functions as a neurotransmitter, and is controlled by a set of mechanisms that are common to all neurotransmitters. After synthesis, dopamine is transported from the cytosol into synaptic vesicles by the vesicular monoamine transporter 2 (VMAT2). Dopamine is stored in and remains in these vesicles until an action potential occurs and causes the contents of the vesicles to be ejected into the synaptic cleft. Once in the synapse, dopamine binds to and activates dopamine receptors, which can be located either on postsynaptic target cells or on the membrane of the dopamine-releasing cell itself (i.e., autoreceptors). After an action potential, the dopamine molecules quickly become unbound from their receptors. They are then absorbed back into the presynaptic cell, via reuptake mediated either by the high-affinity dopamine transporter (DAT) or by the low-affinity plasma membrane monoamine transporter (PMAT). Once back in the cytosol, dopamine is subsequently repackaged into vesicles by VMAT2, making it available for future release.

Degradation
Dopamine is broken down into inactive metabolites by a set of enzymes, monoamine oxidase (MAO), aldehyde dehydrogenase (ALDH), and catechol-O-methyl transferase (COMT), acting in sequence. Both isoforms of MAO, MAO-A and MAO-B, are equally effective. The metabolites produced by these processes are: DOPAL (3,4-Dihydroxyphenylacetaldehyde) DOPAC (3,4-Dihydroxyphenylacetic acid) DOPET (3,4-dihydroxyphenylethanol, also known as Hydroxytyrosol) MOPET (3-methoxy-4-hydroxyphenylethanol, also known as Homovanillyl alcohol) 3-MT (3-Methoxytyramine) HVA (Homovanillic acid) All of these are intermediate metabolites except MOPET and HVA, which are filtered from the bloodstream by the kidneys and then excreted in the urine.

Dopamine degradation

Dopamine The specific reactions that make up these pathways are: Dopamine DOPAL, mediated by MAO DOPAL DOPAC, mediated by ALDH DOPAL DOPET, mediated by aldose reductase (minor pathway) DOPAC HVA, mediated by COMT DOPET MOPET, mediated by COMT Dopamine 3-MT, mediated by COMT 3-MT HVA, mediated by MAO

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In most areas of the brain, including the striatum and basal ganglia, dopamine is inactivated by reuptake via the DAT, then enzymatic breakdown by MAO into DOPAC. In the prefrontal cortex, however, there are very few DAT proteins, and dopamine is inactivated instead by reuptake via the norepinephrine transporter (NET), presumably on neighboring norepinephrine neurons, then enzymatic breakdown by COMT into 3-MT.[72] The DAT pathway is roughly an order of magnitude faster than the NET pathway: in mice, dopamine concentrations decay with a half-life of 200 milliseconds in the caudate nucleus (which uses the DAT pathway) versus 2,000 milliseconds in the prefrontal cortex.[73] Dopamine that is not broken down by enzymes is repackaged into vesicles for future release.

Chemistry

Dopamine

Phenethylamine structure

Catechol structure

Chemically, a dopamine molecule consists of a catechol structure (a benzene ring with two hydroxyl side groups) with one amine group attached. As such, dopamine is the simplest possible catecholamine, a family that also includes the neurotransmitters norepinephrine and epinephrine. The presence of a benzene ring with an attached amine group makes it a phenethylamine, a family that includes numerous psychoactive drugs. Dopamine, like most amines, is an organic base. At neutral or acidic pH levels it is generally protonated. The protonated form is highly water-soluble and relatively stable, though it is capable of oxidizing if exposed to oxygen or other oxidants. At basic pH levels, dopamine becomes deprotonated. In this free base form it is less soluble and also highly reactive and easily oxidized. Because of this pH-dependence, dopamine is supplied for chemical or pharmaceutical use in the form of dopamine hydochloride, that is, the hydrochloride salt that is created when dopamine is combined with hydrochloric acid. In dry form, dopamine hydrochloride is a fine colorless powder. When dissolved in distilled water it gives a solution that is mildly acidic and therefore relatively stable. It cannot, however, be combined with alkaline solutions such as a bicarbonate buffer without being rendered inactive.

Oxidation
Dopamine in the body is normally broken down by oxidation catalyzed by the enzyme monoamine oxidase. However, dopamine is also capable of autoxidation, that is, direct reaction with oxygen, yielding quinones plus various free radicals as products.[] The rate of autoxidation can be increased by the presence of ferrous iron or other factors. The ability of dopamine autoxidation to produce quinones and free radicals makes it a potent cell toxin, and there is evidence that this mechanism may contribute to cell loss that occurs in Parkinson's disease or other conditions.[74]

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Polydopamine
Research motivated by mussel adhesive proteins led to the discovery in 2007 that a wide variety of materials, if placed in a solution of dopamine at slightly basic pH, will become coated with a layer of polymerized dopamine, often referred to as "polydopamine". This polymerized dopamine forms by a spontaneous oxidation reaction, and is formally a type of melanin.[] Polydopamine coatings can form on objects ranging in size from nanoparticles to large surfaces. Polydopamine layers have chemical properties that have the potential to be extremely useful, and numerous studies have examined their possible applications. At the simplest level, they can be used for protection against damage by light, or to form capsules for drug delivery. At a more sophisticated level, their adhesive properties may make them useful as substrates for biosensors or other biologically active macromolecules.[]

History
Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Laboratories in London, England.[75] It was named dopamine because it is a monoamine whose precursor in the Barger-Ewens synthesis is 3,4-dihydroxyphenylalanine (levodopamine or L-DOPA). Dopamine's function as a neurotransmitter was first recognized in 1958 by Arvid Carlsson and Nils-ke Hillarp at the Laboratory for Chemical Pharmacology of the National Heart Institute of Sweden.[76] Carlsson was awarded the 2000 Nobel Prize in Physiology or Medicine for showing that dopamine is not only a precursor of norepinephrine (noradrenaline) and epinephrine (adrenaline), but also a neurotransmitter.

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=51-61-6 [2] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=62-31-7 [3] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=681 [4] http:/ / www. chemspider. com/ 661 [5] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=VTD58H1Z2X [6] http:/ / www. drugbank. ca/ drugs/ DB00988 [7] http:/ / www. kegg. jp/ entry/ D07870 [8] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=18243 [9] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL59 [10] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01CA04 [11] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=c1cc%28c%28cc1CCN%29O%29O [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=464188976& page2=Dopamine [21] http:/ / www. genenames. org/ data/ hgnc_data. php?match=DRD1 [22] http:/ / www. genenames. org/ data/ hgnc_data. php?match=DRD5 [23] http:/ / www. genenames. org/ data/ hgnc_data. php?match=DRD2 [24] http:/ / www. genenames. org/ data/ hgnc_data. php?match=DRD3 [25] http:/ / www. genenames. org/ data/ hgnc_data. php?match=DRD4 [30] http:/ / onlinelibrary. wiley. com/ doi/ 10. 1207/ s15516709cog0000_50/ abstract [31] http:/ / www. jneurosci. org/ content/ 13/ 3/ 900. full. pdf [38] http:/ / www. williams. edu/ imput/ synapse/ pages/ IIIB5. htm [39] http:/ / bjp. rcpsych. org/ cgi/ content/ full/ 181/ 4/ 271 [41] Methamphetamine 101 (http:/ / 74. 125. 153. 132/ search?q=cache:b3pkrTPLeT0J:www. stopmethinflorida. org/ documents/ Methamphetamine101. ppt+ www. stopmethinflorida. org/ documents/ Methamphetamine101. ppt& cd=1& hl=en& ct=clnk& gl) [43] Cardinal, R.N. & Bullmore, E.T., The Diagnosis of Psychosis, Cambridge University Press, 2011, ISBN 978-0-521-16484-9 [44] The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia (http:/ / www. sciencedirect. com/ science/ article/ pii/ S0893133X98000608) [71] R. J. Lewis (Ed.) (2004), Sax's Dangerous Properties of Industrial Materials, 11th Ed., p. 1552, Wiley & Sons, Hoboken, NJ. [75] Fahn, Stanley, "The History of Levodopa as it Pertains to Parkinson's disease," Movement Disorder Society's 10th International Congress of Parkinson's Disease and Movement Disorders on November 1, 2006, in Kyoto, Japan. (http:/ / movementdisorders. org/ education/ onlinecme/ levodopa/ print. pdf)

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External links
DrugBank APRD00085 (http://www.drugbank.ca/drugs/APRD00085) U.S. National Library of Medicine: Drug Information Portal - Dopamine (http://druginfo.nlm.nih.gov/ drugportal/dpdirect.jsp?name=Dopamine)

Dopaminergic pathways
Dopaminergic pathways are neural pathways in the brain which transmit the neurotransmitter dopamine from one region of the brain to another.[] The neurons of the dopaminergic pathways have axons which run the entire length of the pathway. The neurons' soma produce the enzymes that synthesize dopamine, and they are then transmitted via the projecting axons to their synaptic destinations, where most of the dopamine is produced. Dopaminergic nerve cell bodies in such areas as the substantia nigra tend to be pigmented due to the presence of the black pigment melanin.
Mesolimbic dopaminergic and serotonergic pathways.

Examples
There are eight dopaminergic pathways, but the four major ones are:
Name Description Disorders schizophrenia

mesolimbic pathway The mesolimbic pathway transmits dopamine from the ventral tegmental area (VTA) to the limbic system via the nucleus accumbens. The VTA is located in the midbrain, and the nucleus accumbens is in the ventral striatum. The "meso-" prefix in the word "mesolimbic" refers to the midbrain, or "middle brain", since "meso" means "middle" in Greek. mesocortical pathway The mesocortical pathway transmits dopamine from the VTA to the frontal cortex. The "meso-" prefix in "mesocortical" refers to the VTA which is located in the midbrain, and "cortical" refers to the cortex.

schizophrenia

nigrostriatal pathway tuberoinfundibular pathway

The nigrostriatal pathway transmits dopamine from the substantia nigra to the striatum. This pathway Parkinson's disease, is associated with motor control. chorea The tuberoinfundibular pathway transmits dopamine from the hypothalamus to the pituitary gland. This pathway influences the secretion of certain hormones, including prolactin. "Infundibular" in the word "tuberoinfundibular" refers to the cup or infundibulum out of which the pituitary gland develops. hyperprolactinaemia

Minor ones include the incertohypothalamic pathway within the hypothalamus, which has a role in sexual behaviour.

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References
The Reward Circuit (http://www.thebrain.mcgill.ca/flash/a/a_03/a_03_cl/a_03_cl_que/a_03_cl_que.html). Part of "The Brain From Top To Bottom". The content of this page is copylefted and has been used in this article.

Mesocortical pathway
Dopaminergic pathways are neural pathways in the brain which transmit signals from one region of the brain to another, resulting in release of the neurotransmitter dopamine in the receiving region. [] The mesocortical pathway is a neural pathway that connects the ventral tegmentum to the cerebral cortex, particularly the frontal lobes. It is one of the four major dopamine pathways in the brain. It is essential to the normal cognitive function of the dorsolateral prefrontal cortex (part of the frontal lobe), and is thought to be involved in motivation and emotional response.

Dopaminergic and serotonergic pathways. Mesocortical pathway can be seen projecting to the prefrontal cortex from the VTA.

This pathway may be the brain system that is abnormal or functioning abnormally in psychoses, such as schizophrenia.[1] It is thought to be associated with the negative symptoms of schizophrenia which include avolition, alogia and flat affect. This pathway is closely associated with the mesolimbic pathway, which is also known as the mesolimbic reward pathway.

Other dopamine pathways

Other major dopamine pathways include: mesolimbic pathway nigrostriatal pathway tuberoinfundibular pathway

References
[1] Diaz, Jaime. How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall, 1996.

External links
Diagram (http://gslc.genetics.utah.edu/units/addiction/reward/pathways.cfm)

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Mesolimbic pathway
The mesolimbic pathway is a dopaminergic pathway in the brain. The pathway begins in the ventral tegmental area of the midbrain and connects to the limbic system via the nucleus accumbens, the amygdala, and the hippocampus as well as to the medial prefrontal cortex. The mesolimbic dopamine system is widely believed to be a "reward" pathway, but that hypothesis is not universally accepted.[1]

Anatomy
The following structures are considered to be a part of the mesolimbic pathway: Ventral Tegmental Area The ventral tegmental area (VTA) is a part of the midbrain. It consists of dopaminergic, GABAergic, and glutamatergic neurons.[2] The VTA communicates with the nucleus accumbens via the medial forebrain bundle. Nucleus Accumbens The nucleus accumbens is found in the ventral striatum and is composed of medium spiny neurons.[3][4] It is subdivided into limbic and motor subregions known as the shell and core.[2] The medium spiny neurons receive input from both the dopaminergic neurons of the VTA and the glutamatergic neurons of the hippocampus, amygdala, and medial prefrontal cortex. When they are activated by these inputs, the medium spiny neurons' projections release GABA onto the ventral pallidum.[2] The release of dopamine in this structure drives the mesolimbic system. Amygdala The amygdala is a large nuclear mass in the temporal lobe anterior to the hippocampus. It has been associated with the assignment of emotions, especially fear and anxiety. There are two, one in each temporal lobe, and their functions may be lateralized. Hippocampus The hippocampus is located in the medial portion of the temporal lobe. It is known for its association with double memory (i.e., both procedural and declarative memory). Bed Nucleus of the Stria Terminalis
Mesolimbic dopaminergic and serotonergic pathways.

Controversy over mesolimbic dopamine function

There is some controversy regarding dopamines role in the reward system. Three hypotheses hedonia, learning, and incentive salience have been proposed as explanations for dopamines function in the reward system.[1] The hedonia hypothesis suggests that dopamine in the nucleus accumbens acts as a 'pleasure neurotransmitter'. Historically, in the late 1970s, it was found that some drugs of abuse involved dopamine activity, particularly in the nucleus accumbens, to cause the "high" or euphoric state. However, not all rewards or pleasurable things involve activation of the reward system, which may suggest that the mesolimbic pathway may not be just a system that

Mesolimbic pathway works merely off enjoyable things (hedonia).[5] Learning, on the other hand, deals with predictions of future rewards and association formation. Studies have shown that rats that had their ventral tegmental area and nucleus accumbens destroyed do not lose their learning capabilities, but rather lack the motivation to work for a reward.[1] Incentive salience (wanting) stands out as a possible role for dopamine as it regards this molecule as being released when there is a stimulus worth working hard for, thus making an individual work to get it. This is one of the reasons why dopamine transport has been extensively studied in the case of ADD and ADHD. It is now widely understood that most people suffering from some form of attention deficit disorder most likely lack dopamine stimulation. This also explains why dopamine reuptake inhibitors and stimulants often dramatically improve symptoms of attention disorders. In self-administration studies, animals have been trained to give an operant response (lever press, nose poke, wheel turn, etc.) in order to obtain either a drug or mate. It has been shown that the animals will continue to perform the required task until the reward is received, or fatigue sets in.[2][5]

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Clinical significance
Since the mesolimbic pathway is shown to be associated with feelings of reward and desire, this pathway is heavily implicated in neurobiological theories of addiction, schizophrenia, and depression.[6][7][8] Drug addiction, the loss of control over drug use or the compulsive seeking and taking of drugs despite adverse consequences, with the four major classes of abused drugs (psychostimulants, opiates, ethanol, and nicotine) are due to increased dopamine transmission in the limbic system-each by different mechanisms.[2][9] Like drug addiction, schizophrenia and depression have similar structural changes with dopamine transmission.[6]

Other dopamine pathways

The other dopamine pathways are: mesocortical pathway nigrostriatal pathway tuberoinfundibular pathway

References
[1] Berridge KC. 2007. The debate over dopamine's role in reward: the case for incentive salience. Psychopharmacology 191:391-431 [2] Pierce RC, Kumaresan V. 2006. The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse? Neuroscience and Biobehavioral Reviews 30:215-38 [3] Zhang TA, Maldve RE, Morrisett RA. 2006. Coincident signaling in mesolimbic structures underlying alcohol reinforcement. Biochemical Pharmacology 72:919-27 [4] Purves D et al. 2008. Neuroscience. Sinauer 4ed. 754-56 [5] Neill D. Emory University. Personal Interview. 14 Oct. 2008 [6] Van den Heuval DMA, Pasterkamp RJ. 2008. Getting connected in the dopamine system. Progress in Neurobiology 85:75-93 [7] Laviolette SR. 2007. Dopamine modulation of emotional processing in cortical and subcortical neural circuits: evidence for a final common pathway in schizophrenia? Schizoprenia Bulletin 33:971-981 [8] Diaz J. 1996. How Drugs Influence Behavior: A Neurobehavorial Approach. Prentice Hall [9] Janhunen S, Ahtee L. 2007. Differential nicotinic regulation of the nigrostriatal and mesolimbic dopaminergic pathways: Implications for drug development. Neuroscience and Biobehavioral Reviews 31:287-314

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Ventral tegmental area

Brain: Ventral tegmentum

Transverse section of mid-brain at level of superior colliculi. (Tegmentum labeled at center right.) Latin NeuroNames NeuroLex ID Area tegmentalis ventralis hier-512
[1] [2]

birnlex_1415

The ventral tegmentum (tegmentum is Latin for covering), better known as the ventral tegmental area (VTA), is a group of neurons located close to the midline on the floor of the midbrain (mesencephalon). The VTA is the origin of the dopaminergic cell bodies of the mesocorticolimbic dopamine system and is widely implicated in the drug and natural reward circuitry of the brain. It is important in cognition, motivation, drug addiction, intense emotions relating to love, and several psychiatric disorders. The VTA contains neurons that project to numerous areas of the brain, from the prefrontal cortex (PFC) to the caudal brainstem and several regions in between.

Anatomy
Neurobiologists have often had great difficulty distinguishing the VTA in humans and other primate brains from the substantia nigra (SN) and surrounding nuclei. Originally, the ventral tegmentum was designated as a nucleus, but over time area became the more appropriate term used because of the heterogeneous cytoarchitectonic features of the region and the lack of clear borders that separate it from adjacent regions. Because of the selective limbic-related afferents to the VTA, the cells of the VTA are given the designation A10 to differentiate them from surrounding cells.

Anatomical location of VTA in humans.

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Location
The VTA is in the midbrain between several other major areas, some of which are described here. The mammilary bodies and the posterior hypothalamus, both included in the diencephalon, extend rostrally from the VTA. The nucleus ruber (red nucleus) is situated lateral and oculomotor fibers are situated ventromedial to the VTA. The pons and the hindbrain (rhombencephalon) lie caudally to the VTA. Finally, the substantia nigra is located laterally to the VTA.

Structure
In 1987, Oades identified four primary nuclei in the VTA A10 group of cells: the nucleus paranigralis (Npn), the nucleus parabrachialis pigmentosus (Npbp), the nucleus interfascicularis (Nif), and the nucleus linearis (Nln) caudalis and rostralis. Presently, scientists divide the VTA up into four similar zones that are called the paranigral nucleus (PN), the parabrachial pigmented area (PBP), the parafasciculus retroflexus area (PFR), and the ventral tegmental tail (VTT), which approximately adhere to the previous divisions. Some definitions of the VTA also include the midline nuclei (i.e. the interfascicular nucleus, rostral linear nucleus, and central linear nucleus). The PN and PBP are rich in dopaminergic cells, whereas the other two regions have low densities of these neurons. The PFR and VTT contain a low density of tyrosine hydroxylase (TH)-positive cell bodies that are small in size and lightly stain. On the other hand, the PN and PBP consist mainly of medium to large sized TH-positive cell bodies that stain moderately.

Function
As stated above, the VTA, particularly the VTA dopamine neurons, serve several functions in the reward system, motivation, cognition, drug addiction, and may be the focus of several psychiatric disorders. It has also been shown to process various types of emotion output from the amygdala, where it may also play a role in avoidance and fear-conditioning. Electrophysiological recordings have demonstrated that VTA neurons respond to novel stimuli, unexpected rewards, and reward predictive sensory cues. The firing pattern of these cells is consistent with the encoding of a reward expectancy error. In 2006 MRI Studies by Helen Fisher and her research team found and documented various emotional states relating to intense love correlated with activity in the VTA, which may help explain obsessive behaviors of rejected partners since this is shared by the reward system.

Presence of gap junctions

The VTA has been shown to have a large network of GABAergic neurons that are interconnected via gap junctions. This network allows for electrical conduction, which is considerably faster than the chemical conduction of signals between synapses.

Development
Because they develop from common embryonic tissue and partly overlap in their projection fields, Dopaminergic cell groups lack clear anatomical boundaries. During the development of the mammalian brain, both substantia nigra (SN) and VTA neurons initially project to the dorsolateral and ventromedial striatum. However, at birth the SN dopaminergic neurons project exclusively into the dorsolateral striatum, and the VTA dopaminergic neurons project solely into the ventromedial striatum. This pruning of connections occurs through the elimination of the unnecessary collaterals.

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Neural composition
The VTA, like the substantia nigra, is populated with melanin-pigmented dopaminergic neurons [3]. Recent studies have suggested that dopaminergic neurons comprise 50-60% of all neurons in the VTA,[4] which is contrary to previous evidence which noted 77% of neurons within the VTA to be dopaminergic.[5] Additionally, there is a sizable population of GABAergic neurons in the VTA. These GABAergic neurons regulate the firing of their dopaminergic counterparts and send projections throughout the brain to, but not limited to, the following regions: the prefrontal cortex, the nucleus accumbens, and the locus coeruleus. The VTA also contains a small percentage of excitatory glutamatergic neurons.

Comparative anatomy
All studies since 1964 have emphasized the impressive general similarity between the VTA of all mammals from rodents to humans. These studies have focused their efforts on rats, rabbits, dogs, cats, opossum, non-human primates, and humans. There have been slight differences noted, such as changes in the dorsal extent of the A10 cells. More specifically, the dorsal peak of A10 cells is more extensive in primates when compared to other mammals. Furthermore, the number of dopaminergic cells in the VTA increases with phylogenetic progression; for instance, the VTA of the mouse contains approximately 25,000 neurons, while the VTA of a 33 year-old man contains around 450,000 cell bodies.

Outputs
The two primary efferent fiber projections of the VTA are the mesocortical and the mesolimbic pathways. Three less important pathways also exists: the mesostriatal, the mesodiencephalic, and the mesorhombencephalic pathways. Below is a brief summary of where each pathway originates and terminates: Mesostriatal: originates in the SN and VTA; innervates the anteromedial striatum Mesocortical: originates in the VTA; innervates the prefrontal and insular cortices Mesolimbic: originates in the VTA; innervates the limbic cortices, septo-hippocampal complex, nucleus accumbens (NAC), and amygdala Mesencephalic: originates in the SN and VTA; innervates several thalamic nuclei and several hypothalamic nuclei Mesorhombencephalic: originates in the SN and VTA; innervates the monoaminergic nuclei, superior colliculus, reticular formation, and periaqueductal gray The large mesolimbic pathway projects primarily to the NAC and the olfactory tubercle. The projection is so named to contrast it with the nigro-striatal dopamine system that runs parallel to it but connects the substantia nigra to the dorsal striatum. Other projections of the VTA dopamine neurons include the limbic-related regions (i.e. septum, hippocampus, amygdala, and prefrontal cortex). The mesocortical pathway projects to sensory, motor, limbic, and polysensory association cortices. The prefrontal, orbitofrontal, and cingulate cortices receive the majority of innervation from the VTA. Most of these connections are unilateral, but some project to one or more areas.

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Inputs
Almost all areas receiving projections from the VTA project back to it. Thus, the ventral tegmentum is reciprocally connected with a wide range of structures throughout the brain suggesting that it has a role in the control of function in the phylogenetically new and highly developed neocortex, as well as that of the phylogenetically older limbic areas. There are excitatory glutamatergic afferents that arise from almost every structure that projects into the VTA, except the NAC and the lateral septum. These glutamatergic afferents play a key role in regulating VTA cell firing. When the glutamatergic neurons are activated, the firing rates of the dopamine neurons increase in the VTA and induce burst firing. Studies have shown that these glutamatergic actions in the VTA are critical to the effects of drugs of abuse. Subpallidal afferents into the VTA are mainly GABAergic and, thus, inhibitory. There is a substantial pathway from the subpallidal area to the VTA. When this pathway is disinhibited, an increase in the dopamine release in the mesolimbic pathway amplifies locomotor activity.

Limbic loop
The limbic loop is very similar to the direct pathway motor loop of the basal ganglia. In both systems, there are major excitatory inputs from the cortex to the striatum (accumbens nucleus), the midbrain project neuromodulatory dopamine neurons to the striatum, the striatum makes internuclear connections to the pallidum, and the pallidum has outputs to the thalamus, which projects to the cortex, thus completing the loop. The limbic loop is distinguished from the motor loop by the source and nature of the cortical input, the division of the striatum and pallidum that process the input, the source of the dopaminergic neurons form the midbrain, and the thalamic target of the pallidal output.

CA3 loop
Linking context to reward is important for reward seeking. Recently a group of researchers documented a VTA-CA3 loop that uses the lateral septum as an intermediary. They used a pseudo-rabies virus (PRV) as a transsnyaptic tracer, and injected it into the VTA. They found that unilateral injection into the VTA resulted in bilateral PRV labeling in CA3 beginning 48 hours after injection. Lesions of the caudodorsal lateral septum (cd-LS) prior to VTA PRV injection resulted in significantly less PRV labeled neurons in CA3. Theta wave stimulation of CA3 resulted in increased firing rates for dopamine cells in the VTA, and decreased firing rates for GABA neurons in the VTA. The identity of VTA neurons was confirmed by neurobiotin labeling of the recording neuron, and then histological staining for tyrosine hydroxylase (TH). Temporary inactivation of CA3 via GABA agonists prevented context induced reinstatement of lever pressing for intravenous cocaine.[] The authors propose a functional circuit loop where activation of glutamatergic cells in CA3 causes activation of GABAergic cells in cd-LS, which inhibits GABA interneurons in the VTA, releasing the dopamine cells from the tonic inhibition, and leading to an increased firing rate for the dopamine cells. []

Reward system
The dopamine reward circuitry in the human brain involves two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. First, the posteromedial VTA and central linear raphe cells selectively project to the ventromedial striatum, which includes the medial olfactory tubercle and the medial NAC shell. Secondly, the lateral VTA largely projects to the ventrolateral striatum, which includes the NAC core, the medial NAC shell, and the lateral olfactory tubercle. These pathways are respectively called the meso-ventromedial and the meso-ventrolateral striatal dopamine systems. The medial projection system is important in the regulation of arousal characterized by affect and drive and plays a different role in goal-directed behavior than the lateral projection system. Unlike the lateral part, the medial one is activated not by rewarding but by noxious stimuli.[6]

Ventral tegmental area Therefore, the NAC shell and the posterior VTA are the primary areas involved in the reward system. Normally, the dopaminergic neurons are only phasically active. When they are excited they fire a barrage of action potentials and dopamine is released in the NAC. The medium spiny neurons of the NAC are much more responsive to this increase in dopamine if there is coincident excitatory input form the telencephalic structures such as the amygdala and orbital-medial prefrontal cortex. The activated striatal neurons (NAC neurons) then project to the ventral pallidum where they inhibit the inhibitory GABA neurons. This inhibition in the pallidum disinhibits the thalamic target of the limbic loop, which is the mediodorsal nucleus. The thalamus then innervates the cortical division of the limbic forebrain. This final connection is reinforced by activity in direct cortical projections from the dopaminergic neurons of the VTA.

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Clinical relevance
Disorders
The dopaminergic neurons of the substantia nigra and the ventral tegmental area of the midbrain project to the dorsolateral caudate/putamen and to the ventromedially located nucleus accumbens, respectively, establishing the mesostriatal and the mesolimbic pathways. The close proximity of these two pathways causes them to be grouped together under dopaminergic projections. Several disorders result from the disruption of these two pathways: schizophrenia, Parkinson's disease, and attention deficit hyperactivity disorder (ADHD). Current research is examining the subtle difference between the neurons that are involved in these diseases and trying to find a way to selectively treat a specific dopamine projection.

Drug addiction
The nucleus accumbens (NAc) and the ventral tegmental area (VTA) are the primary sites where drugs of abuse act. The following are commonly considered abused drugs: heroin, cocaine, alcohol, opiates, marijuana, nicotine, amphetamine and their synthetic analogs. These drugs alter the neuromodulatory influence of dopamine on the processing of reinforcement signals by prolonging the action of dopamine in the nucleus accumbens or by potentiating the activation of neurons in the VTA and NAc. The most common drugs of abuse stimulate the release of dopamine, which creates both their rewarding and the psychomotor effects. Compulsive drug taking behaviors are a result of the permanent functional changes in the mesolimbic dopamine system arising from repetitive dopamine stimulation. Molecular and cellular adaptations are responsible for a sensitized dopamine activity in the VTA and along the mesolimbic dopamine projection in response to drug abuse. In the VTA of addicted individuals, the activity of the dopamine-synthesizing enzyme tyrosine hydroxylase increases, as does the ability of these neurons to respond to excitatory inputs. The latter effect is secondary to increases in the activity of the transcription factor CREB and the up regulation of GluR1, an important subunit of AMPA receptors for glutamate. These alterations in neural processing could account for the waning influence of adaptive emotional signals in the operation of decision making faculties as drug-seeking and drug-taking behaviors become habitual and compulsive. Experiments in rats have shown that animals learn to press a lever for the administration of drugs such as nicotine, carbachol, opiates, cocaine, and ethanol into the posterior VTA more readily than into the anterior VTA. Other studies have shown that microinjections of dopaminergic drugs into the NAc shell increase locomotor activity and exploratory behaviors, conditioned approach responses, and anticipatory sexual behaviors. The withdrawal phenomenon occurs because the deficit in reward functioning causes the organism to enter a distress cycle where the drugs become necessary to restore the normal homeostatic state. Recent research has shown that even after the final stages of withdrawal have been passed, an organism will reinstate the drug-seeking behavior if exposed to the drug or drug-related stimuli.

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Notes
[1] [2] [3] [4] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=512 http:/ / www. neurolex. org/ wiki/ birnlex_1415 http:/ / cogprints. org/ 1390/ 2/ vta-rev-87. pdf Margolis EB, Lock H, Hjelmstad GO, Fields HL. 2006b. The ventral tegmental area revisited: Is there an electrophysiological marker for dopaminergic neurons? J. Physiol. 577(Pt. 3):90724 [5] Johnson, S.W., & North, R.A., (1992). TWO TYPES OF NEURONE IN THE RAT VENTRAL TEGMENTAL AREA AND THEIR SYNAPTIC INPUTS. Journal of Physiology, 450, p. 455-468

References
Alcaro A, Huber R, Panksepp J. Behavioral functions of the mesolimbic dopaminergic system: An affective neuroethological perspective. Brain Research Reviews. 2007 Dec;56(2):283-321. Geisler S, Derst C, Veh RW, Zahm DS. Glutamatergic afferents of the ventral tegmental area in the rat. Journal of Neuroscience. 2007 May;27(21):5730-43. Hikosaka O, Bromberg-Martin E, Hong S, Matsumoto M. New insights on the subcortical representation of reward. Current Opinion in Neurobiology. 2008 Apr;18(2):203-8. Hu ZL, Cooper M, Crockett DP, Zhou RP. Differentiation of the midbrain dopaminergic pathways during mouse development. Journal of Comparative Neurology. 2004 Aug;476(3):301-11. Ikemoto S. Dopamine reward circuitry: Two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Research Reviews. 2007 Nov;56(1):27-78. Lammel S, Hetzel A, Haeckel O, Jones I, Liss B, Roeper J. Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron. 2008 Mar;57(5):760-73. Lu XY, Ghasemzadeh MB, Kalivas PW. Expression of D-1 receptor, D-2 receptor, substance P and enkephalin messenger RNAs in the neurons projecting from the nucleus accumbens. Neuroscience. 1998 Feb;82(3):767-80. Margolis EB, Lock H, Hjelmstad GO, Fields HL. The ventral tegmental area revisited: is there an electrophysiological marker for dopaminergic neurons ? Journal of Physiology-London. 2006 Dec;577(3):907-24. Oades RD, Halliday GM. VENTRAL TEGMENTAL (A10) SYSTEM - NEUROBIOLOGY .1. ANATOMY AND CONNECTIVITY. Brain Research Reviews. 1987 May;12(2):117-65. Olson VG, Nestler EJ. Topographical organization of GABAergic neurons within the ventral tegmental area of the rat. Synapse. 2007 Feb;61(2):87-95. Purves D, Augustin GJ, Fitzpatrick D, Hall WC, LaMantia AS, McNamara JO, White LE. Neuroscience. 4th ed. Sunderland: Sinauer Associates, Inc., 2008. Sziraki I, Sershen H, Hashim A, Lajtha A. Receptors in the ventral tegmental area mediating nicotine-induced dopamine release in the nucleus accumbens. Neurochemical Research. 2002 Mar;27(3):253-61. vanFurth WR, vanRee JM. Sexual motivation: Involvement of endogenous opioids in the ventral tegmental area. Brain Research. 1996 Aug;729(1):20-8. Wu M, Hrycyshyn AW, Brudzynski SM. Subpallidal outputs to the nucleus accumbens and the ventral tegmental area: Anatomical and electrophysiological studies. Brain Research. 1996 Nov;740(1-2):151-61.

References

Frontal lobe

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Frontal lobe
Brain: Frontal lobe

Principal fissures and lobes of the cerebrum viewed laterally. (Frontal lobe is shown in blue.)

Latin Gray's Part of Artery Acronym(s) NeuroNames MeSH NeuroLex ID

lobus frontalis subject #189 821 Cerebrum Anterior cerebral Middle cerebral FL hier-37
[2] [3] [1]

Frontal+Lobe birnlex_928

[4]

The frontal lobe is an area in the brain of mammals, located at the front of each cerebral hemisphere and positioned anterior to (in front of) the parietal lobe and superior and anterior to the temporal lobes. It is separated from the parietal lobe by a space between tissues called the central sulcus, and from the temporal lobe by a deep fold called the lateral (Sylvian) sulcus. The precentral gyrus, forming the posterior border of the frontal lobe, contains the primary motor cortex, which controls voluntary movements of specific body parts. The frontal lobe contains most of the dopamine-sensitive neurons in the cerebral cortex. The dopamine system is associated with reward, attention, short-term memory tasks, planning, and motivation. Dopamine tends to limit and select sensory information arriving from the thalamus to the fore-brain. A report from the National Institute of Mental Health says a gene variant that reduces dopamine activity in the prefrontal cortex is related to poorer performance and inefficient functioning of that brain region during working memory tasks.

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Anatomy
On the lateral surface of the human brain, the central sulcus separates the frontal lobe from the parietal lobe. The lateral sulcus separates the frontal lobe from the temporal lobe. The frontal lobe can be divided into a lateral, polar, orbital (above the orbit; also called basal or ventral), and medial part. Each of these parts consists of particular gyri: Lateral part: Precentral gyrus, lateral part of the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus. Polar part: Transverse frontopolar gyri, frontomarginal gyrus. Orbital part: Lateral orbital gyrus, anterior orbital gyrus, posterior orbital gyrus, medial orbital gyrus, gyrus rectus.
Animation. Frontal lobe (red) of left cerebral hemisphere.

Medial part: Medial part of the superior frontal gyrus, cingulate gyrus.

The gyri are separated by sulci. E.g., the precentral gyrus is in front of the central sulcus, and behind the precentral sulcus. The superior and middle frontal gyri are divided by the superior frontal sulcus. The middle and inferior frontal gyri are divided by the inferior frontal sulcus. In humans, the frontal lobe reaches full maturity around only after the 20s,[5] marking the cognitive maturity associated with adulthood. A small amount of atrophy, however, is normal in the aging persons frontal lobe. Fjell, in 2009, studied atrophy of the brain in people aged 6091 years. The 142 healthy participants were scanned using MRI (magnetic resonance imaging). Their results were compared to those of 122 participants with Alzheimers disease. The participants returned one year later, and the researchers noted that although volumetric decline was clearly evident in large amounts in the AD participants, it was also evident in small quantities in the healthy individuals. A decline in frontal lobe volume of approximately .5% over that year seemed to be average.[6] These findings corroborate those of Coffey, who in 1992 indicated that the frontal lobe decreases in volume approximately .55%-1% per year.[7] Dr. Arthur Toga, a UCLA professor of neurology, found increased myelin in the frontal lobe white matter of young adults compared to that of teens. A typical onset of schizophrenia in early adult years correlates with poorly myelinated and thus inefficient connections between cells in the fore-brain.

Function
The executive functions of the frontal lobes involve the ability to recognize future consequences resulting from current actions, to choose between good and bad actions (or better and best), override and suppress socially unacceptable responses, and determine similarities and differences between things or events. The frontal lobes also play an important part in retaining longer term memories which are not task-based. These are often memories associated with emotions derived from input from the brain's limbic system. The frontal lobe modifies those emotions to generally fit socially acceptable norms. Psychological tests that measure frontal lobe function include finger tapping, Wisconsin Card Sorting Task, and measures of verbal and figural fluency.[8]

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Psychosurgery
In the early 20th century, a medical treatment for mental illness, first developed by Portuguese neurologist Egas Moniz, involved damaging the pathways connecting the frontal lobe to the limbic system. Frontal lobotomy (sometimes called frontal leucotomy) successfully reduced distress but at the cost of often blunting the subject's emotions, volition and personality. The indiscriminate use of this psychosurgical procedure, combined with its severe side effects and dangerous nature, gained it a bad reputation. The frontal lobotomy has largely died out as a psychiatric treatment. More precise psychosurgical procedures are still used, although rarely. They may include anterior capsulotomy (bilateral thermal lesions of the anterior limbs of the internal capsule) or the bilateral cingulotomy (involving lesions of the anterior cingulate gyri) and might be used to treat otherwise untreatable obsessional disorders or clinical depression.

Theories of function
Theories of frontal lobe function can be differentiated into four categories: Single-process theories. Posit "that damage to a single process or system is responsible for a number of different dysexecutive symptoms (Burgess, 2003, p.309). Multi-process theories. Propose that the frontal lobe executive system consists of a number of components that typically work together in everyday actions [(heterogeneity of function)] (Burgess, 2003, p.310). Construct-led theories. Assume that most if not all frontal functions can be explained by one construct (homogeneity of function) such as working memory or inhibition (Stuss, 1999, p.348; cf. Burgess & Simons, 2005). Single-symptom theories. Suggest that a specific dysexecutive symptom (e.g., confabulation) is related to the processes and construct of the underlying structures (cf. Burgess & Simons, 2005). Stuss (1999) suggests a differentiation into two categories according to homogeneity and heterogeneity of function. Further theoretical approaches to frontal lobe function include: Grafman's managerial knowledge units (MKU) / structured event complex (SEC) approach (cf. Wood & Grafman, 2003) Miller & Cohen's integrative theory of prefrontal functioning (e.g. Miller & Cohen, 2001) Rolls's stimulus-reward approach and Stuss's anterior attentional functions (Burgess & Simons, 2005; Burgess, 2003; Burke, 2007). It may be highlighted that the theories described above differ in their focus on certain processes/systems or construct-lets. Stuss (1999) remarks that the question of homogeneity (single construct) or heterogeneity (multiple processes/systems) of function may represent a problem of semantics and/or incomplete functional analysis rather than an unresolvable dichotomy (p.348). However, further research will show if a unified theory of frontal lobe function that fully accounts for the diversity of functions will be available.

Damage
Stuss, et al. discuss in a review of many studies how damage to the frontal lobe can occur in an assortment of ways and result in many different consequences. Transient ischemic attacks (TIAs) and/or strokes are common causes of frontal lobe damage in older adults (ages 65 and older). These strokes and TIAs (or mini-strokes) can occur due to blockage of blood flow to the brain or because of the rupturing of a blood vessel/aneurysm inside of the brain. Other ways in which injury can occur include head injuries such as concussions incurred during accidents, diagnoses such as Alzheimers Disease or Parkinsons Disease (which cause dementia symptoms), and frontal lobe epilepsy (which can occur at any age).[9] Common effects of damage to the frontal lobe are varied. Patients who have experienced frontal lobe trauma may know the appropriate response to a situation but display inappropriate responses to those same situations in real

Frontal lobe life. Similarly, emotions that are felt may not be expressed in the face or voice. For example, someone who is feeling happy would not smile, and his or her voice would be devoid of emotion. Along the same lines, though, the person may also exhibit excessive, unwarranted displays of emotion. Depression is common in stroke patients; it affects a great number of those who have experienced one. Also common along with depression is a loss of or decrease in motivation. Someone might not want to carry out normal daily activities and would not feel up to it.[9] Those who are close to the person who has experienced the damage may notice that the person no longer behaves like him or herself.[10] This personality change is characteristic of damage to the frontal lobe and was exemplified in the case of Phineas Gage. The frontal lobe is the same part of the brain that is responsible for executive functions such as planning for the future, judgment, decision-making skills, attention span, and inhibition. These functions can decrease drastically in someone whose frontal lobe is damaged.[9] Consequences that are seen less frequently are also varied. Confabulation may be the most frequently indicated less common effect. In the case of confabulation, someone gives false information while maintaining the belief that it is the truth; he or she cannot remember the accurate information. In a small number of patients, uncharacteristic cheerfulness can be noted. This effect is seen mostly in patients with lesions to the right frontal portion of the brain.[9][11] Another infrequent effect is that of reduplicative paramnesia, in which patients believe that the location in which they currently reside is a replica of one located somewhere else. Similarly, in those who experience Capgras syndrome after frontal lobe damage, believe that an identical replacement has taken the identity of a close friend, relative, or other person and is posing as that person. This last effect is seen mostly in schizophrenic patients who also have a neurological disorder in the frontal lobe.[9][12]

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Evolution
For many years, many scientists thought that the frontal lobe was disproportionately enlarged in humans compared to other primates. They thought that this was an important feature of human evolution and was the primary reason why human cognition is different from that of the other primates. However, this view has been challenged by newer research. Using magnetic resonance imaging to determine the volume of the frontal cortex in humans, all extant ape species and several monkey species, Semendeferi et al. found that the human frontal cortex was not relatively larger than the cortex in the other great apes but was relatively larger than the frontal cortex in the lesser apes and the monkeys.[13]

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Additional images
Left frontal lobe (click to view animation)

Lobes

Base of brain.

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Human brain showing the four major lobes of the cerebrum. Beneath the cerebral cortex are the cerebellum, pons, olive, and medulla oblongata

Drawing to illustrate the relations of the brain to the skull.

Frontal lobe

Frontal lobe

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Frontal lobe

References
[1] [2] [3] [4] [6] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=189#p821 http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=37 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Frontal+ Lobe http:/ / www. neurolex. org/ wiki/ birnlex_928 Fjell, A. M., Walhovd, K. B., Fennema-Notestine, C., McEvoy, L. K., Hagler, D. J., Holland, D., & ... Dale, A. M. (2009). One-year brain atrophy evident in healthy aging. The Journal Of Neuroscience, 29(48), 15223-15231. [7] Coffey, C., Wilkinson, W., Parashos, I., Soady, S., Sullivan, R., Patterson, L., & Djang, W. (1992). Quantitative cerebral anatomy of the aging human brain: a cross-sectional study using magnetic resonance imaging. Neurology, 42(3 Pt 1), 527-536. [8] Kimberg, D.Y., Farah, M.J. A unified account of cognitive impairments following frontal lobe damage: the role of working memory in complex, organized behavior. J. Exp. Psychol. Gen. 1993 122(4):411-28 [9] Stuss, D. T., Gow, C. A., & Hetherington, C. (1992). 'No longer gage': Frontal lobe dysfunction and emotional changes. Journal Of Consulting And Clinical Psychology, 60(3), 349-359. [10] Rowe, A. D., Bullock, P. R., Polkey, C. E., & Morris, R. G. (2001). 'Theory of mind' impairments and their relationship to executive functioning following frontal lobe excisions. Brain: A Journal Of Neurology, 124(3), 600-616. [11] Robinson, R. G, Kubos, K. L., Starr, L. B., Rao, K., & Price, T. R.(1984). Mood disorders in stroke patients. Importance of location of lesion. Brain, 107, 81-93. [12] Durani, S. K., Ford, R., & Sajjad, S. H. (1991). Capgras syndrome associated with a frontal lobe tumour. Irish Journal Of Psychological Medicine, 8(2), 135-136.

External links
NIF Search - Frontal Lobe (https://www.neuinfo.org/mynif/search.php?q=Frontal Lobe&t=data&s=cover& b=0&r=20) via the Neuroscience Information Framework

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Nucleus accumbens
Brain: Nucleus accumbens

Nucleus accumbens visible in red.

Medial surface, person facing to the left. Nucleus accumbens is very roughly in the area labeled 34. Latin NeuroNames MeSH NeuroLex ID nucleus accumbens septi hier-259
[1] [2]

Nucleus+Accumbens birnlex_727
[3]

The nucleus accumbens (NAcc), also known as the accumbens nucleus or as the nucleus accumbens septi (Latin for nucleus adjacent to the septum) is a region of the human brain in the basal forebrain rostral to the preoptic area.[4] It is considered to be a critical component in the brain's pleasure center due to its association with the ventral striatum. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum, which is part of the basal ganglia.[5] Each brain hemisphere has its own nucleus accumbens. It is located where the head of the caudate and the anterior portion of the putamen meet just lateral to the septum pellucidum. The nucleus accumbens can be divided into two structuresthe nucleus accumbens core and the nucleus accumbens shell. These structures have different morphology and function. Research has indicated the nucleus accumbens has an important role in reward, pleasure, reinforcement learning, laughter, addiction, aggression, fear, impulsivity and the placebo effect.[6][7][8][9]

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Cell types
The principal neuronal cell type found in the nucleus accumbens is the medium spiny neuron. The neurotransmitter produced by these neurons is gamma-aminobutyric acid (GABA), one of the main inhibitory neurotransmitters of the central nervous system. These neurons are also the main projection or output neurons of the nucleus accumbens. While 95% of the neurons in the nucleus accumbens are medium spiny GABA-ergic projection neurons, other neuronal types are also found such as large aspinous cholinergic interneurons.

Output and input

Output
The output neurons of the nucleus accumbens send axon projections to the basal ganglia and the ventral analog of the globus pallidus, known as the ventral pallidum (VP). The VP, in turn, projects to the medial dorsal nucleus of the dorsal thalamus, which projects to the prefrontal cortex as well as the striatum. Other efferents from the nucleus accumbens include connections with the substantia nigra, and the pontine reticular formation.[4]

Input
Major inputs to the nucleus accumbens include prefrontal association cortices, basolateral amygdala, and dopaminergic neurons located in the ventral tegmental area (VTA), which connect via the mesolimbic pathway. Thus the nucleus accumbens is often described as one part of a cortico-striato-thalamo-cortical loop. Dopaminergic input from the VTA is thought to modulate the activity of neurons within the nucleus accumbens. These terminals are also the site of action of highly-addictive drugs such as cocaine and amphetamine, which cause a manifold increase in dopamine levels in the nucleus accumbens. Another major source of input comes from the CA1 and ventral subiculum of the hippocampus to the dorsomedial area of the Nucleus accumbens. The neurons of the hippocampus have a noteworthy correlation to slight depolarizations of cells in the nucleus accumbens, which makes them more positive and therefore more excitable. The correlated cells of these excited states of the medium spiny neurons in the Nucleus accumbens are shared equally between the subiculum and CA1. The subiculum neurons are found to hyperpolarize (increase negativity) while the CA1 neurons "ripple" (fire > 50Hz) in order to accomplish this priming.[10]

Research
Addiction and Drug Use
Research using microdialysis has shown that the levels of dopamine in the extracellular fluid of the nucleus accumbens increases when rats are injected with addictive drugs such as cocaine, heroin, nicotine, or alcohol.[11] This increase in dopamine is believed to be responsible for the reinforcing effects that later stimulate drug-taking behavior. Functional-imaging studies in humans has shown that environmental cues associated with addictive drugs releases dopamine in the nucleus accumbens. However, when administered methylphenidate, drug addicted subjects had a much smaller release of dopamine in this area than non-addicted subjects. These findings suggest the notion that the nucleus accumbens is associated with the beginnings of drug addiction and the dorsal striatum is responsible for the augmentation of the drug habit.[11] The nucleus accumbens has been targeted by stereotactic surgery for ablation as a treatment in China for alcoholism.[12] Deep brain stimulation has recently been used to study its effects on drug addiction. Mantione et al. has found that the stimulation of the nucleus accumbens in one subject showed a decrease in nicotine use.[13]

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Pleasure and Reinforcement

Although the nucleus accumbens has traditionally been studied for its role in addiction, it plays an equal role in processing many rewards such as food and sex. The nucleus accumbens is selectively activated during the perception of pleasant, emotionally arousing pictures and during mental imagery of pleasant, emotional scenes.[][] A 2005 study found that it is involved in the regulation of emotions induced by music,[14] perhaps consequent to its role in mediating dopamine release. The nucleus accumbens plays a role in rhythmic timing and is considered to be of central importance to the limbic-motor interface (Mogensen). In the 1950s, James Olds and Peter Milner implanted electrodes into the septal area of the rat and found that the rat chose to press a lever which stimulated it. It continued to prefer this even over stopping to eat or drink. This suggests that the area is the "pleasure center" of the brain and is involved in reinforcement learning.[15] In rats, stimulation of the ventral tegmental area causes the release of dopamine in the nucleus accumbens much in the same way as addictive drugs and natural reinforcers, such as water or food, initiate the release of dopamine in the nucleus accumbens.[16] The same results have been seen in human subjects in functional imaging studies. For example, increased dopamine concentration is seen in the extracellular fluid of the nucleus accumbens when subjects believed they were being given money, and when heterosexual males were presented pictures of attractive women.[17]

Maternal Behavior
An fMRI study conducted in 2005 found that when mother rats were in the presence of their pups the regions of the brain involved in reinforcement, including the nucleus accumbens, were highly active.[18] Levels of dopamine increase in the nucleus accumbens during maternal behavior, while lesions in this area upset maternal behavior.[19] When human mothers are presented pictures of their children, fMRIs show an increased brain activity in the nucleus accumbens and other reinforcing brain regions and a decrease in activity in areas of the brain involved with negative emotions.

Deep Brain Stimulation

In April 2007, two research teams reported on having inserted electrodes into the nucleus accumbens in order to use deep brain stimulation to treat severe depression.[20] In 2010 experiments conducted by Bewernick et al. reported that deep brain stimulation of the nucleus accumbens was successful in decreasing depression symptoms in 50% of patients who did not respond to other treatments such as electroconvulsive therapy.[21]

Placebo Effect
In addition, in July 2007, researcher Jon-Kar Zubieta published findings that the nucleus accumbens is central to the machinery of the placebo effect. His group has confirmed that specific neural circuits and neurotransmitter systems respond to the expectation of benefit during placebo administration and that these expectations induce measurable physiological changes.[22]

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Additional images

Dopamine and serotonin

MRI coronal slice showing nucleus accumbens outlined in red

Sagittal MRI slice with highlighting (red) indicating the nucleus accumbens.

References
[1] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=259 [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Nucleus+ Accumbens [3] http:/ / www. neurolex. org/ wiki/ birnlex_727 [4] Carlson, Neil R. Physiology of Behavior. 11th ed. Boston: Pearson, 2013. Print. [5] Nucleus Accumbens (http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Nucleus+ Accumbens) [7] The Placebo Effect in the NAC (http:/ / www. brightsurf. com/ news/ headlines/ 31647/ Brain_region_central_to_placebo_effect_identified. html) [8] Dopamine Involved In Aggression - Medical News Today (http:/ / www. medicalnewstoday. com/ articles/ 94023. php) [9] Basar, Koray, Thibaut Sesia, Henk Groenewegen, Harry W.M. Steinbusch, Veerle Visser-Vandewalle, and Yasin Temel. "Nucleus Accumbens and Impulsivity."Progress in Neurobiology 92.4 (2010): 533-57. Print. [11] Carlson, Neil R. Physiology of Behavior. 11th ed. Boston: Pearson, 2013. Print [12] Wu HM, Wang XL, Chang CW, Li N, Gao L, Geng N, Ma JH, Zhao W, Gao GD. (2010). Preliminary findings in ablating the nucleus accumbens using stereotactic surgery for alleviating psychological dependence on alcohol. Neurosci Lett. 473: 7781 PMID 20156524 [13] Mantione, M., van de Brink, W., Schuurman, P. R., and Denys, D. Smoking cessation and weight loss after chronic deep brain stimulation of the nucleus accumbens: Therapeutic and research implications: Case report. Neurosurgery, 2010, 66, E2018. [14] Menon, Vinod & Levitin, Daniel J. (2005) The rewards of music listening: Response and physiological connectivity of themesolimbic system." NeuroImage 28(1), pp. 175-184 [15] article (http:/ / www. wadsworth. com/ psychology_d/ templates/ student_resources/ 0155060678_rathus/ ps/ ps02. html) [16] Nakahara, D., Ozaki, N., Miura, Y., Miura, H., et al. Increased dopamine and serotonin metabolism in rat nucleus accumbens produced by intracranial sel-stimulation of medial forebrain bundle as measured by in vivo microdialysis. Brain Research, 1989, 495, 178-181. [17] Aharon, L., Etcoff, N., Ariely, D., CHabris, C. F., et al. Beautiful faces have variable reward value: fMRI and behavioral evidence. Neuron 2001, 32, 357-551. [18] Ferris, C.F., Kulkarni, P., Sullivan, J.M., Harder, J.A., et al. Pup sucking is more rewarding than cocaine: Evidence from functional magnetic resonance imaging and three-dimensional computational analysis. Journal of Neuroscience, 2005, 25, 149-156. [19] Numan, M. Motivational systems and the neural circuitry of maternal behavior in the rat. Developmental Psychobiology, 2007, 49, 12-21. [20] Brain Electrodes Help Treat Depression (http:/ / www. technologyreview. com/ Biotech/ 18590/ ), Technology Review, 26 April 2007 [21] Bewernick, B. H., Hurlemann, R., Matusch, A., et al. Nucleus accumbens deep brain stimulation decreases ratings of depression and anciety in treatment-resistant depresssion. Biological Psychiatry, 2009, 67, 110-116. [22] http:/ / www. eurekalert. org/ pub_releases/ 2007-07/ cp-brc071607. php Brain region central to placebo effect identified

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External links
The role of the nucleus accumbens in the reward circuit. (http://www.thebrain.mcgill.ca/flash/i/i_03/ i_03_cr/i_03_cr_par/i_03_cr_par.html) Part of "The Brain From Top to Bottom." at thebrain.mcgill.ca Nucleus Accumbens - Cell Centered Database (http://ccdb.ucsd.edu/sand/main?stype=lite&keyword=nucleus accumbens&Submit=Go&event=display&start=1) BrainMaps at UCDavis nucleus%20accumbens (http://brainmaps.org/index.php?q=nucleus accumbens)

Nigrostriatal pathway
Dopaminergic pathways are neural pathways in the brain which transmit the neurotransmitter dopamine from one region of the brain to another.[] The nigrostriatal pathway is a neural pathway that connects the substantia nigra with the striatum. It is one of the four major dopamine pathways in the brain, and is particularly involved in the production of movement, as part of a system called the basal ganglia motor loop. Loss of dopamine neurons in the substantia nigra is one of the main pathological features of Parkinson's disease,[1] leading to Dopaminergic and serotonergic pathways. Nigrostriatal pathway can be seen a marked reduction in dopamine function in projecting upward from the substantia nigra to the striatum. this pathway. The symptoms of the disease typically do not show themselves until 80-90% of dopamine function has been lost. This pathway is also implicated in producing tardive dyskinesia, one of the side-effects of antipsychotic drugs. These medications (particularly the older typical antipsychotics) block D2 dopamine receptors in multiple pathways in the brain. The desired clinical effect of reducing psychotic symptoms is thought to be associated with blocking dopamine function in the mesolimbic pathway only. However, as many of these drugs are not selective, they block dopamine in all pathways. When this happens in the nigrostriatal pathway, similar movement problems to those found in Parkinson's disease can occur.

Nigrostriatal pathway

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Other dopamine pathways

Other major dopamine pathways include: mesocortical pathway mesolimbic pathway tuberoinfundibular pathway

References
[1] Diaz, Jaime. How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall, 1996.

External links
NeuroNames ancil-491 (http://braininfo.rprc.washington.edu/Scripts/ancilcentraldirectory.aspx?ID=491) Diagram (http://gslc.genetics.utah.edu/units/addiction/reward/pathways.cfm)

Substantia nigra pars compacta

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Substantia nigra pars compacta

Brain: Pars compacta
Latin Gray's Pars compacta substantiae nigrae subject #188 802
[1]

NeuroNames hier-528 [2]

The pars compacta is a portion of the substantia nigra.

Anatomy
In humans, the nerve cell bodies of the pars compacta are coloured black by the pigment neuromelanin. The degree of pigmentation increases with age. This pigmentation is visible as a distinctive black stripe in brain sections and is the origin of the name given to this volume of the brain. The neurons have particularly long and thick dendrites (Franois et al.). The ventral dendrites, particularly, go down deeply in the pars reticulata. Other similar neurons are more sparsely distributed in the mesencephalon and constitute "groups" with no well-defined borders, although continuous to the pars compacta, in a prerubral position. These have been given, in early works in rats (with not much respect for the anatomical subdivisions), the name of "area A8" and "A10". The pars compacta itself ("A9") is usually subdivided into a ventral and a dorsal tier, the last being calbindin positive.[3] The ventral tier is considered as A9v. The dorsal tier A9d is linked to an ensemble comprising also A8 and A10,[4] A8, A9d and A10 representing 28% of dopaminergic neurons. The long dendrites of compacta neurons receive striatal information. This cannot be the case for the more posterior groups that are located outside the striato-pallidonigral bundle territory. Neurons of the pars compacta receive inhibiting signals from the collateral axons from the neurons of the pars reticulata.[5] All these neurons send their axons along the nigrostriatal pathway to the striatum where they release the neurotransmitter dopamine. There is an organization in which dopaminergic neurons of the fringes (the lowest) go to the sensorimotor striatum and the highest to the associative striatum. Dopaminergic axons also innervate other elements of the basal ganglia system including the lateral and medial pallidum,[6] substantia nigra pars reticulata, and the subthalamic nucleus.[7]

Function
The function of the dopamine neurons in the substantia nigra pars compacta is complex. Contrary to what was thought initially it is not directly linked to movements. "Dopamine neurons are activated by novel, unexpected stimuli, by primary rewards in the absence of predictive stimuli and during learning".[8] Dopamine neurons are thought to be involved in learning to predict which behaviours will lead to a reward (for example food or sex). In particular, it is suggested that dopamine neurons fire when a reward is greater than that previously expected; a key component of many reinforcement learning models. This signal can then be used to update the expected value of that action. Many drugs of abuse, such as cocaine, mimic this reward responseproviding an explanation for their addictive nature.

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Pathology
Degeneration of pigmented neurons in this region is the principal pathology that underlies Parkinson's disease. In a few people, the cause of Parkinson's disease is genetic, but in most cases, the reason for the death of these dopamine neurons is unknown. Parkinsonism can also be produced by viral infections such as encephalitis or a number of toxins, such as MPTP, an industrial toxin which can be mistakenly produced during synthesis of the meperidine analog MPPP. Many such toxins appear to work by producing reactive oxygen species. Binding to neuromelanin by means of charge transfer complexes may concentrate radical-generating toxins in the substantia nigra. Pathological changes to the dopaminergic neurons of the pars compacta are also thought to be involved in schizophrenia (see the dopamine hypothesis of schizophrenia) and psychomotor retardation sometimes seen in clinical depression.

References
[1] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=188#p802 [2] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=528

Striatum

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Striatum
Brain: Striatum

purple=caudate and putamen, orange=thalamus

Two views of a model of the striatum. A: lateral aspect, B: medial aspect. (The lenticular nucleus is an alternative name for the putamen and globus pallidus.) Latin NeuroNames Corpus striatum, neostriatum hier-207
[1]

The striatum, also known as the neostriatum or striate nucleus, is a subcortical (i.e., inside, rather than on the outside) part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex. In primates (including humans), the striatum is divided by a white matter tract called the internal capsule into two sectors called the caudate nucleus and putamen. The term corpus striatum occasionally refers to the striatum combined with the globus pallidus, a structure closely related to the putamen, and the lenticular nucleus refers to the putamen together with the globus pallidus.[]

History
In the seventeenth and eighteenth centuries, the term "corpus striatum" was used to designate many distinct, deep, infracortical elements of the hemisphere.[2] In 1941, Ccile and Oskar Vogt simplified the nomenclature by proposing the term striatum for all elements built with striatal elements (see primate basal ganglia system): the caudate, the putamen, and the fundus striati, that ventral part linking the two preceding together ventrally to the inferior part of the internal capsule. The term neostriatum was forged by comparative anatomists comparing the subcortical structures between vertebrates, because it was thought to be a phylogenetically newer section of the corpus striatum. The term is still used by some sources, including Medical Subject Headings.[3]

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Cell types
The striatum is heterogeneous in terms of its component neurons.[4] Spiny projection neurons, commonly referred to as medium spiny neurons, are the principal neurons of the striatum. They are GABAergic and thus are classified as inhibitory neurons. Depending on the species, spiny projection neurons comprise 90-95% of the total neuronal population. Cholinergic interneurons release acetylcholine, which has a variety of important effects in the striatum. In humans, non-human primates and rodents, these interneurons respond to salient environmental stimuli with stereotyped responses which are temporally aligned with the responses of dopaminergic neurons of the substantia nigra.[5][6] There are many types of GABAergic interneurons.[4] The best known are parvalbumin expressing interneurons, also known as fast-spiking interneurons, which participate in powerful feed-forward inhibition of principal neurons.[7] Additionally there are GABAergic interneurons which express tyrosine hydroxylase,[8] somatostatin, nitric oxide synthase and neuropeptide-Y. Recently, two types of neuropeptide-y expressing GABAergic interneurons have been described in detail,[9] one of which translates synchronous activity of cholinergic interneurons into inhibition of principal neurons.[10]

Organization
Anatomical subdivisions
The observable anatomical subdivisions of the dorsal striatum (caudate nucleus and putamen) essentially induced by the internal capsule do not completely overlap with now accepted anatomo-functional subdivisions. The selective distribution of the axonal terminal arborisations of cortical sources differentiate the sensorimotor striatum, mainly putaminal but located in its dorsal part and in the lateroinferior part of the caudate. A great part of the remaining of the volume (essentially caudate) receiving from axonal endings from the frontal, parietal, temporal cortex forms the associative striatum. The separation between these two territories is rather clearcut and observable using calbindin immunochemistry. A third entity, the most inferomedial, raises more problems as there is no general agreement about its border with the associative striatum. The striatum can also be differentiated based on immunochemical characteristicsparticularly with regard to acetylcholinesteraseinto "compartments", consisting of 'striosomes' and 'matrisomes'.

This is a transverse section of the striatum from a structural MR image. The striatum includes the caudate nucleus (red, top) and putamen (red, right). The image also includes the globus pallidus (red, lower left), which is sometimes included when using the term corpus striatum.

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Inputs (afferent connections)

The most important afferent in terms of quantity of axons is the corticostriatal connection. Many parts of the neocortex innervate the dorsal striatum. The cortical pyramidal neurons projecting to the striatum are located in layers II-VI, but the most dense projections come from layer V.[11] They end mainly on the spines of the spiny neurons. They are glutamatergic, exciting striatal neurons. Another well known afferent is the nigrostriatal connection arising from the neurons of the substantia nigra pars compacta. While cortical axons synapse mainly on spine heads of spiny neurons, nigral axons synapse mainly on spine shafts. In primates, the thalamostriatal afferent essentially comes from the center median-parafascicular complex of the thalamus (see primate basal ganglia system). This afferent is glutamatergic. The participation of truly intralaminar neurons is much more limited. The striatum also receives afferents from other elements of the basal ganglia such as the subthalamic nucleus (glutamatergic) or the external globus pallidus (GABAergic).

Targets (efferent connections)

The basal ganglia core is made up of the striatum along with the regions to which it projects directly, via the striato-pallidonigral bundle. The striato-pallidonigral bundle is a very dense bundle of sparsely myelinated axons, giving a whitish appearance. This projection comprises successively the external globus pallidus (GPe), the internal globus pallidus (GPi), the pars compacta of the substantia nigra (SNc) and the pars reticulata of substantia nigra (SNr). The neurons of this projection are inhibited by GABAergic synapses from the dorsal striatum. Among these targets, the GPe does not send axons outside the system. Others send axons to the superior colliculus. Two others comprise the output to the thalamus, forming two separate channels: one through the internal segment of the globus pallidus to the ventral oralis nuclei of the thalamus and from there to the cortical supplementary motor area (SMA) and another through the substantia nigra to the ventral anterior nuclei of the thalamus and from there to the frontal cortex and the occulomotor cortex.

Overview of the main circuits of the basal ganglia. Striatum is shown in blue. Picture shows 2 coronal slices that have been superimposed to include the involved basal ganglia structures. + and - signs at the point of the arrows indicate respectively whether the pathway is excitatory or inhibitory in effect. Green arrows refer to excitatory glutamatergic pathways, red arrows refer to inhibitory GABAergic pathways and turquoise arrows refer to dopaminergic pathways that are excitatory on the direct pathway and inhibitory on the indirect pathway.

Function
Metabotropic dopamine receptors are present both on spiny neurons and on cortical axon terminals. Second messenger cascades triggered by activation of these dopamine receptors can modulate pre- and postsynaptic function, both in the short term and in the long term.[citation needed] The striatum is best known for its role in the planning and modulation of movement pathways but is also potentially involved in a variety of other cognitive processes involving executive function, such as working memory.[12] In humans the striatum is activated by stimuli

Striatum associated with reward, but also by aversive, novel, unexpected or intense stimuli, and cues associated with such events. Recent fMRI evidence [13] suggests that the common property linking these stimuli, to which the striatum is reacting, is saliency under the conditions of presentation. A number of other brain areas and circuits are also related to reward such as frontal areas. Research [14] at the Wellcome Trust Centre for Neuroimaging at UCL (University College London) shows it to be associated with novelty-related decision making behaviors. For sources regarding saliency of the reward pathway (thought to be related to dopamine) one can look to the work of Dr. John D. Salamone (early to late 1990s) and Wolfram Schultz.[] The ventral tegmental dopaminergic neurons that innervate portions of the striatum have long been accepted to be the site of rewarding feeling. Intracranial stimulation studies from the 1960s show implants in this brain area will elicit bar pressing from rats for many hours at a time. However the collective works of researchers in the 1990s show that blocking dopamine receptors does not remove rewarding sensations, rather it affects how much the animal is willing to work, triggering more motivation to seek eventual reward rather than immediate reward. As rewarding sensations are difficult to assess in animals, hundreds of studies over more than 30 years have shown that interference with dopamine neurotransmission impairs behavioral reward processes and their underlying neuronal mechanisms.[citation needed]

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Pathology
Parkinson's disease
Parkinson's disease results in loss of dopaminergic innervation to the striatum (and other basal ganglia) and a cascade of subsequent consequences. Atrophy of the striatum is also involved in Huntington's disease, choreas, choreoathetosis, and dyskinesias.[] It is also thought that addiction involves plasticity at striatal synapses.

Bipolar disorder
There is an association between striatal expression of the PDE10A gene and some bipolar disorder I patients.[15]

References
[1] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=207 [2] Raymond Vieussens, 1685 [4] Tepper JM, Tecuapetla F, Kos T, Ibez-Sandoval O. Front Neuroanat. 2010 Dec 29;4:150. doi: 10.3389/fnana.2010.00150. PMID 21228905 [5] Goldberg JA, Reynolds JN. Neuroscience. 2011 Dec 15;198:27-43. doi: 10.1016/j.neuroscience.2011.08.067. Epub 2011 Sep 8. Review. PMID 21925242 [6] Morris G, Arkadir D, Nevet A, Vaadia E, Bergman H. Neuron. 2004 Jul 8;43(1):133-43. PMID 15233923 [7] Kos T, Tepper JM. Nat Neurosci. 1999 May;2(5):467-72. PMID 10321252 [8] Ibez-Sandoval O, Tecuapetla F, Unal B, Shah F, Kos T, Tepper JM. J Neurosci. 2010 May 19;30(20):6999-7016. doi: 10.1523/JNEUROSCI.5996-09.2010. PMID 20484642 [9] Ibez-Sandoval O, Tecuapetla F, Unal B, Shah F, Kos T, Tepper JM. J Neurosci. 2011 Nov 16;31(46):16757-69. doi: 10.1523/JNEUROSCI.2628-11.2011. PMID 22090502 [10] English DF, Ibanez-Sandoval O, Stark E, Tecuapetla F, Buzski G, Deisseroth K, Tepper JM, Koos T. Nat Neurosci. 2011 Dec 11;15(1):123-30. doi: 10.1038/nn.2984. PMID 22158514 [14] http:/ / www. ucl. ac. uk/ news/ news-articles/ 0806/ 08062502|Further [15] Science Daily: Scientists pinpoint gene variations linked to higher risk of bipolar disorder (http:/ / www. sciencedaily. com/ releases/ 2012/ 10/ 121010151422. htm?utm_source=feedburner& utm_medium=email& utm_campaign=Feed:+ sciencedaily+ (ScienceDaily:+ Latest+ Science+ News))

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External links
BrainMaps at UCDavis striatum (http://brainmaps.org/index.php?q=striatum) NeuroNames hier-207 (http://braininfo.rprc.washington.edu/Scripts/hiercentraldirectory.aspx?ID=207) Corpus Striatum (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Corpus+Striatum) at the US National Library of Medicine Medical Subject Headings (MeSH)

Tuberoinfundibular pathway
The tuberoinfundibular pathway refers to a population of dopamine neurons in the arcuate nucleus of the mediobasal hypothalamus (the 'tuberal region') that project to the median eminence (the 'infundibular region'). It is one of the four major dopamine pathways in the brain. Dopamine released at this site regulates the secretion of prolactin from the anterior pituitary gland. Some antipsychotic drugs block dopamine in the tuberoinfundibular pathway, which can cause an increase in blood prolactin levels (hyperprolactinemia). This can cause abnormal lactation (even in men), disruptions to the menstrual cycle in women, visual problems, headache and sexual dysfunction.

Other dopamine pathways

Other major dopamine pathways include: mesocortical pathway mesolimbic pathway nigrostriatal pathway

External links
NeuroNames ancil-745 [1] Diagram [2]

References
[1] http:/ / braininfo. rprc. washington. edu/ Scripts/ ancilcentraldirectory. aspx?ID=745 [2] http:/ / gslc. genetics. utah. edu/ units/ addiction/ reward/ pathways. cfm

Hypothalamus

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Hypothalamus
Brain: Hypothalamus

Location of the human hypothalamus

Diencephalon Latin Gray's hypothalamus subject #189 812

[1]

NeuroNames hier-358 [2] MeSH Hypothalamus

[3]

NeuroLex ID birnlex_734 [4]

The hypothalamus (from Greek = under and = room, chamber) is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland (hypophysis). The hypothalamus is located below the thalamus, just above the brain stem. In the terminology of neuroanatomy, it forms the ventral part of the diencephalon. All vertebrate brains contain a hypothalamus. In humans, it is roughly the size of an almond. The hypothalamus is responsible for certain metabolic processes and other activities of the autonomic nervous system. It synthesizes and secretes certain neurohormones, often called hypothalamic-releasing hormones, and these in turn stimulate or inhibit the secretion of pituitary hormones. The hypothalamus controls body temperature, hunger, important aspects of parenting and attachment behaviors, thirst,[5] fatigue, sleep, and circadian cycles.

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Structure and inputs

The hypothalamus is a brain structure composed of distinct nuclei and less anatomically distinct areas. It is found in all vertebrate nervous systems. In mammals, the axons of magnocellular neurosecretory cells of the paraventricular nucleus and the supraoptic nucleus, which contain oxytocin and vasopressin (also called antidiuretic hormone), comprise the posterior pituitary. Parvocellular neurons of the paraventricular nucleus contain neurons that release corticotropin-releasing hormone and other hormones into the hypophyseal portal system where these hormones diffuse to the anterior pituitary. The hypothalamus coordinates many hormonal and behavioural circadian rhythms, complex patterns of neuroendocrine outputs, complex homeostatic mechanisms,[6] and important behaviours. The hypothalamus must therefore respond to many different signals, some of which are generated externally and some internally. The hypothalamus is thus richly connected with many parts of the central nervous system, including the brainstem reticular formation and autonomic zones, the limbic forebrain (particularly the amygdala, septum, diagonal band of Broca, and the olfactory bulbs, and the cerebral cortex).
Human hypothalamus (animation, shown in red)

The hypothalamus is responsive to: Light: daylength and photoperiod for regulating circadian and seasonal rhythms Olfactory stimuli, including pheromones Steroids, including gonadal steroids and corticosteroids Neurally transmitted information arising in particular from the heart, the stomach, and the reproductive tract Autonomic inputs Blood-borne stimuli, including leptin, ghrelin, angiotensin, insulin, pituitary hormones, cytokines, plasma concentrations of glucose and osmolarity etc. Stress Invading microorganisms by increasing body temperature, resetting the body's thermostat upward.

Olfactory stimuli
Olfactory stimuli are important for sex and neuroendocrine function in many species. For instance if a pregnant mouse is exposed to the urine of a 'strange' male during a critical period after coitus then the pregnancy fails (the Bruce effect). Thus during coitus, a female mouse forms a precise 'olfactory memory' of her partner which persists for several days. Pheromonal cues aid synchronisation of oestrus in many species; in women, synchronised menstruation may also arise from pheromonal cues, although the role of pheromones in humans is doubted by many.Wikipedia:Avoid weasel words

Blood-borne stimuli
Peptide hormones have important influences upon the hypothalamus, and to do so they must evade the bloodbrain barrier. The hypothalamus is bounded in part by specialized brain regions that lack an effective bloodbrain barrier; the capillary endothelium at these sites is fenestrated to allow free passage of even large proteins and other molecules. Some of these sites are the sites of neurosecretion - the neurohypophysis and the median eminence. However others are sites at which the brain samples the composition of the blood. Two of these sites, the SFO (subfornical organ) and the OVLT (organum vasculosum of the lamina terminalis) are so-called circumventricular organs, where neurons are in intimate contact with both blood and CSF. These structures are densely vascularized,

Hypothalamus and contain osmoreceptive and sodium-receptive neurons which control drinking, vasopressin release, sodium excretion, and sodium appetite. They also contain neurons with receptors for angiotensin, atrial natriuretic factor, endothelin and relaxin, each of which is important in the regulation of fluid and electrolyte balance. Neurons in the OVLT and SFO project to the supraoptic nucleus and paraventricular nucleus, and also to preoptic hypothalamic areas. The circumventricular organs may also be the site of action of interleukins to elicit both fever and ACTH secretion, via effects on paraventricular neurons.[citation needed] It is not clear how all peptides that influence hypothalamic activity gain the necessary access. In the case of prolactin and leptin, there is evidence of active uptake at the choroid plexus from blood into CSF. Some pituitary hormones have a negative feedback influence upon hypothalamic secretion; for example, growth hormone feeds back on the hypothalamus, but how it enters the brain is not clear. There is also evidence for central actions of prolactin.[citation
needed]

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Findings have suggested that thyroid hormone (T4) is taken up by the hypothalamic glial cells in the infundibular nucleus/ median eminence, and that it is here converted into T3 by the type 2 deiodinase (D2). Subsequently, T3 is transported into the thyrotropin-releasing hormone (TRH) producing neurons in the paraventricular nucleus. There has been found thyroid hormone receptors in these neurons, indicating that they are indeed sensitive to T3 stimuli. Additionally these neurons expressed MCT8, a thyroid hormone transporter, supporting the theory that T3 is transported into them. T3 could then bind to the thyroid hormone receptor in these neurons, and affect the production of thyrotropin-releasing hormone, and thereby regulating thyroid hormone production. [7] The hypothalamus functions as a type of thermostat for the body.[] It sets a desired body temperature, and stimulates either heat production and retention to raise the blood temperature to a higher setting, or sweating and vasodilation to cool the blood to a lower temperature. All fevers result from a raised setting in the hypothalamus; elevated body temperatures due to any other cause are classified as hyperthermia.[] Rarely, direct damage to the hypothalamus, such as from a stroke, will cause a fever; this is sometimes called a hypothalamic fever. However, it is more common for such damage to cause abnormally low body temperatures.[]

Steroids
The hypothalamus contains neurons that react strongly to steroids and glucocorticoids (the steroid hormones of the adrenal gland, released in response to ACTH). It also contains specialized glucose-sensitive neurons (in the arcuate nucleus and ventromedial hypothalamus), which are important for appetite. The preoptic area contains thermosensitive neurons; these are important for TRH secretion.

Neural inputs
The hypothalamus receives many inputs from the brainstem; notably from the nucleus of the solitary tract, the locus coeruleus, and the ventrolateral medulla. Oxytocin secretion in response to suckling or vagino-cervical stimulation is mediated by some of these pathways; vasopressin secretion in response to cardiovascular stimuli arising from chemoreceptors in the carotid body and aortic arch, and from low-pressure atrial volume receptors, is mediated by others. In the rat, stimulation of the vagina also causes prolactin secretion, and this results in pseudo-pregnancy following an infertile mating. In the rabbit, coitus elicits reflex ovulation. In the sheep, cervical stimulation in the presence of high levels of estrogen can induce maternal behavior in a virgin ewe. These effects are all mediated by the hypothalamus, and the information is carried mainly by spinal pathways that relay in the brainstem. Stimulation of the nipples stimulates release of oxytocin and prolactin and suppresses the release of LH and FSH. Cardiovascular stimuli are carried by the vagus nerve, but the vagus also conveys a variety of visceral information, including for instance signals arising from gastric distension to suppress feeding. Again this information reaches the hypothalamus via relays in the brainstem. In addition hypothalamic function is responsive to --and regulated by-- levels of all three classical monoamine neurotransmitters, i.e. noradrenaline, dopamine and 5-hydroxytryptamine (serotonin), in those tracts from which it

Hypothalamus receives enervation. For example noradrenergic inputs arising from the locus coeruleus have important regulatory effects upon CRH levels.

238

Nuclei
The hypothalamic nuclei include the following:[8][9][10]

A cross section of the monkey hypothalamus displays 2 of the major hypothalamic nuclei on either side of the fluid-filled 3rd ventricle.

Hypothalamic nuclei

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Hypothalamic nuclei on one side of the hypothalamus, shown in a 3-D computer reconstruction[citation needed]

Region

Area

Nucleus

Function

[11]

Anterior Medial Medial preoptic nucleus

Regulates the release of gonadotropic hormones from the adenohypophysis Contains the sexually dimorphic nucleus, which releases GnRH, differential development between sexes is based upon in utero testosterone levels Vasopressin release thyrotropin-releasing hormone release corticotropin-releasing hormone release oxytocin release thermoregulation panting sweating thyrotropin inhibition Circadian rhythms

Supraoptic nucleus (SO) Paraventricular nucleus* (PV)

Anterior hypothalamic nucleus (AH)

Suprachiasmatic nucleus (SC) Lateral Lateral preoptic nucleus Lateral nucleus (LT) Part of supraoptic nucleus (SO)

thirst and hunger

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Blood Pressure Heart Rate GI stimulation satiety neuroendocrine control Growth hormone-releasing hormone (GHRH) feeding Dopamine thirst and hunger

Tuberal

Medial Dorsomedial hypothalamic nucleus (DM)

Ventromedial nucleus (VM)

Arcuate nucleus (AR)

Lateral Lateral nucleus (LT) Lateral tuberal nuclei Posterior Medial Mammillary nuclei (part of mammillary bodies) (MB) Posterior nucleus (PN)

memory

Increase blood pressure pupillary dilation shivering vasopressin release

Lateral Lateral nucleus (LT)

- Note: Paraventricular nucleus is not to be confused with periventricular nucleus. See also: ventrolateral preoptic nucleus, periventricular nucleus.

Outputs
The outputs of the hypothalamus can be divided into two categories: neural projections, and endocrine hormones.[12]

Neural projections
Most fiber systems of the hypothalamus run in two ways (bidirectional). Projections to areas caudal to the hypothalamus go through the medial forebrain bundle, the mammillotegmental tract and the dorsal longitudinal fasciculus. Projections to areas rostral to the hypothalamus are carried by the mammillothalamic tract, the fornix and terminal stria. Projections to areas of the sympathetic motor system (lateral horn spinal segments T1-L2/L3) are carried by the hypothalamospinal tract and they activate the sympathetic motor pathway

Endocrine hormones
The hypothalamus has a central neuroendocrine function, most notably by its control of the anterior pituitary, which in turn regulates various endocrine glands and organs. Hypothalamic hormones are produced in hypothalamus nuclei then transported along axons to either the median eminence or the posterior pituitary, where they are stored and released as needed.[13] Hypothalamic-adenohypophyseal (anterior pituitary) axis In the hypothalamic-adenohypophyseal axis, hypophysiotropic hormones are released from the median eminence, itself a prolongation of the hypothalamus, into the hypophyseal portal system, which leads them to the anterior pituitary where they exert their regulatory functions on the secretion of adenohypopyseal hormones.[]

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Secreted hormone

Abbreviation

Produced by Parvocellular neurosecretory cells of the paraventricular nucleus

Effect Stimulate thyroid-stimulating hormone (TSH) release from anterior pituitary (primarily) Stimulate prolactin release from anterior pituitary Stimulate adrenocorticotropic hormone (ACTH) release from anterior pituitary Inhibit prolactin release from anterior pituitary

Thyrotropin-releasing TRH, TRF, or hormone PRH (Prolactin-releasing hormone) Corticotropin-releasing hormone CRH or CRF

Parvocellular neurosecretory cells of the paraventricular nucleus Dopamine neurons of the arcuate nucleus

Dopamine DA or PIH (Prolactin-inhibiting hormone) Growth hormone-releasing hormone Gonadotropin-releasing hormone GHRH

Neuroendocrine neurons of the Arcuate Stimulate Growth hormone (GH) release from nucleus anterior pituitary Stimulate follicle-stimulating hormone (FSH) release from anterior pituitary Stimulate luteinizing hormone (LH) release from anterior pituitary Inhibit Growth hormone (GH) release from anterior pituitary Inhibit (moderately) thyroid-stimulating hormone (TSH) release from anterior pituitary

GnRH or LHRH Neuroendocrine cells of the Preoptic area

[14] Somatostatin (growth hormone-inhibiting hormone)

SS, GHIH, or SRIF

Neuroendocrine cells of the Periventricular nucleus

Other hormones secreted from the median eminence include vasopressin, oxytocin, neurotensin and orexin.[][15][16][17] Hypothalamic-neurohypophyseal (posterior pituitary) axis In the hypothalamic-neurohypophyseal axis, neurohypophysial hormones are released from the posterior pituitary, which is actually a prolongation of the hypothalamus, into the circulation.
Secreted hormone Oxytocin Abbreviation Produced by Effect

OXY or OXT Magnocellular neurosecretory cells of the Uterine contraction paraventricular nucleus and supraoptic Lactation (letdown reflex) nucleus ADH or AVP Magnocellular neurosecretory cells of the Increase in the permeability to water of the cells of distal tubule and paraventricular nucleus and supraoptic collecting duct in the kidney and thus allows water reabsorption and nucleus excretion of concentrated urine

Vasopressin (antidiuretic hormone)

Other hormones are known to be released from the posterior pituitary.[18]

Control of food intake

The extreme lateral part of the ventromedial nucleus of the hypothalamus is responsible for the control of food intake. Stimulation of this area causes increased food intake. Bilateral lesion of this area causes complete cessation of food intake. Medial parts of the nucleus have a controlling effect on the lateral part. Bilateral lesion of the medial part of the ventromedial nucleus causes hyperphagia and obesity of the animal. Further lesion of the lateral part of the ventromedial nucleus in the same animal produces complete cessation of food intake. There are different hypotheses related to this regulation:[19] 1. Lipostatic hypothesis: this hypothesis holds that adipose tissue produces a humoral signal that is proportionate to the amount of fat and acts on the hypothalamus to decrease food intake and increase energy output. It has been evident that a hormone leptin acts on the hypothalamus to decrease food intake and increase energy output. 2. Gutpeptide hypothesis: gastrointestinal hormones like Grp, glucagons, CCK and others claimed to inhibit food intake. The food entering the gastrointestinal tract triggers the release of these hormones which acts on the brain

Hypothalamus to produce satiety. The brain contains both CCK-A and CCK-B receptors. 3. Glucostatic hypothesis: the activity of the satiety center in the ventromedial nuclei is probably governed by the glucose utilization in the neurons. It has been postulated that when their glucose utilization is low and consequently when the arteriovenous blood glucose difference across them is low, the activity across the neurons decrease. Under these conditions, the activity of the feeding center is unchecked and the individual feels hungry. Food intake is rapidly increased by intraventricular administration of 2-deoxyglucose therefore decreasing glucose utilization in cells. 4. Thermostatic hypothesis: according to this hypothesis, a decrease in body temperature below a given set point stimulates appetite, while an increase above the set point inhibits appetite.

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Sexual dimorphism
Several hypothalamic nuclei are sexually dimorphic; i.e. there are clear differences in both structure and function between males and females.[citation needed] Some differences are apparent even in gross neuroanatomy: most notable is the sexually dimorphic nucleus within the preoptic area. However most of the differences are subtle changes in the connectivity and chemical sensitivity of particular sets of neurons.[citation needed] The importance of these changes can be recognised by functional differences between males and females. For instance, males of most species prefer the odor and appearance of females over males, which is instrumental in stimulating male sexual behavior. If the sexually dimorphic nucleus is lesioned, this preference for females by males diminishes. Also, the pattern of secretion of growth hormone is sexually dimorphic, and this is one reason why in many species, adult males are much larger than females.[citation needed]

Responses to ovarian steroids

Other striking functional dimorphisms are in the behavioral responses to ovarian steroids of the adult. Males and females respond differently to ovarian steroids, partly because the expression of estrogen-sensitive neurons in the hypothalamus is sexually dimorphic; i.e. estrogen receptors are expressed in different sets of neurons.[citation needed] Estrogen and progesterone can influence gene expression in particular neurons or induce changes in cell membrane potential and kinase activation, leading to diverse non-genomic cellular functions. Estrogen and progesterone bind to their cognate nuclear hormone receptors, which translocate to the cell nucleus and interact with regions of DNA known as hormone response elements (HREs) or get tethered to another transcription factor's binding site. Estrogen receptor (ER) has been shown to transactivate other transcription factors in this manner, despite the absence of an estrogen response element (ERE) in the proximal promoter region of the gene. ERs and progesterone receptors (PRs) are generally gene activators, with increased mRNA and subsequent protein synthesis following hormone exposure.[citation needed] Male and female brains differ in the distribution of estrogen receptors, and this difference is an irreversible consequence of neonatal steroid exposure. Estrogen receptors (and progesterone receptors) are found mainly in neurons in the anterior and mediobasal hypothalamus, notably[citation needed]: the preoptic area (where LHRH neurons are located) the periventricular nucleus (where somatostatin neurons are located) the ventromedial hypothalamus (which is important for sexual behavior).

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Gonadal steroids in neonatal life of rats

In neonatal life, gonadal steroids influence the development of the neuroendocrine hypothalamus. For instance, they determine the ability of females to exhibit a normal reproductive cycle, and of males and females to display appropriate reproductive behaviors in adult life.[citation needed] If a female rat is injected once with testosterone in the first few days of postnatal life (during the "critical period" of sex-steroid influence), the hypothalamus is irreversibly masculinized; the adult rat will be incapable of generating an LH surge in response to estrogen (a characteristic of females), but will be capable of exhibiting male sexual behaviors (mounting a sexually receptive female).[citation needed] By contrast, a male rat castrated just after birth will be feminized, and the adult will show female sexual behavior in response to estrogen (sexual receptivity, lordosis behavior).[citation needed]

Androgens in primates
In primates, the developmental influence of androgens is less clear, and the consequences are less understood. Within the brain, testosterone is aromatized to (estradiol), which is the principal active hormone for developmental influences. The human testis secretes high levels of testosterone from about week 8 of fetal life until 56 months after birth (a similar perinatal surge in testosterone is observed in many species), a process that appears to underlie the male phenotype. Estrogen from the maternal circulation is relatively ineffective, partly because of the high circulating levels of steroid-binding proteins in pregnancy.[citation needed]

Human sexual orientation and the hypothalamus

According to D. F. Swaab, writing in a July 2008 paper, "Neurobiological research related to sexual orientation in humans is only just gathering momentum, but the evidence already shows that humans have a vast array of brain differences, not only in relation to gender, but also in relation to sexual orientation."[20] Swaab first reported on the relationship between sexual orientation in males and the hypothalamus's "clock", the suprachiasmatic nucleus (SCN). In 1990, Swaab and Hofman[21] reported that the suprachiasmatic nucleus in homosexual men was significantly larger than in heterosexual men. Then in 1995, Swaab et al.[22] linked brain development to sexual orientation by treating male rats both pre- and postnatally with ATD, an aromatase blocker in the brain. This produced an enlarged SCN and bisexual behavior in the adult male rats. In 1991, LeVay showed that part of the sexually dimorphic nucleus (SDN) known as the 3rd interstitial nucleus of the anterior hypothalamus (INAH 3), is nearly twice as large in heterosexual men than in homosexual men and heterosexual women, in terms of volume. In 2004 and 2006, two studies by Berglund, Lindstrm, and Savic[23][24] used Positron Emission Tomography (PET) to observe how the hypothalamus responds to smelling common odors, the scent of testosterone found in male sweat, and the scent of estrogen found in female urine. These studies showed that the hypothalamus of heterosexual men and homosexual women both respond to estrogen. Also, the hypothalamus of homosexual men and heterosexual women both respond to testosterone. The hypothalamus of all four groups did not respond to the common odors, which produced a normal olfactory response in the brain.

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Other influences upon hypothalamic development

Sex steroids are not the only important influences upon hypothalamic development; in particular, pre-pubertal stress in early life (of rats) determines the capacity of the adult hypothalamus to respond to an acute stressor.[25] Unlike gonadal steroid receptors, glucocorticoid receptors are very widespread throughout the brain; in the paraventricular nucleus, they mediate negative feedback control of CRF synthesis and secretion, but elsewhere their role is not well understood.

Fear processing
The medial zone of hypothalamus is part of a circuitry that controls motivated behaviors, like defensive behaviors.[] Analyses of Fos-labeling showed that a series of nuclei in the "behavioral control column" is important in regulating the expression of innate and conditioned defensive behaviors.[]

Antipredatory defensive behavior

Exposure to a predator (such as a cat) elicits defensive behaviors in laboratory rodents, even when the animal has never been exposed to a cat.[] In the hypothalamus, this exposure causes an increase in Fos-labeled cells in the anterior hypothalamic nucleus, the dorsomedial part of the ventromedial nucleus, and in the ventrolateral part of the premammillary nucleus (PMDvl).[] The premammillary nucleus has an important role in expression of defensive behaviors towards a predator, since lesions in this nucleus abolish defensive behaviors, like freezing and flight.[][] The PMD does not modulate defensive behavior in other situations, as lesions of this nucleus had minimal effects on post-shock freezing scores.[] The PMD has important connections to the dorsal periaqueductal gray, an important structure in fear expression.[][] In addition, animals display risk assessment behaviors to the environment previously associated with the cat. Fos-labeled cell analysis showed that the PMDvl is the most activated structure in the hypothalamus, and inactivation with muscimol prior to exposure to the context abolishes the defensive behavior.[] Therefore, the hypothalamus, mainly the PMDvl, has an important role in expression of innate and conditioned defensive behaviors to a predator.

Social defeat
Likewise, the hypothalamus has a role in social defeat: nuclei in medial zone are also mobilized during an encounter with an aggressive conspecific. The defeated animal has an increase in Fos levels in sexually dimorphic structures, such as the medial pre-optic nucleus, the ventrolateral part of ventromedial nucleus, and the ventral premammilary nucleus.[] Such structures are important in other social behaviors, such as sexual and aggressive behaviors. Moreover, the premammillary nucleus also is mobilized, the dorsomedial part but not the ventrolateral part.[] Lesions in this nucleus abolish passive defensive behavior, like freezing and the "on-the-back" posture.[]

Additional images

Median sagittal section of brain of human embryo of three months.

Human brain left dissected midsagittal view

Endocrine glands in the human head and neck and their hormones

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References
[1] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=189#p812 [2] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=358 [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Hypothalamus [4] http:/ / www. neurolex. org/ wiki/ birnlex_734 [5] Definition of hypothalamus - NCI Dictionary of Cancer Terms (http:/ / www. cancer. gov/ dictionary?CdrID=46359) [6] hypothalamus (http:/ / www. sci. uidaho. edu/ med532/ hypothal. htm) [8] Diagram of Nuclei (psycheducation.org) (http:/ / www. psycheducation. org/ emotion/ pics/ big hypothalamus. htm) [9] Diagram of Nuclei (universe-review.ca) (http:/ / universe-review. ca/ I10-80-nuclei. jpg) [10] Diagram of Nuclei (utdallas.edu) (http:/ / www. utdallas. edu/ ~tres/ integ/ hom3/ display13_04. html) [11] Unless else specified in table, then ref is: Guyton Twelfth Edition [12] Hypothalamus and ANS (http:/ / thalamus. wustl. edu/ course/ hypoANS. html) [13] Overview of Hypothalamic and Pituitary Hormones (http:/ / www. vivo. colostate. edu/ hbooks/ pathphys/ endocrine/ hypopit/ overview. html)

Added reference
de Vries, GJ, and Sodersten P (2009) Sex differences in the brain: the relation between structure and function. Hormones and Behavior 55:589-596.

External links
BrainMaps at UCDavis Hypothalamus (http://brainmaps.org/index.php?q=Hypothalamus) The Hypothalamus and Pituitary at endotexts.org (http://www.endotext.org/neuroendo/neuroendo3b/ neuroendo3b.htm) NIF Search - Hypothalamus (https://www.neuinfo.org/mynif/search.php?q=Hypothalamus&t=data& s=cover&b=0&r=20) via the Neuroscience Information Framework Space-filling and cross-sectional diagrams of hypothalamic nuclei: right hypothalamus (http://www. netterimages.com/image/8535.htm), anterior (http://www.netterimages.com/image/8584.htm), tubular (http://www.netterimages.com/image/8586.htm), posterior (http://www.netterimages.com/image/8588. htm).

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Pituitary gland
Pituitary gland

Located at the base of the brain, the pituitary gland is protected by a bony structure called the sella turcica of the sphenoid bone.

Median sagittal through the hypophysis of an adult monkey. Semidiagrammatic. Latin Gray's Artery hypophysis, glandula pituitaria subject #275 1275
[1]

superior hypophyseal artery, infundibular artery, prechiasmal artery, inferior hypophyseal artery, capsular artery, [2] artery of the inferior cavernous sinus neural and oral ectoderm, including Rathke's pouch Pituitary+Gland
[3]

Precursor MeSH

Dorlands/Elsevier Pituitary gland [4]

In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 5 grams (0.18oz) in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity (sella turcica) covered by a dural fold (diaphragma sellae). The pituitary is functionally connected to the hypothalamus by the median eminence via a small tube called the infundibular stem (Pituitary stalk). The pituitary fossa, in which the pituitary gland sits, is situated in the sphenoid bone in the middle cranial fossa at the base of the brain. The pituitary gland secretes nine hormones that regulate homeostasis.

Anatomy
The pituitary gland is a pea-sized gland that sits in a protective bony enclosure called the sella turcica. It is composed of three lobes: anterior, intermediate, and posterior. In many animals, these three lobes are distinct. However, in humans, the intermediate lobe is but a few cell layers thick and indistinct; as a result, it is often considered part of the anterior pituitary. In all animals, the fleshy, glandular anterior pituitary is distinct from the neural composition of the posterior pituitary. It belongs to the diencephalon.

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Embryology
Anterior
The anterior pituitary arises from an invagination of the oral ectoderm and forms Rathke's pouch. This contrasts with the posterior pituitary, which originates from neuroectoderm. The anterior pituitary synthesizes and secretes the following important endocrine hormones: Somatotrophins: Growth hormone (also referred to as 'Human Growth Hormone', 'HGH' or 'GH' or somatotropin), released under influence of hypothalamic Growth Hormone-Releasing Hormone (GHRH); inhibited by hypothalamic Somatostatin Thyrotrophins: Thyroid-stimulating hormone (TSH), released under influence of hypothalamic Thyrotropin-releasing hormone (TRH) Corticotropins: Adrenocorticotropic hormone (ACTH), released under influence of hypothalamic Corticotropin-Releasing Hormone (CRH) Beta-endorphin, released under influence of hypothalamic Corticotropin-Releasing Hormone (CRH)[5] Lactotrophins: Prolactin (PRL), also known as 'Luteotropic' hormone (LTH), whose release is inconsistently stimulated by hypothalamic TRH, oxytocin, vasopressin, vasoactive intestinal peptide, angiotensin II, neuropeptide Y, galanin, substance P, bombesin-like peptides (gastrin-releasing peptide, neuromedin B and C), and neurotensin, and inhibited by hypothalamic dopamine.[] Gonadotropins: Luteinizing hormone (also referred to as 'Lutropin' or 'LH' or, in males, 'Interstitial Cell-Stimulating Hormone' (ICSH)) Follicle-stimulating hormone (FSH), both released under influence of Gonadotropin-Releasing Hormone (GnRH) Melanotrophins Melanocytestimulating hormones (MSHs) or "intermedins," as these are released by the pars intermedia, which is "the middle part"; adjacent to the posterior pituitary lobe, pars intermedia is a specific part developed from the anterior pituitary lobe. These hormones are released from the anterior pituitary under the influence of the hypothalamus. Hypothalamic hormones are secreted to the anterior lobe by way of a special capillary system, called the hypothalamic-hypophysial portal system. The anterior pituitary is divided into anatomical regions known as the pars tuberalis, pars intermedia, and pars distalis. It develops from a depression in the dorsal wall of the pharynx (stomodial part) known as Rathke's pouch.

Posterior
The posterior lobe develops as an extension of the hypothalamus. The magnocellular neurosecretory cells of the posterior side possess cell bodies located in the hypothalamus that project axons down the infundibulum to terminals in the posterior pituitary. This simple arrangement differs sharply from that of the adjacent anterior pituitary, which does not develop from the hypothalamus. Endocrine cells of the anterior pituitary are controlled by regulatory hormones released by parvocellular neurosecretory cells in the hypothalamus. The latter release regulatory hormones into hypothalamic capillaries leading to infundibular blood vessels, which in turn lead to a second capillary bed in

Pituitary gland the anterior pituitary. This vascular relationship constitutes the hypothalamo-hypophyseal portal system. Diffusing out of the second capillary bed, the hypothalamic regulatory hormones then bind to anterior pituitary endocrine cells, upregulating or downregulating their release of hormones. Hence, the release of pituitary hormones by both the anterior and posterior lobes is under the control of the hypothalamus, albeit in different ways.[6] The posterior pituitary stores and secretes the following important endocrine hormones: Magnocellular Neurons: Oxytocin, most of which is released from the paraventricular nucleus in the hypothalamus Antidiuretic hormone (ADH, also known as vasopressin and AVP, arginine vasopressin), the majority of which is released from the supraoptic nucleus in the hypothalamus Oxytocin is one of the few hormones to create a positive feedback loop. For example, uterine contractions stimulate the release of oxytocin from the posterior pituitary, which, in turn, increases uterine contractions. This positive feedback loop continues throughout labour.

248

Intermediate lobe
Although rudimentary in humans (and often considered part of the anterior pituitary), the intermediate lobe located between the anterior and posterior pituitary is important to many animals. For instance, in fish, it is believed to control physiological color change. In adult humans, it is just a thin layer of cells between the anterior and posterior pituitary. The intermediate lobe produces melanocyte-stimulating hormone (MSH), although this function is often (imprecisely) attributed to the anterior pituitary. The intermediate lobe is, in general, not well developed in tetrapods, and is entirely absent in birds.[]

Variations among vertebrates

The pituitary gland is found in all vertebrates, but its structure varies between different groups. The division of the pituitary described above is typical of mammals, and is also true, to varying degrees, of all tetrapods. However, only in mammals does the posterior pituitary have a compact shape. In lungfishes, it is a relatively flat sheet of tissue lying above the anterior pituitary, and, in amphibians, reptiles, and birds, it becomes increasingly well developed. The intermediate lobe is, in general, not well developed in tetrapods, and is entirely absent in birds.[] Apart from lungfishes, the structure of the pituitary in fish is generally different from that in tetrapods. In general, the intermediate lobe tends to be well developed, and may equal the remainder of the anterior pituitary in size. The posterior lobe typically forms a sheet of tissue at the base of the pituitary stalk, and in most cases sends irregular finger-like projection into the tissue of the anterior pituitary, which lies directly beneath it. The anterior pituitary is typically divided into two regions, a more anterior rostral portion and a posterior proximal portion, but the boundary between the two is often not clearly marked. In elasmobranchs there is an additional, ventral lobe beneath the anterior pituitary proper.[] The arrangement in lampreys, which are among the most primitive of all fish, may indicate how the pituitary originally evolved in ancestral vertebrates. Here, the posterior pituitary is a simple flat sheet of tissue at the base of the brain, and there is no pituitary stalk. Rathke's pouch remains open to the outside, close to the nasal openings. Closely associated with the pouch are three distinct clusters of glandular tissue, corresponding to the intermediate lobe, and the rostral and proximal portions of the anterior pituitary. These various parts are separated by meningial membranes, suggesting that the pituitary of other vertebrates may have formed from the fusion of a pair of separate, but associated, glands.[] Most armadillo also possess a urophysis, a neural secretory gland very similar in form to the posterior pituitary, but located in the tail and associated with the spinal cord. This may have a function in osmoregulation.[] There is an analogous structure in the octopus brain.[7]

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Functions
Hormones secreted from the pituitary gland help control the following body processes: Growth (Excess of HGH can lead to gigantism and acromegaly.) Blood pressure Some aspects of pregnancy and childbirth including stimulation of uterine contractions during childbirth Breast milk production Sex organ functions in both males and females Thyroid gland function The conversion of food into energy (metabolism) Water and osmolarity regulation in the body Water balance via the control of reabsorption of water by the kidneys Temperature regulation Pain relief
Compared with the hand of an unaffected person (left), the hand of someone with acromegaly (right) is enlarged.

Diseases involving the pituitary gland

Some of the diseases involving the pituitary gland are: Hypopituitarism, the decreased (hypo) secretion of one or more of the eight hormones normally produced by the pituitary gland. If there is decreased secretion of most pituitary hormones, the term panhypopituitarism (pan meaning "all") is used. Pituitary tumours. Pituitary adenomas, noncancerous tumors that occur in the pituitary gland.

Additional images

Location of the pituitary gland in the human brain

Pituitary and pineal glands

The arteries of the base of the brain.

Mesal aspect of a brain sectioned in the median sagittal plane.

Pituitary

Pituitary gland

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References
[1] [3] [4] [5] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=275#p1275 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Pituitary+ Gland http:/ / www. mercksource. com/ pp/ us/ cns/ cns_hl_dorlands_split. jsp?pg=/ ppdocs/ us/ common/ dorlands/ dorland/ nine/ 000955852. htm Knepel W, Homolka L, Vlaskovska M, Nutto D. (1984). Stimulation of adrenocorticotropin/beta-endorphin release by synthetic ovine corticotropin-releasing factor in vitro. Enhancement by various vasopressin analogs. Neuroendocrinology. 38(5):344-50.

External links
NeuroNames hier-382 (http://braininfo.rprc.washington.edu/Scripts/hiercentraldirectory.aspx?ID=382) BU Histology Learning System: 14201loa (http://www.bu.edu/histology/p/14201loa.htm) The Pituitary Gland, from the UMM Endocrinology Health Guide (http://www.umm.edu/endocrin/pitgland. htm) Oklahoma State, Endocrine System (http://instruction.cvhs.okstate.edu/Histology/HistologyReference/ HREndoframe.htm) Pituitary apoplexy mimicking pituitary abscess (http://www.ispub.com/ostia/index.php?xmlPrinter=true& xmlFilePath=journals/ijns/vol4n1/pituitary.xml) (http://www.pituitary.org.uk/content/view/19/28/) The Pituitary Foundation

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Epinephrine
(R)-()-L-Epinephrine or (R)-()-L-adrenaline

Systematic (IUPAC) name

(R)-4-(1-hydroxy2-(methylamino)ethyl)benzene-1,2-diol
Clinical data AHFS/Drugs.com monograph [1] MedlinePlus Pregnancy cat. Legal status Routes a603002 [2]

A (AU) C (US) Prescription Only (S4) (AU) POM (UK) -only (US) IV, IM, endotracheal, IC Pharmacokinetic data

Bioavailability Metabolism Half-life Excretion

Nil (oral) adrenergic synapse (MAO and COMT) 2 minutes Urine Identifiers

CAS number ATC code PubChem IUPHAR ligand DrugBank ChemSpider UNII KEGG

51-43-4

[3]

B02BC09 [5] C01CA24 [6] R01AA14 [7] R03AA01 [8] S01EA01 [9]

A01AD01 CID 5816 479 [11]

[4]

[10]

DB00668 5611 [13]

[12] [14]

YKH834O4BH D00095 [15]

Epinephrine
[16] [17]

252
ChEBI ChEMBL

CHEBI:28918 CHEMBL679

Chemical data

Formula Mol. mass

C9H13NO3 183.204 g/mol

(what is this?) (verify)

[18]

Epinephrine (also known as adrenaline or adrenalin) is a hormone and a neurotransmitter.[19] Epinephrine has many functions in the body, regulating heart rate, blood vessel and air passage diameters, and metabolic shifts; epinephrine release is a crucial component of the fight-or-flight response of the sympathetic nervous system.[20] In chemical terms, epinephrine is one of a group of monoamines called the catecholamines. It is produced in some neurons of the central nervous system, and in the chromaffin cells of the adrenal medulla from the amino acids phenylalanine and tyrosine.[]

Medical uses
Adrenaline is used to treat a number of conditions including: cardiac arrest, anaphylaxis, and superficial bleeding.[] It has been used historically for bronchospasm and hypoglycemia, but newer treatments for these, such as salbutamol, a synthetic epinephrine derivative, and dextrose, respectively, are currently preferred.[]

Cardiac arrest
Adrenaline is used as a drug to treat cardiac arrest and other cardiac dysrhythmias resulting in diminished or absent cardiac output. Its actions are to increase peripheral resistance via 1receptor-dependent vasoconstriction and to increase cardiac output via its binding to 1 receptors. There are ever growing doubts amongst healthcare professionals about the efficacy of adrenaline in cardiac arrest.[21]

Anaphylaxis
Due to its vasoconstrictive effects, adrenaline is the drug of choice for treating anaphylaxis. Allergy[22] patients undergoing immunotherapy may receive an adrenaline rinse before the allergen extract is administered, thus reducing the immune response to the administered allergen. Because of various expressions of 1 or 2 receptors, depending on the Epinephrine ampoule, 1mg (Suprarenin) patient, administration of adrenaline may raise or lower blood pressure, depending on whether or not the net increase or decrease in peripheral resistance can balance the positive inotropic and chronotropic effects of adrenaline on the heart, effects that increase the contractility and rate, respectively, of the heart.[citation needed] The usual concentration for SC or IM injection is 0.3 - 0.5mg 1:1,000.

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Asthma
Adrenaline is also used as a bronchodilator for asthma if specific 2 agonists are unavailable or ineffective.[23] When given by the subcutaneous or intramuscular routes for asthma, an appropriate dose is 300-500 mcg.[24][25]

Croup
Racemic epinephrine has historically been used for the treatment of croup.[26][] Racemic adrenaline is a 1:1 mixture of the dextrorotatory (d) and levorotatory (l) isomers of adrenaline.[] The l- form is the active component.[] Racemic adrenaline works by stimulation of the -adrenergic receptors in the airway, with resultant mucosal vasoconstriction and decreased subglottic edema, and by stimulation of the -adrenergic receptors, with resultant relaxation of the bronchial smooth muscle.[]

In local anesthetics
Adrenaline is added to injectable forms of a number of local anesthetics, such as bupivacaine and lidocaine, as a vasoconstrictor to slow the absorption and, therefore, prolong the action of the anesthetic agent. Due to epinephrine's vasoconstricting abilities, the use of epinephrine in localized anesthetics also helps to diminish the total blood loss the patient sustains during minor surgical procedures. Some of the adverse effects of local anesthetic use, such as apprehension, tachycardia, and tremor, may be caused by adrenaline. Epinephrine/adrenalin is frequently combined with dental and spinal anesthetics and can cause panic attacks in susceptible patients at a time when they may be unable to move or speak due to twilight drugs.[27]

Autoinjectors
Adrenaline is available in an autoinjector delivery system. Jext's, EpiPens, AuviQs, Anapens, and Twinjects all use adrenaline as their active ingredient. Twinjects contain a second dose of adrenaline in a separate syringe and needle delivery system contained within the body of the autoinjector. Though both EpiPen and Twinject are trademark names, common usage of the terms is drifting toward the generic context of any adrenaline autoinjector.[citation needed]

Adverse effects
Adverse reactions to adrenaline include palpitations, tachycardia, arrhythmia, anxiety, panic attack, headache, tremor, hypertension, and acute pulmonary edema.[28] Use is contraindicated in people on nonselective -blockers, because severe hypertension and even cerebral hemorrhage may result.[] Although commonly believed that administration of adrenaline may cause heart failure by constricting coronary arteries, this is not the case. Coronary arteries have only 2 receptors, which cause vasodilation in the presence of adrenaline.[] Even so, administering high-dose adrenaline has not been definitively proven to improve survival or neurologic outcomes in adult victims of cardiac arrest.[]

Terminology
This chemical is widely referred to as "adrenaline" outside the United States; however, its United States Adopted Name and International Nonproprietary Name is epinephrine. Epinephrine was chosen as the generic name in the United States because John Abel, who prepared extracts from the adrenal glands in 1897, used that name for his extracts.[] In 1901, Jokichi Takamine patented a purified adrenal extract, and called it "adrenalin", which was trademarked by Parke, Davis & Co in the U.S.[] In the belief that Abel's extract was the same as Takamine's, a belief since disputed, epinephrine became the generic name in the U.S.[] The British Approved Name and European Pharmacopoeia term for this chemical is adrenaline and is indeed now one of the few differences between the INN

Epinephrine and BAN systems of names.[29] Among American health professionals and scientists, the term epinephrine is used over adrenaline. However, pharmaceuticals that mimic the effects of epinephrine are often called adrenergics, and receptors for epinephrine are called adrenergic receptors or adrenoceptors.

254

Mechanism of action
Physiologic responses to epinephrine by organ
Organ Heart Lungs Effects Increases heart rate Increases respiratory rate

Systemic Vasoconstriction or vasodilation Liver Stimulates glycogenolysis

Systemic Triggers lipolysis Systemic Muscle contraction

As a hormone and neurotransmitter, epinephrine acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of adrenergic receptors. For example, high levels of epinephrine causes smooth muscle relaxation in the airways but causes contraction of the smooth muscle that lines most arterioles. Epinephrine acts by binding to a variety of adrenergic receptors. Epinephrine is a nonselective agonist of all adrenergic receptors, including the major subtypes 1, 2, 1, 2, and 3.[] Epinephrine's binding to these receptors triggers a number of metabolic changes. Binding to -adrenergic receptors inhibits insulin secretion by the pancreas, stimulates glycogenolysis in the liver and muscle, and stimulates glycolysis in muscle.[] -Adrenergic receptor binding triggers glucagon secretion in the pancreas, increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and increased lipolysis by adipose tissue. Together, these effects lead to increased blood glucose and fatty acids, providing substrates for energy production within cells throughout the body.[]

Measurement in biological fluids

Adrenaline may be quantified in blood, plasma, or serum as a diagnostic aid, to monitor therapeutic administration, or to identify the causative agent in a potential poisoning victim. Endogenous plasma adrenaline concentrations in resting adults are normally less than 10ng/L, but may increase by 10-fold during exercise and by 50-fold or more during times of stress. Pheochromocytoma patients often have plasma adrenaline levels of 1000-10,000ng/L. Parenteral administration of adrenaline to acute-care cardiac patients can produce plasma concentrations of 10,000 to 100,000ng/L.[30][31]

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Biosynthesis and regulation

Adrenaline is synthesized in the medulla of the adrenal gland in an enzymatic pathway that converts the amino acid tyrosine into a series of intermediates and, ultimately, adrenaline. Tyrosine is first oxidized to L-DOPA, which is subsequently decarboxylated to give dopamine. Oxidation gives norepinephrine, which is methylated to give epinephrine. Adrenaline is synthesized via methylation of the primary amine of noradrenaline by phenylethanolamine N-methyltransferase (PNMT) in the cytosol of adrenergic neurons and cells of the adrenal medulla (so-called chromaffin cells). PNMT is found in the cytosol of only cells of adrenal medullary cells. PNMT uses S-adenosylmethionine (SAMe) as a cofactor to donate the methyl group to noradrenaline, creating adrenaline.[citation
needed]

Epinephrine and Psychology

Epinephrine and Emotional Response Every emotional response has a behavioral component, an autonomic component, and a hormonal component. The hormonal component includes the release of epinephrine, an adrenomedullary response that occurs in response to stress and that is controlled by the sympathetic nervous system. The major emotion studied in relation to epinephrine is fear. In an experiment, subjects who were injected with epinephrine expressed more negative and fewer positive facial expressions to fear films compared to a control group. These subjects also reported a more intense fear from the films and greater mean intensity of negative memories than control subjects.[32] The findings from this study demonstrate that there are learned associations between negative feelings and levels of epinephrine. Overall, the greater amount of epinephrine is positively correlated with an arousal state of negative feelings. These findings can be an effect in part that epinephrine elicits physiological sympathetic responses including an increased heart rate and knee shaking, which can be attributed to the feeling of fear regardless of the actual level of fear elicited from the video. Although studies have found a definite relation between epinephrine and fear, other emotions have not had such results. In the same study, subjects did not express a greater amusement to an amusement film nor greater anger to an anger film.[32] Similar findings were also supported in a study that involved rodent subjects that either were able or unable to produce epinephrine. Findings support the idea that epinephrine does have a role in facilitating the encoding of emotionally arousing events, contributing to higher levels of arousal due to fear.[33] Epinephrine and Memory It has been found that adrenergic hormones, such as epinephrine, can produce retrograde enhancement of long-term memory in humans. The release of epinephrine due to emotionally stressful events, which is endogenous epinephrine, can modulate memory consolidation of the events, insuring memory strength that is proportional to memory importance. Post-learning epinephrine activity also interacts with the degree of arousal associated with the initial coding.[34] There is evidence that suggests epinephrine does have a role in long-term stress adaptation and emotional memory encoding specifically. Epinephrine may also play a role in elevating arousal and fear memory under particular pathological conditions including post-traumatic stress disorder, PTSD,.[33] Overall, the general findings through most studies supports that endogenous epinephrine released during learning modulate the formation of long-lasting memories for arousing events.[35] Studies have also found that recognition memory involving epinephrine depends on a mechanism that depends on B-adrenoceptors.[35] Epinephrine does not readily cross the blood-brain barrier, so its effects on memory consolidation are at least partly initiated by B-adrenoceptors in the periphery. Studies have found that sotalol, a B-adrenoceptor antagonist that also does not readily enter the brain, blocks the enhancing effects of peripherally administered epinephrine on memory.[36] These findings suggest that B-adrenoceptors are necessary for epinephrine to have an effect on memory consolidation.

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For noradrenaline to be acted upon by PNMT in the cytosol, it must first be shipped out of granules of the chromaffin cells. This may occur via the catecholamine-H+ exchanger VMAT1. VMAT1 is also responsible for transporting newly synthesized adrenaline from the cytosol back into chromaffin granules in preparation for release.[citation needed] In liver cells, adrenaline binds to the -adrenergic receptor, which changes conformation and helps Gs, a G protein, exchange GDP to GTP. This trimeric G protein dissociates to Gs alpha and Gs beta/gamma subunits. Gs alpha binds to adenyl cyclase, thus converting ATP into cyclic AMP. Cyclic AMP binds to the regulatory subunit of protein kinase A: Protein kinase A phosphorylates phosphorylase kinase. Meanwhile, Gs beta/gamma binds to the calcium channel and allows calcium ions to enter the cytoplasm. Calcium ions bind to calmodulin proteins, a protein present in all eukaryotic cells, which then binds to phosphorylase kinase and finishes its activation. Phosphorylase kinase phosphorylates glycogen phosphorylase, which then phosphorylates glycogen and converts it to glucose-6-phosphate. [citation needed]

Regulation
The major physiologic triggers of adrenaline release center upon stresses, such as physical threat, excitement, noise, bright lights, and high ambient temperature. All of these stimuli are processed in the central nervous system.[37]

The biosynthesis of adrenaline involves a series of enzymatic reactions.

Adrenocorticotropic hormone (ACTH) and the sympathetic nervous system stimulate the synthesis of adrenaline precursors by enhancing the activity of tyrosine hydroxylase and dopamine--hydroxylase, two key enzymes involved in catecholamine synthesis.[citation needed] ACTH also stimulates the adrenal cortex to release cortisol, which increases the expression of PNMT in chromaffin cells, enhancing adrenaline synthesis. This is most often done in response to stress.[citation needed] The sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of adrenaline. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and, thus, the release of adrenaline (and noradrenaline) into the bloodstream.[citation needed] Unlike many other hormones adrenaline (as with other catecholamines) does not exert negative feedback to down-regulate its own synthesis.[38] Abnormally elevated levels of adrenaline can occur in a variety of conditions, such as surreptitious epinephrine administration, pheochromocytoma, and other tumors of the sympathetic ganglia. Its action is terminated with reuptake into nerve terminal endings, some minute dilution, and metabolism by monoamine oxidase and catechol-O-methyl transferase.

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Chemical synthesis
Epinephrine may be synthesized by the reaction of catechol (1) with chloroacetyl chloride (2), followed by the reaction with methylamine to give the ketone (4), which is reduced to the desired hydroxy compound (5). The racemic mixture may be separated using tartaric acid.

Synthetic route for adrenaline

For isolation from the adrenal glands tissue of livestock: J. Takamine, J. Soc. Chem. Ind., 20, 746 (1901). J. B. Aldrich, Am. J. Physiol., 5, 457 (1901). Synthetic production: A. F. Stolz, Chem. Ber., 37, 4149 (1904). K. R. Payne, Ind. Chem. Chem. Manuf., 37, 523 (1961). H. Loewe, Arzneimittel-Forsch., 4, 583 (1954). Farbenwerke Meister Lucins & Bruning in Hochst a.M., DE 152814 [39] (1903). Farbenwerke Meister Lucins & Bruning in Hochst a.M., DE 157300 [40] (1903). Farbenwerke Meister Lucins & Bruning in Hochst a.M., DE 222451 [41] (1908). Tullar, B. F. (1948). "The resolution of dl-arterenol". Journal of the American Chemical Society 70 (6): 20672068. doi:10.1021/ja01186a024 [42]. PMID18863798 [43]. D. Flacher, Z. Physiol. Chem., 58, 189 (1908).

History
Extracts of the adrenal gland were first obtained by Polish physiologist Napoleon Cybulski in 1895. These extracts, which he called nadnerczyna, contained adrenaline and other catecholamines.[44] Japanese chemist Jokichi Takamine and his assistant Keizo Uenaka independently discovered adrenaline in 1900.[45][] In 1901, Takamine successfully isolated and purified the hormone from the adrenal glands of sheep and oxen.[46] Adrenaline was first synthesized in the laboratory by Friedrich Stolz and Henry Drysdale Dakin, independently, in 1904.[]

Adrenaline junkie
An adrenaline junkie is somebody who appears to be addicted to endogenous epinephrine. The "high" is caused by self-inducing a fight-or-flight response by intentionally engaging in stressful or risky behavior, which causes a release of epinephrine by the adrenal gland. Adrenaline junkies appear to favor stressful activities for the release of epinephrine as a stress response. Whether or not the positive response is caused specifically by epinephrine is difficult to determine, as endorphins are also released during the fight-or-flight response to such activities.[47][48]

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References
[1] http:/ / www. drugs. com/ monograph/ epinephrine. html [2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a603002. html [3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=51-43-4& rn=1 [4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=A01AD01 [5] http:/ / www. whocc. no/ atc_ddd_index/ ?code=B02BC09 [6] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01CA24 [7] http:/ / www. whocc. no/ atc_ddd_index/ ?code=R01AA14 [8] http:/ / www. whocc. no/ atc_ddd_index/ ?code=R03AA01 [9] http:/ / www. whocc. no/ atc_ddd_index/ ?code=S01EA01 [10] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5816 [11] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=479 [12] http:/ / www. drugbank. ca/ drugs/ DB00668 [13] http:/ / www. chemspider. com/ Chemical-Structure. 5611 [14] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=YKH834O4BH [15] http:/ / www. kegg. jp/ entry/ D00095 [16] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:28918 [17] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL679 [18] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=464189734& page2=Epinephrine [21] JAMA. 2012;307(11):1198-1200. doi:10.1001/jama.2012.313. [24] Soar, Perkins, et al (2010) European Resuscitation Council Guidelines for Resuscitation 2010 Section 8. Cardiac arrest in special circumstances: Electrolyte abnormalities, poisoning, drowning, accidental hypothermia, hyperthermia, asthma, anaphylaxis, cardiac surgery, trauma, pregnancy, electrocution. Resuscitation. Oct. pp.1400-1433 [25] Fisher, Brown, Cooke (Eds) (2006) Joint Royal Colleges Ambulance Liaison Committee. UK Ambulance Clinical Practice Guidelines. [27] R. Rahn and B. Ball. Local Anesthesia in Dentistry, 3M ESPE AG, ESPE Platz, Seefeld, Germany, 2001, 44 pp. [28] About.com (http:/ / stress. about. com/ od/ stressmanagementglossary/ g/ Epinephrine. htm) - "The Definition of Epinephrine" [29] Changes to medicines names: BANs to rINNs (http:/ / www. mhra. gov. uk/ Howweregulate/ Medicines/ Namingofmedicines/ ChangestomedicinesnamesBANstorINNs/ index. htm), Medicines and Healthcare products Regulatory Agency [32] Mezzacappa, E.S., Katkin, E.S., and Palmer, S.N. (1999). Epinephrine, arousal, and emotion: A new look at two-factor theory. Cognition and Emotion, 13(2), 181-199. doi: 10.1080/026999399379320 [33] Mate, T., et al. (2013). Impaired conditioned fear response and startle reactivity in epinephrine-deficient mice. Behavioural Pharmacology, 24(1), 1-9. doi: 10.1097/FBP.0b013e32835cf408 [34] Cahill, L. and Alkire, M.T. (2002). Epinephrine enhancement of human memory consolidation; Interaction with arousal at encoding. Neurobiology of Learning and Memory, 79(2), 194-198. doi: 10.1016/S1074-7427(02)00036-9 [35] Dornelles, A., et al. (2007). Adrenergic enhancement of consolidation of object recognition memory. Neurobiology of Learning and Memory, 88(1), 137-142. doi: 10.1016/j.nlm.2007.01.005 [36] Roozendaal, B., and James, L.M., (2011). Theoretical review: Memory Modulation. Behavioral Neuroscience, 125(6), 797-824. doi: 10.1037/a0026187 [38] http:/ / www. worldofmolecules. com/ emotions/ adrenaline. htm [39] http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=DE152814 [40] http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=DE157300 [41] http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=DE222451 [42] http:/ / dx. doi. org/ 10. 1021%2Fja01186a024 [43] http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 18863798 [47] What Is An Adrenaline Junkie? What Can You Do If You Are One? (http:/ / stress. about. com/ od/ situationalstress/ a/ adrenaline0528. htm) by Elizabeth Scott, M.S. (updated: November 1, 2007) About.com Health's Disease and Condition content is reviewed by the Medical Review Board. [48] Fight-or-flight reaction (http:/ / changingminds. org/ explanations/ brain/ fight_flight. htm) - Explanations - Brain -ChangingMinds.org.

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General references
Boron WF, Boulpaep EL (2005). Medical Physiology: A Cellular And Molecular Approach. Philadelphia, PA: Elsevier/Saunders. ISBN1-4160-2328-3. OCLC 56191776 (http://www.worldcat.org/oclc/56191776). Voet D, Voet J (2004). Biochemistry (3rd ed.). USA: Wiley. ISBN0-471-19350-X. OCLC 154657578 (http:// www.worldcat.org/oclc/154657578).

External links
U.S. National Library of Medicine: Drug Information Portal - Epinephrine (http://druginfo.nlm.nih.gov/ drugportal/dpdirect.jsp?name=Epinephrine)

Neurotensin
Neurotensin

Available structures PDB Ortholog search: PDBe [1], RCSB [2] List of PDB id codes 2LNE
[3]

, 2LNF

[4]

, 2LNG

[5]

, 2LYW

[6]

, 3F6K

[7]

Identifiers Symbols External IDs NTS

[8]

; NMN-125; NN; NT; NT/N; NTS1

[9]

OMIM: 162650

MGI: 1328351

[10]

HomoloGene: 4506

[11]

GeneCards: NTS Gene

[12]

Gene Ontology Molecular function neuropeptide hormone activity [7] Cellular component extracellular region [11] [13] transport vesicle Biological process signal transduction [14] regulation of blood vessel size
[15] [18]

Sources: Amigo

/ QuickGO

[16]

RNA expression pattern

Neurotensin

260

More reference expression data Orthologs Species Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Human 4922
[18] [20]

[17]

Mouse 67405
[19] [21]

ENSG00000133636 P30990
[22] [24]

ENSMUSG00000019890 Q9D3P9
[23] [25]

NM_006183 NP_006174

NM_024435 NP_077755

[26]

[27]

Location (UCSC) Chr 12: [28] 86.27 86.28 Mb PubMed search

[30]

Chr 10: [29] 102.48 102.49 Mb

[31]

Neurotensin/neuromedin N precursor
Identifiers Symbol Pfam InterPro OPM superfamily OPM protein Pro-NT_NN PF07421 [32] [33]

IPR008055 294 [34] [35]

2oyv

Available protein structures: Pfam PDB structures [36] [37] ; PDBe [38]

RCSB PDB

PDBsum structure summary [39]

Neurotensin

261

Neurotensin

Identifiers CAS number PubChem 39379-15-2 16129680 Properties Molecular formula Molar mass
(verify) [42] [40]

[41]

C78H121N21O20 1672.92

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system. Neurotensin was first isolated from extracts of bovine hypothalamus based on its ability to cause a visible vasodilation in the exposed cutaneous regions of anesthetized rats.[] Neurotensin is distributed throughout the central nervous system, with highest levels in the hypothalamus, amygdala and nucleus accumbens. It induces a variety of effects, including: analgesia, hypothermia and increased locomotor activity. It is also involved in regulation of dopamine pathways. In the periphery, neurotensin is found in endocrine cells of the small intestine, where it leads to secretion and smooth muscle contraction.[]

Sequence and biosynthesis

Neurotensin shares significant sequence similarity in its 6 C-terminal amino acid residues with several other neuropeptides, including neuromedin N (which is derived from the same precursor). This C-terminal region is responsible for the full biological activity, the N-terminal portion having a modulatory role. The neurotensin/neuromedin N precursor can also be processed to produce large 125-138 amino acid peptides with the neurotensin or neuromedin N sequence at their C-terminus. These large peptides appear to be less potent than their smaller counterparts, but are also less sensitive to degradation and may represent endogenous, long-lasting activators in a number of pathophysiological situations. The sequence of bovine neurotensin was determined to be [] pyroGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH. Neurotensin is synthesized as part of a 169-170 amino acid precursor protein that also contains the related neuropeptide neuromedin N.[][] The peptide coding domains are located in tandem near the carboxyl terminal end of the precursor and are bounded and separated by paired basic amino acid (lysine-arginine) processing sites.

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262

Clinical significance
Neurotensin is a potent mitogen for colorectal cancer.[] Neurotensin has been implicated in the modulation of dopamine signaling, and produces a spectrum of pharmacological effects resembling those of antipsychotic drugs, leading to the suggestion that neurotensin may be an endogenous neuroleptic. Neurotensin-deficient mice display defects in responses to several antipsychotic drugs consistent with the idea that neurotensin signaling is a key component underlying at least some antipsychotic drug actions.[43] These mice exhibit modest defects in prepulse inhibition (PPI) of the startle reflex, a model that has been widely used to investigate antipsychotic drug action in animals. Antipsychotic drug administration augments PPI under certain conditions. Comparisons between normal and neurotensin-deficient mice revealed striking differences in the ability of different antipsychotic drugs to augment PPI. While the atypical antipsychotic drug clozapine augmented PPI normally in neurotensin-deficient mice, the conventional antipsychotic haloperidol and the newer atypical antipsychotic quetiapine were ineffective in these mice, in contrast to normal mice where these drugs significantly augmented PPI. These results suggest that certain antipsychotic drugs require neurotensin for at least some of their effects. Neurotensin-deficient mice also display defects in striatal activation following haloperidol, but not clozapine administration in comparison to normal wild type mice, indicating that striatal neurotensin is required for the full spectrum of neuronal responses to a subset of antipsychotic drugs.[44] Neurotensin is an endogenous neuropeptide involved in thermoregulation that can induce hypothermia and neuroprotection in experimental models of cerebral ischemia.[]

References
[1] http:/ / www. ebi. ac. uk/ pdbe/ searchResults. html?display=both& term=Q6FH20%20or%20P30990%20or%20P10673%20or%20P01156%20or%20Q9D3P9 [2] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=UpAccessionIdQuery& accessionIdList=Q6FH20,P30990,P10673,P01156,Q9D3P9 [3] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=2LNE [4] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=2LNF [5] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=2LNG [6] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=2LYW [7] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=3F6K [8] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=8038 [9] http:/ / omim. org/ entry/ 162650 [10] http:/ / www. informatics. jax. org/ searches/ accession_report. cgi?id=MGI:1328351 [11] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=4506 [12] http:/ / www. genecards. org/ cgi-bin/ carddisp. pl?id_type=entrezgene& id=4922 [13] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030133 [14] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0050880 [15] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ gp-assoc. cgi?gp=UniProtKB:P30990 [16] http:/ / www. ebi. ac. uk/ QuickGO/ GProtein?ac=P30990 [17] http:/ / biogps. org/ gene/ 4922/ [18] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=4922& rn=1 [19] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=67405& rn=1 [20] http:/ / www. ensembl. org/ Homo_sapiens/ geneview?gene=ENSG00000133636;db=core [21] http:/ / www. ensembl. org/ Mus_musculus/ geneview?gene=ENSMUSG00000019890;db=core [22] http:/ / www. uniprot. org/ uniprot/ P30990 [23] http:/ / www. uniprot. org/ uniprot/ Q9D3P9 [24] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_006183 [25] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_024435 [26] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_006174 [27] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_077755 [28] http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Human& db=hg19& position=chr12:86268073-86276767 [29] http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Mouse& db=mm9& position=chr10:102481760-102490418 [30] http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=4922

Neurotensin
[31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=67405 http:/ / pfam. sanger. ac. uk/ family?acc=PF07421 http:/ / www. ebi. ac. uk/ interpro/ entry/ IPR008055 http:/ / opm. phar. umich. edu/ families. php?superfamily=294 http:/ / opm. phar. umich. edu/ protein. php?search=2oyv http:/ / pfam. sanger. ac. uk/ family/ PF07421?tab=pdbBlock http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=PfamIdQuery& pfamID=PF07421 http:/ / www. ebi. ac. uk/ pdbe-srv/ PDBeXplore/ pfam/ ?pfam=PF07421 http:/ / www. ebi. ac. uk/ thornton-srv/ databases/ cgi-bin/ pdbsum/ GetPfamStr. pl?pfam_id=PF07421 http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=39379-15-2 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=16129680 http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=445374882& page2=Neurotensin

263

External links
Neurotensin (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Neurotensin) at the US National Library of Medicine Medical Subject Headings (MeSH)

Melatonin

264

Melatonin
Melatonin

Systematic (IUPAC) name

N-[2-(5-methoxy-1H-indol-3-yl)ethyl] acetamide
Clinical data AHFS/Drugs.com Consumer Drug Information [1] Pregnancy cat. Legal status Routes ? Prescription Only (S4) (AU) OTC (US) In humans: orally, as capsules, tablets or liquid, sublingually, or as transdermal patches. In lab animals: also injection. Pharmacokinetic data Bioavailability Metabolism Half-life Excretion 30 50% Hepatic via CYP1A2 mediated 6-hydroxylation 35 to 50 minutes Urine Identifiers CAS number ATC code PubChem IUPHAR ligand 73-31-4 [2]

N05CH01 CID 896 224 [5]

[3]

[4]

Melatonin
[6]

265
DrugBank ChemSpider UNII KEGG ChEBI ChEMBL

DB01065 872 [7]

JL5DK93RCL D08170 [9]

[8]

CHEBI:16796 CHEMBL45

[10]

[11]

Chemical data Formula Mol. mass C13H16N2O2 232.278 g/mol

(what is this?) (verify)

[12]

i Melatonin /mltonn/, is also known chemically as N-acetyl-5-methoxytryptamine,[13] is a naturally occurring compound found in animals, plants, and microbes.[][] In animals, circulating levels of the hormone melatonin vary in a daily cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions.[]

Many biological effects of melatonin are produced through activation of melatonin receptors,[] while others are due to its role as a pervasive and powerful antioxidant,[] with a particular role in the protection of nuclear and mitochondrial DNA.[] The full effects of long-term exogenous supplementation in humans have not yet been ascertained.[] Melatonin is categorized by the US Food and Drug Administration (FDA) as a dietary supplement, not a drug.[] A prescription-only, timed release melatonin product for people aged 55 and over was approved for use by the European Medicines Agency in 2007, despite having shown only small effects,[] and in Australia in 2009.[]

Plants
Melatonin has been identified in many plants including feverfew (Tanacetum parthenium), St John's wort (Hypericum perforatum).,[] rice, corn, tomato and edible fruits.[] The physiological roles of melatonin in plants involve regulation of their response to photoperiod, defense against harsh environments, and the function of an antioxidant. The latter may be the original function of melatonin in organisms with the others being added during evolution.[] Melatonin also regulates plant growth by its ability to slow root formation, while promoting above ground growth.[] Melatonin has been reported in foodstuffs including cherries to about 0.1713.46ng/g,[] bananas and grapes, rice and cereals, herbs, olive oil, wine[] and beer. When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.[] When humans consume foods rich in melatonin such as banana, pineapple and orange the blood levels of melatonin significantly increase.[]

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Animals
Many animals use the variation in duration of melatonin production each day as a seasonal clock.[] In animals including humans[] the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organisation of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behaviour, coat growth and camouflage colouring in seasonal animals.[] In seasonal breeders that do not have long gestation periods and that mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds[] and hamsters.[] In mammals, melatonin is biosynthesized in four enzymatic steps from the essential dietary amino acid tryptophan, with serotonin produced at the second step. Melatonin is secreted into the blood by the pineal gland in the brain. Known as the "hormone of darkness," it is secreted in darkness in both day-active (diurnal) and night-active (nocturnal) animals.[] It may also be produced by a variety of peripheral cells such as bone marrow cells,[][14] lymphocytes, and epithelial cells. Usually, the melatonin concentration in these cells is much higher than that found in the blood, but it does not seem to be regulated by the photoperiod.

Mammals
Melatonin, produced in the pineal gland which is outside of the bloodbrain barrier, acts as an endocrine hormone since it is released into the blood.[] Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin. During the night, melatonin regulates leptin, lowering its levels. Light/dark information reaches the suprachiasmatic nuclei (SCN) from retinal photosensitive ganglion cells, which are intrinsically photosensitive photoreceptor cells that are distinct from those involved in the primary (at least, from one point of view) image formation function of the eye (that is the rods and cones of the retina). These cells represent approximately 2% of all retinal ganglion cells in humans and express the photopigment melanopsin.[] Melanopsin, often confused with melatonin because of its similar name, is structurally unrelated to the hormone. It is a conventional 7-transmembrane opsin protein with the usual vitamin A-like cis-retinal cofactor having a peak absorption at 484nm, in the blue light part of the visible spectrum.[] The photoperiod cue created by blue light (from a blue image of the sky) entrains a circadian rhythm, and thus governs resultant production of specific "dark"- and "light"-induced neural and endocrine signals that regulate behavioral and physiological circadian rhythms associated with melatonin. Melatonin is secreted in darkness in both day-active (diurnal) and night-active (nocturnal) animals.[]

Humans
Circadian rhythm
In humans, melatonin is produced by the pineal gland, a small endocrine gland[] located in the center of the brain but outside the bloodbrain barrier. The melatonin signal forms part of the system that regulates the sleepwake cycle by chemically causing drowsiness and lowering the body temperature, but it is the central nervous system (specifically the suprachiasmatic nuclei, or SCN)[] that controls the daily cycle in most components of the paracrine and endocrine systems[][] rather than the melatonin signal (as was once postulated). Infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 08:00 (8 AM).[]

Melatonin In humans, 90% of melatonin is cleared in a single passage through the liver, a small amount is excreted in urine,[] and a small amount is found in saliva. Human melatonin production decreases as a person ages.[] It is believed that as children become teenagers, the nightly schedule of melatonin release is delayed, leading to later sleeping and waking times.[15] Light dependence Production of melatonin by the pineal gland is inhibited by light to the retina and permitted by darkness. Its onset each evening is called the dim-light melatonin onset (DLMO). It is principally blue light, around 460 to 480nm, that suppresses melatonin,[] proportional to the light intensity and length of exposure. Until recent history, humans in temperate climates were exposed to few hours of (blue) daylight in the winter; their fires gave predominantly yellow light. The incandescent light bulb widely used in the twentieth century produced relatively little blue light.[16] Wearing glasses that block blue light in the hours before bedtime may decrease melatonin loss. Kayumov et al. showed that light containing only wavelengths greater than 530nm does not suppress melatonin in bright-light conditions.[] Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes sleepiness.[17] When used several hours before sleep according to the phase response curve for melatonin in humans, small amounts (0.3mg[]) of melatonin shift the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.[]

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Antioxidant
Besides its function as synchronizer of the biological clock, melatonin was found to be a powerful free-radical scavenger and wide-spectrum antioxidant in 1993.[] In many less complex life forms, this is its only known function.[] Melatonin is an antioxidant that can easily cross cell membranes[] and the bloodbrain barrier.[][] This antioxidant is a direct scavenger of radical oxygen and nitrogen species including: OH, O2, and NO.[][] Melatonin works with other antioxidants to improve the overall effectiveness from each antioxidant.[]

Immune system
While it is known that melatonin interacts with the immune system,[][] the details of those interactions are unclear. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete clinical trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production,[] and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease[] including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.[] Endogenous melatonin in human lymphocytes has been related to interleukin-2 (IL-2) production and to the expression of IL-2 receptor.[] This suggests that melatonin is involved in the clonal expansion of antigen-stimulated human T lymphocytes. In rheumatoid arthritis patients, melatonin production has been found increased when compared to age-matched healthy controls.[] Although it has not yet been clearly demonstrated whether melatonin increases non-specific immunity with resulting contraindication in autoimmune diseases, an increase in the production of IL-2 and IL-1 was noted in cultured splenocytes.[]

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Dreaming
Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin (50mg) dramatically increased REM sleep time and dream activity in people both with and without narcolepsy.[] It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs emulate melatonin activity in the awakened state and that both act on the same areas of the brain.[]

Autism
Some individuals with autism spectrum disorders (ASD) may have lower than normal levels of melatonin.[18] A 2008 study found that unaffected parents of individuals with ASD also have lower melatonin levels, and that the deficits were associated with low activity of the ASMT gene, which encodes the last enzyme of melatonin synthesis.[] Multiple small studies have demonstrated that 2 to 10mg of melatonin may benefit children with ASD who have trouble falling asleep and/or maintaining sleep.[19] A small 2011 randomized crossover trial found that the administration of melatonin, when compared to placebo, decreased sleep latency and increased total sleep time, but had no effect on the number of night time awakenings.[] At this time, no official guidelines exist for the use of melatonin in children with ASD.

Aging
Research has supported the anti-aging properties of melatonin. Younger children hit their peak melatonin production at night, and some researchers believe that the level of melatonin peaks earlier as people get older. This may explain why older adults go to bed earlier, wake up earlier, and have more sleep problems than children do.[] Some studies have shown that melatonin plays a crucial part in the aging process and that it may act as an anti-aging agent when administered to older mice. It has been reported in one study that administration of melatonin in elderly mice may reverse this change in expression of some 13 genes, thus making them similar to those of younger mice.[] Consuming melatonin may neutralize oxidative damage and delay the neurodegenerative process of aging.[] When small amounts of melatonin were administered to lab mice, it reduced the oxidative damage caused by aging and delayed the inflammatory process, which in turn increased the longevity of the mice.[]

Diabetes
Single-nucleotide polymorphisms of the human melatonin MT2 receptor have been linked to an increased risk of developing type 2 diabetes.[] Furthermore women with low levels of melatonin secretion have been found to more likely to develop type 2 diabetes than women with high levels.[]

Pediatrics
While the packaging of melatonin often warns against use in children, at least one long-term study does assess effectiveness and safety in children. No serious safety concerns were noted in any of the 94 cases studied by means of a structured questionnaire for the parents. With a mean follow-up time of 3.7 years, long-term medication was effective against sleep onset problems in 88% of the cases. Other studies warn against potential side effects[]

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Medical uses
Melatonin has been studied as a potential treatment of gastroesophageal reflux disease,[] cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), circadian rhythm sleep disorders, sexual dysfunction[20] and insomnia in the elderly.[20][][][] Prolonged release melatonin has shown good results in treating insomnia in older adults (2007).[] It may ameliorate circadian misalignment and SAD.[][] Basic research indicates that melatonin may play a role in modulating the effects of drugs of abuse such as cocaine.[][] Melatonin is also a geroprotector.[] A 2004 review found that melatonin significantly increased total sleep time in people suffering from sleep restriction.[] For many types of sleep disorders, melatonin is not effective. A 2006 review found that although it is safe for short term use (of three months or less), there is "no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder."[]

A bottle of melatonin tablets

In a 2005 study, researchers concluded that while "there is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome(DSPS), ...there is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less)."[]

Circadian rhythm disorders

Exogenous melatonin taken in the evening is, together with light therapy upon awakening, the standard treatment for delayed sleep phase syndrome (DSPS) and non-24-hour sleep-wake syndrome where circadian rhythms are not entrained to the environmental cycle. It appears to have some use against other circadian rhythm sleep disorders as well, such as jet lag and the problems of people who work rotating or night shifts. Melatonin reduces sleep onset latency to a greater extent in people with DSPS than in people with insomnia.[] A very small dose taken several hours before bedtime in accordance with the phase response curve for melatonin in humans (PRC) doesn't cause sleepiness but, acting as a chronobiotic (affecting aspects of biological time structure),[21] advances the phase slightly and is additive to the effect of using light therapy upon awakening. Light therapy may advance the phase about one to two-and-a-half hours and an oral dose of 0.3 or 3mg of melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the ~2 hour advance achieved with light therapy. There was no difference in the average magnitude of phase shift induced by the 2 doses.[]

Learning, memory and Alzheimer's

Melatonin receptors appear to be important in mechanisms of learning and memory in mice,[] and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). The first published evidence that melatonin may be useful in Alzheimer's disease was the demonstration that this neurohormone prevents neuronal death caused by exposure to the amyloid beta protein, a neurotoxic substance that accumulates in the brains of patients with the disorder.[] Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates that, it seems, underlie the neurotoxicity of this protein, causing death of neurons and formation of neurofibrillary tangles, the other neuropathological landmark of Alzheimer's disease.[] Melatonin has been shown to prevent the hyperphosphorylation of the tau protein in rats. Hyperphosphorylation of tau protein can also result in the formation of neurofibrillary tangles. Studies in rats suggest that melatonin may be effective for treating Alzheimer's disease.[] These same neurofibrillary tangles can be found in the hypothalamus in

Melatonin patients with Alzheimer's, adversely affecting their bodies' production of melatonin. Another study has implicated heightened afternoon agitation found in many Alzheimer's patients, called sundowning, with a phase delay in core body temperature.[] This may suggest a possible connection to melatonin production.

270

Delirium
A randomized placebo-controlled trial showed that low-dose melatonin supplementation to 72 elderly patients admitted to acute medicine services significantly reduced delirium.[]

Stimulants
Research shows that after melatonin is administered to ADHD patients on methylphenidate, the time needed to fall asleep is significantly reduced. Furthermore, the effects of the melatonin after three months showed no change from its effects after one week of use.[]

Headaches
Several clinical studies indicate that supplementation with melatonin is an effective preventive treatment for migraines and cluster headaches.[][]

Mood disorders
Melatonin has been shown to be effective in treating seasonal affective disorder,[22] a form of depression, and is being considered for bipolar and other disorders in which circadian disturbances are involved.[] It was observed in 1985 that bipolar disorder might have elevated sensitivity to light, i.e., a greater decrease in melatonin secretion in response to light exposure at night, as a "trait marker" (a characteristic of being bipolar, which does not change with state).[] This could be contrasted with drug-free recovered bipolar patients showing normal light sensitivity.[]

Cancer
A systematic review of unblinded clinical trials involving a total of 643 cancer patients using melatonin found a reduced incidence of death but that blinded and independently conducted randomized controlled trials are needed.[] The National Cancer Institute's review of the evidence found that it remains inconclusive.[23]

Gallbladder stones
Melatonin presence in the gallbladder has many protective properties, such as converting cholesterol to bile, preventing oxidative stress, and increasing the mobility of gallstones from the gallbladder.[] It also decreases the amount of cholesterol produced in the gallbladder by regulating the cholesterol that passes through the intestinal wall. In guinea pigs, melatonin administration restored normal function by reducing inflammation after induced cholecystitis, whether administered before or after onset of inflammation.[] Concentration of melatonin in the bile is 23 times higher than the otherwise very low daytime melatonin levels in the blood across many diurnal mammals, including humans.[]

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Amyotrophic lateral sclerosis

In animal models, melatonin has been shown to ameliorate glutamate-induced neuronal death, it is presumed due to its antioxidant effects. In a clinical safety study involving 31 ALS patients, high-dose rectal melatonin (300mg/day for 2 years) was shown to be tolerated well.[]

Obesity
Melatonin is involved in energy metabolism and body weight control in small animals. Many studies show that chronic melatonin supplementation in drinking water reduces body weight and abdominal fat in experimental animals, especially in the middle-aged rats[] and the weight loss effect did not require the animals to eat less and to be physically more active. A potential mechanism is that melatonin promotes the recruitment of brown adipose tissue (BAT) as well as enhances its activity.[] This effect would raise the basal metabolic rate by stimulating thermogenesis, heat generation through uncoupling oxidative phosphorylation in mitochondria. Whether the results of animal studies can be extrapolated to human obesity is a matter of future clinical trials, since substantially active BAT has been identified in adult humans.[citation needed]

Protection from radiation

Both animal[] and human[][] studies have shown melatonin to be potentially radioprotective. Moreover, it is a more efficient protector than amifostine,[] a commonly used agent for this purpose. The mechanism of melatonin in protection against ionizing radiation is thought to involve scavenging of free radicals.[] It is estimated that nearly 70% of biological damage caused by ionizing radiation is attributable to the free radical, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes. Melatonin has been suggested as a radioprotective agent, with the proposed advantages of being broadly protective, readily available, orally self-administered, and without major known side effects.[]

Tinnitus
Several medical studies involving adult patients indicate that melatonin can be beneficial in the treatment of tinnitus.[][][][]

Other
Melatonin was used to treat periodic limb movement disorder, a common neurological condition, which, when severe, adversely affects sleep and causes excessive daytime fatigue, in a small trial conducted by Kunz D and Bes F. In this condition, the sufferer is affected by mini arousals during sleep and limb movements that occur in a frequent rhythmic fashion. This often involves leg kicking, but sometimes also involves arm movement. Those affected are often not aware of the condition, and partners are often the first to notice the condition. 7 out of the 9 participants in the trial showed significant improvement.[] In recent trial for use in irritable bowel syndrome treatment, melatonin relieved some symptoms, as published in 2010.[24] A research team in Italy has found that melatonin supplementation in the evening in perimenopausal women produces an improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.[] One study reported that melatonin taken in the evening raised prolactin levels in six out of seven women.[]

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Adverse effects
Melatonin appears to cause very few side-effects in the short term, up to three months, when healthy people take it at low doses. A systematic review[] in 2006 looked specifically at efficacy and safety in two categories of melatonin usage: first, for sleep disturbances that are secondary to other diagnoses and, second, for sleep disorders such as jet lag and shift work that accompany sleep restriction.[] The study concluded that "There is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. There is evidence that melatonin is safe with short term use".[] A similar analysis[] by the same team a year earlier on the efficacy and safety of exogenous melatonin in the management of primary sleep disorders found that: "There is evidence to suggest that melatonin is safe with short-term use (3 months or less)." Unwanted effects in some people may include nausea, next-day grogginess, irritability,[25] reduced blood flow and hypothermia.[] While no large, long-term studies that might reveal side-effects have been conducted, there do exist case reports about patients having taken melatonin for months.[] Melatonin can cause somnolence (drowsiness), and, therefore, caution should be shown when driving, operating machinery, etc. In individuals with auto-immune disorders, there is conflicting evidence whether melatonin supplementation may either ameliorate or exacerbate symptoms due to immunomodulation.[][] Individuals experiencing orthostatic intolerance, a cardiovascular condition that results in reduced blood pressure and blood flow to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at Penn State College of Medicine's Milton S. Hershey Medical Center suggests. Melatonin can exacerbate symptoms by reducing nerve activity in those experiencing the condition, the study found.[26] Melatonin has been found to lower FSH levels.[] Effects of the hormone on human reproduction remain unclear,[] although it was with some effect tried as a contraceptive in the 1990s.[27] Melatonin was thought to have a very low maternal toxicity in rats.[] Newer studies, though, have found that it is toxic to photoreceptor cells in rats' retinas[] and increases tumours in white mice.[][]

Availability
Legal availability of melatonin varies in different countries, ranging from being available without prescription (e.g. in most of North America) to being available only on prescription or not at all (although its possession and use may not be illegal). In the UK it is available on prescription only. The hormone may be administered orally, as capsules, tablets or liquid, sublingually, or as transdermal patches. The use of melatonin derived from animal pineal tissue may carry the risk of contamination or the means of transmitting viral material. The synthetic form of this medication does not carry this risk.[][28]

Dietary supplement
In the USA, because it is sold as a dietary supplement, sometimes combined with other ingredients, such as vitamins and herbal extracts, and not as a drug, the Food and Drug Administration (FDA) regulations that apply to medications are not applicable to melatonin.[] However, new FDA rules required that by June 2010 all production of dietary supplements must comply with "current good manufacturing practices" (cGMP), and be manufactured with "controls that result in a consistent product free of contamination, with accurate labeling."[29] In addition, the industry has been required to report to the FDA "all serious dietary supplement related adverse events" and the FDA has, within the cGMP guidelines, begun enforcement of that requirement.[citation needed]

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Food products
As reported in the New York Times in May 2011,[] melatonin is sold in grocery stores, convenience stores, and clubs in both beverage and snack forms. The FDA is considering whether these food products can continue to be sold with the label "dietary supplements". On January 13, 2010, they issued a warning letter to Innovative Beverage, creators of several beverages marketed as "relaxation drinks," stating that melatonin is not approved as a food additive because it is not generally recognized as safe.[]

Prolonged release
Melatonin is available as a prolonged-release prescription drug, trade-name Circadin, manufactured by Neurim Pharmaceuticals. The European Medicines Agency (EMA) has approved Circadin 2mg (prolonged-release melatonin) for patients aged 55 or over, as monotherapy for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor quality of sleep.[30]

History

Circadin 2mg, prolonged-release melatonin

Melatonin is related to the mechanism by which some amphibians and reptiles change the color of their skin and, indeed, it was in this connection the substance first was discovered.[][] As early as 1917, Carey Pratt McCord and Floyd P. Allen discovered that feeding extract of the pineal glands of cows lightened tadpole skin by contracting the dark epidermal melanophores.[][] In 1958 dermatology professor Aaron B. Lerner and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated the hormone from bovine pineal gland extracts and named it melatonin.[] In the mid-70s Lynch et al. demonstrated[] that the production of melatonin exhibits a circadian rhythm in human pineal glands. The discovery that melatonin is an antioxidant was made in 1993.[] The first patent for its use as a low dose sleep aid was granted to Richard Wurtman at MIT in 1995.[31] Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.[] The New England Journal of Medicine editorialized in 2000: "The hype and the claims of the so-called miraculous powers of melatonin several years ago did a great disservice to a scientific field of real importance to human health. With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear. Our 24-hour society, with its chaotic time cues and lack of natural light, may yet reap substantial benefits."[]

References
[1] http:/ / www. drugs. com/ cdi/ melatonin. html [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=73-31-4& rn=1 [3] http:/ / www. whocc. no/ atc_ddd_index/ ?code=N05CH01 [4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=896 [5] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=224 [6] http:/ / www. drugbank. ca/ drugs/ DB01065 [7] http:/ / www. chemspider. com/ Chemical-Structure. 872 [8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=JL5DK93RCL [9] http:/ / www. kegg. jp/ entry/ D08170 [10] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:16796 [11] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL45 [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=420231802& page2=Melatonin [16] Cornell University, Light source spectra (http:/ / www. graphics. cornell. edu/ online/ measurements/ source-spectra/ index. html) [20] http:/ / www. mayoclinic. com/ health/ melatonin/ NS_patient-melatonin/ DSECTION=evidence [21] The reference discusses several chronobiotic substances, but not melatonin. [26] (MS Word Format)

Melatonin
[27] Cohen M, van Heusden AM, Verdonk HER, Wijnhamer P: Melatonin/Norethisterone contraception. In Melatonin and the Pineal GlandFrom Basic Science to Clinical Application. Edited by Touitou Y, Arendt J and Pevet P. Amsterdam, Elsevier Science Publishers; 1993:339-345. [30] Medical News Today (http:/ / www. medicalnewstoday. com/ articles/ 69195. php) Circadin (Prolonged-Release Melatonin) For Primary Insomnia Recommended For Approval In The EU (27 Apr 2007)

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Further reading
Wade AG, Ford I, Crawford G, McConnachie A, Nir T, Laudon M, Zisapel N (2010). "Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety" (http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2933606). BMC Med 8: 51. doi: 10.1186/1741-7015-8-51 (http://dx.doi.org/10.1186/1741-7015-8-51). PMC 2933606 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933606). PMID 20712869 (http://www. ncbi.nlm.nih.gov/pubmed/20712869).

External links
Melatonin entry in TiHKAL info (http://tihkal.info/read.php?domain=tk&id=35)

N-Acetylserotonin

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N-Acetylserotonin
N-Acetylserotonin

Identifiers CAS number PubChem ChemSpider MeSH ChEBI ChEMBL Jmol-3D images 1210-83-9 903 879
[2] [3] [4] [1]

N-Acetylserotonin CHEBI:17697
[5]

CHEMBL33103 Image 1 Properties

[7]

[6]

Molecular formula Molar mass Density

(verify) [8]

C H NO

12 14 2 2

218.252 g/mol 1.268 g/mL

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

N-Acetylserotonin (NAS), also known as normelatonin, is a naturally occurring chemical intermediate in the endogenous production of melatonin from serotonin.[][] It is produced from serotonin by the enzyme aralkylamine N-acetyltransferase (AANAT) and is converted to melatonin by acetylserotonin O-methyltransferase (ASMT). Like melatonin, NAS is an agonist at the melatonin receptors MT1, MT2, and MT3, and may be considered to be a neurotransmitter.[][][][] In addition, NAS is distributed in some areas of the brain where serotonin and melatonin are not, suggesting that it may have unique central duties of its own instead of merely functioning as a precursor in the synthesis of melatonin.[] Recently, NAS has been shown to act as a potent TrkB receptor agonist, while serotonin and melatonin are not.[] It produces robust antidepressant, neuroprotective, and neurotrophic effects that are TrkB-mediated.[] In addition, AANAT knockout mice which lack NAS display significantly greater immobility times versus control mice in assays

N-Acetylserotonin of depression like the forced swim test.[] NAS may also play a major role in the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs).[] The SSRI fluoxetine and the MAO-A inhibitor clorgyline upregulate AANAT indirectly through serotonergic mechanisms and thereby increase NAS levels after chronic administration, and this correlates with the onset of their antidepressant effects.[][] Furthermore, light exposure inhibits the synthesis of NAS and reduces the antidepressant effects of MAOIs.[] These data strongly support a role for NAS in mood regulation and in antidepressant-induced therapeutic benefits. Through a currently unidentified mechanism, NAS may be the cause of the orthostatic hypotension seen with clinical treatment of MAOIs.[][] It reduces blood pressure in rodents, and pinealectomy (the pineal gland being a major site of NAS and melatonin synthesis) abolishes the hypotensive effects of clorgyline.[][] Why orthostatic hypotension is commonly seen with MAOIs but not SSRIs (both of which increase NAS levels) however, is unknown.

276

References
[1] [2] [3] [4] [5] [6] [7] [8] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=1210-83-9 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=903 http:/ / www. chemspider. com/ 879 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=''N''-Acetylserotonin https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=17697 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL33103 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CC%28%3DO%29NCCC1%3DCNC2%3DC1C%3DC%28C%3DC2%29O http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=462257090& page2=N-Acetylserotonin

Norepinephrine

277

Norepinephrine
Norepinephrine[1]

Identifiers CAS number PubChem ChemSpider DrugBank KEGG ChEBI ChEMBL ATC code Jmol-3D images (l) 51-41-2 (l) 439260 388394
[4] [5] [2]

, 138-65-8

[3]

(dl)

DB00368 D00076

[6] [8]

[7]

CHEBI:18357

CHEMBL1437 C01 CA03 Image 1 Properties

[10]

[9]

[11]

Molecular formula Molar mass Density Melting point Boiling point Vapor pressure Acidity (pK )
a

C H NO
8 11

169.18 g mol1 1.3970.06 g/cm^3 (20C and 760 Torr) L: 216.5218C (decomposes) D/L: 191C (decomp.) 442.640.0C (760 Torr) 1.30e-8 Torr 9.570.10
(verify) [12] [] [] [] []

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Norepinephrine

278
Infobox references

Norepinephrine (INN) (abbreviated norepi or NE), or noradrenaline (BAN) (abbreviated NA, NAd, or norad), is a catecholamine with multiple roles including as a hormone and a neurotransmitter.[13] Areas of the body that produce or are affected by norepinephrine are described as noradrenergic. The terms noradrenaline (from the Latin) and norepinephrine (from the Greek) are interchangeable, with noradrenaline being the common name in most parts of the world. However, to avoid confusion and achieve consistency, medical authorities [14] have promoted norepinephrine as the favored nomenclature, and this is the term used throughout this article. One of the most important functions of norepinephrine is its role as the neurotransmitter released from the sympathetic neurons affecting the heart. An increase in norepinephrine from the sympathetic nervous system increases the rate of contractions.[15] As a stress hormone, norepinephrine affects parts of the brain, such as the amygdala, where attention and responses are controlled.[16] Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. It increases the brain's oxygen supply.[17] Norepinephrine can also suppress neuroinflammation when released diffusely in the brain from the locus coeruleus.[18] When norepinephrine acts as a drug, it increases blood pressure by increasing vascular tone (tension of vascular smooth muscle) through -adrenergic receptor activation; a reflex bradycardia homeostatic baroreflex is overcome by a compensatory reflex preventing an otherwise inevitable drop in heart rate to maintain blood pressure. Norepinephrine is synthesized from dopamine by dopamine -hydroxylase in the secretory granules of the medullary chromaffin cells.[19] It is released from the adrenal medulla into the blood as a hormone, and is also a neurotransmitter in the central nervous system and sympathetic nervous system, where it is released from noradrenergic neurons in the locus coeruleus. The actions of norepinephrine are carried out via the binding to adrenergic receptors.

Chemistry
Norepinephrine is a catecholamine and a phenethylamine. The natural stereoisomer is L-()-(R)-norepinephrine. The prefix nor- indicates that norepinephrine is the next-lower homolog of epinephrine. The two structures differ only in that epinephrine has a methyl group attached to its nitrogen, whereas the methyl group is replaced by a hydrogen atom in norepinephrine. The prefix nor- is derived as an abbreviation of the word "normal", used to indicate a demethylated compound.[][][]

Origins
Norepinephrine is released when a host of physiological changes are activated by a stressful event. In the brain, this is caused in part by activation of an area of the brain stem called the locus coeruleus. This nucleus is the origin of most norepinephrine pathways in the brain. Noradrenergic neurons project bilaterally (send signals to both sides of the brain) from the locus ceruleus along distinct pathways to many locations, including the cerebral cortex, limbic system, and the spinal cord, forming a neurotransmitter system. Norepinephrine is also released from postganglionic neurons of the sympathetic nervous system, to transmit the fight-or-flight response in each tissue, respectively. The adrenal medulla can also be counted to such postganglionic nerve cells, although they release norepinephrine into the blood.

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279

Norepinephrine system
The noradrenergic neurons in the brain form a neurotransmitter system, that, when activated, exerts effects on large areas of the brain. The effects are alertness and arousal, and influences on the reward system. The noradrenergic neurons originate both in the locus coeruleus and the lateral tegmental field. The axons of the neurons in the locus coeruleus act on adrenergic receptors in: Amygdala Cingulate gyrus Cingulum Hippocampus Hypothalamus Neocortex Spinal cord Striatum Thalamus Some Brainstem nuclei Cerebellum

On the other hand, axons of neurons of the lateral tegmental field act on adrenergic receptors in hypothalamus, for example. This structure explains some of the clinical uses of norepinephrine, since a modification of the system affects large areas of the brain.

Role in decision making

Cortical norepinephrine (NE) release during attention paradigms (patterns) can increase the alteration detection rate (number of times an alteration was selected) in multiple-cue probability learning during tasks involving giving predictive cues (such as auditory or visual), and thereby enhance subsequent learning.[20] A. J. Yu et al. developed a Bayesian framework to examine NE release in instances of "unexpected uncertainty," where a drastic alteration in sensory information produces a large disparity between top-down expectations and what actually occurs.[] The model predicts that NE levels spike when the predictive context is switched, then subside. It has also been shown that lesions of the locus coeruleus (LC) impair this attentional shift.[] In a similar vein, several studies have implicated the LC-NE system in eliciting the P300, a cortical event-related potential that responds to environmental stimuli that have behaviorally relevant, motivational, or attention grabbing properties.[21][22][23][24][25] The P300 may reflect updating of prior knowledge regarding stimuli relevant for accurate and efficient decision making. Several studies have searched for a P300 generator in the brain and have ultimately concluded that the potential must have a source that is distributed, synchronous and localized in cortex.[26] This definition is ideally satisfied both functionally and anatomically by the LC neuromodulatory system. Given its broad projection pattern and the correlation between NE release and increased sensory signal transmission,[27] it seems likely that noradrenergic cortical release is the neuronal mechanism of the P300. Examination of the LCs tonic firing pattern has led to speculation that it is important for the exploratory behavior essential for learning relations between sensory input, decision processing, motor output, and behavioral feedback.[28] Tonic activation within the range of 05Hz has been shown to correlate with levels of drowsiness, accurate task performance, and when slightly more elevated, distractibility and erratic task performance. Furthermore, phasic activation of the LC is observed in response to both highly salient unconditioned and task-relevant stimuli. The phasic response occurs after stimulation and precedes a behavioral response in a time-locked fashion.[29] As such, phasic activation of the LC-NE system is proposed to enhance signal processing and behavioral responses specifically to task-relevant stimuli. Given the contrasting functional roles of LC tonic and

Norepinephrine phasic activity, it is plausible that projections from this brain region are important for maintaining a balance between exploratory and goal-directed behaviors that regulate probabilistic environmental learning and corresponding decision making. The LC-NE system receives convergent input from the orbitofrontal (OFC) and anterior cingulate cortices (ACC). The OFC has been associated with evaluation of reward. For example, Tremblay et al. found that the response magnitude of single-units in this region is varied with the hedonic value of a stimulus.[30] Additionally, neurons in this region are activated by rewarding stimuli but not by identification of the stimulus or corresponding response preparation. Activation of the ACC appears to reflect some evaluation of cost-benefit. Several studies show ACC activation in response to performance error, negative feedback or monetary loss.[31][32][33] Additionally, ACC responds to task difficulty.[34] Therefore, ACC activation may serve to integrate evaluations of task difficulty with corresponding outcome information to gauge the benefits of engaging an action in regards to a particular environmental stimulus. Conceivably, the functions of the ACC and OFC are directly related to decision-making, and their projections to LC may modulate the phasic release of NE in order to gain-modulate cortical responses to decision outcomes. LC-NE may play a significant role in synchronizing cortical activity in response to a decision process. In computational modeling of decision, the most accurate and efficient decision mechanisms are mathematically defined random walk or drift-diffusion processes that utilize single-layer neural networks to calculate the disparity in evidence between two options.[35] NE release gated by the LC-NE system is elicited after neurons processing sensory information have presumably reached a decision threshold.[36] Thus, the phasic burst can alter activation in all cortical processing layers in a temporally dependent manner, essentially collapsing the vast information processing circuit to the outcome of a single decision layer. Brown et al. found that the addition of a phasic LC mechanism was sufficient to yield optimal performance from a single layer decision network.[37]

280

Mechanism
Norepinephrine is synthesized from tyrosine as a precursor, and packed into synaptic vesicles. It performs its action by being released into the synaptic cleft, where it acts on adrenergic receptors, followed by the signal termination, either by degradation of norepinephrine or by uptake by surrounding cells.

Biosynthesis
Norepinephrine is synthesized by a series of enzymatic steps in the adrenal medulla and postganglionic neurons of the sympathetic nervous system from the amino acid tyrosine.

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281

Vesicular transport
Between the decarboxylation and the final -oxidation, norepinephrine is transported into synaptic vesicles. This is accomplished by vesicular monoamine transporter (VMAT) in the lipid bilayer. This transporter has equal affinity for norepinephrine, epinephrine and isoprenaline.[38]

Release
To perform its functions, norepinephrine must be released from synaptic vesicles. Many substances modulate this release, some inhibiting it and some stimulating it. An action potential reaches the presynaptic membrane, which changes the membrane polarisation. Calcium ions thus enter, resulting in vesicular fusion, releasing norepinephrine. For instance, there are inhibitory 2 adrenergic receptors presynaptically that give negative feedback on release by homotropic modulation.

Receptor binding
Norepinephrine performs its actions on the target cell by binding to and activating adrenergic receptors. The target cell expression of different types of receptors determines the ultimate cellular effect, and thus norepinephrine has different actions on different cell types.
Biosynthesis of norepinephrine

Termination
Signal termination is a result of reuptake and degradation. Uptake Extracellular uptake of norepinephrine into the cytosol is done either presynaptically (uptake 1) or by non-neuronal cells in the vicinity (uptake 2). Furthermore, there is a vesicular uptake mechanism from the cytosol into synaptic vesicles.

Comparison of norepinephrine uptake

Uptake Transporter Vmax (n KM [39] mol/g/min) 1.2 0.3 [39] Specificity [40] Location Other substrates [40] Inhibitors [41]

Uptake 1 Norepinephrine [41] transporter

norepinephrine > epinephrine > isoprenaline

presynaptic

methylnoradrenaline (nasal decongestant) tyramine guanethidine

Cocaine Tricyclic antidepressants (e.g. desipramine) Phenoxybenzamine Amphetamine Reboxetine

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282
100 250 epinephrine > norepinephrine > isoprenaline dopamine 5-HT histamine [41] dopamine [41] 5-HT [41] guanethidine [41] MPP+ normetanephrine steroid hormones (e.g., corticosterone) phenoxybenzamine [41] Reserpine Tetrabenazine

Uptake 2

cell membrane of non-neuronal [38] cells Synaptic vesicle [41] membrane

Vesicular VMAT[41]

[41]

~0.2

[41]

norepinephrine > epinephrine > [41] isoprenaline

Degradation In mammals, norepinephrine is rapidly degraded to various metabolites. The principal metabolites are: Normetanephrine (via the enzyme catechol-O-methyl transferase, COMT) 3,4-Dihydroxymandelic acid (via monoamine oxidase, MAO) Vanillylmandelic acid (3-Methoxy-4-hydroxymandelic acid), also referred to as vanilmandelate or VMA (via MAO) 3-Methoxy-4-hydroxyphenylethylene glycol, "MHPG" or "MOPEG" (via MAO) Epinephrine (via PNMT)[42] In the periphery, VMA is the major metabolite of catecholamines, and is excreted unconjugated in the urine. A minor metabolite (although the major one in the central nervous system) is MHPG, which is partly conjugated to sulfate or glucuronide derivatives and excreted in the urine.[41]

Norepinephrine degradation. Enzymes are shown in boxes.

[41]

Noradrenergic agents
By indication
Norepinephrine may be used for the indications attention-deficit/hyperactivity disorder, depression, and hypotension. Norepinephrine, as with other catecholamines, cannot cross the bloodbrain barrier, so drugs such as amphetamines are necessary to increase brain levels. Attention-deficit/hyperactivity disorder Norepinephrine, like dopamine, has come to be recognized as playing a large role in attention and focus. For people with ADHD, psychostimulant medications such as methylphenidate (Ritalin/Concerta) and amphetamines (Adderall, Desoxyn,) are prescribed to help increase levels of norepinephrine and dopamine. Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor, and is a unique ADHD medication, as it affects only norepinephrine, rather than dopamine. As a result, Strattera has a lower abuse potential. However, it may not be as effective as psychostimulants for many people with ADHD. Consulting with a physician is needed to find the appropriate medication and dosage. (Other SNRIs, currently approved as antidepressants, have also been used off-label for treatment of ADHD.)

Norepinephrine Depression Differences in the norepinephrine system are implicated in depression. Serotonin-norepinephrine reuptake inhibitors are antidepressants that treat depression by increasing the amount of serotonin and norepinephrine available to postsynaptic cells in the brain. There is some recent evidence implying that SNRIs may also increase dopamine transmission.[43] This is because SNRIs work by inhibiting reuptake, i.e. inhibiting the serotonin and norepinephrine transporters from taking their respective neurotransmitters back to their storage vesicles for later use. If the norepinephrine transporter normally recycles some dopamine too, then SNRIs will also enhance dopaminergic transmission. Therefore, the antidepressant effects associated with increasing norepinephrine levels may also be partly or largely due to the concurrent increase in dopamine (in particular in the prefrontal cortex of the brain). Tricyclic antidepressants (TCAs) increase norepinephrine activity as well. Most of them also increase serotonin activity, but tend to produce unwanted side-effects due to the nonspecific inactivation of histamine, acetylcholine, and alpha-1 adrenergic receptors. Common side-effects include sedation, dry mouth, constipation, sinus tachycardia, memory impairment, orthostatic hypotension, blurred vision, and weight gain.[44] For this reason, they have largely been replaced by newer selective reuptake drugs. These include the SSRIs, e.g. fluoxetine (Prozac), which however have little or no effect on norepinephrine, and the newer SNRIs described above, such as venlafaxine (Effexor) and duloxetine (Cymbalta). Schizophrenia A commonly known side-effect associated with schizo-affective patients known as akathisia (commonly mistaken for schizophrenic symptoms) was found to be associated with increased levels of norepinephrine.[45] Data supports the efficacy of novel antipsychotics that deal with agonism of the NMDA glutamate receptors,[46] associated with regulating uptake of norepinephrine,[47] which in turn affects the trafficking of glutamate.[48] This suggests that schizophrenia may in fact have a greater association with abnormal norepinephrine-reuptake kinetics and less with dopamine, which may actually be responsible for a large part of the mechanism of glutamate release.[48] Hypotension Norepinephrine is also used as a vasopressor medication (for example, brand name Levophed) for patients with critical hypotension. It is given intravenously and acts on both 1 and 2 adrenergic receptors to cause vasoconstriction. Its effects are often limited to the increasing of blood pressure through agonist activity on 1 and 2 receptors, and causing a resultant increase in peripheral vascular resistance. At high doses, and especially when it is combined with other vasopressors, it can lead to limb ischemia and limb death. Norepinephrine is used mainly to treat patients in vasodilatory shock states such as septic shock and neurogenic shock, while showing fewer adverse side-effects compared to dopamine treatment.[49]

283

By site of action
Different medications affecting norepinephrine function have their targets at different points in the mechanism, from synthesis to signal termination. Synthesis modulators -Methyltyrosine is a substance that intervenes in norepinephrine synthesis by substituting tyrosine for tyrosine hydroxylase, and blocking this enzyme. Vesicular transport modulators This transportation can be inhibited by reserpine and tetrabenazine.[38]

Norepinephrine Release modulators

284

Inhibitors of norepinephrine release

Substance acetylcholine [50] Receptor [50]

muscarinic receptor

norepinephrine (itself)/epinephrine 2 receptor 5-HT adenosine PGE histamine enkephalin dopamine ATP 5-HT receptor P1 receptor EP receptor H2 receptor receptor D2 receptor P2 receptor

Stimulators of norepinephrine release

Substance [50] Receptor [50]

epinephrine angiotensin II

2 receptor AT1 receptor

Receptor binding modulators Examples include alpha blockers for the -receptors, and beta blockers for the -receptors. Termination modulators Uptake modulators Inhibitors[38] of uptake 1 include: cocaine tricyclic antidepressants desipramine phenoxybenzamine amphetamine reboxetine Inhibitors[38] of uptake 2 include: normetanephrine steroid hormones phenoxybenzamine

Norepinephrine Anti-inflammatory agent role in Alzheimers Disease The norepinephrine from locus ceruleus cells in addition to its neurotransmitter role locally diffuses from "varicosities". As such, it provides an endogenous anti-inflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus.[18] Up to 70% of norepinephrine projecting cells are lost in Alzheimers Disease. It has been shown that norepinephrine stimulates mouse microglia to suppress A-induced production of cytokines and their phagocytosis of A, suggesting this loss might have a role in causing this disease.[18]

285

Nutritional sources
The synthesis of norepinephrine depends on the presence of tyrosine, an amino acid found in proteins such as meat, nuts, and eggs. Dairy products such as cheese also contain high amounts of tyrosine (the amino acid is named for "tyros", the Greek word for cheese). However, the body can synthesise tyrosine from phenylalanine, an essential amino acid. Tyrosine is the precursor to dopamine, which in turn is a precursor to epinephrine and norepinephrine.

Serotonin, a neurotransmitter that is in many ways the opposite of the catecholamines, is also directly synthesized from an amino acid (tryptophan). However, tryptophan has a somewhat different process of degradation. When serotonin is catabolized in the body, it does not break down into useful substrates in the way that dopamine is further degraded into epinephrine and norepinephrine. Instead, it breaks down into 5-hydroxyindoleacetic acid (5-HIA), an organic acid that may be harmful in high amounts. Tryptophan can further be catabolized into kynurenate, quinolinate, and picolinate, harmful substances that are generally regarded as markers of bodily inflammation.
[]

Shown here is the chemical structure of L-tyrosine. The biosynthesis of norepinephrine depends upon the presence of L-tyrosine, an amino acid building-block of many proteins in meat, nuts, and eggs, for example.

References
[1] Merck Index, 11th Edition, 6612. [2] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=51-41-2 [3] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=138-65-8 [4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=439260 [5] http:/ / www. chemspider. com/ 388394 [6] http:/ / www. drugbank. ca/ drugs/ DB00368 [7] http:/ / www. kegg. jp/ entry/ D00076 [8] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=18357 [9] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL1437 [10] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01CA03 [11] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=Oc1ccc%28cc1O%29%5BC%40%40H%5D%28O%29CN [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477170789& page2=Norepinephrine [16] Tanaka2000 Tanaka M, et al. (2000). Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies. [17] The Hormone Foundation. "The Endocrine System & Types of Hormones." (http:/ / www. hormone. org/ endocrine_system. cfm) [18] Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, Kummer MP. (2010). Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. (http:/ / www. pnas. org. libproxy. ucl. ac. uk/ content/ 107/ 13/ 6058. full. pdf) Proc Natl Acad Sci U S A. 17:60586063 PMID 20231476 [19] Link redirected to commercial site! [20] Devauges V, Sara SJ, Activation of the noradrenergic system facilitates an attentional shift in the rat. Behav. Brain Res., 1990 Jun 18;39(1):1928.

Norepinephrine
[23] Swick, D., Pineda, J. a, Schacher, S., & Foote, S. L. (1994). Locus coeruleus neuronal activity in awake monkeys: relationship to auditory P300-like potentials and spontaneous EEG. Experimental brain research. Experimentelle Hirnforschung. Exprimentation crbrale, 101(1), 8692. [25] Pineda, J.A., Shafer, K., & Belamonte, M (1993). Noradrinergic modulation of auditory and visual P300 in parietal-temporal cortex. Society for Neuroscience Abstracts, 19, 1607. [26] Lutzenberger, W., Elbert, T., Rockstroth, B. (1987). A brief tutorial on the implications of volume conduction for the interpretation of the EEG. Journal of Psychophysiology, 33. S56. [27] Berridge, C.W., Waterhouse, B.D. (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Research Reviews, 42. 3384. [29] Clayton, E. C., Rajkowski, J., Cohen, J. D., & Aston-Jones, G. (2004). Phasic activation of monkey locus ceruleus neurons by simple decisions in a forced-choice task. J.Neurosci. 24(44), 991420. [30] Tremblay, L., Schultz, W., (1999). Relative reward preference in primate orbitofrontal cortex. Nature, 398. 704708. [32] Falkenstein M, Hohnsbein J, Hoorman J, Blanke L. (1991). Effects of crossmodal divided attention on late ERP components: II. Error processing in choice reaction tasks. Electroencephalogr. Clin. Neurophysiol. 78:44755 [35] Bogacz, R., Cohen, J.D., (2004). Parameterization of connectionist models. Behav. Res. Methods, Instruments, & Computers, 36(4), pp. 732741. [37] Brown, E. T., Gilzenrat, M. S., & Cohen, J. D. (2004). The locus coeruleus, adaptive gain, and the optimization of simple decision tasks. Technical Report No. 0402. [38] Page 167 [39] These values are from rat heart. Unless else specified in table, then ref is: Page 167 [40] Unless else specified in table, then ref is: Page 167 [41] Unless else specified in boxes, then ref is: [42] "Endokrynologia Kliniczna" ISBN 83-200-0815-8, page 502 [43] http:/ / stahlonline. cambridge. org/ prescribers_drug. jsf?page=0521683505c95_p539-544. html. therapeutics& name=Venlafaxine& title=Therapeutics [44] http:/ / www. preskorn. com/ columns/ 9803. html [46] http:/ / www. nature. com/ npp/ journal/ v31/ n4/ abs/ 1300838a. html [47] http:/ / www. sciencedirect. com/ science?_ob=ArticleURL& _udi=B6WN4-4CCGGN1-9P& _user=10& _coverDate=11%2F30%2F1984& _rdoc=1& _fmt=high& _orig=search& _origin=search& _sort=d& _docanchor=& view=c& _searchStrId=1520587233& _rerunOrigin=scholar. google& _acct=C000050221& _version=1& _urlVersion=0& _userid=10& md5=5e43884bdf1f204eb2356e02096708bc& searchtype=a [48] http:/ / sciencelinks. jp/ j-east/ article/ 200707/ 000020070707A0194475. php [50] Unless else specified in table, then ref is: Page 129

286

External links
Mental Health: A report of surgeon general. Etiology of Anxiety Disorders (http://www.surgeongeneral.gov/ library/mentalhealth/chapter4/sec2_1.html) http://www.biopsychiatry.com/nordop.htm

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Neuropeptide Y
Neuropeptide Y

Structure of Neuropeptide Y. From PDB 1ron Available structures PDB Ortholog search: PDBe [2], RCSB [3] List of PDB id codes 1QFA
[4]

[1]

, 1RON

[5]

Identifiers Symbols External IDs NPY

[6]

; PYY4
[7]

OMIM: 162640

MGI: 97374

[8]

HomoloGene: 697

[9]

GeneCards: NPY Gene

[10]

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288

Gene Ontology Molecular function G-protein coupled receptor binding [11] [12] G-protein coupled receptor activity [13] receptor binding [7] neuropeptide hormone activity [14] calcium channel regulator activity Cellular component extracellular region [11] [12] extracellular space [15] cell Biological process calcium ion transport [17] cellular component movement G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
[18] [16]

neuropeptide signaling pathway [18] synaptic transmission [20] digestion [20] behavior [21] feeding behavior [22] blood circulation [23] regulation of blood pressure [24] cell proliferation [25] adult feeding behavior [26] central nervous system neuron development [27] cerebral cortex development [28] neuron projection development [29] positive regulation of appetite Sources: Amigo
[30]

[19]

/ QuickGO

[31]

RNA expression pattern

More reference expression data Orthologs Species Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Location (UCSC) Human 4852
[33] [35]

[32]

Mouse 109648
[34] [36]

ENSG00000122585 P01303
[37] [39]

ENSMUSG00000029819 P57774
[38] [40]

NM_000905 NP_000896

NM_023456 NP_075945

[41]

[42]

Chr 7: [43] 24.32 24.33 Mb

Chr 6: [44] 49.82 49.83 Mb

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PubMed search

[45]

[46]

Neuropeptide Y
Clinical data Pregnancy cat. ? Legal status ? Identifiers CAS number ATC code ChEMBL 82785-45-3 ? CHEMBL267633 Chemical data Formula Mol. mass C190H287N55O57 4253.7 [49] [48] [47]

(what is this?) (verify)

Neuropeptide Y (NPY) is a 36-amino acid neuropeptide that acts as a neurotransmitter in the brain and in the autonomic nervous system of humans; slight variations of the peptide are found in many other animals.[] In the autonomic system it is mainly produced by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue.[] In the brain it is produced in various locations including the hypothalamus, and is thought to have several functions, including: increasing food intake and storage of energy as fat, reducing anxiety and stress, reducing pain perception, affecting the circadian rhythm, reducing voluntary alcohol intake, lowering blood pressure and controlling epileptic seizures.[][]

Discovery
Following the isolation of neuropeptide-y (NPY) from the porcine hypothalamus in 1982, researchers began to speculate about the involvement of NPY in hypothalamic-mediated functions. In a 1983 study, NPY-ergic axon terminals were located in the paraventricular nucleus (PVN) of the hypothalamus, and the highest levels of NPY immunoreactivity was found within the PVN of the hypothalamus.[] Six years later, in 1989, Morris et al. homed in on the location of NPYergic nuclei in the brain. Furthermore, in situ hybridization results from the study showed the highest cellular levels of NPY mRNA in the arcuate nucleus (ARC) of the hypothalamus.[] In 1989, Haas & George reported that local injection of NPY into the PVN resulted in an acute release of corticotropin-releasing hormone (CRH) in the rat brain, proving that NPYergic activity directly stimulates the release and synthesis of CRH.[] The latter became a hallmark paper in NPY studies. A significant amount of work had already been done in the 1970s on CRH and its involvement in stress and eating disorders such as obesity.[] These studies, collectively, marked the beginning of the role of NPY in orexigenesis or food intake.

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The role of NPY in food intake

Behaviorial assays in orexigenic studies, in which rats are the model organism, have been done collectively with immunoassays and in situ hybridization studies to confirm that elevating NPYergic activity does indeed increase food intake. In these studies, exogenous NPY,[] an NPY agonist such as dexamethasone[] or N-acetyl [Leu 28, Leu31] NPY (24-36)[50] are injected into the third ventricle[] or at the level of the hypothalamus with a cannula.[][51] Furthermore, these studies unanimously demonstrate that the stimulation of NPYergic activity via the administration of certain NPY agonists increases food intake compared to baseline data in rats. The effects of NPYergic activity on food intake is also demonstrated by the blockade of certain NPY receptors (Y1 and Y5 receptors), which, as was expected, inhibited NPYergic activity; thus, decreases food intake. However, a 1999 study by King et al. demonstrated the effects of the activation of the NPY autoreceptor Y2, which has been shown to inhibit the release of NPY and thus acts to regulate food intake upon its activation.[52] In this study a highly selective Y2 antagonist, BIIE0246 was administered locally into the ARC. Radioimmunoassay data, following the injection of BIIE0246, shows a significant increase in NPY release compared to the control group. Though the pharmacological half-life of exogenous NPY, other agonists, and antagonist is still obscure, the effects are not long lasting and the rat body employs an excellent ability to regulate and normalize abnormal NPY levels and therefore food consumption.[]

The role of NPY in obesity

Dryden et al., conducted a study in 1995 using genetically obese rats to demonstrate the role of NPY in eating disorders such as obesity. The study revealed four underlying factors that contributed to obesity in rats: (1) an increase in glucocorticosteroid concentrations in plasma; (2) insensitivity or resistance to insulin; (3) mutation of leptin receptor; and (4) an increase in NPY mRNA and NPY release.[53] Furthermore, these factors also correlate with each other. The sustained high levels of glucocorticosteroids stimulate gluconeogenesis, which subsequently causes an increase of blood glucose that activates the release of insulin to regulate glucose levels by causing its reuptake and storage as glycogen in the various tissues in the body. In the case of obesity, which researchers speculate to have a strong genetic and a dietary basis, insulin resistance prevents high blood glucose regulation, resulting in morbid levels of glucose and diabetes mellitus.[54] Furthermore, high levels of glucocorticosteroids causes an increase of NPY by directly activating type II glucocorticosteroids receptors (which are activated only by relatively high levels of glucocorticosteroids) and, indirectly, by abolishing the negative feedback of corticotropin-releasing factor (CRF) on NPY synthesis and release. Meanwhile, obesity-induced insulin resistance and the mutation of the leptin receptor (ObRb) results in the abolition of inhibition of NPYergic activity and ultimately food intake via other negative feedback mechanisms to regulate them. Furthermore, obesity in rats was significantly reduced by adrenalectomy[55] or hypophysectomy.[56]

Correlation with stress and diet

Studies of mice and monkeys show that repeated stress and a high-fat, high-sugar diet stimulate the release of neuropeptide Y, causing fat to build up in the abdomen. Researchers believe that by manipulating levels of NPY, they could make fat melt from areas where it was not desired and accumulate at sites where it is needed.[][57] Higher levels of NPY may be associated with resilience against and recovery from posttraumatic stress disorder[] and with dampening the fear response, allowing individuals to perform better under extreme stress.[58]

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Alcoholism
Two results suggest that NPY might protect against alcoholism: knock-out mice in which a type of NPY receptor has been removed show a higher voluntary intake of alcohol and a higher resistance to alcohol's sedating effects, compared to normal mice;[] the common fruit fly has a neuropeptide that is similar to NPY, known as neuropeptide F. The levels of neuropeptide F are lowered in sexually frustrated male flies, and this causes the flies to increase their voluntary intake of alcohol.[59]

Receptors
The receptor protein that NPY operates on is a G protein-coupled receptor in the rhodopsin like 7-transmembrane GPCR family. Five subtypes of the NPY receptor have been identified in mammals, four of which are functional in humans.[] Subtypes Y1 and Y5 have known roles in the stimulation of feeding while Y2 and Y4 seem to have roles in appetite inhibition (satiety). Some of these receptors are among the most highly conserved neuropeptide receptors.

References
[1] http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=1ron

[2] http:/ / www. ebi. ac. uk/ pdbe/ searchResults. html?display=both& term=A4D158%20or%20P01303%20or%20E2R499%20or%20Q6RUW3%20or%20B5M4A4%20or%20P57774%20or%20F2W8A6%20or%20P07808%20or%2 [3] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=UpAccessionIdQuery& accessionIdList=A4D158,P01303,E2R499,Q6RUW3,B5M4A4,P57774,F2W8A6,P07808,P28673,Q9I8P3,Q1LW93 [4] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1QFA [5] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1RON [6] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=7955 [7] http:/ / omim. org/ entry/ 162640 [8] http:/ / www. informatics. jax. org/ searches/ accession_report. cgi?id=MGI:97374 [9] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=697 [10] http:/ / www. genecards. org/ cgi-bin/ carddisp. pl?id_type=entrezgene& id=4852 [11] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0001664 [12] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0004930 [13] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005102 [14] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005246 [15] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005623 [16] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006816 [17] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006928 [18] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007187 [19] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007218 [20] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007610 [21] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007631 [22] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0008015 [23] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0008217 [24] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0008283 [25] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0008343 [26] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0021954 [27] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0021987 [28] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0031175 [29] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032100 [30] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ gp-assoc. cgi?gp=UniProtKB:P01303 [31] http:/ / www. ebi. ac. uk/ QuickGO/ GProtein?ac=P01303 [32] http:/ / biogps. org/ gene/ 4852/ [33] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=4852& rn=1 [34] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=109648& rn=1 [35] http:/ / www. ensembl. org/ Homo_sapiens/ geneview?gene=ENSG00000122585;db=core [36] http:/ / www. ensembl. org/ Mus_musculus/ geneview?gene=ENSMUSG00000029819;db=core

Neuropeptide Y
[37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] http:/ / www. uniprot. org/ uniprot/ P01303 http:/ / www. uniprot. org/ uniprot/ P57774 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_000905 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_023456 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_000896 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_075945 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Human& db=hg19& position=chr7:24323782-24331484 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Mouse& db=mm9& position=chr6:49822710-49829507 http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=4852 http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=109648 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=82785-45-3& rn=1 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL267633 http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=462259803& page2=Neuropeptide+ Y

292

External links
EMBL receptor database entry (http://www.ebi.ac.uk/interpro/IEntry?ac=IPR000611) Neuropeptide Y (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Neuropeptide+Y) at the US National Library of Medicine Medical Subject Headings (MeSH)

Arcuate nucleus

293

Arcuate nucleus
Brain: Arcuate nucleus

Arcuate nucleus is 'AR', at bottom center, in green. Latin Part of NeuroNames MeSH nucleus arcuatus hypothalami Hypothalamus hier-378
[1] [2]

Arcuate+nucleus

The arcuate nucleus (or infundibular nucleus[3]) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important populations of neurons, including: neuroendocrine neurons, centrally-projecting neurons, and others.

Neuroendocrine neurons
Neuroendocrine neurons with nerve endings in the median eminence release dopamine into the hypophysial portal blood. These are sometimes called the "tuberoinfundibular dopamine" (TIDA) neurons. In lactating females, TIDA neurons are inhibited by the stimulus of suckling. Dopamine released from their nerve endings at the median eminence is transported to the anterior pituitary gland, where it regulates the secretion of prolactin; dopamine inhibits prolactin secretion, so when the TIDA neurons are inhibited, there is increased secretion of prolactin, which stimulates lactogenesis (milk production). Prolactin acts in a short-loop negative feedback manner to decrease its levels by stimulating the release of dopamine. Dopaminergic neurons of the arcuate also inhibit the release of gonadotropin-releasing hormone, explaining in part why lactating (or otherwise hyperprolactinemic) women experience oligomenorrhea or amenorrhea (infrequency or absence of menses). Neuroendocrine neurons, mainly in the ventrolateral part of the nucleus, make growth hormone-releasing hormone (GHRH). Like the TIDA neurons, these neurons have nerve endings in the median eminence. GHRH released into the hypophysial portal blood is transported to the anterior pituitary gland, where it regulates the secretion of growth hormone; GHRH stimulates growth hormone secretion. These neurons are inhibited by somatostatin. The reciprocal relationship between the electrical activity of GHRH neurons and somatostatin neurons leads to pulsatile secretion of growth hormone, a pattern of secretion that is important for its biological effectiveness.

Arcuate nucleus

294

Centrally-projecting neurons
Centrally-projecting neurons contain neuropeptide Y (NPY), agouti-related protein (AGRP), and the inhibitory neurotransmitter GABA. These neurons, in the most ventromedial part of the nucleus, project strongly to the lateral hypothalamus and to the paraventricular nucleus of the hypothalamus, and are important in the regulation of appetite. When activated, these neurons can produce ravenous eating. These neurons are inhibited by leptin, insulin, and peptide YY and activated by ghrelin. Centrally-projecting neurons that contain peptide products of pro-opiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART). These neurons have widespread projections to many brain areas, including to all nuclei in the hypothalamus. These cells are important in the regulation of appetite, and, when activated, they inhibit feeding. These neurons are activated by circulating concentrations of leptin and insulin, and they are directly innervated and inhibited by the NPY neurons.[4] POMC neurons that project to the medial preoptic nucleus are also involved in the regulation of sexual behavior in both males and females. The expression of POMC is regulated by gonadal steroids. The release of a POMC product, beta-endorphin is regulated by NPY. Centrally-projecting neurons that make somatostatin; the neurosecretory somatostatin neurons that regulate growth hormone secretion are a different population, located in the periventricular nucleus.

Other
A small population of neurons that synthesise ghrelin. The role of this population is not known; many neurons in the arcuate nucleus express receptors for ghrelin, but these are thought to respond mainly to blood-borne ghrelin. The arcuate nucleus also contains a population of specialized ependymal cells, called tanycytes.

Footnotes
[1] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=378 [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Arcuate+ nucleus [3] onderzoekinformatie.nl - Project: Does activation of neurons in the infundibular nucleus in menopause prevent the occurrence of Alzheimer changes? (http:/ / www. onderzoekinformatie. nl/ en/ oi/ nod/ onderzoek/ OND1289935/ ) [4] Arora and Anubhuti. Role of neuropeptides in appetite regulation and obesity--a review. Neuropeptides (2006) vol. 40 (6) pp. 375-401

References
Kawano H, Daikoku S (1988). "Somatostatin-containing neuron systems in the rat hypothalamus: retrograde tracing and immunohistochemical studies". J. Comp. Neurol. 271 (2): 2939. doi: 10.1002/cne.902710209 (http:/ /dx.doi.org/10.1002/cne.902710209). PMID 2897982 (http://www.ncbi.nlm.nih.gov/pubmed/2897982). Cone RD (2005). " Anatomy and regulation of the central melanocortin system (http://dept.wofford.edu/ neuroscience/neuroseminar/pdfSpring2006/o6.pdf)". Nature Neurosci. 8 (5): 5718. doi: 10.1038/nn1455 (http://dx.doi.org/10.1038/nn1455). PMID 15856065 (http://www.ncbi.nlm.nih.gov/pubmed/15856065).

Locus coeruleus

295

Locus coeruleus
Brain: Locus coeruleus

Rhomboid fossa. (Locus coeruleus not labeled, but is very near [just lateral to] colliculus facialis, which is labeled at center left.)

Micrograph showing the locus coeruleus. HE-LFB stain. Latin Gray's NeuroNames NeuroLex ID locus caeruleus subject #187 778 hier-578
[2] [3] [1]

birnlex_905

The locus coeruleus (also spelled locus caeruleus) is a nucleus in the pons (part of the brainstem) involved with physiological responses to stress and panic. It was discovered in the 18th century by Flix Vicq-d'Azyr,[] or maybe later by Johann Christian Reil.[] The locus coeruleus is the principal site for brain synthesis of norepinephrine (noradrenaline). The locus coeruleus and the areas of the body affected by the norepinephrine it produces are described collectively as the locus coeruleus-noradrenergic system or LC-NA system.[4] Norepinephrine may also be released directly into the blood from the adrenal medulla. The name is derived from the Latin words coeruleus and locus. Literally, this means "the dark blue spot", a name derived from its azure appearance in unstained brain tissue. The color is due to light scattering from melanin in noradrenergic (producing or activated by norepinephrine) nerve cell bodies. The phenomenon is magnified by the Falck-Hillarp technique, which combines freeze-dried tissue and formaldehyde to fluoresce the catecholamines and serotonin contained in the tissue. Caeruleus is the classical Latin spelling, but coeruleus is the more common spelling. The spelling ceruleus, formed by contraction of the digraph ae or oe into e, is an American English form. The etymology is probably from " caelum" meaning "sky" [ whence ceiling ].

Locus coeruleus

296

Anatomy
The locus coeruleus (or "LC") is located in the posterior area of the rostral pons in the lateral floor of the fourth ventricle. It is composed of mostly medium-size neurons. Melanin granules inside the neurons of the LC contribute to its blue color. Thus, it is also known as the nucleus pigmentosus pontis, meaning "heavily pigmented nucleus of the pons." The neuromelanin is formed by the polymerization of noradrenaline and is analogous to the black dopamine-based neuromelanin in the substantia nigra. In adult humans (19-78) the locus coeruleus has 22,000 to 51,000 total pigmented neurons that range in size between 31,000 to 60, 000 m3.[5]

Connections
The projections of this nucleus reach far and wide. For example, they innervate the spinal cord, the brain stem, cerebellum, hypothalamus, the thalamic relay nuclei, the amygdala, the basal telencephalon, and the cortex. The norepinephrine from the LC has an excitatory effect on most of the brain, mediating arousal and priming the brains neurons to be activated by stimuli.

As an important homeostatic control center of the body, the locus coeruleus receives afferents from the hypothalamus. The cingulate gyrus and the amygdala also innervate the LC, allowing emotional pain and stressors to trigger noradrenergic responses. The cerebellum and afferents from the raphe nuclei also project to the LC, particularly the nucleus raphes pontis and nucleus raphes dorsalis. The locus coeruleus receives inputs from a number of other brain regions, primarily: Medial prefrontal cortex, whose connection is constant, excitatory, and increases in strength with raised activity levels in the subject Nucleus paragigantocellularis, which integrates autonomic and environmental stimuli Nucleus praepositus hypoglossi, which is involved in gaze Lateral hypothalamus, which releases orexin, which, as well as its other functions, is excitatory in the locus coeruleus.

Micrograph showing the locus coeruleus (upper-right of image) in an axial section of the pons. The fourth ventricle (quasi-triangular white area) is in the upper left of the image. The midline is seen on the left. The large white area in the upper-left corner is where the cerebellum would be. HE-LFB stain.

Function
It is related to many functions via its widespread projections. The LC-NA system modulates cortical, subcortical, cerebellar, brainstem and spinal cord circuits. Some of the most important functions influenced by this system are:[6] Neuroplasticity Arousal and sleep-wake cycle Attention and memory Emotions Behavioral flexibility, behavioral inhibition and stress (psychological) Posture and balance.

Locus coeruleus The locus coeruleus may figure in clinical depression, panic disorder, and anxiety. Some medications including norepinephrine reuptake inhibitors (reboxetine, atomoxetine), serotonin-norepinephrine reuptake inhibitors (venlafaxine, duloxetine), and norepinephrine-dopamine reuptake inhibitors (bupropion) are believed to show efficacy by acting upon neurons in this area.

297

In stress
The locus coeruleus is responsible for mediating many of the sympathetic effects during stress. The locus coeruleus is activated by stress, and will respond by increasing norepinephrine secretion, which in turn will alter cognitive function (through the prefrontal cortex), increase motivation (through nucleus accumbens), activate the hypothalamic-pituitary-adrenal axis, and increase the sympathetic discharge/inhibit parasympathetic tone (through the brainstem). Specific to the activation of the hypothalamo-pituitary adrenal axis, norepinephrine will stimulate the secretion of corticotropin-releasing factor from the hypothalamus, which induces adrenocorticotropic hormone release from the anterior pituitary and subsequent cortisol synthesis in the adrenal glands. Norepinephrine released from locus coeruleus will feedback to inhibit its production, and corticotropin-releasing hormone will feedback to inhibit its production, while positively feeding to the locus coeruleus to increase norepinephrine production.[6] The LC's role in cognitive function in relation to stress is complex and multi-modal. Norepinephrine released from the LC can act on 2 receptors to increase working memory, or an excess of NE may decrease working memory by binding to the lower affinity 1 receptors.[7] Psychiatric research has documented that enhanced noradrenergic postsynaptic responsiveness in the neuronal pathway (brain circuit) that originates in the locus coeruleus and end in the basolateral nucleus of the amygdala is a major factor in the pathophysiology of most stress-induced fear-circuitry disorders and especially in posttraumatic stress disorder (PTSD). The LC neurons are probably the origin of the first or second leg of the "PTSD circuit." An important 2005 study of deceased American army veterans from World War II, was shown combat-related PTSD to be associated with a postmortem diminished number of neurons in the locus coeruleus (LC) on the right side of the brain.[8]

In opiate withdrawal
Opioids inhibit the firing of neurons in the locus coeruleus. When opioid consumption is stopped, the increased activity of the locus coeruleus contributes to the symptoms of opiate withdrawal. The alpha2 adrenoceptor agonist clonidine is used to counteract this withdrawal effect by decreasing adrenergic neurotransmission from the locus coeruleus.[9]

Rett syndrome
The genetic defect of the transcriptional regulator MECP2 is responsible for Rett syndrome.[10] A MECP2 deficiency has been associated to catecholaminergic dysfunctions related to autonomic and sympathoadrenergic system in mouse models of Rett Syndrome (RTT). The Locus Coeruleus is the major source of noradrenergic innervation in the brain and sends widespread connections to rostral (cerebral cortex, hippocampus, hypothalamus) and caudal (cerebellum, brainstem nuclei) brain areas[11] and.[12] Indeed, an alteration of this structure could contribute to several symptoms observed in MECP2-deficient mice. Changes in the electrophysiological properties of cells in the locus ceruleus were shown. These Locus Coeruleus cell changes include hyperexcitability and decreased functioning of its noradrenergic innervation.[] Interestingly, a reduction of the tyrosine hydroxylase (TH) mRNA level, the rate-limiting enzyme in catecholamine synthesis, was detected in the whole pons of MECP2-null male as well as in adult heterozygous female mice. Using immunoquantification techniques, a decrease of TH protein staining level, number of locus coeruleus TH-expressing neurons and density of dendritic arborization surrounding the structure was shown in symptomatic MECP2-deficient mice.[13] However, locus coeruleus cells are not dying but are more likely losing their fully mature phenotype since no apoptotic neurons in the pons were detected.[13] Researchers have

Locus coeruleus concluded that "Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett Syndrome, such as respiration and cognition, we hypothesize that the locus ceruleus is a critical site at which loss of MECP2 results in CNS dysfunction. Restoration of normal locus ceruleus function may therefore be of potential therapeutic value in the treatment of Rett Syndrome.[] This could explain why a norepinephrine reuptake inhibitor (desipramine, DMI) which enhances the extracellular NE levels at all noradrenergic synapses ameliorated some Rett syndrome symptoms in a mouse model of Rett syndrome.[13]

298

Neurodegenerative diseases
The locus ceruleus is affected in many forms of neurodegenerative diseases: genetic and idiopathic Parkinson's disease, progressive supranuclear palsy, Pick's disease or Alzheimer's disease. It is also affected in Down syndrome.[14] For example there is up to 70% loss of locus ceruleus neurons in Alzheimer's disease.[15] Mouse models of Alzheimer's disease show accelerated progression after chemical destruction of the locus ceruleus [16] The norepinephrine from locus ceruleus cells in addition to its neurotransmitter role locally defuses from "varicosities". As such it provides an endogenous anti-inflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus.[17] It has been shown that norepinephrine stimulates mouse microglia to suppress A-induced production of cytokines and their phagocytosis of A.[17] This suggests that degeneration of the locus ceruleus might be responsible for increased A deposition in AD brains.[17]

References
[1] [2] [3] [6] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=187#p778 http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=578 http:/ / www. neurolex. org/ wiki/ birnlex_905 Benarroch EE. The locus ceruleus norepinephrine system: functional organization and potential clinical significance. Neurology. 2009 Nov 17;73(20):1699-704. [7] Ramos BP, Arnsten AF. Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol Ther 2007; 113: 523-536. [9] P. Devenyi, A. Mitwalli, and W. Graham Clonidine therapy for narcotic withdrawal. Can Med Assoc 1982 November 15; 127(10): 10091011. http:/ / www. ncbi. nlm. nih. gov/ pmc/ articles/ PMC1862300/ ?page=1 [10] Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett Syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 Nat Genet. 1999 Oct 23(2):185-8 [11] Hokfelt T,Martensson R,Bjorklund A,Kleinau S,Goldstein M. 1984. Distribution maps of tyrosine-hydroxylase-immunoreactive neurons in the rat brain. In Handbook of Chemical Neuroanatomy, Vol. 2. Classical Transmitters in the CNS, Part I ( A. Bjorklund and T. Hokfelt, eds.) pp. 277-379. Elsevier, New York. [12] Berridge CW,Waterhouse BD 2003 The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev 42: 33-84 [13] Roux JC, Panayotis N, Dura E, Villard L. (2009) Progressive Noradrenergic Deficits in the Locus Coeruleus of MECP2 Deficient Mice J Neurosci Res http:/ / www3. interscience. wiley. com/ cgi-bin/ fulltext/ 123208150/ HTMLSTART [14] Esiri MM. et al. (2004). Neuropathology of dementia. 2th Ed. Cambridge University Press. [15] Bondareff W, Mountjoy CQ, Roth M. Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology. 1982 Feb;32(2):164-8. [16] Heneka MT, Ramanathan M, Jacobs AH, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T, Sastre M, Galldiks N, Zimmer A, Hoehn M, Heiss WD, Klockgether T, Staufenbiel M. Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci. 2006 Feb 1;26(5):1343-54. [17] Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, Kummer MP. (2010). Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. (http:/ / www. pnas. org. libproxy. ucl. ac. uk/ content/ 107/ 13/ 6058. full. pdf) Proc Natl Acad Sci U S A. 107:60586063 PMID 20231476

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299

External links
"A Lecture, Higher Brain Function: Activation of the Brain and Levels of Consciousness" (http://faculty.etsu. edu/currie/ras.htm) at East Tennessee State University BrainMaps at UCDavis locus coeruleus (http://brainmaps.org/index.php?q=locus coeruleus) Diagram (http://homepage.psy.utexas.edu/homepage/class/Psy301/Salinas/sec2/Brain/31.GIF) at University of Texas at Austin Diagram (http://www.healthsystem.virginia.edu/internet/pediatrics/hcp/adhdbrainanatomy.cfm) at University of Virginia http://www2.umdnj.edu/~neuro/studyaid/Practical2000/Q45.htm

Solitary nucleus

300

Solitary nucleus
Brain: Solitary nucleus

The cranial nerve nuclei schematically represented; dorsal view. Motor nuclei in red; sensory in blue.

Transverse section of medulla oblongata of human embryo. Latin NeuroNames MeSH NeuroLex ID Nucleus tractus solitarii medullae oblongatae hier-739
[1] [2]

Solitary+Nucleus birnlex_1429
[3]

In the human brain, the solitary nucleus (nucleus of the solitary tract, nucleus tractus solitarii, NTS) is a series of nuclei (clusters of nerve cell bodies) forming a vertical column of grey matter embedded in the medulla oblongata. Through the center of the NTS runs the solitary tract, a white bundle of nerve fibers, including fibers from the facial, glossopharyngeal and vagus nerves that synapse on neurons of the NTS. The NTS projects to, among other regions, the reticular formation, parasympathetic preganglionic neurons, hypothalamus and thalamus, forming circuits that contribute to autonomic regulation. Cells within the NTS are arranged according to function; for instance, cells involved in taste are located in the higher, more forward ("rostral") part, while those regulating cardio-respiratory processes are found in the lower, more posterior ("caudal") part.[][]

Inputs to the NTS

Taste information from the facial nerve (anterior 2/3 of the tongue), glossopharyngeal nerve (posterior 1/3) and vagus nerve (small area on the epiglottis) Chemoreceptors in the carotid body via glossopharyngeal nerve, and aortic bodies via the vagus nerve Chemically and mechanically sensitive neurons with endings located in the heart, lungs, airways, gastrointestinal system, and liver via the glossopharyngeal and vagus nerves Neurons that synapse in the NTS mediate the gag reflex, the carotid sinus reflex, the aortic reflex, the cough reflex, the baroreceptor and chemoreceptor reflexes, several respiratory reflexes and reflexes within the gastrointestinal system regulating motility and secretion.

Solitary nucleus Information about the gut wall, the stretch of the lungs, and the dryness of mucous membranes also synapse at the NTS. The first central neurons within the NTS can participate in simple autonomic reflexes.

301

Outputs from the NTS

Information goes from the NTS to a large number of other regions of the brain including the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala, as well as to other nuclei in the brainstem (such as the parabrachial area and other visceral motor or respiratory networks).[4] The signals projected from the NTS to the parabrachial area originate in the oral cavity and gastrointestinal tract. The pathways for gastric and gustatory (taste) processes are believed to terminate in different subdivisions of the parabrachial area, but still interact in the NTS.[5][6] Some neuronal subpopulations in the NTS, such as the noradrenergic A2 neurons and the aldosterone-sensitive HSD2 neurons project as far rostrally as the bed nucleus of the stria terminalis.[7][8]

Additional images

Section of the medulla oblongata at about the middle of the olive.

Primary terminal nuclei of the afferent (sensory) cranial nerves schematically represented; lateral view.

References
[1] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=739 [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Solitary+ Nucleus [3] http:/ / www. neurolex. org/ wiki/ birnlex_1429

External links
BrainMaps at UCDavis solitary tract (http://brainmaps.org/index.php?q=solitary tract)

Galanin

302

Galanin
Galanin/GMAP prepropeptide
Identifiers Symbols External IDs GAL
[1]

; GAL-GMAP; GALN; GLNN; GMAP

[2]

OMIM: 137035

MGI: 95637

[3]

HomoloGene: 7724

[4]

GeneCards: GAL Gene

[5]

Gene Ontology Molecular function neuropeptide hormone activity [7] Cellular component cellular_component [6] [11] extracellular region [7] Golgi apparatus [8] secretory granule Biological process smooth muscle contraction [10] inflammatory response [19] neuropeptide signaling pathway [11] nervous system development [21] feeding behavior [12] insulin secretion [13] growth hormone secretion [14] regulation of glucocorticoid metabolic process [15] response to insulin stimulus [25] response to drug [25] positive regulation of apoptotic process [16] response to estrogen stimulus [17] negative regulation of lymphocyte proliferation Sources: Amigo
[18] [9]

/ QuickGO

[19]

RNA expression pattern

More reference expression data Orthologs Species Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Human 51083
[21] [23]

[20]

Mouse 14419
[22] [24]

ENSG00000069482 P22466
[25] [27]

ENSMUSG00000024907 P47212
[26] [28]

NM_015973 NP_057057

NM_010253 NP_034383

[29]

[30]

Galanin

303
Location (UCSC) Chr 11: [31] 68.45 68.46 Mb PubMed search
[33]

Chr 19: [32] 3.41 3.41 Mb

[34]

Galanin
Clinical data Pregnancy cat. ? Legal status ? Identifiers CAS number ATC code ChEMBL 88813-36-9 ? CHEMBL501079 Chemical data Formula Mol. mass C146H213N43O40 3210.56 g/mol [37] [36] [35]

(what is this?) (verify)

Galanin is a neuropeptide encoded by the GAL gene,[] that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors.[] The functional role of galanin remains largely unknown; however, galanin is predominately involved in the modulation and inhibition of action potentials in neurons. Galanin has been implicated in many biologically diverse functions, including: nociception, waking and sleep regulation, cognition, feeding, regulation of mood, regulation of blood pressure, it also has roles in development as well as acting as a trophic factor.[] Galanin is linked to a number of diseases including Alzheimer's disease, epilepsy as well as depression, eating disorders and cancer.[][] Galanin appears to have neuroprotective activity as its biosynthesis is increased 2-10 fold upon axotomy in the peripheral nervous system as well as when seizure activity occurs in the brain. It may also promote neurogenesis.[] Galanin is predominantly an inhibitory, hyperpolarizing neuropeptide[] and as such inhibits neurotransmitter release. Galanin is often co-localized with classical neurotransmitters such as acetylcholine, serotonin, and norepinephrine, and also with other neuromodulators such as neuropeptide Y, substance P, and vasoactive intestinal peptide.[]

Discovery
Galanin was first identified from porcine intestinal extracts in 1978 by Professor Viktor Mutt and colleagues at the Karolinska Institute, Sweden[] using a chemical assay technique that detects peptides according to its C-terminal alanine amide structure. Galanin is so-called because it contains an N-terminal glycine residue and a C-terminal alanine.[] The structure of galanin was determined in 1983 by the same team, and its cDNA of galanin was cloned from rat anterior pituitary library in 1987.[]

Galanin

304

Tissue distribution
Galanin is located predominantly in the central nervous system and gastrointestinal tract. Within the central nervous system, highest concentrations are found in the hypothalamus, with lower levels in the cortex and brainstem. Gastrointestinal galanin is most abundant in the duodenum, with lower concentrations in the stomach, small intestine, and colon.[]

Structure
Endogenously occurring galanin sequences
Species Pig 1 6 11 16 21 26 !

GWTLN SAGYL LGPHA IDNHR

SFHDK YGLA*

Human G W T L N S A G Y L L G P H A V G N H R S F S D K N G L T S ** Cow Rat GWTLN SAGYL LGPHA LDSHR GWTLN SAGYL LGPHA IDNHR SFQDK HGLA* S F S D K H G L T*

* C-terminal amide ** C-terminal free acid

Galanin is a peptide consisting of a chain of 29 amino acids (30 amino acids in humans) produced from the cleavage of a 123-amino acid protein known as preprogalanin, which is encoded by the GAL gene.[] The sequence of this gene is highly conserved among mammals, showing over 85% homology between rat, mouse, porcine, bovine, and human sequences.[] In these animal forms, the first 15 amino acids from the N-terminus are identical, but amino acids differ at several positions on the C-terminal end of the protein. These slight differences in protein structure have far-reaching implications on their function. For example, porcine and rat galanin inhibit glucose-induced insulin secretion in rats and dogs but have no effect on insulin secretion in humans. This demonstrates that it is essential to study the effects of galanin, and other regulatory peptides, in their autologous species.[] The galanin family of protein consists of four proteins, of which GAL was the first to be identified. The second was galanin message-associated protein (GMAP), a 59- or 60-amino acid peptide also formed from the cleavage of preprogalanin.[] The other two peptides, galanin-like peptide (GALP) and alarin, were identified relatively recently and are both encoded for in the same gene, the preproGALP gene. GALP and alarin are produced by different post-translational splicing of this gene.[]

Galanin
Identifiers Symbol Pfam InterPro PROSITE Galanin PF01296 [38] [39] [40]

IPR008174

PDOC00673

Galanin

305

Available protein structures: Pfam PDB structures [41] [42] ; PDBe [43]

RCSB PDB

PDBsum structure summary [44]

Galanin message associated peptide (GMAP)

Identifiers Symbol Pfam InterPro GMAP PF06540 [45] [46]

IPR013068

Available protein structures: Pfam PDB structures [47] [48] ; PDBe [49]

RCSB PDB

PDBsum structure summary [50]

Receptors
Galanin signalling occurs through three classes of receptors, GALR1, GALR2, and GALR3, which are all part of the G protein-coupled receptor (GPCR) superfamily. Galanin receptors are expressed in the central nervous system, in the pancreas, and on solid tumours. The level of expression of the different receptors varies at each location, and this distribution changes after injury to neurons.[] Experiments into the function of the receptor subtypes involve mostly genetic knockout mice. The location of the receptor and the combination of receptors that are inhibited or stimulated heavily affect the outcome of galanin signalling.[]

Clinical characteristics
Alzheimer's disease
One of the pathological features of the brain in the later stages of Alzheimer's disease is the presence of overgrown GAL-containing fibres innervating the surviving cholinergic neurons.[] Another feature is an increase in the expression of GAL and GAL receptors, in which increases of up to 200% have been observed in post-mortem brains of Alzheimer's patients.[][] The cause and role of this increase is poorly understood.[][] It has been suggested that the hyper-innervation acts to promote the death of these neurons and that the inhibitory effect of galanin on cholinergic neurons worsened the degeneration of cognitive function in patients by decreasing the amount of acetylcholine available to these neurons.[][] A second hypothesis has been generated based on data that suggest GAL is involved in protecting the hippocampus from excitotoxic damage and the neurons in the cholinergic basal forebrain from amyloid toxicity.[] It is interesting to note that studies of gene expression of CBF tissue suggests that the hyperinnervation of cholinergic neurons by GAL up regulates the transcription of factors that promote neuron function and survival. It is still unclear as to

Galanin whether galanin acts to protect cholinergic neurons and promote their firing or whether it worsens the symptoms of this disease.

306

Epilepsy
Galanin in the hippocampus is an inhibitor of glutamate but not of GABA. This means that galanin is capable of increasing the seizure threshold [] and, therefore, is expected to act as an anticonvulsant. To be specific, GalR1 has been linked to the suppression of spontaneous seizures.[][] Agonist antiepileptic drug candidate NAX 5055.[][]

In development
It has been shown that galanin plays a role in the control of the early post-natal neural development of the dorsal root ganglion (DRG).[] Galanin-mutant animals show a 13% decrease in the number of adult DRG cells as well as a 24% decrease in the percentage of cells expressing substance P. This suggests that the cell loss by apoptosis that usually occurs in the developing DRG is regulated by galanin and that the absence of galanin results in an increase in the number of cells that die.

After injury
In vitro experiments show that DRG cells removed from galanin mutants have impaired abilities to extend neurites in culture, in that the number of cells producing neurites is decreased by a third and the mean length of these processes was halved when compared to wild-type controls. In vivo, many of the actions of galanin in the brain after an injury are similar to those observed in the developing DRG. Adult mutant animals have been shown to be 35% less capable of regenerating the sciatic nerve after crush injury, which is linked to long-term functional problems.

References
[1] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=4114 [2] http:/ / omim. org/ entry/ 137035 [3] http:/ / www. informatics. jax. org/ searches/ accession_report. cgi?id=MGI:95637 [4] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=7724 [5] http:/ / www. genecards. org/ cgi-bin/ carddisp. pl?id_type=entrezgene& id=51083 [6] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005575 [7] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005794 [8] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030141 [9] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006939 [10] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006954 [11] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007399 [12] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030073 [13] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030252 [14] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0031943 [15] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032868 [16] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043627 [17] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0050672 [18] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ gp-assoc. cgi?gp=UniProtKB:P22466 [19] http:/ / www. ebi. ac. uk/ QuickGO/ GProtein?ac=P22466 [20] http:/ / biogps. org/ gene/ 51083/ [21] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=51083& rn=1 [22] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=14419& rn=1 [23] http:/ / www. ensembl. org/ Homo_sapiens/ geneview?gene=ENSG00000069482;db=core [24] http:/ / www. ensembl. org/ Mus_musculus/ geneview?gene=ENSMUSG00000024907;db=core [25] http:/ / www. uniprot. org/ uniprot/ P22466 [26] http:/ / www. uniprot. org/ uniprot/ P47212 [27] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_015973 [28] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_010253 [29] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_057057

Galanin
[30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_034383 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Human& db=hg19& position=chr11:68451247-68458643 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Mouse& db=mm9& position=chr19:3409919-3414472 http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=51083 http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=14419 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=88813-36-9& rn=1 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL501079 http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=403760667& page2=Galanin http:/ / pfam. sanger. ac. uk/ family?acc=PF01296 http:/ / www. ebi. ac. uk/ interpro/ entry/ IPR008174 http:/ / www. expasy. org/ cgi-bin/ prosite-search-ac?PDOC00673 http:/ / pfam. sanger. ac. uk/ family/ PF01296?tab=pdbBlock http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=PfamIdQuery& pfamID=PF01296 http:/ / www. ebi. ac. uk/ pdbe-srv/ PDBeXplore/ pfam/ ?pfam=PF01296 http:/ / www. ebi. ac. uk/ thornton-srv/ databases/ cgi-bin/ pdbsum/ GetPfamStr. pl?pfam_id=PF01296 http:/ / pfam. sanger. ac. uk/ family?acc=PF06540 http:/ / www. ebi. ac. uk/ interpro/ entry/ IPR013068 http:/ / pfam. sanger. ac. uk/ family/ PF06540?tab=pdbBlock http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=PfamIdQuery& pfamID=PF06540 http:/ / www. ebi. ac. uk/ pdbe-srv/ PDBeXplore/ pfam/ ?pfam=PF06540 http:/ / www. ebi. ac. uk/ thornton-srv/ databases/ cgi-bin/ pdbsum/ GetPfamStr. pl?pfam_id=PF06540

307

Further reading
Vrontakis ME (2003). "Galanin: a biologically active peptide.". Current drug targets. CNS and neurological disorders 1 (6): 53141. doi: 10.2174/1568007023338914 (http://dx.doi.org/10.2174/1568007023338914). PMID 12769595 (http://www.ncbi.nlm.nih.gov/pubmed/12769595). Mufson EJ, Counts SE, Perez SE, Binder L (2005). "Galanin plasticity in the cholinergic basal forebrain in Alzheimer's disease and transgenic mice.". Neuropeptides 39 (3): 2337. doi: 10.1016/j.npep.2004.12.005 (http:// dx.doi.org/10.1016/j.npep.2004.12.005). PMID 15893372 (http://www.ncbi.nlm.nih.gov/pubmed/ 15893372). Robinson JK, Bartfai T, Langel U (2006). "Galanin/GALP receptors and CNS homeostatic processes.". CNS & neurological disorders drug targets 5 (3): 32734. doi: 10.2174/187152706777452281 (http://dx.doi.org/10. 2174/187152706777452281). PMID 16787232 (http://www.ncbi.nlm.nih.gov/pubmed/16787232). McKnight GL, Karlsen AE, Kowalyk S, et al. (1992). "Sequence of human galanin and its inhibition of glucose-stimulated insulin secretion from RIN cells.". Diabetes 41 (1): 827. doi: 10.2337/diabetes.41.1.82 (http:/ /dx.doi.org/10.2337/diabetes.41.1.82). PMID 1370155 (http://www.ncbi.nlm.nih.gov/pubmed/ 1370155). Gai WP, Geffen LB, Blessing WW (1990). "Galanin immunoreactive neurons in the human hypothalamus: colocalization with vasopressin-containing neurons.". J. Comp. Neurol. 298 (3): 26580. doi: 10.1002/cne.902980302 (http://dx.doi.org/10.1002/cne.902980302). PMID 1698834 (http://www.ncbi. nlm.nih.gov/pubmed/1698834). Burleigh DE, Furness JB (1991). "Distribution and actions of galanin and vasoactive intestinal peptide in the human colon.". Neuropeptides 16 (2): 7782. doi: 10.1016/0143-4179(90)90115-F (http://dx.doi.org/10.1016/ 0143-4179(90)90115-F). PMID 1701228 (http://www.ncbi.nlm.nih.gov/pubmed/1701228). Fried G, Meister B, Rdestad A (1991). "Peptide-containing nerves in the human pregnant uterine cervix: an immunohistochemical study exploring the effect of RU 486 (mifepristone).". Hum. Reprod. 5 (7): 8706. PMID 1702449 (http://www.ncbi.nlm.nih.gov/pubmed/1702449). Hyde JF, Engle MG, Maley BE (1991). "Colocalization of galanin and prolactin within secretory granules of anterior pituitary cells in estrogen-treated Fischer 344 rats.". Endocrinology 129 (1): 2706. doi: 10.1210/endo-129-1-270 (http://dx.doi.org/10.1210/endo-129-1-270). PMID 1711463 (http://www.ncbi. nlm.nih.gov/pubmed/1711463).

Galanin Bennet WM, Hill SF, Ghatei MA, Bloom SR (1991). "Galanin in the normal human pituitary and brain and in pituitary adenomas.". J. Endocrinol. 130 (3): 4637. doi: 10.1677/joe.0.1300463 (http://dx.doi.org/10.1677/ joe.0.1300463). PMID 1719117 (http://www.ncbi.nlm.nih.gov/pubmed/1719117). Schmidt WE, Kratzin H, Eckart K, et al. (1992). "Isolation and primary structure of pituitary human galanin, a 30-residue nonamidated neuropeptide." (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC53150). Proc. Natl. Acad. Sci. U.S.A. 88 (24): 114359. doi: 10.1073/pnas.88.24.11435 (http://dx.doi.org/10.1073/pnas.88.24. 11435). PMC 53150 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC53150). PMID 1722333 (http:// www.ncbi.nlm.nih.gov/pubmed/1722333). Bauer FE, Christofides ND, Hacker GW, et al. (1986). "Distribution of galanin immunoreactivity in the genitourinary tract of man and rat.". Peptides 7 (1): 510. doi: 10.1016/0196-9781(86)90052-5 (http://dx.doi. org/10.1016/0196-9781(86)90052-5). PMID 2423990 (http://www.ncbi.nlm.nih.gov/pubmed/2423990). Bauer FE, Adrian TE, Christofides ND, et al. (1986). "Distribution and molecular heterogeneity of galanin in human, pig, guinea pig, and rat gastrointestinal tracts.". Gastroenterology 91 (4): 87783. PMID 2427385 (http:/ /www.ncbi.nlm.nih.gov/pubmed/2427385). Tainio H, Vaalasti A, Rechardt L (1987). "The distribution of substance P-, CGRP-, galanin- and ANP-like immunoreactive nerves in human sweat glands.". Histochem. J. 19 (6-7): 37580. doi: 10.1007/BF01680455 (http://dx.doi.org/10.1007/BF01680455). PMID 2444569 (http://www.ncbi.nlm.nih.gov/pubmed/ 2444569). Maggi CA, Santicioli P, Patacchini R, et al. (1988). "Galanin: a potent modulator of excitatory neurotransmission in the human urinary bladder.". Eur. J. Pharmacol. 143 (1): 1357. doi: 10.1016/0014-2999(87)90744-8 (http:// dx.doi.org/10.1016/0014-2999(87)90744-8). PMID 2446889 (http://www.ncbi.nlm.nih.gov/pubmed/ 2446889). Marti E, Gibson SJ, Polak JM, et al. (1988). "Ontogeny of peptide- and amine-containing neurones in motor, sensory, and autonomic regions of rat and human spinal cord, dorsal root ganglia, and rat skin.". J. Comp. Neurol. 266 (3): 33259. doi: 10.1002/cne.902660304 (http://dx.doi.org/10.1002/cne.902660304). PMID 2447134 (http://www.ncbi.nlm.nih.gov/pubmed/2447134). Beal MF, Clevens RA, Chattha GK, et al. (1988). "Galanin-like immunoreactivity is unchanged in Alzheimer's disease and Parkinson's disease dementia cerebral cortex.". J. Neurochem. 51 (6): 193541. doi: 10.1111/j.1471-4159.1988.tb01181.x (http://dx.doi.org/10.1111/j.1471-4159.1988.tb01181.x). PMID 2460590 (http://www.ncbi.nlm.nih.gov/pubmed/2460590). Berrettini WH, Kaye WH, Sunderland T, et al. (1989). "Galanin immunoreactivity in human CSF: studies in eating disorders and Alzheimer's disease.". Neuropsychobiology 19 (2): 648. doi: 10.1159/000118436 (http:// dx.doi.org/10.1159/000118436). PMID 2465504 (http://www.ncbi.nlm.nih.gov/pubmed/2465504).

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External links
Galanin (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Galanin) at the US National Library of Medicine Medical Subject Headings (MeSH)

Enkephalin

309

Enkephalin

Met-enkephalin 3D structure, alpha-carbons shown as balls and labeled by residue. Identifiers Symbol Entrez HUGO OMIM RefSeq UniProt PENK 5179 8831 [2] [3] [4] [5]

[1]

131330

NM_006211 P01210 Other data [6]

Locus

Chr. 8 q23-q24

[7]

An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin were revealed, one containing leucine ("leu"), and the other containing methionine ("met"). Both are products of the proenkephalin gene.[] Met-enkephalin is Tyr-Gly-Gly-Phe-Met. Leu-enkephalin has Tyr-Gly-Gly-Phe-Leu.

Endogenous opioid peptides

There are three well-characterized families of opioid peptides produced by the body: enkephalins, endorphins, and dynorphins. The met-enkephalin peptide sequence is coded for by the enkephalin gene; the leu-enkephalin peptide sequence is coded for by both the enkephalin gene and the dynorphin gene.[8] The proopiomelanocortin gene (POMC) also contains the met-enkephalin sequence on the N-terminus of beta-endorphin, but the endorphin peptide is not processed into enkephalin.

Enkephalin

310

Enkephalin receptor
The receptors for enkephalin are the delta opioid receptors. Opioid receptors are a group of G-protein-coupled receptors, with other opioids as ligands as well. The other endogenous opioids are dynorphins (that bind to kappa receptors), endorphins (mu receptors), endomorphins, and nociceptin/orphanin FQ. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs).

References
[1] [2] [3] [4] [5] [6] [7] [8] ; http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& amp;cmd=retrieve& amp;dopt=default& amp;list_uids=5179& rn=1 http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=8831 http:/ / www. omim. org/ 131330 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?Submit=Submit& position=NM_006211& rn=1 http:/ / www. uniprot. org/ uniprot/ P01210 http:/ / omim. org/ search?index=geneMap& search=8q23 Opioid peptides: Molecular pharmacology, biosynthesis and analysis (http:/ / drugabuse. gov/ pdf/ monographs/ 70. pdf), R.S. Rapaka and R. L. Hawks (editors) in a National Institute on Drug Abuse Research Monograph (#70), 1986.

External links
Enkephalins (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Enkephalins) at the US National Library of Medicine Medical Subject Headings (MeSH) Physiology at MCG 6/6ch2/s6ch2_36 (http://web.archive.org/web/20080401093403/http://www.lib.mcg. edu/edu/eshuphysio/program/section6/6ch2/s6ch2_36.htm)

Serotonin

311

Serotonin
Serotonin

Identifiers CAS number PubChem ChemSpider UNII KEGG MeSH ChEBI ChEMBL IUPHAR ligand Jmol-3D images 50-67-9 5202 5013
[2] [3] [4] [1]

333DO1RDJY C00780
[5]

Serotonin

[6] [7]

CHEBI:28790 CHEMBL39 5
[9] [10]

[8]

Image 1

Properties Molecular formula C H N O

10 12 2

Molar mass Appearance

176.215 g/mol White powder

Serotonin
[11] [12]

312
Melting point Boiling point

121122C (ligroin)

416 30.0C (at 760 Torr)

Solubility in water slightly soluble Dipole moment 2.98 D Hazards MSDS LD50 External MSDS
[13] [] []

750 mg/kg (subcutaneous, rat), 4500 mg/kg (intraperitoneal, rat), 60 mg/kg (oral, rat)
(verify) [14]

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Serotonin /srtonn/ or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS) of animals and humans. It is popularly thought to be a contributor to feelings of well-being and happiness.[15] Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the alimentary canal (gut), where it is used to regulate intestinal movements.[][] The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants. Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing. Serotonin is mainly metabolized to 5-HIAA, chiefly by the liver. Metabolism involves first oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the indole acetic acid derivative. The latter is then excreted by the kidneys. One type of tumor, called carcinoid, sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome of flushing, diarrhea, and heart problems. Because of serotonin's growth-promoting effect on cardiac myocytes, persons with serotonin-secreting carcinoid may suffer a right heart (tricuspid) valve disease syndrome, caused by proliferation of myocytes onto the valve. In addition to animals, serotonin is found in fungi and plants.[] Serotonin's presence in insect venoms and plant spines serves to cause pain, which is a side effect of serotonin injection. Serotonin is produced by pathogenic amoebae, and its effect on the gut causes diarrhea. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds.

Functions
Serotonin is a neurotransmitter and is found in all bilateral animals [citation needed], where it mediates gut movements and the animals' perceptions of resource availability. In the simplest animals, resources are equivalent with food, but in advanced animals, such as arthropods and vertebrates, resources also can mean social dominance. In response to the perceived abundance or scarcity of resources, an animal's growth, reproduction or mood may be elevated or lowered[citation needed].

Serotonin

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Gauge of food availability (appetite)

Serotonin functions as a neurotransmitter in the nervous systems of simple, as well as complex, animals. For example, in the roundworm Caenorhabditis elegans, which feeds on bacteria, serotonin is released as a signal in response to positive events, e.g., finding a new source of food or in male animals finding a female with which to mate[citation needed]. When a well-fed worm feels bacteria on its cuticle, dopamine is released, which slows it down; if it is starved, serotonin also is released, which slows the animal down further. This mechanism increases the amount of time animals spend in the presence of food.[] The released serotonin activates the muscles used for feeding, while octopamine suppresses them.[] Serotonin diffuses to serotonin-sensitive neurons, which control the animal's perception of nutrient availability. When humans smell food, dopamine is released to increase the appetite. But unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs which block 5-HT2C receptors make the body unable to shut off appetite, and are associated with increased weight gain,[] especially in people who have a low number of receptors.[] The expression of 5-HT2C receptors in the hippocampus follows a diurnal rhythm,[] just as the serotonin release in the ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest.[] Effects of food content In humans, serotonin levels are affected by diet. An increase in the ratio of tryptophan to phenylalanine and leucine will increase serotonin levels. Fruits with a good ratio include dates, papayas and bananas. Research also suggests eating a diet rich in carbohydrates and low in protein will increase serotonin by secreting insulin, which helps in amino acid competition.[] However, increasing insulin for a long period may trigger the onset of insulin resistance, obesity, type 2 diabetes, and lower serotonin levels.[16][17] Muscles use many of the amino acids except tryptophan, allowing more muscular individuals to produce more serotonin.[] In the digestive tract (emetic) The gut is surrounded by enterochromaffin cells, which release serotonin in response to food in the lumen. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin. If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting.[18] The enterochromaffin cells not only react to bad food, but they are also very sensitive to irradiation and cancer chemotherapy. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose.[19] Gauge of social situation How much food an animal gets not only depends on the abundance of food, but also on the animal's ability to compete with others. This is especially true for social animals, where the stronger individuals might steal food from the weaker. Thus, serotonin is not only involved in the perception of food availability, but also of social rank. If a lobster is injected with serotonin, it behaves like a dominant animal, while octopamine causes subordinate behavior.[] A frightened crayfish flips its tail to flee, and the effect of serotonin on this behavior depends on the animal's social status. Serotonin inhibits the fleeing reaction in subordinates, but enhances it in socially dominant or isolated individuals. The reason for this is social experience alters the proportion between serotonin receptors (5-HT receptors) that have opposing effects on the fight-or-flight response.Wikipedia:Please clarify The effect of 5-HT1 receptors predominates in subordinate animals, while 5-HT2 receptors predominates in dominants.[] In humans, levels of 5-HT1A receptor activation in the brain show negative correlation with aggression,[20] and a mutation in the gene that codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype.[] Most of the

Serotonin brain serotonin is not degraded after use, but is collected by serotonergic neurons by serotonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy.[]

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Growth and reproduction

In the nematode C. elegans, artificial depletion of serotonin or the increase of octopamine cues behavior typical of a low-food environment: C. elegans becomes more active, and mating and egg-laying are suppressed, while the opposite occurs if serotonin is increased or octopamine is decreased in this animal.[] Serotonin is necessary for normal nematode male mating behavior,[] and the inclination to leave food to search for a mate.[] The serotonergic signaling used to adapt the worm's behaviour to fast changes in the environment affects insulin-like signaling and the TGF beta signaling pathway,[21] which control long-term adaption.

Aging and age-related phenotypes

Serotonin is known to regulate aging, learning and memory. The first evidence comes from the study of longevity in C. elegans.[22] During early phase of aging, the level of serotonin increases, which alters locomotory behaviors and associative memory.[23] The effect is restored by mutations and drugs (including mianserin and methiothepin) that inhibit serotonin receptors. The observation does not contradict with the notion that the serotonin level goes down in mammals and humans, which is typically seen in late but not early phase of aging.

Bone metabolism
In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass.[][][][] Mice that lack brain serotonin have osteopenia, while mice that lack gut serotonin have high bone density. In humans, increased blood serotonin levels have been shown to be significant negative predictor of low bone density. Serotonin can also be synthesized, albeit at very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. Through Htr1b receptors, it negatively regulates bone mass, while it does so positively through Htr2b and Htr2c. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts culminating in FoxO1/ Creb and ATF4 dependent transcriptional events.[] These studies have opened a new area of research in bone metabolism that can be potentially harnessed to treat bone mass disorders.[]

Behavior
In the fruitfly, where insulin both regulates blood sugar and acts as a growth factor, serotonergic neurons regulate the adult body size by affecting insulin secretion.[][] Serotonin has also been identified as the trigger for swarm behavior in locusts.[] In humans, though insulin regulates blood sugar and IGF regulates growth, serotonin controls the release of both hormones, so serotonin suppresses insulin release from the beta cells in the pancreas,[] and exposure to SSRIs reduces fetal growth.[] Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors.[] Serotonin present in the blood then stimulates cellular growth to repair liver damage.[] 5HT2B receptors also activate osteocytes, which build up bone[] However, serotonin also inhibits osteoblasts, through 5-HT1B receptors.[]

Cardiovascular growth factor

Serotonin, in addition, evokes endothelial nitric oxide synthase activation and stimulates, through a 5-HT1B receptor-mediated mechanism, the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.[] In blood, serotonin is collected from plasma by platelets, which store it. It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic (growth factor), to aid healing.[]

Serotonin Some serotonergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as cardiac valve fibrosis.[] In the past, three groups of serotonergic drugs have been epidemiologically linked with these syndromes. They are the serotonergic vasoconstrictive antimigraine drugs (ergotamine and methysergide),[] the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-Parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific lisuride.[] As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was declining in use since reported in 2003 to be associated with cardiac fibrosis.[24] Two independent studies published in the New England Journal of Medicine in January 2007, implicated pergolide, along with cabergoline, in causing valvular heart disease.[][] As a result of this, the FDA removed pergolide from the U.S. market in March, 2007.[25] (Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease).[] Local effects of injection: venoms and pain Since serotonin is an indicator of bleeding, a sudden large increase in peripheral levels causes pain. The reason wasps and deathstalker scorpions have serotonin in their venom [][] may be to increase the pain of their stings on large animals, and also to cause lethal vasoconstriction in smaller prey.

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Deficiency
Genetically altered C.elegans worms that lack serotonin have an increased reproductive lifespan, may become obese, and sometimes present with arrested development at a dormant larval state.[][] Serotonin in mammals is made by two different tryptophan hydroxylases: TPH1 produces serotonin in the pineal gland[citation needed] and the enterochromaffin cells, while TPH2 produces it in the raphe nuclei and in the myenteric plexus. Genetically altered mice lacking TPH1 develop progressive loss of heart strength early on. They have pale skin and breathing difficulties, are easily tired, and eventually die of heart failure.[] Genetically altered mice that lack TPH2 are normal when they are born. However, after three days, they appear to be smaller and weaker, and have softer skin than their siblings. In a purebred strain, 50% of the mutants died during the first four weeks, but in a mixed strain, 90% survived. Normally, the mother weans the litter after three weeks, but the mutant animals needed five weeks. After that, they caught up in growth and had normal mortality rates. Subtle changes in the autonomic nervous system are present, but the most obvious difference from normal mice is the increased aggressiveness and impairment in maternal care of young.[] Despite the bloodbrain barrier, the loss of serotonin production in the brain is partially compensated by intestinal serotonin. The behavioural changes become greatly enhanced if one crosses TPH1- with TPH2-lacking mice and gets animals that lack TPH entirely.[] In humans, defective signaling of serotonin in the brain may be the root cause of sudden infant death syndrome (SIDS). Scientists from the European Molecular Biology Laboratory in Monterotondo, Italy[26] genetically modified lab mice to produce low levels of the neurotransmitter serotonin. The results showed the mice suffered drops in heart rate and other symptoms of SIDS, and many of the animals died at an early age. Researchers now believe low levels of serotonin in the animals' brainstems, which control heartbeat and breathing, may have caused sudden death, they said in the July 4, 2008 issue of Science.[] If neurons that make serotonin serotonergic neurons are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).[] Recent research conducted at Rockefeller University shows, in both patients who suffer from depression and mice that model the disorder, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain.[]

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In the brain
Gross anatomy
The neurons of the raphe nuclei are the principal source of 5-HT release in the brain.[27] There are 7 or 8 raphe nuclei (some scientists chose to group the nuclei raphes lineares into one nucleus), all of which are located along the midline of the brainstem, and centered around the reticular formation.[28] Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord, while the axons of the higher nuclei spread out in the entire brain.

Serotonin system, contrasted with the dopamine system

Microanatomy
Serotonin is released into the space between neurons, and diffuses over a relatively wide gap (>20m) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons. Receptors The 5-HT receptors, the receptors for serotonin, are located on the cell membrane of nerve cells and other cell types in animals, and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. With the exception of the 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G protein-coupled, seven transmembrane (or heptahelical) receptors that activate an intracellular second messenger cascade.[] Termination Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). Interestingly, a 2006 study conducted by the University of Washington suggested a newly discovered monoamine transporter, known as PMAT, may account for "a significant percentage of 5-HT clearance".[] Contrasting with the high-affinity SERT, the PMAT has been identified as a low-affinity transporter, with an apparent Km of 114 micromoles/l for serotonin; approximately 230 times higher than that of SERT. However, the PMAT, despite its relatively low serotonergic affinity, has a considerably higher transport 'capacity' than SERT, "..resulting in roughly comparable uptake efficiencies to SERT in heterologous expression systems." The study also suggests some SSRIs, such as fluoxetine and sertraline, inhibit PMAT but at IC50 values which surpass the therapeutic plasma concentrations by up to four orders of magnitude; therefore, SSRI monotherapy is "ineffective" in PMAT inhibition. At present, no known pharmaceuticals are known to appreciably inhibit PMAT at normal therapeutic doses. The PMAT also suggestively transports dopamine and norepinephrine, albeit at Km values even higher than that of 5-HT (33015,000 moles/L).

Serotonin Serotonylation Serotonin can also signal through a nonreceptor mechanism called serotonylation, in which serotonin modifies proteins.[] This process underlies serotonin effects upon platelet-forming cells (thrombocytes) in which it links to the modification of signaling enzymes called GTPases that then trigger the release of vesicle contents by exocytosis.[] A similar process underlies the pancreatic release of insulin.[] The effects of serotonin upon vascular smooth muscle tone (this is the biological function from which serotonin originally got its name) depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.[]

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Biosynthesis
In animals including humans, serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan hydroxylase (TPH) and amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a neuron-specific isoform.[] Serotonin can be synthesized from tryptophan in the lab using Aspergillus niger and Psilocybe coprophila as catalysts. The first phase to 5-hydroxytryptophan would require letting tryptophan sit in ethanol and water for 7 days, then mixing in enough HCl (or other acid) to bring the pH to 3, and then adding NaOH to make a pH of 13 for 1 hour. Asperigillus niger would be the catalyst for this first phase. The second phase to synthesizing tryptophan itself from the 5-hydroxytryptophan intermediate would require adding ethanol and water, and letting sit for 30 days this time. The next two steps would be the same as the first phase: adding HCl to make the pH = 3, and then adding NaOH to make the pH very basic at 13 for 1 hour. This phase uses the Psilocybe coprophila as the catalyst for the reaction.[29] Serotonin taken orally does not pass into the serotonergic The pathway for the synthesis of serotonin from pathways of the central nervous system, because it does not tryptophan. cross the bloodbrain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and do cross the bloodbrain barrier. These agents are available as dietary supplements, and may be effective serotonergic agents. One product of serotonin breakdown is 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in the urine. Serotonin and 5-HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors.

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Drugs targeting the 5-HT system

Several classes of drugs target the 5-HT system, including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs, as well as the psychedelic drugs and empathogens.

Psychedelic drugs
The psychedelic drugs psilocin/psilocybin, DMT, mescaline, and LSD are agonists, primarily at 5HT2A/2C receptors.[][] The empathogen-entactogen MDMA releases serotonin from synaptic vesicles of neurons.[]

Antidepressants
Drugs which alter serotonin levels are used in depression, generalized anxiety disorder and social phobia. Monoamine oxidase inhibitors (MAOIs) prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content, and certain drugs. Some drugs inhibit the reuptake of serotonin, making it stay in the synaptic cleft longer. The tricyclic antidepressants (TCAs) inhibit the reuptake of both serotonin and norepinephrine. The newer selective serotonin reuptake inhibitors (SSRIs) have fewer side effects and fewer interactions with other drugs. The side effects that have become apparent recently include a decrease in bone mass in elderly and increased risk for osteoporosis. However, it is not yet clear whether it is due to SSRI action on peripheral serotonin production and or action in the gut or in the brain.[] Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases. This has been connected to the observation that the benefit of SSRIs may decrease in selected patients after a long-term treatment. A switch in medication will usually resolve this issue (up to 70% of the time).[] The novel antidepressant tianeptine, a selective serotonin reuptake "enhancer", has mood-elevating effects. This provides evidence for the theory that serotonin is most likely used to regulate the extent or intensity of moods, rather than level directly correlating with mood. In fact, the 5-HTTLPR gene codes for the number of serotonin transporters in the brain, with more serotonin transporters causing decreased duration and magnitude of serotonergic signaling.[30] The 5-HTTLPR polymorphism (l/l) causing more serotonin transporters to be formed is also found to be more resilient against depression and anxiety.[31][32] Therefore, increasing levels of extracellular serotonin may be associated with increased affect, for good or for worse. Although phobias and depression might be attenuated by serotonin-altering drugs, this does not mean the individual's situation has been improved, but only the individual's perception of the environment. Sometimes, a lower serotonin level might be beneficial, for example in the ultimatum game, where players with normal serotonin levels are more prone to accept unfair offers than participants whose serotonin levels have been artificially lowered.[] Serotonin syndrome Extremely high levels of serotonin can cause a condition known as serotonin syndrome, with toxic and potentially fatal effects. In practice, such toxic levels are essentially impossible to reach through an overdose of a single antidepressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI.[33] The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at nontoxic levels.[]

Antiemetics
Some 5-HT3 antagonists, such as ondansetron, granisetron, and tropisetron, are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in the treatment of postoperative nausea and vomiting.

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In unicellular organisms
Serotonin is used by a variety of single-cell organisms for various purposes. SSRIs have been found to be toxic to algae.[] The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients.[][] Patients infected with E. histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.[] E. histolytica also responds to the presence of serotonin by becoming more virulent.[] This means serotonin secretion not only serves to increase the spread of enteamoebas by giving the host diarrhea, but also to coordinate their behaviour according to their population density, a phenomenon known as quorum sensing. Outside a host, the density of entoamoebas is low, hence also the serotonin concentration. Low serotonin signals to the entoamoebas they are outside a host and they become less virulent to conserve energy. When they enter a new host, they multiply in the gut, and become more virulent as the serotonin concentration increases.

In plants
In drying seeds, serotonin production is a way to get rid of the buildup of poisonous ammonia. The ammonia is collected and placed in the indole part of L-tryptophan, which is then decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by a cytochrome P450 monooxygenase, yielding serotonin.[] However, since serotonin is a major gastrointestinal tract modulator, it may be produced by plants in fruits as a way of speeding the passage of seeds through the digestive tract, in the same way as many well-known seed and fruit associated laxatives. Serotonin is found in mushrooms, fruits and vegetables. The highest values of 25400mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genera. Serotonin concentrations of 330mg/kg have been found in plantains, pineapples, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.13mg/kg have been found in a wide range of tested vegetables.[34] Serotonin is one compound of the poison contained in stinging nettles (Urtica dioica), where it causes pain on injection in the same manner as its presence in insect venoms (see above). It is also naturally found in Paramuricea clavata, or the Red Sea Fan.[35] Serotonin and tryptophan have been found in chocolate with varying cocoa contents. The highest serotonin content (2.93ug g-1) was found in chocolate with 85% cocoa, and the highest tryptophan content (13.27-13.34ug g-1) was found in 70-85% cocoa. The intermediate in the synthesis from tryptophan to serotonin, 5-hydroxytryptophan, was not found.[36] Unlike its precursors, 5-HTP and tryptophan, serotonin does not cross the bloodbrain barrier, which means ingesting serotonin in the diet has no effect on brain serotonin levels.

Methyl-tryptamines and hallucinogens

Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH2) and (OH) groups, are N-oxides, or miss the OH group. These compounds do reach the brain, although some portion of them are metabolized by MAO-B enzymes in the liver. Examples are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff. These compounds are widely present in the leaves of many plants, and may serve as deterrents for animal ingestion. Serotonin occurs in several mushrooms of the genus Panaeolus.[37] Serotonin is also naturally occurring in toad venom.[38]

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History
In 1935, Italian Vittorio Erspamer showed an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline, but two years later, Erspamer was able to show it was a previously unknown amine, which he named "enteramine".[] In 1948, Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone, they named it serotonin.[] In 1952, enteramine was shown to be the same substance as serotonin, and as the broad range of physiological roles was elucidated, the abbreviation 5-HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field.[] Synonyms of serotonin include: 5-hydroxytriptamine, thrombotin, enteramin, substance DS, and 3-(-Aminoethyl)-5-hydroxyindole.[39]

References
[1] [2] [3] [4] [5] [6] [7] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=50-67-9 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5202 http:/ / www. chemspider. com/ 5013 http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=333DO1RDJY http:/ / www. kegg. jp/ entry/ C00780 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Serotonin https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=28790

[8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL39 [9] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=5 [10] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=c1cc2c%28cc1O%29c%28c%5BnH%5D2%29CCN [11] Pietra, S.;Farmaco, Edizione Scientifica 1958, Vol. 13, pp. 759. [12] Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (19942011 ACD/Labs) [13] http:/ / www. chemcas. com/ msds/ cas/ msds70/ 50-67-9. asp [14] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477173047& page2=Serotonin [21] Murakami H, Bessinger K, Hellmann J, Murakami S. Aging-dependent and -independent modulation of associative learning behavior by insulin/insulin-like growth factor-1 signal in Caenorhabditis elegans. J Neurosci. 2005 Nov 23;25(47):10894-904. PMID 16306402 (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 17559503) [24] Free full text (http:/ / www. tga. gov. au/ adr/ aadrb/ aadr0408. htm) from the Australian Therapeutic Goods Administration [28] The Raphe nuclei group of neurons are located along the brain stem from the labels 'Mid Brain' to 'Oblongata', centered on the pons. (See relevant image.) [29] Alarcon, J. Biotransformation of indole derivatives by mycelial cultures. Zeitschrift fr Naturforschung.C, A journal of biosciences 2008, 63, 82. [35] Penez, N.; Culioli, G.; Briand, J.; Blache, Y.; Perez, T.; Thomas, O. P. Antifouling Properties of Simple Indole and Purine Alkaloids from the Mediterranean Gorgonian Paramuricea clavata. J. Nat. Prod. 2011, 74, 2304-2308. [36] Guillen-Casla, V.; Rosales-Conrado, N.; Leon-Gonzalez, M. E.; Perez-Arribas, L. V.; Polo-Diez, L. M. Determination ofserotonin and its precursors in chocolate samples by capillary liquid chromatography with mass spectrometry detection. J. Chromatogr. A. 2012, 1232, 158-165. [38] Zhang, P.; Cui, Z.; Liu, Y.; Wang, D.; Liu, N.; Yoshikawa, M. Quality Evaluation of Drug Toad Venom fromDifferent Origins through a Simultaneous Determination of Bufogeninsand Indole Alkaloids by HPLC. Chem. Pharm. Bull. 2005, 53, 1582-1586. [39] SciFinder Serotonin Substance Detail. Accessed (4-11-2012).

External links
Serotonin bound to proteins (http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=SRO) in the PDB PsychoTropicalResearch (http://www.psychotropical.com/) Extensive reviews on serotonergic drugs and Serotonin Syndrome. Molecule of the Month: Serotonin (http://www.chm.bris.ac.uk/motm/serotonin/home1.htm) at University of Bristol 60-Second Psych: No Fair! My Serotonin Level Is Low (http://www.sciam.com/podcast/episode. cfm?id=68FC98F1-E48A-251D-8F65277181DB9A4E), Scientific American Serotonin Test Interpretation on ClinLab Navigator (http://www.clinlabnavigator.com/Tests/Serotonin.html).

Serotonin Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation (http://www.ncbi.nlm.nih.gov/pubmed/17176492) at the National Center for Biotechnology Information.

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Serotonin pathways
Serotonin pathways are pathways that help to regulate mood control.[1] Dysregulation can be association with obsessive-compulsive disorder, anxiety disorders, and depression.[2]

References
[1] http:/ / www. bio. davidson. edu/ Courses/ genomics/ 2003/ mccord/ 5-HTT. html [2] http:/ / learn. genetics. utah. edu/ content/ addiction/ reward/ pathways. html

Mesolimbic dopaminergic and serotonergic pathways.

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Raphe nuclei
Brain: Raphe nuclei

Section of the medulla oblongata at about the middle of the olive. (Raphe nuclei not labeled, but 'raphe' labeled at left.)

Horizontal cross section of the brainstem at the lower pons. The raphe nucleus is labeled #18 in the middle. Latin MeSH nuclei raphe Raphe+Nuclei
[1]

The raphe nuclei ("raffe", Greek: = seam) are a moderate-size cluster of nuclei found in the brain stem. Their main function is to release serotonin to the rest of the brain.[2] Selective serotonin reuptake inhibitor (SSRI) antidepressants are believed to act in these nuclei, as well as at their targets.[3]

Anatomy
The raphe nuclei are traditionally considered to be the medial portion of the reticular formation, and they appear as a ridge of cells in the center and most medial portion of the brain stem. In order from caudal to rostral, the raphe nuclei are known as the nucleus raphe obscurus, the nucleus raphe magnus, the nucleus raphe pontis, the nucleus raphe pallidus, the median raphe nucleus, dorsal raphe nucleus, nuclei linearis intermedius and linearis rostralis.[4] Some scientists chose to group the nuclei lineares into one nucleus, shrinking the number of raphe to seven, e.g., NeuroNames makes the following ordering:[5] Raphe nuclei of medulla oblongata Nucleus raphe obscurus Nucleus raphe magnus Nucleus pallidus Raphe nuclei of the pontine reticular formation Nucleus raphe pontis Nucleus centralis inferior Raphe nuclei of the midbrain reticular formation

Raphe nuclei Nucleus centralis superior (median raphe nucleus) Nucleus raphe dorsalis

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Nomenclature
The Latin names commonly used for most of these nuclei are grammatically incorrect. Latin grammar would require nucleus raphe magnus to be changed to nucleus raphes magnus, for example. Terminologia Anatomica, the main authority on anatomical names, uses the "raphes" form, and so do some scientific papers, but in recent years more than 95% of scientific publications have continued to use the "raphe" form, as this article does.

Projections
These nuclei interact with almost every pertinent portion of the brain, but only a few of them have specifically independent interaction. These select nuclei are discussed as follows. Overall, the caudal raphe nuclei, including the nucleus raphe magnus, nucleus raphe pallidus and nucleus raphe obscurus, all project towards the spinal cord and brain stem. The more-rostral nuclei, including the nucleus raphe pontis, nucleus centralis superior (also called median raphe nucleus) and nucleus raphe dorsalis project towards the brain areas of higher function[6]

Function
The raphe nuclei have a vast impact upon the central nervous system. Many of the neurons in the nuclei (but not the majority) are serotonergic; i.e., contain serotonin, a type of monoamine neurotransmitter. It is important to note that pharmacology traditionally affects global serotonin levels, while the actions of the raphe nuclei are dependent on the complex interplay between nuclei.[citation needed] Projections from the raphe nuclei also terminate in the dorsal horn of spinal gray matter where they regulate the release of enkephalins, which inhibit pain sensation.
Dopamine and serotonin pathways in the brain

The raphe nuclei provide feedback to the suprachiasmatic nuclei (SCN), thus contributing in circadian rhythms in animals. The SCN transmits to the raphe nuclei via the dorsomedial hypothalamus nucleus altering serotonin levels for sleep/wake states. The raphe nuclei will then transmit feedback to the SCN about the animal's vigilance and levels of alertness. This reciprocal feedback between the two structures provides an adaptable yet stable basis of circadian rhythms.[7]

Further reading
Currie, David (2005). "A Lecture, Higher Brain Function: Activation of the Brain and Levels of Consciousness" [8] . East Tennessee State University. Retrieved 18 April 2006. Sari, Youssef (October 2004). "Serotonin1B receptors: from protein to physiological function and behavior" [9]. Neuroscience & Biobehavioral Reviews 28 (6): 565582. doi:10.1016/j.neubiorev.2004.08.008 [10]. PMID15527863 [11]. Retrieved 2006-04-18. McKittrick,, Christina; Carolineblanchard, D; Blanchard, R; McEwen, B; Sakai, R (August 1995). "Serotonin Receptor Binding in a Colony Model of Chronic Social Stress" [12]. Biological Psychiatry 37 (6): 383393. doi:10.1016/0006-3223(94)00152-S [13]. PMID7772647 [14]. Retrieved 2010-08-30.

Raphe nuclei

324

References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Raphe+ Nuclei [8] http:/ / faculty. etsu. edu/ currie/ ras. htm [9] http:/ / www. sciencedirect. com/ science?_ob=ArticleURL& _udi=B6T0J-4DPCHW4-2& _coverDate=10%2F01%2F2004& _alid=299916628& _rdoc=1& _fmt=& _orig=search& _qd=1& _cdi=4864& _sort=d& view=c& _acct=C000002898& _version=1& _urlVersion=0& _userid=27541& md5=ed404d8b8b83823517993851bd03c937 [10] http:/ / dx. doi. org/ 10. 1016%2Fj. neubiorev. 2004. 08. 008 [11] http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 15527863 [12] http:/ / www. biologicalpsychiatryjournal. com/ article/ PII000632239400152S/ abstract [13] http:/ / dx. doi. org/ 10. 1016%2F0006-3223%2894%2900152-S [14] http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 7772647

Anterior raphespinal tract

325

Anterior raphespinal tract

Anterior raphespinal tract
Latin tractus raphespinalis anterior

The anterior raphespinal tract is a tract in the spinal cord. The way upper centers such as CNS have an interpretation on pain.

Lateral raphespinal tract

326

Lateral raphespinal tract

Lateral raphespinal tract
Latin tractus raphespinalis lateralis

The lateral raphespinal tract is a tract in the spinal cord.

Thyrotropin-releasing hormone
thyrotropin-releasing hormone

Structural formula of TRH Identifiers Symbol Entrez HUGO OMIM RefSeq UniProt TRH 7200 [1] [2] [3] [4]

12298

275120

NM_007117 P20396 Other data [5]

Locus

Chr. 3 q13.3-q21

[6]

Thyrotropin-releasing hormone
Clinical data Pregnancy cat. ? Legal status ?

Identifiers CAS number ATC code ChEMBL 24305-27-9 V04CJ02 [7]

[8] [9]

CHEMBL1472

Chemical data

Thyrotropin-releasing hormone

327
Formula Mol. mass C16H22N6O4 362.38367 g/mol

Thyrotropin-releasing hormone (TRH), also called thyrotropin-releasing factor (TRF), thyroliberin or protirelin, is a tropic, tripeptidal hormone that stimulates the release of TSH (thyroid-stimulating hormone) and prolactin from the anterior pituitary. TRH has been used clinically for the treatment of spinocerebellar degeneration and disturbance of consciousness in humans.[]

Synthesis
TRH is produced by the hypothalamus in medial neurons of the periventricular nucleus.[] At the beginning, it is synthesized as a 242-amino acid precursor polypeptide that contains 6 copies of the sequence -Glu-His-Pro-Gly-, flanked by di-basic peptides that are later processed through proteolysis to give the mature TRH molecule. It travels across the median eminence to the anterior pituitary gland via the hypophyseal portal system where it stimulates the release of thyroid-stimulating hormone from cells called thyrotropes[] and excess levels inhibit dopamine which will then stimulate the release of prolactin which in turn decreases GnRH. TRH can also be detected in other areas of the body including the gastrointestinal system and pancreatic islets, as well as in the brain.
The system of the thyroid hormones T3 and T4. [10]

History

The sequence of TRH was first determined, and the hormone synthesized, by Roger Guillemin and Andrew V. Schally in 1969.[][] Both parties insisted their labs determined the sequence first: Schally first suggested the possibility in 1966, but abandoned it after Guillemin proposed TRH was not actually a peptide. Guillemin's chemist began concurring with these results in 1969, as NIH threatened to cut off funding for the project, leading both parties to return to work on synthesis.[] Schally and Guillemin shared the 1977 Nobel Prize in Medicine "for their discoveries concerning the peptide hormone production of the brain."[] News accounts of their work often focused on their "fierce competition" and use of a very large amount of sheep and pig brains to locate the hormone.[]

Thyrotropin-releasing hormone

328

Chemical properties
Its molecular weight is 359.5 Da. Its tripeptide structure is: (pyro)Glu-His-Pro-NH2. Its logp octanol/water is -2.46
[11]

Clinical significance
TRH is used clinically by intravenous injection (brand name Relefact TRH) to test the response of the anterior pituitary gland; this procedure is known as a TRH test. This is done as diagnostic test of thyroid disorders such as secondary hypothyroidism and in acromegaly. TRH has anti-depressant and anti-suicidal properties,[] and in 2012 the U.S. Army awarded a research grant to develop a TRH nasal spray in order to prevent suicide amongst its ranks.[][12]

Side Effects
Side effects after intravenous TRH administration are minimal.[] Nausea, flushing, urinary urgency, and mild rise in blood pressure have been reported.[] After intrathecal administration, shaking, sweating, shivering, restlessness, and mild rise in blood pressure were observed.[]

Related peptides
Thyrotropin-releasing hormone (TRH)
Identifiers Symbol Pfam InterPro TRH PF05438 [13] [14]

IPR008857

Available protein structures: Pfam PDB structures [15] [16] ; PDBe [17]

RCSB PDB

PDBsum structure summary [18]

TRH belongs to a family of several thyrotropin-releasing hormones.

Thyrotropin-releasing hormone

329

References
[1] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& amp;cmd=retrieve& amp;dopt=default& amp;list_uids=7200& rn=1 [2] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=12298 [3] http:/ / www. omim. org/ 275120 [4] http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?Submit=Submit& position=NM_007117& rn=1 [5] http:/ / www. uniprot. org/ uniprot/ P20396 [6] http:/ / omim. org/ search?index=geneMap& search=3q13. 3 [7] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=24305-27-9& rn=1 [8] http:/ / www. whocc. no/ atc_ddd_index/ ?code=V04CJ02 [9] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL1472 [10] References used in image are found in image article in Commons:Commons:File:Thyroid_system.png#References. [11] CSID:554166, http:/ / www. chemspider. com/ Chemical-Structure. 554166. html (accessed 00:54, Aug 29, 2012) [13] http:/ / pfam. sanger. ac. uk/ family?acc=PF05438 [14] http:/ / www. ebi. ac. uk/ interpro/ entry/ IPR008857 [15] http:/ / pfam. sanger. ac. uk/ family/ PF05438?tab=pdbBlock [16] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=PfamIdQuery& pfamID=PF05438 [17] http:/ / www. ebi. ac. uk/ pdbe-srv/ PDBeXplore/ pfam/ ?pfam=PF05438 [18] http:/ / www. ebi. ac. uk/ thornton-srv/ databases/ cgi-bin/ pdbsum/ GetPfamStr. pl?pfam_id=PF05438

Purine

330

Purine
Purine

Identifiers CAS number PubChem ChemSpider KEGG MeSH ChEBI ChEMBL Jmol-3D images 120-73-0 1044 1015
[2] [3] [4] [1]

C15587 Purine

[5] [6] [7]

CHEBI:17258

CHEMBL302239 Image 1 Properties

[8]

Molecular formula Molar mass Melting point

(verify) [9]

CHN

5 4 4

120.11 g mol1 214C, 487K, 417F

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

A purine is a heterocyclic aromatic organic compound. It consists of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely occurring nitrogen-containing heterocycle in nature.[10]

Purine Purines and pyrimidines make up the two groups of nitrogenous bases, including the two groups of nucleotide bases. Two of the four deoxyribonucleotides and two of the four ribonucleotides, the respective building-blocks of DNA and RNA, are purines.

331

Notable purines
There are many naturally occurring purines. Two of the five bases in nucleic acids, adenine (2) and guanine (3), are purines. In DNA, these bases form hydrogen bonds with their complementary pyrimidines thymine and cytosine, respectively. This is called complementary base pairing. In RNA, the complement of adenine is uracil instead of thymine. Other notable purines are hypoxanthine (4), xanthine (5), theobromine (6), caffeine (7), uric acid (8) and isoguanine (9).

Functions
Aside from the crucial roles of purines (adenine and guanine) in DNA and RNA, purines are also significant components in a number of other important biomolecules, such as ATP, GTP, cyclic AMP, NADH, and coenzyme A. Purine (1) itself, has not been found in nature, but it can be produced by organic synthesis. They may also function directly as neurotransmitters, acting upon purinergic receptors. Adenosine activates adenosine receptors.

History
The word purine (purum uricum)[] was coined by the German chemist Emil Fischer in 1884. He synthesized it for the first time in 1899.[11] The starting material for the reaction sequence was uric acid (8), which had been isolated from kidney stones by Scheele in 1776.[12] Uric acid (8) was reacted with PCl5 to give 2,6,8-trichloropurine (10), which was converted with HI and PH4I to give 2,6-diiodopurine (11). The product was reduced to purine (1) using zinc-dust. Purines are also much larger than pyrimidines.

Purine

332

Metabolism
Many organisms have metabolic pathways to synthesize and break down purines. Purines are biologically synthesized as nucleosides (bases attached to ribose). Defects in enzymes that control purine production and breakdown can severely alter a cells DNA sequences, which may explain why people who carry certain genetic variants of purine metabolic enzymes have a higher risk for some types of cancer.

Sources
Purines are found in high concentration in meat and meat products, especially internal organs such as liver and kidney. In general, plant-based diets are low in purines.[13] Examples of high-purine sources include: sweetbreads, anchovies, sardines, liver, beef kidneys, brains, meat extracts (e.g., Oxo, Bovril), herring, mackerel, scallops, game meats, beer (from the yeast) and gravy. A moderate amount of purine is also contained in beef, pork, poultry, other fish and seafood, asparagus, cauliflower, spinach, mushrooms, green peas, lentils, dried peas, beans, oatmeal, wheat bran, wheat germ, and hawthorn.[14] Higher levels of meat and seafood consumption are associated with an increased risk of gout, whereas a higher level of consumption of dairy products is associated with a decreased risk. Moderate intake of purine-rich vegetables or protein is not associated with an increased risk of gout.[15] In August 2011, a report, based on NASA studies with meteorites found on Earth, was published suggesting purine and related organic molecules (including the DNA and RNA components, adenine and guanine) may have been formed extraterrestrially in outer space.[][]

Laboratory synthesis
In addition to in vivo synthesis of purines in purine metabolism, purine can also be created artificially. Purine (1) is obtained in good yield when formamide is heated in an open vessel at 170 C for 28 hours.[]

This remarkable reaction and others like it have been discussed in the context of the origin of life.[] Oro, Orgel and co-workers have shown that four molecules of HCN tetramerize to form diaminomaleodinitrile (12), which can be converted into almost all natural-occurring purines.[16][17][18][19][20]

Purine

333

The Traube purine synthesis (1900) is a classic reaction (named after Wilhelm Traube) between an amine-substituted pyrimidine and formic acid.[21]

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=120-73-0 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=1044 [3] http:/ / www. chemspider. com/ 1015 [4] http:/ / www. kegg. jp/ entry/ C15587 [5] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Purine [6] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=17258 [7] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL302239 [8] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=c1c2c%28nc%5BnH%5D2%29ncn1 [9] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=464376451& page2=Purine [10] Rosemeyer, H. Chemistry & Biodiversity 2004, 1, 361. [11] Fischer, E. Berichte der Deutschen Chemischen Gesellschaft 1899, 32, 2550. [12] Scheele, V. Q. Examen Chemicum Calculi Urinari, Opuscula, 1776, 2, 73. [13] http:/ / www. dietaryfiberfood. com/ purine-food. php [14] Gout Diet: Limit High Purine Foods (http:/ / www. healthcastle. com/ gout. shtml) [15] NEJM - Purine-Rich Foods, Dairy and Protein Intake, and the Risk of Gout in Men (http:/ / content. nejm. org/ cgi/ content/ abstract/ 350/ 11/ 1093) [20] Houben-Weyl, Vol . E5, p. 1547

Purine
[21] Organic Syntheses Based on Name Reactions, Alfred Hassner, C. Stumer ISBN 008043259X2002

334

External links
Purine Content in Food (http://www.dietaryfiberfood.com/purine-food.php)

Adenosine

335

Adenosine
Adenosine

Systematic (IUPAC) name

(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
Clinical data Trade names Adenocard

AHFS/Drugs.com monograph [1] Pregnancy cat. Legal status Routes C POM (UK) -only (US) Intravenous, injection Pharmacokinetic data Bioavailability Protein binding Metabolism Half-life Excretion Rapidly cleared from circulation via cellular uptake No Rapidly converted to inosine and adenosine monophosphate cleared plasma <30 seconds half life <10 seconds can leave cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid Identifiers CAS number ATC code 58-61-7 [2]

C01EB10

[3]

Adenosine
[4]

336
PubChem IUPHAR ligand DrugBank ChemSpider UNII KEGG ChEBI ChEMBL

CID 60961 2844 [5]

DB00640 54923 [7]

[6] [8]

K72T3FS567 C00212 [9]

CHEBI:16335 CHEMBL477

[10] [11]

Chemical data

Formula Mol. mass

C10H13N5O4 267.241 g/mol

(what is this?) (verify)

[12]

Adenosine (ADO) is a purine nucleoside comprising a molecule of adenine attached to a ribose sugar molecule (ribofuranose) moiety via a -N9-glycosidic bond. Adenosine plays an important role in biochemical processes, such as energy transferas adenosine triphosphate (ATP) and adenosine diphosphate (ADP)as well as in signal transduction as cyclic adenosine monophosphate, cAMP. It is also an inhibitory neurotransmitter, believed to play a role in promoting sleep and suppressing arousal.

Pharmacological effects
Adenosine is an endogenous purine nucleoside that modulates many physiological processes. Cellular signaling by adenosine occurs through four known adenosine receptor subtypes (A1, A2A, A2B, and A3).[] Extracellular adenosine concentrations from normal cells are approximately 300 nM; however, in response to cellular damage (e.g. in inflammatory or ischemic tissue), these concentrations are quickly elevated (6001,200 nM). Thus, in regard to stress or injury, the function of adenosine is primarily that of cytoprotection preventing tissue damage during instances of hypoxia, ischemia, and seizure activity. Activation of A2A receptors produces a constellation of responses that in general can be classified as anti-inflammatory. In the USA, Adenosine is marketed as Adenocard.

Adenosine receptors
The different adenosine receptor subtypes (A1, A2A, A2B, and A3) are all seven transmembrane spanning G-protein coupled receptors. These four receptor subtypes are further classified based on their ability to either stimulate or inhibit adenylate cyclase activity. The A2A and A2B receptors couple to Gs and mediate the stimulation of adenylate cyclase, while the A1 and A3 adenosine receptors couple to Gi which inhibits adenylate cyclase activity. Additionally, A1 receptors couple to Go, which has been reported to mediate adenosine inhibition of Ca2+ conductance, whereas A2B and A3 receptors also couple to Gq and stimulate phospholipase activity. Researchers at Cornell University have recently shown Adenosine receptors to be key in opening the Blood Brain Barrier(BBB). Mice dosed with Adenosine have shown increased transport across the BBB of amyloid plaque antibodies and prodrugs associated with parkinsons disease, alzheimers, multiple sclerosis and cancers of the central nervous system.

Adenosine

337

Anti-inflammatory properties
Adenosine is believed to be an anti-inflammatory agent at the A2A receptor.[][] Topical treatment of adenosine to foot wounds in diabetes mellitus has been shown in lab animals to drastically increase tissue repair and reconstruction. Topical administration of adenosine for use in wound healing deficiencies and diabetes mellitus in humans is currently under clinical investigation. Methotrexate's anti-inflammatory effect may be due to its stimulation of adenosine release.

Action on the heart

When administered intravenously, adenosine causes transient heart block in the Atrioventricular (AV) node. This is mediated via the A1 receptor, inhibiting adenylyl cyclase, reducing cAMP and so causing cell hyperpolarization by increasing outward K+ flux. It also causes endothelial dependent relaxation of smooth muscle as is found inside the artery walls. This causes dilation of the "normal" segments of arteries; i.e. where the endothelium is not separated from the tunica media by atherosclerotic plaque. This feature allows physicians to use adenosine to test for blockages in the coronary arteries, by exaggerating the difference between the normal and abnormal segments. In individuals suspected of suffering from a supraventricular tachycardia (SVT), adenosine is used to help identify the rhythm. Certain SVTs can be successfully terminated with adenosine.[] This includes any re-entrant arrhythmias that require the AV node for the re-entry, e.g., AV reentrant tachycardia (AVRT), AV nodal reentrant tachycardia (AVNRT). In addition, atrial tachycardia can sometimes be terminated with adenosine. Adenosine has an indirect effect on atrial tissue causing a shortening of the refractory period. When administered via a central lumen catheter, adenosine has been shown to initiate atrial fibrillation because of its effect on atrial tissue. In individuals with accessory pathways, the onset of atrial fibrillation can lead to a life-threatening ventricular fibrillation.
An electrocardiogram showing the conversion of SVT with adenosine

Fast rhythms of the heart that are confined to the atria (e.g., atrial fibrillation, atrial flutter) or ventricles (e.g., monomorphic ventricular tachycardia) and do not involve the AV node as part of the re-entrant circuit are not typically converted by adenosine. However, the ventricular response rate is temporarily slowed with adenosine in such cases. Because of the effects of adenosine on AV node-dependent SVTs, adenosine is considered a class V antiarrhythmic agent. When adenosine is used to cardiovert an abnormal rhythm, it is normal for the heart to enter ventricular asystole for a few seconds. This can be disconcerting to a normally conscious patient, and is associated with angina-like sensations in the chest.[13]

Adenosine

338

By nature of caffeine's purine structure[] it binds to some of the same receptors as adenosine.[] With the proviso that theophylline and theobromine cross the blood brain barrier very poorly (thus a low CNS effects on the heart), the pharmacological effects of adenosine may therefore be blunted in individuals who are taking large quantities of methylxanthines (e.g., caffeine, found in coffee, or theophylline in tea, or theobromine, as found in chocolate).
[14][citation needed]

Caffeine's principal mode of action is as an antagonist of adenosine receptors in the brain.

Action on the lungs

Adenosine receptors are connected to Gi and Go coupled receptors, which in turn, causes a decrease production in Cyclic adenosine monophosphate and therefore, causes bronchospasm. Non-selective adenosine antagonists such as caffeine or theophylline counteracts adenosine and its receptors. The relaxation effect of the airways dominate by the blocked action of adenosinergic neurons that are seen in patients that take methylxanthines to manage symptoms of an asthma attack.

Action in the central nervous system

In general, adenosine has an inhibitory effect in the central nervous system (CNS). Caffeine's stimulatory effects, on the other hand, are primarily (although not entirely) credited to its inhibition of adenosine by binding to the same receptors, and therefore effectively blocking adenosine receptors in the CNS. This reduction in adenosine activity leads to increased activity of the neurotransmitters dopamine and glutamate. [citation needed]

Dosage
When given for the evaluation or treatment of a supraventricular tachycardia (SVT), the initial dose is 6mg, given as a rapid parenteral infusion. Due to adenosine's extremely short half-life, the IV line is started as proximal (near) to the heart as possible, such as the cubital fossa. The IV push is often followed with an immediate flush of 10-20ccs of saline. If this has no effect (i.e. no evidence of transient AV block), a 12mg dose can be given 12 minutes after the first dose. Some clinicians may prefer to administer a higher dose (typically 18mg), rather than repeat a dose that apparently had no effect.Wikipedia:Disputed statement When given to dilate the arteries, such as in a "stress test", the dosage is typically 0.14mg/kg/min, administered for 4 or 6 minutes, depending on the protocol. The recommended dose may be increased in patients on theophylline since methylxanthines prevent binding of adenosine at receptor sites. The dose is often decreased in patients on dipyridamole (Persantine) and diazepam (Valium) because adenosine potentiates the effects of these drugs. The recommended dose is also reduced by half in patients who are presenting congestive heart failure, myocardial infarction, shock, hypoxia, and/or hepatic or renal insufficiency, and in elderly patients.

Adenosine

339

Drug interactions
Dopamine may precipitate toxicity in the patient. Carbamazepine may increase heart block. Theophylline and caffeine (methylxanthines) competitively antagonize adenosine's effects; an increased dose of adenosine may be required. Dipyridamole potentiates the action of adenosine, requiring the use of lower doses.

Contraindications
Common Contraindications for adenosine are: 2nd or 3rd degree heart block (without a pacemaker) Sick sinus syndrome (without a pacemaker) Long QT syndrome Severe hypotension Decompensated heart failure Asthma, traditionally considered an absolute CI. This is being contended and it is now considered a relative CI (however, selective adenosine antagonists are being investigated for use in treatment of asthma)[] Poison/drug-induced tachycardia In Wolff-Parkinson-White syndrome, adenosine may be administered if equipment for cardioversion is immediately available as a backup.

Side effects
Many individuals experience facial flushing, a temporary rash on the chest, lightheadedness, diaphoresis, or nausea after administration of adenosine due to its vasodilatory effects. Metallic taste is a hallmark side effect of adenosine administration. These symptoms are transitory, usually lasting less than one minute. It is classically associated with a sense of "impending doom", more prosaically described as apprehension. This lasts a few seconds after administration of a bolus dose, during transient asystole induced by intravenous administration. In some cases adenosine can make patients' limbs feel numb for about 25 minutes after administration intravenously depending on the dosage (usually above 12mg).

Metabolism
Adenosine used as a second messenger can be the result of de novo purine biosynthesis via adenosine monophosphate (AMP), though it is possible other pathways exist.[15] When adenosine enters the circulation, it is broken down by adenosine deaminase, which is present in red cells and the vessel wall. Dipyridamole, an inhibitor of adenosine deaminase, allows adenosine to accumulate in the blood stream. This causes an increase in coronary vasodilatation. Adenosine deaminase deficiency is a known cause of immunodeficiency.

Analogs and viruses

The adenosine analog, NITD008 has been reported to directly inhibit the recombinant an RNA-dependent RNA polymerase of the dengue virus by terminating its RNA chain synthesis. This suppresses peak viremia, rise in cytokines and prevented infected animal from death raising the possibility of a new treatment for this flavivirus.[16] The 7-deaza-adenosine analog has been shown to inhibit the replication of the hepatitis C virus.[17] Such adenosine analogs are potentially clinically useful since they can be taken orally.

Adenosine

340

References
[1] http:/ / www. drugs. com/ monograph/ adenosine. html [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=58-61-7& rn=1 [3] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01EB10 [4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=60961 [5] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=2844 [6] http:/ / www. drugbank. ca/ drugs/ DB00640 [7] http:/ / www. chemspider. com/ Chemical-Structure. 54923 [8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=K72T3FS567 [9] http:/ / www. kegg. jp/ entry/ C00212 [10] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:16335 [11] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL477 [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477242323& page2=Adenosine [16] Yin Z, Chen YL, Schul W, Wang QY, Gu F, Duraiswamy J, Reddy Kondreddi R, Niyomrattanakit P, Lakshminarayana SB, Goh A, Xu HY, Liu W, Liu B, Lim JY, Ng CY, Qing M, Lim CC, Yip A, Wang G, Chan WL, Tan HP, Lin K, Zhang B, Zou G, Bernard KA, Garrett C, Beltz K, Dong M, Weaver M, He H, Pichota A, Dartois V, Keller TH, Shi PY. (2009). Proc Natl Acad Sci U S A. 106: 2043520439 PMID 19918064

Adenosine diphosphate

341

Adenosine diphosphate
Adenosine diphosphate

Identifiers CAS number PubChem ChemSpider EC number DrugBank ChEBI ChEMBL IUPHAR ligand RTECS number Jmol-3D images 58-64-0 6022 5800
[2] [3] [4] [1]

218-249-0 DB03431

[5] [6]

CHEBI:16761

CHEMBL14830 1712
[8]

[7]

AU7467000 Image 1 [10] Image 2 Properties

[9]

Molecular formula

C 10H 15N 5O 10P 2 427.201 g/mol white powder 2.49 g/mL 877.7C, 1151K, 1612F -2.640 Hazards

Molar mass Appearance Density Boiling point log P

Adenosine diphosphate
[11]

342

MSDS
(verify) [12]

MSDS

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Adenosine diphosphate, abbreviated ADP, is an important organic compound in metabolism and is essential to the flow of energy in living cells. A molecule of ADP consists of three important structural components: a sugar backbone which is attached to a molecule of adenosine and two phosphate groups located around its ring structure. The carbon molecules that makeup the ring structure of a sugar can be named in a way which more specifically designates the location of the phosphate and adenosine attachments. The sugar backbone of ADP is known as a pentose sugar and consists of five carbon molecules. The two phosphate groups of ADP are added in series to the 5 carbon of the sugar backbone, while the adenosine molecule attaches to the 1 carbon.[24] The two phosphates in ADP can be correlated with ATP and AMP. ATP consists of three phosphate groups attached in series to the 5carbon location, whereas ADP contains two phosphate groups attached to the 5 position, and AMP contains only one phosphate group attached at the 5 position. Energy transfer used by all living things is a result of dephosphorylation of ATP by enzymes known as ATPases. The cleavage of a phosphate group from ATP results in the coupling of energy to metabolic reactions and a by-product; a molecule of ADP.[24] Being the "molecular unit of currency", ATP is continually being formed from lower energy molecules of ADP and AMP. The biosynthesis of ATP is achieved throughout processes such as substrate level phosphorylation, oxidative phosphorylation, and photophosphorylation, all of which facilitate the addition of a phosphate group to an ADP molecule.

Bioenergetics
ADP-ATP cycling supplies the energy needed to do work in a biological system; the thermodynamic process of transferring energy from one source to another. There are two types of energy: potential energy and kinetic energy. Potential energy can be thought of as stored energy, or usable energy which is available to do work. Kinetic energy is the energy of an object as a result of its motion. The significance of ATP is in it's ability to store potential energy within the phosphate bonds. The energy stored between these bonds can then be transferred to do work. For example, the transfer of energy from ATP to the protein myosin causes a conformational change when connecting to actin during muscle contraction. It takes multiple reactions between myosin and actin to effectively produce one muscle contraction and therefore the availability of large amounts of ATP is required to produce each muscle contraction. For this reason biological processes have evolved to produce efficient ways to replenishment the potential energy of ATP from ADP.[] Breaking one of ATPs phosphorus bonds generates approximately 31 kilojoules per Mole of ATP (7.3 kcal).[] ADP can be converted, or powered back to ATP through the process of releasing the chemical energy available in food; in humans this is constantly performed via aerobic respiration in the mitochondria.[] Plants use photosynthetic pathways to convert and store energy from sunlight, also conversion of ADP to ATP.[] Animals use the energy released in the breakdown of glucose and other molecules to convert ADP to ATP, which can then be used to fuel necessary growth and cell maintenance.[]

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Cellular respiration
Catabolism
The ten step catabolic pathway of glycolysis is the initial phase of free energy release in the breakdown of glucose and can be split into two phases; the preparatory phase and payoff phase. ADP and phosphate are needed as precursors to synthesize ATP in the payoff reactions of the TCA cycle and oxidative phosphorylation mechanism.[13] During the payoff phase of glycolysis the enzymes phosphoglycerate kinase and pyruvate kinase facilitate the addition of a phosphate group to ADP by way of substrate level phosphorylation.[14]

Glycolysis
Glycolysis is performed by all living organisms and consists of 10 steps. The net reaction for the overall process of glycolysis is: Glucose + 2NAD+ + 2 Pi + 2 ADP = 2 pyruvate + 2 ATP + 2 NADH + 2 H2O.[15] Steps 1 and 3 require the input of energy derived from the hydrolysis of ATP to ADP and Pi (inorganic phosphate) whereas steps 7 and 10 require the input of an ADP molecule and each yield an ATP molecule.[16] The enzymes necessary to break down glucose are found in the cytoplasm, the viscous fluid that fills living cells, where the glycolytic reactions take place.

Citric acid cycle

The citric acid cycle, also known as the Krebs cycle or the TCA (tricarboxylic acid) cycle is an 8 step process which takes the pyruvate generated by glycolysis and generates 4NADH, FADH2 and GTP, which is further converted to ATP.[17] It is only in step 5, where GTP is generated, by succinyl-CoA synthetase, and then converted to ATP, that ADP is used (GTP + ADP GDP + ATP).[18]

Glycolysis overview

Oxidative phosphorylation
Oxidative phosphorylation produces 26 of the 30 molecules of ATP generated in cellular respiration by transferring electrons from NADH or FADH2 to O2 through electron carriers.[19] The energy released when electrons are passed from higher energy NADH or FADH2 to the chemical conversion of GTP to ATP lower energy O2 is required to phosphorylate ADP and once again generate ATP.[20] It is this energy coupling and phosphorylation of ADP to ATP, that gives the electron transport chain the name oxidative phosphorylation.

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Mitochondrial ATP synthase complex During the initial phases of glycolysis and the TCA cycle cofactors such as NAD+ donate and accept electrons[21] which aid in the electron transport chain's ability to produce a proton gradient across the inner mitochondrial membrane.[22] The ATP synthase complex exists both within the mitochondrial membrane (F0 portion) and protrudes into the matrix (F1portion). The energy derived as a result of the chemical gradient is then used to synthesize ATP by coupling the reaction of inorganic phosphate to ADP in the active site of the ATP synthase enzyme; the equation for this can be written as ADP + Pi ATP.

Blood platelet activation

Normally, small disk shaped platelets circulate the blood freely and without interaction with one another. ADP is stored in dense bodies inside blood platelets and is released upon platelet activation. ADP interacts with a family of ADP receptors found on platelets (P2Y1, P2Y12 and P2X1), which leads to platelet activation.[23] P2Y1 receptors initiate platelet aggregation and shape change as a result of interactions with ADP.
ATP-Synthase

P2Y12 receptors further amplify the response to ADP and draw forth the completion of aggregation. ADP in the blood is converted to adenosine by the action of ecto-ADPases, inhibiting further platelet activation via adenosine receptors.

References
[1] [2] [3] [4] [5] [6] [7] [8] [9]

http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=58-64-0 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=6022 http:/ / www. chemspider. com/ 5800 http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=218-249-0 http:/ / www. drugbank. ca/ drugs/ DB03431 https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=16761 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL14830 http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=1712 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DP%28O%29%28O%29OP%28%3DO%29%28O%29OC%5BC%40H%5D3O%5BC%40%40H%5D%28n2cnc1c%28ncnc12%29N%29%5BC [10] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=c1nc%28c2c%28n1%29n%28cn2%29%5BC%40H%5D3%5BC%40%40H%5D%28%5BC%40%40H%5D%28%5BC%40H%5D%28O3%29CO%5B [11] http:/ / www. sigmaaldrich. com/ MSDS/ MSDS/ DisplayMSDSPage. do?country=PL& language=EN-generic& productNumber=01905& brand=SIGMA& PageToGoToURL=http%3A/ / www. sigmaaldrich. com/ catalog/ product/ sigma/ 01905%3Flang%3Dpl [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477242390& page2=Adenosine+ diphosphate

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Adenosine monophosphate
Adenosine monophosphate

Identifiers CAS number ChemSpider UNII DrugBank KEGG MeSH ChEBI ChEMBL IUPHAR ligand Jmol-3D images 61-19-8 5858
[2] [1] [3]

415SHH325A DB00131 C00020

[4]

[5]

Adenosine+monophosphate CHEBI:16027 CHEMBL752 2455

[9] [10] [7] [8]

[6]

Image 1 [11] Image 2 Properties

Molecular formula Molar mass Appearance Density Melting point Boiling point Acidity (pK )
a

C H NOP
10 14 5 7

347.22 g/mol white crystalline powder 2.32 g/mL 178-185C, 451-458K, 352-365F 798.5C, 1072K, 1469F 0.9, 3.8, 6.1
(verify) [12]

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

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Infobox references

Adenosine monophosphate (AMP), also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in DNA and RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine. As a substituent it takes the form of the prefix adenylyl-.

Production and degradation

AMP can be produced during ATP synthesis by the enzyme adenylate kinase by combining two ADP molecules: 2 ADP ATP + AMP Or AMP may be produced by the hydrolysis of one high energy phosphate bond of ADP: ADP AMP + Pi AMP can also be formed by hydrolysis of ATP into AMP and pyrophosphate: ATP AMP + PPi When RNA is broken down by living systems, nucleoside monophosphates, including adenosine monophosphate, are formed. AMP can be regenerated to ATP as follows: AMP + ATP 2 ADP (adenylate kinase in the opposite direction) ADP + Pi ATP (this step is most often performed in aerobes by the ATP synthase during oxidative phosphorylation) AMP can be converted into IMP by the enzyme myoadenylate deaminase, freeing an ammonia group. In a catabolic pathway, adenosine monophosphate can be converted to uric acid, which is excreted from the body.

cAMP
AMP can also exist as a cyclic structure known as cyclic AMP (or cAMP). Within certain cells the enzyme adenylate cyclase makes cAMP from ATP, and typically this reaction is regulated by hormones such as adrenaline or glucagon. cAMP plays an important role in intracellular signaling.

References

[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=61-19-8 [2] http:/ / www. chemspider. com/ 5858 [3] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=415SHH325A [4] http:/ / www. drugbank. ca/ drugs/ DB00131 [5] http:/ / www. kegg. jp/ entry/ C00020 [6] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Adenosine+ monophosphate [7] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=16027 [8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL752 [9] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=2455 [10] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DP%28O%29%28O%29OC%5BC%40H%5D3O%5BC%40%40H%5D%28n2cnc1c%28ncnc12%29N%29%5BC%40H%5D%28O%29%5BC% [11] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=c1nc%28c2c%28n1%29n%28cn2%29%5BC%40H%5D3%5BC%40%40H%5D%28%5BC%40%40H%5D%28%5BC%40H%5D%28O3%29COP%2 [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477242440& page2=Adenosine+ monophosphate

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External links
Ming D, Ninomiya Y, Margolskee RF (1999). "Blocking taste receptor activation of gustducin inhibits gustatory responses to bitter compounds" (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC22308). Proc. Natl. Acad. Sci. USA 96 (17): 99039908. doi: 10.1073/pnas.96.17.9903 (http://dx.doi.org/10.1073/pnas.96.17.9903). PMC 22308 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC22308). PMID 10449792 (http://www.ncbi. nlm.nih.gov/pubmed/10449792).

Adenosine triphosphate

348

Adenosine triphosphate
Adenosine triphosphate

Identifiers CAS number PubChem ChemSpider UNII DrugBank KEGG ChEBI ChEMBL IUPHAR ligand Jmol-3D images 56-65-5 5957 5742
[2] [3] [4] [1]

8L70Q75FXE DB00171 C00002

[5]

[6]

CHEBI:15422

[7]

CHEMBL14249 1713
[9] [10]

[8]

Image 1 [11] Image 2 Properties

Molecular formula Molar mass

C H NO P

10 16 5 13 3

507.18 g mol1

Adenosine triphosphate

349

Density Melting point Acidity (pKa)

(verify) [12]

1.04 g/cm3 (disodium salt) 187 C (disodium salt) decomposes 6.5

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Adenosine-5'-triphosphate (ATP) is a nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer.[13] ATP transports chemical energy within cells for metabolism. It is one of the end products of photophosphorylation, cellular respiration, and fermentation and used by enzymes and structural proteins in many cellular processes, including biosynthetic reactions, motility, and cell division.[14] One molecule of ATP contains three phosphate groups, and it is produced by a wide variety of enzymes, including ATP synthase, from adenosine diphosphate (ADP) or adenosine monophosphate (AMP) and various phosphate group donors. Substrate level phosphorylation, oxidative phosphorylation in cellular respiration, and photophosphorylation in photosynthesis are three major mechanisms of ATP biosynthesis. Metabolic processes that use ATP as an energy source convert it back into its precursors. ATP is therefore continuously recycled in organisms: the human body, which on average contains only 250 grams (8.8oz) of ATP,[15] turns over its own body weight equivalent in ATP each day.[16] ATP is used as a substrate in signal transduction pathways by kinases that phosphorylate proteins and lipids, as well as by adenylate cyclase, which uses ATP to produce the second messenger molecule cyclic AMP. The ratio between ATP and AMP is used as a way for a cell to sense how much energy is available and control the metabolic pathways that produce and consume ATP.[17] Apart from its roles in energy metabolism and signaling, ATP is also incorporated into nucleic acids by polymerases in the process of transcription. ATP is the neurotransmitter believed to signal the sense of taste.[18] The structure of this molecule consists of a purine base (adenine) attached to the 1' carbon atom of a pentose sugar (ribose). Three phosphate groups are attached at the 5' carbon atom of the pentose sugar. It is the addition and removal of these phosphate groups that inter-convert ATP, ADP and AMP. When ATP is used in DNA synthesis, the ribose sugar is first converted to deoxyribose by ribonucleotide reductase. ATP was discovered in 1929 by Karl Lohmann, Fiske and Y.Subba Rao of Harvard Medical School[19] but its correct structure was not determined until some years later.[citation needed] It was proposed to be the main energy transfer molecule in the cell by Fritz Albert Lipmann in 1941, that is, being the intermediary molecule between energy-yielding (exergonic) and energy-requiring (endergonic) reactions.[20] It was first artificially synthesized by Alexander Todd in 1948.[21]

Physical and chemical properties

ATP consists of adenosine composed of an adenine ring and a ribose sugar and three phosphate groups (triphosphate). The phosphoryl groups, starting with the group closest to the ribose, are referred to as the alpha (), beta (), and gamma () phosphates. Consequently, it is closely related to the adenosine nucleotide, a monomer of RNA. ATP is highly soluble in water and is quite stable in solutions between pH6.87.4, but is rapidly hydrolysed at extreme pH. Consequently, ATP is best stored as an anhydrous salt.[22] ATP is an unstable molecule in unbuffered water, in which it hydrolyses to ADP and phosphate. This is because the strength of the bonds between the phosphate groups in ATP is less than the strength of the hydrogen bonds (hydration bonds), between its products (ADP + phosphate), and water. Thus, if ATP and ADP are in chemical equilibrium in water, almost all of the ATP will eventually be converted to ADP. A system that is far from equilibrium contains Gibbs free energy, and is capable of doing work. Living cells maintain the ratio of ATP to ADP

Adenosine triphosphate at a point ten orders of magnitude from equilibrium, with ATP concentrations fivefold higher than the concentration of ADP. This displacement from equilibrium means that the hydrolysis of ATP in the cell releases a large amount of free energy.[] Two high-energy phosphate bonds (phosphoanhydride bonds) (those that connect adjacent phosphates) in an ATP molecule are responsible for the high energy content of this molecule.[] In the context of biochemical reactions, these anhydride bonds are frequentlyand sometimes controversiallyreferred to as high-energy bonds.[23] Energy stored in ATP may be released upon hydrolysis of the anhydride bonds.[] The primary phosphate group on the ATP molecule that is hydrolyzed when energy is needed to drive anabolic reactions is the -phosphate group. Located the farthest from the ribose sugar, it has a higher energy of hydrolysis than either the - or -phosphate. The bonds formed after hydrolysisor the phosphorylation of a residue by ATPare lower in energy than the phosphoanhydride bonds of ATP. During enzyme-catalyzed hydrolysis of ATP or phosphorylation by ATP, the available free energy can be harnessed by a living system to do work.[24][25] Any unstable system of potentially reactive molecules could potentially serve as a way of storing free energy, if the cell maintained their concentration far from the equilibrium point of the reaction.[] However, as is the case with most polymeric biomolecules, the breakdown of RNA, DNA, and ATP into simpler monomers is driven by both energy-release and entropy-increase considerations, in both standard concentrations, and also those concentrations encountered within the cell. The standard amount of energy released from hydrolysis of ATP can be calculated from the changes in energy under non-natural (standard) conditions, then correcting to biological concentrations. The net change in heat energy (enthalpy) at standard temperature and pressure of the decomposition of ATP into hydrated ADP and hydrated inorganic phosphate is 20.5kJ/mol, with a change in free energy of 3.4kJ/mol.[26] The energy released by cleaving either a phosphate (Pi) or pyrophosphate (PPi) unit from ATP at standard state of 1M are:[27] ATP + H 2O ADP + P G = 30.5kJ/mol (7.3kcal/mol) i ATP + H 2O AMP + PP G = 45.6kJ/mol (10.9kcal/mol) i These values can be used to calculate the change in energy under physiological conditions and the cellular ATP/ADP ratio. However, a more representative value (which takes AMP into consideration) called the Energy charge is increasingly being employed. The values given for the Gibbs free energy for this reaction are dependent on a number of factors, including overall ionic strength and the presence of alkaline earth metal ions such as Mg2+ and Ca2+ . Under typical cellular conditions, G is approximately 57kJ/mol (14kcal/mol).[28]

350

Ionization in biological systems

ATP(adenosine triphosphate) has multiple groups with different acid dissociation constants. In neutral solution, ATP is ionized and exists mostly as ATP4, with a small proportion of ATP3.[] As ATP has several negatively charged groups in neutral solution, it can chelate metals with very high affinity. The binding constant for various metal ions are (given as per mole) as Mg2+ (9 554), Na+ (13), Ca2+ (3 722), K+ (8), Sr2+ (1 381) and Li+ (25).[29] Due to the strength of these interactions, ATP exists in the cell mostly in a complex with Mg2+ .[][30]

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Biosynthesis
The ATP concentration inside the cell is typically 110 mM.[31] ATP can be produced by redox reactions using simple and complex sugars (carbohydrates) or lipids as an energy source. For complex fuels to be synthesized into ATP, they first need to be broken down into smaller, more simple molecules. Carbohydrates are hydrolysed into simple sugars, such as glucose and fructose. Fats (triglycerides) are metabolised to give fatty acids and glycerol. The overall process of oxidizing glucose to carbon dioxide is known as cellular respiration and can produce about 30 molecules of ATP from a single molecule of glucose.[] ATP can be produced by a number of distinct cellular processes; the three main pathways used to generate energy in eukaryotic organisms are glycolysis and the citric acid cycle/oxidative phosphorylation, both components of cellular respiration; and beta-oxidation. The majority of this ATP production by a non-photosynthetic aerobic eukaryote takes place in the mitochondria, which can make up nearly 25% of the total volume of a typical cell.[]

Glycolysis
In glycolysis, glucose and glycerol are metabolized to pyruvate via the glycolytic pathway. In most organisms, this process occurs in the cytosol, but, in some protozoa such as the kinetoplastids, this is carried out in a specialized organelle called the glycosome.[32] Glycolysis generates a net two molecules of ATP through substrate phosphorylation catalyzed by two enzymes: PGK and pyruvate kinase. Two molecules of NADH are also produced, which can be oxidized via the electron transport chain and result in the generation of additional ATP by ATP synthase. The pyruvate generated as an end-product of glycolysis is a substrate for the Krebs Cycle.[]

Glucose
In the mitochondrion, pyruvate is oxidized by the pyruvate dehydrogenase complex to Acetyl group, which is fully oxidized to carbon dioxide by the citric acid cycle (also known as the Krebs Cycle). Every "turn" of the citric acid cycle produces two molecules of carbon dioxide, one molecule of the ATP equivalent guanosine triphosphate (GTP) through substrate-level phosphorylation catalyzed by succinyl-CoA synthetase, three molecules of the reduced coenzyme NADH, and one molecule of the reduced coenzyme FADH2. Both of these latter molecules are recycled to their oxidized states (NAD+ and FAD, respectively) via the electron transport chain, which generates additional ATP by oxidative phosphorylation. The oxidation of an NADH molecule results in the synthesis of 2-3 ATP molecules, and the oxidation of one FADH2 yields between 1-2 ATP molecules.[] The majority of cellular ATP is generated by this process. Although the citric acid cycle itself does not involve molecular oxygen, it is an obligately aerobic process because O 2 is needed to recycle the reduced NADH and FADH to their oxidized states. In the absence of oxygen the citric 2 acid cycle will cease to function due to the lack of available NAD+ and FAD.[] The generation of ATP by the mitochondrion from cytosolic NADH relies on the malate-aspartate shuttle (and to a lesser extent, the glycerol-phosphate shuttle) because the inner mitochondrial membrane is impermeable to NADH and NAD+. Instead of transferring the generated NADH, a malate dehydrogenase enzyme converts oxaloacetate to malate, which is translocated to the mitochondrial matrix. Another malate dehydrogenase-catalyzed reaction occurs in the opposite direction, producing oxaloacetate and NADH from the newly transported malate and the mitochondrion's interior store of NAD+. A transaminase converts the oxaloacetate to aspartate for transport back across the membrane and into the intermembrane space.[] In oxidative phosphorylation, the passage of electrons from NADH and FADH2 through the electron transport chain powers the pumping of protons out of the mitochondrial matrix and into the intermembrane space. This creates a proton motive force that is the net effect of a pH gradient and an electric potential gradient across the inner mitochondrial membrane. Flow of protons down this potential gradient that is, from the intermembrane space to the matrix provides the driving force for ATP synthesis by ATP synthase. This enzyme contains a rotor subunit that physically rotates relative to the static portions of the protein during ATP synthesis.[33]

Adenosine triphosphate Most of the ATP synthesized in the mitochondria will be used for cellular processes in the cytosol; thus it must be exported from its site of synthesis in the mitochondrial matrix. The inner membrane contains an antiporter, the ADP/ATP translocase, which is an integral membrane protein used to exchange newly synthesized ATP in the matrix for ADP in the intermembrane space.[] This translocase is driven by the membrane potential, as it results in the movement of about 4 negative charges out of the mitochondrial membrane in exchange for 3 negative charges moved inside. However, it is also necessary to transport phosphate into the mitochondrion; the phosphate carrier moves a proton in with each phosphate, partially dissipating the proton gradient.

352

Beta oxidation
Fatty acids can also be broken down to acetyl-CoA by beta-oxidation. Each round of this cycle reduces the length of the acyl chain by two carbon atoms and produces one NADH and one FADH2 molecule, which are used to generate ATP by oxidative phosphorylation. Because NADH and FADH2 are energy-rich molecules, dozens of ATP molecules can be generated by the beta-oxidation of a single long acyl chain. The high energy yield of this process and the compact storage of fat explain why it is the most dense source of dietary calories.[34]

Fermentation
Fermentation entails the generation of energy via the process of substrate-level phosphorylation in the absence of an respiratory electron transport chain. In most eukaryotes, glucose is used as both an energy store and an electron donor. The equation for the oxidation of glucose to lactic acid is: C 6H 12O 2CH 3CH(OH)COOH + 2 ATP
6

Anaerobic respiration
Anaerobic respiration is the process of respiration using an electron acceptor other than O 2. In prokaryotes, multiple electron acceptors can be used in anaerobic respiration. These include nitrate, sulfate or carbon dioxide. These processes lead to the ecologically important processes of denitrification, sulfate reduction and acetogenesis, respectively.[35][36]

ATP replenishment by nucleoside diphosphate kinases

ATP can also be synthesized through several so-called "replenishment" reactions catalyzed by the enzyme families of nucleoside diphosphate kinases (NDKs), which use other nucleoside triphosphates as a high-energy phosphate donor, and the ATP:guanido-phosphotransferase family,

ATP production during photosynthesis

In plants, ATP is synthesized in thylakoid membrane of the chloroplast during the light-dependent reactions of photosynthesis in a process called photophosphorylation. Here, light energy is used to pump protons across the chloroplast membrane. This produces a proton-motive force and this drives the ATP synthase, exactly as in oxidative phosphorylation.[37] Some of the ATP produced in the chloroplasts is consumed in the Calvin cycle, which produces triose sugars.

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ATP recycling
The total quantity of ATP in the human body is about 0.2mole. The majority of ATP is not usually synthesised de novo, but is generated from ADP by the aforementioned processes. Thus, at any given time, the total amount of ATP + ADP remains fairly constant. The energy used by human cells requires the hydrolysis of 100 to 150moles of ATP daily, which is around 50 to 75kg. A human will typically use up his or her body weight of ATP over the course of the day.[] This means that each ATP molecule is recycled 500 to 750 times during a single day (100 / 0.2 = 500). ATP cannot be stored, hence its consumption closely follows its synthesis. However a total of around 5g of ATP is used by cell processes at any time in the body.

Regulation of biosynthesis
ATP production in an aerobic eukaryotic cell is tightly regulated by allosteric mechanisms, by feedback effects, and by the substrate concentration dependence of individual enzymes within the glycolysis and oxidative phosphorylation pathways. Key control points occur in enzymatic reactions that are so energetically favorable that they are effectively irreversible under physiological conditions. In glycolysis, hexokinase is directly inhibited by its product, glucose-6-phosphate, and pyruvate kinase is inhibited by ATP itself. The main control point for the glycolytic pathway is phosphofructokinase (PFK), which is allosterically inhibited by high concentrations of ATP and activated by high concentrations of AMP. The inhibition of PFK by ATP is unusual, since ATP is also a substrate in the reaction catalyzed by PFK; the biologically active form of the enzyme is a tetramer that exists in two possible conformations, only one of which binds the second substrate fructose-6-phosphate (F6P). The protein has two binding sites for ATP the active site is accessible in either protein conformation, but ATP binding to the inhibitor site stabilizes the conformation that binds F6P poorly.[] A number of other small molecules can compensate for the ATP-induced shift in equilibrium conformation and reactivate PFK, including cyclic AMP, ammonium ions, inorganic phosphate, and fructose 1,6 and 2,6 biphosphate.[] The citric acid cycle is regulated mainly by the availability of key substrates, particularly the ratio of NAD+ to NADH and the concentrations of calcium, inorganic phosphate, ATP, ADP, and AMP. Citrate the molecule that gives its name to the cycle is a feedback inhibitor of citrate synthase and also inhibits PFK, providing a direct link between the regulation of the citric acid cycle and glycolysis.[] In oxidative phosphorylation, the key control point is the reaction catalyzed by cytochrome c oxidase, which is regulated by the availability of its substratethe reduced form of cytochrome c. The amount of reduced cytochrome c available is directly related to the amounts of other substrates:

which directly implies this equation:

Thus, a high ratio of [NADH] to [NAD+] or a low ratio of [ADP] [Pi] to [ATP] imply a high amount of reduced cytochrome c and a high level of cytochrome c oxidase activity.[] An additional level of regulation is introduced by the transport rates of ATP and NADH between the mitochondrial matrix and the cytoplasm.[]

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Functions in cells
Metabolism, synthesis, and active transport
ATP is consumed in the cell by energy-requiring (endothermic) processes and can be generated by energy-releasing (exothermic) processes. In this way ATP transfers energy between spatially separate metabolic reactions. ATP is the main energy source for the majority of cellular functions. This includes the synthesis of macromolecules, including DNA and RNA (see below), and proteins. ATP also plays a critical role in the transport of macromolecules across cell membranes, e.g. exocytosis and endocytosis.

Roles in cell structure and locomotion

ATP is critically involved in maintaining cell structure by facilitating assembly and disassembly of elements of the cytoskeleton. In a related process, ATP is required for the shortening of actin and myosin filament crossbridges required for muscle contraction. This latter process is one of the main energy requirements of animals and is essential for locomotion and respiration.

Cell signalling
Extracellular signalling ATP is also a signalling molecule. ATP, ADP, or adenosine are recognised by purinergic receptors. Purinoreceptors might be the most abundant receptors in mammalian tissues.[] In humans, this signalling role is important in both the central and peripheral nervous system.[] Activity-dependent release of ATP from synapses, axons and glia activates purinergic membrane receptors known as P2.[38] The P2Y receptors are metabotropic, i.e. G protein-coupled and modulate mainly intracellular calcium and sometimes cyclic AMP levels. Though named between P2Y1 and P2Y15, only nine members of the P2Y family have been cloned, and some are only related through weak homology and several (P2Y5, P2Y7, P2Y9, P2Y10) do not function as receptors that raise cytosolic calcium. The P2X ionotropic receptor subgroup comprises seven members (P2X1P2X7), which are ligand-gated Ca2+ -permeable ion channels that open when bound to an extracellular purine nucleotide. In contrast to P2 receptors (agonist order ATP > ADP > AMP > ADO), purinergic nucleoside triphosphates like ATP are not strong agonists of P1 receptors, which are strongly activated by adenosine and other nucleosides (ADO > AMP > ADP > ATP). P1 receptors have A1, A2a, A2b, and A3 subtypes ("A" as a remnant of old nomenclature of adenosine receptor), all of which are G protein-coupled receptors, A1 and A3 being coupled to Gi, and A2a and A2b being coupled to Gs.[39] All adenosine receptors were shown to activate at least one subfamily of mitogen-activated protein kinases. The actions of adenosine are often antagonistic or synergistic to the actions of ATP. In the CNS, adenosine has multiple functions, such as modulation of neural development, neuron and glial signalling and the control of innate and adaptive immune systems.[]

Adenosine triphosphate Intracellular signaling ATP is critical in signal transduction processes. It is used by kinases as the source of phosphate groups in their phosphate transfer reactions. Kinase activity on substrates such as proteins or membrane lipids are a common form of signal transduction. Phosphorylation of a protein by a kinase can activate this cascade such as the mitogen-activated protein kinase cascade.[40] ATP is also used by adenylate cyclase and is transformed to the second messenger molecule cyclic AMP, which is involved in triggering calcium signals by the release of calcium from intracellular stores.[41] This form of signal transduction is particularly important in brain function, although it is involved in the regulation of a multitude of other cellular processes.[42]

355

DNA and RNA synthesis

In all known organisms, the Deoxyribonucleotides that make up DNA are synthesized by the action of ribonucleotide reductase (RNR) enzymes on their corresponding ribonucleotides.[] These enzymes reduce the sugar residue from ribose to deoxyribose by removing oxygen from the 2' hydroxyl group; the substrates are ribonucleoside diphosphates and the products deoxyribonucleoside diphosphates (the latter are denoted dADP, dCDP, dGDP, and dUDP respectively.) All ribonucleotide reductase enzymes use a common sulfhydryl radical mechanism reliant on reactive cysteine residues that oxidize to form disulfide bonds in the course of the reaction.[] RNR enzymes are recycled by reaction with thioredoxin or glutaredoxin.[] The regulation of RNR and related enzymes maintains a balance of dNTPs relative to each other and relative to NTPs in the cell. Very low dNTP concentration inhibits DNA synthesis and DNA repair and is lethal to the cell, while an abnormal ratio of dNTPs is mutagenic due to the increased likelihood of the DNA polymerase incorporating the wrong dNTP during DNA synthesis.[] Regulation of or differential specificity of RNR has been proposed as a mechanism for alterations in the relative sizes of intracellular dNTP pools under cellular stress such as hypoxia.[] In the synthesis of the nucleic acid RNA, adenosine derived from ATP is one of the four nucleotides incorporated directly into RNA molecules by RNA polymerases. The energy driving this polymerization comes from cleaving off a pyrophosphate (two phosphate groups).[43] The process is similar in DNA biosynthesis, except that ATP is reduced to the deoxyribonucleotide dATP, before incorporation into DNA.

Amino acid activation in protein synthesis

Aminoacyl-tRNA synthetase enzymes utilise ATP as an energy source to attach a tRNA molecule to its specific amino acid, forming an aminoacyl-tRNA complex, ready for translation at ribosomes. The energy is made available by ATP hydrolysis to adenosine monophosphate (AMP) as two phosphate groups are removed.[44]

Binding to proteins
Some proteins that bind ATP do so in a characteristic protein fold known as the Rossmann fold, which is a general nucleotide-binding structural domain that can also bind the coenzyme NAD.[45] The most common ATP-binding proteins, known as kinases, share a small number of common folds; the protein kinases, the largest kinase superfamily, all share common structural features specialized for ATP binding and phosphate transfer.[] ATP in complexes with proteins, in general, requires the presence of a divalent cation, almost always magnesium, which binds to the ATP phosphate groups. The presence of magnesium greatly decreases the dissociation constant of ATP from its protein binding partner without affecting the ability of the enzyme to catalyze its reaction once the ATP has bound.[] The presence of magnesium ions can serve as a mechanism for kinase regulation.[]

Adenosine triphosphate

356

ATP analogues
Biochemistry laboratories often use in vitro studies to explore ATP-dependent molecular processes. Enzyme inhibitors of ATP-dependent enzymes such as kinases are needed to examine the binding sites and transition states involved in ATP-dependent reactions. ATP analogs are also used in X-ray crystallography to determine a protein structure in complex with ATP, often together with other substrates. Most useful ATP analogs cannot be hydrolyzed as ATP would be; instead they trap the enzyme in a structure closely related to the ATP-bound state. Adenosine 5'-(gamma-thiotriphosphate) is an extremely An example of the Rossmann fold, a structural domain of a decarboxylase enzyme common ATP analog in which one of the from the bacterium Staphylococcus epidermidis (PDB ID 1G5Q) with a bound flavin mononucleotide cofactor. gamma-phosphate oxygens is replaced by a sulfur atom; this molecule is hydrolyzed at a dramatically slower rate than ATP itself and functions as an inhibitor of ATP-dependent processes. In crystallographic studies, hydrolysis transition states are modeled by the bound vanadate ion. However, caution is warranted in interpreting the results of experiments using ATP analogs, since some enzymes can hydrolyze them at appreciable rates at high concentration.[]

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=56-65-5 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5957

[3] http:/ / www. chemspider. com/ 5742 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=8L70Q75FXE [5] http:/ / www. drugbank. ca/ drugs/ DB00171 [6] http:/ / www. kegg. jp/ entry/ C00002 [7] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=15422 [8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL14249 [9] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=1713 [10] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DP%28O%29%28O%29OP%28%3DO%29%28O%29OP%28%3DO%29%28O%29OC%5BC%40H%5D3O%5BC%40%40H%5D%28n2cnc1c [11] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=c1nc%28c2c%28n1%29n%28cn2%29%5BC%40H%5D3%5BC%40%40H%5D%28%5BC%40%40H%5D%28%5BC%40H%5D%28O3%29CO%5B [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477228486& page2=Adenosine+ triphosphate [44] Eldra P. Solomon, Linda R. Berg, Diana W. Martin. Biology (8th Ed). ISBN 978-0-495-30978-9

Adenosine triphosphate

357

External links
ATP bound to proteins (http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=ATP) in the PDB ScienceAid: Energy ATP and Exercise (http://www.scienceaid.co.uk/biology/biochemistry/atp.html) PubChem entry for Adenosine Triphosphate (http://pubchem.ncbi.nlm.nih.gov/summary/summary. cgi?cid=5957) KEGG entry for Adenosine Triphosphate (http://www.genome.jp/dbget-bin/www_bget?cpd:C00002)

References External links

ATP bound to proteins (http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=ATP) in the PDB ScienceAid: Energy ATP and Exercise (http://www.scienceaid.co.uk/biology/biochemistry/atp.html) PubChem entry for Adenosine Triphosphate (http://pubchem.ncbi.nlm.nih.gov/summary/summary. cgi?cid=5957) KEGG entry for Adenosine Triphosphate (http://www.genome.jp/dbget-bin/www_bget?cpd:C00002)

Trace amine
Trace amines are an endogenous group of amines structurally and metabolically related to classical monoamine neurotransmitters, such as dopamine, norepinephrine, and serotonin. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although, they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.[1] Trace amines may play very significant roles in the coordination of biogenic monoamine-based synaptic physiology. At high concentrations, they have well-characterized presynaptic amphetamine-like effects on monoamine release, reuptake and biosynthesis; at lower concentrations, they possess postsynaptic modulatory effects that potentiate the activity of other neurotransmitters, particularly dopamine and serotonin.[2] A family of G protein coupled receptors known as TAARs (trace amine associated receptors) has been characterized to be responsive to trace amines[3] and structurally related psychoactive drugs, such as amphetamine, MDMA, LSD, and DMT.[4] Like dopamine, noradrenaline, and serotonin, the trace amines have been implicated in a vast array of human disorders of affect and cognition, such as depression[5] and schizophrenia.[6] A thorough review of trace amines and trace amine receptors that discusses the historical evolution of this research particularly well is that of Grandy.[7]

Trace amine

358

List of trace amines

Phenethylamines (related to catecholamines, such as dopamine and norepinephrine): -Phenethylamine (PEA) m-Tyramine p-Tyramine m-Octopamine p-Octopamine Thyronamines, such as 3-iodothyronamine (T1AM), compounds derived from thyroid hormones Tryptamines (indoleamines, related to serotonin): Tryptamine N,N-Dimethyltryptamine (DMT), an endogenous psychedelic compound

References
[1] Burchett SA, Hicks TP. The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain. Prog Neurobiol. 2006 Aug;79(5-6):223-46. [2] Burchett SA, Hicks TP. The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain. Prog Neurobiol. 2006 Aug;79(5-6):223-46. [3] Lindemann L, Ebeling M, Kratochwil NA, Bunzow JR, Grandy DK, Hoener MC. Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors. Genomics. 2005 Mar;85(3):372-85. [4] Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001 Dec;60(6):1181-8. [5] Davis, B.A., Boulton, A.A., 1994. The trace amines and their acidic metabolites in depressionan overview. Prog. Neuropsychopharmacol. Biol. Psychiatry 18, 1745. [6] OReilly, R.L., Davis, B.A., 1994. Phenylethylamine and schizophrenia. Prog Neuropsychopharmacol. Biol. Psychiatry 18, 6375. [7] D. K. Grandy (2007). "Trace amine-associated receptor 1Family archetype or iconoclast?" Pharmacology & Therapeutics 116 (3) 355-390.

3-Iodothyronamine

359

3-Iodothyronamine
3-Iodothyronamine

Identifiers CAS number ChemSpider Jmol-3D images 712349-95-6 8126125

[2] [1]

Image 1 [4] Image 2 Properties

[3]

Molecular formula Molar mass

(verify) [5]

C14H14INO2 355.17 g/mol

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

3-Iodothyronamine (T1AM) is an endogenous thyronamine. T1AM is a high-affinity ligand for the trace amine-associated receptor TAAR1 (TAR1, TA1), a recently discovered G protein-coupled receptor.[6][7] T1AM is the most potent TAAR1 agonist yet discovered.[] Activation of TAAR1 by T1AM results in the production of large amounts of cAMP. This effect is coupled with decreased body temperature and cardiac output.[8] Wu et al have pointed out that this relationship is not typical of the endocrine system, indicating that TAAR1 activity may not be coupled to G-proteins in some tissues, or that T1AM may interact with other receptor subtypes.[] T1AM may be part of a signaling pathway to modulate cardiac function, as the compound can induce negative inotropic effects and decrease cardiac output.[9]

External links
3-iodothyronamine [10] at the US National Library of Medicine Medical Subject Headings (MeSH)

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=712349-95-6 [2] http:/ / www. chemspider. com/ 8126125 [3] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=OC1%3DCC%3DC%28OC2%3DC%28I%29C%3DC%28CCN%29C%3DC2%29C%3DC1 [4] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=Ic2cc%28ccc2Oc1ccc%28O%29cc1%29CCN [5] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=399311871& page2=3-Iodothyronamine [10] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=3-iodothyronamine

5-MeO-DMT

360

5-MeO-DMT
5-MeO-DMT

Systematic (IUPAC) name

2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine
Clinical data Pregnancy cat. Legal status Routes ? Class A (UK) Schedule I(US) Smoked, Insufflated Identifiers CAS number ATC code PubChem IUPHAR ligand ChemSpider KEGG ChEBI ChEMBL 1019-45-0 ? CID 1832 145 [3] [4] [5] [6] [2] [1]

1766

C08309

CHEBI:2086

CHEMBL7257 Chemical data

[7]

Formula Mol. mass

C13H18N2O 218.298 g/mol

(what is this?) (verify)

[8]

5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) is a powerful psychedelic tryptamine. It is found in a wide variety of plant and psychoactive toad species and, like its close relatives DMT and bufotenin (5-HO-DMT), it has been used as an entheogen by South American shamans for thousands of years.

5-MeO-DMT

361

Chemistry
5-MeO-DMT was first synthesized in 1936, and in 1959 it was isolated as one of the psychoactive ingredients of Anadenanthera peregrina seeds used in preparing Yopo snuff. It was once believed to be a major component of the psychoactive effects of the snuff. It occurs in many organisms that contain bufotenin (5-OH-DMT), and is the O-methyl analogue of that compound. It is metabolized mainly by CYP2D6.[9]

History
Traditionally 5-MeO-DMT has been used in psychedelic snuff made from virola bark resin, and may be a trace constituent of ayahuasca when plants such as Diplopterys cabrerana are used as an admixture. 5-MeO-DMT is also found in the venom of the Colorado River toad (Bufo alvarius), although there is no direct evidence this was used as a hallucinogen until recent times.

Religious use
5-MeO-DMT is a sacrament of the Church of the Tree of Life. From approximately 1971 to the late 1980s 5-MeO-DMT was discreetly available to members of the Church of the Tree of Life from Inner Center and after 1986 was also available to some other religious groups from Inner Center.[] Between 1970 and 1990 smoking of 5-MeO-DMT on parsley was probably one of the two most common forms of ingestion in the United States.[] A member of the Church of the Tree of Life estimates there were fewer than 6000 active members in 1979.[]

Pharmacology
5-MeO-DMT is a methoxy analogue of DMT. Its pharmacological action is mainly through serotonin (5-HT) receptors. Specifically, this molecule shows high affinity for the 5-HT2 and 5-HT1A subtypes.[] Additional mechanisms of action such as inhibition of monoamine reuptake may be involved also.[]

Use and effects

When used as a drug in its purified form, 5-MeO-DMT is vaporized, insufflated, or injected and is active at a dose of as little as 2mg. 5-MeO-DMT is also active orally, when taken with a MAOI, but according to numerous reports, the combination with MAOI is extremely unpleasant and has a strong body load. Additional mechanisms of action such as inhibition of MAOI may be involved also. According to the researcher Jonathan Ott, 5-MeO-DMT is active orally with doses over 30mg without aid of an MAOI. The onset of effects occurs within seconds after vaporizing/injecting, or minutes after Bufo alvarius, which has 5-MeO-DMT in its venom and skin. insufflating, and the experience is sometimes described as similar to a near-death experience. Peak effects last for approximately 510 minutes when vaporized. When insufflated, the peak effects are considerably less intense, but last for 1525 minutes on average.

5-MeO-DMT Although similar in many respects to its close relatives DMT and bufotenin (5-OH-DMT), the effects are typically not as visual. Some users report experiencing no visual effects from it even at very high doses.[] Some report the effects to be unpleasant causing nausea and the feeling of being "sat on by an elephant".[] Erowid lists the following effects for vaporized 5-MeO-DMT:[]

362

Positive
immersive experiences powerful "rushing" sensation radical perspective shifting profound life-changing spiritual experiences occasional euphoria internal visions (actual visual effects not as common)

Neutral
short duration change in perception of time experience of "the void" lack of memory of experience muscle jerking, twitching, abnormal vocalizations unconsciousness / nonresponsiveness lasting 520 minutes dissociation

Negative
overly intense experiences, Fear, Dysphoria, Panic nausea[] sense of pressure in the body[] difficulty integrating experiences fast onset and intensity can lead to problems if not prepared (dropped pipe, knocking things over, falling & hitting head, etc.)

Legality
International Law
Denmark As of December 1, 2004, 5-MeO-DMT is legally restricted to "medical or scientific purposes". See EMCDDA.[citation needed] Germany Schedule I / Highest level of control, unable to be prescribed, manufactured, or possessed as of Sep, 1999. (listed as [2-(5-Methoxyindol-3-yl)ethyl]dimethylazan)[10] Greece 5-MeO-DMT became a controlled substance in Greece on February 18, 2003 [EU Legal Database].[citation needed]

5-MeO-DMT New Zealand 5-MeO-DMT is Schedule I (Class A) in New Zealand.[citation needed] Sweden Controlled in Sweden as of October 1, 2004 (see notisum.se)[citation needed] Switzerland 5-MeO-DMT is Schedule I in Switzerland.[citation needed] Romania 5-MeO-DMT is illegal in Romania since February 2010.[citation needed]

363

US Federal Law
On August 21, 2009, the Drug Enforcement Administration issued a Notice of Proposed Rulemaking to initiate placing 5-MeO-DMT into Schedule I of the Controlled Substances Act (the most restrictive category).[] Comment DEA-2009-0008-0007.1 requested a 180 day extension of the period for public comment and requests for hearings, objected to the proposed rule on multiple grounds including Constitutional issues, identified the submitter as a person who would be "adversely affected and aggrieved by the proposed ruling" and requested an exemption for religious use if DEA did place 5-MeO-DMT in Schedule I "as an attempt to define and clarify some legal issues."[] On September 29 and 30, 2009, the DEA posted the Supporting & Related Materials for the NPRM while retaining the September 21, 2009 Due date for comments.[11] On October 28, 2009 DEA reopened the period for public comment because it had not posted two Supporting & Related Materials documents online during the original period for public comment. Documents and comments were split between Docket ID: DEA-2009-0008 and Docket ID: DEA-2009-0013 in a manner which creates difficulty and in viewing all documents and determining where and how to submit comments online. The two Supporting & Related Materials documents were not posted to Docket ID: DEA-2009-0013 until November 3, 2009 but the 30 day period for public comment was not changed from November 27, 2009.[12] 5-MeO-DMT has been added to Schedule I, effective January 19, 2011. This means it is illegal to manufacture, buy, possess, or distribute (sell, trade or give) without a DEA license.[13]

US State Law
Nebraska Schedule I[] Oklahoma Schedule I[] S. Dakota Schedule I[]

References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=1019-45-0& rn=1 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=1832 [3] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=145 [4] http:/ / www. chemspider. com/ Chemical-Structure. 1766 [5] http:/ / www. kegg. jp/ entry/ C08309

5-MeO-DMT
[6] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:2086 [7] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL7257 [8] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477224937& page2=5-MeO-DMT [10] see Deutsche BtMG or http:/ / www. silicium-sensei. de/ projecte/ drugs/ news/ news. html

364

External links
TiHKAL #38 on Erowid (http://www.erowid.org/library/books_online/tihkal/tihkal38.shtml) and Erowid's 5-MeO-DMT Vault (http://www.erowid.org/chemicals/5meo_dmt/5meo_dmt.shtml) 5-MeO-DMT Entry in TiHKAL info (http://tihkal.info/read.php?domain=tk&id=38)

Bufotenin

365

Bufotenin
Bufotenin

Systematic (IUPAC) name

3-(2-dimethylaminoethyl)-1H-indol-5-ol
Clinical data Pregnancy cat. Legal status Routes ? Schedule I (US) Parenteral Identifiers CAS number ATC code PubChem 487-93-4 None CID 10257 [2] [1]

IUPHAR ligand 144 [3] DrugBank ChemSpider KEGG ChEBI ChEMBL Synonyms DB01445 9839 [5] [6] [7] [8] [4]

C08299

CHEBI:3210

CHEMBL416526

N,N-dimethyl-5-hydroxytryptamine, 5-hydroxy-dimethyltryptamine, bufotenine, cebilcin Chemical data

Formula Mol. mass

C12H16N2O 204.268 g/mol

Physical data

Bufotenin

366
Melt. point Boiling point 146147C (295297F) 320C (608F) (what is this?) (verify) [9]

Bufotenin (5-HO-DMT, N,N-dimethylserotonin), is a tryptamine related to the neurotransmitter serotonin. It is an alkaloid found in the skin of some species of toads; in mushrooms, higher plants, and mammals.[10] The name bufotenin originates from the Bufo genus of toads, which includes several species of psychoactive toads, most notably Bufo alvarius, that secrete bufotoxins from their parotoid glands.[11] Bufotenin is similar in chemical structure to the psychedelics psilocin (4-HO-DMT), 5-MeO-DMT, and DMT, chemicals which also occur in some of the same fungus, plant, and animal species as bufotenin. The psychoactivity of bufotenin has been disputed, though recent studies suggest it is similar in nature to 5-MeO-DMT.

Nomenclature
Bufotenin (bufotenine) is also known by the chemical names 5-hydroxy-N,N-dimethyltryptamine (5-HO-DMT), N,N-dimethyl-5-hydroxytryptamine, dimethyl serotonin,[] and mappine.[]

History
Bufotenin was first isolated, from toad skin, and named by the Austrian chemist Handovsky at the University of Prague during World War I.[] The structure of bufotenine was first confirmed in 1934 by Heinrich Wielands laboratory in Munich, and the first reported synthesis of bufotenine was by Toshio Hoshino in 1936.[]

Sources
Toads
Bufotenin is a chemical constituent in the venom and eggs of several species of toads belonging to the Bufo genus, but most notably in the Colorado River toad (Bufo alvarius) as it is the only toad species in which bufotenin is present in large enough quantities for a psychoactive effect. Extracts of toad venom, containing bufotenin and other bioactive compounds, have been used in some traditional medicines such as chan su (probably derived from Bufo gargarizans), which has been used medicinally for centuries in China.[] The toad was "recurrently depicted in Mesoamerican art,"[12] which some authors have interpreted as indicating that the effects of ingesting Bufo secretions have been known in Mesoamerica for many years; however, others doubt that this art provides sufficient "ethnohistorical evidence" to support the claim.[] In addition to bufotenine, Bufo venoms also contain digoxin-like cardiac glycosides, and ingestion of the venom can be fatal. Ingestion of Bufo toad venom and eggs by humans has resulted in several reported cases of poisoning,[][][] some of which resulted in death.[][][13] Contemporary reports indicate that bufotenine-containing toad venom has been used as a street drug; that is, as a supposed aphrodisiac (it is not an aphrodisiac but definitely is a lethal poison[14]), ingested orally in the form of chan su,[] and as a psychedelic, by smoking or orally ingesting Bufo toad venom or dried Bufo skins. The use of chan'su and love stone (a related toad venom preparation used as an aphrodisiac in the West Indies) has resulted in several cases of poisoning and at least one death.[][] The practice of orally ingesting toad venom has been referred to in popular culture and in the scientific literature as toad licking and has drawn media attention.[15][16] Albert Most, founder of the Church of the Toad of Light and a proponent of recreational use of Bufo alvarius venom, published a booklet titled Bufo alvarius: The Psychedelic Toad of the Sonoran Desert[][17] in 1983 which explained how to extract and smoke the secretions.

Bufotenin Bufotenin is also present in the skin secretion of three arboreal amphibian species of the Osteocephalus genus (Osteocephalus taurinus, Osteocephalus oophagus, and Osteocephalus langsdorffii) from the Amazon and Atlantic rain forests.[]

367

Anadenanthera seeds
Bufotenin is a constituent of the seeds of Anadenanthera colubrina and Anadenanthera peregrina trees. Anadenanthera seeds have been used as an ingredient in psychedelic snuff preparations by indigenous cultures of the Caribbean, Central and South America.[18]

Other sources
Bufotenin has been identified as a component in the latex of the takini (Brosimum acutifolium) tree, which is used as a psychedelic by South American shamans,[] and in the seeds of Mucuna pruriens []

Pharmacology
Uptake and elimination
In rats, subcutaneously administered bufotenin (1100 g/kg) distributes mainly to the lungs, heart, and blood, and to a much lesser extent, the brain (hypothalamus, brain stem, striatum, and cerebral cortex) and liver. It reaches peak concentrations at 1 hour and is nearly completely eliminated within 8 hours.[] In humans, intravenous administration of bufotenin results in excretion of (70%) of injected drug in the form of 5-HIAA, an endogenous metabolite of serotonin, while roughly 4% is eliminated unmetabolized in the urine. Orally administered bufotenine undergoes extensive first-pass metabolism by the enzyme monoamine oxidase.

Lethal dose
The acute toxicity (LD50) of bufotenin in rodents has been estimated at 200 to 300mg/kg. Death occurs by respiratory arrest.[18]

Effects in humans
Fabing & Hawkins (1955) In 1955, Fabing and Hawkins administered bufotenin intravenously at doses of up to 16mg to prison inmates at Ohio State Penitentiary.[] A troubling toxic blood circulation effect causing a purpling of the face was seen in these tests. A subject given 1mg reported a tight feeling in the chest and prickling as if he had been jabbed by needles. This was accompanied by a fleeting sensation of pain in both thighs and a mild nausea. [] Another subject given 2mg reported tightness in his throat. He had tightness in the stomach, tingling in pretibial areas, and developed a purplish hue in the face indicating blood circulation problems. He vomited after 3 minutes.[] Another subject given 4mg complained of chest oppression and that a load is pressing down from above and my body feels heavy. The subject also reported numbness of the entire body and a pleasant Martini feeling-my body is taking charge of my mind. The subject reported he saw red spots passing before his eyes and red-purple spots on the floor, and the floor seemed very close to his face. Within 2 minutes these visual effects were gone, and replaced by a yellow haze, as if he were looking through a lens filter.[] Fabing and Hawkins commented that bufotenins psychedelic effects were "reminiscent of LSD and mescaline but develop and disappear more quickly, indicating rapid central action and rapid degradation of the drug".

Bufotenin Isbell (1956) In 1956, Dr. Harris S. Isbell at the Public Health Service Hospital in Lexington, Kentucky experimented with bufotenine as a snuff. He reported no subjective or objective effects were observed after spraying with as much as 40 mg bufotenine; however subjects who received 1012mg injected intramuscularly reported elements of visual hallucinations consisting of a play of colors, lights, and patterns.[] Turner & Merlis (1959) Turner and Merlis (1959) [] experimented with intravenous administration of bufotenine (as the water soluble creatinine sulfate salt) to schizophrenics at a New York state hospital. They reported that when one subject received 10mg during a 50-second interval, the peripheral nervous system effects were extreme: at 17 seconds, flushing of the face, at 22 seconds, maximal inhalation, followed by maximal hyperventilation for about 2 minutes, during which the patient was unresponsive to stimuli; her face was plum-colored". Finally, Turner and Merlis reported that: on one occasion, which essentially terminated our study, a patient who received 40 mg intramuscularly, suddenly developed an extremely rapid heart rate; no pulse could be obtained; no blood pressure measured. There seemed to have been an onset of auricular fibrillationextreme cyanosis developed. Massage over the heart was vigorously executed and the pulse returned to normalshortly thereafter the patient, still cyanotic, sat up saying: Take that away. I dont like them. After pushing doses to the morally admissible limit without producing visuals, Turner and Merlis conservatively concluded: We must reject bufotenineas capable of producing the acute phase of Cohoba intoxication.[] McLeod and Sitaram (1985) A 1985 study by McLeod and Sitaram in humans reported that bufotenine administered intranasally at a dose of 116mg had no effect, other than intense local irritation. When given intravenously at low doses (24mg), bufotenine oxalate caused anxiety but no other effects; however, a dose of 8mg resulted in profound emotional and perceptual changes, involving extreme anxiety, a sense of imminent death, and visual disturbance associated with color reversal and distortion, and intense flushing of the cheeks and forehead.[] Ott (2001) In 2001, ethnobotanist Jonathan Ott published the results of a study in which he self-administered free base bufotenine via insufflation (5100mg), sublingually (50mg), intrarectally (30mg), orally (100mg) and via vaporization (28mg).[] Ott reported visionary effects" of intranasal bufotenine and that the "visionary threshold dose" by this route was 40mg, with smaller doses eliciting perceptibly psychoactive effects. He reported that "intranasal bufotenine is throughout quite physically relaxing; in no case was there facial rubescence, nor any discomfort nor disesteeming side effects". At 100mg, effects began within 5 minutes, peaked at 3540 minutes, and lasted up to 90 minutes. Higher doses produced effects that were described as psychedelic, such as "swirling, colored patterns typical of tryptamines, tending toward the arabesque". Free base bufotenin taken sublingually was found to be identical to intranasal use. The potency, duration, and psychedelic action was the same. Ott found vaporized free base bufotenin active from 28mg with 8mg producing "ring-like, swirling, colored patterns with eyes closed". He noted that the visionary effects of insufflated bufotenine were verified by one colleague, and those of vaporized bufotenine by several volunteers. Ott concluded that free base bufotenin taken intranasally and sublingually produced effects similar to those of Yopo without the toxic peripheral symptoms, such as facial flushing, observed in other studies in which the drug was administered intravenously.

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Bufotenin

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Association with schizophrenia and other mental disorders

A study conducted in the late 1960s reported the detection of bufotenin in the urine of schizophrenic subjects;[] however, subsequent research has failed to confirm these findings.[][][][] Studies have detected endogenous bufotenin in urine specimens from individuals with other psychiatric disorders,[] such as infant autistic patients.[] Another study indicated that paranoid violent offenders or those who committed violent behaviour towards family members have higher bufotenin levels in their urine than other violent offenders.[] A 2010 study utilized a mass spectrometry approach to detect levels of bufotenin in the urine of individuals with severe autism spectrum disorder (ASD), schizophrenia, and asymptomatic subjects. Their results indicate significantly higher levels of bufotenin in the urine of the ASD and schizophrenic groups when compared to asymptomatic individuals.[]

Legal status
Bufotenine is regulated as a Schedule I drug (ID number 7403) by the U.S. Drug Enforcement Agency.[] It is classified as a Schedule I controlled substance according to the Criminal Code Regulations of the Government of the Commonwealth of Australia.[] In the UK, the substance is a Class A drug under the 1971 Misuse of Drugs Act.

References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=487-93-4& rn=1 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=10257 [3] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=144 [4] http:/ / www. drugbank. ca/ drugs/ DB01445 [5] http:/ / www. chemspider. com/ Chemical-Structure. 9839 [6] http:/ / www. kegg. jp/ entry/ C08299 [7] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:3210 [8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL416526 [9] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=443669819& page2=Bufotenin [10] CID 10257. (http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=10257) PubChem. Accessed on May 6, 2007. [11] Bufo Alvarius. (http:/ / amphibiaweb. org/ cgi/ amphib_query?query_src=aw_lists_soundInclude_& where-genus=Bufo& where-species=alvarius) AmphibiaWeb. Accessed on May 6, 2007. [14] http:/ / www. ehealthstrategies. com/ files/ aphrodisia. pdf [15] The Dog Who Loved to Suck on Toads. (http:/ / www. npr. org/ templates/ story/ story. php?storyId=6376594) NPR. Accessed on May 6, 2007. [16] Psychoactive toad: Cultural references [17] How bout them toad suckers? Aint they clods? (http:/ / www. smokymountainnews. com/ issues/ 11_06/ 11_01_06/ out_naturalist. html) Smoky Mountain News. Accessed on May 6, 2007 [18] Anadenanthera: Visionary Plant Of Ancient South America By Constantino Manuel Torres, David B. Repke, 2006, ISBN 0-7890-2642-2

External links
Erowid's Bufotenin Vault (http://www.erowid.org/chemicals/bufotenin/bufotenin.shtml) TiHKAL entry on Bufotenin (http://www.erowid.org/library/books_online/tihkal/tihkal19.shtml) Bufotenin (5-HO-DMT) entry in TiHKAL info (http://tihkal.info/read.php?domain=tk&id=19)

Dimethyltryptamine

370

Dimethyltryptamine
Dimethyltryptamine

Systematic (IUPAC) name

2-(1H-indol-3-yl)-N,N-dimethylethanamine
Clinical data Pregnancy cat. Legal status Routes ? Prohibited (S9) (AU) Schedule III (CA) CD Lic (UK) Schedule I (US) Oral (with an MAOI), Insufflated, Rectal, vaporized, IM, IV Identifiers CAS number ATC code PubChem 61-50-7 None CID 6089 [2] [1]

IUPHAR ligand 141 [3] DrugBank ChemSpider UNII KEGG ChEBI ChEMBL DB01488 5864 [5] [6] [4]

WUB601BHAA C08302 [7]

CHEBI:28969

[8]

Chemical data

CHEMBL12420

[9]

Formula Mol. mass

C12H16N2 188.269 g/mol

Physical data

Dimethyltryptamine

371
Density Melt. point Boiling point 1.099g/mlg/cm 40C (104F) 160C (320F) @ 0.6 Torr [10] also reported as 80 135 C @ 0.03 Torr [12] [11]

(what is this?) (verify)

N,N-Dimethyltryptamine (DMT or N,N-DMT) is a psychedelic compound of the tryptamine family. Its presence is widespread throughout the plant kingdom.[][] DMT occurs in trace amounts in mammals, including humans, where it putatively functions as a trace amine neurotransmitter/neuromodulator.[] It is originally derived from the essential amino acid tryptophan and ultimately produced by the enzyme INMT during normal metabolism.[] The significance of its widespread natural presence remains undetermined. Structurally, DMT is analogous to the neurotransmitter serotonin (5-HT), the hormone melatonin, and other psychedelic tryptamines, such as 5-MeO-DMT, bufotenin, psilocin and psilocybin. When ingested, DMT acts as a psychedelic drug.[] Depending on the dose and method of administration, its subjective effects can range from short-lived milder psychedelic states to powerful immersive experiences; these are often described as a total loss of connection to conventional reality with the encounter of ineffable spiritual/alien realms.[] Indigenous Amazonian Amerindian cultures consume DMT as the primary psychoactive in ayahuasca, a shamanistic brew used for divinatory and healing purposes. Pharmacologically, ayahuasca combines DMT with an MAOI, an enzyme inhibitor that allows DMT to be orally active.[]

History
DMT was first synthesized in 1931 by Canadian chemist Richard Helmuth Fredrick Manske (19011977).[13][] Its discovery as a natural product is generally credited to Brazilian chemist and microbiologist Oswaldo Gonalves de Lima (19081989) who, in 1946, isolated an alkaloid he named nigerina (nigerine) from the root bark of jurema preta, that is, Mimosa tenuiflora.[][][14] However, in a careful review of the case Jonathan Ott shows that the empirical formula for nigerine determined by Gonalves de Lima, which notably contains an atom of oxygen, can only match a partial, "impure" or "contaminated" form of DMT.[] It was only in 1959, when Gonalves de Lima provided American chemists a sample of Mimosa tenuiflora roots, that DMT was unequivocally identified in this plant material.[][15] Less ambiguous is the case of isolation and formal identification of DMT in 1955 in seeds and pods of Anadenanthera peregrina by a team of American chemists led by Evan Horning (19161993).[][16] Since 1955 DMT has been found in a host of organisms: in at least 50 plant species belonging to 10 families,[] and in at least 4 animal species, including one gorgonian[17] and 3 mammalian species (see Endogenous DMT). Another historical milestone is the discovery of DMT in plants frequently used by Amazonian natives as additive to the vine Banisteriopsis caapi to make ayahuasca decoctions. In 1957, American chemists Francis Hochstein and Anita Paradies identified DMT in an "aqueous extract" of leaves of a plant they named Prestonia amazonicum (sic) and described as "commonly mixed" with B. caapi.[18] The lack of a proper botanical identification of Prestonia amazonica in this study led American ethnobotanist Richard Evans Schultes (19152001) and other scientists to raise serious doubts about the claimed plant identity.[19][] A better evidence is produced in 1965 by French pharmacologist Jacques Poisson who isolated DMT as sole alkaloid from leaves, provided and used by Aguaruna Indians, identified as pertaining to the vine Diplopterys cabrerana (then known as Banisteriopsis rusbyana).[] Published in 1970, the first identification of DMT in the other commonly used additiveWikipedia:Please clarify plant Psychotria viridis[] was made by a team of American researchers led by pharmacologist Ara der Marderosian.[20] Not only did they detect DMT in leaves of P. viridis obtained from Cashinahua Indians, but they also were the first to identify it in a sample of an ayahuasca decoction, prepared by the same Indians.[]

Dimethyltryptamine

372

Biosynthesis
Dimethyltryptamine is an indole alkaloid derived from the shikimate pathway. Its biosynthesis is relatively simple and summarized in the picture to the left. In plants, the parent amino acid L-tryptophan is produced endogenously where in animals L-tryptophan is an essential amino acid coming from diet. No matter the source of L-tryptophan, the biosynthesis begins with its decarboxylation by an aromatic amino acid decarboxylase (AADC) enzyme (step 1). The resulting decarboxylated tryptophan analog is tryptamine. Tryptamine then undergoes a transmethylation (step 2): the enzyme indolethylamine-N-methyltransferase (INMT) catalyzes the transfer of a methyl group from cofactor S-adenosyl-methionine (SAM), via nucleophilic attack, to tryptamine. This reaction transforms SAM into S-adenosylhomocysteine (SAH), and gives the intermediate product N-methyltryptamine (NMT).[][] NMT is in turn transmethylated by the same process (step 3) to form the end product N,N-dimethyltryptamine. Tryptamine transmethylation is regulated by two products of the reaction: SAH,[][][] and DMT[][] were shown ex vivo to be among the most potent inhibitors of rabbit INMT activity. This transmethylation mechanism has been repeatedly and consistently proven by radiolabeling of SAM methyl group with carbon-14 (14C-CH3)SAM).[][][][][]

Evidence in mammals
Published in Science in 1961, Julius Axelrod found an N-methyltransferase enzyme capable of mediating biotransformation of tryptamine into DMT in a rabbit's lung.[] This finding initiated a still ongoing scientific interest in endogenous DMT Biosynthetic pathway for production in humans and other mammals.[][] From then on, two major N,N-dimethyltryptamine complementary lines of evidence have been investigated: localization and further characterization of the N-methyltransferase enzyme, and analytical studieslooking for endogenously produced DMT in body fluids and tissues.[] INMT Before techniques of molecular biology were used to localize indolethylamine N-methyltransferase (INMT),[][] characterization and localization went on a par: samples of the biological material where INMT is hypothesized to be active are subject to enzyme assay. Those enzyme assays are performed either with a radiolabeled methyl donor like (14C-CH3)SAM to which known amounts of unlabeled substrates like tryptamine are added,[] or with addition of a radiolabeled substrate like (14C)NMT to demonstrate in vivo formation.[][] As qualitative determination of the radioactively tagged product of the enzymatic reaction is sufficient to characterize INMT existence and activity (or lack of), analytical methods used in INMT assays aren't required to be as sensitive as those needed to directly detect and quantify the minute amounts of endogenously formed DMT (see DMT subsection below). The essentially qualitative method thin layer chromatography (TLC) was thus used in a vast majority of studies.[] Also, robust evidence that INMT can catalyze transmethylation of tryptamine into NMT and DMT could be provided with reverse isotope dilution analysis coupled to mass spectrometry for rabbit[][] and human[] lung during the early 1970s. Selectivity rather than sensitivity proved to be an Achilles heel for some TLC methods with the discovery in 19741975 that incubating rat blood cells or brain tissue with (14C-CH3)SAM and NMT as substrate mostly yields tetrahydro--carboline derivatives,[][][] and negligible amounts of DMT in brain tissue.[] It is indeed simultaneously realized that the TLC methods used thus far in almost all published studies on INMT and DMT biosynthesis are incapable to resolve DMT from those tetrahydro--carbolines.[] These findings are a blow for all previous claims of

Dimethyltryptamine evidence of INMT activity and DMT biosynthesis in avian[] and mammalian brain,[][] including in vivo,[][] as they all relied upon use of the problematic TLC methods:[] their validity is doubted in replication studies that make use of improved TLC methods, and fail to evidence DMT-producing INMT activity in rat and human brain tissues.[][] Published in 1978, the last study attempting to evidence in vivo INMT activity and DMT production in brain (rat) with TLC methods finds biotransformation of radiolabeled tryptamine into DMT to be real but "insignificant".[] Capability of the method used in this latter study to resolve DMT from tetrahydro--carbolines is questioned later.[] To localize INMT, a qualitative leap is accomplished with use of modern techniques of molecular biology, and of immunohistochemistry. In humans, a gene encoding INMT is determined to be located on chromosome 7.[] Northern blot analyses reveal INMT messenger RNA (mRNA) to be highly expressed in rabbit lung,[] and in human thyroid, adrenal gland, and lung.[][21] Intermediate levels of expression are found in human heart, skeletal muscle, trachea, stomach, small intestine, pancreas, testis, prostate, placenta, lymph node, and spinal cord.[][21] Low to very low levels of expression are noted in rabbit brain,[] and human thymus, liver, spleen, kidney, colon, ovary, and bone marrow.[][21] INMT mRNA expression is absent in human peripheral blood leukocytes, whole brain, and in tissue from 7 specific brain regions (thalamus, subthalamic nucleus, caudate nucleus, hippocampus, amygdala, substantia nigra, and corpus callosum).[][21] Immunohistochemistry showed INMT to be present in large amounts in glandular epithelial cells of small and large intestines, and to be absent in neurons.[] Endogenous DMT The first claimed detection of mammalian endogenous DMT was published in June 1965: German researchers F. Franzen and H. Gross report to have evidenced and quantified DMT, along with its structural analog bufotenin (5-OH-DMT), in human blood and urine.[] In an article published four months later, the method used in their study is strongly criticized, and credibility of their results challenged.[] In 2001, surveys, made in research articles, point that few of the analytical methods previously used to measure levels of endogenously formed DMT had enough sensitivity and selectivity to produce reliable results.[][] Gas chromatography, preferably coupled to mass spectrometry (GC-MS), is considered a minimum requirement.[] A study published in 2005[] implements the most sensitive and selective method ever used to measure endogenous DMT:[] liquid chromatography-tandem mass spectrometry with electrospray ionization (LC-ESI-MS/MS) allows to reach limits of detection (LODs) 12 to 200 fold lower (that is, better) than those attained by the best methods employed in the 1970s. The data summarized in the table below are from studies conforming to the abovementioned requirements (abbreviations used: CSF = cerebrospinal fluid; LOD = limit of detection; n = number of samples; ng/L and ng/kg = nanograms (109 g) per litre, and nanograms per kilogram, respectively):

373

DMT in body fluids and tissues (NB: units have been harmonized)
Species Sample < LOD (n = 66) [] Results

Human Blood serum

Blood plasma < LOD (n = 71)[] < LOD (n = 38); 1,000 & 10,600ng/L (n = 2)[] Whole blood Urine Feces Kidney Lung Lumbar CSF < LOD (n = 20); 50790ng/L (n = 20) []

[] [] [] < 100ng/L (n = 9) < LOD (n = 60); 160540ng/L (n = 5) Detected in n = 10 by GC-MS < 50ng/kg (n= 12); 130ng/kg (n = 1) 15ng/kg (n = 1) 14ng/kg (n = 1) [] [] [] []

100,370ng/L (n = 1); 2,3307,210ng/L (n = 3); 350 & 850ng/L (n = 2)

Dimethyltryptamine
[] []

374

Rat

Kidney Lung Liver Brain

12 &16ng/kg (n = 2)

22 & 12ng/kg (n = 2) 6 & 10ng/kg (n = 2)

[]

[] [] 10 &15ng/kg (n = 2) Measured in synaptic vesicular fraction < 10ng/kg (n = 1) []

Rabbit Liver

Physical and chemical properties

DMT is commonly handled and stored as a fumarate,[citation needed] as other DMT acid salts are generally very hygroscopic and will not readily crystallize. Its freebase form, although less stable than DMT fumarate, is favored by recreational users choosing to vaporize the chemical because it has a lower boiling point.[citation needed] In contrast to DMT's base, its salts are water-soluble. DMT in solution degrades relatively quickly and should be stored protected from air, light, and heat in a freezer.[citation needed]
DMT crystals

Pharmacology
Pharmacokinetics
DMT peak levels concentrations (Cmax) measured in whole blood after intramuscular (IM) injection (0.7mg/kg, n = 11)[] and in plasma following intravenous (IV) administration (0.4mg/kg, n = 10)[] of fully psychedelic doses are in the range of 14 to 154 g/L and 32 to 204 g/L, respectively. The corresponding molar concentrations of DMT are therefore in the range of 0.0740.818 M in whole blood and 0.1701.08 M in plasma. However, several studies have described active transport and accumulation of DMT into rat and dog brain following peripheral administration.[][][][][] Similar active transport, and accumulation processes likely occur in human brain and may concentrate DMT in brain by several-fold or more (relatively to blood), resulting in local concentrations in the micromolar or higher range. Such concentrations would be commensurate with serotonin brain tissue concentrations which have been consistently determined to be in the 1.5-4 M range.[][] Closely coextending with peak psychedelic effects, mean time to reach peak concentrations (Tmax) was determined to be 1015 minutes in whole blood after IM injection,[] and 2 minutes in plasma after IV administration.[] When taken orally mixed in an ayahuasca decoction, and in freeze-dried ayahuasca gel caps, DMT Tmax is considerably delayed: 107.59 32.5 minutes,[] and 90120 minutes,[] respectively. The pharmacokinetics for smoking DMT have not been studied or reported.

Pharmacodynamics
DMT binds non-selectively with affinities < 0.6 M to the following serotonin receptors: 5-HT1A,[][][] 5-HT1B,[][] 5-HT1D,[][][] 5-HT2A,[][][][] 5-HT2B,[][] 5-HT2C,[][][] 5-HT6,[][] and 5-HT7.[][] An agonist action has been determined at 5-HT1A,[] 5-HT2A and 5-HT2C.[][][] Its efficacies at other serotonin receptors remain to be determined. Of special interest will be the determination of its efficacy at human 5-HT2B receptor as two in vitro assays evidenced DMT high affinity for this receptor: 0.108 M[] and 0.184 M.[] This may be of importance because chronic or frequent

Dimethyltryptamine uses of serotonergic drugs showing preferential high affinity and clear agonism at 5-HT2B receptor have been causally linked to valvular heart disease.[][][22] It has also been shown to possess affinity for the dopamine D1, 1-adrenergic, 2-adrenergic, imidazoline-1, sigma-1 (1), and trace amine-associated receptors.[][][] Agonism was demonstrated at 1 M at the rat trace amine-associated receptor 1 (TAAR1)[] and converging lines of evidence established activation of the 1 receptor at concentrations of 50100 M.[] Its efficacies at the other receptor binding sites are unclear. It has also been shown in vitro to be a substrate for the cell-surface serotonin transporter (SERT) and the intracellular vesicular monoamine transporter 2 (VMAT2), inhibiting SERT-mediated serotonin uptake in human platelets at an average concentration of 4.00 0.70 M and VMAT2-mediated serotonin uptake in vesicles (of army worm Sf9 cells) expressing rat VMAT-2 at an average concentration of 93 6.8 M.[] As with other so-called "classical hallucinogens",[] a large part of DMT psychedelic effects can be attributed to a functionally selective activation of the 5-HT2A receptor.[][][][][][][] DMT concentrations eliciting 50% of its maximal effect (half maximal effective concentration = EC50 or Kact) at the human 5-HT2A receptor in vitro are in the 0.1180.983 M range.[][][][] This range of values coincides well with the range of concentrations measured in blood and plasma after administration of a fully psychedelic dose (see Pharmacokinetics). As DMT has been shown to have slightly better efficacy (EC50) at human serotonin 2C receptor than at 2A receptor,[][] 5-HT2C highly likely also is implicated in DMT's overall effects.[][] Other receptors, such as 5-HT1A[][][] 1,[][] and TAAR1[][][] may also play a role.

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In 2009 it was hypothesized that DMT may be an endogenous ligand for the 1 receptor.[][] The concentration of DMT needed for 1 activation in vitro (50100 M) is similar to the behaviorally active concentration measured in mouse brain of approximately 106 M [] This is minimally 4 orders of magnitude (104) higher than the average concentrations measured in rat brain tissue or human plasma under basal conditions (see Endogenous DMT), so 1 receptors are likely to be activated only under conditions of high local DMT concentrations. If DMT is stored in synaptic vesicles,[] such concentrations might occur during vesicular release. To illustrate, while the average concentration of serotonin in brain tissue is in the 1.5-4 M range,[][] the concentration of serotonin in synaptic vesicles was measured at 270 mM.[] Following vesicular release, the resulting concentration of serotonin in the synaptic cleft, to which serotonin receptors are exposed, is estimated to be about 300 M. Thus, while in vitro receptor binding affinities, efficacies, and average concentrations in tissue or plasma are useful, they are not likely to predict DMT concentrations in the vesicles or at synaptic or intracellular receptors. Under these conditions, notions of receptor selectivity are moot, and it seems probable that most of the receptors identified as targets for DMT (see above) participate in producing its psychedelic effects.

Psychedelic properties
"So I did it and...there was a something, like a flower, like a chrysanthemum in orange and yellow that was sort of spinning, spinning, and then it was like I was pushed from behind and I fell through the chrysanthemum into another place that didn't seem like a state of mind, it seemed like another place. And what was going on in this place aside from the tastefully soffited indirect lighting, and the crawling geometric hallucinations along the domed walls, what was happening was that there were a lot of beings in there, what I call self-transforming machine elves. Sort of like jewelled basketballs all dribbling their way toward me. And if they'd had faces they would have been grinning, but they didn't have faces. And they assured me that they loved me and they told me not to be amazed; not to give way to astonishment." Terence McKenna, on his first experience with DMT
[23]

DMT is produced naturally in many species of plants often in conjunction with its close chemical relatives 5-MeO-DMT and bufotenin (5-OH-DMT).[18] DMT-containing plants are commonly used in South American Shamanic practices. It is usually one of the main active constituents of the drink ayahuasca,[][] however ayahuasca is sometimes brewed with plants which don't produce DMT. It occurs as the primary psychoactive alkaloid in several plants including Mimosa tenuiflora, Diplopterys cabrerana, and Psychotria viridis. DMT is found as a minor

Dimethyltryptamine alkaloid in snuff made from Virola bark resin in which 5-MeO-DMT is the main active alkaloid.[18] DMT is also found as a minor alkaloid in bark, pods, and beans of Anadenanthera peregrina and Anadenanthera colubrina used to make Yopo and Vilca snuff in which bufotenin is the main active alkaloid.[18][] Psilocin, an active chemical in many psychedelic mushrooms, is structurally similar to DMT. The psychotropic effects of DMT were first studied scientifically by the Hungarian chemist and psychologist Dr. Stephen Szra who performed research with volunteers in the mid-1950s. Szra, who later worked for the US National Institutes of Health, had turned his attention to DMT after his order for LSD from the Swiss company Sandoz Laboratories was rejected on the grounds that the powerful psychotropic could be dangerous in the hands of a communist country.[14] DMT can produce powerful psychedelic experiences including intense visuals, euphoria and hallucinations.[] DMT is generally not active orally unless it is combined with a monoamine oxidase inhibitor (MAOI) such as a reversible inhibitor of monoamine oxidase A (RIMA), for example, harmaline.[] Without an MAOI, the body quickly metabolizes orally administered DMT, and it therefore has no hallucinogenic effect unless the dose exceeds monoamine oxidase's metabolic capacity. Other means of ingestion such as smoking, injecting, or insufflating the drug can produce powerful hallucinations and entheogenic activity for a short time (usually less than half an hour), as the DMT reaches the brain before it can be metabolized by the body's natural monoamine oxidase. Taking a MAOI prior to vaporizing or injecting DMT prolongs and potentiates the effects.[]

376

Inhalation
A standard dose for vaporized DMT is between 1560mg. This is generally DMT during various stages of purification inhaled in a few successive breaths. The effects last for a short period of time, usually 5 to 15 minutes, dependent on the dose. The onset after inhalation is very fast (less than 45 seconds) and peak effects are reached within a minute. In the 1960s, DMT was known as a "businessman's trip" in the US because of the relatively short duration (and rapid onset) of action when vaporized.[24] The most common way to administer DMT among people who use it is to vaporize it. The inhalation of DMT is most effectively achieved by vaporizing it through the use of a glass pipe. Combining DMT with plant matter or depositing it upon a substrate of ash also facilitates use of an ordinary smoking pipe or a vaporizer. The vapor is sometimes described as harsh, and some users even compare its flavor and aroma to that of burning plastic or mothballs.[citation needed]

Insufflation
Insufflating DMT (commonly as a freebase or fumarate) requires a higher dose than inhalation. The duration is markedly increased, and some users report diminished euphoria but an intensified otherworldly experience. A dose of approximately 70 to 120mg of insufflated DMT will induce medium to strong effects. If successful in containing this pain inducing insufflation, the trip can last anywhere from 20 to 50 minutes, with undefinable peak(s).

Injection
Injected DMT produces an experience that is similar to inhalation in duration, intensity, and characteristics. In a study conducted from 1990 through 1995, University of New Mexico psychiatrist Rick Strassman found that some volunteers injected with high doses of DMT reported experiences with perceived alien entities. Usually, the reported entities were experienced as the inhabitants of a perceived independent reality the subjects reported visiting

Dimethyltryptamine while under the influence of DMT.[14] In a September 2009 interview with Examiner.com, Strassman described the effects on participants in the study: "Subjectively, the most interesting results were that high doses of DMT seemed to allow the consciousness of our volunteers to enter into non-corporeal, free-standing, independent realms of existence inhabited by beings of light who oftentimes were expecting the volunteers, and with whom the volunteers interacted. While 'typical' near-death and mystical states occurred, they were relatively rare."

377

Oral ingestion
DMT is broken down by the digestive enzyme monoamine oxidase through a process called deamination, and is therefore inactive if taken orally unless combined with a monoamine oxidase inhibitor (MAOI).[] The traditional South American beverage ayahuasca, or yage, is derived by boiling the ayahuasca vine (Banisteriopsis caapi) with leaves of one or more plants containing DMT, such as Psychotria viridis, Psychotria carthagenensis, or Diplopterys cabrerana.[] The Ayahuasca vine contains harmala alkaloids,[] highly active reversible inihibitors of monoamine oxidase A (RIMAs),[] rendering the DMT orally active by protecting it from deamination.[] A variety of different recipes are used to make the brew depending on the purpose of the ayahuasca session,[] or local availability of ingredients. Two common sources of DMT in the western US are reed canary grass (Phalaris arundinacea) and Harding grass (Phalaris aquatica). These invasive grasses contain low levels of DMT and other alkaloids. In addition, Jurema (Mimosa tenuiflora) shows evidence of DMT content: the pink layer in the inner rootbark of this small tree contains a high concentration of N,N-DMT.[citation needed] Taken orally with an appropriate MAOI, DMT produces a long lasting (over 3 hour), slow, deep metaphysical experience similar to that of psilocybin mushrooms, but more intense.[] MAOIs should be used with extreme caution as they can have lethal complications with some prescription drugs such as SSRI antidepressants, some over-the-counter drugs,[] and many common foods.[25] Induced DMT experiences can include profound time-dilation, visual and auditory illusions, and other experiences that, by most firsthand accounts, defy verbal or visual description. Some users report intense erotic imagery and sensations and utilize the drug in a ritual sexual context.[][26][27]

Distinguish from 5-MeO-DMT

5-MeO-DMT, a psychedelic drug structurally similar to N,N-DMT, is sometimes referred to as DMT through abbreviation. As a white, crystalline solid, it is also similar in appearance to DMT. However, it is considerably more potent (5-MeO-DMT typical vaporized dose: 520mg), and care should be taken to clearly differentiate between the two drugs to avoid accidental overdose.[28]

Detection in body fluids

DMT may be quantitated in blood, plasma or urine using chromatographic techniques as a diagnostic tool in clinical poisoning situations or to aid in the medicolegal investigation of suspicious deaths. Blood or plasma DMT levels in recreational users of the drug are generally in the 1030 g/L range during the first several hours post-ingestion.[citation needed] Less than 0.1% of an oral dose is eliminated unchanged in the 24-hour urine of humans.[29][30]

Side effects
Similar to other psychedelic drugs, there are relatively few physical side effects associated with acute DMT exposure. When inhaled, its vapor has been described as "very harsh."[31] According to a "Dose-response study of N,N-dimethyltryptamine in humans" by Rick Strassman, "Dimethyltryptamine dose slightly elevated blood pressure, heart rate, pupil diameter, and rectal temperature, in addition to elevating blood concentrations of beta-endorphin, corticotropin, cortisol, and prolactin. Growth hormone blood levels rose equally in response to all doses of DMT,

Dimethyltryptamine and melatonin levels were unaffected."[] Psychologically, the DMT experience can be intense, leading to introspection and difficulty integrating experiences [citation needed] Wikipedia:Please clarify if one is not mentally prepared. Furthermore, due to the intense nature of the experience, DMT is generally considered to have no addiction potential. Just as with all psychedelics, there is a chance for an onset of paranoia, or a 'bad trip'. This risk is more prevalent with DMT, as it is more intense than normal psychedelics. [citation needed]

378

Conjecture
Several speculative and yet untested hypotheses suggest that endogenous DMT is produced in the human brain and is involved in certain psychological and neurological states. DMT is naturally occurring in small amounts in rat brain, human cerebrospinal fluid, and other tissues of humans and other mammals.[][][] It may play a role in mediating the visual effects of natural dreaming, and also near-death experiences, religious visions and other [32] states. Wikipedia:Verifiability A biochemical mechanism for this was proposed by the medical researcher J. C. Callaway, who suggested in 1988 that DMT might be connected with visual dream phenomena: brain DMT levels DMT crystal at 400x magnification. would be periodically elevated to induce visual dreaming and possibly other natural states of mind.[33] A new hypothesis proposed is that in addition to being involved in altered states of consciousness, endogenous DMT may be involved in the creation of normal waking states of consciousness. It is proposed that DMT and other endogenous hallucinogens mediate their neurological abilities by acting as neurotransmitters at a sub class of the trace amine receptors; a group of receptors found in the CNS where DMT and other hallucinogens have been shown to have activity. Wallach further proposes that in this way waking consciousness can be thought of as a controlled psychedelic experience. It is when the control of these systems becomes loosened and their behavior no longer correlates with the external world that the altered states arise.[] Dr. Rick Strassman, while conducting DMT research in the 1990s at the University of New Mexico, advanced the controversial hypothesis that a massive release of DMT from the pineal gland prior to death or near death was the cause of the near death experience (NDE) phenomenon. Several of his test subjects reported NDE-like audio or visual hallucinations. His explanation for this was the possible lack of panic involved in the clinical setting and possible dosage differences between those administered and those encountered in actual NDE cases. Several subjects also reported contact with 'other beings', alien like, insectoid or reptilian in nature, in highly advanced technological environments[14] where the subjects were 'carried,' 'probed,' 'tested,' 'manipulated,' 'dismembered,' 'taught,' 'loved,' and even 'raped' by these 'beings.' Basing his reasoning on his belief that all the enzymatic material needed to produce DMT is found in the pineal gland (see evidence in mammals), and moreover in substantially greater concentrations than in any other part of the body, Strassman ([14] p.69) has speculated that DMT is made in the pineal gland. Currently there is no published reliable scientific evidence supporting this hypothesis. In the 1950s, the endogenous production of psychoactive agents was considered to be a potential explanation for the hallucinatory symptoms of some psychiatric diseases as the transmethylation hypothesis[] (see also adrenochrome), though this hypothesis does not account for the natural presence of endogenous DMT in otherwise normal humans, rats and other laboratory animals. In 2011, Nicholas V. Cozzi, of the University of Wisconsin School of Medicine and Public Health, concluded that INMT, an enzyme that may be associated with the biosynthesis of DMT and endogenous hallucinogens, is present in

Dimethyltryptamine the primate (rhesus macaque) pineal gland, retinal ganglion neurons, and spinal cord.[34] In August 2012, Steven Barker, Ethan McIlHenny, and Rick Strassman, developed a new method to measure the three known endogenous hallucinogens and their major N-oxide metabolites in blood, urine, cerebrospinal fluid, ocular fluid and/or other tissues by using state-of-the-art liquid chromatography-mass spectrometry (LC/MS) equipment. For the first time in history, they were able to detect the DMT-N-oxide metabolite in blood and urine.[35] Writers on DMT include Terence McKenna, Jeremy Narby and Graham Hancock. In his writings and speeches, Terence McKenna recounts encounters with entities he sometimes describes as "Self-Transforming Machine Elves" among other phrases. McKenna believed DMT to be a tool that could be used to enhance communication and allow for communication with other-worldly entities. Many usersWikipedia:Avoid weasel words report visitation from external intelligences attempting to impart information.

379

Legal status
International law
DMT is classified as a Schedule I drug under the UN 1971 Convention on Psychotropic Substances, meaning that use of DMT is supposed to be restricted to scientific research and medical use and international trade in DMT is supposed to be closely monitored. Natural materials containing DMT, including ayahuasca, are explicitly not regulated under the 1971 Psychotropic Convention.[36]

Australia
The Australian Federal Government is considering changes to the Australian Criminal Code that would classify any plants containing any amount of DMT as "controlled plants".[37] As of February 2012, the Therapeutic Goods Administration and federal authority made a motion to not reschedule DMT or DMT containing substances as they may still hold potential entheogenic value to native and/or religious peoples. The final decision is to be handed down 2 May 2012.[38][citation needed]

Canada
DMT is classified in Canada as a Schedule III drug.

France
DMT, along with most of its plant sources, is classified in France as a stupfiant (narcotic).

New Zealand
DMT is classified in New Zealand as a Class A drug under the Misuse of Drugs Act 1975.[39][]

United Kingdom
DMT is classified in the United Kingdom as a Class A drug.

United States
DMT is classified in the United States as a Schedule I drug under the Controlled Substances Act of 1970. In December 2004, the Supreme Court lifted a stay, thereby allowing the Brazil-based Unio do Vegetal (UDV) church to use a decoction containing DMT in their Christmas services that year. This decoction is a tea made from boiled leaves and vines, known as hoasca within the UDV, and ayahuasca in different cultures. In Gonzales v. O Centro Espirita Beneficente Uniao do Vegetal, the Supreme Court heard arguments on November 1, 2005, and unanimously ruled in February 2006 that the U.S. federal government must allow the UDV to import and consume

Dimethyltryptamine the tea for religious ceremonies under the 1993 Religious Freedom Restoration Act. In September, 2008, the three Santo Daime churches filed suit in federal court to gain legal status to import DMT-containing ayahuasca tea. The case, Church of the Holy Light of the Queen v. Mukasey,[40] presided over by Judge Owen M. Panner, was ruled in favor of the Santo Daime church. As of March 21, 2009, a federal judge says members of the church in Ashland can import, distribute and brew ayahuasca. U.S. District Judge Owen Panner issued a permanent injunction barring the government from prohibiting or penalizing the sacramental use of "Daime tea." Panner's order said activities of The Church of the Holy Light of the Queen are legal and protected under freedom of religion. His order prohibits the federal government from interfering with and prosecuting church members who follow a list of regulations set out in his order.[41]

380

Culture
In South America there are a number of indigenous traditions and more recent religious movements based on the use of ayahuasca, usually in an animistic context that may be mixed with Christian imagery. There are three main groups using DMT-MAOI based sacraments in South America: The Amazon Basin's indigenous population. There are many indigenous cultures in South America, mostly in the Upper Amazon Basin whose traditional religious practices include the use of ayahuasca. These are the oldest cultures in the whole of South America that continue to use ayahuasca or analogue brews, such as the ones made from Jurema in the Pernambuco, near Recife or Iquitos in Peru. Santo Daime ("Holy Give Unto Me") and Barquinha ("Little Boat"). A syncretic religion from Brazil. The former was founded by Raimundo Irineu Serra in the early 1930s, as an esoteric Christian religion with shamanic tendencies. The Barquinha was derived from this one. The Santo Daime also includes children in their Entheogenic rituals; studies done by the Brazilian government concluded that there were no physical or mental damage caused by this practice, so it is allowed. Unio do Vegetal ("Union of the Plants" or UDV). Another Christian ayahuasca religion from Brazil, a single unified organization with a structure resembling Freemasonry.

Popular culture
DMT was the subject of a 2010 American documentary titled DMT: The Spirit Molecule.[42] DMT was one of the mainly used psychedelic drugs used in 2009 French movie, titled Enter The Void.[43]

References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=61-50-7& rn=1 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=6089 [3] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=141 [4] http:/ / www. drugbank. ca/ drugs/ DB01488 [5] http:/ / www. chemspider. com/ Chemical-Structure. 5864 [6] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=WUB601BHAA [7] http:/ / www. kegg. jp/ entry/ C08302 [8] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:28969 [9] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL12420 [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477166524& page2=Dimethyltryptamine [14] () [21] General annotation of Human INMT (O95050) entry in UniProtKB/Swiss-Prot (http:/ / www. uniprot. org/ uniprot/ O95050) [23] Alien Dreamtime a multimedia event recorded live. (27 February 1993) [30] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp. 525526. [34] http:/ / www. neurophys. wisc. edu/ ~cozzi/ Indolethylamine%20N-methyltransferase%20expression%20in%20primate%20nervous%20tissue. pdf [37] DMT itself is already controlled under current laws. The changes include other similar blanket bans for other substances such as a ban on any and all plants containing Mescaline or Ephedrine.

Dimethyltryptamine
[38] http:/ / www. dmtsite. com/ dmt/ information/ law. html [40] Church of the Holy Light of the Queen v. Mukasey (http:/ / csp. org/ society/ docs/ SantoDaimeAshland20090318. pdf) [42] http:/ / www. imdb. com/ title/ tt1340425/

381

External links
Identifying Spiritual Content in First-Person Reports from Ayahuasca Sessions (http://www.neuroquantology. com/index.php/journal/article/view/410) DMT Vault (http://www.erowid.org/chemicals/dmt/) Erowid DMT (http://www.thesite.org/drinkanddrugs/drugsafety/drugsatoz/dmt) TheSite.org DMT chapter from TiHKAL (http://www.erowid.org/library/books_online/tihkal/tihkal06.shtml) DMT: The Spirit Molecule (http://www.rickstrassman.com/index.php?option=com_content&view=article& id=54&Itemid=54), an overview by its author, Rick Strassman DMT: The Spirit Molecule (http://www.imdb.com/title/tt1340425/) at the Internet Movie Database CRFDL (http://www.crfdl.org), a database of scientific research on psychedelics

Norfenefrine

382

Norfenefrine
Norfenefrine

Systematic (IUPAC) name

3-(2-amino-1-hydroxyethyl)phenol
Clinical data AHFS/Drugs.com Pregnancy cat. Legal status International Drug Names ? Prescription only Identifiers CAS number [2] 536-21-0 15308-34-6 (hydrochloride) C01CA05 CID 4538 4379 [5] [6] [3] [4] [1]

ATC code PubChem ChemSpider UNII KEGG ChEMBL Synonyms

D2P3M6SRN5 D08286 [7]

CHEMBL358040

[8]

Norfenephrine Norphenephrine Norphenylephrine meta-Norsynephrine meta-Octopamine 3-Octopamine Chemical data

Formula Mol. mass

C8H11NO2 153.178 g/mol

(what is this?) (verify)

[9]

Norfenefrine (INN; brand names Coritat, Energona, Hypolind, and Novadral), also known as m-octopamine (or 3-octopamine) and 3,-dihydroxyphenethylamine, is an adrenergic agent used as a sympathomimetic drug which is marketed in Europe, Japan, and Mexico.[][] Along with its structural isomer p-octopamine and the tyramines,

Norfenefrine norfenefrine is a naturally occurring, endogenous trace amine and plays a role as a minor neurotransmitter in the brain.[]

383

References
[1] [2] [3] [4] [5] [6] [7] [8] [9] http:/ / www. drugs. com/ international/ norfenefrine. html http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=536-21-0& rn=1 http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01CA05 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=4538 http:/ / www. chemspider. com/ Chemical-Structure. 4379 http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=D2P3M6SRN5 http:/ / www. kegg. jp/ entry/ D08286 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL358040 http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=462263073& page2=Norfenefrine

Octopamine

384

Octopamine
Octopamine

Systematic (IUPAC) name

(RS)-4-(2-amino-1-hydroxy-ethyl)phenol
Clinical data Pregnancy cat. Legal status Routes ? Prescription only Oral Pharmacokinetic data Half-life 15 Minutes in insects. Theorized to be longer in vertebrates. Identifiers CAS number ATC code PubChem 104-14-3 [1]

C01CA18 CID 4581

[2] [3]

IUPHAR ligand 2149 [4] ChemSpider UNII ChEBI ChEMBL Synonyms 4420 [5] [6] [7]

14O50WS8JD CHEBI:17134

CHEMBL53929

[8]

Norsympathol, Norsynephrine, para-Octopamine, beta-Hydroxytyramine, para-hydroxy-phenyl-ethanolamine Chemical data

Formula Mol. mass

C8H11NO2 153.178 g/mol

(what is this?) (verify)

[9]

Octopamine (,4-dihydroxyphenethylamine) is an endogenous biogenic amine that is closely related to norepinephrine, and has effects on the adrenergic and dopaminergic systems. It is also found naturally in numerous plants, including bitter orange.[10][] Biosynthesis of the D-()-enantiomer of octopamine is by -hydroxylation of tyramine via the enzyme dopamine -hydroxylase. Under the trade names Epirenor, Norden, and Norfen, octopamine is also used clinically as a sympathomimetic agent.[][]

Octopamine

385

Role in invertebrates
Octopamine was first discovered by Italian scientist Vittorio Erspamer in 1948[11] in the salivary glands of the octopus and has since been found to act as a neurotransmitter, neurohormone and neuromodulator in invertebrates. Although Erspamer discovered its natural occurrence and named it, octopamine had actually existed for many years as a pharmaceutical product.[] It is widely used in energy-demanding behaviors by all insects, crustaceans (crabs, lobsters, crayfish), and spiders. Such behaviors include flying, egg-laying, and jumping. Octopamine acts as the insect equivalent of norepinephrine and has been implicated in regulating aggression in invertebrates, with different effects on different species. Studies have shown that reducing the neurotransmitter octopamine and preventing coding of tyramine beta hydroxylase (an enzyme that converts tyramine to octopamine) decreases aggression in Drosophila without influencing other behaviors.[12] The best-understood role for octopamine is in the locust jump. Here it modulates muscle activity, making the leg muscles contract more effectively. This is at least in part due to an increase in the rate of contraction and of relaxation. In the honey bee and fruit fly, octopamine has a major role in learning and memory. In the firefly, octopamine release leads to light production in the lantern. Octopamine also plays a role in mollusks, though the role of octopamine has been examined only in the central nervous system of the model organism, the pond snail. In lobsters, octopamine seems to direct and coordinate neurohormones to some extent in the central nervous system, and it was observed that injecting octopamine into a lobster and crayfish resulted in limb and abdomen extension.[13] Heberlein et al.[14] have conducted studies of alcohol tolerance in fruit flies; they found that a mutation that caused octopamine deficiency also caused lower alcohol tolerance.[15][16][17][18] The emerald cockroach wasp stings the host for its larvae (a cockroach) in the head ganglion (brain). The venom blocks octopamine receptors[19] and the cockroach fails to show normal escape responses, grooming itself excessively. It becomes docile and the wasp leads it to the wasp's den by pulling its antenna like a leash.[20]

Role in vertebrates
In vertebrates, octopamine replaces norepinephrine in sympathetic neurons with chronic use of monoamine oxidase inhibitors. It may be responsible for the common side effect of orthostatic hypotension with these agents, though there is also evidence that it is actually mediated by increased levels of N-acetylserotonin. One study noted that octopamine might be an important amine that influences the therapeutic effects of inhibitors such as monoamine oxidase inhibitors, especially because a large increase in octopamine levels was observed when animals were treated with this inhibitor. Octopamine was positively identified in the urine samples of mammals such as humans, rats, and rabbits treated with monoamine oxidase inhibitors. Very small amounts of octopamine were also found in certain animal tissues. It was observed that within a rabbit's body, the heart and kidney held the highest concentrations of octopamine.[] In mammals, octopamine may mobilize the release of fat from adipocytes (fat cells), which has led to its promotion on the internet as a slimming aid. However, the released fat is likely to be promptly taken up into other cells, and there is no evidence that octopamine facilitates weight loss. Octopamine may also increase blood pressure significantly when combined with other stimulants, as in some weight loss supplements.[21][22] Owing to lack of research, much is not known about octopamine or its role in humans.

Octopamine

386

References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=104-14-3& rn=1 [2] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01CA18 [3] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=4581 [4] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=2149 [5] http:/ / www. chemspider. com/ Chemical-Structure. 4420 [6] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=14O50WS8JD [7] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:17134 [8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL53929 [9] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=408985899& page2=Octopamine [17] Bar Flies: What our insect relatives can teach us about alcohol tolerance. (http:/ / www. thenakedscientists. com/ HTML/ Columnists/ ruthwilliamscolumn1. htm), Ruth Williams, Naked Scientist [18] Hangover gene is key to alcohol tolerance (http:/ / www. newscientist. com/ article. ns?id=dn7830), Gaia Vince, NewScientist.com news service, 22 August 2005 [19] How to make a zombie cockroach (http:/ / www. nature. com/ news/ 2007/ 071129/ full/ news. 2007. 312. html), Nature News, 29 September 2007

Further reading
P.D. Evans, "Octopamine", in Comprehensive Insect Physiology, 11, 499, Oxford University Press 1985.

Meta-Tyramine

387

Meta-Tyramine
meta-Tyramine

Identifiers CAS number PubChem ChemSpider Jmol-3D images 588-05-6 11492 11008
[2] [3] [4] [1]

Image 1 Properties

Molecular formula Molar mass

C8H11NO 137.18 g mol

1

Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa) Infobox references

meta-Tyramine, also known as m-tyramine or 3-tyramine as well as 3-hydroxyphenylethylamine, is an endogenous monoamine compound and trace amine of the phenethylamine class.[][][] It is a positional isomer of para-tyramine, and similarly to it, has effects on the adrenergic and dopaminergic systems.[][]

References
[1] [2] [3] [4] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=588-05-6 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=11492 http:/ / www. chemspider. com/ 11008 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=Oc1cc%28ccc1%29CCN

Tyramine

388

Tyramine
Tyramine

Identifiers CAS number PubChem ChemSpider UNII KEGG MeSH ChEBI ChEMBL Jmol-3D images 51-67-2 5610 5408
[2] [3] [4] [1]

X8ZC7V0OX3 C00483
[5]

Tyramine

[6] [7]

CHEBI:15760

CHEMBL11608 Image 1 Properties

[9]

[8]

Molecular formula Molar mass Appearance Density Melting point Boiling point Solubility in water Acidity (pK )
a

C H NO
8 11

137.179 g/mol colorless solid 1.20 g/cm 3 164-165C

[10]

[11] [12] [12]

205-207C at 25 mm Hg; 166C at 2 mm Hg 1 g in 95 mL at 15C

[12] [13]

9.74 (OH); 10.52 (NH +)

3

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

(verify)

[14]

Infobox references

Tyramine Tyramine (4-hydroxyphenethylamine; para-tyramine, mydrial or uteramin) is a naturally occurring monoamine compound and trace amine derived from the amino acid tyrosine.[10] Tyramine acts as a catecholamine ( dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline)]) releasing agent. Notably, however, it is unable to cross the blood-brain barrier, resulting in only nonpsychoactive peripheral sympathomimetic effects. A hypertensive crisis can result from ingestion of tyramine-rich foods in conjunction with monoamine oxidase inhibitors (MAOIs).

389

Occurrence
Tyramine occurs widely in plants[15] and animals, and is metabolized by the enzyme monoamine oxidase. In foods, it is often produced by the decarboxylation of tyrosine during fermentation or decay. Foods containing considerable amounts of tyramine include meats that are potentially spoiled or pickled, aged, smoked, fermented, or marinated (some fish, poultry, and beef); most pork (except cured ham); chocolate; alcoholic beverages; and fermented foods, such as most cheeses (except ricotta, cottage, cream and Neufchtel cheeses), sour cream, yogurt, shrimp paste, soy sauce, soybean condiments, teriyaki sauce, tofu, tempeh, miso soup, sauerkraut, broad (fava) beans, green bean pods, Italian flat (Romano) beans, snow peas, avocados, bananas, pineapple, eggplants, figs, red plums, raspberries, peanuts, Brazil nuts, coconuts, processed meat, yeast, and an array of cacti.

Physical effects and pharmacology

Tyramine is physiologically metabolized by MAOA. In humans, if monoamine metabolism is compromised by the use of monoamine oxidase inhibitors (MAOIs) and foods high in tyramine are ingested, a hypertensive crisis can result, as tyramine can cause the release of stored monoamines, such as dopamine, norepinephrine and epinephrine. The first signs of this were discovered by a neurologist who noticed his wife, who at the time was on MAOI medication, had severe headaches when eating cheese.[16] For this reason, the crisis is still called the "cheese effect" or "cheese crisis", though other foods can cause the same problem.[17]:30-31 Most processed cheeses do not contain enough tyramine to cause hypertensive effects, although some aged cheeses (such as Stilton) do.[18][19] A large dietary intake of tyramine (or a dietary intake of tyramine while taking MAO inhibitors) can cause the tyramine pressor response, which is defined as an increase in systolic blood pressure of 30 mmHg or more. The displacement of norepinephrine (noradrenaline) from neuronal storage vesicles by acute tyramine ingestion is thought to cause the vasoconstriction and increased heart rate and blood pressure of the pressor response. In severe cases, adrenergic crisis can occur.[medical citation needed] However, if one has had repeated exposure to tyramine, there is a decreased pressor response; tyramine is degraded to octopamine, which is subsequently packaged in synaptic vesicles with norepinephrine (noradrenaline). Therefore, after repeated tyramine exposure, these vesicles contain an increased amount of octopamine and a relatively reduced amount of norepinephrine. When these vesicles are secreted upon tyramine ingestion, there is a decreased pressor response, as less norepinephrine is secreted into the synapse, and octopamine does not activate alpha or beta adrenergic receptors. [medical citation needed] When using a MAO inhibitor (MAOI), the intake of approximately 10 to 25mg of tyramine is required for a severe reaction compared to 6 to 10mg for a mild reaction.[medical citation needed] The possibility that tyramine acts directly as a neurotransmitter was revealed by the discovery of a G protein-coupled receptor with high affinity for tyramine, called TA1. The TA1 receptor is found in the brain, as well as peripheral tissues, including the kidneys. The existence of a receptor with high affinity for tyramine supports the hypothesis that tyramine may also act directly to affect blood pressure regulation.[medical citation needed] Dietary tyramine intake has also been associated with migraine in select populations, leading many sufferers to restrict foods high in tyramine.[20] Reports on the tyramine-migraine link have been both affirmed and denied. At the Department of Neurology and EEG at The London Hospital, a double-blind study has shown no significant relationship between tyramine ingestion and migraines.[21] The EEG changes observed, however, do support

Tyramine tyramine as playing a role on the central nervous system in some subjects. A 2007 review published in Neurological Sciences[22] presented data showing migraine and cluster headaches are characterised by an increase of circulating neurotransmitters and neuromodulators (including tyramine, octopamine and synephrineWikipedia:Disputed statement) in the hypothalamus, amygdala and dopaminergic system.

390

Biosynthesis
Biochemically, tyramine is produced by the decarboxylation of tyrosine via the action of the enzyme tyrosine decarboxylase.[23] Tyramine can, in turn, be converted to methylated alkaloid derivatives N-methyltyramine, N,N-dimethyltyramine (hordenine), and N,N,N-trimethyltyramine (candicine).

Tyramine

N-Methyltyramine

N,N-Dimethyltyramine (hordenine)

N,N,N-Trimethyltyramine (candicine)

Chemistry
In the laboratory, tyramine can be synthesized in various ways, in particular by the decarboxylation of tyrosine.[24][25][26]

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=51-67-2 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5610 [3] http:/ / www. chemspider. com/ 5408 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=X8ZC7V0OX3 [5] http:/ / www. kegg. jp/ entry/ C00483 [6] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Tyramine [7] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=15760 [8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL11608 [9] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=Oc1ccc%28cc1%29CCN [10] PubChem (http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5610) [11] A. M. Andersen (1977). "The crystal and molecular structure of tyramine hydrochloride." Acta Chem. Scandinavica B 31 162-166. [12] The Merck Index, 10th Ed. (1983), p.1405, Rahway: Merck & Co. [14] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=415653517& page2=Tyramine [15] T. A. Smith (1977) Phytochem. 16 9-18. [16] Sathyanarayana Rao TS and Vikram K. Yeragani VK (2009) Hypertensive crisis and cheese (http:/ / www. ncbi. nlm. nih. gov/ pmc/ articles/ PMC2738414/ ) Indian J Psychiatry. 51(1): 6566. [17] E. Siobhan Mitchell Antidepressants (http:/ / iftandcs. org/ Addictions/ Drugs The Straight Facts, Antidepressants. pdf), chapter in Drugs, the Straight Facts, edited by David J. Triggle. 2004, Chelsea House Publishers [19] Tyramine-restricted Diet (http:/ / web. squ. edu. om/ med-lib/ med_cd/ e_cds/ Griffith's Instructions Patients/ pdf/ Pg570. pdf) 1998, W.B. Saunders Company.

Tyramine
[23] Tyrosine metabolism - Reference pathway (http:/ / www. genome. jp/ kegg/ pathway/ map/ map00350. html), Kyoto Encyclopedia of Genes and Genomes (KEGG)

391

N-Methyltryptamine
N-Methyltryptamine

Systematic (IUPAC) name

2-(1H-Indol-3-yl)-N-methylethanamine
Clinical data Pregnancy cat. Legal status ? ? Identifiers CAS number ATC code PubChem ChemSpider KEGG ChEBI ChEMBL 61-49-4 ? CID 6088 5863 [3] [4] [5] [6] [2] [1]

C06213

CHEBI:28136

CHEMBL348588

Chemical data Formula Mol. mass C11H14N2 174.245 g/mol

Physical data Melt. point 8789C (189192F) [7]

(what is this?) (verify)

N-Methyltryptamine (NMT), or methyltryptamine, is a member of the tryptamine chemical class. It is an alkaloid, probably derived from L-tryptophan, that has been found in the bark, shoots and leaves of several plant species, including Virola, Acacia, Mimosa and Desmanthus often together with the related compounds N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).[8] It is also synthesized in the human body as a metabolic endproduct of the amino acid L-tryptophan.[9] It was found to be a natural trace component in human urine.[10]

N-Methyltryptamine Orally administered NMT appears to produce no psychoactive effects, likely as a result of extensive first-pass metabolism.[11] However, it may become active upon combination with a MAOA inhibitor (MAOI).[11] By vaporization NMT shows activity at 50100mg, with a duration of 4570 minutes; duration of visual effects 1530 seconds.[12][13] NMT has been shown to act as an agonist of the TAAR1, similarly to its relatives tryptamine and N,N-dimethyltryptamine (DMT).[]

392

References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=61-49-4& rn=1 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=6088 [3] http:/ / www. chemspider. com/ Chemical-Structure. 5863 [4] http:/ / www. kegg. jp/ entry/ C06213 [5] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:28136 [6] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL348588 [7] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=464372446& page2=N-Methyltryptamine [8] see wikipedia list of psychedlic plants for references [9] Tryptophan metabolism (http:/ / www. genome. jp/ kegg/ pathway/ map/ map00380. html) [10] Scand J Clin Lab Invest. 2001;61(7):547-56. Determination of potentially hallucinogenic N-dimethylated indoleamines in human urine by HPLC/ESI-MS-MS. Forsstrm T, Tuominen J, Karkkinen J. [11] Foye's principles of medicinal chemistry By William O. Foye, Thomas L. Lemke, David A. Williams [12] Shulgin & Shulgin "TIKHAL" 1997 [13] Nen 2011 - lecture presented EGA conference, Victoria. 4/12/2011.

External links
NMT Entry in TIHKAL (http://www.erowid.org/library/books_online/tihkal/tihkal50.shtml) NMT Entry in TiHKAL info (http://tihkal.info/read.php?domain=tk&id=50)

Phenethylamine

393

Phenethylamine
Phenethylamine

Systematic (IUPAC) name

phenylethan-2-amine
Clinical data Pregnancy cat. Legal status Routes ? Uncontrolled Oral Pharmacokinetic data Metabolism Half-life MAO-A, MAO-B, ALDH, DBH, CYP2D6 ~5-10 minutes Identifiers CAS number ATC code PubChem 64-04-0 ? CID 1001 [2] [1]

IUPHAR ligand 2144 [3] ChemSpider UNII ChEBI ChEMBL 13856352 [4] [5] [6] [7]

327C7L2BXQ CHEBI:18397 CHEMBL610

NIAID ChemDB 018561 [8]

Phenethylamine

394
Synonyms 2-phenylethylamine, -phenylethylamine, 1-amino-2-phenylethane Chemical data Formula Mol. mass C8H11N 121.18 g/mol

Physical data Boiling point 195C (383F) (what is this?) (verify) [9]

Phenethylamine /fnlmin/ (PEA), -phenethylamine, or phenylethylamine is an organic compound and a natural monoamine alkaloid, a trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects.[] Phenylethylamine functions as a neuromodulator or neurotransmitter in the mammalian central nervous system.[] It is biosynthesized from the amino acid phenylalanine by enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation. It is sold as a dietary supplement for purported mood and weight loss-related therapeutic benefits; however, orally ingested phenethylamine is usually inactive because of extensive first-pass metabolism by monoamine oxidase (MAO) into phenylacetic acid. This prevents significant concentrations from reaching the brain.[][] The group of phenethylamine derivatives is referred to as the phenethylamines. Substituted phenethylamines, substituted amphetamines, and substituted methylenedioxyphenethylamines (MDxx) are a series of broad and diverse classes of compounds derived from phenethylamine that include stimulants, psychedelics, and entactogens, as well as anorectics, bronchodilators, decongestants, and antidepressants, among others.

Occurrence
Phenethylamine is widely distributed throughout the plant kingdom.[10]

Chemistry
Phenethylamine is a primary amine, the amino-group being attached to a benzene ring through a two-carbon, or ethyl group. It is a colorless liquid at room temperature. Phenethylamine is soluble in water, ethanol, and ether. Similar to other low-molecular-weight amines, it has a fishy odor. Upon exposure to air, it forms a solid carbonate salt with carbon dioxide. Phenethylamine is strongly basic, pKb = 4.17 (or pKa = 9.83), as measured using the HCl salt,[11] and forms a stable crystalline hydrochloride salt with a melting point of 217C. Phenethylamine is also a skin irritant and possible sensitizer[citation needed]. Its density is 0.962 g/ml.

Synthesis
An older method for preparing -phenethylamine is given in Organic Syntheses, and involves the reduction of benzyl cyanide with hydrogen in liquid ammonia, in the presence of a Raney-Nickel catalyst, at a temperature of 130C and a pressure of 13.8 MPa. Alternative syntheses are outlined in the footnotes to this preparation.[12] A much more convenient method for the synthesis of -phenethylamine is the reduction of -nitrostyrene by lithium aluminum hydride in ether, which was first reported by Nystrom and Brown in 1948.[13]

Phenethylamine

395

Pharmacology
Phenethylamine, similar to amphetamine in its action, releases norepinephrine and dopamine.[14][15][16] When taken orally, though, it is rapidly metabolized.[17] Abnormally low concentrations of endogenous phenethylamine are found in those suffering from attention-deficit hyperactivity disorder (ADHD),[18] whereas abnormally high concentrations have been discovered to have a strong, positive correlation with the incidence of schizophrenia.[19]

Pharmacokinetics
Phenylethylamine's half-life is 5 to 10 minutes.[] It is metabolized by MAOA,[] MAOB,[] aldehyde dehydrogenase, and dopamine-beta-hydroxylase.[] When the initial phenylethylamine brain concentration is low, brain levels can be increased 1000-fold when taking an MAO inhibitor (MAOI), and by 3-4 times when the initial concentration is high.[]

Toxicity
Acute toxicity studies on phenethylamine show an LD50 = 100mg/kg, after intravenous administration to mice.[20]

Chocolate theory of love

In the early 1980s, psychiatrist Michael Liebowitz, author of the popular 1983 book The Chemistry of Love, remarked to reporters, "chocolate is loaded with PEA [ or Phenethylamine ]". This became the focus for an article in The New York Times, which was then taken up by the wire services and then by magazine free-lancers, evolving into the now-eponymous "chocolate theory of love".[21] However, as noted earlier, phenethylamine is rapidly metabolized by the enzyme MAOB, preventing significant concentrations from reaching the brain, thus contributing no perceptible psychoactive effect without the use of an MAOI.

References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=64-04-0& rn=1 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=1001 [3] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=2144 [4] http:/ / www. chemspider. com/ Chemical-Structure. 13856352 [5] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=327C7L2BXQ [6] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:18397 [7] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL610 [8] http:/ / chemdb. niaid. nih. gov/ CompoundDetails. aspx?AIDSNO=018561 [9] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=464200154& page2=Phenethylamine [10] T. A. Smith (1977). "Phenethylamine and related compounds in plants." Phytochem. 16 9 18. [11] E. B. Leffler, H. M. Spencer and A. Burger (1951) J. Am. Chem. Soc. 73 2611-2613. [12] J. C. Robinson and H. R. Snyder (1955). Organic Syntheses, Coll. Vol. 3, p. 720. http:/ / www. orgsyn. org/ orgsyn/ pdfs/ CV3P0720. pdf [13] R. F. Nystrom and W. G. Brown (1948)."Reduction of organic compounds by lithium aluminum hydride. III. Halides, quinones, miscellaneous nitrogen compounds." J. Am. Chem. Soc. 70 3738-3740. [20] A. M. Lands and J. I. Grant (1952). "The vasopressor action and toxicity of cyclohexylethylamine derivatives." J. Pharmacol. Exp. Ther. 106 341-345. [21] Liebowitz, Michael, R. (1983). The Chemistry of Love. Boston: Little, Brown, & Co.

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External links
Book II of PiHKAL (http://www.erowid.org/library/books_online/pihkal/pihkal.shtml) online Phenethylamine entry in PiHKAL info (http://pihkal.info/read.php?domain=pk&id=142) Review and summary of PiHKAL, including table of 300+ phenethylamines: ascii (http://www.erowid.org/ archive/hyperreal/drugs/psychedelics/phenethylamines/pihkal.review) postscript (http://www.erowid.org/ archive/hyperreal/drugs/psychedelics/phenethylamines/pihkal.review.ps) A Structural Tour of PiHKAL (http://www.erowid.org/archive/rhodium/chemistry/pihkaltour/)

Synephrine

397

Synephrine
Synephrine

Identifiers CAS number PubChem ChemSpider KEGG ChEBI ChEMBL ATC code Jmol-3D images 94-07-5 7172 6904
[2] [3] [4] [5] [1]

D07148

CHEBI:29081

CHEMBL33720 C01 CA08 Image 1 Properties

[7]

[6]

[8]

Molecular formula Molar mass Appearance Melting point Solubility in water

C9H13NO2 167.21 g/mol colorless solid 162-164C (R-(-)-enantiomer); 184-185C (racemate) soluble

Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa) Infobox references

Synephrine, or, more specifically, p-synephrine, is an alkaloid, occurring naturally in some plants and animals, as well as a synthetic drug (known by such names as Sympatol and Oxedrine) which has various adrenergic effects. This substance is present in many citrus fruits, and so is found in common foodstuffs such as orange juice and other orange (Citrus species) products, both of the "sweet" and "bitter" variety. Extracts and preparations of "bitter orange" (Citrus aurantium), which contain synephrine amongst many other constituents, have long been used as herbal medicines, particularly in Chinese Traditional Medicine. Synephrine is currently marketed, usually in combinations with other drugs such as caffeine, as an over-the-counter stimulant and weight-loss-promoting dietary supplement for oral consumption. The effectiveness and safety of these preparations are controversial, but have generated more opinions, in publications and on the Internet, than research. This article will focus, insofar as possible, on synephrine itself, rather than on the drug mixtures containing it. Synephrine, as a single substance, has been as thoroughly investigated as many other similar drugs, and its properties are a matter of record in the scientific literature. As a pharmaceutical, synephrine was once used as a sympathomimetic (i.e. for its hypertensive and vasoconstrictor properties), as well as for the treatment of bronchial problems associated with asthma and hay-fever. Such use is now largely obsolete in the USA.[9]

Synephrine It is important to distinguish between studies concerning synephrine as a single chemical entity (and even here it should be borne in mind that synephrine can exist in the form of either of two stereoisomers, d- and l-synephrine, which are chemically and pharmacologically distinct), and synephrine which is mixed with other drugs and/or botanical extracts in a "Supplement", as well as synephrine which is present as only one chemical component in a naturally-occurring mixture of phytochemicals such as the rind or fruit of a bitter orange. Mixtures containing synephrine as only one of their chemical components (regardless of whether these are of synthetic or natural origin) should not be assumed to produce exactly the same biological effects as synephrine alone.[10] In physical appearance, synephrine is a colorless, crystalline solid and is water-soluble. Its molecular structure is based on a phenethylamine skeleton, and is related to those of many other drugs, and to the major neurotransmitters epinephrine and norepinephrine.

398

Natural occurrences
Synephrine, although already known as a synthetic organic compound, was first isolated as a natural product from the leaves of various Citrus trees, and its presence noted in different Citrus juices, by Stewart and co-workers in the early 1960s.[11][12] A survey of the distribution of synephrine amongst the higher plants was published in 1970 by Wheaton and Stewart.[13] It has subsequently been detected in Evodia[14] and Zanthoxylum species,[15] all plants of the family Rutaceae. Trace levels (0.003%) of synephrine have also been detected in the dried leaves of Pogostemon cablin (patchouli, Lamiaceae).[16] It is also found in certain cactus species of the genera Coryphantha and Dolichothele.[17] However, this compound is found predominantly in a number of Citrus species, including "bitter" and "sweet" orange varieties.

In Citrus
Extracts of unripe fruit from Asian cultivars of Citrus aurantium (commonly known as "bitter" orange), collected in China, were reported to contain synephrine levels of about 0.1 - 0.3%, or ~ 1 3mg/g;[18] Analysis of dried fruit of C. aurantium grown in Italy showed a concentration of synephrine of ~ 1mg/g, with peel containing over three times more than the pulp.[19] Sweet oranges of the Tarocco, Naveline and Navel varieties, bought on the Italian market, were found to contain ~ 13-34 g/g (corresponding to 1334mg/kg) synephrine (with roughly equal concentrations in juice and separated pulp); from these results, it was calculated that eating one "average" Tarocco orange would result in the consumption of ~ 6mg of synephrine.[20] An analysis of 32 different orange "jams", originating mostly in the US and UK, but including samples from France, Italy, Spain, or Lebanon, showed synephrine levels ranging from 0.05mg/g - 0.0009mg/g[21] in those jams made from bitter oranges, and levels of 0.05mg/g - 0.006mg/g[22] of synephrine in jams made from sweet oranges.[23] Synephrine has been found in marmalade made from Citrus unshiu (Satsuma mandarin)[24] obtained in Japan, at a concentration of ~ 0.12mg/g (or about 2.4mg/20g serving).[25] Most of the orange marmalades made in the US are produced using "sweet" oranges (C. sinensis), whereas "bitter" or Seville oranges (C. aurantium) are used for making the more traditional, bitterer marmalades in the United Kingdom.[26] A sample of commercial Japanese C. unshiu juice was found to contain ~ 0.36mg/g synephrine (or roughly 360mg/L),[25] while in juice products obtained from a Satsuma mandarin variety grown in California, levels of synephrine ranged from 55 to 160mg/L .[27] Juices from "sweet" oranges purchased in Brazilian markets were found to contain ~ 1022mg/L synephrine; commercial orange soft drinks obtained on the Brazilian market had an average synephrine content of ~ 1mg/L.[28] Commercial Italian orange juices contained ~ 1332mg/L of synephrine[20]

Synephrine In a survey of over 50 citrus fruit juices, either commercially-prepared or hand-squeezed from fresh fruit, obtained on the US market, Avula and co-workers found synephrine levels ranging from ~ 4 60mg/L;[29] no synephrine was detected in juices from grapefruit, lime, or lemon.[23] An analysis of the synephrine levels in a range of different citrus fruits, carried out on juices that had been extracted from fresh, peeled fruit, was reported by Uckoo and co-workers, with the following results: Marrs sweet orange (C. sinensis Tan.): ~ 85mg/L; Nova tangerine (C. reticulata Tan.): ~ 78mg/L; clementine (C. clementina Tan.): ~ 115mg/L; Meyer lemon (C. limon Tan.) ~ 3mg/kg; Ugli tangelo (C. reticulata C. paradisi) ~ 47mg/kg. No synephrine was detected in: Rio Red grapefruit (C. paradisi Macf.); Red-fleshed pummelo (C. grandis Tan.); or Wekiwa tangelo (C. reticulata C. paradisi).[24][30] Numerous additional comparable analyses of the synephrine content of Citrus fruits and products derived from them may be found in the research literature.

399

In Humans and other animals

Low levels of synephrine have been found in normal human urine,[31][32] as well as in other mammalian tissue.[33][34] To reduce the likelihood that the synephrine detected in urine had a dietary origin, the subjects tested by Ibrahim and co-workers abstained from the consumption of any citrus products for 48 hours prior to providing urine samples.[31] A recent study of synephrine in human blood platelets by D'Andrea and co-workers showed increased levels in platelets from patients suffering from aura-associated migraine (0.72ng/108 platelets, compared to 0.33ng/108 platelets in control subjects).[35] Earlier, the same research group had reported a normal human blood plasma level of synephrine of 0.90-13.69ng/mL.[36]

Stereoisomers
Since synephrine exists as either of two enantiomers (see Chemistry section below for further discussion), which do not produce identical biological effects (see Pharmacology section below) some researchers have examined the stereoisomeric composition of synephrine extracted from natural sources. Although it seems clear that synephrine is found in those Citrus species which have been studied predominantly as the l-isomer,[25][37] low levels of d-synephrine have been detected in juice and marmalade made from C. unshiu,[25] and low levels (0.002%) have been reported in fresh fruit from C. aurantium.[37] There are indications that some d-synephrine may be formed by the racemization of l-synephrine as a result of the processing of fresh fruit, although this matter has not been completely clarified.[38][39] However, regardless of the situation in Citrus species, Ranieri and McLaughlin reported the isolation of racemic (i.e. a mixture of equal amounts of d- and l- stereoisomers) synephrine from a cactus of the Dolichothele genus, under conditions that would be unlikely to cause a significant amount of racemization.[40]

Biosynthesis
The biosynthesis of synephrine in Citrus species is believed to follow the pathway: tyrosine tyramine N-methyltyramine synephrine, involving the enzymes tyrosine decarboxylase in the first step, tyramine N-methyltransferase in the second, and N-methyl-tyramine--hydroxylase in the third.[41][42] This pathway differs from that thought to occur in animals, involving octopamine: tyramine octopamine synephrine, where the conversion of tyramine to octopamine is mediated by dopamine--hydroxylase, and the conversion of octopamine to synephrine by phenylethanolamine N-methyltransferase.[36][41]

Synephrine

400

Presence in Nutritional/Dietary Supplements

Some dietary supplements, sold for the purposes of promoting weight-loss or providing energy, contain synephrine as one of several constituents. Usually, the synephrine is present as a natural component of Citrus aurantium ("bitter orange"), bound up in the plant matrix, but could also be of synthetic origin, or a purified phytochemical (i.e. extracted from a plant source and purified to chemical homogeneity).[26][43][44] The concentration range found by Santana and co-workers in five different supplements purchased in the US was about 5 14mg/g.[43]

Pharmaceutical Use
As a synthetic drug, synephrine first appeared on the scene in Europe in the late 1920s, under the name of Sympatol. One of the earliest papers describing its pharmacological and toxicological properties was written by Lasch, who obtained it from the Viennese company Syngala.[45] By 1930, Sympatol was referred to as a Boehringer product,[46] while one of the first US Patents describing its preparation and use was assigned to Frederick Stearns & Co. in 1933.[47] Despite the date of this patent, clinical and pharmacological research on synephrine obtained from Frederick Stearns & Co was being carried out in the US by 1930.[48][49] Writing in 1931, Hartung reported that in 1930 the Council on Pharmacy and Chemistry of the American Medical Association had accepted synephrine for inclusion in its list of New and Non-Official Remedies as an agent for the treatment, by either oral or parenteral administration, "of attacks of hay fever, asthma, coughing, spasms of asthma and pertussis (whooping cough)."[50][51] However, synephrine was dropped from the Council's list in 1934, and its apparent re-advertising as a new drug by the Stearns company ten years later elicited a scathing comment from the Editors of the Journal of the American Medical Association.[52] The third edition (1965) of Drill's Pharmacology in Medicine stated, with reservations, that synephrine was "advertised as an antihistaminic to be used in the treatment of the common cold...", under the trade name of "Synephrin Tartrate", and indicated that the dose was 100mg, given intramuscularly, or subcutaneously.[53] Published in 1966, the Textbook of Organic Medicinal and Pharmaceutical Chemistry described synephrine (in the form of its racemic tartrate) as a sympathomimetic agent that was "less effective than epinephrine", and which had been used for the treatment of chronic hypertension, collapse due to shock, and other conditions leading to hypotension.[54] In a later (1972) textbook, synephrine was described as a drug, sold in Europe, that was administered in situations involving shock, such as surgical or bacteremic shock, and spinal anesthesia-related shock. The recommended dose was given here as 2550mg, by intravenous, intramuscular or subcutaneous administration.[55] There is no mention of synephrine in editions of Drill's Pharmacology in Medicine later than the 3rd, nor is there any reference to synephrine in the 2012 Physicians' Desk Reference, nor in the current FDA "Orange Book". One current reference source describes synephrine as a vasoconstrictor that has been given to hypotensive patients, orally or by injection, in doses of 20 100mg.[56] One Website from a healthcare media company, accessed in February, 2013, refers to Oxedrine (another trade name for synephrine) as being indicated for hypotensive states, in oral doses of 100150mg tid, and as a "conjunctival decongestant" to be topically applied as a 0.5% solution.[57] However, no supporting references are provided.

Names
There has been some confusion about the biological effects of synephrine because of the similarity of this un-prefixed name to the names m-synephrine, Meta-synephrine and Neosynephrine, all of which refer to a related drug and naturally-occurring amine more commonly known as phenylephrine. Although there are chemical and pharmacological similarities between synephrine and phenylephrine, they are nevertheless different substances. The confusion is compounded by the fact that synephrine has been marketed as a drug under numerous different names, including Sympatol, Sympathol, Synthenate, and Oxedrine, while phenylephrine has also been called m-Sympatol. The synephrine with which this article deals is sometimes referred to as p-synephrine in order to distinguish it from

Synephrine its positional isomers, m-synephrine and o-synephrine. A comprehensive listing of alternative names for synephrine may be found in the ChemSpider entry (see Chembox, at right). Confusion over the distinctions between p- and m-synephrine has even contaminated the primary research literature.[58] However, an examination of the references cited in support of this statement show that all the evidence for the presence of m-synephrine in C. aurantium derives from a report by Penzak and co-workers,[59] whose Abstract states that m-synephrine was found in C. aurantium, whereas a close reading of the text of the paper itself reveals that the authors (although apparently uncertain about which synephrine regio-isomer had been found in the plant by earlier investigators) were aware that their analytical technique could not distinguish between m- and p-synephrine, and did not claim that m-synephrine was present. Thus the Abstract is at variance with the experimental findings given in the full text of the paper, but this error has propagated through subsequent publications.</ref> Even the name "p-synephrine" is not unambiguous, since it does not specify stereochemistry. The only completely unambiguous names for synephrine are: R-(-)-4-[1-hydroxy-2-(methylamino)ethyl]phenol (for the l-enantiomer); S-(+)-4-[1-hydroxy-2-(methylamino)ethyl]phenol (for the d-enantiomer); and R,S-4-[1-hydroxy-2-(methylamino)ethyl]phenol (for the racemate, or d,l-synephrine)(see Chemistry section, below).

401

Chemistry
Properties
In terms of molecular structure, synephrine has a phenethylamine skeleton, with a phenolic hydroxy- group, an alcoholic hydroxy- group, and an N-methylated amino- group. Alternatively, synephrine might be described as a phenylethanolamine with an N-methyl and p-hydroxy substituent. The amino-group confers basic properties on the molecule, whereas the phenolic -OH group is weakly acidic: the apparent (see original article for discussion) pKas for protonated synephrine are 9.55 (phenolic H) and 9.79 (ammonium H).[60] Common salts of racemic synephrine are its hydrochloride, C9H13NO2.HCl, m.p.150-152 ,[61] the oxalate (C9H13NO2)2.C2H2O4, m.p.221-222C ,[11] and the tartrate (Sympatol), (C9H13NO2)2.C4H6O6, m.p.188-190C.[54][62] The presence of the hydroxy-group on the benzylic C of the synephrine molecule creates a chiral center, so the compound exists in the form of two enantiomers, d- and l- synephrine, or as the racemic mixture, d,l- synephrine. The dextrorotatory d-isomer corresponds to the S-configuration, and the levorotatory l-isomer to the R-configuration.[63] Racemic synephrine has been resolved using ammonium 3-bromo-camphor-8-sulfonate.[19][63] The enantiomers were not characterized as their free bases, but converted to the hydrochloride salts, with the following properties:[63] S-(+)-C9H13NO2.HCl: m.p.178C; [] = +42.0, c 0.1 (H2O); R-(-)-C9H13NO2.HCl: m.p.176C; [] = -39.0, c 0.2 (H2O) (-)-Synephrine, as the free base isolated from a Citrus source, has m.p.162-164C (with decomposition).[11][12] The X-ray structure for synephrine has been determined.[63]

Synthesis
Early and seemingly inefficient syntheses of synephrine were discussed by Priestley and Moness, writing in 1940.[64] These chemists optimized a route beginning with the O-benzoylation of p-hydroxy-phenacyl chloride, followed by reaction of the resulting O-protected chloride with N-methyl-benzylamine to give an amino-ketone. This intermediate was then hydrolyzed with HCl/alcohol to the p-hydroxy-aminoketone, and the product then reduced catalytically to give (racemic) synephrine. A later synthesis, due to Bergmann and Sulzbacher, began with the O-benzylation of p-hydroxy-benzaldehyde, followed by a Reformatskii reaction of the protected aldehyde with ethyl bromoacetate/Zn to give the expected

Synephrine -hydroxy ester. This intermediate was converted to the corresponding acylhydrazide with hydrazine, then the acylhydrazide reacted with HNO2, ultimately yielding the p-benzyloxy-phenyloxazolidone. This was N-methylated using dimethyl sulfate, then hydrolyzed and O-debenzylated by heating with HCl, to give racemic synphrine.[65]

402

Structural Relationships
Much has been made in the literature (both lay and professional) of the structural kinship of synephrine with ephedrine, or with phenylephrine, often with the implication that the perceived similarities in structure should result in similarities in pharmacological properties. However, from a chemical perspective, synephrine is also related to a very large number of other drugs whose structures are based on the phenethylamine skeleton, and although some properties are common, others are not, making unqualified comparisons and generalizations inappropriate. Thus, replacement of the N-methyl group in synephrine with a hydrogen atom gives octopamine; replacement of the -hydroxy group in synephrine by a H atom gives N-methyltyramine; replacement of the synephrine phenolic 4-OH group by a -H gives halostachine. If the synephrine phenolic 4-OH group is shifted to the meta-, or 3-position on the benzene ring, the compound known as phenylephrine (or m-synephrine, or "Neo-synephrine") results; if the same group is shifted to the ortho-, or 2-position on the ring, o-synephrine results. Addition of another phenolic -OH group to the 3-position of the benzene ring produces the neurotransmitter epinephrine; addition of a methyl group to the -position in the side-chain of synephrine gives oxilofrine (or "methylsynephrine")(although it should be noted that four stereoisomers and two racemic modifications are possible for this substance). Extension of the synephrine N-methyl substituent by one methylene unit to an N-ethyl gives the hypotensive experimental drug "Sterling #573"/"Aethyl-Sympatol".[66][67] The above structural relationships all involve a change at one position in the synephrine molecule, and numerous other similar changes, many of which have been explored, are possible. However, the structure of ephedrine differs from that of synephrine at two different positions: ephedrine has no substituent on the phenyl ring where synephrine has a 4-OH group, and ephedrine has a methyl group on the position - to the N in the side-chain, where syneprine has only a H atom. Furthermore, "synephrine" exists as either of two enantiomers, while "ephedrine" exists as one of four different enantiomers; there are, in addition, racemic mixtures of these enantiomers.

Pharmacology
Synopsis
Classical pharmacological studies on animals and isolated animal tissues showed that the principal actions of parenterally-administered synephrine included raising blood-pressure, dilating the pupil, and constricting peripheral blood vessels. There is now ample evidence that synephrine produces most of its biological effects by acting as an agonist at (i.e. stimulating) adrenergic receptors, with a distinct preference for the 1 over the 2 sub-type. However, the potency of synephrine at these receptors is relatively low (i.e. relatively large concentrations of the drug are required to activate them). The potency of synephrine at adrenergic receptors of the -class (regardless of sub-type) is much lower than at -receptors. There is some evidence that synephrine also has weak activity at 5-HT receptors, and that it interacts with TAAR1 (trace adrenergic amine receptors). In common with virtually all other simple phenylethanolamines (-hydroxy-phenethylamines), the R-(-)-, or l-, enantiomer of synephrine is more potent than the S-(+)-, or d-, enantiomer in most, but not all preparations studied. However, the majority of studies have been conducted with a racemic mixture of the two enantiomers.

Synephrine Since the details regarding such variables as test species, receptor source, route of administration, drug concentration, and stereochemical composition are important but often incomplete in other Reviews and Abstracts of research publications, many are provided in the more technical review below, in order to support as fully as possible the broad statements made in this Synposis.

403

Pharmacology Research
Pharmacological studies on synephrine date back to the late 1920s, when it was observed that injected synephrine raised blood pressure, constricted peripheral blood vessels, dilated pupils, stimulated the uterus, and relaxed the intestines in experimental animals.[45][45][68][69] Representative of this early work is the paper by Tainter and Seidenfeld, who were the first researchers to systematically compare the different effects of the two synephrine enantiomers, d- and l- synephrine, as well as of the racemate, d,l-synephrine, in various animal assays.[49] In experiments on anesthetized cats, Tainter and Seidenfeld confirmed earlier reports of the increase in blood pressure produced by intravenous doses of synephrine, showing that the median pressor doses for the isomers were: l-synephrine: 0.5mg/kg; d,l-synephrine: 1.0mg/kg; and d-synephrine: 220mg/kg. These effects lasted 23 minutes, peaking at ~30 seconds after administration. l-Synephrine was thus the more potent enantiomer, with about 1/60 x the potency of the standard pressor l-epinephrine in the same assay. A later study, by Lands and Grant, showed that a dose of ~ 0.6mg/kg of racemic synephrine, given intravenously to anesthetized dogs, produced a rise in blood pressure of 34mm Hg lasting 5 10 minutes, and estimated that this pressor activity was about 1/300 x that of epinephrine.[70] Using cats and dogs, Tainter and Seidenfeld observed that neither d- nor l-synephrine caused any changes in the tone of normal bronchi, in situ, even at "maximum" doses. Furthermore, the marked brocho-constriction produced by injections of histamine was not reversed by either l-synephrine or d,l-synephrine.[49] In experiments with isolated sheep carotid artery, d-, l- and d,l-synephrine all showed some vasoconstrictor activity: l-synephrine was the most potent, producing strong contractions at a concentration of 1:10000[71]. d-Synephrine was about 1/2 as potent as the l-isomer, but d,l-synephrine (which would have been expected to have a potency of 1/2 that of l-synephrine even if the d-isomer were completely inactive) did not produce significant and irregular contractions until a concentration of 1:2500[72]had been reached, implying an inhibitory interaction between the two enantiomers.[49] Qualitatively similar results were obtained in a rabbit ear preparation: 25mg l-synephrine produced significant (50%) vasoconstriction, while the same concentration of d-synephrine elicited essentially no response. In contrast, d,l-synephrine did not produce any constriction up to 25mg, but 25 50mg caused a relaxation of the blood vessels, which again suggested that the d-isomer might be inhibiting the action of the l-isomer.[49] Experiments on strips of rabbit duodenum showed that l-synephrine caused a modest reduction in contractions at a concentration of 1:17000[73], but that the effects of the d- and d,l- forms were much weaker.[49] Racemic synephrine, given intramuscularly, or by instillation, was found to significantly reduce the inflammation caused by instillation of mustard oil into the eyes of rabbits.[49] Subcutaneous injection of racemic synephrine into rabbits was reported to cause a large rise in blood sugar.[51] In experiments on anesthetized cats, Papp and Szekeres found that synephrine (stereochemistry unspecified) raised the thresholds for auricular and ventricular fibrillation, an indication of anti-arrhythmic properties.[74] Evidence that synephrine might have some central effects comes from the research of Song and co-workers, who studied the effects of synephrine in mouse models[75] of anti-depressant activity.[76] These researchers observed that oral doses of 0.3 10mg/kg of racemic syephrine were effective in shortening the duration of immobility[77] produced in the assays, but did not cause any changes in spontaneous motor activity in separate tests. This characteristic immobility could be counteracted by the pre-administration of prazosin.[78] Subsequent experiments using the individual enanatiomers of synephrine revealed that although the d-isomer significantly reduced the

Synephrine duration of immobility in the tail suspension test, at an oral dose of 3mg/kg, the l-isomer had no effect at the same dose. In mice pre-treated with reserpine[79], an oral dose of 0.3mg/kg d-synephrine significantly reversed the hypothermia, while l-synephrine required a dose of 1mg/kg to be effective. Experiments with slices of cerebral cortex taken from rat brain showed that d-synephrine inhibited the uptake of [3H]-norepinephrine with an IC50 = 5.8 M; l-synephrine was less potent (IC50 = 13.5 M). d-Synephrine also competitively inhibited the binding of nisoxetine[80] to rat brain cortical slices, with a Ki = 4.5 M; l-synephrine was less potent (Ki = 8.2 M). In experiments on the release of [3H]-norepinephrine from rat brain cortical slices, however, the l-isomer of synephrine was a more potent enhancer of the release (EC50 = 8.2 M) than the d-isomer (EC50 = 12.3 M). This enhanced release by l-synephrine was blocked by nisoxetine.[81] Burgen and Iversen, examining the effect of a broad range of phenethylamine-based drugs on [14C]-norepinephrine-uptake in the isolated rat heart, observed that racemic synephrine[82] was a relatively weak inhibitor (IC50 = 0.12 M) of the uptake.[83] Another receptor-oriented study by Wikberg revealed that synephrine (stereochemistry unspecified) was a more potent agonist at guinea pig aorta 1 receptors (pD2 = 4.81) than at ileum 2 receptors (pD2 = 4.48), with a relative affinity ratio of 2/1 = 0.10. Although clearly indicating a selectivity of synephrine for 1 receptors, its potency at this receptor sub-class is still relatively low, in comparison with that of phenylephrine (pD2 at 1 = 6.32).[84] Brown and co-workers examined the effects of the individual enantiomers of synephrine on 1 receptors in rat aorta, and on 2 receptors in rabbit saphenous vein. In the aorta preparation, l-synephrine gave a pD2 = 5.38 (potency relative to norepinephrine = 1/1000), while d-synephrine had a pD2 = 3.50 (potency relative to norepinephrine = 1/50000); in comparison, l-phenylephrine had pD2 = 7.50 (potency relative to norepinephrine 1/6). No antagonism of norepinephrine was produced by concentrations of l-synephrine up to 106 M. In the rabbit saphenous assay, the pD2 of l-synephrine was 4.36 (potency relative to norepinephrine 1/1700), and that of d-synephrine was < 3.00; in comparison, l-phenylephrine had pD2 = 5.45 (potency relative to norepinephrine 1/140). No antagonism of norepinephrine was produced by concentrations of l-synephrine up to 105 M.[85] A study of the effects of synephrine (stereochemistry unspecified) on strips of guinea pig aorta and on the field-stimulated guinea pig ileum showed that synephrine had an agonist potency of -logKa = 3.75 in the aorta assay. In comparison, epinephrine had a potency of -logKa = 5.70. There was no significant effect on the ileum at synephrine concentrations up to about 2 x 104M, indicating selectivity for the 1 receptor, but relatively low potency.[86] In binding experiments with central adrenergic receptors, using a preparation from rat cerebral cortex, l-synephrine had pIC50 = 3.35, and d-synephrine had pIC50 = 2.42 in competition against [3H]-prazosin (standard 1 ligand); against [3H]-yohimbine (standard 2 ligand), l-synephrine showed a pIC50 = 5.01, and d-synephrine showed a pIC50 = 4.17.[85] Experiments conducted by Hibino and co-workers also showed that synephrine (stereochemistry unspecified) produced a dose-dependent constriction of isolated rat aorta strips, in the concentration range 105 - 3 x 106 M. This constriction was found to be competitively antagonized by prazosin (a standard 1 antagonist) and ketanserin[87], with prazosin being the more potent antagonist (pA2 = 9.38, vs pA2 = 8.23 for ketanserin). Synephrine constrictions were also antagonized by BRL-15,572{{Used here as a selective 5-HT1D antagonist.}}, but not by SB-216,641{{Used here as a selective 5-HT1B antagonist.}}, or by propranolol (a common antagonist).[88] In studies on guinea pig atria and trachea, Jordan and co-workers also found that synephrine had negligible activity on 1 and 2 receptors, being about 40000 x less potent than norepinephrine.[89] Experiments with cultured white fat cells from several animal species, including human, by Carpn and co-workers showed that racemic synephrine produced lipolytic effects, but only at high concentrations (0.1-1 mM). The potency, expressed in terms of pD2 of synephrine in these species was as follows: rat: 4.38; hamster: 5.32; guinea pig: 4.31; human: 4.94. In comparison, isoprenaline had a pD2 = 8.29 and norepinephrine had pD2 = 6.80 in human white fat cells. The lipolytic effect of 1 mM/L of synephrine on rat white fat cells was antagonized by various -antagonists

404

Synephrine with the following inhibitory concentrations (IC50): bupranolol[90]: 0.11 M; CGP-20,712A (1 antagonist): 6.09 M; ICI-118,551 (2 antagonist): 3.58 M; SR-5923A (3 antagonist): 17 M.[91] The binding of racemic synephrine to cloned human adrenergic receptors has been examined: Ma and co-workers found that synephrine bound to 1A, 2A and 2C with low affinity (pKi = 4.11 for 1A; 4.44 for 2A; 4.61 for 2C). Synephrine behaved as a partial agonist at 1A receptors, but as an antagonist at 2A and 2C sub-types.[92] Racemic synephrine has been shown to be an agonist of the TAAR1,[] although its potency at the human TAAR1 is relatively low (EC50 = 23700 nM; Emax = 81.2%).[93]

405

Pharmacokinetics
The pharmacokinetics of synephrine were studied by Hengstmann and Aulepp, who reported a peak plasma concentration at 12 hours, with an elimination half-life (T1/2) of ~ 2 hours.[94]

Metabolism
Studies of the metabolism of synephrine by monoamine oxidases derived from rat brain mitochondria showed that synephrine was a substrate for deamination by both MAO-A and MAO-B, with Km = 250 M and Vmax = 32.6 nM/mg protein/30 minutes; there was some evidence for preferential deamination by MAO-A.[95]

Effects in man
A number of studies of the effects of synephrine in man, most of them focusing on its cardio-vascular properties, have been performed since its introduction as a synthetic drug around 1930.[48][96][97][98][99][100] The paper by Stockton and co-workers is representative, describing the effects of racemic synephrine in man with particular attention to differences resulting from different routes of administration. Thus, it was shown by these investigators that intramuscular injections (average effective dose = 200mg) of the drug produced an increase in systolic blood pressure and pulse rate, without affecting the diastolic pressure. The blood pressure increase reached a maximum (~ 25mm Hg)in 5 minutes following the injection, then gradually returned to normal over the course of 1 hour. Doses of drug greater than 200mg caused side-effects such as heart palpitations, headache, sweating, and feelings of apprehension. When given intravenously, doses of 2550mg sufficed to produce a mean maximum increase in the blood pressure of 29mm Hg in 2 minutes, and a return to baseline within 30 minutes. Respiration was generally not affected during these experiments. Subcutaneous administration of synephrine in doses 200mg had no effects on blood pressure or pulse rate. Oral doses of 500 1500mg of the drug did not affect blood pressure or respiration, but pulse rate was increased by ~ 12%, and the highest doses caused nausea and vomiting.[48] The i.m. administration of 75 500mg of synephrine did not relieve acute asthma attacks, contradicting an earlier claim.[101] However, the topical application of 1 - 3% solutions of the drug to the nasal mucosa of patients with sinusitis did produce a beneficial constriction without local irritation.[48] A more recent study showed that the administration of synephrine by continuous intravenous infusion, at the rate of 4mg/minute, significantly increased mean arterial and systolic pressure, but diastolic pressure and heart rate were unaltered.;[100] further details of this investigation are summarized in a review by Fugh-Berman and Myers.[102] There are a number of studies, references to many of which may be found in the review by Stohs and co-workers.[103] dealing with the effects produced by dietary supplements and herbal medications that contain synephrine as only one of many different chemical ingredients. These are outside the scope of the present article (see also the "Safety/Efficacy/Controversy" sub-section, below).

Synephrine

406

Toxicology
The acute toxicities of racemic synephrine in different animals, reported in terms of "maximum tolerated dose" after s.c administration, were as follows: mouse: 300mg/kg; rat: 400mg/kg; guinea pig: 400mg/kg. "Lethal doses", given s.c., were found to be: mouse: 400mg/kg; rat: 500mg/kg; guinea pig: 500mg/kg.[45] Another study of this compound[104], administered i.v. in mice, gave an LD50 = 270mg/kg.[70] The "subchronic toxicity" of synephrine was judged to be low in mice, after administration of oral doses of 30 and 300mg/kg over a period of 28 days, in a recent study employing modern methodology carried out by Arbo and co-workers. Generally, this treatment did not result in significant alterations in biochemical or hematological parameters, nor in relative organ weights, but some changes were noted in glutathione (GSH) concentration, and in the activity of glutathione peroxidase (GPx).[105]

Safety/Efficacy/Controversy
Information about the safety and efficacy of synephrine used as a single drug may be deduced from the foregoing review of the literature in this Article. This information is, by and large, not contended. However, there exists considerable controversy about the safety and/or efficacy of synephrine-containing preparations, which are often confused with synephrine alone, sometimes with m-synephrine, and much has been written about such preparations in the medical literature and on the Internet.[26][][103][106][107][108][109][110][111][112][113][114] Since this body of literature deals with mixtures containing synephrine as only one of several biologically-active components, even, in some cases, without explicit confirmation of the presence of synephrine, further discussion is outside the scope of this article.

Invertebrates
In insects, synephrine has been found to be a very potent agonist at many invertebrate octopamine receptor preparations, and is even more potent than octopamine at a locust (Schistocerca americana gregaria) nerve-muscle preparation.[115] Synephrine (racemic) is also more potent than octopamine (racemic) at inducing light-emission in the firefly (Photinus species) light organ.[116] Synephrine exhibits similarly high potency in stimulating adenylate cyclase activity and in decreasing clotting time in lobster (Homarus americanus) hematocytes.[117] Racemic synephrine was found to increase cAMP in the abdominal epidermis of the blood-sucking bug, Rhodnius prolixus.[118] Rachinsky reported that synephrine was equipotent with octopamine in stimulating JH (juvenile hormone) release in the corpora allata of honey bee (Apis mellifera),[119] but Woodring and Hoffmann found that synephrine had no effect on the synthesis of JH III, in in vitro preparations from the cricket, Gryllus bimaculatus.[120]

Footnotes
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=94-07-5 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=7172 [3] http:/ / www. chemspider. com/ 6904 [4] http:/ / www. kegg. jp/ entry/ D07148 [5] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=29081 [6] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL33720 [7] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01CA08 [8] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=OC%28c1ccc%28O%29cc1%29CNC [9] Synephrine does not appear in the current FDA "Orange Book" or the 2012 Physicians' Desk Reference. [10] H. Wagner and G. Ulrich-Merzenich (2009). "Synergy research: approaching a new generation of phytopharmaceuticals." Phytomed. 16 97-110. [11] I. Stewart, W. F. Newhall, and G. J. Edwards (1964). "The isolation and identification of synephrine in the leaves and fruit of Citrus." J. Biol. Chem. 239 930-932. [12] http:/ / www. fshs. org/ Proceedings/ Password%20Protected/ 1963%20Vol. %2076/ 242-245%20%28STEWART%29. pdf

Synephrine
[13] T. A. Wheaton and I. Stewart (1970). "The distribution of tyramine, N-methyltyramine, hordenine, octopamine and synephrine in higher plants. Lloydia 33 244-254. [14] H. C. Ko, K. T. Chen, C. F. Chen, J. P. Su, C. M. Chen, and G. J. Wang (2006). "Chemical and biological comparisons on Evodia with two related species of different locations and conditions." J. Ethnopharmacol. 108 257-263. [15] J. A. Swinehart, and F. R. Stermitz (1980). "Bishordeninyl terpene alkaloids and other constituents of Zanthoxylum culantrillo and Z. coriaceum. Phytochem. 19 1219-1223. [16] S. P. Kim, E. Moon, S. H. Nam, and M. Friedman (2012). "Composition of Herba Pogostemonis water extract and protection of infected mice against Salmonella typhimurium-induced liver damage and mortality by stimulation of innate immune cells." J. Agric. Food Chem. 60 1212212130. [18] F. Kusu, X.-D. Li, and K. Takamura (1992). "Determination of synephrine and N-methyltyramine in Zhishi and Zhike (immature Citrus fruits) by high-performance liquid chromatography with electrochemical detection." Chem. Pharm. Bull. 40 3284-3286. [19] F. Pellati, S. Benvenuti, and M. Melegari (2005). "Enantioselective LC analysis of synephrine in natural products on a protein-based chiral stationary phase." J. Pharm. Biomed. Anal. 37 839-849. [20] L. Mattoli, F. Cangi, A. Maidecchi, C. Ghiara, M. Tubaro, and P. Traldi (2005). "A rapid liquid chromatography electrospray ionization mass spectrometry method for evaluation of synephrine in Citrus aurantium L. samples." J. Agric. Fd. Chem. 53 98609866. [21] About 1.0 - 0.02 mg/serving, based on a serving size of ~ 20g. [22] About 1.0 - 0.1 mg/serving. [23] B. Avula, S. K. Upparapalli, and I. A. Khan (2007). "Simultaneous analysis of adrenergic amines and flavonoids in citrus peel jams and fruit juices by liquid chromatography: part 2." J. AOAC Int. 90 633-40. [24] Cross-reference for Citrus species and common names: http:/ / www. plantnames. unimelb. edu. au/ Sorting/ Citrus. html [25] F. Kusu, K. Matsumoto, K. Arai and K. Takamura (1996). "Determination of synephrine enantiomers in food and conjugated synephrine in urine by high-performance liquid chromatography with electrochemical detection." Anal. Biochem. 235 191-194. [26] http:/ / abc. herbalgram. org/ site/ DocServer/ Bitter_Orange_Peel_and_Synephrine. pdf [27] K. Dragull, A. P. Breksa, and B. Cain (2008). "Synephrine content of juice from Satsuma Mandarins (Citrus unshiu Marcovitch.)" J. Ag. Fd. Chem. 56 8874-8878;doi=10.1021;PMID=18771270 [28] S. M. Vieira, K. H. Theodoro, M. B. A. Glria (2007). "Profile and levels of bioactive amines in orange juice and orange soft drink." Food Chem. 100 895-903. [29] Corresponding to roughly 1 - 15 mg/serving, assuming a 1-cup or 250 mL serving size. [30] R. M. Uckoo, G. K. Jayaprakasha, S. D. Nelson, B. S. Patil (2011). "Rapid simultaneous determination of amines and organic acids in citrus using high-performance liquid chromatography". Talanta 83 948-54; doi:10.1016; PMID 21147342 [31] K. E. Ibrahim, M. W. Couch, C. M. Williams, M. B. Budd, R. A. Yost, and J. M. Midgley (1984). "Quantitative measurement of octopamines and synephrines in urine using capillary column gas chromatography negative ion chemical ionization mass spectrometry." Anal. Chem. 56 16951699; DOI: 10.1021/ac00273a037 [32] R. Wang, L. Wan, Q. Li, X. Liu and Y. Huang (2007). "Chemiluminescence of synephrine based on the cerium(IV)rhodamine B system." Luminescence 22 140146. [33] D.G. Watson, J.M. Midgley, R.N. Chen, W. Huang, G.M. Bain, N.M. McDonald, J.L. Reid, and C.N.J. McGhee (1990). "Analysis of biogenic amines and their metabolites in biological tissues and fluids by gas chromatographynegative ion chemical ionization mass spectrometry (GC-NICIMS)." J. Pharm. Biomed. Anal. 8 899-904. [34] K. E. Ibrahim, M. W. Couch, C. M. Williams, M. J. Fregly and J. M. Midgley (1985). "m-Octopamine: normal occurrence with p-octopamine in mammalian sympathetic nerves." J. Neurochem. 44 18621867. [35] G. DAndrea, F. Granella, M. Leone, F. Perini, A. Farruggio, and G. Bussone (2006). "Abnormal platelet trace amine profiles in migraine with and without aura." Cephalalgia 26 968972. [36] G. DAndrea, S. Terrazzino, D. Fortina, A. Farruggioa, L. Rinaldi, and A. Leon (2003). "HPLC electrochemical detection of trace amines in human plasma and platelets and expression of mRNA transcripts of trace amine receptors in circulating leukocytes." Neurosci. Lett. 346 8992. [37] F. Pellati, S. Benvenuti, M. Melegari, and F. Firenzuoli (2002). "Determination of adrenergic agonists from extracts and herbal products of Citrus aurantium L. var. amara by LC." J. Pharm. Biomed. Anal. 29 1113-1119. [38] F. Pellati, G. Cannazza, and S. Benvenuti (2010). "Study on the racemization of synephrine by off-column chiral high-performance liquid chromatography." J. Chrom. A 1217 3503-3510. [39] F. Kusu, K. Matsumoto, and K. Takamura (1995). "Direct separation and determination of synephrine enantiomers by high-performance liquid chromatography with electrochemical detection." Chem. Pharm. Bull. 43 1158-1161. https:/ / www. jstage. jst. go. jp/ article/ cpb1958/ 43/ 7/ 43_7_1158/ _pdf [40] R. L. Ranieri, J. L. McLaughlin (1976). "Cactus alkaloids. XXVIII. -Phenethylamine and tetrahydroisoquinoline alkaloids from the Mexican cactus Dolichothele longimamma. J. Org. Chem. 41 319-323. [41] T. A. Wheaton and I. Stewart (1969). "Biosynthesis of synephrine in citrus." Phytochem. 8 8592. [42] G. E. Bartley, A. P. Breksa III, and B. K. Ishida (2010). "PCR amplification and cloning of tyrosine decarboxylase involved in synephrine biosynthesis in Citrus." New Biotech. 27 308-316. [43] J. Santana, K. E. Sharpless, and B. C. Nelson (2008). "Determination of para-synephrine and meta-synephrine positional isomers in bitter orange-containing dietary supplements by LC/UV and LC/MS/MS." Food Chem. 109 675682.

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Synephrine
[44] C. A. Haller, N. L. Benowitz, and P. Jacob III (1978). "Hemodynamic effects of ephedra-free weight-loss supplements in humans." Am. J. Med. 118 998-1003. [45] F. Lasch (1927). "ber die Pharmakologie des Sympathols, einer neuen adrenalinhnlichen Substanz. (Zugleich ein Beitrag zur Frage der chemischen Konstitution und pharmakodynamischen Wirkung). Naunyn-Schmiedebergs Archiv fr Experimentelle Pathologie und Pharmakologie 124 231-244. [46] M. Hochrein and J. Keller (1930). "ber die Wirkung des Adrenalins und adrenalinverwandter Krper (Sympatol und Ephetonin) auf den Kreislauf." Naunyn-Schmiedebergs Archiv fr Experimentelle Pathologie und Pharmakologie. 156 37-63. [47] H. Legerlotz, US Patent 1,932,347 (Oct. 24, 1933). [48] A. B. Stockton, P. T. Pace and M. L. Tainter (1931). "Some clinical actions and therapeutic uses of racemic synephrine." J. Pharmacol. Exp. Ther. 41 11-20. [49] M. L. Tainter and M. A. Seidenfeld (1930). "Comparative actions of sympathomimetic compounds: synephrine-isomers and -ketone." J. Pharmacol. Exp. Ther. 40 23-42. [50] Council on Pharmacy and Chemistry (1930), J. Am. Med. Assoc. 94 1404. [51] W. Hartung (1931). "Epinephrine and related compounds: influence of structure on physiological activity." Chem. Rev. 9(3) 389-468. [52] Editorial comment (1944). "Sympatol-Stearns - A triumph of medical misinformation for physicians." JAMA 124 988. [53] J. R. DiPalma (Ed.) (1965),Drill's Pharmacology in Medicine,3rd Ed., p.494, McGraw-Hill, New York. [54] C. O. Wilson, O. Gisvold, and R. F. Doerge (Eds.) (1966). Textbook of Organic Medicinal and Pharmaceutical Chemistry, 5th ed., p.438, Lippincott, Philadelphia. [55] D. M. Aviado (Ed.), 1972. Krantz & Carr's Pharmacologic Principles of Medical Practice, 8th Ed., p.526, Williams & Wilkins, Baltimore. [56] R. C. Baselt (2008). Disposition of Toxic Drugs and Chemicals in Man (8th Ed..) pp. 14712, Biomedical Publications, Foster City, California. ISBN 978-0-9626523-7-0. [57] http:/ / www. mims. com/ USA/ drug/ info/ oxedrine/ ?type=full& mtype=generic [58] For example, a recent review paper concerning the use of synephrine-containing nutritional supplements states that: "There is no consensus regarding which synephrines positional isomers are present in CA [Citrus aurantium]. The majority of authors state that only p-synephrine can be found in CA fruits...although others claim that m-synephrine is also present..."<ref name="G. Rossato, V. M 2011">L. G. Rossato, V. M. Costa, R. P. Limberger, M. de Lourdes Bastos, and F. Remio (2011). "Synephrine: from trace concentrations to massive consumption in weight-loss." Food Chem. Toxicol. 49 8-16. [59] S. R. Penzak, M. W. Jann, J. A. Cold, Y. Y. Hon, H. D. Desai, and B. J. Gurley (2001). "Seville (sour) orange juice: Synephrine content and cardiovascular effects in normotensive adults." J. Clin. Pharmacol. 41 1059-1063. [60] T. Kappe and M. D. Armstrong (1965). "Ultraviolet absorption spectra and apparent acidic dissociation constants of some phenolic amines." J. Med. Chem. 8 368-374. [61] E. D. Bergmann and M. Sulzbacher (1951). "A new synthesis of 1-(m- and p-hydroxyphenyl)-2-methylaminoethanol (m- and p-sympathol)." J. Org. Chem. 16 84-89. [62] The Merck Index, 10th Ed. (1983), p. 1295, Merck & Co., Rahway, NJ. [63] J. M. Midgley, C. M. Thonoor, A. F. Drake, C. M. Williams, A. E. Koziol and G. J. Palenik (1989). "The resolution and absolute configuration by X-ray crystallography of the isomeric octopamines and synephrines." J. Chem. Soc., Perkin Trans. 2 963-969. [64] H. M. Priestley and E. Moness (1940). "A study of the intermediates in the preparation of sympathol." J. Org. Chem. 40 355-361. [65] E. D. Bergmann and M. Sulzbacher (1951). "A new synthesi of 1-(m- and p-hydroxyphenyl)-2-methylaminoethanol (m- and p-sympathol)." J. Org. Chem. 16 84-89. [66] A. M. Lands, E. E. Rickards, V. L. Nash, and K. Z. Hooper (1947). "The pharmacology of vasodepressor compounds structurally related to the sympathomimetic amines." J. Pharmacol. Exp. Ther. 89 297-305. [67] K. Unna (1951). "Pharmakologische Untersuchungen ber neue Sympatolabkmmlinge." Naunyn-Schmiedebergs Archiv fr Experimentelle Pathologie und Pharmakologie 213 207-234. [68] O. Ehrismann, and G. Maloff (1928). "ber zwei Gifte der Adrenalingruppe (p-Oxyphenylthanolmethylamin und sein Keton." Naunyn-Schmiedebergs Archiv fr Experimentelle Pathologie und Pharmakologie 136 172-184. [69] G. Kuschinsky (1930). "Untersuchungen ber Sympatol, einen adrenalinhnlichen Krper." Naunyn-Schmiedebergs Archiv fr Experimentelle Pathologie und Pharmakologie 156 290 - 308. [70] A. M. Lands and J. I. Grant (1952). "The vasopressor action and toxicity of cyclohexylethylamine derivatives." J. Pharmacol. Exp. Ther. 106 341-345. [71] ~ 5 x 10-4M. [72] ~ 2 x 10-3M. [73] ~ 3 x 10-4M. [74] J. Gy. Papp, L. Szekeres (1968). "The arrhythmogenic action of sympathomimetic amines." Eur. J. Pharmacol. 3 4-14. [75] Tail suspension and enforced swimming. [76] D.-K. Song, H.-W. Suh, J.-S. Jung, M.-B. Wie, K.-H. Son, and Y.-H. Kim (1996). "Antidepressant-like effects of p-synephrine in mouse models of immobility tests." Neurosci. Lett. 214 107-110. [77] Ostensibly correlated to anti-depressant activity. [78] An adrenergic antagonist selective for 1 receptors. [79] Reversal of reserpine-induced hypothermia by a drug is a classical test for potential anti-depressant properties.

408

Synephrine
[80] A selective inhibitor of the norepinephrine transporter. [81] K.-W. Kim, H.-D. Kim, J.-S. Jung, R.-S. Woo, H.-S. Kim, H.-W. Suh, Y.-H. Kim, and D.-K. Song (2001). "Characterization of antidepressant-like effects of p-synephrine stereoisomers." Naunyn-Schmiedebergs Arch. Pharmacol. 364 2126. [82] Referred to here as "Oxedrine". [83] A. S. V. Burgen and L. L. Iversen (1964). "The inhibition of noradrenaline uptake by sympathomimetic amines in the rat isolated heart." Brit. J. Pharmacol. 25 34-49. [84] J. E. S. Wikberg (1978). "Pharmacological classification of adrenergic receptors in the guinea pig." Nat. 273 164-166. [85] C.M. Brown, J.C. McGrath, J.M. Midgley, A.G.B. Muir, J.W. O'Brien, C.M. Thonoor, C.M. Williams and V.G. Wilson (1988). "Activities of octopamine and synephrine stereoisomers on -adrenoceptors." Brit. J. Pharmacol. 93 417-429. [86] R. R. Ruffolo, and J. E. Waddell (1983). "Aromatic and benzylic hydroxyl substitution of imidazolines and phenethylamines: differences in activity at alpha-1 and alpha-2 adrenergic receptors." J. Pharmacol. Exp. Ther. 224 559-566. [87] A drug often used as a selective 5-HT2A antagonist. [88] T. Hibino, M. Yuzurihara, Y. Kase, and A. Takeda (2009). "Synephrine, a component of Evodiae Fructus, constricts isolated rat aorta via adrenergic and serotonergic receptors." J. Pharmacol. Sci. 111 73-81. https:/ / www. jstage. jst. go. jp/ article/ jphs/ 111/ 1/ 111_09077FP/ _pdf [89] R. Jordan, J. M. Midgley, C. M. Thonoor, and C. M. Williams (1987). "Beta-adrenergic activities of octopamine and synephrine stereoisomers on guinea-pig isolated atria and trachea." J. Pharm. Pharmacol. 39 752-754. [90] Used as a non-selective -antagonist [91] C. Carpn, J. Galitzky, E. Fontana, C. Atgi, M. Lafontan, and M. Berlan (1999). "Selective activation of 3-adrenoceptors by octopamine: comparative studies in mammalian fat cells." Naunyn-Schmiedebergs Arch. Pharmacol. 359 310321. [92] G. Ma, S. A. Bavadeka, B. T. Schaneberg, I. A. Khan, and D. R. Feller (2010). "Effects of synephrine and beta-phenylephrine on human alpha-adrenoreceptor subtypes." Planta Medica 76 981986. [93] D. B. Wainscott, S. P. Little, T. Yin, Y. Tu, V. P. Rocco, J. X. He, and D. L. Nelson (2007). "Pharmacologic characterization of the cloned human Trace Amine-Associated Receptor1 (TAAR1) and evidence for species differences with the rat TAAR1." J. Pharmacol. Exp. Ther. 320 475485. [94] J. H. Hengstmann and H. Aulepp (1978). "Pharmacokinetics and metabolism of 3H-synephrine." Arzneimittelforschung 28 2326-2331. [95] O. Suzuki, T. Matsumoto, M. Oya, and Y. Katsumata (1979). "Oxidation of synephrine by type A and type B monoamine oxidase." Exper. 35 1283 1284. [96] U. von Euler and G. Liljestrand (1929). Skand. Arch. Physiol. 55 1. [97] F. Pohle and H. Sarre (1940). "Der Wirkungsmechanismus eines neuen peripheren Kreislaufmittels im Vergleich mit Veritol und Sympatol beim Menschen." Naunyn-Schmiedebergs Archiv fr Experimentelle Pathologie und Pharmakologie 196 408 - 430. [98] F. Heim (1948). "ber die Blutdruckwirksamkeit von Sympatol an Menschen nach Vorbehandlung mit Ephedrin, Veritol und Pervitin." Naunyn-Schmiedebergs Archiv fr Experimentelle Pathologie und Pharmakologie 205 470 - 479. [99] M. H. Nathanson and H. Miller (1950). The effect of new drugs on the rhythmic function of the heart." Calif. Med. 72 215-221. [100] R. Hofstetter, J. Kreuder, and G. von Bernuth G. (1985). "The effect of oxedrine on the left ventricle and peripheral vascular resistance [English translation]." Arzneimittelforschung 35 18441846. http:/ / www. researchgate. net/ publication/ 19064931_The_effect_of_oxedrine_on_the_left_ventricle_and_peripheral_vascular_resistance [101] K. Tiefensee (1932). "[Therapy of bronchial asthma with adrenalin and the adrenalin derivatives ephedrine and Sympatol]." Mnchen med. Wchnschr. 2 1824. Abstracted in J. Allergy (1932) 4 81. [102] A. Fugh-Berman and A. Myers (2004). "Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical and basic research." Exp. Biol. Med. 229 698-704. http:/ / ebm. rsmjournals. com/ content/ 229/ 8/ 698#BIBL [103] S. J. Stohs, H. G. Preuss and M. Shara (2011). "The Safety of Citrus aurantium (Bitter Orange) and its primary protoalkaloid p-synephrine." Phytother. Res. 25 1421-1428. [104] Referred to as "Sympathol". [105] M. D. Arbo, G. C. Schmitt, M. F. Limberger, M. F. Charo, . M. Moro, G. L. Ribeiro, E. Dallegrave, S. C. Garcia, M. B. Leal, and R. P. Limberger (2009). "Subchronic toxicity of Citrus aurantium L. (Rutaceae) extract and p-synephrine in mice." Regulatory Toxicol. Pharmacol. 54 114-117. [106] J. M. Nasir, S. J. Durning, M. Ferguson, H. S. Barold, and M. C. Haigney (2004). "Exercise-induced syncope associated with QT prolongation and Ephedra-free Xenadrine." Mayo Clin. Proc. 79 1059-1062. [107] N. Bouchard and R. S. Hoffman (2004). "Synephrine is not Neo-Synephrine". Mayo Clin. Proc. 79 1589-1590. [108] S. Bent, A. Padula, and J. Neuhaus (2004). "Safety and efficacy of Citrus aurantium for weight loss." Am. J. Cardiol. 94 1359-1361. [109] N. C. Bouchard, M. A. Howland, H. A. Greller, R. S. Hoffman, and L. S. Nelson (2005). "Ischemic stroke associated with use of an Ephedra-free dietary supplement containing synephrine." Mayo Clin. Proc. 80 541-545. [110] F. Firenzuoli, L. Gori, C. Galapai (2005). "Adverse reaction to an adrenergic herbal extract (Citrus aurantium)." Phytomedicine 12 247-248. [111] S. Haaz, K. R. Fontaine, G. Cutter, N. Limdi, S. Perumean-Chaney, and D. B. Allison (2006). "Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update." Obes. Rev. 7 7988. [112] J. E. Thomas, J. A. Munir, P. Z. McIntyre, and M. A. Ferguson (2009). "STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: a case report and review of the literature." Tex. Heart Inst. J. 36 58690.

409

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[113] J. E. Thomas, J. A. Munir, P. Z. McIntyre, and M. A. Ferguson (2010). "Lack of evidence that p-synephrine is responsible for STEMI." Tex. Heart Inst. J. 37 383384. [114] S. J. Stohs (2010). "Assessment of the adverse event reports associated with Citrus aurantium (bitter orange) from April 2004 to October 2009." J. Funct. Foods 2 235-239. [115] P. D. Evans (1981). "Multiple receptor types for octopamine in the locust." J. Physol. 318 99-122. [116] A. D. Carlson (1968). "Effect of drugs on luminescence in larval fireflies." J. Exp. Biol. 49 195-199. [117] A. Battelle and E. A. Kravitz (1978). "Targets of octopamine action in the lobster: cyclic nucleotide changes and physiological effects in hemolymph, heart and exoskeletal muscle." J. Pharmacol. Exp. Ther. 205 438-448. [118] M. Barrett and I. Orchard (1990). "Serotonin-induced elevation of cAMP levels in the epidermis of the blood-sucking bug, Rhodnius prolixus." J. Insect Physiol. 36 625-633. [119] A. Rachinsky (1994). "Octopamine and serotonin influence on corpora allata activity in honey bee (Apis mellifera) larvae." J. Insect Physiol. 40 549-554. [120] J. Woodring, and K. H. Hoffmann (1994). "The effects of octopamine, dopamine and serotonin on juvenile hormone synthesis, In vitro, in the cricket, Gryllus bimaculatus." J. Insect Physiol. 40 797-802.

410

References

Thyronamine

411

Thyronamine
Thyronamine

Identifiers CAS number PubChem ChemSpider MeSH ChEMBL Jmol-3D images 500-78-7 3083601 2340781
[1] [2] [3] [4] [5]

thyronamine

CHEMBL201896 Image 1 Properties

[6]

Molecular formula Molar mass

(verify) [7]

C14H15NO2 229.27 g mol

1

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Thyronamine refers both to a molecule, and to derivatives of that molecule: a family of decarboxylated and deiodinated metabolites of the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3).

Types
The group includes: Thyronamine (T0AM) 3-Iodothyronamine (T1AM), which is the most notable one as it is a trace amine found in the nervous system. It is a possible candidate for the natural ligand of the trace amine-associated receptor TAAR1 (TAR1), a G protein-coupled receptor located in the cell membrane[8] 3,5-Diiodothyronamine (T2AM) 3,5,3'-Triiodothyronamine (T3AM)

Thyronamine

412

References
[1] [2] [3] [4] [5] [6] [7] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=500-78-7 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=3083601 http:/ / www. chemspider. com/ 2340781 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=thyronamine https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL201896 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%28c1ccc%28cc1%29CCN%29c2ccc%28O%29cc2 http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=418302300& page2=Thyronamine

Tryptamine

413

Tryptamine
Tryptamine

Identifiers CAS number PubChem ChEMBL IUPHAR ligand Jmol-3D images 61-54-1 1150
[2] [3] [1]

CHEMBL6640 125
[4] [5]

Image 1 Properties

Molecular formula Molar mass

(verify) [6]

C10H12N2 160.22 g mol

1

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

Tryptamine is a monoamine alkaloid found in plants, fungi, and animals. It contains an indole ring structure, and is structurally similar to the amino acid tryptophan, from which it derives its name. Tryptamine is found in trace amounts in the brains of mammals and is believed to play a role as a neuromodulator or neurotransmitter.[7] The tryptamine chemical structure is the backbone for a group of compounds termed collectively tryptamines. This group includes many biologically active compounds, including neurotransmitters and psychedelic drugs. The concentration of tryptamine in rat brains is about 3.5 pmol/g.[8]

Tryptamine

414

Plants containing tryptamine

Many plants contain small amounts of tryptamine, for example, as a possible intermediate in one biosynthetic pathway to the plant hormone indole-3-acetic acid.[] Higher concentrations can be found in many Acacia species.

Role in vertebrates
Tryptamine acts as a serotonin releasing agent[9] and a serotonergic activity enhancer.[10] It is metabolised by MAO-A and MAO-B.[11]

Tryptamine derivatives
Well-known tryptamines include serotonin, an important neurotransmitter, and melatonin, a hormone involved in regulating the sleep-wake cycle. Tryptamine alkaloids found in fungi, plants and animals are sometimes used by humans for their psychotropic effects. Prominent examples include psilocybin (from "magic mushrooms") and DMT (from numerous plant sources, e.g. chacruna, often used in ayahuasca brews). Many synthetic tryptamines have also been made, including the migraine drug sumatriptan and its relatives. The tables below list some tryptamines. The tryptamine structure, in particular its indole ring, may be part of the structure of some more complex compounds, for example: LSD, ibogaine and yohimbine. A thorough investigation of dozens of tryptamine compounds was published by Ann and Alexander Shulgin under the title TiHKAL.

General structure of substituted tryptamines

Short Name Tryptamine Bufotenin

Origin Natural Natural H H H

R H H H

R4 H OH OH

R5 H CH3 CH3 H CH3

RN1 H CH3 H

RN2

Full Name 3-(2-aminoethyl)indole / 2-(1H-indol-3-yl)ethanamine 5-hydroxy-N,N-dimethyltryptamine 5-hydroxy-N-methyltryptamine

N-methylserotonin Natural (norbufotenin) Serotonin DMT Melatonin 5-Bromo-DMT 5-MeO-DMT 5-MeO-NMT NMT Norbaeocystin Baeocystin Psilocybin Psilocin Tryptophan Natural Natural Natural Natural Natural Natural Natural Natural Natural Natural Natural Natural

H H H H H H H H H H H COOH

H H H H H H H OPO3H2 OPO3H2 PO4 OH H

OH H OCH3 Br OCH3 OCH3 H H H H H H

H CH3 H CH3 CH3 H CH3 H H CH3 CH3 H

5-hydroxytryptamine N,N-dimethyltryptamine 5-methoxy-N-acetyltryptamine 5-bromo-N,N-dimethyltryptamine 5-methoxy-N,N-dimethyltryptamine 5-methoxy-N-methyltryptamine N-methyltryptamine 4-phosphoryloxy-tryptamine 4-phosphoryloxy-N-methyl-tryptamine 4-phosphoryloxy-N,N-dimethyltryptamine 4-hydroxy-N,N-dimethyltryptamine -carboxyltryptamine

O=C-CH3 CH3 CH3 CH3 H H CH3 CH3 CH3 H

Tryptamine

415
artificial CH2CH3 H artificial CH3 artificial H artificial H artificial H artificial H artificial CH3 artificial H artificial H artificial H artificial H artificial H artificial H artificial H artificial H artificial H Origin R H H H H H H H OH H H H H H H OCH3 OCH3 H H H H H -ethyltryptamine -methyltryptamine

ET MT DALT DET DiPT DPT 5-MeO-MT 5-MeO-DALT 4-HO-DET 4-AcO-DMT 4-HO-MET 4-HO-DIPT 5-MeO-DIPT 4-HO-MiPT Sumatriptan Zolmitriptan Short Name

H2C=CH-CH2 H2C=CH-CH2 N,N-diallyltryptamine CH2CH3 CH(CH3)2 CH2CH2CH3 H CH2CH3 CH(CH3)2 CH2CH2CH3 H N,N-diethyltryptamine N,N-diisopropyltryptamine N,N-dipropyltryptamine 5-methoxy--methyltryptamine

H2C=CH-CH2 H2C=CH-CH2 5-methoxy-N,N-diallyltryptamine CH2CH3 CH3 CH3 CH(CH3)2 CH(CH3)2 CH(CH3)2 CH3 CH2CH3 CH3 CH2CH3 CH(CH3)2 CH(CH3)2 CH3 CH3 CH3 RN1 RN2 4-hydroxy-N,N-diethyltryptamine 4-acetoxy-N,N-dimethyltryptamine 4-hydroxy-N-methyl-N-ethyltryptamine 4-hydroxy-N,N-diisopropyltryptamine 5-methoxy-N,N-diisopropyltryptamine 4-hydroxy-N-isopropyl-N-methyltryptamine 5-(methylaminosulfonylmethylene)-N,N-dimethyltryptamine 5-( 4-(S)-1,3-oxazolidin-2-one)-N,N-dimethyltryptamine Full Name

OCOCH3 H OH OH H OH H H R4 H H OCH3 H CH2SO2NHCH3

-(CHNHC=OOCH2) CH3 R5

|+ Selected Tryptamines |+ (see also Table of naturally occurring tryptamines)

Synthesis
The AbramovitchShapiro tryptamine synthesis is an organic reaction for the synthesis of tryptamines starting from a -carboline.[12]

Tryptamine

416

References
[1] [2] [3] [4] [5] [6] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=61-54-1 http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=1150 https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL6640 http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=125 http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=C1%3DCC%3DC2C%28%3DC1%29C%28%3DCN2%29CCN http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=413418001& page2=Tryptamine

External links
Tryptamine FAQ (http://www.erowid.org/psychoactives/faqs/faqs_tryptamine.shtml) Tryptamine Hallucinogens and Consciousness (http://www.tryptamind.com/tryptamine.html) Tryptamind Psychoactives (http://www.tryptamind.com/), reference site on tryptamine and other psychoactives. Tryptamine (T) entry in TiHKAL info (http://tihkal.info/read.php?domain=tk&id=53)

1,4-Butanediol

417

1,4-Butanediol
1,4-Butanediol

Identifiers CAS number ChemSpider UNII EC-number DrugBank ChEMBL RTECS number Jmol-3D images 110-63-4
[1] [3]

13835209

[2]

7XOO2LE6G3 203-786-5 DB01955

[4]

[5] [6]

CHEMBL171623 EK0525000 Image 1 [8] Image 2

[9][10] [7]

Properties Molecular formula Molar mass Density Melting point Boiling point Solubility in water Solubility in ethanol Refractive index (n )
D

C4H10O2 90.12 g mol

1

1.0171 g/cm3 (20 C) 20.1C, 293K, 68F 235C, 508K, 455F Miscible Soluble 1.4460 (20 C) Hazards
[10][11]

GHS pictograms

GHS signal word GHS hazard statements GHS precautionary statements EU Index

WARNING H302 P264, P270, P301+312, P330, P501 not listed

1,4-Butanediol

418
NFPA 704

Flash point Autoignition temperature

121 C (open cup) 350 C Related compounds

Related butanediols

1,2-Butanediol 1,3-Butanediol 2,3-Butanediol Succinaldehyde Succinic acid

(verify) [12]

Related compounds

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

1,4-Butanediol is the organic compound with the formula HOCH2CH2CH2CH2OH. This colorless viscous liquid is derived from butane by placement of alcohol groups at each end of the chain. It is one of four stable isomers of butanediol.

Synthesis
In its industrial synthesis, acetylene reacts with two equivalents of formaldehyde to form 1,4-butynediol, also known as but-2-yne-1,4-diol. This type of acetylene-based process is illustrative of what is known as "Reppe chemistry", after German chemist Walter Reppe. Hydrogenation of 1,4-butynediol gives 1,4-butanediol. LyondellBasell manufactures 1,4-butanediol in a proprietary, multi-step process without the use of acetylene. First, propylene oxide is converted to allyl alcohol. The allyl alcohol is then hydroformylated to 4-hydroxybutyraldehyde. Hydrogenation of the 4-hydroxybutyraldehyde yields 1,4-butanediol.[13] It is also manufactured on an industrial scale from maleic anhydride in the Davy process (Davy Process Technology), which is first converted to the methyl maleate ester, then hydrogenated. Other routes are from butadiene, allyl acetate and succinic acid.[14] Genomatica (a San Diego-based company) has genetically engineered E. coli to metabolize sugar into 1,4-butanediol. They expect to build and begin operating a pilot plant by the end of 2009. Genomatica CEO Christopher Gann said the process consumes 32,000BTU per pound of 1,4-butanediol (75MJ/kg), far less than the acetylene-based process, and does not have any by-products.[15][16] Commercial Scale Production was announced in 2013 by Genomatica and DuPont Tate & Lyle Bio Products Co. with a successful compaign that produced 2000 metric tons of BDO by direct fermentation.[]

1,4-Butanediol

419

Industrial use
1,4-Butanediol is used industrially as a solvent and in the manufacture of some types of plastics, elastic fibers and polyurethanes. In organic chemistry, 1,4-butanediol is used for the synthesis of -butyrolactone (GBL). In the presence of phosphoric acid and high temperature, it dehydrates to the important solvent tetrahydrofuran.[17] At about 200 C in the presence of soluble ruthenium catalysts, the diol undergoes dehydrogenation to form butyrolactone.[18] World production of 1,4-butanediol was claimed to be about one million metric tons per year and market price is about 2,000USD (1,600EUR) per ton (2005). In 2013, worldwide production was claimed to be billions of lbs (consistent with approximately one million metric tons).[] Almost half of it is dehydrated to tetrahydrofuran to make fibers such as Spandex.[19] The largest producer is BASF.[20]

Health effects and use as a drug

It is also used as a recreational drug known by some users as "One Comma Four", "One Four Bee" or "One Four B-D-O". It exerts effects similar to -hydroxybutyrate (GHB), which is a metabolic product of 1,4-butanediol.[21][22] Anecdotal reports indicate that 1,4-butanediol produces a strong toxic feeling not present with GHB when ingested.[23] These reports also indicate that it may cause damage to the liver as well as to other vital organs.[24] Abuse has also resulted in addiction and death.[25][26][27]

Pharmacokinetics
1,4-Butanediol is converted into GHB by the enzymes alcohol dehydrogenase and aldehyde dehydrogenase and differing levels of these enzymes may account for differences in effects and side effects between users.[28] Because these enzymes are also responsible for metabolizing alcohol there is a strong chance of a dangerous drug interaction.[28][29] Emergency room patients who overdose on both alcohol and 1,4-butanediol FDA warning against products containing GHB and its prodrugs, such as often present with symptoms of ethanol 1,4-Butanediol. intoxication initially and as the ethanol is metabolized the 1,4-butanediol is then able to better compete for the enzyme and a second period of intoxication ensues as the 1,4-butanediol is converted into GHB.[28]

1,4-Butanediol

420

Metabolic pathway of 1,4-butanediol, -butyrolactone and -hydroxybutyric acid (GHB).

Pharmacodynamics
1,4-Butanediol seems to have two types of pharmacological actions. The major psychoactive effects of 1,4-butanediol are because it is metabolized into GHB; however there is some evidence that 1,4-butanediol may have inherent alcohol-like pharmacological effects that are not due to this conversion.[29] Like GHB, 1,4 is only safe in small amounts, usually between 1cc to 1.5 cc. Adverse effects in higher doses include, nausea, vomiting, dizziness, sedation, vertigo, and potentially death if ingested in large amounts. Anxiolytic effects are diminished and side effects increased when used in combination with alcohol.

Legality
While 1,4-butanediol is not currently scheduled federally in the United States, a number of states have classified 1,4-butanediol as a controlled substance. Additionally, individuals have been prosecuted for 1,4-butanediol under the Federal Analog Act as substantially similar to GHB.[30] A federal case in New York in 2002 ruled that 1,4-butanediol could not be considered an analogue of GHB under federal law.[31] Scheduling of 1,4-butanediol on a federal level may be unlikely considering its legitimate industrial applications. However, in the United Kingdom 1,4-butanediol was scheduled (along with another GHB precursur, gamma-butyrolactone) as a Class C controlled substance, in December 2009.

1,4-Butanediol

421

2007 contamination of Bindeez toy

A toy called "Bindeez" ("Aqua Dots" in North America) was recalled by the distributor in November 2007 because of the presence of 1,4-butanediol. The toy consists of small beads that stick to each other by sprinkling water. 1,4-Butanediol was detected by GC-MS.[32] The production plant seems to have intended to cut costs by replacing less toxic 1,5-pentanediol with 1,4-butanediol. ChemNet China listed the price of 1,4 butanediol at between about US$1,3502,800 per metric ton, while the price for 1,5-pentanediol is about US$9,700 per metric ton.[33]

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=110-63-4 [2] http:/ / www. chemspider. com/ 13835209 [3] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=7XOO2LE6G3 [4] http:/ / ecb. jrc. ec. europa. eu/ esis/ index. php?GENRE=ECNO& ENTREE=203-786-5 [5] http:/ / www. drugbank. ca/ drugs/ DB01955 [6] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL171623 [7] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=OCCCCO [8] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=C%28CCO%29CO [9] . [10] . [11] . [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477205926& page2=1%2C4-Butanediol [13] ACS Patent Watch - December 7, 2009 (http:/ / portal. acs. org/ portal/ PublicWebSite/ patent/ archive/ CNBP_023576), The American Chemical Society [14] Ashford's Dictionary of Industrial Chemicals, 3rd edition, 2011, ISBN 978-0-9522674-3-0, page 1517 [15] . [16] . [17] . [19] . [20] . [21] . [22] . [23] . [24] . [25] . [26] . [27] . [28] . [29] . [30] USA v Washam (2002) 312 F.3d 926, 930; http:/ / cases. justia. com/ us-court-of-appeals/ F3/ 312/ 926/ 608696/ [31] http:/ / www. erowid. org/ chemicals/ 14b/ 14b_law1. shtml [32] . [33] .

External links
International Chemical Safety Card 1104 (http://www.inchem.org/documents/icsc/icsc/eics1104.htm) SIDS Initial Assessment Report for 1,4-Butanediol (http://www.inchem.org/documents/sids/sids/110634. pdf) from the Organisation for Economic Co-operation and Development (OECD) NLM Hazardous Substances Data Bank entry for 1,4-Butanediol (http://toxnet.nlm.nih.gov/cgi-bin/sis/ search/r?dbs+hsdb:@term+@na+1,4-Butanediol)

Acetylcholine

422

Acetylcholine
Acetylcholine

Identifiers Abbreviations CAS number PubChem ChemSpider UNII EC number DrugBank KEGG MeSH ChEBI ChEMBL IUPHAR ligand Beilstein Reference Gmelin Reference 3DMet Jmol-3D images ACh 51-84-3 187 182
[2] [3] [4] [1]

N9YNS0M02X 200-128-9
[5] [6]

EXPT00412 C01996
[7]

Acetylcholine CHEBI:15355 CHEMBL667 294

[11]

[8] [9] [10]

1764436 326108 B00379 Image 1 Properties

[12] [13]

Molecular formula

C 7NH 16O+ 2 146.2074 g mol-1 Pharmacology

Molar mass

Elimination half-life

2 min

Acetylcholine

423
[14]

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

(verify)

Infobox references

Acetylcholine (ACh, pron. ah-See-tul-KO-leen) is an organic, polyatomic cation that acts as a neurotransmitter in both the peripheral nervous system (PNS) and central nervous system (CNS) in many organisms, including humans. It is an ester of acetic acid and choline, with chemical formula CH 3COO(CH 2) N+ 2 (CH 3) and systematic name 2-acetoxy-N,N,N-trimethylethanaminium. 3 Acetylcholine is one of many neurotransmitters in the autonomic nervous system (ANS) and is the only neurotransmitter used in the motor division of the somatic nervous system (sensory neurons use glutamate and various peptides at their synapses). Acetylcholine is also the principal neurotransmitter in all autonomic ganglia.
[citation needed]

In cardiac tissue acetylcholine neurotransmission has an inhibitory effect, which lowers heart rate. However, acetylcholine also behaves as an excitatory neurotransmitter at neuromuscular junctions in skeletal muscle.[15]

History
Acetylcholine (ACh) was first identified in 1914 by Henry Hallett Dale for its actions on heart tissue. It was confirmed as a neurotransmitter by Otto Loewi, who initially gave it the name Vagusstoff because it was released from the vagus nerve. Both received the 1936 Nobel Prize in Physiology or Medicine for their work. Acetylcholine was also the first neurotransmitter to be identified.

Function
Acetylcholine
Abbreviation Sources Targets Receptors Agonists Antagonists Precursor ACh many many nicotinic; muscarinic nicotine, muscarine curare, atropine choline

Synthesizing enzyme Choline acetyltransferase (ChAT) Metabolizing enzyme Acetylcholinesterase (AChE)

Acetylcholine has functions both in the peripheral nervous system (PNS) and in the central nervous system (CNS) as a neuromodulator. Its receptors have very high binding constants. In the peripheral nervous system, acetylcholine activates muscles, and is a major neurotransmitter in the autonomic nervous system. In the central nervous system, acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic system, which tends to cause anti-excitatory actions.

Acetylcholine

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In the peripheral nervous system

In the peripheral nervous system, acetylcholine activates muscles, and is a major neurotransmitter in the autonomic nervous system. When acetylcholine binds to acetylcholine receptors on skeletal muscle fibers, it opens ligand-gated sodium channels in the cell membrane. Sodium ions then enter the muscle cell, initiating a sequence of steps that finally produce muscle contraction. Although acetylcholine induces contraction of skeletal muscle, it acts via a different type of receptor (muscarinic) to inhibit contraction of cardiac muscle fibers. In the autonomic nervous system, acetylcholine is released in the following sites: all pre- and post-ganglionic parasympathetic neurons all preganglionic sympathetic neurons preganglionic sympathetic fibers to suprarenal medulla, the modified sympathetic ganglion; on stimulation by acetylcholine, the suprarenal medulla releases epinephrine and norepinephrine some postganglionic sympathetic fibers sudomotor neurons to sweat glands.

In the central nervous system

In the central nervous system, ACh has a variety of effects as a neuromodulator upon plasticity, arousal and reward. ACh has an important role in the enhancement of sensory perceptions when we wake up[16] and in sustaining attention.[17] Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be plausibly associated with the memory deficits associated with Alzheimer's disease.[18] ACh has also been shown to promote REM sleep.[19] Pathways There are three ACh pathways in the CNS.[citation needed] Pons to thalamus and cortex Magnocellular forebrain nucleus to cortex Septohippocampal Structure Acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic system from the brainstem and basal forebrain that projects axons to many areas of the brain. In the brainstem it originates from the Pedunculopontine nucleus and laterodorsal tegmental nucleus collectively known as the mesopontine tegmentum area or pontomesencephalotegmental complex.[][] In the basal forebrain, it originates from the basal optic nucleus of Meynert and medial septal nucleus: The pontomesencephalotegmental complex acts mainly on M1 receptors in the brainstem, deep cerebellar nuclei, pontine nuclei, locus caeruleus, raphe nucleus, lateral reticular nucleus and inferior olive.[] It also projects to the thalamus, tectum, basal ganglia and basal forebrain.[] Basal optic nucleus of Meynert acts mainly on M1 receptors in the neocortex. Medial septal nucleus acts mainly on M1 receptors in the hippocampus and neocortex. In addition, ACh acts as an important "internal" transmitter in the striatum, which is part of the basal ganglia. It is released by cholinergic interneurons. In humans, non-human primates and rodents, these interneurons respond to salient environmental stimuli with stereotyped responses which are temporally aligned with the responses of

Micrograph of the nucleus basalis (of Meynert), which produces acetylcholine in the CNS. LFB-HE stain.

Acetylcholine dopaminergic neurons of the substantia nigra.[20][21] Excitability and inhibition Acetylcholine also has other effects on neurons. One effect is to cause a slow depolarization[citation needed] by blocking a tonically active K+ current, which increases neuronal excitability. Alternatively, acetylcholine can activate non-specific cation conductances to directly excite neurons.[] An effect upon postsynaptic M4-muscarinic ACh receptors is to open inward-rectifier potassium ion channel (Kir) and cause inhibition.[] The influence of acetylcholine on specific neuron types can be dependent upon the duration of cholinergic stimulation. For instance, transient exposure to acetylcholine (up to several seconds) can inhibit cortical pyramidal neurons via M1 type muscarinic receptors that are linked to Gq-type G-protein alpha subunits. M1 receptor activation can induce calcium-release from intracellular stores, which then activate a calcium-activated potassium conductance which inhibits pyramidal neuron firing.[] On the other hand, tonic M1 receptor activation is strongly excitatory. Thus, ACh acting at one type of receptor can have multiple effects on the same postsynaptic neuron, depending on the duration of receptor activation.[] Recent experiments in behaving animals have demonstrated that cortical neurons indeed experience both transient and persistent changes in local acetylcholine levels during cue-detection behaviors.[] In the cerebral cortex, tonic ACh inhibits layer 4 medium spiny neurons, the main targets of thalamocortical inputs while exciting pyramidal cells in layers 2/3 and layer 5.[] This filters out weak sensory inputs in layer 4 and amplifies inputs that reach the layers 2/3 and layer L5 excitatory microcircuits. As a result, these layer-specific effects of ACh might function to improve the signal noise ratio of cortical processing.[] At the same time, acetylcholine acts through nicotinic receptors to excite certain groups of inhibitory interneurons in the cortex, which further dampen down cortical activity.[]

425

Role in Decision Making

One well-supported function of acetylcholine (ACh) in cortex is increased responsiveness to sensory stimuli, a form of attention. Phasic increases of ACh during visual,[22] auditory [23] and somatosensory [24] stimulus presentations have been found to increase the firing rate of neurons in the corresponding primary sensory cortices. When cholinergic neurons in the basal forebrain are lesioned, animals' ability to detect visual signals was robustly and persistently impaired.[25] In that same study, animals' ability to correctly reject non-target trials was not impaired, further supporting the interpretation that phasic ACh facilitates responsiveness to stimuli. Looking at ACh's effect on thalamocortical connections, a known pathway of sensory information, in vitro application of cholinergic agonist carbachol to mouse auditory cortex enhanced thalamocortical activity.[] In addition, Gil et al. (1997) applied a different cholinergic agonist, nicotine, and found that activity was enhanced at thalamocortical synapses.[] This finding provides further evidence for a facilitative role of ACh in transmission of sensory information from the thalamus to selective regions of cortex. An additional suggested function of ACh in cortex is suppression of intracortical information transmission. Gil et al. (1997) applied the cholinergic agonist muscarine to neocortical layers and found that excitatory post-synaptic potentials between intracortical synapses were depressed.[] In vitro application of cholinergic agonist carbachol to mouse auditory cortex suppressed intracortical activity as well.[] Optical recording with a voltage-sensitive dye in rat visual cortical slices demonstrated significant suppression in intracortical spread of excitement in the presence of ACh.[26] Some forms of learning and plasticity in cortex appear dependent on the presence of acetylcholine. Bear et al. (1986) found that the typical synaptic remapping in striate cortex that occurs during monocular deprivation is reduced when there is a depletion of cholinergic projections to that region of cortex.[27] Kilgard et al. (1998) found that repeated stimulation of the basal forebrain, a primary source of ACh neurons, paired with presentation of a tone at a specific frequency, resulted in remapping of the auditory cortex to better suit processing of that tone.[28] Baskerville et al.

Acetylcholine (1996) investigated the role of ACh in experience-dependent plasticity by depleting cholinergic inputs to the barrel cortex of rats.[29] The cholinergic depleted animals had a significantly reduced amount of whisker-pairing plasticity. Apart from the cortical areas, Crespo et al. (2006) found that the activation of nicotinic and muscarinic receptors in the nucleus accumbens is necessary for the acquisition of an appetitive task.[] ACh has been implicated in the reporting of expected uncertainty in the environment [30] based both on the suggested functions listed above and results recorded while subjects perform a behavioral cuing task. Reaction time difference between correctly cued trials and incorrectly cued trials, called the cue validity, was found to vary inversely with ACh levels in primates with pharmacologically (e.g. Witte et al., 1997) and surgically (e.g. Voytko et al., 1994) altered levels of ACh.[31][32] The result was also found in Alzheimer's disease patients (Parasuraman et al., 1992) and smokers after nicotine (an ACh agonist) consumption.[33][34] The inverse covariance is consistent with the interpretation of ACh as representing expected uncertainty in the environment, further supporting this claim.

426

Synthesis and degradation

Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. Cholinergic neurons are capable of producing ACh. An example of a central cholinergic area is the nucleus Basilis of Meynert in the basal forebrain.[citation needed] The enzyme acetylcholinesterase converts acetylcholine into the inactive metabolites choline and acetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essential for proper muscle function. Certain neurotoxins work by inhibiting acetylcholinesterase, thus leading to excess acetylcholine at the neuromuscular junction, causing paralysis of the muscles needed for breathing and stopping the beating of the heart.

Receptors
There are two main classes of acetylcholine receptor (AChR), nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). They are named for the ligands used to activate the receptors.

Nicotinic
Nicotinic AChRs are ionotropic receptors permeable to sodium, potassium, and calcium ions. They are stimulated by nicotine and acetylcholine. They are of two main types, muscle type and neuronal type. The former can be selectively blocked by curare and the latter by hexamethonium. The main location of nicotinic AChRs is on muscle end plates, autonomic ganglia (both sympathetic and parasympathetic), and in the CNS.[35] Myasthenia gravis The disease myasthenia gravis, characterized by muscle weakness and fatigue, occurs when the body inappropriately produces antibodies against acetylcholine nicotinic receptors, and thus inhibits proper acetylcholine signal transmission. Over time, the motor end plate is destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g., neostigmine, physostigmine, or primarily pyridostigmine) are effective in treating this disorder. They allow endogenously released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in the synaptic cleft (the space between nerve and muscle).

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Muscarinic
Muscarinic receptors are metabotropic, and affect neurons over a longer time frame. They are stimulated by muscarine and acetylcholine, and blocked by atropine. Muscarinic receptors are found in both the central nervous system and the peripheral nervous system, in heart, lungs, upper GI tract and sweat glands. Extracts from the plant Deadly nightshade included this compound (atropine), and the blocking of the muscarinic AChRs increases pupil size as used for attractiveness in many European cultures in the past. Now, ACh is sometimes used during cataract surgery to produce rapid constriction of the pupil. It must be administered intraocularly because corneal cholinesterase metabolizes topically administered ACh before it can diffuse into the eye. It is sold by the trade name Miochol-E (CIBA Vision). Similar drugs are used to induce mydriasis (dilation of the pupil), in cardiopulmonary resuscitation and many other situations.

Drugs acting on the cholinergic system

Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine. Drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the system, or antagonists, inhibiting it.

ACh and its receptors

Drug Nm Nn M1 M2 M3 + + + + +

ACh, Charbacol, AChEi (Physostigmine, Galantamine, Neostigmine, Pyridostigmine) + Nicotine, Varenicline Succinylcholine Atracurium, Vecuronium, Tubocurarine, Pancuronium Epibatidine, DMPP Trimethaphan, Mecamylamine, Bupropion, Dextromethorphan, Hexamethonium Muscarine, Methacholine, Oxotremorine, Bethanechol, Pilocarpine Atropine, Tolterodine, Oxybutynin Vedaclidine, Talsaclidine, Xanomeline, Ipatropium Pirenzepine, Telenzepine Methoctramin Darifenacin, 4-DAMP, Darifenacin, Solifenacin + +/-

+ + + + + -

ACh receptor agonists/antagonists

Acetylcholine receptor agonists and antagonists can either have an effect directly on the receptors or exert their effects indirectly, e.g., by affecting the enzyme acetylcholinesterase, which degrades the receptor ligand. Agonists increase the level of receptor activation, antagonists reduce it. Associated disorders ACh Receptor Agonists are used to treat myasthenia gravis and Alzheimer's disease. Alzheimer's disease Since 42 AchRs are reduced in Alzheimer's disease, drugs that inhibit acetylcholinesterase, e.g. galantamine hydrobromide (a competitive and reversible cholinesterase inhibitor), are commonly used in its treatment.

Acetylcholine Direct acting These are drugs that mimic acetylcholine on the receptor. In low doses, they stimulate the receptors, in high doses they numb them due to depolarisation block.
[36] Acetyl l-carnitine Acetylcholine itself Bethanechol Carbachol Cevimeline Muscarine Nicotine Pilocarpine Suberylcholine Suxamethonium

428

Cholinesterase inhibitors Most indirect acting ACh receptor agonists work by inhibiting the enzyme acetylcholinesterase. The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands, and central nervous system. They are examples of enzyme inhibitors, and increase the action of acetylcholine by delaying its degradation; some have been used as nerve agents (Sarin and VX nerve gas) or pesticides (organophosphates and the carbamates). In clinical use, they are administered to reverse the action of muscle relaxants, to treat myasthenia gravis, and to treat symptoms of Alzheimer's disease (rivastigmine, which increases cholinergic activity in the brain). Reversible The following substances reversibly inhibit the enzyme acetylcholinesterase (which breaks down acetylcholine), thereby increasing acetylcholine levels. [citation needed] Many medications in Alzheimer's disease Donepezil Galantamine Rivastigmine Tacrine Edrophonium (differs myasthenic and cholinergic crisis) Neostigmine (commonly used to reverse the effect of neuromuscular blockers used in anaesthesia, or less often in myasthenia gravis) Physostigmine (in glaucoma and anticholinergic drug overdoses) Pyridostigmine (in myasthenia gravis) Carbamate insecticides (e.g., Aldicarb) Huperzine A

Irreversible Semi-permanently inhibit the enzyme acetylcholinesterase. Echothiophate Isofluorophate Organophosphate Insecticides (Malathion, Parathion, Azinphos methyl, Chlorpyrifos, among others) Organophosphate-containing nerve agents (e.g., Sarin, VX)

Victims of organophosphate-containing nerve agents commonly die of suffocation as they cannot relax their diaphragm.

Acetylcholine Reactivation of acetylcholine esterase Pralidoxime

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ACh receptor antagonists

Antimuscarinic agents Atropine Ipratropium Scopolamine Tiotropium Diphenhydramine

Ganglionic blockers Mecamylamine Hexamethonium Trimethaphan Bupropion

Dextromethorphan Neuromuscular blockers

Atracurium Cisatracurium Doxacurium Metocurine Mivacurium Pancuronium Rocuronium Succinylcholine Tubocurarine Vecuronium Hemicholine

Synthesis inhibitors Organic mercurial compounds, such as methylmercury, have a high affinity for sulfhydryl groups, which causes dysfunction of the enzyme choline acetyltransferase. This inhibition may lead to acetylcholine deficiency, and can have consequences on motor function. Release inhibitors Botulin acts by suppressing the release of acetylcholine; where the venom from a black widow spider (alpha-latrotoxin) has the reverse effect. ACh inhibition causes paralysis. When bitten by a black widow spider, one experiences the wastage of ACh supplies and the muscles begin to contract. If and when the supply is depleted paralysis occurs. Other/uncategorized/unknown Surugatoxin

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Notes
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=51-84-3 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=187 [3] http:/ / www. chemspider. com/ 182 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=N9YNS0M02X [5] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=200-128-9 [6] http:/ / www. drugbank. ca/ drugs/ EXPT00412 [7] http:/ / www. kegg. jp/ entry/ C01996 [8] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Acetylcholine [9] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=15355 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL667 [11] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=294 [12] http:/ / www. 3dmet. dna. affrc. go. jp/ html/ B00379. html [13] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=CC%28%3DO%29OCC%5BN%2B%5D%28C%29%28C%29C [14] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=401028016& page2=Acetylcholine [18] http:/ / www. biopsychiatry. com/ alzheim. htm [20] Goldberg JA, Reynolds JN. Neuroscience. 2011 Dec 15;198:27-43. doi: 10.1016/j.neuroscience.2011.08.067. Epub 2011 Sep 8. Review. PMID 21925242 [21] Morris G, Arkadir D, Nevet A, Vaadia E, Bergman H. Neuron. 2004 Jul 8;43(1):133-43. PMID 15233923

References
Brenner, G.M.; Stevens, C.W. (2006). Pharmacology (2nd ed.). Philadelphia PA: W.B. Saunders. ISBN1-4160-2984-2. Canadian Pharmacists Association (2000). Compendium of Pharmaceuticals and Specialties (25th ed.). Toronto ON: Webcom. ISBN0-919115-76-4. Carlson, NR (2001). Physiology of Behavior (7th ed.). Needham Heights MA: Allyn and Bacon. ISBN0-205-30840-6. Gershon, Michael D. (1998). The Second Brain. New York NY: HarperCollins. ISBN0-06-018252-0. Siegal, A.; Sapru, H.N. (2006). "Ch. 15". Essential Neuroscience (Revised 1st ed.). Philadelphia: Lippincott, Williams & Wilkins. pp.255267. Hasselmo ME (February 1995). "Neuromodulation and cortical function: modeling the physiological basis of behavior" (http://linkinghub.elsevier.com/retrieve/pii/016643289400113T). Behav. Brain Res. 67 (1): 127. doi: 10.1016/0166-4328(94)00113-T (http://dx.doi.org/10.1016/0166-4328(94)00113-T). PMID 7748496 (http://www.ncbi.nlm.nih.gov/pubmed/7748496). as PDF (http://people.bu.edu/hasselmo/ HasselmoBBR1995.pdf) Yu, AJ; Dayan, P (May 2005). "Uncertainty, neuromodulation, and attention" (http://linkinghub.elsevier.com/ retrieve/pii/S0896-6273(05)00362-4). Neuron 46 (4): 68192. doi: 10.1016/j.neuron.2005.04.026 (http://dx. doi.org/10.1016/j.neuron.2005.04.026). PMID 15944135 (http://www.ncbi.nlm.nih.gov/pubmed/ 15944135). as PDF (http://www.gatsby.ucl.ac.uk/~dayan/papers/yud2005.pdf)

External links
Warning over combining common medicines for elderly (http://www.bbc.co.uk/news/health-13880553)

Nucleus basalis of Meynert

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Nucleus basalis of Meynert

Brain: Nucleus basalis of Meynert

MRI showing a coronal plane of the head with marks showing the location of the substantia innominata, the region in which the nucleus basalis is found.

Intermediate magnification micrograph of the nucleus basalis (of Meynert). LFB-HE stain. Latin Gray's NeuroNames MeSH nucleus basalis telencephali subject #189 813 hier-257
[2] [3] [1]

Basal+nucleus+of+Meynert

Nucleus basalis of Meynert, abbreviated NBM and also known as the nucleus basalis, is a group of neurons in the substantia innominata of the basal forebrain which has wide projections to the neocortex and is rich in acetylcholine and choline acetyltransferase.

Clinical significance
In Parkinson and Alzheimer diseases the nucleus undergoes degeneration. A decrease in acetylcholine production is seen in Alzheimer's disease, Lewy body dementia and some Parkinson disease patients showing abnormal brain function, leading to a general decrease of mental capacity and learning. Most pharmacological treatments of dementia focus on compensating for a faltering NBM function through artificially increasing acetylcholine levels.

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Anatomy
The NBM is inferior to the globus pallidus and within an area known as the substantia innominata. The NBM is immediately inferior to the Anterior Commissure and superior and lateral to the anterior portion of the Hypothalamus.

Cholinergic neurons/cell bodies

The primary concentration of cholinergic neurons/cell bodies that project to the neocortex are in the basal nucleus of Meynert which is located in the substantia innominata of the anterior perforated substance. These cholinergic neurons have a number of important functions in particular with respect to modulating the ratio of reality and virtual reality components of visual perception.[4] Experimental evidence has shown that normal visual perception has two components.[4] The first (A) is a bottom-up component in which the input to the higher visual cortex (where conscious perception takes place) NBM in relation to the globus pallidus (top of image). comes from the retina via the lateral geniculate body and V1. This carries information about what is actually outside. The second (B) is a top-down component in which the input to the higher visual cortex comes from other areas of the cortex. This carries information about what the brain computes is most probably outside. In normal vision, what is seen at the center of attention is carried by A, and material at the periphery of attention is carried mainly by B. When a new potentially important stimulus is received, the Nucleus Basalis is activated. The axons it sends to the visual cortex provide collaterals to pyramidal cells in layer IV (the input layer for retinal fibres) where they activate excitatory nicotinic receptors and thus potentiate retinal activation of V1.[] The cholinergic axons then proceed to layers 1-11 (the input layer for cortico-cortical fibres) where they activate inhibitory muscarinic receptors of pyramidal cells, and thus inhibit cortico-cortical conduction.[] In this way activation of Nucleus Basalis promotes (A) and inhibits (B) thus allowing full attention to be paid to the new stimulus. Goard and Dan,[] and Kuo et al.[] report similar findings. Gerrard Reopit, in 1984, confirmed the reported findings in his research.

Eponym
It is named for Theodor Meynert.[5]

Additional images

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NBM in relation to the globus pallidus and putamen - very low magnification.

NBM - very high magnification.

References
[1] [2] [3] [4] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=189#p813 http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=257 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Basal+ nucleus+ of+ Meynert Smythies, J. (2009) Philosophy, Perception and Neuroscience. Philosophy 38, 63851.

External links
location at univ-rennes1.fr (http://www.med.univ-rennes1.fr/etud/pharmaco/media/alzheimerGB. htm#Noyau basal de Meynert (NbM)) This article incorporates text from a public domain edition of Gray's Anatomy.

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Neocortex
Brain: Neocortex
NeuroNames ancil-754 [1] MeSH Neocortex
[2]

NeuroLex ID birnlex_2547 [3]

The neocortex, (Latin for "new bark" or "new rind"), also called the neopallium ("new mantle") and isocortex ("equal rind"), is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI (with VI being the innermost and I being the outermost). The neocortex is part of the cerebral cortex (along with the archicortex and paleocortex, which are cortical parts of the limbic system). In all mammals, it is involved in "higher functions" such as sensory perception, generation of motor commands, spatial reasoning, conscious thought and language.[]

Anatomy
The neocortex consists of the grey matter, or neuronal cell bodies and unmyelinated fibers, surrounding the deeper white matter (myelinated axons) in the cerebrum. The neocortex is smooth in rodents and other small mammals, whereas in primates and other larger mammals it has deep grooves (sulci) and wrinkles (gyri). These folds allow the surface area of the neocortex to increase far beyond what could otherwise be fit in the same size skull. All human brains have the same overall pattern of main gyri and sulci, although they differ in detail from one person to another. The mechanism by which the gyri form during embryogenesis is not entirely clear. However, it may be due to differences in cellular proliferation rates in different areas of the cortex early in embryonic development.[] The neocortex contains two primary types of neurons, excitatory pyramidal neurons (~80% of neocortical neurons) and inhibitory interneurons (~20%). The structure of the neocortex is relatively uniform (hence the alternative names "iso-" and "homotypic" cortex), consisting of six horizontal layers segregated principally by cell type and neuronal connections. However, there are many exceptions to this uniformity; for example, the motor cortex lacks layer IV. There is some canonical circuitry within the cortex; for example, pyramidal neurons in the upper layers II and III project their axons to other areas of neocortex, while those in the deeper layers V and VI project primarily out of the cortex, e.g. to the thalamus, brainstem, and spinal cord. Neurons in layer IV receive all of the synaptic connections from outside the cortex (mostly from thalamus), and themselves make short-range, local connections to other cortical layers. Thus, layer IV receives all incoming sensory information and distributes it to the other layers for further processing. The neurons of the neocortex are also arranged in vertical structures called neocortical columns. These are patches of the neocortex with a diameter of about 0.5mm (and a depth of 2mm). Each column typically responds to a sensory stimulus representing a certain body part or region of sound or vision. These columns are similar, and can be thought of as the basic repeating functional units of the neocortex. In humans, the neocortex consists of about a half-million of these columns, each of which contains approximately 70,000 neurons.[4] The neocortex is derived embryonically from the dorsal telencephalon, which is the rostral part of the forebrain. The neocortex is divided into frontal, parietal, occipital, and temporal lobes, which perform different functions. For example, the occipital lobe contains the primary visual cortex, and the temporal lobe contains the primary auditory cortex. Further subdivisions or areas of neocortex are responsible for more specific cognitive processes. In humans, the frontal lobe contains areas devoted to abilities that are enhanced in or unique to our species, such as complex language processing localized to the ventrolateral prefrontal cortex (Broca's area). In humans and other primates, social and emotional processing is localized to the orbitofrontal cortex. (See Cerebral cortex and Cerebrum.)

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Evolution
The neocortex is the newest part of the cerebral cortex to evolve (hence the prefix "neo"); the other parts of the cerebral cortex are the paleocortex and archicortex, collectively known as the allocortex. The cellular organization of the allocortex is different from the six-layer structure mentioned above. In humans, 90% of the cerebral cortex is neocortex. The six-layer cortex appears to be a distinguishing feature of mammals; it has been found in the brains of all mammals, but not in any other animals.[] There is some debate,[5][6] however, as to the cross-species nomenclature for neocortex. In avians, for instance, there are clear examples of cognitive processes that are thought to be neocortical in nature, despite the lack of the distinctive six-layer neocortical structure.[7] In a similar manner, reptiles, such as turtles, have primary sensory cortices. A consistent, alternative name has yet to be agreed upon.

Neocortex ratio
The neocortex ratio of a species is the ratio of the size of the neocortex to the rest of the brain. A high neocortex ratio is thought to correlate with a number of social variables such as group size and the complexity of social mating behaviors.[8] (See Dunbar's number) Humans have a large neocortex as a percentage of total brain matter when compared with other mammals. For example, there is only a 30:1 ratio of neocortical gray matter to the size of the medulla in the brainstem of chimpanzees, while the ratio is 60:1 in humans.[9]

References
[1] [2] [3] [4] http:/ / braininfo. rprc. washington. edu/ Scripts/ ancilcentraldirectory. aspx?ID=754 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Neocortex http:/ / www. neurolex. org/ wiki/ birnlex_2547 bluebrain.epfl.ch

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Septal nuclei
Brain: Septal area
Latin Gray's nuclei septales subject #189 840
[1]

NeuroNames hier-241 [2] BAMS SEPTAL-NUCLEI

[3]

The septal nuclei (medial olfactory area) are a set of structures that lie below the rostrum of the corpus callosum, anterior to the lamina terminalis (the layer of gray matter in the brain connecting the optic chiasma and the anterior commissure where the latter becomes continuous with the rostral lamina). The septal nuclei are composed of medium-size neurons which are classified into medial, lateral, and posterior groups. The septal nuclei receive reciprocal connections from the olfactory bulb, hippocampus, amygdala, hypothalamus, midbrain, habenula, cingulate gyrus, and thalamus. The septal area (medial olfactory area) has no relation to the smell, but it is considered a pleasure zone in animals. The septal nuclei play a role in reward and reinforcement along with the nucleus accumbens. In the 1950s, Olds & Milner showed that rats with electrodes implanted in this area will self-stimulate repeatedly (i.e. press a bar to receive electrical current that will stimulate the neurons).[4]

Connections with other structures

The dorsal septum projects to the lateral preoptic area, lateral hypothalamus, periventricular hypothalamus and midline thalamus. Fibers from the ventral half of the septum project topographically to the hippocampal formation, thalamus, hypothalamus and midbrain. Specifically, neurons located along the midline in the vertical limb of the diagonal band of Broca project through the dorsal fornix to all CA fields of the dorsal hippocampus and adjacent subicular cortex. Other fibers from this region project through the stria medullaris to the medial and lateral habenular nuclei, the paratenial and anteromedial nucleus of the thalamus, and through the medial forebrain bundle to the pars posterior of the medial mammillary nucleus. Cells located in the intermediolateral septum also project through the lateral part of the fimbria to all CA fields of the ventral hippocampus and adjacent subicular and entorhinal cortices. These cells also send fibers through the stria medullaris to the lateral habenular nucleus and mediodorsal thalamic nucleus. Other axons arising from these cells descend through the medial forebrain bundle to terminate in a region dorsal to the interpeduncular nucleus. The lateral septum is a relay center for connections from the CA3 of the hippocampus to the ventral tegmental area. These connections help link reward signals with the context in which they occur.[5] Fibers from the most lateral part of the ventral septum (i.e., bed nucleus of the anterior commissure) project through the stria terminalis to the ventral subiculum. In addition, cells located in the horizontal limb of the diagonal band project massively to the pars posterior of the medial mammillary nucleus, the ventral tegmental area, and amygdala.

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External links
BrainMaps at UCDavis septal%20nuclei [6]

References
[1] [2] [3] [6] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=189#p840 http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=241 http:/ / brancusi1. usc. edu/ brain_parts/ SEPTAL-NUCLEI/ http:/ / brainmaps. org/ index. php?q=septal%20nuclei

Neuroanatomy book of mansoura faculty of medicine(Egypt)

Medial septal nucleus

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Medial septal nucleus

Brain: Medial septal nucleus
Latin nucleus septalis medialis

The medial septal nucleus is one of the septal nuclei. Neurons in this nucleus give rise to the bulk of efferents from the septal nuclei. A major projection from the medial septal nucleus terminates in the hippocampal formation.[1] It plays a role in the generation of theta waves.[]

References

Fornix of the brain

439

Fornix of the brain

Brain: Fornix of the brain

Diagram of the fornix. Right=anterior

Scheme of rhinencephalon. Latin Gray's Fornix subject #189 838

[1]

NeuroNames hier-250 [2] MeSH Fornix+(Brain)

[3]

NeuroLex ID birnlex_705 [4]

The fornix (Latin, "vault" or "arch") is a C-shaped bundle of fibers (axons) in the brain, and carries signals from the hippocampus to the hypothalamus.

Structure
The fibres begin in the hippocampus on each side of the brain (where they are also known as the fimbria); the separate left and right side are each called the crus of the fornix. The bundles of fibres come together in the midline of the brain, forming the body of the fornix. The inferior edge of the septum pellucidum (a membrane that separates the two lateral ventricles) is attached to the upper face of the fornix body. The body of the fornix travels anteriorly and divides again near the anterior commissure. The left and right parts reseparate, but there is also an anterior/posterior divergence. The posterior fibres (called the postcommissural fornix) of each side continue through the hypothalamus to the mammillary bodies; then to the anterior nuclei of thalamus, which maps to cingulate cortex. The anterior fibers (precommissural fornix) end at the septal nuclei and nucleus accumbens of each half of the brain.

Fornix of the brain

440

Additional images

Velum interpositum.

Medial aspect of a brain sectioned in the median sagittal plane.

Coronal section of brain through intermediate mass of third ventricle.

Coronal section of lateral and third ventricles.

Central part and anterior and posterior cornua of lateral ventricles exposed from above.

Tela chorioidea of the third ventricle, and the choroid plexus of the left lateral ventricle, exposed from above.

Diagram showing the positions of the three principal subarachnoid cistern.

Fornix

Fornix

Fornix of the brain

External links
Photo at umdnj.edu [5] BrainMaps at UCDavis Fornix [6] Roche Lexicon - illustrated navigator, at Elsevier 13048.000-3 [7] NIF Search - Fornix [8] via the Neuroscience Information Framework More info at BrainInfo [9]

Fornix of the brain

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References
[1] [2] [3] [4] [5] [6] [7] [8] [9] http:/ / education. yahoo. com/ reference/ gray/ subjects/ subject?id=189#p838 http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=250 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Fornix+ (Brain) http:/ / www. neurolex. org/ wiki/ birnlex_705 http:/ / www2. umdnj. edu/ ~neuro/ studyaid/ Practical2000/ Q26. htm http:/ / brainmaps. org/ index. php?q=Fornix http:/ / www. tk-online. de/ rochelexikon/ pics/ s13048. 000-3. html https:/ / www. neuinfo. org/ mynif/ search. php?q=Fornix& t=data& s=cover& b=0& r=20 http:/ / braininfo. rprc. washington. edu/ centraldirectory. aspx?ID=268

Vasoactive intestinal peptide

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Vasoactive intestinal peptide

Vasoactive intestinal peptide
Available structures PDB Ortholog search: PDBe [1], RCSB [2] List of PDB id codes 2RRH
[3]

, 2RRI

[4]

Identifiers Symbols External IDs VIP

[5]

; PHM27
[6]

OMIM: 192320 [10] Gene

MGI: 98933

[7]

HomoloGene: 2539

[8]

ChEMBL: 5737

[9]

GeneCards: VIP

Gene Ontology Molecular function hormone activity [10] [7] neuropeptide hormone activity Cellular component Biological process extracellular region [13] neuronal cell body
[11]

positive regulation of endothelial cell proliferation [16] G-protein coupled receptor signaling pathway [12] body fluid secretion [13] learning or memory [21] positive regulation of cell proliferation [14] regulation of signal transduction positive regulation of adenylate cyclase activity involved in G-protein coupled receptor signaling pathway
[15]

[11]

regulation of protein localization [17] negative regulation of apoptotic process [18] negative regulation of potassium ion transport [19] positive regulation of protein catabolic process [20] positive regulation of vasodilation [21] negative regulation of smooth muscle cell proliferation [28] regulation of sensory perception of pain Sources: Amigo
[22]

[16]

/ QuickGO

[23]

RNA expression pattern

More reference expression data

[24]

Vasoactive intestinal peptide

443
Orthologs

Species Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Location (UCSC)

Human 7432
[25] [27]

Mouse 22353
[26] [28]

ENSG00000146469 P01282
[29] [31]

ENSMUSG00000019772 P32648
[30] [32]

NM_003381 NP_003372

NM_011702 NP_035832

[33]

[34]

Chr 6: [35] 153.07 153.08 Mb

[37]

Chr 10: [36] 5.64 5.65 Mb

[38]

PubMed search

Vasoactive intestinal peptide also known as the vasoactive intestinal polypeptide or VIP is a peptide hormone containing 28 amino acid residues. VIP is neuropeptide which belongs to a glucagon/secretin superfamily, the ligand of class II G protein-coupled receptors.[39] VIP is produced in many tissues of vertebrates including the gut, pancreas and suprachiasmatic nuclei of the hypothalamus in the brain.[][] VIP stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder. In humans, the vasoactive intestinal peptide is encoded by the VIP gene.[] VIP has a half-life (t) in the blood of about two minutes.

Function
VIP has an effect on several tissues: With respect to the digestive system, VIP seems to induce smooth muscle relaxation (lower esophageal sphincter, stomach, gallbladder), stimulate secretion of water into pancreatic juice and bile, and cause inhibition of gastric acid secretion and absorption from the intestinal lumen.[] Its role in the intestine is to greatly stimulate secretion of water and electrolytes,[] as well as stimulating contraction of enteric smooth muscle, dilating peripheral blood vessels, stimulating pancreatic bicarbonate secretion, and inhibiting gastrin-stimulated gastric acid secretion. These effects work together to increase motility.[] It also has the function of stimulating pepsinogen secretion by chief cells.[] It is also found in the brain and some autonomic nerves. One region of the brain includes a specific area of the suprachiasmatic nuclei (SCN), the location of the 'master circadian pacemaker'. The SCN coordinates daily timekeeping in the body and VIP plays a key role in communication between individual brain cells within this region. Further, VIP is also involved in synchronising the timing of SCN function with the environmental light-dark cycle. Combined, these roles in the SCN make VIP a crucial component of the mammalian circadian timekeeping machinery. VIP helps to regulate prolactin secretion;[] it stimulates prolactin release in the domestic turkey. It is also found in the heart and has significant effects on the cardiovascular system. It causes coronary vasodilation[] as well as having a positive inotropic and chronotropic effect. Research is being performed to see if it may have a beneficial role in the treatment of heart failure. VIP provokes vaginal lubrication in normal women, doubling the total volume of lubrication produced in one study.[40] The growth-hormone-releasing hormone (GH-RH) is a member of the VIP family and stimulates Growth Hormone secretion in the anterior pituitary gland.

Vasoactive intestinal peptide

444

Pathology
VIP is overproduced in VIPoma.[] Can be associated with Multiple Endocrine Neoplasia Type 1 (Pituitary, parathyroid and pancreatic tumors). Symptoms are typically: Profuse non-bloody/non-mucoid diarrhea (3L+) causing dehydration and the associated electrolyte disturbances such as hypokalemia and metabolic acidosis. Lethargy and exhaustion may ensue

References
[1] http:/ / www. ebi. ac. uk/ pdbe/ searchResults. html?display=both& term=P01282%20or%20F1PE02%20or%20P81401%20or%20P32648%20or%20B0LF71 [2] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=UpAccessionIdQuery& accessionIdList=P01282,F1PE02,P81401,P32648,B0LF71 [3] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=2RRH [4] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=2RRI [5] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=12693 [6] http:/ / omim. org/ entry/ 192320 [7] http:/ / www. informatics. jax. org/ searches/ accession_report. cgi?id=MGI:98933 [8] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=2539 [9] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ target/ inspect/ CHEMBL5737 [10] http:/ / www. genecards. org/ cgi-bin/ carddisp. pl?id_type=entrezgene& id=7432 [11] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0001938 [12] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007589 [13] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007611 [14] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0009966 [15] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0010579 [16] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032880 [17] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043066 [18] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043267 [19] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045732 [20] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045909 [21] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0048662 [22] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ gp-assoc. cgi?gp=UniProtKB:P01282 [23] http:/ / www. ebi. ac. uk/ QuickGO/ GProtein?ac=P01282 [24] http:/ / biogps. org/ gene/ 7432/ [25] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=7432& rn=1 [26] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=22353& rn=1 [27] http:/ / www. ensembl. org/ Homo_sapiens/ geneview?gene=ENSG00000146469;db=core [28] http:/ / www. ensembl. org/ Mus_musculus/ geneview?gene=ENSMUSG00000019772;db=core [29] http:/ / www. uniprot. org/ uniprot/ P01282 [30] http:/ / www. uniprot. org/ uniprot/ P32648 [31] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_003381 [32] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_011702 [33] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_003372 [34] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_035832 [35] http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Human& db=hg19& position=chr6:153071933-153080900 [36] http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Mouse& db=mm9& position=chr10:5639218-5647614 [37] http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=7432 [38] http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=22353 [40] Ottesen B, Pedersen B, Nielsen J, Dalgaard D, Wagner G, Fahrenkrug J. Vasoactive intestinal polypeptide (VIP) provokes vaginal lubrication in normal women (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 3432128) Peptides. 1987 Sep-Oct;8(5):797-800. PMID: 3432128

Vasoactive intestinal peptide

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Further reading
Fahrenkrug J (2002). "Gut/brain peptides in the genital tract: VIP and PACAP". Scand. J. Clin. Lab. Invest. Suppl. 234: 359. PMID 11713978 (http://www.ncbi.nlm.nih.gov/pubmed/11713978). Delgado M, Pozo D, Ganea D (2004). "The significance of vasoactive intestinal peptide in immunomodulation". Pharmacol. Rev. 56 (2): 24990. doi: 10.1124/pr.56.2.7 (http://dx.doi.org/10.1124/pr.56.2.7). PMID 15169929 (http://www.ncbi.nlm.nih.gov/pubmed/15169929). Conconi MT, Spinazzi R, Nussdorfer GG (2006). "Endogenous ligands of PACAP/VIP receptors in the autocrine-paracrine regulation of the adrenal gland". Int. Rev. Cytol. 249: 151. doi: 10.1016/S0074-7696(06)49001-X (http://dx.doi.org/10.1016/S0074-7696(06)49001-X). PMID 16697281 (http://www.ncbi.nlm.nih.gov/pubmed/16697281). Hill JM (2007). "Vasoactive intestinal peptide in neurodevelopmental disorders: therapeutic potential". Curr. Pharm. Des. 13 (11): 107989. doi: 10.2174/138161207780618975 (http://dx.doi.org/10.2174/ 138161207780618975). PMID 17430171 (http://www.ncbi.nlm.nih.gov/pubmed/17430171). Gonzalez-Rey E, Varela N, Chorny A, Delgado M (2007). "Therapeutical approaches of vasoactive intestinal peptide as a pleiotropic immunomodulator". Curr. Pharm. Des. 13 (11): 111339. doi: 10.2174/138161207780618966 (http://dx.doi.org/10.2174/138161207780618966). PMID 17430175 (http:// www.ncbi.nlm.nih.gov/pubmed/17430175). "Quaternary structure of rabbit skeletal muscle glycogen synthetase" [Quaternary structure of rabbit skeletal muscle glycogen synthetase]. Doklady Akademii Nauk SSSR 222 (4): 9971000. 1975. PMID 807467 (http:// www.ncbi.nlm.nih.gov/pubmed/807467). Kitamura K, Kangawa K, Kawamoto M, et al. (1992). "Isolation and characterization of peptides which act on rat platelets, from a pheochromocytoma". Biochem. Biophys. Res. Commun. 185 (1): 13441. doi: 10.1016/S0006-291X(05)80966-0 (http://dx.doi.org/10.1016/S0006-291X(05)80966-0). PMID 1318039 (http://www.ncbi.nlm.nih.gov/pubmed/1318039). Glowa JR, Panlilio LV, Brenneman DE, et al. (1992). "Learning impairment following intracerebral administration of the HIV envelope protein gp120 or a VIP antagonist". Brain Res. 570 (1-2): 4953. doi: 10.1016/0006-8993(92)90562-N (http://dx.doi.org/10.1016/0006-8993(92)90562-N). PMID 1617429 (http:/ /www.ncbi.nlm.nih.gov/pubmed/1617429). Theriault Y, Boulanger Y, St-Pierre S (1991). "Structural determination of the vasoactive intestinal peptide by two-dimensional H-NMR spectroscopy". Biopolymers 31 (4): 45964. doi: 10.1002/bip.360310411 (http://dx. doi.org/10.1002/bip.360310411). PMID 1863695 (http://www.ncbi.nlm.nih.gov/pubmed/1863695). Gozes I, Giladi E, Shani Y (1987). "Vasoactive intestinal peptide gene: putative mechanism of information storage at the RNA level". J. Neurochem. 48 (4): 113641. doi: 10.1111/j.1471-4159.1987.tb05638.x (http://dx. doi.org/10.1111/j.1471-4159.1987.tb05638.x). PMID 2434617 (http://www.ncbi.nlm.nih.gov/pubmed/ 2434617). Yamagami T, Ohsawa K, Nishizawa M, et al. (1988). "Complete nucleotide sequence of human vasoactive intestinal peptide/PHM-27 gene and its inducible promoter". Ann. N. Y. Acad. Sci. 527 (1 Vasoactive In): 87102. doi: 10.1111/j.1749-6632.1988.tb26975.x (http://dx.doi.org/10.1111/j.1749-6632.1988.tb26975.x). PMID 2839091 (http://www.ncbi.nlm.nih.gov/pubmed/2839091). Bodner M, Fridkin M, Gozes I (1985). "Coding sequences for vasoactive intestinal peptide and PHM-27 peptide are located on two adjacent exons in the human genome" (http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC397822). Proc. Natl. Acad. Sci. U.S.A. 82 (11): 354851. doi: 10.1073/pnas.82.11.3548 (http://dx.doi.org/ 10.1073/pnas.82.11.3548). PMC 397822 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC397822). PMID 2987932 (http://www.ncbi.nlm.nih.gov/pubmed/2987932). DeLamarter JF, Buell GN, Kawashima E, et al. (1985). "Vasoactive intestinal peptide: expression of the prohormone in bacterial cells". Peptides. 6. Suppl 1: 95102. doi: 10.1016/0196-9781(85)90016-6 (http://dx. doi.org/10.1016/0196-9781(85)90016-6). PMID 2995945 (http://www.ncbi.nlm.nih.gov/pubmed/

Vasoactive intestinal peptide 2995945). Linder S, Barkhem T, Norberg A, et al. (1987). "Structure and expression of the gene encoding the vasoactive intestinal peptide precursor" (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC304259). Proc. Natl. Acad. Sci. U.S.A. 84 (2): 6059. doi: 10.1073/pnas.84.2.605 (http://dx.doi.org/10.1073/pnas.84.2.605). PMC 304259 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC304259). PMID 3025882 (http://www.ncbi.nlm. nih.gov/pubmed/3025882). Gotoh E, Yamagami T, Yamamoto H, Okamoto H (1989). "Chromosomal assignment of human VIP/PHM-27 gene to 6q26----q27 region by spot blot hybridization and in situ hybridization". Biochem. Int. 17 (3): 55562. PMID 3202886 (http://www.ncbi.nlm.nih.gov/pubmed/3202886). Yiangou Y, Di Marzo V, Spokes RA, et al. (1987). "Isolation, characterization, and pharmacological actions of peptide histidine valine 42, a novel prepro-vasoactive intestinal peptide-derived peptide". J. Biol. Chem. 262 (29): 140103. PMID 3654650 (http://www.ncbi.nlm.nih.gov/pubmed/3654650). Gozes I, Bodner M, Shani Y, Fridkin M (1986). "Structure and expression of the vasoactive intestinal peptide (VIP) gene in a human tumor". Peptides. 7. Suppl 1: 16. doi: 10.1016/0196-9781(86)90156-7 (http://dx.doi. org/10.1016/0196-9781(86)90156-7). PMID 3748844 (http://www.ncbi.nlm.nih.gov/pubmed/3748844). Tsukada T, Horovitch SJ, Montminy MR, et al. (1985). "Structure of the human vasoactive intestinal polypeptide gene". DNA 4 (4): 293300. PMID 3899557 (http://www.ncbi.nlm.nih.gov/pubmed/3899557).

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Heinz-Erian P, Dey RD, Flux M, Said SI (1985). "Deficient vasoactive intestinal peptide innervation in the sweat glands of cystic fibrosis patients". Science 229 (4720): 14078. doi: 10.1126/science.4035357 (http://dx.doi. org/10.1126/science.4035357). PMID 4035357 (http://www.ncbi.nlm.nih.gov/pubmed/4035357). Bloom SR, Christofides ND, Delamarter J, et al. (1984). "Diarrhoea in vipoma patients associated with cosecretion of a second active peptide (peptide histidine isoleucine) explained by single coding gene". Lancet 2 (8360): 11635. doi: 10.1016/S0140-6736(83)91215-1 (http://dx.doi.org/10.1016/S0140-6736(83)91215-1). PMID 6139527 (http://www.ncbi.nlm.nih.gov/pubmed/6139527).

External links
Pathway at biocarta.com (http://www.biocarta.com/pathfiles/vipPathway.gif) Physiology at MCG 6/6ch2/s6ch2_34 (http://web.archive.org/web/20080401093403/http://www.lib.mcg. edu/edu/eshuphysio/program/section6/6ch2/s6ch2_34.htm)

Substance P

447

Substance P
tachykinin, precursor 1

Spacefilling model of substance P Identifiers Symbol Alt. symbols Entrez HUGO OMIM RefSeq UniProt TAC1 TAC2, NKNA 6863 [1] [2] [3] [4]

11517

162320

NM_003182 P20366 Other data [5]

Locus

Chr. 7 q21-q22

[6]

Substance P

Identifiers CAS number PubChem ChemSpider MeSH ChEMBL 33507-63-0 36511 33558
[8] [9] [10] [11] [7]

Substance+P

CHEMBL235363 Properties

Molecular formula

C H N O S
63 98 18 13

Substance P

448
Molar mass
(verify) [12]

1347.63 g/mol

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Infobox references

In the field of neuroscience, substance P (SP) is a neuropeptide - a substance that functions as a neurotransmitter and as a neuromodulator.[][] Specifically, substance P is an undecapeptide - a peptide composed of a chain of 11 amino acid residues. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:[13] Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met (RPKPQQFFGLM) with an amidation at the C-terminus.[] Substance P is released from the terminals of specific sensory nerves, it is found in the brain and spinal cord, and is associated with inflammatory processes and pain.

Discovery
Substance P was originally discovered in 1931 by Ulf von Euler and John H. Gaddum as a tissue extract that caused intestinal contraction in vitro.[] Its tissue distribution and biologic actions were further investigated over the following decades.[] In 1983, NKA (previously known as substance K or neuromedin L) was isolated from porcine spinal cord and was also found to stimulate intestinal contraction.[]

Receptor
The endogenous receptor for substance P is neurokinin 1 receptor (NK1-receptor, NK1R).[] It belongs to the tachykinin receptor sub-family of GPCRs.[] Other neurokinin subtypes and neurokinin receptors that interact with SP have also been reported. Amino acid residues that are responsible for the binding of SP and its antagonists are present in the extracellular loops and transmembrane regions of NK-1. Binding of SP to NK-1 results in internalization by the clathrin-dependent mechanism to the acidified endosomes where the complex disassociates. SP is subsequently degraded and NK-1 is re-expressed on the cell surface.[] Substance P and the NK1 receptor are widely distributed in the brain and are specifically found in brain regions that regulate emotion (hypothalamus, amygdala, and the periaqueductal gray).[] They are also found in close association with serotonin (5-HT) and neurons containing norepinephrine that are targeted by the currently used antidepressant drugs.[] The SP receptor promoter contains regions that are sensitive to cAMP, AP-1, AP-4, CEBPB[] and epidermal growth factor. Because these regions are related to complexed signal transduction pathways mediated by cytokines, it has been proposed that cytokines and neurotropic factors can induce NK-1. SP can also induce the cytokines that are capable of inducing NK-1 transcription factors.[]

Function
Substance P is an important element in pain perception. The sensory function of substance P is thought to be related to the transmission of pain information into the central nervous system. Substance P coexists with the excitatory neurotransmitter glutamate in primary afferents that respond to painful stimulation.[] Substance P has been associated with the regulation of mood disorders, anxiety, stress,[] reinforcement,[] neurogenesis,[] respiratory rhythm,[] neurotoxicity, nausea/emesis,[] pain and nociception.[] Substance P and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve fibers in the skin, muscle and joints. It is proposed that this release is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infection or injury.[] The regulatory function of SP also involves the regulation of its high-affinity receptor, NK-1. Substance P receptor antagonists may have important therapeutic applications in the treatment of a variety of stress-related illnesses, in

Substance P addition to their potential as analgesics.

449

Vomiting
The vomiting center in the medulla contains high concentrations of substance P and its receptor, in addition to other neurotransmitters such as choline, histamine, dopamine, serotonin, and opioids. Their activation stimulates the vomiting reflex. Different emetic pathways exist, and substance P/NK1R appears to be within the final common pathway to regulate vomiting.[] Substance P antagonist (SPA) aprepitant is available in the market in the treatment of chemotherapy-induced nausea/emesis.

Pain
Substance P is involved in nociception, transmitting information about tissue damage from peripheral receptors to the central nervous system to be converted to the sensation of pain. It has been theorized that it plays a part in fibromyalgia. Capsaicin has been shown to reduce the levels of substance P, it is presumed, by reducing the number of C-fibre nerves or causing these nerves to be more tolerant. Thus, capsaicin is clinically used as an analgesic and an anti-inflammatory agent to reduce pain associated with arthritis and many types of neuralgia. A role of substance P and NKA in nociception is suggested by the reduction in response thresholds to noxious stimuli by central administration of K2 and K3 agonists. Based on recent studies, it was proposed that NK1, and possibly NK2 receptor antagonists, could be developed as analgesic drugs. It has been studied that the mice carrying a disruption of the gene encoding SP/NKA show severely reduced nociceptive pain responses when the stimuli are moderate to intense. Pain behaviors induced by mechanical, thermal, and chemical stimulation of somatic and visceral tissues were reduced in the mutant mice lacking SP/NKA. However, it has been proposed that the importance of SP and NKA in animal's pain response apply only to a certain 'window' of pain intensities, and, when the intensity of the pain stimuli is further increased, the responses of the knockout mice is not severely different from the wild-type mice.[] Substance P increases glutamate activity (NMDA) in central nervous system, and it is associated with the development of brain edema and functional deficits after traumatic brain injury.[]

Cell growth
Substance P has been known to stimulate cell growth in culture,[] and it was shown that substance P could promote wound healing of non-healing ulcers in humans.[]

Diabetes
Substance P injected into pancreatic nerves has been shown to reverse diabetes in mice[][] but effects to insulin secretion seem to be species dependent. In humans, substance P given intravenously seems to decrease insulin release and causes fluctuations in blood sugar levels.[]

Vasodilation
Substance P also has effects as a potent vasodilator. Substance P-induced vasodilatation is dependent on nitric oxide release.[] Substance P is involved in the axon reflex-mediated vasodilatation to local heating and wheal and flare reaction. It has been shown that vasodilatation to substance P is dependent on the NK1 receptor located on the endothelium. In contrast to other neuropeptides studied in human skin, substance P-induced vasodilatation has been found to decline during continuous infusion. This possibly suggests an internalization of neurokinin-1 (NK1).[] As is typical with many vasodilators, it also has bronchoconstrictive properties, administered through the non-adrenergic, non-cholinergic nervous system (branch of the vagal system).

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Clinical significance
Eczema
High levels of BDNF and substance P have been found associated with increased itching in eczema.[][]

Gastrointestinal infection
Entamoeba histolytica is a single-celled parasitic protozoan that infects the lower gastrointestinal tract of humans. The symptoms of infection are diarrhea, constipation, and abdominal pain.[14][] This protozoan was found to secrete serotonin[15] as well as substance P and neurotensin.[16]

Denervation supersensitivity
When the innervation to substance P nerve terminals is lost, post-synaptic cells compensate for the loss of adequate neurotransmitter by increasing the expression of post-synaptic receptors. This, ultimately, leads to a condition known as Denervation Supersensitivity as the post-synaptic nerves will become hypersensitive to any invasion of substance P into the synaptic cleft.

Deficiency
Naked mole rats lack cutaneous C fibers reactive to substance P (SP) and many small neurons that are normally SP-positive. Thus, these animals are insensitive to pain when painful stimuli are administered to the skin.[17][18] New studies have shown that when the function of SP is genetically disrupted in mice, the animals demonstrated reduced responses to painful stimuli. Moreover, the response to capsaicin was absent or severely reduced in knockout mice.[]

References
[1] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& amp;cmd=retrieve& amp;dopt=default& amp;list_uids=6863& rn=1 [2] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=11517 [3] http:/ / www. omim. org/ 162320 [4] http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?Submit=Submit& position=NM_003182& rn=1 [5] http:/ / www. uniprot. org/ uniprot/ P20366 [6] http:/ / omim. org/ search?index=geneMap& search=7q21 [7] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=33507-63-0 [8] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=36511 [9] http:/ / www. chemspider. com/ 33558 [10] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Substance+ P [11] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL235363 [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=414512791& page2=Substance+ P [13] Campbell, Neil A, and Jane B Reece. Biology. 7th ed. San Francisco: Pearson Education, Inc., n.d.Print.

External links
Russell J (2001-09-14). "Neurochemical Substance P is Key to Understanding Pain Process" (http://www. fibromyalgiasupport.com/library/showarticle.cfm/id/3097). Fibromyalgia Library. ProHealth.com. Retrieved 2008-11-01.

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Hippocampus
Brain: Hippocampus

The hippocampus is located in the medial temporal lobe of the brain. In this lateral view of the human brain, the frontal lobe is at left, the occipital lobe at right, and the temporal and parietal lobes have largely been removed to reveal the hippocampus underneath. Part of NeuroNames MeSH NeuroLex ID Temporal lobe hier-164
[1] [2]

Hippocampus birnlex_721

[3]

The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is a part of the cerebral cortex; and in primates it is located in the medial temporal lobe, underneath the cortical surface. It contains two main interlocking parts: Ammon's horn[4] and the dentate gyrus. In Alzheimer's disease, the hippocampus is one of the first regions of the brain to suffer damage; memory loss and disorientation are included among the early symptoms. Damage to the hippocampus can also result from oxygen starvation (hypoxia), encephalitis, or medial temporal lobe epilepsy. People with extensive, bilateral hippocampal damage may experience anterograde amnesiathe inability to form or retain new memories.

MRI coronal view of a hippocampus shown in red

In rodents, the hippocampus has been studied extensively as part of a brain system responsible for spatial memory and navigation. Many neurons in the rat and mouse hippocampus respond as place cells: that is, they fire bursts of action potentials when the animal passes through a specific part of its environment. Hippocampal place cells interact extensively with head direction cells, whose activity acts as an inertial compass, and conjecturally with grid cells in the neighboring entorhinal cortex. Since different neuronal cell types are neatly organized into layers in the hippocampus, it has frequently been used as a model system for studying neurophysiology. The form of neural plasticity known as long-term potentiation (LTP) was first discovered to occur in the hippocampus and has often been studied in this structure. LTP is widely believed to be one of the main neural mechanisms by which memory is stored in the brain.

Hippocampus

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Name
The earliest description of the ridge running along the floor of the temporal horn of the lateral ventricle comes from the Venetian anatomist Julius Caesar Aranzi (1587), who initially likened it to a seahorse, using the Latin: hippocampus (from Greek: , "horse" and Greek: , "coiled"). The German anatomist Duvernoy (1729), the first to illustrate the structure, also wavered between "seahorse" and "silkworm." "Ram's horn" was proposed by the Danish anatomist Jacob Winslw in 1732; and a decade later his fellow Parisian, the surgeon de Garengeot, used "cornu Ammonis" - horn of (the ancient Egyptian god) Amun.[5]

The Hungarian neuroscientist Lszl Seress' 1980 preparation of the human hippocampus and fornix compared with a seahorse.

Another mythological reference appeared with the term pes hippocampi, which may date back to Diemerbroeck in 1672, introducing a comparison with the shape of the folded back forelimbs and webbed feet of the Classical hippocampus (Greek: ), a sea monster with a horse's forequarters and a fish's tail. The hippocampus was then described as pes hippocampi major, with an adjacent bulge in the occipital horn, the calcar avis, being named pes hippocampi minor.[5] The renaming of the hippocampus as hippocampus major, and the calcar avis as hippocampus minor, has been attributed to Flix Vicq-d'Azyr systematising nomenclature of parts of the brain in 1786. Mayer mistakenly used the term hippopotamus in 1779, and was followed by some other authors until Karl Friedrich Burdach resolved this error in 1829. In 1861 the hippocampus minor became the centre of a dispute over human evolution between Thomas Henry Huxley and Richard Owen, satirised as the Great Hippocampus Question. The term hippocampus minor fell from use in anatomy textbooks, and was officially removed in the Nomina Anatomica of 1895.[6] Today, the structure is called the hippocampus rather than hippocampus major, with pes hippocampi often being regarded as synonymous with De Garengeot's "cornu Ammonis",[5] a term which survives in the names of the four main histological divisions of the hippocampus: CA1, CA2, CA3 and CA4.[7]

Functions
Historically, the earliest widely held hypothesis was that the hippocampus is involved in olfaction. This idea was cast into doubt by a series of anatomical studies that did not find any direct projections to the hippocampus from the olfactory bulb.[8] However, later work did confirm that the olfactory bulb does project into the ventral part of the lateral entorhinal cortex, and field CA1 in the ventral hippocampus sends axons to the main olfactory bulb,[9] the anterior olfactory nucleus, and to the primary olfactory cortex. There continues to be some interest in hippocampal olfactory responses, particularly the role of the hippocampus in memory for odors, but few specialists today believe that olfaction is its primary function.[10][11] Over the years, three main ideas of hippocampal function have dominated the literature: inhibition, memory, and space. The behavioral inhibition theory (caricatured by O'Keefe and Nadel as "slam on the brakes!")[12] was very popular up to the 1960s. It derived much of its justification from two observations: first, that animals with hippocampal damage tend to be hyperactive; second, that animals with hippocampal damage often have difficulty learning to inhibit responses that they have previously been taught, especially if the response requires remaining quiet as in a passive avoidance test. Jeffrey Gray developed this line of thought into a full-fledged theory of the role of the hippocampus in anxiety.[13] The inhibition theory is currently the least popular of the three.[14] The second major line of thought relates the hippocampus to memory. Although it had historical precursors, this idea derived its main impetus from a famous report by William Beecher Scoville and Brenda Milner[15] describing the results of surgical destruction of the hippocampi (in an attempt to relieve epileptic seizures), in Henry Molaison,[16] known until his death in 2008 as "Patient H.M." The unexpected outcome of the surgery was severe anterograde and

Hippocampus partial retrograde amnesia; Molaison was unable to form new episodic memories after his surgery and could not remember any events that occurred just before his surgery, but he did retain memories of events that transpired many years earlier extending back into his childhood. This case attracted such widespread professional interest that Molaison reportedly became the most intensively studied subject in medical history.[17] In the ensuing years, other patients with similar levels of hippocampal damage and amnesia (caused by accident or disease) have been studied as well, and thousands of experiments have studied the physiology of activity-driven changes in synaptic connections in the hippocampus. There is now almost universal agreement that the hippocampi play some sort of important role in memory; however, the precise nature of this role remains widely debated.[18][19] The third important theory of hippocampal function relates the hippocampus to space. The spatial theory was originally championed by O'Keefe and Nadel, who were influenced by E.C. Tolman's theories about "cognitive maps" in humans and animals. O'Keefe and his student Dostrovsky in 1971 discovered neurons in the rat hippocampus that appeared to them to show activity related to the rat's location within its environment.[20] Despite skepticism from other investigators, O'Keefe and his co-workers, especially Lynn Nadel, continued to investigate this question, in a line of work that eventually led to their very influential 1978 book The Hippocampus as a Cognitive Map.[21] As with the memory theory, there is now almost universal agreement that spatial coding plays an important role in hippocampal function, but the details are widely debated.[22]

453

Role in memory
Psychologists and neuroscientists generally agree that the hippocampus plays an important role in the formation of new memories about experienced events (episodic or autobiographical memory).[19][23] Part of this function is hippocampal involvement in the detection of novel events, places and stimuli.[24] Some researchers regard the hippocampus as part of a larger medial temporal lobe memory system responsible for general declarative memory (memories that can be explicitly verbalizedthese would include, for example, memory for facts in addition to episodic memory).[18] Due to bilateral symmetry the brain has a hippocampus in each cerebral hemisphere, so every normal brain has two of them. If damage to the hippocampus occurs in only one hemisphere, leaving the structure intact in the other hemisphere, the brain can retain near-normal memory functioning.[25] Severe damage to the hippocampi in both hemispheres results in profound difficulties in forming new memories (anterograde amnesia) and often also affects memories formed before the damage occurred (retrograde amnesia). Although the retrograde effect normally extends many years back before the brain damage, in some cases older memories remain. This retention of older memories leads to the idea that consolidation over time involves the transfer of memories out of the hippocampus to other parts of the brain.[26] Damage to the hippocampus does not affect some types of memory, such as the ability to learn new skills (playing a musical instrument or solving certain types of puzzles, for example). This fact suggests that such abilities depend on different types of memory (procedural memory) and different brain regions. Furthermore, amnesic patients frequently show "implicit" memory for experiences even in the absence of conscious knowledge. For example, patients asked to guess which of two faces they have seen most recently may give the correct answer most of the time in spite of stating that they have never seen either of the faces before. Some researchers distinguish between conscious recollection, which depends on the hippocampus, and familiarity, which depends on portions of the medial temporal cortex.[27]

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Role in spatial memory and navigation

Studies conducted on freely moving rats and mice have shown that many hippocampal neurons have "place fields", that is, they fire bursts of action potentials when a rat passes through a particular part of the environment. Evidence for place cells in primates is limited, perhaps in part because it is difficult to record brain activity from freely moving monkeys. Place-related hippocampal neural activity has been reported in monkeys moving around inside a room while seated in a restraint chair;[28] on the other hand, Edmund Rolls and his colleagues instead Spatial firing patterns of 8 place cells recorded from the CA1 layer of a rat. The rat described hippocampal cells that fire in ran back and forth along an elevated track, stopping at each end to eat a small food relation to the place a monkey is looking at, reward. Dots indicate positions where action potentials were recorded, with color rather than the place where its body is indicating which neuron emitted that action potential. [29] located. In humans, cells with location-specific firing patterns have been reported in a study of patients with drug-resistant epilepsy who were undergoing an invasive procedure to localize the source of their seizures, with a view to surgical resection. The patients had diagnostic electrodes implanted in their hippocampus and then used a computer to move around in a virtual reality town.[30] Place responses in rats and mice have been studied in hundreds of experiments over four decades, yielding a large quantity of information.[22] Place cell responses are shown by pyramidal cells in the hippocampus proper, and granule cells in the dentate gyrus. These constitute the great majority of neurons in the densely packed hippocampal layers. Inhibitory interneurons, which make up most of the remaining cell population, frequently show significant place-related variations in firing rate that are much weaker than those displayed by pyramidal or granule cells. There is little if any spatial topography in the representation; cells lying next to each other in the hippocampus generally have uncorrelated spatial firing patterns. Place cells are typically almost silent when a rat is moving around outside the place field but reach sustained rates as high as 40 Hertz when the rat is near the center. Neural activity sampled from 30 to 40 randomly chosen place cells carries enough information to allow a rat's location to be reconstructed with high confidence. The size of place fields varies in a gradient along the length of the hippocampus, with cells at the dorsal end showing the smallest fields, cells near the center showing larger fields, and cells at the ventral tip fields that cover the entire environment.[22] In some cases, the firing rate of rat hippocampal cells depends not only on place but also on the direction a rat is moving, the destination toward which it is traveling, or other task-related variables.[31] The discovery of place cells in the 1970s led to a theory that the hippocampus might act as a cognitive map a neural representation of the layout of the environment.[32] Several lines of evidence support the hypothesis. It is a frequent observation that without a fully functional hippocampus, humans may not remember where they have been and how to get where they are going: getting lost is one of the most common symptoms of amnesia.[33] Studies with animals have shown that an intact hippocampus is required for initial learning and long-term retention of some spatial memory tasks, particularly ones that require finding the way to a hidden goal.[34][35][36][37] The "cognitive map hypothesis" has been further advanced by recent discoveries of head direction cells, grid cells, and border cells in several parts of the rodent brain that are strongly connected to the hippocampus.[22][38] Brain imaging shows that people have more active hippocampi when correctly navigating, as tested in a computer-simulated "virtual" navigation task.[39] Also, there is evidence that the hippocampus plays a role in finding

Hippocampus shortcuts and new routes between familiar places. For example, London's taxi drivers must learn a large number of places and the most direct routes between them (they have to pass a strict test, The Knowledge, before being licensed to drive the famous black cabs). A study at University College London by Maguire, et al.. (2000)[40] showed that part of the hippocampus is larger in taxi drivers than in the general public, and that more experienced drivers have bigger hippocampi. Whether having a bigger hippocampus helps an individual to become a better cab driver, or if finding shortcuts for a living makes an individual's hippocampus grow is yet to be elucidated. However, in that study Maguire, et al.. examined the correlation between size of the grey matter and length of time that had been spent as a taxi driver, and found a positive correlation between the length of time an individual had spent as a taxi driver and the volume of the right hippocampus. It was found that the total volume of the hippocampus remained constant, from the control group vs. taxi drivers. That is to say that the posterior portion of a taxi driver's hippocampus is indeed increased, but at the expense of the anterior portion. There have been no known detrimental effects reported from this disparity in hippocampal proportions.[40]

455

Anatomy
Anatomically, the hippocampus is an elaboration of the edge of the cerebral cortex.[41] The structures that line the edge of the cortex make up the so-called limbic system (Latin limbus = border): these include the hippocampus, cingulate cortex, olfactory cortex, and amygdala. Paul MacLean once suggested, as part of his triune brain theory, that the limbic structures comprise the neural basis of emotion. Some neuroscientists no longer believe that the concept of a unified "limbic system" is valid, though.[42] However, the hippocampus is anatomically connected to parts of the brain that are involved with emotional behavior the septum, the hypothalamic mammillary body and the anterior nuclear complex in the thalamus, so its role as a limbic structure cannot be completely dismissed.

Nissl-stained coronal section of the brain of a macaque monkey, showing hippocampus (circled). Source: brainmaps.org

The hippocampus as a whole has the shape of a curved tube, which has been variously compared to a seahorse, a ram's horn (Cornu Ammonis, hence the subdivisions CA1 through CA4), or a banana.[41] It can be distinguished as a zone where the cortex narrows into a single layer of densely packed pyramidal neurons 3 to 6 cells deep in rats, which curl into a tight U shape; one edge of the "U," field CA4, is embedded into a backward-facing, strongly flexed, V-shaped cortex, the dentate gyrus. It consists of ventral and dorsal portions, both of which are of similar composition but are parts of different neural circuits.[43] This general layout holds across the full range of mammalian species, from hedgehog to human, although the details vary. In the rat, the two hippocampi resemble a pair of bananas, joined at the stems by the hippocampal commissure that crosses the midline under the anterior corpus callosum. In human or monkey brains, the portion of the hippocampus down at the bottom, near the base of the temporal lobe, is much broader than the part at the top. One of the consequences of this complex geometry is that cross-sections through the hippocampus can show a variety of shapes, depending on the angle and location of the cut.

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The entorhinal cortex (EC), located in the parahippocampal gyrus, is considered to be part of the hippocampal region because of its anatomical connections. The EC is strongly and reciprocally connected with many other parts of the cerebral cortex. In addition, the medial septal nucleus, the anterior nuclear complex and nucleus reuniens of the thalamus and the supramammillary nucleus of the hypothalamus, as well as the raphe nuclei Basic circuit of the hippocampus, as drawn by Santiago Ramon y Cajal. DG: and locus coeruleus in the brainstem send dentate gyrus. Sub: subiculum. EC: entorhinal cortex axons to the EC. The main output pathway (perforant path, first described by Ramon y Cajal) of EC axons comes from the large stellate pyramidal cells in layer II that "perforate" the subiculum and project densely to the granule cells in the dentate gyrus, apical dendrites of CA3 get a less dense projection, and the apical dendrites of CA1 get a sparse projection. Thus, the perforant path establishes the EC as the main "interface" between the hippocampus and other parts of the cerebral cortex. The dentate granule cell axons (called mossy fibers) pass on the information from the EC on thorny spines that exit from the proximal apical dendrite of CA3 pyramidal cells. Then, CA3 axons exit from the deep part of the cell body and loop up into the region where the apical dendrites are located, then extend all the way back into the deep layers of the entorhinal cortex the Shaffer collaterals completing the reciprocal circuit; field CA1 also sends axons back to the EC, but these are more sparse than the CA3 projection. Within the hippocampus, the flow of information from the EC is largely unidirectional, with signals propagating through a series of tightly packed cell layers, first to the dentate gyrus, then to the CA3 layer, then to the CA1 layer, then to the subiculum, then out of the hippocampus to the EC, mainly due to collateralization of the CA3 axons. Each of these layers also contains complex intrinsic circuitry and extensive longitudinal connections.[41] Several other connections play important roles in hippocampal function.[41] Beyond the output to the EC, additional output pathways go to other cortical areas including the prefrontal cortex. A very important large output goes to the lateral septal area and to the mammillary body of the hypothalamus. The hippocampus receives modulatory input from the serotonin, norepinephrine, and dopamine systems, and from nucleus reuniens of the thalamus to field CA1. A very important projection comes from the medial septal area, which sends cholinergic and GABAergic fibers to all parts of the hippocampus. The inputs from the septal area play a key role in controlling the physiological state of the hippocampus; destruction of the septal area abolishes the hippocampal theta rhythm and severely impairs certain types of memory.[44] The cortical region adjacent to the hippocampus is known collectively as the parahippocampal gyrus (or parahippocampus).[45] It includes the EC and also the perirhinal cortex which derives its name from the fact that it lies next to the rhinal sulcus. The perirhinal cortex plays an important role in visual recognition of complex objects. There is also substantial evidence that it makes a contribution to memory which can be distinguished from the contribution of the hippocampus. Complete amnesia apparently occurs only when both the hippocampus and the parahippocampus are damaged.[45]

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Hippocampal Formation
Various sections of the hippocampal formation are shown to be functionally and anatomically distinct. The dorsal (DH), ventral (VH) and intermediate regions of the hippocampal formation serve different functions, project with differing pathways, and have varying degrees of place field neurons (Fanselow & Dong, 2009). The dorsal region of the hippocampal formation serves for spatial memory, verbal memory, and learning of conceptual information. Using the radial arm maze Pothuizen et al. (2004), found lesions in the DH to cause spatial memory impairment while VH lesions did not. Its projecting pathways include the medial septal complex and supramammillary nucleus. The dorsal hippocampal formation also has more place field neurons than both the ventral and intermediate hippocampal formation (Jung et al., 1994). The intermediate hippocampus has overlapping characteristics with both the ventral and dorsal hippocampus (Fanselow & Dong, 2009). Using PHAL anterograde tracing methods, Cenquizca and Swanson (2007) located the moderate projections to two primary olfactory cortical areas and prelimbic areas of the mPFC. This region has the least amount of place field neurons. The ventral hippocampus functions in fear conditioning and affective processes. Anagnostaras et al. (2002) showed that alterations to the ventral hippocampus reduced the amount of information sent to the amygdala by the dorsal and ventral hippocampus, consequentially altering fear conditioning in rats.

Physiology
The hippocampus shows two major "modes" of activity, each associated with a distinct pattern of neural population activity and waves of electrical activity as measured by an electroencephalogram (EEG). These modes are named after the EEG patterns associated with them: theta and large irregular activity (LIA). The main characteristics described below are for the rat, which is the animal most extensively studied.[46] The theta mode appears during states of active, alert behavior (especially locomotion), and also during REM (dreaming) sleep.[47] In the theta mode, the EEG is dominated by large regular waves with a frequency range of 6 to 9 Hertz, and the main groups of hippocampal neurons Examples of rat hippocampal EEG and CA1 neural activity in the theta (pyramidal cells and granule cells) show (awake/behaving) and LIA (slow-wave sleep) modes. Each plot shows 20 seconds sparse population activity, which means that of data, with a hippocampal EEG trace at the top, spike rasters from 40 in any short time interval, the great majority simultaneously recorded CA1 pyramidal cells in the middle (each raster line of cells are silent, while the small remaining represents a different cell), and a plot of running speed at the bottom. The top plot represents a time period during which the rat was actively searching for scattered fraction fire at relatively high rates, up to 50 food pellets. For the bottom plot the rat was asleep. spikes in one second for the most active of them. An active cell typically stays active for half a second to a few seconds. As the rat behaves, the active cells fall silent and new cells become active, but the overall percentage of active cells remains more or less constant. In many situations cell activity is determined largely by the spatial location of the animal, but other behavioral variables also clearly influence it.

Hippocampus The LIA mode appears during slow-wave (non-dreaming) sleep, and also during states of waking immobility such as resting or eating.[47] In the LIA mode the EEG is dominated by sharp waves which are randomly-timed large deflections of the EEG signal lasting for 25-50 millisecond. Sharp waves are frequently generated in sets with sets containing up to 5 or more individual sharp waves and lasting up to 500 ms. The spiking activity of neurons within the hippocampus is highly correlated with sharp wave activity. Most neurons decrease their firing rate between sharp waves; however, during a sharp wave there is a dramatic increase of firing rate in up to 10% of the hippocampal population These two hippocampal activity modes can be seen in primates as well as rats, with the exception that it has been difficult to see robust theta rhythmicity in the primate hippocampus. There are, however, qualitatively similar sharp waves and similar state-dependent changes in neural population activity.[48]

458

Theta rhythm
Because of its densely packed neural layers, the hippocampus generates some of the largest EEG signals of any brain structure. In some situations the EEG is dominated by regular waves at 3 to 10 Hertz, often continuing for many seconds. These reflect subthreshold membrane potentials and strongly modulate the spiking of hippocampal neurons and synchronise across the hippocampus in a travelling wave pattern.[49] This EEG pattern is known as a theta rhythm.[50] Theta rhythmicity is very obvious in rabbits and rodents and also clearly present in cats and dogs. Whether theta can be seen in primates is a vexing question.[51] In rats (the animals that have been the most extensively studied), theta is seen mainly in two conditions: first, when an animal is walking or in some other way actively interacting with its surroundings; second, during REM sleep.[52] The function of theta has not yet been convincingly explained although numerous theories have been proposed.[46] The most popular hypothesis has been to relate it to learning and memory. An example would be the phase with which theta rhythms, at the time of stimulation of a neuron, shape the effect of that stimulation upon its synapses. What is meant here is that theta rhythms may affect those aspects of learning and memory which are dependent upon synaptic plasticity.[53] It is well established that lesions of the medial septum the central node of the theta system cause severe disruptions of memory. However, the medial septum is more than just the controller of theta; it is also the main source of cholinergic projections to the hippocampus.[41] It has not been established that septal lesions exert their effects specifically by eliminating the theta rhythm.[54]

Sharp waves
During sleep or during waking states when an animal is resting or otherwise not engaged with its surroundings, the hippocampal EEG shows a pattern of irregular slow waves, somewhat larger in amplitude than theta waves. This pattern is occasionally interrupted by large surges called sharp waves.[55] These events are associated with bursts of spike activity lasting 50 to 100 milliseconds in pyramidal cells of CA3 and CA1. They are also associated with short-lived high-frequency EEG oscillations called "ripples", with frequencies in the range 150 to 200 Hertz in rats. Sharp waves are most frequent during sleep when they occur at an average rate of around 1 per second (in rats) but in a very irregular temporal pattern. Sharp waves are less frequent during inactive waking states and are usually smaller. Sharp waves have also been observed in humans and monkeys. In macaques, sharp waves are robust but do not occur as frequently as in rats.[48] One of the most interesting aspects of sharp waves is that they appear to be associated with memory. Wilson and McNaughton 1994,[56] and numerous later studies, reported that when hippocampal place cells have overlapping spatial firing fields (and therefore often fire in near-simultaneity), they tend to show correlated activity during sleep following the behavioral session. This enhancement of correlation, commonly known as reactivation, has been found to occur mainly during sharp waves.[57] It has been proposed that sharp waves are, in fact, reactivations of neural activity patterns that were memorized during behavior, driven by strengthening of synaptic connections within the hippocampus.[58] This idea forms a key component of the "two-stage memory" theory, advocated by Buzski and

Hippocampus others, which proposes that memories are stored within the hippocampus during behavior and then later transferred to the neocortex during sleep. Sharp waves are suggested to drive Hebbian synaptic changes in the neocortical targets of hippocampal output pathways.[59]

459

Long-term potentiation
Since at least the time of Ramon y Cajal, psychologists have speculated that the brain stores memory by altering the strength of connections between neurons that are simultaneously active.[60] This idea was formalized by Donald Hebb in 1948,[61] but for many years thereafter, attempts to find a brain mechanism for such changes failed. In 1973, Tim Bliss and Terje Lmo described a phenomenon in the rabbit hippocampus that appeared to meet Hebb's specifications: a change in synaptic responsiveness induced by brief strong activation and lasting for hours or days or longer. [62] This phenomenon was soon referred to as long-term potentiation, abbreviated LTP. As a candidate mechanism for memory, LTP has since been studied intensively, and a great deal has been learned about it. The hippocampus is a particularly favorable site for studying LTP because of its densely packed and sharply defined layers of neurons, but similar types of activity-dependent synaptic change have now been observed in many other brain areas.[63] The best-studied form of LTP occurs at synapses that terminate on dendritic spines and use the transmitter glutamate. Several of the major pathways within the hippocampus fit this description and exhibit LTP.[64] The synaptic changes depend on a special type of glutamate receptor, the NMDA receptor, which has the special property of allowing calcium to enter the postsynaptic spine only when presynaptic activation and postsynaptic depolarization occur at the same time.[65] Drugs that interfere with NMDA receptors block LTP and have major effects on some types of memory, especially spatial memory. Transgenic mice, genetically modified in ways that disable the LTP mechanism, also generally show severe memory deficits.[65]

Pathology
Aging
Age-related conditions such as Alzheimer's disease (for which hippocampal disruption is one of the earliest signs[66]) have a severe impact on many types of cognition, but even normal aging is associated with a gradual decline in some types of memory, including episodic memory and working memory. Because the hippocampus is thought to play a central role in memory, there has been considerable interest in the possibility that age-related declines could be caused by hippocampal deterioration.[67] Some early studies reported substantial loss of neurons in the hippocampus of elderly people, but later studies using more precise techniques found only minimal differences.[67] Similarly, some MRI studies have reported shrinkage of the hippocampus in elderly people, but other studies have failed to reproduce this finding. There is, however, a reliable relationship between the size of the hippocampus and memory performance meaning that not all elderly people show hippocampal shrinkage, but those who do tend to perform less well on some memory tasks.[68] There are also reports that memory tasks tend to produce less hippocampal activation in elderly than in young subjects.[68] Furthermore, a randomized-control study published in 2011 found that aerobic exercise could increase the size of the hippocampus in adults aged 55 to 80 and also improve spatial memory.[69] In rats, where detailed studies of cellular physiology are possible, aging does not cause substantial cell loss in the hippocampus, but it alters synaptic connectivity in several ways.[70] Functional synapses are lost in the dentate gyrus and CA1 region, and NMDA receptor-mediated responses are reduced. These changes may account for deficits in induction and maintenance of long-term potentiation, a form of synaptic plasticity that has been implicated in memory. There are also age-related declines in hippocampal expression of several genes associated with synaptic plasticity.[71] Finally, there are differences in the stability of "place cell" representations. In young rats, the arrangement of place fields is usually altered if the rat is moved into a different environment but remains the same if a rat is returned to an environment it has visited previously. In aged rats, the place fields frequently fail to "remap"

Hippocampus when a rat is moved to a different environment and also frequently fail to restore the original "map" when the rat is returned to the same environment.

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Stress
The hippocampus contains high levels of glucocorticoid receptors which make it more vulnerable to long-term stress than most other brain areas.[72] Stress-related steroids affect the hippocampus in at least three ways: first, by reducing the excitability of some hippocampal neurons; second, by inhibiting the genesis of new neurons in the dentate gyrus; third, by causing atrophy of dendrites in pyramidal cells of the CA3 region. There is evidence that humans who have experienced severe, long-lasting traumatic stress show atrophy of the hippocampus more than of other parts of the brain.[73] These effects show up in post-traumatic stress disorder,[74] and they may contribute to the hippocampal atrophy reported in schizophrenia[75] and severe depression.[76] A recent study has also revealed atrophy as a result of depression, but this can be stopped with anti-depressants even if they are not effective in relieving other symptoms.[77] Hippocampal atrophy is also frequently seen in Cushing's syndrome, a disorder caused by high levels of cortisol in the bloodstream. At least some of these effects appear to be reversible if the stress is discontinued. There is, however, evidence mainly derived from studies using rats that stress occurring shortly after birth can affect hippocampal function in ways that persist throughout life.[78] Sex-specific responses to stress have also been demonstrated to have an effect on the hippocampus. During situations in which adult male and female rats were exposed to chronic stress the females were shown to be better able to cope.[79]

Epilepsy
The hippocampus is often the focus of epileptic seizures: hippocampal sclerosis is the most commonly visible type of tissue damage in temporal lobe epilepsy.[80] It is not yet clear, though, whether the epilepsy is usually caused by hippocampal abnormalities or whether the hippocampus is damaged by cumulative effects of seizures.[81] In experimental settings where repetitive seizures are artificially induced in animals, hippocampal damage is a frequent result. this may be a consequence of the hippocampus being one of the most electrically excitable parts of the brain. It may also have something to do with the fact that the hippocampus is one of very few brain regions where new neurons continue to be created throughout life.[82]

Schizophrenia
The causes of schizophrenia are not at all well understood, but numerous abnormalities of brain structure have been reported. The most thoroughly investigated alterations involve the cerebral cortex, but effects on the hippocampus have also been described. Many reports have found reductions in the size of the hippocampus in schizophrenic subjects.[83] The changes probably result from altered development rather than tissue damage and show up even in subjects who have never been medicated. Several lines of evidence implicate changes in synaptic organization and connectivity.[83] It is unclear whether hippocampal alterations play any role in causing the psychotic symptoms that are the most important feature of schizophrenia. Anthony Grace and his co-workers have suggested, on the basis of experimental work using animals, that hippocampal dysfunction might produce an alteration of dopamine release in the basal ganglia, thereby indirectly affecting the integration of information in the prefrontal cortex.[84] Others have suggested that hippocampal dysfunction might account for disturbances in long term memory frequently observed in people with schizophrenia.[85]

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Transient global amnesia

A current hypothesis as to one cause of transient global amnesia a dramatic, sudden, temporary, near-total loss of short-term memory is that it may be due to venous congestion of the brain,[86] leading to ischemia of structures, such as the hippocampus, that are involved with memory.[87]

Evolution
The hippocampus has a generally similar appearance across the range of mammal species, from monotremes such as the echidna to primates such as humans.[88] The hippocampal-size-to-body-size ratio broadly increases, being about twice as large for primates as for the echidna. It does not, however, increase at anywhere close to the rate of the neocortex-to-body-size ratio. Therefore, the hippocampus takes up a much larger fraction of the cortical mantle in rodents than in primates. In adult humans the volume of the hippocampus on each side of the brain is about 3.0 to 3.5 cm3 as compared to 320 to 420 cm3 for the volume of the neocortex.[89] There is also a general relationship between the size of the hippocampus and spatial memory. When comparisons are made between similar species, those that have a greater capacity for spatial memory tend to have larger hippocampal volumes.[90] This relationship also extends to sex differences; in species where males and females show strong differences in spatial memory ability they also tend to show corresponding differences in hippocampal volume.[91] Non-mammalian species do not have a brain structure that looks like the mammalian hippocampus, but they have one that is considered homologous to it. The hippocampus, as pointed out above, is essentially the medial edge of the cortex. Only mammals have a fully developed cortex, but the structure it evolved from, called the pallium, is present in all vertebrates, even the most primitive ones such as the lamprey or hagfish.[92] The pallium is usually divided into three zones: medial, lateral and dorsal. The medial pallium forms the precursor of the hippocampus. It does not resemble the hippocampus visually because the layers are not warped into an S shape or enfolded by the dentate gyrus, but the homology is indicated by strong chemical and functional affinities. There is now evidence that these hippocampal-like structures are involved in spatial cognition in birds, reptiles and fish.[93] In birds, the correspondence is sufficiently well established that most anatomists refer to the medial pallial zone as the "avian hippocampus".[94] Numerous species of birds have strong spatial skills, particularly those that cache food. There is evidence that food-caching birds have a larger hippocampus than other types of birds and that damage to the hippocampus causes impairments in spatial memory.[95] The story for fish is more complex. In teleost fish (which make up the great majority of existing species), the forebrain is distorted in comparison to other types of vertebrates: most neuroanatomists believe that the teleost forebrain is essentially everted, like a sock turned inside-out, so that structures that lie in the interior, next to the ventricles, for most vertebrates, are found on the outside in teleost fish, and vice versa.[96] One of the consequences of this is that the medial pallium ("hippocampal" zone) of a typical vertebrate is thought to correspond to the lateral pallium of a typical fish. Several types of fish (particularly goldfish) have been shown experimentally to have strong spatial memory abilities, even forming "cognitive maps" of the areas they inhabit.[90] There is evidence that damage to the lateral pallium impairs spatial memory.[97][98] Thus, the role of the hippocampal region in navigation appears to begin far back in vertebrate evolution, predating splits that occurred hundreds of millions of years ago.[99] It is not yet known whether the medial pallium plays a similar role in even more primitive vertebrates, such as sharks and rays, or even lampreys and hagfish. Some types of insects, and molluscs such as the octopus, also have strong spatial learning and navigation abilities, but these appear to work differently from the mammalian spatial system, so there is as yet no good reason to think that they have a common evolutionary origin; nor is there sufficient similarity in brain structure to enable anything resembling a "hippocampus" to be identified in these species. Some have proposed, though, that the insect's mushroom bodies may have a function similar to that of the hippocampus.[100]

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Notes
[1] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=164 [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Hippocampus [3] http:/ / www. neurolex. org/ wiki/ birnlex_721 [4] Pearce, 2001 [5] Duvernoy, 2005 [6] Gross, 1993 [7] Wechsler, 2004 [8] Finger, p. 183 [9] cite pmid 690266 [10] Eichenbaum et al., 1991 [11] Vanderwolf, 2001 [12] Nadel et al., 1975 [13] Gray and McNaughton, 2000 [14] Best & White, 1999 [15] Scoville and Milner, 1957 [16] N.Y. Times, 12-06-2008 [17] Squire, 2009 [18] Squire, 1992 [19] Eichenbaum and Cohen, 1993 [20] O'Keefe and Dostrovsky, 1971 [21] [22] [23] [24] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] O'Keefe and Nadel, 1978 Moser et al., 2008 Squire and Schacter, 2002 VanElzakker et al., 2008 Squire and Schacter, 2002, Ch. 1 Diana et al., 2007 Matsumara et al., 1999 Rolls and Xiang, 2006 Ekstrom et al., 2003 Smith and Mizumori, 2006 O'Keefe and Nadel Chiu et al., 2004 Morris et al., 1982 Sutherland et al., 1982 Sutherland et al., 2001 Clark et al., 2005 Solstad et al., 2008 Maguire et al., 1998 Maguire et al., 2000 Amaral and Lavenex, 2006 Ktter & Stephan, 1997 Moser and Moser, 1998 Winson, 1978 Eichenbaum et al, 2007 Buzski, 2006 Buzski et al., 1990 Skaggs et al., 2007 Lubenov & Siapas, 2009 Buzski, 2002 Cantero et al., 2003 Vanderwolf, 1969 Huerta & Lisman, 1993 Kahana et al., 2001 Buzski, 1986

[56] Wilson & McNaughton, 1994 [57] Jackson et al., 2006 [58] Sutherland & McNaughton, 2000

Hippocampus
[59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [76] [77] [78] [80] [81] [82] [83] Buzski, 1989 Ramon y Cajal, 1894 Hebb, 1948 Bliss & Lmo, 1973 Cooke & Bliss, 2006 Malenka & Bear, 2004 Nakazawa et al., 2004 Hampel et al., 2008 Prull et al., 2000, p. 105 Prull et al., 2000, p. 107 Erickson et al., 2011 Rosenzweig & Barnes, 2003 Burke & Barnes, 2006 Joels, 2008 Fu et al, 2010 see also MRI database at www.depressiondatabase.org (http:/ / sites. google. com/ site/ depressiondatabase/ ) Campbell & MacQueen, 2004 Garcia-Segura, pp. 17071 Chang and Lowenstein, 2003 Sloviter, 2005 Kuruba et al., 2009 Harrison, 2004

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[84] Goto & Grace, 2008 [85] Boyer et al., 2007 [88] West, 1990 [89] Suzuki et al, 2005 [90] Jacobs, 2003 [91] Jacobs et al., 1990 [92] Aboitiz et al., 2003 [93] Rodrguez et al., 2002 [94] Colombo and Broadbent, 2000 [95] Shettleworth, 2003 [96] Nieuwenhuys, 1982 [97] Portavella et al., 2002 [98] Vargas et al., 2006 [99] Broglio et al., 2005 [100] Mizunami et al., 1998

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Further reading
Journals
Hippocampus (http://www.wiley.com/WileyCDA/WileyTitle/productCd-HIPO.html) (Wiley)

Books
Per Andersen, Richard Morris, David Amaral, Tim Bliss and John O'Keefe, ed. (2007). The Hippocampus Book. Oxford University Press. ISBN978-0-19-510027-3. Henri M. Duvernoy, F. Cattin (2005). The Human Hippocampus: Functional Anatomy, Vascularization, and Serial Sections with MRI. Springer. ISBN978-3-540-23191-2. Howard Eichenbaum (2002). The Cognitive Neuroscience of Memory. Oxford University Press US. ISBN978-0-19-514175-7. edited by Patricia E. Sharp. (2002). Patricia E. Sharp, ed. The Neural Basis of Navigation: Evidence from Single Cell Recording. Springer. ISBN978-0-7923-7579-1. Philippe Taupin (2007). The Hippocampus: Neurotransmission and Plasticity in the Nervous System. Nova Publishers. ISBN978-1-60021-914-6. John H Byrne, ed. (2008). Learning and Memory: A comprehensive reference. Elsevier. ISBN978-0-12-370509-9.

External links
BrainMaps at UCDavis hippocampus (http://brainmaps.org/index.php?q=hippocampus) Diagram of a Hippocampal Brain Slice (http://www.stanford.edu/group/maciverlab/hippocampal.html) Hippocampus Cell Centered Database (http://ccdb.ucsd.edu/sand/main?stype=lite& keyword=hippocampus&Submit=Go&event=display&start=1) Temporal-lobe.com An interactive diagram of the rat parahippocampal-hippocampal region (http://www. temporal-lobe.com) Search Hippocampus on BrainNavigator (http://www.brainnav.com/browse?highlight=8d89b5&specid=2) via BrainNavigator Gyorgy Buzsaki (2010) Hippocampus. Scholarpedia. 6(1):1468. (http://www.scholarpedia.org/article/ Hippocampus)

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Gamma-Butyrolactone
gamma-Butyrolactone[1][]

Identifiers CAS number PubChem ChemSpider UNII DrugBank KEGG ChEBI ChEMBL RTECS number Jmol-3D images 96-48-0 7302 7029
[3] [4] [5] [2]

OL659KIY4X DB04699 C01770

[6]

[7]

CHEBI:42639

[8]

CHEMBL95681 LU3500000 Image 1

[10]

[9]

Properties Molecular formula Molar mass Appearance Density Melting point Boiling point Solubility in water Solubility Acidity (pK )
a

CHO

4 6 2

86.089 g mol1 Colorless oily liquid 1.1286 g/mL (15 C), 1.1296 g/mL (20 C) -43.53C, 230K, -46F 204C, 477K, 399F Miscible soluble in CCl , methanol, ethanol, acetone, benzene, ethyl ether
4

4.5
D

Refractive index (n ) Viscosity

1.435, 1.4341 (20 C) 1.7 cp (25 C)

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Hazards

R-phrases S-phrases Main hazards Flash point LD50

R22 R36 S26 S36 Harmful 98 C (closed cup) 17.2 mL/kg (orally, rat)

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

(verify)

[11]

Infobox references

gamma-Butyrolactone (-butyrolactone or GBL) is a hygroscopic colorless oily liquid with a weak characteristic odor and is soluble in water. GBL is a common solvent and reagent in chemistry and is used as an aroma compound, as a stain remover, as a superglue remover, as a paint stripper, and as a solvent in some wet aluminium electrolytic capacitors. In humans it acts as a prodrug for GHB, and it is used as a recreational intoxicant with effects similar to alcohol.

Occurrence
GBL has been found in extracts from samples of unadulterated wines.[] This finding indicates that GBL is a naturally occurring component in some wines and may be present in similar products. The concentration detected was approximately 5 g/mL and was easily observed using a simple extraction technique followed by GC/MS analysis.

Preparation
GBL can be synthesized from gamma-hydroxybutyric acid (GHB) by removal of water or by distillation from such a mixture. It may also be obtained via oxidation of tetrahydrofuran (THF). One such process, which affords GBL in yields of up to 80%, utilises bromine generated in situ from an aqueous solution of sodium bromate and potassium hydrogen sulfate.[12] Another process can proceed by using commercially-available calcium hypochlorite in the presence of activating acetic acid and an appropriate solvent such as acetonitrile. -Aminobutryic acid (GABA) can also be converted into GBL via a quite simple Sandmeyer reaction.[citation needed]

Chemistry
GBL is a lactone. It is hydrolyzed under basic conditions, for example in a sodium hydroxide solution into sodium gamma-hydroxybutyrate, the sodium salt of gamma-hydroxybutyric acid. Under acidic conditions it forms an equilibrium mixture of both compounds. These compounds then may go on to form a polymer. When treated with a non-nucleophilic base, like lithium diisopropylamide, GBL can become an alpha-carbon nucleophile. Related compound caprolactone can be used to make a polyester in this manner.

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Pharmacology
GBL is not active in its own right; its mechanism of action stems from its identity as a prodrug of GHB. The hypnotic effect of GHB is enhanced by combination with alcohol. A 2003 rat study showed that GBL in combination with ethanol showed a potentiated hypnotic effect, as the sleep-timing measure was longer than both of the individual components combined.[13]

Pharmacokinetics
GBL is rapidly converted into GHB by lactonase enzymes found in the blood. GBL is more lipophilic (fat soluble) than GHB, and so is absorbed faster and has higher bioavailability; the paradox is that this can mean that GBL has a faster onset of effects than GHB itself, even though it is a prodrug. The levels of lactonase enzyme can vary between individuals, meaning that first-time users can show unpredictable results, even from small doses. In many this manifests as slow onset of effects, followed by headaches, semi-consciousness which is distinct from GBL sleep in normal users. If the user decides to try again at a later date, they appear to be able to enjoy the effects normally. Because of these pharmacokinetic differences, GBL tends to be more potent and faster-acting than GHB, but has a shorter duration; whereas the related compound 1,4-butanediol (1,4-B) tends to be slightly less potent, slower to take effect but longer-acting than GHB.

Metabolic pathway of 1,4-butanediol, GBL and GHB.

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Use as a nutritional supplement

Due to its property of being a prodrug of GHB, GBL was sold as a nutritional supplement after the scheduling of GHB, under the names Revivarant and Renewtrient in the U.S. at least until the end of 1999. GBL (as well as GHB), when taken internally in therapeutic doses without the presence of other drugs (especially alcohol, as mixing the two can be fatal), has been shown to elevate growth hormone levels in humans to at least 5 times the baseline. [citation needed]

Recreational use
GBL is a prodrug of GHB. To bypass GHB restriction laws, home synthesis kits were introduced to transform GBL and/or 1,4-B into GHB. GBL can also be used as a recreational drug by itself.[14] GBL overdose can cause irrational behaviour, severe sickness, coma and death.[15] Metabolism takes place in stomach and blood plasma. Both the duration and onset of GBL are shorter than of GHB. Otherwise, effects are similar to GHB, although weight for weight GBL is significantly more powerful due to being absorbed faster and its higher bioavailability, meaning dosage must Jugs of seized GBL. be lowered accordingly. If taken undiluted by mouth, GBL can cause esophageal and gastro-intestinal irritation. It is possible for oral ingestion of GBL to cause nausea and other similar problems, possibly more so than with GHB.

Dangers
GHB (gamma hydroxybutyrate) and GBL (gamma butyrolactone) are substances which are often used as recreational drugs. GHB has two effects, at low doses it has a euphoric effect (which is why it is sometimes referred to as liquid ecstasy). GHB also has a sedative effect[16] and at higher doses it can cause unconsciousness.[] There have been news reports of several deaths associated with GBL.[]

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Addictiveness
Frequent use of GHB/GBL, even when taken long-term and in moderate doses, does not appear to cause significant physical dependency in the greater majority of its users. In many people, quitting or temporarily abstaining from use of the drugs is achieved with minimal or no difficulty. However, when consumed in excessive amounts with a high frequency of dosing, physical and psychological dependence can develop.[17][18]

FDA warning against products containing GHB and its prodrugs, such as GBL.

Frequent use of alcohol (which induces similar effects) can directly translate to physical and usually psychological addiction, where the heavy user can suffer painful and even life-threatening withdrawals. There are some reports of GHB/GBL users adopting a '24/7' dosing regime.[19] This is where the user has become tolerant to the effects of the drug, increasing the dosage and frequency of dosage simply to avoid withdrawal symptoms. For those users who do report withdrawal symptoms upon quitting the use of GHB/GBL, symptoms seem to depend on the dosage and the length of time the drug was used for. Light to moderate users often experience insomnia and sleep-related problems, whereas heavy, prolonged use can cause severe withdrawal symptoms similar to Benzodiazepine withdrawal syndrome (BWS).

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Dose
A milliliter of pure GBL metabolizes to the equivalent 1.65g of NaGHB, the common form, so doses are measured in the single milliliter range, either taken all at once or sipped over the course of a night. GBL has a distinctive taste and odour, described as being comparable to stale water, synthetic melon aroma or burnt plastic. This differs significantly from GHB, which is described as having a decidedly "salty" taste.[20]

Legal status of GBL

Australia: GBL is a border controlled substance and is illegal to import into Australia without a permit. The importation of a commercial quantity of a border controlled drug (over 1kg of GBL) is punishable by up to life imprisonment and/or an $825,000 fine.[21] Canada: GBL is a Controlled Substance under Schedule VI of the "Controlled Drugs and Substances Act" in Canada. Schedule VI of the "Controlled Drugs and Substances Act" requires vendors to collect information regarding purchases of GBL. The Act also prohibits the import and export of GBL into or out of Canada classifying it as either an indictable offense punishable with up to 10 years in prison or an offense punishable on summary conviction liable to imprisonment for up to eighteen months.[22] It is not illegal for an individual to possess GBL in Canada.[citation needed] Germany: GBL is not listed in the narcotics law, but its distribution is controlled. Possession is not illegal, but may be punished according to the Medicines Act, when intended to be sold for human consumption or synthesis of GHB. In recent years, an increase of GBL consumption has been observed due to the prohibition of GHB. Hong Kong SAR: GBL is a dangerous drug controlled under Schedule 1 of the Dangerous Drugs Ordinance, Cap.134 (with exemption clause at Paragraph 16D). Any person who is found to have in his possession of it not in accordance with this Ordinance can be liable, on conviction upon indictment, a fine of HK$1,000,000 and to imprisonment for 7 years. Israel: GBL was classified as a proscribed substance from 2007.[23] The Netherlands: GBL can be freely bought as a cleaning agent. Retailers do not need a licence to sell the substance.[24] Poland: GBL is not classified as a drug and can be purchased in chemistry shops as a solvent. Sweden: GBL is not classified as a drug but as a health-endangering substance.[25] Although recently passed legislation to enter into force on 1 April 2011 will make it possible to handle narcotics for industrial purposes will enable GBL and 1,4-Butanediol to be classified as controlled substances.[26] United Kingdom: GBL was classified as a Class C drug from 23 December 2009, with a prison term of up to two years for possession and 14 years for dealing, by the end of 2009.[27] United States: GBL is regulated as a List 1 controlled chemical. As a GHB analog, it is treated as a controlled substance under Schedule I of the "Controlled Substances Act" if intended for human consumption.[28]

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References
[1] Merck Index, 12th Edition, 1632. [2] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=96-48-0 [3] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=7302 [4] http:/ / www. chemspider. com/ 7029 [5] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=OL659KIY4X [6] http:/ / www. drugbank. ca/ drugs/ DB04699 [7] http:/ / www. kegg. jp/ entry/ C01770 [8] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=42639 [9] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL95681 [10] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DC1OCCC1 [11] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=443831866& page2=Gamma-Butyrolactone [15] http:/ / www. usdoj. gov/ ndic/ pubs4/ 4532/ 4532p. pdf [17] GHB addiction, GHB physical n psychological dependancy levels (http:/ / www. psychoactive. org. uk/ GHB/ addiction. htm) [18] ADANZ - ghb (http:/ / www. adanz. org. nz/ Helpline/ Subnav/ Drug Information/ ghb) [19] Crew 2000 | GHB/ GBL Dependancy | | Drugs information, advice & support, Scotland, UK (http:/ / www. crew2000. org. uk/ news/ 9/ 91/ GHB-GBL-Dependancy. html) [21] LAW AND JUSTICE LEGISLATION AMENDMENT (SERIOUS DRUG OFFENCES AND OTHER MEASURES) ACT 2005 NO. 129, 2005 - SCHEDULE 1 http:/ / www. austlii. edu. au/ au/ legis/ cth/ num_act/ lajladoaoma2005722/ sch1. html [22] Controlled Drugs and Substances Act (S.C. 1996, c. 19) http:/ / laws-lois. justice. gc. ca/ eng/ acts/ C-38. 8/ page-3. html [23] section 7c of chapter B of part A of the 1st appendix of the Dangerous Drugs Act 1973 http:/ / www. nevo. co. il/ Law_word/ law01/ P170_001. doc [25] GBL [26] Socialutskottets betnkande 2010/11:SoU5 - Riksdagen (http:/ / www. riksdagen. se/ Webbnav/ index. aspx?nid=3120& doktyp=betankande& bet=2010/ 11:SoU5) [27] The Misuse of Drugs Act 1971 (Amendment) Order 2009 http:/ / www. opsi. gov. uk/ si/ si2009/ draft/ ukdsi_9780111486610_en_1 [28] Information Bulletin: GHB Analogs; GBL, BD, GHV, and GVL (http:/ / www. justice. gov/ archive/ ndic/ pubs1/ 1621/ index. htm)

External links
Erowid on GBL (http://www.erowid.org/chemicals/ghb/gbl_info1.shtml) "The paint stripper drug that kills" (http://news.bbc.co.uk/2/hi/uk_news/magazine/4261788.stm). BBC News. October 7, 2005. "All About GHB," (http://www.nida.nih.gov/whatsnew/meetings/GHB/default.html) a NIDA Neuroscience Consortium and OSPC "Cutting Edge" colloquium (27 June 2000 at the Doubletree hotel, Rockville, MD)

Gamma-Hydroxybutyric acid

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Gamma-Hydroxybutyric acid
-Hydroxybutyric acid

Systematic (IUPAC) name

4-Hydroxybutanoic acid
Clinical data Pregnancy cat. B Legal status Routes Prohibited (S9) (AU) Schedule III (CA) Class C (UK) Class B (NZ), Schedule I and III (US) Usually oral; intravenous Pharmacokinetic data Bioavailability 25% (oral) Metabolism Half-life Excretion 95%, mainly Hepatic, also in blood and tissues 3060 minutes 5%, renal Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL Synonyms 591-81-1 [1] N07XX04 [4] [3]

N01AX11

[2]

CID 3037032 DB01440 9984 [6] [5]

30IW36W5B2 C00989 [8]

[7]

CHEBI:30830

[9]

CHEMBL1342

[10]

-Hydroxybutyric acid -Hydroxybutyrate GHB Chemical data

Formula

C4H8O3

Gamma-Hydroxybutyric acid

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104.10 g/mol (GHB) 126.09 g/mol (sodium salt) 142.19 g/mol (potassium salt)

Mol. mass

(what is this?) (verify)

[11]

-Hydroxybutyric acid (GHB), also known as 4-hydroxybutanoic acid, is a naturally occurring substance found in the human central nervous system, as well as in wine, beef, small citrus fruits, and almost all animals in small amounts.[] It is also categorized as an illegal drug in many countries.[12] It is currently regulated in Australia and New Zealand, Canada, most of Europe and in the US. GHB as the sodium salt, known as sodium oxybate (INN) or by the trade name Xyrem,[13] is used to treat cataplexy[14] and excessive daytime sleepiness in patients with narcolepsy. GHB has been used in a medical setting as a general anesthetic, to treat conditions such as insomnia, clinical depression, narcolepsy, and alcoholism, and to improve athletic performance.[] It is also used as an intoxicant (illegally in many jurisdictions) or as a date rape drug.[] GHB is naturally produced in the human body's cells and is structurally related to the ketone body beta-hydroxybutyrate. As a supplement or drug, it is used most commonly in the form of a salt, such as sodium gamma-hydroxybutyrate (Na.GHB, sodium oxybate, or Xyrem) or potassium gamma-hydroxybutyrate (K.GHB, potassium oxybate). GHB is also produced as a result of fermentation, and so is found in small quantities in some beers and wines. Succinic semialdehyde dehydrogenase deficiency is a disease that causes GHB to accumulate in the blood.

Medical use
The only common medical applications for GHB today are in the treatment of narcolepsy and more rarely alcoholism.[15] GHB is the active ingredient in the prescription medication sodium oxybate (Xyrem). Sodium oxybate is approved by the U.S. Food and Drug Administration (FDA) for the treatment of cataplexy associated with narcolepsy [16] and excessive daytime sleepiness (EDS) associated with narcolepsy.[17] GHB has been shown to reliably increase slow-wave sleep.[18]

Recreational use
GHB is a central nervous system depressant used as an intoxicant.[] It has many street names, including "Georgia Home Boy","Lollipops", "Juice", "Liquid Ecstasy", "Mils", "G", "Liquid X", and "Liquid G", as well as "Fantasy". Its effects have been described anecdotally as comparable with alcohol and ecstasy use, such as euphoria, disinhibition, enhanced sensuality and empathogenic states. At higher doses, GHB may induce nausea, dizziness, drowsiness, agitation, visual disturbances, depressed breathing, amnesia, unconsciousness, gamma-hydroxybutyrate powder and death. The effects of GHB can last from 1.5 to 3 hours, or even longer if large doses have been consumed.[] Consuming GHB with alcohol is dangerous as it can lead to vomiting in combination with unrouseable sleep, a potentially lethal combination.[19] In general, the doses used recreationally are between 500mg and 3,000mg. When used as a recreational drug, GHB may be found as the sodium or potassium salt, which is a white crystalline powder, or as GHB salt dissolved in water to form a clear solution. The sodium salt of GHB has a salty taste.[] Other salt forms such as calcium GHB and

Gamma-Hydroxybutyric acid magnesium GHB have also been reported, but the sodium salt is by far the most common. Some chemicals convert to GHB in the stomach and blood stream. GBL, or gamma-butyrolactone, is one such prodrug. Other prodrugs include 1,4-butanediol. There may be additional toxicity concerns with these precursors. 1,4-B and GBL are normally found as pure liquids, though they may be mixed with other more harmful solvents when intended for industrial use, e.g., as paint stripper or varnish thinner. GHB can be easily manufactured at home with very little knowledge of chemistry, as it only involves the mixing of its two precursors, GBL and an alkali hydroxide (such as sodium hydroxide) to form the resulting GHB salt. Due to the ease of manufacture and the availability of its precursors, its production is not done in relatively few illicit laboratories like most other synthetic drugs, but in private homes by low level producers instead. While available as a prescription for rare and severe forms of sleep disorders such as narcolepsy in some other countries, notably most of Europe, GHB was banned (in the U.S.) by the FDA in 1990. However, on 17 July 2002, GHB was approved for treatment of cataplexy, often associated with narcolepsy. GHB is "colourless and odorless".[]

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Club and rave scene use

GHB is often taken because users find that it enhances their experiences of being in a club, party, or rave; small doses of GHB can act as a stimulant and aphrodisiac. GHB is sometimes referred to as liquid ecstasy, lollipops, liquid X or liquid E due to its tendency to produce euphoria and sociability and its use in the dance party scene.[20] Despite this nickname, GHB has entirely separate chemical and pharmacological modes of action compared to MDMA (ecstasy).

Sports and athletics

Some athletes also use GHB, as GHB has been shown to elevate human growth hormone in vivo.[21] One study found that it doubled growth hormone secretion in normal young males.[22] The growth hormone elevating effects of GHB are mediated through muscarinic acetylcholine receptors and can be prevented by prior administration of pirenzepine, a muscarinic acetylcholine receptor blocking agent.[23] As certain succinate salts have been shown to elevate growth hormone in vitro,[24] and because GHB is metabolized into succinate some people have suggested this may play a role in the growth hormone elevations from GHB. There is however currently no evidence to show that succinate plays any role in the growth hormone elevations from GHB.

As a date rape drug

Like alcohol and potent benzodiazepines such as flunitrazepam (Rohypnol), GHB has been labeled as a date rape drug.[] The sodium form of GHB

FDA warning against products containing GHB and its prodrugs.

Gamma-Hydroxybutyric acid has an extremely salty taste but, as it is colourless and odorless,[] it has been described as "very easy to add to drinks"[] that mask the flavor. Allegedly, GHB has been used in cases of drug-related sexual assault, usually when the victim is vulnerable due to intoxication with a sedative, generally alcohol.[25] It is difficult to establish how often GHB is used to facilitate rape as it is difficult to detect in a urine sample after a day, and many victims may not recall the rape until some time after this,[26][27] although GHB can be detected in hair.[28] Hair testing can be a useful tool in court cases and/or for the victim's own information. Over-the-counter urine test kits only test for date rape drugs that are benzodiazepines, which GHB is not. To detect GHB in urine, the sample must be taken within 812 hours of GHB ingestion, and cannot be tested at home. GHB can be detected in hair for months after GHB ingestion. Other drugs, such as muscle relaxers (Carisoprodol for example), are sometimes mixed with GHB. Therefore, it can be beneficial to request that the hair sample be tested for multiple drugs. There have been several high profile cases of GHB as a date rape drug that received national attention in the United States. In early 1999 a 15 year old girl, Samantha Reid of Rockwood, MI, died from GHB poisoning. Reids death inspired the legislation titled the "Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act of 2000." This is the law that made GHB a schedule 1 controlled substance.[29] GHB produced as a sodium salt (sodium oxybate) may provide a noticeable salty character to the drink, though individual sensitivity to the taste of salt varies.[30] GHB can also be produced as different salts, some of which may not have a taste as distinctive as the sodium salt (e.g., magnesium oxybate), or much less commonly in the unstable free-acid form.[31]

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Adverse effects
Combination with alcohol
In humans, GHB has been shown to inhibit the elimination rate of alcohol. This may explain the respiratory arrest that has been reported after ingestion of both drugs.[32] A review of the details of 194 deaths attributed to or related to GHB over a ten-year period found that most were from respiratory depression caused by interaction with alcohol or other drugs.[33]

Reported deaths
One report has suggested that sodium oxybate overdose may be fatal, based on deaths of three patients who had been prescribed the drug.[34] However, for two of the three cases, post-mortem GHB concentrations were 141 and 110mg/L, which is within the expected range of concentrations for GHB after death, and the third case was a patient with a history of intentional drug overdose.[35] One publication has investigated 226 deaths attributed to GHB.[36] Of 226 deaths included, 213 suffered cardiorespiratory arrest and 13 suffered fatal accidents. Seventy-one deaths (34%) had no co-intoxicants. Postmortem blood GHB was 184400mg/L (median=347) in deaths negative for co-intoxicants. GHB is produced in the body in very small amounts, and blood levels may climb after death to levels in the range of 3050mg/L.[37] Levels higher than this are found in GHB deaths. Levels lower than this may be due to GHB or to postmortem endogenous elevations. A UK parliamentary committee commissioned report found the use of GHB to be less dangerous than tobacco and alcohol in social harms, physical harm and addiction.[38]

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Treatment of overdose
Overdose of GHB can be difficult to treat because of its multiple effects on the body.[][][] GHB tends to cause rapid unconsciousness at doses above 3500mg, with single doses over 7000mg often causing life-threatening respiratory depression, and higher doses still inducing bradycardia and cardiac arrest. Other side-effects include convulsions (especially when combined with stimulants), and nausea/vomiting (especially when combined with alcohol).[] The greatest life threat due to GHB overdose (with or without other substances) is respiratory arrest.[12][] Other relatively common causes of death due to GHB ingestion include aspiration of vomitus, positional asphyxia, and trauma sustained while intoxicated (e.g., motor vehicle accidents while driving under the influence of GHB).[citation needed] The risk of aspiration pneumonia and positional asphyxia risk can be reduced by laying the patient down in the recovery position. People are most likely to vomit as they become unconscious, and as they wake up. It is important to keep the patient/friend awake and moving, plus do not allow them to be alone as death through vomiting can easily happen. Frequently they will be in a good mood but this does not mean they are not in danger. GHB overdose is a medical emergency and immediate assessment in an emergency department is needed. Convulsions from GHB can be treated with diazepam or lorazepam,[] even though these are also CNS depressants they are GABAA agonists, whereas GHB is primarily a GABAB agonist, so the benzodiazepines do not worsen CNS depression as much as might be expected.[citation needed] Because of the faster and more complete absorption of GBL relative to GHB, its dose-response curve is steeper, and overdoses of GBL tend to be more dangerous and problematic than overdoses involving only GHB or 1,4-B. Any GHB/GBL overdose is a medical emergency and should be cared for by appropriately trained personnel. A newer synthetic drug SCH-50911, which acts as a selective GABAB antagonist, quickly reverses GHB overdose in mice.[] However, this treatment has yet to be tried in humans, and it is unlikely that it will be researched for this purpose in humans due to the illegal nature of clinical trials of GHB, and the lack of medical indemnity coverage inherent in using an untested treatment for a life-threatening overdose.Wikipedia:No original research

Detection of use
GHB may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients,[] provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma GHB concentrations are usually in a range of 50250mg/L in persons receiving the drug therapeutically (during general anesthesia), 30100mg/L in those arrested for impaired driving, 50500mg/L in acutely intoxicated patients and 1001000mg/L in victims of fatal overdosage. Urine is often the preferred specimen for routine drug abuse monitoring purposes. Both gamma-butyrolactone (GBL) and 1,4-butanediol are converted to GHB in the body.[39][40][41]

Neurotoxicity
In multiple studies, GHB has been found to impair spatial and working learning and memory in rats with chronic administration.[][][][] These effects are associated with decreased NMDA receptor expression in the cerebral cortex and possibly other areas as well.[] Pedraza et al. (2009) found that repeated administration of GHB to rats for 15 days drastically reduced the number of neurons and non-neuronal cells in the CA1 region of the hippocampus and in the prefrontal cortex. With doses of 10mg/kg of GHB, they were decreased by 61% in the CA1 region and 32% in the prefrontal cortex, and with 100mg/kg, they were decreased by 38% and 9%, respectively. It is interesting to note that GHB has biphasic effects on neuronal loss, with lower doses (10mg/kg) producing the most neurotoxicity, and higher doses (100mg/kg) producing less. Pretreatment with NCS-382, a GHB receptor antagonist, prevents both learning/memory deficits and neuronal loss in GHB-treated animals, suggesting that GHB's neurotoxic actions are mediated via activation of the GHB receptor.[] In

Gamma-Hydroxybutyric acid addition, the neurotoxicity appears to be caused by oxidative stress.[][][]

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Addiction
Although there have been reported fatalities due to GHB withdrawal, reports are inconclusive and further research is needed.[] Addiction occurs when repeated drug use disrupts the normal balance of brain circuits that control rewards, memory and cognition, ultimately leading to compulsive drug taking.[42][43] Colombo reports that rats forced to consume massive doses of GHB will intermittently prefer GHB solution to water, but notes that "no rat showed any sign of withdrawal when GHB was finally removed at the end of the 20-week period" or during periods of voluntary abstinence.[44][45]

Withdrawal
GHB has also been associated with a withdrawal syndrome of insomnia, anxiety, and tremor that usually resolves within three to twenty-one days.[][][] The withdrawal syndrome can be severe producing acute delirium and may require hospitalization in an intensive care unit for management.[] The mainstay of treatment for severe withdrawal is supportive care and benzodiazepines for control of acute delirium, but larger doses are often required compared to acute delirium of other causes (e.g. > 100mg/d of diazepam). Baclofen has been suggested as an alternative or adjunct to benzodiazepines based on anecdotal evidence and some animal data.[46] However, there is less experience with the use of baclofen for GHB withdrawal, and additional research in humans is needed. Baclofen was first suggested as an adjunct because benzodiazepines do not affect GABAB receptors and thus have no cross-tolerance with GHB while baclofen, which works via GABAB receptors, is cross-tolerant with GHB and may be more effective in alleviating withdrawal effects of GHB.[] GHB withdrawal is not widely discussed in text books and some psychiatrists, general practitioners, and even hospital emergency physicians may not be familiar with this withdrawal syndrome.[]

Endogenous production
Cells produce GHB by reduction of succinic semialdehyde via the enzyme succinic semialdehyde dehydrogenase. This enzyme appears to be induced by cAMP levels,[47] meaning substances that elevate cAMP, such as forskolin and vinpocetine, may increase GHB synthesis and release. People with the disorder known as succinic semialdehyde dehydrogenase deficiency, also known as gamma-hydroxybutyric aciduria, have elevated levels of GHB in their urine, blood plasma and cerebrospinal fluid.[48] The precise function of GHB in the body is not clear. It is known, however, that the brain expresses a large amount of receptors that are activated by GHB.[49] These receptors are excitatory and not responsible for the sedative effects of GHB they have been shown to elevate the principal excitatory neurotransmitterglutamate.[] The benzamide antipsychoticsamisulpride, sulpiridehave been shown to bind to this receptor in vivo.[50] Other antipsychotics were tested and were not found to have an affinity for this receptor. It is a precursor to GABA, glutamate, and glycine in certain brain areas.[51] GHB has neuroprotective properties and has been found to protect cells from hypoxia.[52]

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Natural fermentation by-product

GHB is also produced as a result of fermentation and so is found in small quantities in some beers and wines, in particular fruit wines. However, the amount of GHB found in wine is insignificant and not sufficient to produce any effects.[53]

Pharmacology
GHB has at least two distinct binding sites[54] in the central nervous system. GHB is an agonist at the newly characterized GHB receptor, which is excitatory,[55][] and it is a weak agonist at the GABAB receptor, which is inhibitory.[] GHB is a naturally occurring substance that acts in a similar fashion to some neurotransmitters in the mammalian brain.[56] GHB is probably synthesized from GABA in GABAergic neurons, and released when the neurons fire.[] If taken orally, GABA itself does not effectively cross the blood-brain-barrier.[57] GHB induces the accumulation of either a derivative of tryptophan or tryptophan itself in the extracellular space, possibly by increasing tryptophan transport across the bloodbrain barrier. The blood content of certain neutral amino-acids, including tryptophan, is also increased by peripheral GHB administration. GHB-induced stimulation of tissue serotonin turnover may be due to an increase in tryptophan transport to the brain and in its uptake by serotonergic cells. As the serotonergic system may be involved in the regulation of sleep, mood, and anxiety, the stimulation of this system by high doses of GHB may be involved in certain neuropharmacological events induced by GHB administration. However, at therapeutic doses, GHB reaches much higher concentrations in the brain and activates GABAB receptors, which are primarily responsible for its sedative effects.[58] GHB's sedative effects are blocked by GABAB antagonists. The role of the GHB receptor in the behavioural effects induced by GHB is more complex. GHB receptors are densely expressed in many areas of the brain, including the cortex and hippocampus, and these are the receptors that GHB displays the highest affinity for. There has been somewhat limited research into the GHB receptor; however, there is evidence that activation of the GHB receptor in some brain areas results in the release of glutamate, the principal excitatory neurotransmitter.[] Drugs that selectively activate the GHB receptor cause absence seizures in high doses, as do GHB and GABA(B) agonists.[59] Activation of both the GHB receptor and GABA(B) is responsible for the addictive profile of GHB. GHB's effect on dopamine release is biphasic.[60] Low concentrations stimulate dopamine release via the GHB receptor.[61] Higher concentrations inhibit dopamine release via GABA(B) receptors as do other GABA(B) agonists such as baclofen and phenibut.[62] After an initial phase of inhibition, dopamine release is then increased via the GHB receptor. Both the inhibition and increase of dopamine release by GHB are inhibited by opioid antagonists such as naloxone and naltrexone. Dynorphin may play a role in the inhibition of dopamine release via kappa opioid receptors.[63] This explains the paradoxical mix of sedative and stimulatory properties of GHB, as well as the so-called "rebound" effect, experienced by individuals using GHB as a sleeping agent, wherein they awake suddenly after several hours of GHB-induced deep sleep. That is to say that, over time, the concentration of GHB in the system decreases below the threshold for significant GABAB receptor activation and activates predominantly the GHB receptor, leading to wakefulness. Recently, analogs of GHB, such as 4-hydroxy-4-methylpentanoic acid have been synthesised and tested on animals, in order to gain a better understanding of GHB's mode of action.[64] Analogues of GHB such as 3-methyl-GHB, 4-methyl-GHB and 4-phenyl-GHB have been shown to produce similar effects to GHB in some animal studies, but these compounds are even less well researched than GHB itself. Of these analogues, only 4-methyl-GHB (-hydroxyvaleric acid, GHV) and its prodrug form gamma-valerolactone (GVL) have been reported as drugs of abuse in humans, and on the available evidence seem to be less potent but more toxic than GHB, with a particular

Gamma-Hydroxybutyric acid tendency to cause nausea and vomiting. Other prodrug ester forms of GHB have also rarely been encountered by law enforcement, including 1,4-diacetoxybutane, methyl-4-acetoxybutanoate, and ethyl-4-acetoxybutanoate, but these are, in general, covered by analogue laws in jurisdictions where GHB is illegal, and little is known about them beyond their delayed onset and longer duration of action. The intermediate compound 4-hydroxybutaldehyde is also a prodrug for GHB; however, as with all aldehydes this compound is caustic and is strong-smelling and foul-tasting; actual use of this compound as an intoxicant is likely to be unpleasant and result in severe nausea and vomiting.

486

Metabolic pathway of GHB.

Also note that both of the metabolic breakdown pathways shown for GHB can run in either direction, depending on the concentrations of the substances involved, so the body can make its own GHB either from GABA or from succinic semialdehyde. Under normal physiological conditions, the concentration of GHB in the body is rather low, and the pathways would run in the reverse direction to what is shown here to produce endogenous GHB. However, when GHB is consumed for recreational or health promotion purposes, its concentration in the body is much higher than normal, which changes the enzyme kinetics so that these pathways operate to metabolise GHB rather than producing it.

History
Synthesis of the chemical GHB was first reported in 1874 by Alexander Zaytsev,[65] but the first major research into its use in humans was conducted in the early 1960s by Dr. Henri Laborit to use in studying the neurotransmitter GABA.[66] It quickly found a wide range of uses due to its minimal side-effects and short duration of action, the only difficulties being the narrow therapeutic dosage range and the dangers presented by its combination with alcohol and other nervous system depressants.

Gamma-Hydroxybutyric acid GHB was widely used in France, Italy, and other European countries for several decades as a sleeping agent and an anesthetic in childbirth but problems with its abuse potential and development of newer drugs have led to a decrease in legitimate medical use of GHB in recent times. In the Netherlands, GHB could be bought as aphrodisiac and euphoriant in a smartshop for several years, until several incidents caused it to become regulated. The only common medical applications for GHB today are in the treatment of narcolepsy and more rarely alcoholism. In the typical scenario, GHB has been synthesized from -butyrolactone (GBL) by adding sodium hydroxide (lye) in ethanol or water. A popular children's toy, Bindeez (also known as Aqua Dots, in the United States), produced by Melbourne company Moose, was banned in Australia in early November 2007 when it was discovered that 1,4-butanediol (1,4-B), which is metabolized into GHB, had been substituted for the non-toxic plasticiser 1,5-pentanediol in the bead manufacturing process. Three young children were hospitalized as a result of ingesting a large number of the beads, and the toy was recalled.[67]

487

Legal status
In the United States, it was placed on Schedule I of the Controlled Substances Act in March 2000. However, when sold as sodium oxybate, it is considered a Schedule III substance but with Schedule I trafficking penalties, one of several drugs that are listed in multiple schedules.[12][68] On 20 March 2001, the Commission on Narcotic Drugs placed GHB in Schedule IV of the 1971 Convention on Psychotropic Substances.[69] In the UK it was made a class C drug in June 2003.
GHB sold in Italy for therapeutic use.

In Hong Kong, GHB is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined HK$10000. The penalty for trafficking or manufacturing the substance is a HK$150,000 fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a HK$100,000 fine and/or 5 years of jail time. In New Zealand and Australia, GHB, 1,4-B and GBL are all Class B illegal drugs, along with any possible esters, ethers and aldehydes. GABA itself is also listed as an illegal drug in these jurisdictions, which seems unusual given its failure to cross the bloodbrain barrier, but there was a perception among legislators that all known analogues should be covered as far as this was possible. Attempts to circumvent the illegal status of GHB have led to the sale of derivatives such as 4-methyl-GHB (gamma-hydroxyvaleric acid, GHV) and its prodrug form gamma-valerolactone (GVL), but these are also covered under the law by virtue of their being "substantially similar" to GHB or GBL and; so importation, sale, possession and use of these compounds is also considered to be illegal. In Chile, GHB is a controlled drug under the law "Ley de substancias psicotropicas y estupefacientes" (psychotropic substances and narcotics). In Norway[] and in Switzerland,[70] GHB is considered a narcotic and is only available by prescription under the trade name Xyrem (Union Chimique Belge S.A.). Sodium oxybate is also used therapeutically in Italy under the brand name Alcover for treatment of alcohol withdrawal and dependence.[71]

Gamma-Hydroxybutyric acid

488

References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=591-81-1& rn=1 [2] http:/ / www. whocc. no/ atc_ddd_index/ ?code=N01AX11 [3] http:/ / www. whocc. no/ atc_ddd_index/ ?code=N07XX04 [4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=3037032 [5] http:/ / www. drugbank. ca/ drugs/ DB01440 [6] http:/ / www. chemspider. com/ Chemical-Structure. 9984 [7] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=30IW36W5B2 [8] http:/ / www. kegg. jp/ entry/ C00989 [9] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:30830 [10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL1342 [11] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=477230013& page2=Gamma-Hydroxybutyric+ acid [12] Erowid GHB Vault : Legal Status (http:/ / erowid. org/ chemicals/ ghb/ ghb_law. shtml). [19] "The Vaults Of Erowid" (http:/ / www. erowid. org/ chemicals/ ghb/ ghb_health. shtml). Erowid.org (2009-03-18). Retrieved on 2012-09-27. [26] Alcohol and other popular Date Rape Drugs (http:/ / web. archive. org/ web/ 20081007071413/ http:/ / www. udel. edu/ wellspring/ SOS/ drugs. htm). udel.edu [27] "Labs making date-rape drug raided" (http:/ / www. independent. co. uk/ news/ world/ europe/ labs-making-daterape-drug-raided-863938. html), The Independent, 10 July 2008. [28] Testing for GHB in Hair by GC/MS/MS after a Single Exposure. Application to Document Sexual Assault (http:/ / www. hawaii. edu/ hivandaids/ Testing_for_GHB_in_Hair_by_GCMSMS_After_a_Single_Exposure_Doc_Sexual_Assault. pdf). University of Hawaii. Jan 2003. Last accessed 04 Jan 2011. [29] Jackie Harrison Martin (2009-01-16). REMEMBERING SAMANTHA REID: 10th anniversary of teen's GHB death (http:/ / www. thenewsherald. com/ articles/ 2009/ 01/ 16/ news/ doc4970e3f098507043714937. txt). thenewsherald.com. Retrieved on 2012-09-27. [33] Zvosec et al. Proceedings of the American Academy of Forensic Science in Seattle, 2006 (http:/ / web. archive. org/ web/ 20071203005230/ http:/ / www. aafs. org/ pdf/ Seattleabstracts06. pdf). Web.archive.org (2007-12-03). Retrieved on 2011-12-24. [38] Drug classification: making a hash of it? (http:/ / news. bbc. co. uk/ 1/ shared/ bsp/ hi/ pdfs/ 31_07_06_drugsreport. pdf) House of Commons, Science and Technology Committee. Fifth Report of Session 200506 (31 July 2006) [41] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 680684. [42] Department of Health and Human Services, SAMHSA Office of Applied Studies 2005 National Survey on Drug Use and Health (ages 12 years and up); American Heart Association; Johns Hopkins University study, Principles of Addiction Medicine; Psychology Today; National Gambling Impact Commission Study; National Council on Problem Gambling; Illinois Institute for Addiction Recovery; Society for Advancement of Sexual Health; All Psych Journal [43] Addiction and the Brain (http:/ / www. time. com/ time/ interactive/ 0,31813,1640235,00. html). Time [45] Is GHB toxic? Addictive? Dangerous? (http:/ / www. lycaeum. org/ ~ghbfaq/ dangerous. html) lycaeum.org [48] National Organization for Rare Disorders. Succinic Semialdehyde Dehydrogenase Deficiency (http:/ / www. rarediseases. org/ search/ rdbdetail_abstract. html?disname=Succinic Semialdehyde Dehydrogenase Deficiency). Retrieved 6 March 2010. [68] ProjectGHB.org (http:/ / web. archive. org/ web/ 20100116121252/ http:/ / www. projectghb. org/ laws. htm). Web.archive.org (2010-01-16). Retrieved on 2012-09-27. [69] Whitehousedrugpolicy.org (http:/ / www. whitehousedrugpolicy. gov/ publications/ factsht/ gamma/ ). [70] Xyrem untersteht dem Bundesgesetz ber die Betubungsmittel und die psychotropen Stoffe (http:/ / www. kompendium. ch/ MonographieTxt. aspx?lang=de& MonType=fi)

External links
The Cognitive Enhancement Research Institute Research findings on GHB and other substances (http://ceri. com/feature.htm) EMCDDA Report on the risk assessment of GHB in the framework of the joint action on new synthetic drugs (http://www.emcdda.europa.eu/index.cfm?fuseaction=public.Content&nNodeID=431) Erowid GHB Vault (http://www.erowid.org/chemicals/ghb/) (also contains information about addiction and dangers) InfoFacts Rohypnol and GHB (http://www.drugabuse.gov/Infofax/RohypnolGHB.html) (National Institute on Drug Abuse) Pubmed/Medline search on sodium oxybate and alcohol-related disorders (http://www.debernardis.it/ medasq.php?z=sodium+oxybate+[mesh]+and+alcohol-related+disorders+[mesh]&abstract=0&quanti=50&

Gamma-Hydroxybutyric acid highlight=2&daevidenziare=oxybate+alcohol&dovesiamo=0&azione=Show)

489

Histamine
Histamine

Identifiers CAS number PubChem ChemSpider UNII KEGG MeSH ChEBI ChEMBL IUPHAR ligand ATC code 51-45-6 774 753
[2] [3] [4] [1]

820484N8I3 D08040
[5]

Histamine

[6] [7]

CHEBI:18295 CHEMBL90 1204

[9]

[8]

L03 AX14 ,(2HCl) [11] V04 CG03 (phosphate) Image 1

[12]

[10]

Jmol-3D images

Properties Molecular formula C H N Molar mass Melting point Boiling point

5 9 3

111.15 g mol1 83.5 C (182.3 F) 209.5 C (409.1 F)

Solubility in water Easily soluble in cold water, hot water[13] Solubility Easily soluble in methanol. Very slightly soluble in diethyl ether.
(verify) [14] [13]

Easily soluble in ethanol.

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

Histamine

490
Infobox references

Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter.[15] Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues.[16]

Properties
Histamine forms color hygroscopic crystals that melt at 84C, and are easily dissolved in water or ethanol, but not in ether. In aqueous solution histamine exists in two tautomeric forms, N-H-histamine and N-H-histamine. The imidazole ring has two nitrogens. The nitrogen farthest away from the side chain is the 'tele' nitrogen and is denoted by a lowercase tau sign. The nitrogen closest to the side chain is the 'pros' nitrogen and is denoted by the pi sign. The position of the nitrogen with the hydrogen on it determines how the tautomer is named. If the nitrogen with the hydrogen is in the tele position, then histamine is in the tele-tautomer form. The tele-tautomer is preferred in solution. Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group (having a pKa around 9.4) will be Tautomers of histamine protonated, whereas the second nitrogen of the imidazole ring (pKa 5.8) will not be protonated.[] Thus, histamine is normally protonated to a singly charged cation.

Synthesis and metabolism

Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine.

Conversion of histidine to histamine by histidine decarboxylase

Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, histamine-N-methyltransferase or diamine oxidase. In the central nervous system, histamine released into the synapses is primarily broken down by histamine-N-methyltransferase, while in other tissues both enzymes may play a role. Several other enzymes, including MAO-B and ALDH2, further process the immediate metabolites of histamine for excretion or recycling. Bacteria also are capable of producing histamine using histidine decarboxylase enzymes unrelated to those found in animals. A non-infectious form of foodborne disease, scombroid poisoning, is due to histamine production by

Histamine bacteria in spoiled food, particularly fish. Fermented foods and beverages naturally contain small quantities of histamine due to a similar conversion performed by fermenting bacteria or yeasts. Sake contains histamine in the 2040mg/L range; wines contain it in the 210mg/L range.[17]

491

Storage and release

Most histamine in the body is generated in granules in mast cells or in white blood cells called basophils. Mast cells are especially numerous at sites of potential injury the nose, mouth, and feet, internal body surfaces, and blood vessels. Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Another important site of histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach. The most important pathophysiologic mechanism of mast cell and basophil histamine release is immunologic. These cells, if sensitized by Mast cells. IgE antibodies attached to their membranes, degranulate when exposed to the appropriate antigen. Certain amines and alkaloids, including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release. Antibiotics like polymyxin are also found to stimulate histamine release. Histamine release occurs when allergens bind to mast-cell-bound IgE antibodies. Reduction of IgE overproduction may lower the likelihood of allergens finding sufficient free IgE to trigger a mast-cell-release of histamine.

Mechanism of action
Histamine exerts its actions by combining with specific cellular histamine receptors. The four histamine receptors that have been discovered in humans and animals are designated H1 through H4, and are all G protein-coupled receptors (GPCR). Histamine biology is a series of weak interactions. In all of the known physiological reactions, the histamine backbone is unchanged.[] In the H2 receptor mechanism, histamine is protonated at the end-chain amine group. This amine group interacts with aspartic acid in the transmembrane domains of cells. The other nitrogens in the molecule interact with threonine and aspartic acid in different transmembrane domains. This is a three-pronged interaction. It brings the transmembrane domains close to each other, causing a signal transduction cascade.[] Histamine receptors in insects, like Drosophila melanogaster, are histamine-gated chloride channels that function in inhibition of neurons.[18] Histamine-gated chloride channels are implicated in neurotransmission of peripheral sensory information in insects, especially in photoreception/vision. Two receptor subtypes have been identified in Drosophila: HClA and HClB.[19] There are no known GPCRs for histamine in insects.

Histamine

492

Type H1 histamine receptor

Location Found on smooth muscle, endothelium, and central nervous system tissue

Function Causes bronchoconstriction, bronchial smooth muscle contraction, vasodilation, separation of endothelial cells (responsible for hives), and pain and itching due to insect stings; the primary receptors involved in allergic rhinitis symptoms and motion sickness; sleep and appetite suppression. Primarily involved in vasodilation. Also stimulate gastric acid secretion

H2 histamine receptor H3 histamine receptor H4 histamine receptor

Located on parietal cells and vascular smooth muscle cells

Found on central nervous system and to a lesser extent peripheral nervous system tissue Found primarily in the basophils and in the bone marrow. It is also found on thymus, small intestine, spleen, and colon.

Decreased neurotransmitter release: histamine, acetylcholine, norepinephrine, serotonin

Plays a role in chemotaxis.

Effects on nasal mucous membrane

Increased vascular permeability causes fluid to escape from capillaries into the tissues, which leads to the classic symptoms of an allergic reaction: a runny nose and watery eyes. Allergens can bind to IgE-loaded mast cells in the nasal cavity's mucous membranes. This can lead to three clinical responses:[20] 1. sneezing due to histamine-associated sensory neural stimulation 2. hyper-secretion from glandular tissue 3. nasal congestion due to vascular engorgement associated with vasodilation and increased capillary permeability

Roles in the body

Although histamine is small compared to other biological molecules (containing only 17 atoms), it plays an important role in the body. It is known to be involved in 23 different physiological functions. Histamine is known to be involved in so many physiological functions because of its chemical properties that allow it to be so versatile in binding. It is Coulombic (able to carry a charge), conformational, and flexible. This allows it to interact and bind more easily.[]

Sleep regulation
Histamine is released as a neurotransmitter. The cell bodies of histaminergics, the neurons which release histamine, are found in the posterior hypothalamus, in various tuberomammillary nuclei. From here, these neurons project throughout the brain, to the cortex through the medial forebrain bundle. Histaminergic action is known to modulate sleep. Classically, antihistamines (H1 histamine receptor antagonists) produce sleep. Likewise, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain vigilance. Finally, H3 receptor antagonists increase wakefulness. It has been shown that histaminergic cells have the most wakefulness-related firing pattern of any neuronal type thus far recorded. They fire rapidly during waking, fire more slowly during periods of relaxation/tiredness and completely stop firing during REM and NREM (non-REM) sleep. Histaminergic cells can be recorded firing just before an animal shows signs of waking.

Histamine

493

Suppressive effects
While histamine has stimulatory effects upon neurons, it also has suppressive ones that protect against the susceptibility to convulsion, drug sensitization, denervation supersensitivity, ischemic lesions and stress.[21] It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten.[22]

Erection and sexual function

Libido loss and erectile failure can occur following histamine (H2) antagonists such as cimetidine and ranitidine.[] The injection of histamine into the corpus cavernosum in men with psychogenic impotence produces full or partial erections in 74% of them.[23] It has been suggested that H2 antagonists may cause sexual difficulties by reducing the uptakeWikipedia:Please clarify of testosterone.[]

Schizophrenia
Metabolites of histamine are increased in the cerebrospinal fluid of people with schizophrenia, while the efficiency of H(1) receptor binding sites is decreased. Many atypical antipsychotic medications have the effect of increasing histamine turnover.[24]

Multiple sclerosis
Histamine therapy for treatment of multiple sclerosis is currently being studied. The different H receptors have been known to have different effects on the treatment of this disease. The H1 and H4 receptors, in one study, have been shown to be counterproductive in the treatment of MS. The H1 and H4 receptors are thought to decrease permeability in the Blood Brain Barrier, thus increasing infiltration of unwanted cells in the Central Nervous System. This can cause inflammation, and MS symptom worsening. The H2 and H3 receptors are thought to be helpful when treating MS patients. Histamine has been shown to help with T-cell differentiation. This is important because in MS, the immune system attacks its own myelin sheaths on nerve cells (which causes loss of signaling function and eventual nerve degeneration). By helping T cells to differentiate, the T cells will be less likely to attack the body's own cells, and instead attack invaders.[25]

Disorders
As an integral part of the immune system, histamine may be involved in immune system disorders and allergies. Mastocytosis is a rare disease in which there is a proliferation of mast cells that produce excess histamine.[26]

History
The properties of histamine, then called -iminazolylethylamine, were first described in 1910 by the British scientists Henry H. Dale and P.P. Laidlaw.[27] "H substance" or "substance H" are occasionally used in medical literature for histamine or a hypothetical histamine-like diffusible substance released in allergic reactions of skin and in the responses of tissue to inflammation.[citation needed]

Histamine

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References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=51-45-6 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=774 [3] http:/ / www. chemspider. com/ 753 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=820484N8I3 [5] http:/ / www. kegg. jp/ entry/ D08040 [6] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Histamine [7] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=18295 [8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL90 [9] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=1204 [10] http:/ / www. whocc. no/ atc_ddd_index/ ?code=L03AX14 [11] http:/ / www. whocc. no/ atc_ddd_index/ ?code=V04CG03 [12] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=n1cc%28nc1%29CCN [13] http:/ / www. sciencelab. com/ msds. php?msdsId=9924264 [14] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=443858090& page2=Histamine [17] http:/ / astrobiology. berkeley. edu/ PDFs_articles/ WineAnalysisAnalChem. pdf

External links
DrugBank EXPT01785 (http://www.drugbank.ca/drugs/EXPT01785) Histamine bound to proteins (http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=HSM) in the PDB

Vasopressin

495

Vasopressin
Arginine vasopressin

Space-filling model of arginine vasopressin Available structures PDB Ortholog search: PDBe [1], RCSB [2] List of PDB id codes 1jk4
[3]

, 1jk6

[4]

, 1npo

[5]

, 2bn2

[6]

Identifiers Symbols External IDs AVP

[7]

; ADH; ARVP; AVP-NPII; AVRP; VP

[8]

OMIM: 192340

MGI: 88121

[9]

HomoloGene: 417

[10]

GeneCards: AVP Gene

[11]

Vasopressin

496

Gene Ontology Molecular function protein kinase activity [12] [13] signal transducer activity [13] receptor binding [7] neuropeptide hormone activity [14] neurohypophyseal hormone activity [15] V1A vasopressin receptor binding [16] V1B vasopressin receptor binding [17] cysteine-type endopeptidase inhibitor activity involved in apoptotic process Cellular component extracellular region [11] [12] extracellular space [18] cytosol [8] secretory granule [9] dendrite Biological process maternal aggressive behavior [20] positive regulation of systemic arterial blood pressure [21] generation of precursor metabolites and energy [22] protein phosphorylation [23] water transport [18] signal transduction [24] elevation of cytosolic calcium ion concentration [17] cell-cell signaling [25] negative regulation of female receptivity [26] grooming behavior [27] locomotory behavior [21] positive regulation of cell proliferation [28] positive regulation of gene expression [29] positive regulation of glutamate secretion [30] positive regulation of cell growth [31] positive regulation of cAMP biosynthetic process [32] positive regulation of prostaglandin biosynthetic process [33] positive regulation of cellular pH reduction [34] positive regulation of peptidyl-serine phosphorylation [35] response to nicotine [36] social behavior [37] regulation of renal sodium excretion [38] vasoconstriction [39] hyperosmotic salinity response [40] maternal behavior [17] negative regulation of apoptotic process [41] penile erection negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
[42] [19]

sodium-independent organic anion transport [44] response to ethanol [45] positive regulation of vasoconstriction [46] multicellular organismal water homeostasis [47] negative regulation of transmission of nerve impulse [48] transmembrane transport [49] ERK1 and ERK2 cascade [50] protein kinase C signaling cascade [51] negative regulation of release of cytochrome c from mitochondria Sources: Amigo
[52]

[43]

/ QuickGO

[53]

Vasopressin

497
RNA expression pattern

More reference expression data Orthologs Species Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Location (UCSC) Human 551
[55] [57]

[54]

Mouse 11998
[56] [58]

ENSG00000101200 P01185
[59] [61]

ENSMUSG00000037727 P35455
[60] [62]

NM_000490 NP_000481

NM_009732 NP_033862

[63]

[64]

Chr 20: [65] 3.06 3.07 Mb

[67]

Chr 2: [66] 130.58 130.58 Mb

[68]

PubMed search

Arginine vasopressin (AVP), also known as vasopressin, argipressin or antidiuretic hormone (ADH), is a neurohypophysial hormone found in most mammals. Its two primary functions are to retain water in the body and to constrict blood vessels. Vasopressin regulates the body's retention of water by acting to increase water absorption in the collecting ducts of the kidney nephron.[] Vasopressin increases water permeability of the kidney's collecting duct and distal convoluted tubule by inducing translocation of aquaporin-CD water channels in the kidney nephron collecting duct plasma membrane.[] Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's permeability. It also increases peripheral vascular resistance, which in turn increases arterial blood pressure. It plays a key role in homeostasis, by the regulation of water, glucose, and salts in the blood. It is derived from a preprohormone precursor that is synthesized in the hypothalamus and stored in vesicles at the posterior pituitary. Most of it is stored in the posterior pituitary to be released into the bloodstream. However, some AVP may also be released directly into the brain, and accumulating evidence suggests it plays an important role in social behavior, sexual motivation and bonding, and maternal responses to stress.

Physiology
Function
One of the most important roles of AVP is to regulate the body's retention of water; it is released when the body is dehydrated and causes the kidneys to conserve water, thus concentrating the urine and reducing urine volume. At high concentrations, it also raises blood pressure by inducing moderate vasoconstriction. In addition, it has a variety of neurological effects on the brain, having been found, for example, to influence pair-bonding in voles. The high-density distributions of vasopressin receptor AVPr1a in prairie vole ventral forebrain regions have been shown to facilitate and coordinate reward circuits during partner preference formation, critical for pair bond formation.[] A very similar substance, lysine vasopressin (LVP) or lypressin, has the same function in pigs and is often used in human therapy.

Vasopressin Kidney Vasopressin has two effects by which it contributes to increased urine osmolarity (increased concentration) and decreased water excretion. These are: 1. Increasing the water permeability of distal tubule and collecting duct cells in the kidney, thus allowing water reabsorption and excretion of more concentrated urine, i.e., antidiuresis. This occurs through insertion of water channels (Aquaporin-2) into the apical membrane of distal tubule and collecting duct epithelial cells. Aquaporins allow water to move down their osmotic gradient and out of the nephron, increasing the amount of water re-absorbed from the filtrate (forming urine) back into the bloodstream. V2 receptors, which are G protein-coupled receptors on the basolateral plasma membrane of the epithelial cells, couple to the heterotrimeric G-protein Gs, which activates adenylyl cyclases III and VI to convert ATP into cAMP, plus 2 inorganic phosphates. The rise in cAMP then triggers the insertion of aquaporin-2 water channels by exocytosis of intracellular vesicles, recycling endosomes. Vasopressin also increases the concentration of calcium in the collecting duct cells, by episodic release from intracellular stores. Vasopressin, acting through cAMP, also increases transcription of the aquaporin-2 gene, thus increasing the total number of aquaporin-2 molecules in collecting duct cells. Cyclic-AMP activates protein kinase A (PKA) by binding to its regulatory subunits and allowing them to detach from the catalytic subunits. Detachment exposes the catalytic site in the enzyme, allowing it to add phosphate groups to proteins (including the aquaporin-2 protein), which alters their functions. 2. Increasing permeability of the inner medullary portion of the collecting duct to urea by regulating the cell surface expression of urea transporters,[] which facilitates its reabsorption into the medullary interstitium as it travels down the concentration gradient created by removing water from the connecting tubule, cortical collecting duct, and outer medullary collecting duct. Cardiovascular system Vasopressin increases peripheral vascular resistance (vasoconstriction) and thus increases arterial blood pressure. This effect appears small in healthy individuals; however it becomes an important compensatory mechanism for restoring blood pressure in hypovolemic shock such as that which occurs during hemorrhage. Central nervous system Vasopressin released within the brain has many actions: It has been implicated in memory formation, including delayed reflexes, image, short- and long-term memory, though the mechanism remains unknown; these findings are controversial. However, the synthetic vasopressin analogue desmopressin has come to interest as a likely nootropic.
[69] Avp is expressed in the periventricular [] region of the hypothalamus in the adult mouse. Allen Brain Atlases

498

Vasopressin is released into the brain in a circadian rhythm by neurons of the supraoptic nucleus. Vasopressin released from centrally projecting hypothalamic neurons is involved in aggression, blood pressure regulation and

temperature regulation. It is likely that vasopressin acts in conjunction with corticotropin-releasing hormone to modulate the release of corticosteroids from the adrenal gland in response to stress, particularly during pregnancy and lactation in mammals.[][][] Selective AVPr1a blockade in the ventral pallidum has been shown to prevent partner preference in prairie voles, suggesting that these receptors in this ventral forebrain region are crucial for pair bonding.[]

Vasopressin Recent evidence suggests that vasopressin may have analgesic effects. The analgesia effects of vasopressin were found to be dependent on both stress and gender.[] Evidence for this comes from experimental studies in several species, which indicate that the precise distribution of vasopressin and vasopressin receptors in the brain is associated with species-typical patterns of social behavior. In particular, there are consistent differences between monogamous species and promiscuous species in the distribution of AVP receptors, and sometimes in the distribution of vasopressin-containing axons, even when closely related species are compared.[83] Moreover, studies involving either injecting AVP agonists into the brain or blocking the actions of AVP support the hypothesis that vasopressin is involved in aggression toward other males. There is also evidence that differences in the AVP receptor gene between individual members of a species might be predictive of differences in social behavior. One study has suggested that genetic variation in male humans affects pair-bonding behavior. The brain of males uses vasopressin as a reward for forming lasting bonds with a mate, and men with one or two of the genetic alleles are more likely to experience marital discord. The partners of the men with two of the alleles affecting vasopressin reception state disappointing levels of satisfaction, affection, and cohesion.[] Vasopressin receptors distributed along the reward circuit pathway, to be specific in the ventral pallidum, are activated when AVP is released during social interactions such as mating, in monogamous prairie voles. The activation of the reward circuitry reinforces this behavior, leading to conditioned partner preference, and thereby initiates the formation of a pair bond.[]

499

Control
Vasopressin is secreted from the posterior pituitary gland in response to reductions in plasma volume, in response to increases in the plasma osmolality, and in response to cholecystokinin (CCK) secreted by the small intestine: Secretion in response to reduced plasma volume is activated by pressure receptors in the veins, atria, and carotids. Secretion in response to increases in plasma osmotic pressure is mediated by osmoreceptors in the hypothalamus. Secretion in response to increases in plasma CCK is mediated by an unknown pathway. The neurons that make AVP, in the hypothalamic supraoptic nuclei (SON) and paraventricular nuclei (PVN), are themselves osmoreceptors, but they also receive synaptic input from other osmoreceptors located in regions adjacent to the anterior wall of the third ventricle. These regions include the organum vasculosum of the lamina terminalis and the subfornical organ. Many factors influence the secretion of vasopressin: Ethanol (alcohol) reduces the calcium-dependent secretion of AVP by blocking voltage-gated calcium channels in neurohypophyseal nerve terminals.[70] Angiotensin II stimulates AVP secretion, in keeping with its general pressor and pro-volumic effects on the body.[] Atrial natriuretic peptide inhibits AVP secretion, in part by inhibiting Angiotensin II-induced stimulation of AVP secretion.[]

Secretion
The main stimulus for secretion of vasopressin is increased osmolality of plasma. Reduced volume of extracellular fluid also has this effect, but is a less sensitive mechanism. The AVP that is measured in peripheral blood is almost all derived from secretion from the posterior pituitary gland (except in cases of AVP-secreting tumours). Vasopressin is produced by magnocellular neurosecretory neurons in the Paraventricular nucleus of hypothalamus (PVN) and Supraoptic nucleus (SON). It then travels down the axon through the infundibulum within neurosecretory granules that are found within Herring bodies, localized swellings of the axons and nerve terminals. These carry the peptide directly to the posterior pituitary gland, where it is stored until released into the blood. However there are two other sources of AVP with important local effects:

Vasopressin AVP is also synthesized by parvocellular neurosecretory neurons at the PVN, transported and released at the median eminence, which then travels through the hypophyseal portal system to the anterior pituitary where it stimulates corticotropic cells synergistically with CRH to produce ACTH (by itself it is a weak secretagogue).[] Vasopressin is also released into the brain by several different populations of smaller neurons.

500

Receptors
Below is a table summarizing some of the actions of AVP at its four receptors, differently expressed in different tissues and exerting different actions:
Type AVPR1A Second messenger system Locations Actions Vasoconstriction, gluconeogenesis, platelet aggregation, and release [] of factor VIII and von Willebrand factor; social recognition, [] circadian tau Adrenocorticotropic hormone secretion in response to stress; [] social interpretation of olfactory cues []

Phosphatidylinositol/calcium Liver, kidney, peripheral vasculature, brain

AVPR1B or AVPR3 AVPR2

Phosphatidylinositol/calcium Pituitary gland, brain

Adenylate cyclase/cAMP

Basolateral membrane of the cells lining the collecting ducts of the kidneys (especially the cortical and outer medullary collecting ducts)

Insertion of aquaporin-2 (AQP2) channels (water channels). This allows water to be reabsorbed down an osmotic gradient, and so the urine is more concentrated. Release of von Willebrand factor and surface expression of P-selectin through exocytosis of [][] Weibel-Palade bodies from endothelial cells Increases cytosolic calcium and acts as an inverse agonist of cAMP [] accumulation

VACM-1

Phosphatidylinositol/calcium Vascular endothelium and renal collecting tubules

Structure and relation to oxytocin

The vasopressins are peptides consisting of nine amino acids (nonapeptides). (NB: the value in the table above of 164 amino acids is that obtained before the hormone is activated by cleavage). The amino acid sequence of arginine vasopressin is Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly, with the cysteine residues forming a disulfide bond. Lysine vasopressin has a lysine in place of the arginine. The structure of oxytocin is very similar to that of the vasopressins: It is also a nonapeptide with a disulfide bridge and its amino acid sequence differs at only two positions (see table below). The two genes are located on the same chromosome separated by a relatively small distance of less than 15,000 bases in most species. The magnocellular neurons that make vasopressin are adjacent to magnocellular neurons that make oxytocin, and are similar in many respects. The similarity of the two peptides can cause some cross-reactions: oxytocin has a slight antidiuretic function, and high levels of AVP can cause uterine contractions.[][] Below is a table showing the superfamily of vasopressin and oxytocin neuropeptides:
Chemical structure of the argipressin (indicating that this compound is of the vasopressin family with an arginine at the 8th amino acid position.

Chemical structure of oxytocin

Vasopressin

501

Vertebrate Vasopressin Family Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 Argipressin (AVP, ADH) Lypressin (LVP) Phenypressin Vasotocin Most mammals

Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2 Cys-Phe-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Arg-Gly-NH2

Pigs, hippos, warthogs, some marsupials Some marsupials Non-mammals

Vertebrate Oxytocin Family Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2 Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Pro-Gly-NH2 Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Ile-Gly-NH2 Oxytocin (OXT) Prol-Oxytocin Mesotocin Most mammals, ratfish Some New World monkeys, northern tree shrews Most marsupials, all birds, reptiles, amphibians, lungfishes, coelacanths Frogs Bony fishes Skates Sharks

Cys-Tyr-Ile-Gln-Ser-Cys-Pro-Ile-Gly-NH2 Cys-Tyr-Ile-Ser-Asn-Cys-Pro-Ile-Gly-NH2 Cys-Tyr-Ile-Ser-Asn-Cys-Pro-Gln-Gly-NH2

Seritocin Isotocin Glumitocin

Cys-Tyr-Ile-Asn/Gln-Asn-Cys-Pro-Leu/Val-Gly-NH2 Various tocins

Invertebrate VP/OT Superfamily Cys-Leu-Ile-Thr-Asn-Cys-Pro-Arg-Gly-NH2 Cys-Phe-Val-Arg-Asn-Cys-Pro-Thr-Gly-NH2 Cys-Phe-Ile-Arg-Asn-Cys-Pro-Lys-Gly-NH2 Cys-Ile-Ile-Arg-Asn-Cys-Pro-Arg-Gly-NH2 Cys-Tyr-Phe-Arg-Asn-Cys-Pro-Ile-Gly-NH2 Cys-Phe-Trp-Thr-Ser-Cys-Pro-Ile-Gly-NH2 Diuretic Hormone Annetocin Lys-Connopressin Arg-Connopressin Cephalotocin Octopressin Locust Earthworm Geography & imperial cone snail, pond snail, sea hare, leech Striped cone snail Octopus Octopus [71]

Vasotocin is the evolutionary progenitor of all the vertebrate neurohypophysial hormones.

Role in disease
Lack of AVP
Decreased AVP release or decreased renal sensitivity to AVP leads to diabetes insipidus, a condition featuring hypernatremia (increased blood sodium concentration), polyuria (excess urine production), and polydipsia (thirst).

Excess AVP
High levels of AVP secretion may lead to hyponatremia. In many cases, the AVP secretion is appropriate (due to severe hypovolemia), and the state is labelled "hypovolemic hyponatremia". In certain disease states (heart failure, nephrotic syndrome) the body fluid volume is increased but AVP production is not suppressed for various reasons; this state is labelled "hypervolemic hyponatremia". A proportion of cases of hyponatremia feature neither hyper- nor hypovolemia. In this group (labelled "euvolemic hyponatremia"), AVP secretion is either driven by a lack of cortisol or thyroxine (hypoadrenalism and hypothyroidism, respectively) or a very low level of urinary solute excretion (potomania, low-protein diet), or it is entirely inappropriate. This last category is classified as the syndrome of inappropriate antidiuretic hormone (SIADH).[] SIADH in turn can be caused by a number of problems. Some forms of cancer can cause SIADH, particularly small cell lung carcinoma but also a number of other tumors. A variety of diseases affecting the brain or the lung

Vasopressin (infections, bleeding) can be the driver behind SIADH. A number of drugs has been associated with SIADH, such as certain antidepressants (serotonin reuptake inhibitors and tricyclic antidepressants), the anticonvulsant carbamazepine, oxytocin (used to induce and stimulate labor), and the chemotherapy drug vincristine. Finally, it can occur without a clear explanation.[] Hyponatremia can be treated pharmaceutically through the use of vasopressin receptor antagonists.[]

502

Pharmacology
Vasopressin analogues
Vasopressin agonists are used therapeutically in various conditions, and its long-acting synthetic analogue desmopressin is used in conditions featuring low vasopressin secretion, as well as for control of bleeding (in some forms of von Willebrand disease and in mild haemophilia A) and in extreme cases of bedwetting by children. Terlipressin and related analogues are used as vasoconstrictors in certain conditions. Use of vasopressin analogues for esophageal varices commenced in 1970.[] Vasopressin infusion has also been used as a second line of management in septic shock patients not responding to high dose of inotropes (e.g., dopamine or norepinephrine).

The role of vasopressin analogues in cardiac arrest

Injection of vasopressors for the treatment of cardiac arrest was first suggested in the literature in 1896 when Austrian scientist Dr. R. Gottlieb described the vasopressor epinephrine as an "infusion of a solution of suprarenal extract [that] would restore circulation when the blood pressure had been lowered to unrecordable levels by chloral hydrate."[] Modern interest in vasopressors as a treatment for cardiac arrest stem mostly from canine studies performed in the 1960s by anesthesiologists Dr. John W. Pearson and Dr. Joseph Stafford Redding in which they demonstrated improved outcomes with the use of adjunct intracardiac epinephrine injection during resuscitation attempts after induced cardiac arrest.[] Also contributing to the idea that vasopressors may be useful treatments in cardiac arrest are studies performed in the early to mid 1990's that found significantly higher levels of endogenous serum vasopressin in adults after successful resuscitation from out-of-hospital cardiac arrest compared to those who did not live.[][] Results of animal models have supported the use of either vasopressin or epinephrine in cardiac arrest resuscitation attempts, showing improved coronary perfusion pressure[] and overall improvement in short-term survival as well as neurological outcomes.[] Vasopressin vs. epinephrine

Table 1. Meta-analysis of outcomes for patients treated with vasopressin versus epinephrine[]
RR (95% CI) Failure of ROSC Death before hospital admission Death within 24 hours Death before hospital discharge 0.81 (0.58-1.12) 0.72 (0.38-1.39) 0.74 (0.38-1.43) 0.96 (0.87-1.05)

Number of deaths and neurologically impaired survivors 1.00 (0.94-1.07)

Although both vasopressors, vasopressin and epinephrine differ in that vasopressin does not have direct effects on cardiac contractility as epinephrine does.[] Thus, vasopressin is theorized to be of increased benefit over epinephrine in cardiac arrest due to its properties of not increasing myocardial and cerebral oxygen demands.[] This idea has led

Vasopressin to the advent of several studies searching for the presence of a clinical difference in benefit of these two treatment choices. Initial small studies demonstrated improved outcomes with vasopressin in comparison to epinephrine.[] However, subsequent studies have not all been in agreement. Several randomized controlled trials have been unable to reproduce positive results with vasopressin treatment in both return of spontaneous circulation (ROSC) and survival to hospital discharge,[][][][] including a systematic review and meta-analysis completed in 2005 that found no evidence of a significant difference with vasopressin in five studied outcomes (see Table 1).[] Vasopressin and epinephrine vs. epinephrine alone

503

Table 2. Significant outcomes for combined vasopressin and epinephrine treatment

RR (95% CI) [] ROSC Survival to hospital admission [] In subgroup: PEA [] 1.42 (1.14-1.77) 1.42 (1.02-2.04) 0.05 1.30 (0.90-2.06) 0.02 p value

[] In subgroup: Collapse to ED arrival time of 1530 minutes 1.22 (1.01-1.49) 0.05 [] In subgroup: Collapse to ED arrival time of 3045 minutes 1.11 (1.00-1.24) 0.05 Survival to hospital discharge [] 3.69 (1.52-8.95)

There is no current evidence of significant survival benefit with improved neurological outcomes in patients given combinations of both epinephrine and vasopressin during cardiac arrest.[][][72][] A systematic review from 2008 did, however, find one study that showed a statistically significant improvement in ROSC and survival to hospital discharge with this combination treatment; unfortunately, those patients that survived to hospital discharge had overall poor outcomes and many suffered permanent, severe neurological damage.[][] A more recently published clinical trial out of Singapore has shown similar results, finding combination treatment to only improve the rate of survival to hospital admission, especially in the subgroup analysis of patients with longer "collapse to emergency department" arrival times of 15 to 45 minutes.[] Table 2 lists all statistically significant findings of a correlation between combined treatment and positive outcomes found in these two studies. 2010 American Heart Association Guidelines The 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care recommend the consideration of vasopressor treatment in the form of epinephrine in adults with cardiac arrest (Class IIb, LOE A recommendation).[] Due to the absence of evidence that vasopressin administered instead of or in addition to epinephrine has significant positive outcomes, the guidelines do not currently contain vasopressin as a part of the cardiac arrest algorithms.[] It does, however, allow for one dose of vasopressin to replace either the first or second dose of epinephrine in the treatment of cardiac arrest (Class IIb, LOE A recommendation).[]

Vasopressin

504

Vasopressin receptor inhibition

A vasopressin receptor antagonist is an agent that interferes with action at the vasopressin receptors. They can be used in the treatment of hyponatremia.[]

References
[1] http:/ / www. ebi. ac. uk/ pdbe/ searchResults. html?display=both& term=P01185%20or%20P01180%20or%20Q3UUQ5%20or%20P35455%20or%20P24787%20or%20Q8AV79 [2] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=UpAccessionIdQuery& accessionIdList=P01185,P01180,Q3UUQ5,P35455,P24787,Q8AV79 [3] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1jk4 [4] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1jk6 [5] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1npo [6] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=2bn2 [7] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=894 [8] http:/ / omim. org/ entry/ 192340 [9] http:/ / www. informatics. jax. org/ searches/ accession_report. cgi?id=MGI:88121 [10] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=417 [11] http:/ / www. genecards. org/ cgi-bin/ carddisp. pl?id_type=entrezgene& id=551 [12] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0004672 [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0004871 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005185 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0031894 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0031895 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043027 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005829 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0002125 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0003084 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006091 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006468 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006833 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007204 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007621 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007625 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007626 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0010628 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0014049 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030307 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030819 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0031394 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032849 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0033138 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0035094 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0035176 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0035813 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042310 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042538 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042711 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043084 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043154 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043252 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045471 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045907 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0050891 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0051970

[48] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0055085 [49] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0070371 [50] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0070528

Vasopressin
[51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0090201 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ gp-assoc. cgi?gp=UniProtKB:P01185 http:/ / www. ebi. ac. uk/ QuickGO/ GProtein?ac=P01185 http:/ / biogps. org/ gene/ 551/ http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=551& rn=1 http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=11998& rn=1 http:/ / www. ensembl. org/ Homo_sapiens/ geneview?gene=ENSG00000101200;db=core http:/ / www. ensembl. org/ Mus_musculus/ geneview?gene=ENSMUSG00000037727;db=core http:/ / www. uniprot. org/ uniprot/ P01185 http:/ / www. uniprot. org/ uniprot/ P35455 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_000490 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_009732 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_000481 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_033862 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Human& db=hg19& position=chr20:3063202-3065370 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Mouse& db=mm9& position=chr2:130580620-130582554 http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=551 http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=11998 http:/ / mouse. brain-map. org/ experiment/ show/ 78153149

505

Further reading
Rector, Floyd C.; Brenner, Barry M. (2004). Brenner & Rector's the kidney (http://home.mdconsult.com/das/ search/openres/56203699-5?searchisbn=460046813) (7th ed.). Philadelphia: Saunders. ISBN0-7216-0164-2.

External links
Molecular neurobiology of social bonding: Implications for autism spectrum disorders (http://videocast.nih. gov/Summary.asp?File=15521) a lecture by Prof. Larry Young, Jan. 4, 2010.

Dynorphin

506

Dynorphin
prodynorphin
Identifiers Symbol PDYN Entrez HUGO OMIM RefSeq 5173 8820 [1] [2] [3] [4]

131340

NM_024411

UniProt P01213 [5] Other data Locus Chr. 20 pter-p12.2 [6]

Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and /-neo-endorphin.[] Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal.[] Occasionally, prodynorphin is not fully processed, leading to the release of big dynorphin. This 32-amino acid molecule consists of both dynorphin A and dynorphin B.[] Dynorphin A, dynorphin B, and big dynorphin all contain a high proportion of basic amino acid residues, in particular lysine and arginine (29.4%, 23.1%, and 31.2% basic residues, respectively), as well as many hydrophobic residues (41.2%, 30.8%, and 34.4% hydrophobic residues, respectively).[] Although dynorphins are found widely distributed in the CNS, they have the highest concentrations in the hypothalamus, medulla, pons, midbrain, and spinal cord.[] Dynorphins are stored in large (80-120nm diameter) dense-core vesicles that are considerably larger than vesicles storing neurotransmitters. These large dense-core vesicles differ from small synaptic vesicles in that a more intense and prolonged stimulus is needed to cause the large vesicles to release their contents into the synaptic cleft. Dense-core vesicle storage is characteristic of opioid peptides storage.[] The first clues to the functionality of dynorphins came from Goldstein et al.[] in their work with opioid peptides. The group discovered an endogenous opioid peptide in the porcine pituitary that proved difficult to isolate. By sequencing the first 13 amino acids of the peptide, they created a synthetic version of the peptide with a similar potency to the natural peptide. Goldstein et al.[] applied the synthetic peptide to the guinea ileum longitudinal muscle and found it to be an extraordinarily potent opioid peptide. The peptide was called dynorphin (from the Greek dynamis=power) to describe its potency.[] Dynorphins exert their effects primarily through the -opioid receptor (KOR), a G-protein-coupled receptor. Two subtypes of KORs have been identified: K1 and K2.[] Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the -opioid receptor (MOR), -opioid receptor (DOR),and the N-methyl-D-aspartic acid (NMDA)-type glutamate receptor. [][] Different dynorphins show different receptor selectivities and potencies at receptors. Big dynorphin and dynorphin A have the same selectivity for human KOR, but dynorphin A is more selective for KOR over MOR and DOR than is big dynorphin. Big dynorphin is more potent at KORs than is dynorphin A. Both big dynorphin and dynorphin A are more potent and more selective than dynorphin B.[]

Dynorphin

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Production
Dynorphin is produced in many different parts of the brain, including the hypothalamus, the striatum, the hippocampus and the spinal cord. Gene expression patterns from the Allen Brain Atlases in mouse, macaque and humans can be seen here [7]. Dynorphin has many different physiological actions, depending upon its site of production. For example, dynorphin that is made in magnocellular vasopressin neurons of the supraoptic nucleus is important in the patterning of electrical activity. Dynorphin produced in magnocellular oxytocin neurons is a negative feedback inhibitor of oxytocin secretion. Dynorphin produced in the arcuate nucleus and in orexin neurons of the lateral hypothalamus affects the control of appetite.

Analgesia
Dynorphin has been shown to be a modulator of pain response. Han and Xie found that injecting dynorphin into the subarachnoid space of the rat spinal cord produced dose-dependent analgesia that was measured by tail-flick latency.[] Analgesia was partially eliminated by opioid antagonist naloxone.[] Han and Xie found dynorphin to be 6-10 times more potent than morphine on a per mole basis.[] In addition, morphine tolerance did not reduce dynorphin-induced analgesia.[] Ren et al. demonstrated some of the complexities related to dynorphin induced analgesia.[] The authors found that combining subanalgesic levels of morphine and dynorphin A1-13, a version of dynorphin A containing only the first 13 amino acids of the peptide, in the rat spinal cord had additive effects. However, when dynorphin A1-13 was injected into the intracerebroventriulcar (ICV) region of the brain, it had an antagonist effect on morphine-induced analgesia. A study by Lai et al. found that dynorphin might actually stimulate pain.[] The group found that it acts on the bradykinin receptor as well as KOR. The N-terminal tyrosine of dynorphin A is necessary to activate opioid receptors such as KOR, but is unnecessary in binding to bradykinin receptors.[] Lai et al. studied the effects of dynorphin A2-13 that did not contain the N-terminal tyrosine. Based on the results of dynorphin A2-13, the authors proposed a mechanism in which dynorphin A activates bradykinin receptors and thus stimulates pain response.[] According to this mechanism, dynorphin activates bradykinin receptors, which triggers the release of calcium ions into the cell through voltage-sensitive channels in the cell membrane.[] Blocking bradykinin receptors in the lumbar region of the spinal cord reversed persistent pain.[] A multiple pathway system might help explain the conflicting effects of dynorphin in the CNS. Svensson et al. provided another possible mechanism by which dynorphin might cause pain in the spinal cord.[] The authors found that administration of truncated dynorphin A2-17, which does not bind to opioid receptors, causes an increase in phosphorylated p38 mitogen-activated protein kinase (MAPK) in microglia in the dorsal horn of the spinal cord. Activated p38 has been previously linked to the NMDA-evoked prostaglandin release, which causes pain.[] Thus, dynorphin could also induce pain in the spinal cord through a non-opioid p38 pathway. Other studies have identified a role for dynorphin and kappa opioid receptor stimulation in neuropathic pain.[] This same group also showed that the dynorphin-KOR system mediates astrocyte proliferation through the activation of p38 MAPK that was required for the effects of neuropathic pain on analgesic responses.[] Taken together, these reports suggest that dynorphin can elicit multiple effects on both Kappa opioid, and non-opioid pathways to modulate analgesic responses.

Dynorphin

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Addiction
Cocaine addiction results from complex molecular changes in the brain following multiple exposures to cocaine.[] Dynorphins have been shown to be an important part of this process. Although a single exposure to cocaine does not affect brain dynorphin levels, repeated exposures to the drug increases dynorphin concentrations in the striatum and substantia nigra in rats.[] One proposed molecular mechanism for increased dynorphin levels involves transcriptional regulation by CREB (3, 5-monophosphate response element binding protein). According to the model proposed by Carlezon et al., use of cocaine increases the expression of cAMP and cAMP-dependent protein kinase (PKA).[] PKA leads to the activation of CREB, which increases the expression of dynorphin in the nucleus accumbens and dorsal striatum, brain areas important in addiction.[] Dynorphin decreases dopamine release by binding to KORs on dopamine nerve terminals,[] which leads to drug tolerance and withdrawal symptoms (Berke and Hyman, 2000).

Cocaine
Carlezon et al.[] performed several experiments to validate this model. They found that, when mice were injected with cocaine, they preferred to be in the place where they were injected (showed stronger place preference) significantly more than control mice (injected with saline) did. However, in mice overexpressing CREB under a constitutive promoter, place aversion was observed.[] This indicates that increasing CREB reverses the positive effects of cocaine. Northern blot analysis several days after CREB overexpression showed a marked increase in dynorphin mRNA in the nucleus accumbens.[] Blocking KORs with an antagonist (norBNI) blocked the aversive effects caused by CREB overexpression.[] Thus, cocaine use ultimately appears to lead to an increase in the transcription of prodynorphin mRNA. Dynorphin inhibits dopamine release,[] that would counter the pleasurable effects of cocaine caused by the release of dopamine.[] There is also evidence suggesting that increased amounts of dynorphin can protect humans from cocaine addiction. According to research at Rockefeller University, the gene for dynorphin is present in two versions: a high output and a low output functional variation.[] The high output functional variation of the gene contains polymorphisms in the promoter regions that are speculated to cause it to produce more copies of dynorphin mRNA, which would give people carrying this variation a built-in defense system against drug addiction.[]

Stress and depression

Land et al. first described a mechanism of dysphoria in which corticotropin-releasing factor (CRF) provokes dynorphin release.[] While control mice displayed aversive behaviors in response to forced swim tests and foot shocks, mice lacking dynorphin did not show any such signs of aversion. They noted that injecting CRF led to aversive behaviors in mice with functional genes for dynorphin even in the absence of stress, but not in those with dynorphin gene deletions. Place aversion was eliminated when the receptor CRF2 was blocked with an antagonist.[] Together these results led Land et al. to conclude that dysphoric elements of stress occur when CRF2 stimulates dynorphin release and activates KOR.[] The group further postulated that this pathway might be involved in drug seeking behavior. In support of this, it was shown previously that stress can reinstate cocaine-seeking behavior in mice through a CRF mechanism.[] Dynorphin has also been shown to influence drug seeking behavior and is required for stress-induced, but not prime-induced, reinstatement of cocaine seeking.[][] A downstream element of this pathway was later identified by Bruchas et al.[] The authors found that KOR activates p38, a member of the mitogen-activated protein kinase (MAPK) family, through phosphorylation. Activation of p38 is necessary to produce KOR-dependent behaviors.[] Because of its role in mediating dysphoria, dynorphin has also been investigated in relation to depression. Newton et al.[] studied the effects of CREB and dynorphin on learned helplessness (an animal model for depression) in mice. Overexpression of dominant negative CREB (mCREB) in transgenic mice had an antidepressant effect (in terms of

Dynorphin behavior), whereas overexpressing wild-type CREB caused an increase in depression-like symptoms.[] As described previously, CREB increases transcription of prodynorphin, which gives rise to different dynorphin subtypes.[] Newton et al.[] supported this mechanism, as the mCREB was colocalized with decreased expression of prodynorphin. Also, direct antagonism of dynorphin caused antidepressant-like effects similar to those seen with mCREB expression.[] Thus, the CREB-dynorphin pathway regulates mood as well as cocaine rewards. Shirayama et al.[] used several animal depression models in rats to describe the effects of dynorphins A and B in depression. The authors found that learned helplessness increases the levels of dynorphins A and B in the hippocampus and nucleus accumbens and that injecting KOR antagonist norBNI induces recovery from learned helplessness. Immobilization stress causes increases levels of both dynorphins A and B in the hippocampus and nucleus accumbens.[] Forced swim stress increases the levels of dynorphin A in the hippocampus. Shirayama et al.[] concluded that both dynorphins A and B were important in stress response. The authors proposed several mechanisms to account for the effects of the KOR antagonist norBNI on learned helplessness. First, increased dynorphin levels block the release of glutamate, a neurotransmitter involved in plasticity in the hippocampus, which would inhibit new learning.[] Blocking dynorphin effects would allow glutamate to be released and restore functional plasticity in the hippocampus, reversing the phenomenon of learned helplessness. In addition, blocking dynorphin would enhance dopamine signaling and thus reduce depressive symptoms associated with stress.[] The authors suggest that KOR antagonists might have potential in treating depression in humans.

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Appetite and circadian rhythms

Dynorphins are important in maintaining homeostasis through appetite control and circadian rhythms. Przewlocki et al.[] found that, during the day, dynorphins are naturally elevated in the neurointermediate lobe of the pituitary (NI pituitary) and depressed in the hypothalamus. This pattern is reversed at night.[] In addition, mice deprived of food and water, or of water alone, had increased levels of dynorphin in the hypothalamus during the day.[] Deprivation of water alone also decreased the dynorphin levels in the NI pituitary.[] These findings led Przewlocki et al.[] to conclude that dynorphins are essential in maintaining homeostasis. Dynorphin has been implicated as an appetite stimulant. A number of studies[] in rats have shown that increasing the dynorphin levels stimulates eating. Opioid antagonists, such as naloxone, can reverse the effects of elevated dynorphin.[] This inhibition is especially strong in obese animals or animals that have access to particularly appealing food.[] Inui et al.[] found that administering dynorphin to dogs increased both their food and water intake. Dynorphin plays a role in the eating behavior of hibernating animals. Nizeilski et al.[] examined dynorphin levels in the ground squirrel, which undergoes periods of excessive eating and periods of starvation before winter. They found that dynorphin levels increased during the starvation periods. Berman et al.[] studied the levels of dynorphin during periods of food restriction. The group found that while food did not alter the expression of dynorphin B, it increases dynorphin A levels in several rat brain regions (hypothalamus, nucleus accumbens, and bed nucleus of the stria terminalis). Recent research on dynorphin knockout mice did not find differences between knockout and control animals in food intake, but found that fat storage was reduced in male knockout mice.[] Fatty acids were oxidized more quickly in knockout animals.[] Studies have also shown that ingesting a high-fat diet increases the gene expression of dynorphin in the hypothalamus.[] Thus, dynorphin may cause overeating when a high-fat diet is available.[][] were the first to describe the role of opioid peptides in stress-related eating. In their study, mice had their tails pinched (causes stress), which induced eating. Stress-related eating was reduced by injecting naloxone, an opioid peptide antagonist.[] Mandenoff et al.[] proposed that, although endogenous opioids are not necessary to maintain body weight and energy expenditure under predictable circumstances, they become activated under stressful conditions. They found that endogenous opioids, such as dynorphin, stimulate appetite and decrease energy expenditure. Taken together, the

Dynorphin studies above suggest an important evolutionary mechanism in which more food is eaten, more nutrients are stored, and less energy is expended by an organism during times of stress.

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Temperature regulation
In addition to their role in weight control, dynorphins have been found to regulate body temperature. Opioid peptides were first investigated in hyperthermia, where it was found that MOR agonists stimulate this response when injected into the periaqueductal gray (PAG) region of the brain.[] Xin et al.[] showed that delivery of dynorphin A1-17 (a KOR agonist) through microdialysis into the PAG region induced hypothermia in rats. The authors found that the severity of hypothermia was proportional to the dose of dynorphin A1-17 administered. Hypothermia could be prevented by administering KOR antagonist norBNI to the rat.[] Xin et al.[] hypothesized that while MOR agonists mediate hyperthermia, KOR agonists, such as dynorphin, mediate hypothermia. Sharma and Alm[] found that subjecting rats to heat (38C) caused dynorphins to be upregulated in the cerebral cortex, hippocampus, cerebellum, and the brain stem. Further, authors found that administration of nitric oxide synthase (NOS) inhibitors reduced dynorphin A1-17 levels in the brain and attenuated symptoms related to heat stress. Sharma and Alm[] concluded that hyperthermia increases dynorphin levels, which may cause damage and promote heat stress reaction. They further hypothesized that nitric oxide was part of this mechanism. Ansonoff et al.[] found that hypothermic effects are mediated through K1 (-opioid receptor 1), but not K2. The authors applied a KOR agonist to K1 knockout mice, which eliminated hypothermic response. Thus, K2 does not appear to have a role in the hypothermic mechanism

Clinical significance
Recent research has demonstrated that pulmonary delivery may be an effective means of distributing dynorphin derivatives.[8]

References
[1] [2] [3] [4] [5] [6] [7] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& amp;cmd=retrieve& amp;dopt=default& amp;list_uids=5173& rn=1 http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=8820 http:/ / www. omim. org/ 131340 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?Submit=Submit& position=NM_024411& rn=1 http:/ / www. uniprot. org/ uniprot/ P01213 http:/ / omim. org/ search?index=geneMap& search=20pter http:/ / www. brain-map. org/ search/ index. html?query=pdyn

External links
Dynorphins (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Dynorphins) at the US National Library of Medicine Medical Subject Headings (MeSH)

Supraoptic nucleus

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Supraoptic nucleus
Brain: Supraoptic nucleus

Human supraoptic nucleus (SON, dorsolateral and ventromedial components) in this coronal section is indicated by the shaded areas. Dots represent vasopressin (AVP) neurons (also seen in the paraventricular nucleus, PVN). The medial surface is the 3rd ventricle (3V), with more lateral to the left. Latin NeuroNames MeSH NeuroLex ID nucleus supraopticus hier-368
[1] [2]

Supraoptic+nucleus birnlex_1411
[3]

The supraoptic nucleus (SON) is a nucleus of magnocellular neurosecretory cells in the hypothalamus of the mammalian brain. The nucleus is situated at the base of the brain, adjacent to the optic chiasm. In humans, it contains about 3,000 neurons.

Function
The cell bodies produce a peptide hormone: anti-diuretic hormone. In the cell bodies, the hormones are packaged in large, membrane-bound vesicles which are transported down the axons to the nerve endings. The secretory granules are also stored in packets along the axon called Herring bodies. Similar magnocellular neurons are also found in the paraventricular nucleus.

Signaling
Each neuron in the nucleus has one long axon that projects to the posterior pituitary gland, where it gives rise to about 10,000 neurosecretory nerve terminals. The magnocellular neurons are electrically excitable: In response to afferent stimuli from other neurons, they generate action potentials which propagate down the axons. When an action potential invades a neurosecretory terminal, the terminal is depolarised, and calcium enters the terminal through voltage-gated channels. The calcium entry triggers the secretion of some of the vesicles by a process known as exocytosis. The vesicle contents are released into the extracellular space, from where they diffuse into the bloodstream.

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Regulation of supraoptic neurons

The antidiuretic hormone (ADH) is released in response to solute concentration in the blood, decreased blood volume or blood pressure. It also causes vasoconstriction that helps elevate blood pressure. Some other inputs come from the brainstem, including from some of the noradrenergic neurons of the nucleus of the solitary tract and the ventrolateral medulla. However many of the direct inputs to the supraoptic nucleus come from neurons just outside the nucleus (the "perinuclear zone"). Oxytocin neurons respond to stimulation of the nipples (resulting in milk let-down) and in response to uterine contractions and distension of the birth canal (the "Ferguson reflex"), but the pathways by which these stimuli reach the neurons are not fully known. Of the afferent inputs to the supraoptic nucleus, most contain either the inhibitory neurotransmitter GABA or the excitatory neurotransmitter glutamate, but these transmitters often co-exist with various peptides. Other afferent neurotransmitters include noradrenaline (from the brainstem), dopamine, serotonin and acetylcholine.

The supraoptic nucleus as a "model system"

The supraoptic nucleus is an important "model system" in neuroscience. There are many reasons for this: some technical advantages of working on the supraoptic nucleus are that the cell bodies are relatively large, the cells make exceptionally large amounts of their secretory products, and the nucleus is relatively homogeneous and easy to separate from other brain regions. The gene expression and electrical activity of supraoptic neurons has been studied extensively, in many physiological and experimental conditions.[4] These studies have led to many insights of general importance, as in the examples below.

Morphological plasticity in the supraoptic nucleus

Anatomical studies using electron microscopy have shown that the morphology of the supraoptic nucleus is remarkably adaptable.[5][6][7] For example, during lactation there are large changes in the size and shape of the oxytocin neurons, in the numbers and types of synapses that these neurons receive, and in the structural relationships between neurons and glial cells in the nucleus. These changes arise during parturition, and are thought to be important adaptations that prepare the oxytocin neurons for a sustained high demand for oxytocin. Oxytocin is essential for milk let-down in response to suckling. These studies showed that the brain was much more "plastic" in its anatomy than previously recognized, and led to great interest in the interactions between glial cells and neurons generally.

Stimulus-secretion coupling
In response to, for instance, a rise in the plasma sodium concentration, vasopressin neurons also discharge action potentials in bursts, but these bursts are much longer and are less intense than the bursts displayed by oxytocin neurons, and the bursts in vasopressin cells are not synchronised.[8] It seemed strange that the vasopressin cells should fire in bursts. As the activity of the vasopressin cells is not synchronised, the overall level of vasopressin secretion into the blood is continuous, not pulsatile. Richard Dyball and his co-workers speculated that this pattern of activity, called "phasic firing", might be particularly effective for causing vasopressin secretion. They showed this to be the case [9] by studying vasopressin secretion from the isolated posterior pituitary gland in vitro. They found that vasopressin secretion could be evoked by electrical stimulus pulses applied to the gland, and that much more hormone was released by a phasic pattern of stimulation than by a continuous pattern of stimulation. These experiments led to interest in "stimulus-secretion coupling" - the relationship between electrical activity and secretion. Supraoptic neurons are unusual because of the large amounts of peptide that they secrete, and because they secrete the peptides into the blood. However many neurons in the brain, and especially in the hypothalamus,

Supraoptic nucleus synthesize peptides. It is now thought that bursts of electrical activity might be generally important for releasing large amounts of peptide from peptide-secreting neurons.

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Dendritic secretion
Supraoptic neurons have typically 1-3 large dendrites, most of which project ventrally to form a mat of process at the base of the nucleus, called the ventral glial lamina. The dendrites receive most of the synaptic terminals from afferent neurons that regulate the supraoptic neurons, but neuronal dendrites are often actively involved in information processing, rather than being simply passive receivers of information. The dendrites of supraoptic neurons contain large numbers of neurosecretory vesicles that contain oxytocin and vasopressin, and they can be released from the dendrites by exocytosis. The oxytocin and vasopressin that is released at the posterior pituitary gland enters the blood, and cannot re-enter the brain because the bloodbrain barrier does not allow oxytocin and vasopressin through, but the oxytocin and vasopressin that is released from dendrites acts within the brain. Oxytocin neurons themselves express oxytocin receptors, and vasopressin neurons express vasopressin receptors, so dendritically-released peptides "autoregulate" the supraoptic neurons. Francoise Moos and Phillipe Richard first showed that the autoregulatory action of oxytocin is important for the milk-ejection reflex. These peptides have relatively long half-lives in the brain (about 20 minutes in the CSF), and they are released in large amounts in the supraoptic nucleus, and so they are available to diffuse through the extracellular spaces of the brain to act at distant targets. Oxytocin and vasopressin receptors are present in many other brain regions, including the amygdala, brainstem, septum, and most other nuclei in the hypothalamus. Because so much vasopressin and oxytocin are released at this site, studies of the supraoptic nucleus have made an important contribution to understanding how release from dendrites is regulated, and in understanding its physiological significance.

Co-existing peptides
Vasopressin neurons and oxytocin neurons make many other neuroactive substances in addition to vasopressin and oxytocin, though most are present only in small quantities. However, some of these other substances are known to be important. Dynorphin produced by vasopressin neurons is involved in regulating the phasic discharge patterning of vasopressin neurons, and nitric oxide produced by both neuronal types is a negative-feedback regulator of cell activity. Oxytocin neurons also make dynorphin; in these neurons, dynorphin acts at the nerve terminals in the posterior pituitary as a negative feedback inhibitor of oxytocin secretion. Oxytocin neurons also make large amounts of cholecystokinin and cocaine-and amphetamine regulatory transcript (CART).

References
[1] [2] [3] [4] [5] [6] [7] [8] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=368 http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Supraoptic+ nucleus http:/ / www. neurolex. org/ wiki/ birnlex_1411 Burbach JP, Luckman SM, Murphy D, Gainer H. (2001) Gene regulation in the magnocellular hypothalamo-neurohypophysial system. Physiol Rev. 81:1197-267 PMID 11427695 Theodosis DT. (2002) Oxytocin-secreting neurons: A physiological model of morphological neuronal and glial plasticity in the adult hypothalamus. Front Neuroendocrinol. 23:101-35. PMID 11906204 Hatton GI. (2004) Dynamic neuronal-glial interactions: an overview 20 years later. Peptides 25, 403-411 PMID 15134863 Tasker JG, Di S, Boudaba C. (2002) Functional synaptic plasticity in hypothalamic magnocellular neurons. Prog Brain Res. 139:113-9. PMID 12436930 Armstrong WE, Stern JE. (1998) Phenotypic and state-dependent expression of the electrical and morphological properties of oxytocin and vasopressin neurones.Prog Brain Res. 119:101-13. PMID 10074783

[9] Dutton A, Dyball REJ. (1979) Phasic firing enhances vasopressin release from the rat neurohypophysis. J Physiol. 290:433-40. PMID 469785

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External links
BrainMaps at UCDavis Supraoptic nucleus (http://brainmaps.org/index.php?q=Supraoptic nucleus)

CRF
CRF may refer to:

Science and technology

Corticotropin-releasing factor, a polypeptide hormone Chronic renal failure, also known as chronic kidney disease (CKD) Chromatographic response function, is a coefficient which characterizes the quality of the separation in the result of a chromatography Coefficient of Rolling Friction, a coefficient that measures the rolling resistance Cloud Radiative Forcing, the difference between the radiation budget components for average cloud conditions and cloud-free conditions Chemotactic range fitting, a phenomenon in which organisms direct their movements according to certain chemicals Conditional random field, in machine learning, a type of graphical model Controlled Release Fertiliser, a solid form fertilizer Case Report Form, in a clinical trial, the document showing all the evaluated patient data Coupled rangefinder camera

Economy and management

Capital recovery factor, a financial concept Change Request Form, a document containing a call for an adjustment of a system Central Road Fund, a fund collected by the central government of India for the maintenance of national highways by taxing petrol and high speed diesel (HSD) consumers. It was initiated in the year 1929.

Sports and Sporting associations

Circle Rules Football, a variation on football with only one goal. Cyprus Rugby Federation, the governing body for rugby union in Cyprus

Other uses
Carolina Renaissance Festival, a festival held annually in North Carolina, USA Catholic Reaction Force, was a name used by paramilitaries to issue death threats against Protestants in Northern Ireland during "The Troubles" Cave Research Foundation, is an American private, non-profit group dedicated to the exploration, research, and conservation of caves Central Readiness Force, is a military defense unit in Japan Canadian Charter of Rights and Freedoms, a bill of rights entrenched in the Constitution of Canada Clube de Regatas do Flamengo, a popular soccer team in Brazil CRF is the ICAO airline designator for Air Central, an airline in Japan

Paraventricular nucleus of hypothalamus

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Paraventricular nucleus of hypothalamus

Brain: Paraventricular nucleus of hypothalamus

Human paraventricular nucleus (PVN) in this coronal section is indicated by the shaded area. Dots represent vasopressin (AVP) neurons (also seen in the supraoptic nucleus, SON). The medial surface is the 3rd ventricle (3V).

Magnocellular neurons of the PVN and SON project to the posterior "lobe" of the pituitary Latin NeuroNames MeSH NeuroLex ID Nucleus paraventricularis hypothalami hier-370
[1] [2]

Paraventricular+hypothalamic+nucleus birnlex_1407
[3]

The paraventricular nucleus (PVN, PVA, or PVH) is a neuronal nucleus in the hypothalamus. It contains multiple subpopulations of neurons that are activated by a variety of stressful and/or physiological changes. Many PVN neurons project directly to the posterior pituitary where they release oxytocin or vasopressin into the general circulation. Other PVN neurons control various anterior pituitary functions, while still others directly regulate appetite and autonomic functions in the brainstem and spinal cord.

Location
The paraventricular nucleus lies adjacent to the third ventricle, from which it derives its name, "paraventricular" meaning "alongside a ventricle." It does lie within the periventricular zone and must not be confused with the periventricular nucleus, which occupies a more medial position, beneath the third ventricle. The PVN is highly vascularised and is protected by the bloodbrain barrier, although its neuroendocrine neurons extend to sites (in the median eminence and in the posterior pituitary) beyond the bloodbrain barrier.

Paraventricular nucleus of hypothalamus

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Neurons
The PVN contains magnocellular neurosecretory cells whose axons extend into the posterior pituitary, parvocellular neurosecretory cells that project to the median eminence, and several populations of peptide-containing cells that project to many different brain regions.

Magnocellular neurosecretory neurons

The magnocellular cells in the PVN elaborate and secrete two peptide hormones: oxytocin and vasopressin. These hormones are packaged into large vesicles, which are then transported down the unmyelinated axons of the cells and released from neurosecretory nerve terminals residing in the posterior pituitary gland. Similar magnocellular neurons are found in the supraoptic nucleus.

Parvocellular neurosecretory neurons

The axons of the parvocellular neurosecretory neurons of the PVN project to the median eminence, a neurohemal organ at the base of the brain, where their neurosecretory nerve terminals release their hormones at the primary capillary plexus of the hypophyseal portal system. The median eminence contains fiber terminals from many hypothalamic neuroendocrine neurons, secreting different neurotransmitters or neuropeptides, including vasopressin, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), growth hormone-releasing hormone (GHRH), dopamine (DA) and somatostatin (growth hormone release inhibiting hormone, GIH) into blood vessels in the hypophyseal portal system. The blood vessels carry the peptides to the anterior pituitary gland, where they regulate the secretion of hormones into the systemic circulation. The parvocellular neurosecretory cells include those that make: Corticotropin-releasing hormone (CRH), which regulates ACTH secretion from the anterior pituitary gland Vasopressin, which also regulates ACTH secretion (vasopressin and CRH act synergistically to stimulate ACTH secretion) Thyrotropin-releasing hormone (TRH), which regulates TSH and prolactin secretion

Centrally-projecting neurons
As well as neuroendocrine neurons, the PVN contains interneurons and populations of neurons that project centrally (i.e., to other brain regions). The centrally-projecting neurons include Parvocellular oxytocin cells, which project mainly to the brainstem and spinal cord and are involved, respectively, in gastric reflexes and penile erection, Parvocellular vasopressin cells, which project to many points in the hypothalamus and limbic system, as well as to the brainstem and spinal cord (these are involved in blood pressure and temperature regulation), and Parvocellular CRH neurons, which are thought to be involved in stress-related behaviors.

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Afferent inputs to the PVN

The PVN receives afferent inputs from many brain regions. Among these, inputs from neurons in structures adjacent to the anterior wall of the third ventricle (the "AV3V region") carry information about the electrolyte composition of the blood, and about circulating concentrations of such hormones as angiotensin and relaxin, to regulate the magnocellular neurons. Inputs from the brainstem (the nucleus of the solitary tract) and the ventrolateral medulla carry information from the heart and stomach. Inputs from the hippocampus to the CRH neurones are important regulators of stress responses. Inputs from neuropeptide Y-containing neurons in the arcuate nucleus coordinate metabolic regulation (via TRH secretion) with regulation of energy intake. Inputs from suprachiasmatic nucleus about levels of lighting (circadian rhythms). Inputs from glucose sensors within the brain stimulate release of vasopressin and Corticotropin-releasing hormone from Parvocellular neurosecretory cells .

References
[1] http:/ / braininfo. rprc. washington. edu/ Scripts/ hiercentraldirectory. aspx?ID=370 [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Paraventricular+ hypothalamic+ nucleus [3] http:/ / www. neurolex. org/ wiki/ birnlex_1407

External links
Diagram of location in brain at painresearch.utah.edu (http://www.painresearch.utah.edu/cancerpain/ch06f2. html)

Oxytocin
Oxytocin

Systematic (IUPAC) name

mino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-16-(4-hydroxybenzoyl)-13-[(1S)-1-methylpropyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan

Oxytocin

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Clinical data

Trade names

Pitocin

AHFS/Drugs.com monograph Pregnancy cat. A (AU)

[1]

Legal status

POM (UK) -only (US) Intranasal, IV, IM

Routes

Pharmacokinetic data

Bioavailability

nil

Protein binding

30%

Metabolism

hepatic oxytocinases

Half-life

16 min

Excretion

Biliary and renal

Identifiers

CAS number 50-56-6 ATC code

[2]

H01 BB02 PubChem

[3] [4]

CID 439302 IUPHAR ligand 2174 DrugBank DB00107 ChemSpider 388434 UNII

[5] [6] [8]

[7]

1JQS135EYN KEGG D00089 ChEBI CHEBI:7872 ChEMBL

[9]

[10]

CHEMBL395429 Chemical data

[11]

Formula

C H N O S
43 66 12

12 2

Mol. mass

1007.19 g/mol

(what is this?) (verify)

[12]

Oxytocin (Oxt) /kstosn/ is a mammalian neurohypophysial hormone that acts primarily as a neuromodulator in the brain. Oxytocin plays roles in sexual reproduction, in particular during and after childbirth. It is released in large amounts after distension of the cervix and uterus during labor, facilitating birth, maternal bonding, and, after stimulation of the nipples, breastfeeding. Both childbirth and milk ejection result from positive feedback mechanisms.[13] Recent studies have begun to investigate oxytocin's role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, and maternal behaviors.[] For this reason, it is sometimes referred to as the "love hormone". There is some evidence that oxytocin promotes ethnocentric behavior, incorporating the trust and empathy of in-groups with their suspicion and rejection of outsiders.[] Furthermore, genetic differences in the oxytocin receptor gene (OXTR) have been associated with maladaptive social traits such as aggressive behaviour.[]

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Discovery
The word oxytocin was derived from Greek , oxys, and , tokos, meaning "quick birth", after its uterine-contracting properties were discovered by British pharmacologist Sir Henry Hallett Dale in 1906.[] The milk ejection property of oxytocin was described by Ott and Scott in 1910[14] and by Schafer and Mackenzie in 1911.[] The nine amino acid sequence of oxytocin was elucidated by Vincent du Vigneaud et al. and by Tuppy in 1953[] and synthesized biochemically soon after by du Vigneaud et al. in 1953.[15][] Oxytocin was the first polypeptide hormone to be sequenced and synthesized.[]

Structure and relation to vasopressin

Oxytocin is a peptide of nine amino acids (a nonapeptide). Its systematic name is cysteine-tyrosine-isoleucine-glutamine-asparagine-cysteine-proline-leucine-glycine-amine (cys tyr ile gln asn cys pro leu gly NH2, or CYIQNCPLG-NH2). Oxytocin has a molecular mass of 1007 daltons. One international unit (IU) of oxytocin is the equivalent of about 2 micrograms of pure peptide. While the structure of oxytocin is highly conserved in placental mammals, a novel structure of oxytocin was recently reported in marmosets, tamarins, and other new world primates. Genomic sequencing of the gene for oxytocin revealed a single in-frame mutation(thymine for cytosine) which results in a single amino acid substitution at the 8-position (proline for leucine).[] The biologically active form of oxytocin, commonly measured by RIA and/or HPLC techniques, is also known as the octapeptide "oxytocin disulfide" (oxidized form), but oxytocin also exists as a reduced dithiol nonapeptide called oxytoceine.[16] It has been theorized that open chain oxytoceine (the reduced form of oxytocin) may also act as a free radical scavenger (by donating an electron to a free radical); oxytoceine may then be oxidized back to oxytocin via the redox potential of dehydroascorbate <---> ascorbate.[] The structure of oxytocin is very similar to that of vasopressin (cys tyr phe gln asn cys pro arg gly NH2), also a nonapeptide with a sulfur bridge, whose sequence differs from oxytocin by two amino acids. A table showing the sequences of members of the vasopressin/oxytocin superfamily and the species expressing them is present in the vasopressin article. Oxytocin and vasopressin were isolated and synthesized by Vincent du Vigneaud in 1953, work for which he received the Nobel Prize in Chemistry in 1955. Oxytocin and vasopressin are the only known hormones released by the human posterior pituitary gland to act at a distance. However, oxytocin neurons make other Oxytocin (ball-and-stick) bound to its carrier protein neurophysin peptides, including corticotropin-releasing hormone and (ribbons) dynorphin, for example, that act locally. The magnocellular neurons that make oxytocin are adjacent to magnocellular neurons that make vasopressin, and are similar in many respects.

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Actions
Oxytocin has peripheral (hormonal) actions, and also has actions in the brain. Its actions are mediated by specific, high-affinity oxytocin receptors. The oxytocin receptor is a G-protein-coupled receptor that requires Mg2+ and cholesterol. It belongs to the rhodopsin-type (class I) group of G-protein-coupled receptors.

Peripheral (hormonal) actions

The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland. (See oxytocin receptor for more detail on its action.) Letdown reflex: In lactating (breastfeeding) mothers, oxytocin acts at the mammary glands, causing milk to be 'let down' into subareolar sinuses, from where it can be excreted via the nipple.[17] Suckling by the infant at the nipple is relayed by spinal nerves to the hypothalamus. The stimulation causes neurons that make oxytocin to fire action potentials in intermittent bursts; these bursts result in the secretion of pulses of oxytocin from the neurosecretory nerve terminals of the pituitary gland. Uterine contraction: Important for cervical dilation before birth, oxytocin causes contractions during the second and third stages of labor. Oxytocin release during breastfeeding causes mild but often painful contractions during the first few weeks of lactation. This also serves to assist the uterus in clotting the placental attachment point postpartum. However, in knockout mice lacking the oxytocin receptor, reproductive behavior and parturition are normal.[] Social behavior and wound healing: Oxytocin is also thought to modulate inflammation by decreasing certain cytokines. Thus, the increased release in oxytocin following positive social interactions has the potential to improve wound healing. A study by Marazziti and colleagues used heterosexual couples to address this possibility. They found increases in plasma oxytocin following a social interaction were correlated with faster wound healing. They hypothesized this was due to oxytocin reducing inflammation, thus allowing the wound to heal faster. This study provides preliminary evidence that positive social interactions may directly impact aspects of health.[18] The relationship between oxytocin and human sexual response is unclear. At least two uncontrolled studies have found increases in plasma oxytocin at orgasm in both men and women.[][] Plasma oxytocin levels are notably increased around the time of self-stimulated orgasm and are still higher than baseline when measured five minutes after self arousal.[] The authors of one of these studies speculated that oxytocin's effects on muscle contractibility may facilitate sperm and egg transport.[] In a study measuring oxytocin serum levels in women before and after sexual stimulation, the author suggests it serves an important role in sexual arousal. This study found genital tract stimulation resulted in increased oxytocin immediately after orgasm.[] Another study reported increases of oxytocin during sexual arousal could be in response to nipple/areola, genital, and/or genital tract stimulation as confirmed in other mammals.[] Murphy et al. (1987), studying men, found oxytocin levels were raised throughout sexual arousal with no acute increase at orgasm.[] A more recent study of men found an increase in plasma oxytocin immediately after orgasm, but only in a portion of their sample that did not reach statistical significance. The authors noted these changes "may simply reflect contractile properties on reproductive tissue".[] Oxytocin evokes feelings of contentment, reductions in anxiety, and feelings of calmness and security around the mate.[] This suggests oxytocin may be important for the inhibition of the brain regions associated with behavioral control, fear, and anxiety, thus allowing orgasm to occur. Oxytocin also functions to protect against stress. Meta-analyses conducted in 2003 demonstrated that oxytocin can alleviate mood and reduce stress with a good efficiency.[19] Due to its similarity to vasopressin, it can reduce the excretion of urine slightly. In several species, oxytocin can stimulate sodium excretion from the kidneys (natriuresis), and, in humans, high doses can result in hyponatremia.

Oxytocin Oxytocin and oxytocin receptors are also found in the heart in some rodents, and the hormone may play a role in the embryonal development of the heart by promoting cardiomyocyte differentiation.[][] However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies.[] Modulation of hypothalamic-pituitary-adrenal axis activity: Oxytocin, under certain circumstances, indirectly inhibits release of adrenocorticotropic hormone and cortisol and, in those situations, may be considered an antagonist of vasopressin.[] Autism: Oxytocin may play a role in autism and may be an effective treatment for autism's repetitive and affiliative behaviors.[20] Oxytocin treatments also resulted in an increased retention of affective speech in adults with autism.[] Two related studies in adults, in 2003 and 2007, found oxytocin decreased repetitive behaviors and improved interpretation of emotions. More recently, intranasal administration of oxytocin was found to increase emotion recognition in children as young as 12 who are diagnosed with autism spectrum disorders [] Oxytocin has also been implicated in the etiology of autism, with one report suggesting autism is correlated with genomic deletion of the gene containing the oxytocin receptor gene (OXTR). Studies involving Caucasian and Finnish samples and Chinese Han families provide support for the relationship of OXTR with autism.[][] Autism may also be associated with an aberrant methylation of OXTR.[] After treatment with inhaled oxytocin, autistic patients exhibit more appropriate social behavior.[] While this research suggests some promise, further clinical trials of oxytocin are required to demonstrate potential benefit and side effects in the treatment of autism. As such, researchers do not recommend use of oxytocin as a treatment for autism outside of clinical trials. Increasing trust and reducing fear: In a risky investment game, experimental subjects given nasally administered oxytocin displayed "the highest level of trust" twice as often as the control group. Subjects who were told they were interacting with a computer showed no such reaction, leading to the conclusion that oxytocin was not merely affecting risk-aversion.[] Nasally administered oxytocin has also been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses).[] Indeed, studies in rodents have shown oxytocin can efficiently inhibit fear responses by activating an inhibitory circuit within the amygdala. Some researchers have argued oxytocin has a general enhancing effect on all social emotions, since intranasal administration of oxytocin also increases envy and Schadenfreude.[21] Oxytocin affects social distance between adult males and females, and may be responsible at least in part for romantic attraction and subsequent monogamous pair bonding. An oxytocin nasal spray caused men in a monogamous relationship, but not single men, to increase the distance between themselves and an attractive woman during a first encounter by 10 to 15 centimeters. The researchers suggested that oxytocin may help promote fidelity within monogamous relationships.[] Affecting generosity by increasing empathy during perspective taking: In a neuroeconomics experiment, intranasal oxytocin increased generosity in the Ultimatum Game by 80%, but has no effect in the Dictator Game that measures altruism. Perspective-taking is not required in the Dictator Game, but the researchers in this experiment explicitly induced perspective-taking in the Ultimatum Game by not identifying to participants into which role they would be placed.[] Serious methodological questions have arisen, however, with regard to the role of oxytocin in trust and generosity.[22] Empathy in healthy males has been shown to be increased after intranasal oxytocin[][] This is most likely due to the effect of oxytocin in enhancing eye gaze.[] There is some discussion about which aspect of empathy oxytocin might alter for example, cognitive vs. emotional empathy.[] Cognitive function: Certain learning and memory functions are impaired by centrally administered oxytocin.[] Also, systemic oxytocin administration can impair memory retrieval in certain aversive memory tasks.[] Interestingly, oxytocin does seem to facilitate learning and memory specifically for social information. Healthy males administered intranasal oxytocin show improved memory for human faces, in particular happy faces.[][] They also show improved recognition for positive social cues over threatening social cues [][] and improved recognition of fear.[23]

521

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522

Actions within the brain

Oxytocin secreted from the pituitary gland cannot re-enter the brain because of the bloodbrain barrier. Instead, the behavioral effects of oxytocin are thought to reflect release from centrally projecting oxytocin neurons, different from those that project to the pituitary gland, or that are collaterals from them.[] Oxytocin receptors are expressed by neurons in many parts of the brain and spinal cord, including the amygdala, ventromedial hypothalamus, septum, nucleus accumbens, and brainstem. Sexual arousal: Oxytocin injected into the cerebrospinal fluid causes spontaneous erections in rats,[] reflecting actions in the hypothalamus and spinal cord. Centrally administrated oxytocin receptor antagonists can prevent noncontact erections, which is a measure of sexual arousal. Studies using oxytocin antagonists in female rats provide data that oxytocin increases lordosis behavior, indicating an increase in sexual receptivity.[] Bonding: In the prairie vole, oxytocin released into the brain of the female during sexual activity is important for forming a monogamous pair bond with her sexual partner. Vasopressin appears to have a similar effect in males.[24] Oxytocin has a role in social behaviors in many species, so it likely also does in humans. In a 2003 study, both humans and dog oxytocin levels in the blood rose after five to 24 minutes of a petting session. This possibly plays a role in the emotional bonding between humans and dogs.[25] Maternal behavior: Female rats given oxytocin antagonists after giving birth do not exhibit typical maternal behavior.[] By contrast, virgin female sheep show maternal behavior toward foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise.[] Oxytocin is involved in the initiation of maternal behavior, not its maintenance; for example, it is higher in mothers after they interact with unfamiliar children rather than their own.[] Drug interactions: According to some studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol), and reduces withdrawal symptoms.[] MDMA (ecstasy) may increase feelings of love, empathy, and connection to others by stimulating oxytocin activity via activation of serotonin 5-HT1A receptors, if initial studies in animals apply to humans.[] The anxiolytic Buspar (buspirone) also appears to produce some or all of its effect via 5-HT1A receptor-induced oxytocin stimulation.[][] Preparing fetal neurons for delivery: Crossing the placenta, maternal oxytocin reaches the fetal brain and induces a switch in the action of neurotransmitter GABA from excitatory to inhibitory on fetal cortical neurons. This silences the fetal brain for the period of delivery and reduces its vulnerability to hypoxic damage.[] Romantic attachment: In some studies, high levels of plasma oxytocin have been correlated with romantic attachment. For example, if a couple is separated for a long period of time, anxiety can increase due to the lack of physical affection. Oxytocin may aid romantically attached couples by decreasing their feelings of anxiety when they are separated.[]

Drug forms
Synthetic oxytocin is sold as proprietary medication under the trade names Pitocin and Syntocinon, and as generic oxytocin. Oxytocin is destroyed in the gastrointestinal tract, so must be administered by injection or as nasal spray. It has a half-life of typically about three minutes in the blood, and given intravenously does not enter the brain in significant quantities it is excluded from the brain by the bloodbrain barrier. Evidence in rhesus macaques indicates oxytocin by nasal spray does enter the brain.[] Oxytocin nasal sprays have been used to stimulate breastfeeding, but the efficacy of this approach is doubtful.[] Injected oxytocin analogues are used for labor induction and to support labor in case of difficult parturition. It has largely replaced ergometrine as the principal agent to increase uterine tone in acute postpartum hemorrhage. Oxytocin is also used in veterinary medicine to facilitate birth and to stimulate milk release. The tocolytic agent atosiban (Tractocile) acts as an antagonist of oxytocin receptors; this drug is registered in many countries to suppress premature labor between 24 and 33 weeks of gestation. It has fewer side effects than drugs previously used for this

Oxytocin purpose (ritodrine, salbutamol, and terbutaline). The trust-inducing property of oxytocin might help those who suffer from social anxieties and mood disorders,[] but with the potential for abuse with confidence tricks[][] and military applications.[]

523

Potential adverse reactions

Oxytocin is relatively safe when used at recommended doses, and side effects are uncommon.[] The following maternal events have been reported:[] Subarachnoid hemorrhage Increased heart rate Decreased blood pressure Cardiac arrhythmia and premature ventricular contraction Impaired uterine blood flow Pelvic hematoma Afibrinogenonemia, which can lead to hemorrhage and death Anaphylaxis Nausea and vomiting

Excessive dosage or long-term administration (over a period of 24 hours or longer) have been known to result in tetanic uterine contractions, uterine rupture, postpartum hemorrhage, and water intoxication, sometimes fatal. Increased uterine motility has led to the following complications in the fetus/neonate:[] Decreased heart rate or heart rate decelerations Cardiac arrhythmia Brain damage Seizures Death

Synthesis, storage, and release

Oxytocin/neurophysin I prepropeptide
Identifiers Symbols External IDs OXT
[26]

; OT; OT-NPI; OXT-NPI

[27]

OMIM: 167050

MGI: 97453

[28]

HomoloGene: 55494

[29]

GeneCards: OXT Gene

[30]

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Gene Ontology Molecular function neurohypophyseal hormone activity [14] [31] oxytocin receptor binding Cellular component extracellular region [11] [12] extracellular space [8] secretory granule [11] terminal bouton Biological process response to amphetamine [33] regulation of heart rate [19] maternal aggressive behavior [18] signal transduction [24] elevation of cytosolic calcium ion concentration [34] heart development [35] female pregnancy [36] memory [26] grooming behavior [37] response to sucrose stimulus [38] positive regulation of norepinephrine secretion [39] response to activity [40] sleep [41] positive regulation of prostaglandin secretion [42] response to estradiol stimulus [43] response to retinoic acid [44] response to progesterone stimulus [45] response to prostaglandin E stimulus [36] social behavior [46] negative regulation of urine volume [47] positive regulation of renal sodium excretion [48] response to cocaine [39] hyperosmotic salinity response [40] maternal behavior [49] sperm ejaculation [24] eating behavior [50] drinking behavior [51] response to peptide hormone stimulus [52] response to ether [53] negative regulation of blood pressure [54] positive regulation of blood pressure [55] positive regulation of ossification [56] positive regulation of female receptivity [57] positive regulation of synaptic transmission [58] response to glucocorticoid stimulus [59] response to cAMP [60] response to electrical stimulus [28] regulation of sensory perception of pain [61] positive regulation of synapse assembly [62] male mating behavior [63] positive regulation of penile erection [64] positive regulation of hindgut contraction [65] negative regulation of gastric acid secretion [66] positive regulation of uterine smooth muscle contraction Sources: Amigo
[67] [32]

/ QuickGO

[68]

Orthologs

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525
Species Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Human 5020
[69] [71]

Mouse 18429
[70] [72]

ENSG00000101405 P01178
[73] [75]

ENSMUSG00000027301 P35454
[74] [76]

NM_000915 NP_000906

NM_011025 NP_035155

[77]

[78]

Location (UCSC) Chr 20: [79] 3.05 3.05 Mb PubMed search

[81]

Chr 2: [80] 130.58 130.58 Mb

[82]

The oxytocin peptide is synthesized as an inactive precursor protein from the OXT gene.[][][] This precursor protein also includes the oxytocin carrier protein neurophysin I.[] The inactive precursor protein is progressively hydrolyzed into smaller fragments (one of which is neurophysin I) via a series of enzymes. The last hydrolysis that releases the active oxytocin nonapeptide is catalyzed by peptidylglycine alpha-amidating monooxygenase (PAM).[] The activity of the PAM enzyme system is dependent upon vitamin C (ascorbate), which is a necessary vitamin cofactor. By chance, sodium ascorbate by itself was found to stimulate the production of oxytocin from ovarian tissue over a range of concentrations in a dose-dependent manner.[] Many of the same tissues (e.g. ovaries, testes, eyes, adrenals, placenta, thymus, pancreas) where PAM (and oxytocin by default) is found are also known to store higher concentrations of vitamin C.[]

Neural sources
In the hypothalamus, oxytocin is made in magnocellular neurosecretory cells of the supraoptic and paraventricular nuclei, and is stored in Herring bodies at the axon terminals in the posterior pituitary. It is then released into the blood from the posterior lobe (neurohypophysis) of the pituitary gland. These axons (likely, but dendrites have not been ruled out) have collaterals that innervate oxytocin receptors in the nucleus accumbens.[] The peripheral hormonal and behavioral brain effects of oxytocin are thought to be coordinated through its common release through these collaterals.[] Oxytocin is also made by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord.[83] Depending on the species, oxytocin receptor-expressing cells are located in other areas, including the amygdala and bed nucleus of the stria terminalis. In the pituitary gland, oxytocin is packaged in large, dense-core vesicles, where it is bound to neurophysin I as shown in the inset of the figure; neurophysin is a large peptide fragment of the larger precursor protein molecule from which oxytocin is derived by enzymatic cleavage. Secretion of oxytocin from the neurosecretory nerve endings is regulated by the electrical activity of the oxytocin cells in the hypothalamus. These cells generate action potentials that propagate down axons to the nerve endings in the pituitary; the endings contain large numbers of oxytocin-containing vesicles, which are released by exocytosis when the nerve terminals are depolarised.

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Non-neural sources
Outside the brain, oxytocin-containing cells have been identified in several diverse tissues, including the corpus luteum,[][] the interstitial cells of Leydig,[] the retina,[] the adrenal medulla,[] the placenta,[] the thymus[] and the pancreas.[] The finding of significant amounts of this classically "neurohypophysial" hormone outside the central nervous system raises many questions regarding its possible importance in these different tissues. Female Oxytocin is synthesized by corpora lutea of several species, including ruminants and primates. Along with estrogen, it is involved in inducing the endometrial synthesis of prostaglandinF2 to cause regression of the corpus luteum. Male The Leydig cells in some species have also been shown to possess the biosynthetic machinery to manufacture testicular oxytocin de novo, to be specific, in rats (which can synthesize vitamin C endogenously), and in guinea pigs, which, like humans, require an exogenous source of vitamin C (ascorbate) in their diets.[]

Evolution
Virtually all vertebrates have an oxytocin-like nonapeptide hormone that supports reproductive functions and a vasopressin-like nonapeptide hormone involved in water regulation. The two genes are usually located close to each other (less than 15,000 bases apart) on the same chromosome, and are transcribed in opposite directions (however, in fugu,[] the homologs are further apart and transcribed in the same direction). The two genes are believed to result from a gene duplication event; the ancestral gene is estimated to be about 500 million years old and is found in cyclostomata (modern members of the Agnatha).[]

References
[1] http:/ / www. drugs. com/ monograph/ oxytocin. html [2] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=50-56-6& rn=1 [3] http:/ / www. whocc. no/ atc_ddd_index/ ?code=H01BB02 [4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=439302 [5] http:/ / www. iuphar-db. org/ DATABASE/ LigandDisplayForward?ligandId=2174 [6] http:/ / www. drugbank. ca/ drugs/ DB00107 [7] http:/ / www. chemspider. com/ Chemical-Structure. 388434 [8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=1JQS135EYN [9] http:/ / www. kegg. jp/ entry/ D00089 [10] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=CHEBI:7872 [11] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL395429 [12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=456481037& page2=Oxytocin [13] Marieb Human Anatomy & Physiology 9th edition, chapter:16, page:599 [14] Ott I, Scott JC. The Action of Infundibulum upon Mammary Secretion. Proc Soc Exp Biol. (1910) p.8:4849. [17] http:/ / emedicine. medscape. com/ article/ 976504-overview [24] Vacek M, High on Fidelity. What can voles teach us about monogamy? (http:/ / www. americanscientist. org/ issues/ pub/ high-on-fidelity) [25] Kuchinskas Susan, The Chemistry of Connection: How the Oxytocin Response Can Help You Find Trust, Intimacy, and Love p65 (http:/ / books. google. com/ books?hl=en& lr=& id=VO6dp52RxnQC& oi=fnd& pg=PR5& dq=oxytocin+ petting+ dog& ots=mTRRd4zj_9& sig=5xIdHdfrvmOOmZJh0Eak_KgYl2w#v=onepage& q= petting dog& f=false) [26] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=8528 [27] http:/ / omim. org/ entry/ 167050 [28] http:/ / www. informatics. jax. org/ searches/ accession_report. cgi?id=MGI:97453 [29] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=55494 [30] http:/ / www. genecards. org/ cgi-bin/ carddisp. pl?id_type=entrezgene& id=5020 [31] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0031855 [32] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0001975 [33] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0002027

Oxytocin
[34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007507 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007565 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0007613 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0009744 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0010701 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0014823 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0030431 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032308 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032355 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032526 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0032570 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0034695 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0035811 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0035815 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042220 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042713 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0042756 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043434 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045472 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045776 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045777 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045778 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0045925 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0050806 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0051384 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0051591 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0051602 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0051965 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0060179 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0060406 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0060450 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0060455 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0070474 http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ gp-assoc. cgi?gp=UniProtKB:P01178 http:/ / www. ebi. ac. uk/ QuickGO/ GProtein?ac=P01178 http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=5020& rn=1 http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=18429& rn=1 http:/ / www. ensembl. org/ Homo_sapiens/ geneview?gene=ENSG00000101405;db=core http:/ / www. ensembl. org/ Mus_musculus/ geneview?gene=ENSMUSG00000027301;db=core http:/ / www. uniprot. org/ uniprot/ P01178 http:/ / www. uniprot. org/ uniprot/ P35454 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_000915 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_011025 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_000906 http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_035155 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Human& db=hg19& position=chr20:3052266-3053163 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Mouse& db=mm9& position=chr2:130576173-130577054 http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=5020 http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=18429

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Further reading
Lee HJ, Macbeth AH, Pagani JH, Young WS (June 2009). "Oxytocin: the Great Facilitator of Life" (http://www. ncbi.nlm.nih.gov/pmc/articles/PMC2689929). Progress in Neurobiology 88 (2): 12751. doi: 10.1016/j.pneurobio.2009.04.001 (http://dx.doi.org/10.1016/j.pneurobio.2009.04.001). PMC 2689929 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689929). PMID 19482229 (http://www.ncbi.nlm.nih. gov/pubmed/19482229).

Oxytocin Caldwell HK, Young WS III (2006). "Oxytocin and Vasopressin: Genetics and Behavioral Implications" (http:// refworks.springer.com/mrw/fileadmin/pdf/Neurochemistry/0387303480C25.PDF). In Abel L, Lim R. Handbook of neurochemistry and molecular neurobiology. Berlin: Springer. pp.573607. ISBN0-387-30348-0.

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External links
Hug the Monkey (http://kuchinskas.typepad.com/hug_the_monkey/) A weblog devoted entirely to oxytocin The Soft Machine (http://tijmz.files.wordpress.com/2011/06/softmachine4.pdf) Review of oxytocin and bonding in animal and human research (.pdf) A Neurophysiologic Model of the Circuitry of Oxytocin in Arousal, Female Distress and Depression Rainer K. Liedtke, MD (http://www.rkliedtke.de/oxytocin2_us.html) (2004) Oxytocin.org (http://www.oxytocin.org/oxytoc/love-science.html) 'I get a kick out of you: Scientists are finding that, after all, love really is down to a chemical addiction between people', The Economist (February 12, 2004) NewScientist.com (http://www.newscientist.com/channel/sex/mg18925365.500) 'Release of Oxytocin due to penetrative sex reduces stress and neurotic tendencies', New Scientist (January 26, 2006) SMH.com.au (http://smh.com.au/news/mind-matters/to-sniff-at-danger/2006/01/12/1136956247384.html) 'To sniff at danger: Inhalable oxytocin could become a cure for social fears', Boston Globe (January 12, 2006) 'Cuddle chemical' could treat mental illness (http://www.newscientist.com/channel/being-human/ mg19826561.900-cuddle-chemical-could-treat-mental-illness.html) (14 May 2008) New Scientist Molecular neurobiology of social bonding: Implications for autism spectrum disorders (http://videocast.nih. gov/Summary.asp?File=15521) a lecture by Prof. Larry Young, Jan. 4, 2010. A TED talk by Prof.Paul Zak on Trust,Morality & Oxytocin (http://www.ted.com/talks/ paul_zak_trust_morality_and_oxytocin.html)

Cocaine and amphetamine regulated transcript

529

Cocaine and amphetamine regulated transcript

CART prepropeptide
Identifiers Symbol CARTPT Entrez HUGO OMIM RefSeq 9607 [1] [2] [3] [4]

24323

602606

NM_004291

UniProt Q16568 [5] Other data Locus Chr. 5 q13.2 [6]

CART

cocaine and amphetamine regulated transcript Identifiers Symbol Pfam InterPro SCOP SUPERFAMILY CART PF06373 [7] [8]

IPR009106 1hy9 1hy9 [9] [10]

Available protein structures: Pfam PDB structures [11] [12] ; PDBe [13]

RCSB PDB

PDBsum structure summary [14]

Cocaine and amphetamine regulated transcript Cocaine and amphetamine regulated transcript also known as CART is a protein that in humans is encoded by the CARTPT gene.[][] CART appears to have roles in reward, feeding, and stress,[15] and it has the functional properties of an endogenous psychostimulant.[]

530

Function
CART is a neuropeptide that also serves as a neurotransmitter. It produces similar behaviour in animals to cocaine and amphetamine, but conversely blocks the effects of cocaine when they are co-administered. The peptide is found in several areas, among them the ventral tegmental area (VTA) of the brain. When CART is injected into rat VTA, increased locomotor activity is seen, which is one of the signs of "central stimulation" caused by substances such as cocaine and amphetamine. The rats also tended to return to the place where they had been injected. This is called conditioned place preference and is seen after injection of cocaine. CART is found at the same locations where cocaine and methamphetamine mainly act in the brain. This has led to speculation that CART could be an "endogenous cocaine".[] CART peptides, in particular, CART (55102), seem to have an important function in the regulation of energy homeostasis, and interact with several central appetite circuits. CART expression is regulated by several peripheral peptide hormones involved in appetite regulation, including leptin,[] cholecystokinin and ghrelin,[] with CART and cholecystokinin having synergistic effects on appetite regulation.[] CART is released in response to repeated dopamine release in the nucleus accumbens, and may regulate the activity of neurons in this area.[] CART production is upregulated by CREB,[] a protein thought to be involved with the development of drug addiction, and CART may be an important therapeutic target in the treatment of stimulant abuse.[][][16]

Tissue distribution
CART is an anorexigenic peptide and is widely expressed in both the central and peripheral nervous systems, particularly concentrated in the hypothalamus.[] CART is outside of the nervous system also expressed in pituitary endocrine cells, adrenomedullary cells, islet somatostatin cells, and in rat antral gastrin cells.[]

Clinical significance
Studies of CART (54102) action in rat lateral ventricle and amygdala suggest that CART play a role in anxiety-like behavior, induced by ethanol withdrawal in rats.[] Studies on CART knock-out mice indicates that CART modulates the locomotor, conditioned place preference and cocaine self-administration effect of psychostimulants. This suggests a positive neuromodulatory action of CART on psychostimulants effect on rat.[] CART is altered in the ventral tegmental area of cocaine overdose victims, and a mutation in the CART gene associates with alcoholism.[] CART peptides are inhibitors of food intake (anorexigenic) and closely associated with leptin and neuropeptide Y, two important food intake regulators. CART hypoactivity in the hypothalamus of depressed animals is associated with hyperphagia and weight gain.[][] CART peptides are also involved in fear and startle behavior.[] CART is thought to play a key role in the opioid mesolimbic dopamine circuit that modulates natural reward processes.[17]

History
CART was found by examining changes in the brain following cocaine or amphetamine administration. CART mRNA increased with cocaine administration. One of the goals was to find an endogenous anorexigenic substance. CART inhibited rat food intake by as much as 30 percent. When naturally-occurring CART peptides were blocked by means of injecting antibodies to CART, feeding increased. This led to suggestions CART may play a role though not being the only peptide - in satiety. In the end of 1980s, researchers started to synthesize cocaine-like and CART-like-acting substances in order to find medications that could affect eating disorders as well as cocaine abuse.

Cocaine and amphetamine regulated transcript These cocaine-like substances are called phenyltropanes.[]

531

CART Receptor
The putative receptor target for CART has not yet been identified as of 2011, however in vitro studies strongly suggest that CART binds to a specific G protein-coupled receptor coupled to Gi/Go, resulting in increased ERK release inside the cell.[][][][18] Several fragments of CART have been tested to try and uncover the pharmacophore,[][] but the natural splicing products CART 55102 and CART 62102 are still of highest activity, with the reduced activity of smaller fragments thought to indicate that a compact structure retaining all three of CART's disulphide bonds is preferred.[]

References
[1] [2] [3] [4] [5] [6] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& amp;cmd=retrieve& amp;dopt=default& amp;list_uids=9607& rn=1 http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=24323 http:/ / www. omim. org/ 602606 http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?Submit=Submit& position=NM_004291& rn=1 http:/ / www. uniprot. org/ uniprot/ Q16568 http:/ / omim. org/ search?index=geneMap& search=5q13. 2

[7] http:/ / pfam. sanger. ac. uk/ family?acc=PF06373 [8] http:/ / www. ebi. ac. uk/ interpro/ entry/ IPR009106 [9] http:/ / scop. mrc-lmb. cam. ac. uk/ scop/ search. cgi?tlev=fa;& amp;pdb=1hy9 [10] http:/ / supfam. org/ SUPERFAMILY/ cgi-bin/ search. cgi?search_field=1hy9 [11] http:/ / pfam. sanger. ac. uk/ family/ PF06373?tab=pdbBlock [12] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=PfamIdQuery& pfamID=PF06373 [13] http:/ / www. ebi. ac. uk/ pdbe-srv/ PDBeXplore/ pfam/ ?pfam=PF06373 [14] http:/ / www. ebi. ac. uk/ thornton-srv/ databases/ cgi-bin/ pdbsum/ GetPfamStr. pl?pfam_id=PF06373

External links
cocaine- and amphetamine-regulated transcript protein (http://www.nlm.nih.gov/cgi/mesh/2011/ MB_cgi?mode=&term=cocaine-+and+amphetamine-regulated+transcript+protein) at the US National Library of Medicine Medical Subject Headings (MeSH)

Capsaicin

532

Capsaicin
Capsaicin

Identifiers CAS number PubChem ChemSpider UNII EC number KEGG ChEBI ChEMBL ATC code Jmol-3D images 404-86-4 1548943 1265957
[1] [2] [3] [4]

S07O44R1ZM 206-969-8 C06866

[5]

[6]

CHEBI:3374

[7]

[8] [10]

CHEMBL294199 M02 AB01 Image 1 Properties

[9]

,N01 BX04

[11]

Molecular formula Molar mass Appearance Odor Melting point Boiling point Solubility in water Solubility

C H NO
18 27

305.41 g mol1 crystalline white powder

[12]

highly volatile and pungent 62-65C, 335-338K, 144-149F 210-220C, 483-493K, 410-428F (0.01 Torr) 0.0013 g/100 mL soluble in alcohol, ether, benzene slightly soluble in CS . HCl, petroleum
2

Structure Crystal structure monoclinic Hazards MSDS Capsaicin, Natural MSDS

[13]

Capsaicin

533
R-phrases S-phrases Main hazards NFPA 704 R24/25 S26, S36/37/39, S45 Toxic (T)

(what is: / ?) Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)

(verify)

[14]

Infobox references

Capsaicin

Heat

Above Peak (SR: 15,000,000-16,000,000)

Capsaicin (/kpse.sn/; 8-methyl-N-vanillyl-6-nonenamide, is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact. Capsaicin and several related compounds are called capsaicinoids and are produced as secondary metabolites by chili peppers, probably as deterrents against certain mammals and fungi.[15] Pure capsaicin is a volatile, hydrophobic, colorless, odorless, crystalline to waxy compound.

History
The compound[16] was first extracted (albeit in impure form) in 1816 by Christian Friedrich Bucholz (17701818).[17] He called it "capsicin," after the genus Capsicum from which it was extracted. John Clough Thresh (18501932), who had isolated capsaicin in almost pure form,[18][19] gave it the name "capsaicin" in 1876.[20] But it was Karl Micko who first isolated capsaicin in pure form in 1898.[21] Capsaicin's empirical formula (chemical composition) was first determined by E. K. Nelson in 1919; he also partially elucidated capsaicin's chemical structure.[22] Capsaicin was first synthesized in 1930 by E. Spath and S. F. Darling.[23] In 1961, similar substances were isolated from chili peppers by the Japanese chemists S. Kosuge and Y. Inagaki, who named them capsaicinoids.[24][25] In 1873 German pharmacologist Rudolf Buchheim[26] (18201879) and in 1878 the Hungarian doctor Endre Hgyes[27] stated that "capsicol" (partially purified capsaicin[28]) caused the burning feeling when in contact with mucous membranes and increased secretion of gastric juice.

Capsaicin

534

Capsaicinoids
Capsaicin is the main capsaicinoid in chili peppers, followed by dihydrocapsaicin. These two compounds are also about twice as potent to the taste and nerves as the minor capsaicinoids nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin. Dilute solutions of pure capsaicinoids produced different types of pungency; however, these differences were not noted using more concentrated solutions. Capsaicin is believed to be synthesized in the interlocular septum of chili peppers by addition of a branched-chain fatty acid to vanillylamine; specifically, capsaicin is made from vanillylamine and 8-methyl-6-nonenoyl CoA.[29][30] Biosynthesis depends on the gene AT3, which resides at the pun1 locus, and which encodes a putative acyltransferase.[31] Besides the six natural capsaicinoids, one synthetic member of the capsaicinoid family exists. Vanillylamide of n-nonanoic acid (VNA, also PAVA) is used as a reference substance for determining the relative pungency of capsaicinoids.
Capsaicinoid name Abbrev. Typical Scoville Chemical structure relative heat units amount C DHC NDHC 69% 22% 7% 1% 1% 16,000,000 15,000,000 9,100,000 8,600,000 8,600,000 9,200,000

Capsaicin Dihydrocapsaicin Nordihydrocapsaicin

Homodihydrocapsaicin HDHC Homocapsaicin Nonivamide HC PAVA

Natural function
Capsaicin is present in large quantities in the placental tissue (which holds the seeds), the internal membranes and, to a lesser extent, the other fleshy parts of the fruits of plants in the genus Capsicum. The seeds themselves do not produce any capsaicin, although the highest concentration of capsaicin can be found in the white pith of the inner wall, where the seeds are attached.[32] The seeds of Capsicum plants are predominantly dispersed by birds. The TRPV1 channel to which capsaicin binds does not respond to capsaicin and related chemicals in birds (avian vs mammalian TRPV1 show functional diversity and selective sensitivity). Chili pepper seeds consumed by birds pass through the digestive tract and can germinate later, but mammals have molar teeth, which destroy seeds and prevent them from germinating. Thus, natural selection may have led to increasing capsaicin production because it makes the plant less likely to be eaten by animals that do not help it reproduce.[33] In addition, there is evidence that capsaicin evolved as an anti-fungal agent.[34] The fungal pathogen, Fusarium, is known to infect wild chilies which reduces seed viability. Capsaicin deters the fungus, and in doing so limits this form of predispersal seed mortality. In 2006, it was discovered that the venom of a certain tarantula species activates the same pathway of pain as is activated by capsaicin, the first demonstrated case of such a shared pathway in both plant and animal anti-mammal defense.[35]

Capsaicin

535

Uses
Food
Because of the burning sensation caused by capsaicin when it comes in contact with mucous membranes, it is commonly used in food products to give them added spice or "heat" (piquancy). In high concentrations, capsaicin will also cause a burning effect on other sensitive areas of skin. The degree of heat found within a food is often measured on the Scoville scale. In some cases people enjoy the heat; there has long been a demand for capsaicin-spiced food and beverages.[36] There are many cuisines and food products featuring capsaicin such as hot sauce, salsa, and beverages. For information on treatment, see the section Treatment after exposure. It is common for people to experience pleasurable and even euphoriant effects from ingesting capsaicin. Folklore among self-described "chiliheads" attributes this to pain-stimulated release of endorphins, a different mechanism from the local receptor overload that makes capsaicin effective as a topical analgesic. In support of this theory, there is some evidence that the effect can be blocked by naloxone and other compounds that compete for receptor sites with endorphins and opiates.[37]

Medical
Capsaicin is currently used in topical ointments, as well as a high-dose dermal patch (trade name Qutenza), to relieve the pain of peripheral neuropathy such as post-herpetic neuralgia caused by shingles.[38] It may be used in concentrations of between 0.025% and 0.25%. It may be used as a cream for the temporary relief of minor aches and pains of muscles and joints associated with arthritis, simple backache, strains and sprains, often in compounds with other rubefacients.[39] The treatment typically involves the application of a topical anesthetic until the area is numb. Then the capsaicin is applied by a therapist wearing rubber gloves and a face mask. The capsaicin remains on the skin until the patient starts to feel the "heat", at which point it is promptly removed. Capsaicin is also available in large bandages (plasters) that can be applied to the back. Capsaicin creams are used to treat psoriasis as an effective way to reduce itching and inflammation.[40][41] According to animal and human studies, the oral intake of capsaicin may increase the production of heat by the body for a short time. Due to the effect on the carbohydrates breakdown after a meal, cayenne may also be used to regulate blood sugar levels.[42] Capsaicin selectively binds to a protein known as TRPV1 that resides on the membranes of pain and heat sensing neurons.[][] TRPV1 is a heat activated calcium channel, which opens between 37 and 45 C (98.6 and 113 F, respectively). When capsaicin binds to TRPV1, it causes the channel to open below 37 C (normal human body temperature), which is why capsaicin is linked to the sensation of heat. Prolonged activation of these neurons by capsaicin depletes presynaptic substance P, one of the body's neurotransmitters for pain and heat. Neurons that do not contain TRPV1 are unaffected. The result appears to be that the chemical mimics a burning sensation, the nerves are overwhelmed by the influx, and are unable to report pain for an extended period of time. With chronic exposure to capsaicin, neurons are depleted of neurotransmitters, leading to reduction in sensation of pain and blockade of neurogenic inflammation. If capsaicin is removed, the neurons recover.[43][44][citation needed] The American Association for Cancer Research reports studies suggesting capsaicin is able to kill prostate cancer and lung cancer cells by causing them to undergo apoptosis.[][45] The studies were performed on tumors formed by human prostate cancer cell cultures grown in mouse models, and showed tumors treated with capsaicin were about one-fifth the size of the untreated tumors. There have been several mouse studies conducted in Japan and China that showed natural capsaicin directly inhibits the growth of leukemic cells.[] Capsaicin may be able to trigger apoptosis in human lung cancer cells as well.[46]

Capsaicin Capsaicin is also the key ingredient in the experimental drug Adlea, which is in Phase 2 trials as a long-acting analgesic to treat post-surgical and osteoarthritic pain for weeks to months after a single injection to the site of pain.[47] Moreover, it reduces pain resulting from rheumatoid arthritis[48] as well as joint or muscle pain from fibromyalgia or other causes.

536

Less-lethal force
Capsaicin is also the active ingredient in riot control and personal defense pepper spray chemical agents. When the spray comes in contact with skin, especially eyes or mucous membranes, it is very painful, and breathing small particles of it as it disperses can cause breathing difficulty, which serves to discourage assailants. Refer to the Scoville scale for a comparison of pepper spray to other sources of capsaicin. In large quantities, capsaicin can cause death.Wikipedia:Vagueness[] Symptoms of overdose include difficulty breathing, blue skin, and convulsions.[citation needed] The large amount needed to kill an adult human and the low concentration of capsaicin in chilliesWikipedia:Vagueness make the risk of accidental poisoning by chilli consumption negligible.

Pest deterrent
Capsaicin is also used to deter mammalian pests. Specific targets of capsaicin repellants are voles, deer, rabbits, squirrels, insects and attacking dogs.[49] The first pesticide product using solely capsaicin as the active ingredient was registered with the U.S. Department of Agriculture in 1962.[49] A common example is the use of ground-up or crushed dried chili pods in birdseed to deter squirrels,[50] since birds are unaffected by capsaicin. Another example is the use of chili peppers by the Elephant Pepper Development Trust to improve crop security for rural communities in Africa. Although hot chili pepper extract is commonly used as a component of household and garden insect repellent formulas, it is not clear that the capsaicinoid elements of the extract are responsible for its repellency.[] There are manufacturers that sell a capsaicin-based gel product that is reported to be a feral-pigeon (Columba livia) deterrent from specific roosting and loafing areas. Some of these products have an EPA label and NSF approval.

Equestrian sports
Capsaicin is a banned substance in equestrian sports because of its hypersensitizing and pain relieving properties. At the show jumping events of the 2008 Summer Olympics, four horses tested positive for the substance, which resulted in disqualification.[51]

Mechanism of action
The burning and painful sensations associated with capsaicin result from its chemical interaction with sensory neurons. Capsaicin, as a member of the vanilloid family, binds to a receptor called the vanilloid receptor subtype 1 (VR1).[52] First cloned in 1997, VR1 is an ion channel-type receptor. VR1, which can also be stimulated with heat and physical abrasion, permits cations to pass through the cell membrane and into the cell when activated. The resulting depolarization of the neuron stimulates it to signal the brain. By binding to the VR1 receptor, the capsaicin molecule produces similar sensations to those of excessive heat or abrasive damage, explaining why the spiciness of capsaicin is described as a burning sensation. Early research showed capsaicin to evoke a strikingly long-onset current in comparison to other chemical agonists, suggesting the involvement of a significant rate-limiting factor.[53] Subsequently, the VR1 ion channel has been shown to be a member of the superfamily of TRP ion channels, and as such is now referred to as TRPV1 [54]. There are a number of different TRP ion channels that have been shown to be sensitive to different ranges of temperature and probably are responsible for our range of temperature sensation. Thus, capsaicin does not actually cause a

Capsaicin chemical burn, or indeed any direct tissue damage at all, when chili peppers are the source of exposure. The inflammation resulting from exposure to capsaicin is believed to be the result of the body's reaction to nerve excitement. For example, the mode of action of capsaicin in inducing bronchoconstriction is thought to involve stimulation of C fibres [55] culminating in the release of neuropeptides. Essentially, the body inflames tissues as if it has undergone a burn or abrasion and the resulting inflammation can cause tissue damage in cases of extreme exposure, as is the case for many substances that cause the body to trigger an inflammatory response.

537

Toxicity
Acute health effects
Capsaicin is a highly irritant material requiring proper protective goggles, respirators, and proper hazardous material handling procedures. Capsaicin takes effect upon skin contact (irritant, sensitizer), eye contact (irritant), ingestion, and inhalation (lung irritant, lung sensitizer).The LD50 in mice is 47.2mg/kg.[][] Painful exposures to capsaicin-containing peppers are among the most common plant-related exposures presented to poison centers.[citation needed] They cause burning or stinging pain to the skin, and if ingested in large amounts by adults or small amounts by children, can produce nausea, vomiting, abdominal pain and burning diarrhea. Eye exposure produces intense tearing, pain, conjunctivitis and blepharospasm.[] When used for weight loss in capsules, there has been a report of heart attack; this was thought to be due to excess sympathetic output.[56]

Treatment after exposure

The primary treatment is removal from exposure. Contaminated clothing should be removed and placed in airtight bags to prevent secondary exposure. For external exposure, bathing the mucous membrane surfaces that have contacted capsaicin with oily compounds such as vegetable oil, paraffin oil, petroleum jelly (Vaseline), creams, or polyethylene glycol is the most effective way to attenuate the associated discomfort;[citation needed] since oil and capsaicin are both hydrophobic hydrocarbons the capsaicin which has not already been absorbed into tissues will be picked up into solution and easily removed. Capsaicin can also be washed off the skin using soap, shampoo, or other detergents. Plain water is ineffective at removing capsaicin,[] as are vinegar, bleach, sodium metabisulfite and topical antacid suspensions.[citation needed] Capsaicin is soluble in alcohol, which can be used to clean contaminated items.[] Additionally when ingested, cold milk is an effective way to treat the burning sensation (due to caseins having a detergent effect on capsaicin[57]); and room temperature sugar solution (10%) at 20 C (68F) is almost as effective.[58] The cooling sensation may however only have a temporary effect, while drinking any beverage will enhance the burning sensation[citation needed] by spreading the Capsaicin throughout the mouth and maximizing receptors' exposure to it, making bread or white rice a better alternative. The burning sensation will slowly fade away over several hours if no actions are taken. Burning and pain symptoms can also be relieved by cooling, such as from ice, cold water, cold bottles, cold surfaces, or a flow of air from wind or a fan.[citation needed] In severe cases, eye burn might be treated symptomatically with topical ophthalmic anesthetics; mucous membrane burn with lidocaine gel. The gel from the aloe plant has also been shown to be very effective.[citation needed] Capsaicin-induced asthma might be treated with nebulized bronchodilators[citation needed] or oral antihistamines or corticosteroids.[]

Capsaicin

538

Effects of dietary consumption

Ingestion of spicy food or ground jalapeo peppers does not cause mucosal erosions or other abnormalities.[] Some mucosal microbleeding has been found after eating red and black peppers, but there was no significant difference between aspirin (used as a control) and peppers.[] The question of whether chili ingestion increases or decreases risk of stomach cancer is unresolved: a study of Mexican patients found self-reported capsaicin intake levels associated with increased stomach cancer rates (however, this is very likely attributed to Helicobacter pylori[]) while a study of Italians suggests eating hot peppers regularly was protective against stomach cancer.[] Carcinogenic, co-carcinogenic, and anticarcinogenic effects of capsaicin have been reported in animal studies.[][59]

Effects on weight loss and regain

There is no evidence showing that weight loss is directly correlated with ingesting capsaicin, but there is a positive correlation between ingesting capsaicin and a decrease in weight regain. The effects of capsaicin are said to cause "a shift in substrate oxidation from carbohydrate to fat oxidation".[60] This leads to a decrease in appetite as well as a decrease in food intake.[60] Even though ingestion of capsaicin causes thermogenesis, the increase in body temperature does not affect weight loss. However, both oral and gastrointestinal exposure to capsaicin increases satiety and reduces energy as well as fat intake.[61] Oral exposure proves to yield stronger reduction suggesting that capsaicin has sensory effects. Short-term studies suggest that capsaicin aids in the decrease of weight regain. However, long-term studies are limited because of the pungency of capsaicin.[62] Another recent study has suggested that the ingestion of capsaicinoids can increase levels of brown adipose tissue (BAT) through an increase in energy expenditure and oxidation caused by the capsaicin.[63]

References
Footnotes

[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=404-86-4 [2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=1548943 [3] http:/ / www. chemspider. com/ 1265957 [4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=S07O44R1ZM [5] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=206-969-8 [6] http:/ / www. kegg. jp/ entry/ C06866 [7] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=3374 [8] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL294199 [9] http:/ / www. whocc. no/ atc_ddd_index/ ?code=M02AB01 [10] http:/ / www. whocc. no/ atc_ddd_index/ ?code=N01BX04 [11] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=O%3DC%28NCc1cc%28OC%29c%28O%29cc1%29CCCC%2FC%3DC%2FC%28C%29C [12] ChemSpider - Capsaicin (http:/ / www. chemspider. com/ Chemical-Structure. 1265957. html) [13] https:/ / docs. google. com/ viewer?a=v& q=cache:0qEFkQwng5sJ:www. sciencelab. com/ msds. php?msdsId%3D9923296+ capsaiacin+ msds& hl=en& gl=us& pid=bl& srcid=ADGEESiVORhJth5_Ji4WTD0mNETNU8rIwY2C3LTNaj9MfdynWiapqmSB8w7p-TfQqYC3--kKvFWW7u9EZ5QOmriEfLKRsWPquEQtjWo1joKGpqh sig=AHIEtbSLvraa7YE_jZ4cDurp9iX-TCGPiA [14] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=443496864& page2=Capsaicin [15] What Made Chili Peppers So Spicy? (http:/ / www. npr. org/ templates/ story/ story. php?storyId=93636630) Talk of the Nation, 15 August 2008. [16] History of early research on capsaicin: Harvey W. Felter and John U. Lloyd, King's American Dispensatory (Cincinnati, Ohio: Ohio Valley Co., 1898), vol. 1, page 435. Available on-line at: Henriette's Herbal (http:/ / www. henriettesherbal. com/ eclectic/ kings/ capsicum. html).

Andrew G. Du Mez, "A century of the United States pharmocopoeia 1820-1920. I. The galenical oleoresins" (Ph.D. dissertation, University of Wisconsin, 1917), pages 111-132. Available on-line at: Archive.org (http:/ / www. archive. org/ stream/ centuryofuniteds00dumerich/ centuryofuniteds00dumerich_djvu. txt). [17] See:

Capsaicin
C. F. Bucholz (1816) "Chemische Untersuchung der trockenen reifen spanischen Pfeffers" [Chemical investigation of dry, ripe Spanish peppers], Almanach oder Taschenbuch fr Scheideknstler und Apotheker (Weimar) [Almanac or Pocket-book for Analysts (Chemists) and Apothecaries], vol. 37, pages 1-30. [Note: Christian Friedrich Bucholz's surname has been variously spelled as "Bucholz", "Bucholtz", or "Buchholz".] The results of Bucholz's and Braconnot's analyses of Capsicum annuum appear in: Jonathan Pereira, The Elements of Materia Medica and Therapeutics, 3rd U.S. ed. (Philadelphia, Pennsylvania: Blanchard and Lea, 1854), vol. 2, page 506 (http:/ / books. google. com/ books?id=IrXszQ77xhYC& pg=PA506& lpg=PA506#v=onepage& q& f=false). Biographical information about Christian Friedrich Bucholz is available in: Hugh J. Rose, Henry J. Rose, and Thomas Wright, ed.s, A New General Biographical Dictionary (London, England: 1857), vol. 5, page 186 (http:/ / books. google. com/ books?id=nNRySUejNcYC& pg=PA186& lpg=PA186#v=onepage& q& f=false). Biographical information about C. F. Bucholz is also available (in German) on-line at: Allgemeine Deutsche Biographie (http:/ / de. wikisource. org/ wiki/ ADB:Bucholtz,_Christian_Friedrich). Some other early investigators who also extracted the active component of peppers: 1. Benjamin Maurach (1816) "Pharmaceutisch-chemische Untersuchung des spanischen Pfeffers" (Pharmaceutical-chemical investigation of Spanish peppers), Berlinisches Jahrbuch fr die Pharmacie, vol. 17, pages 63-73. Abstracts of Maurach's paper appear in: (i) Repertorium fr die Pharmacie, vol. 6, page 117-119 (http:/ / books. google. com/ books?id=euo8AAAAcAAJ& pg=PA117& lpg=PA117#v=onepage& q& f=false) (1819); (ii) Allgemeine Literatur-Zeitung, vol. 4, no. 18, page 146 (http:/ / books. google. com/ books?id=rRo4AAAAMAAJ& pg=RA2-PA20-IA2& lpg=RA2-PA20-IA2#v=onepage& q& f=false) (Feb. 1821); (iii) "Spanischer oder indischer Pfeffer," System der Materia medica ... , vol. 6, pages 381-386 (http:/ / books. google. com/ books?id=jgA9AAAAcAAJ& pg=PA381& lpg=PA381#v=onepage& q& f=false) (1821) (this reference also contains an abstract of Bucholz's analysis of peppers). 2. French chemist Henri Braconnot (1817) "Examen chemique du Piment, de son principe cre, et de celui des plantes de la famille des renonculaces" (Chemical investigation of the chili pepper, of its pungent principle [constituent, component], and of that of plants of the family Ranunculus), Annales de Chemie et de Physique, vol. 6, pages 122- 131 (http:/ / books. google. com/ books?id=b2luVw2yngoC& pg=PA122#v=onepage& q& f=false). 3. Danish geologist Johann Georg Forchhammer in: Hans C. Oersted (1820) "Sur la dcouverte de deux nouveaux alcalis vgtaux" (On the discovery of two new plant alkalis), Journal de physique, de chemie, d'histoire naturelle et des arts, vol. 90, pages 173-174 (http:/ / books. google. com/ books?id=E-YPAAAAQAAJ& pg=PA173& lpg=PA174#v=onepage& q& f=false). 4. German apothecary Ernst Witting (1822) "Considerations sur les bases vegetales en general, sous le point de vue pharmaceutique et descriptif de deux substances, la capsicine et la nicotianine" (Thoughts on the plant bases in general from a pharmaceutical viewpoint, and description of two substances, capsicin and nicotine), Beitrge fr die pharmaceutische und analytische Chemie, vol. 3, pages 43ff. [18] In a series of articles, J. C. Thresh obtained capsaicin in almost pure form: J. C. Thresh (1876) "Isolation of capsaicin," The Pharmaceutical Journal and Transactions, 3rd series, vol. 6, pages 941-947; J. C. Thresh (8 July 1876) "Capsaicin, the active principle in Capsicum fruits," The Pharmaceutical Journal and Transactions, 3rd series, vol. 7, no. 315, pages 21 ff. [Note: This article is summarized in: "Capsaicin, the active principle in Capsicum fruits," The Analyst, vol. 1, no. 8, pages 148-149 (http:/ / pubs. rsc. org/ en/ Content/ ArticleLanding/ 1876/ AN/ an876010148b), (1876).]. In The Pharmaceutical Journal and Transactions, volume 7, see also pages 259ff and 473 ff and in vol. 8, see pages 187ff; Year Book of Pharmacy (1876), pages 250 and 543; J. C. Thresh (1877) "Note on Capsaicin," Year Book of Pharmacy (http:/ / www. archive. org/ stream/ yearbookofpharma1877londuoft/ yearbookofpharma1877londuoft_djvu. txt), pages 24-25; J. C. Thresh (1877) "Report on the active principle of Cayenne pepper," Year Book of Pharmacy, pages 485-488. [19] Obituary notice of J. C. Thresh: "John Clough Thresh, M.D., D. Sc., and D.P.H.," (http:/ / www. ncbi. nlm. nih. gov/ pmc/ articles/ PMC2521090/ ?page=1) The British Medical Journal, vol. 1, no. 3726, pages 1057-1058 (4 June 1932). [20] J King, H Wickes Felter, J Uri Lloyd (1905) A King's American Dispensatory. Eclectic Medical Publications (ISBN 1888483024) [21] Karl Micko (1898) "Zur Kenntniss des Capsacins" (http:/ / books. google. com/ books?id=8SbOAAAAMAAJ& pg=PA818#v=onepage& q& f=false) (On our knowledge of capsaicin), Zeitschrift fr Untersuchung der Nahrungs- und Genussmittel (Journal for the Investigation of Necessities and Luxuries), vol. 1, pages 818-829. See also: Karl Micko (1899) "ber den wirksamen Bestandtheil des Cayennespfeffers" (http:/ / books. google. com/ books?id=0zwDAAAAYAAJ& pg=PA411#v=onepage& q& f=false) (On the active component of Cayenne pepper), Zeitschrift fr Untersuchung der Nahrungs- und Genussmittel, vol. 2, pages 411-412. [22] E. K. Nelson. "The constitution of capsaicin, the pungent principle of capsicum". (http:/ / books. google. com/ books?id=Ra4UAAAAYAAJ& pg=PA1115& lpg=PA1115#v=onepage& q& f=false) J. Am. Chem. Soc. 1919, 41, 11151121. [23] Ernst Spth, Stephen F. Darling. Synthese des Capsaicins. Chem. Ber. 1930, 63B, 737743. [24] S Kosuge, Y Inagaki, H Okumura (1961). Studies on the pungent principles of red pepper. Part VIII. On the chemical constitutions of the pungent principles. Nippon Nogei Kagaku Kaishi (J. Agric. Chem. Soc.), 35, 923927; (en) Chem. Abstr. 1964, 60, 9827g. [25] (ja) S Kosuge, Y Inagaki (1962) Studies on the pungent principles of red pepper. Part XI. Determination and contents of the two pungent principles. Nippon Nogei Kagaku Kaishi (J. Agric. Chem. Soc.), 36, pp. 251 [26] Rudolf Buchheim (1873) "ber die 'scharfen' Stoffe" (On the "hot" substance), Archiv der Heilkunde (Archive of Medicine), vol. 14, pages 1ff. See also: R. Buchheim (1872) "Fructus Capsici," Vierteljahresschrift fur praktische Pharmazie (Quarterly Journal for Practical

539

Capsaicin
Pharmacy), vol. 4, pages 507ff.; reprinted (in English) in: Proceedings of the American Pharmaceutical Association, vol. 22, pages 106ff (1873). [27] Endre Hgyes, "Adatok a paprika (Capsicum annuum) lettani hatshoz" [Data on the physiological effects of the pepper (Capsicum annuum)], Orvos-termszettudumnyi trsulatot rtestje [Bulletin of the Medical Science Association] (1877); reprinted in: Orvosi Hetilap [Medical Journal] (1878), 10 pages. Published in German as: "Beitrage zur physiologischen Wirkung der Bestandtheile des Capiscum annuum (Spanischer Pfeffer)" [Contributions on the physiological effects of components of Capsicum annuum (Spanish pepper)], Archiv fr Experimentelle Pathologie und Pharmakologie, vol. 9, pages 117-130 (1878). See: http:/ / www. springerlink. com/ content/ n54508568351x051/ . [28] F.A. Flckiger, Pharmakognosie des Pflanzenreiches ( Berlin, Germany: Gaertner's Verlagsbuchhandlung, 1891). [30] I. Guzman, P.W. Bosland, and M.A. O'Connell, "Chapter 8: Heat, Color, and Flavor Compounds in Capsicum Fruit" in David R. Gang, ed., Recent Advances in Phytochemistry 41: The Biological Activity of Phytochemicals (New York, New York: Springer, 2011), pages 117-118 (http:/ / books. google. com/ books?id=--nQIHiE3QwC& pg=PA117& lpg=PA117#v=onepage& q& f=false). [36] A Perk of Our Evolution: Pleasure in Pain of Chilies (http:/ / www. nytimes. com/ 2010/ 09/ 21/ science/ 21peppers. html), New York Times, September 20, 2010 [37] Mary Ann Liebert, Inc. - The Journal of Alternative and Complementary Medicine - 8(3):341 (http:/ / www. liebertonline. com/ doi/ abs/ 10. 1089/ 10755530260128032?cookieSet=1& journalCode=acm) [39] Topical capsaicin for pain relief (http:/ / www. medicine. ox. ac. uk/ bandolier/ booth/ painpag/ Chronrev/ Analges/ CP063. html) [49] 41 [53] Geppetti, Pierangelo & Holzer, Peter (1996). Neurogenic Inflammation. CRC Press, 1996. [54] http:/ / www. genenames. org/ data/ hgnc_data. php?match=TRPV1 [55] Fuller, R. W., Dixon, C. M. S. & Barnes, P. J. (1985). Bronchoconstrictor response to inhaled capsaicin in humans. J. Appl. Physiol., 58, 10801084. PubMed, CAS, Web of Science Times Cited: 174 [56] Sayin MR, et al. A case of acute myocardial infarction due to the use of cayenne pepper pills. Wiener Klinische Wochenschrift-The Central European Journal of Medicine (2012) 124:285-287 [57] General Chemistry Online: Fire and Spice (http:/ / antoine. frostburg. edu/ chem/ senese/ 101/ features/ capsaicin. shtml) [58] Temporal effectiveness of mouth-rinsing on capsaicin mouth-burn. Christina Wu Nasrawia and Rose Marie Pangborn. http:/ / dx. doi. org/ 10. 1016/ 0031-9384(90)90067-E [60] Lejeune, Manuela P. G. M., Eva M. R. Kovacs, and Margriet S. Westerterp- Plantenga. "Effect of Capsaicin on Substrate Oxidation and Weight Maintenance after Modest Body-weight Loss in Human Subjects." British Journal of Nutrition 90.03 (2003): 651. [61] Westerterp-Plantenga, M. S., A. Smeets, and M P G. Lejeune. "Sensory and Gastrointestinal Satiety Effects of Capsaicin on Food Intake." International Journal of Obesity 29.6 (2004): 682-88. [62] Diepvens, K., K. R. Westerterp, and M. S. Westerterp-Plantenga. "Obesity and Thermogenesis Related to the Consumption of Caffeine, Ephedrine, Capsaicin, and Green Tea." AJP: Regulatory, Integrative and Comparative Physiology 292.1 (2006): R77-85. [63] Yoneshiro, Takeshi, Sayuri Aita, Yuko Kawai, Toshihiko Iwanaga, and Mayayuki Saito. "Nonpungent Capsaicin Analogs (capsinoids) Increase Energy Expenditure through the Activation of Brown Adipose Tissue in Humans." American Society for Nutrition (2012).

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Dray A (1992). "Mechanism of action of capsaicin-like molecules on sensory neurons". Life Sci. 51 (23): 175965. doi: 10.1016/0024-3205(92)90045-Q (http://dx.doi.org/10.1016/0024-3205(92)90045-Q). PMID 1331641 (http://www.ncbi.nlm.nih.gov/pubmed/1331641). Garnanez RJ, McKee LH (2001) "Temporal effectiveness of sugar solutions on mouth burn by capsaicin" IFT Annual Meeting 2001 (http://ift.confex.com/ift/2001/techprogram/paper_8185.htm) Henkin R (November 1991). "Cooling the burn from hot peppers". JAMA 266 (19): 2766. doi: 10.1001/jama.266.19.2766b (http://dx.doi.org/10.1001/jama.266.19.2766b). PMID 1942431 (http://www. ncbi.nlm.nih.gov/pubmed/1942431). Nasrawi CW, Pangborn RM (April 1990). "Temporal effectiveness of mouth-rinsing on capsaicin mouth-burn". Physiol. Behav. 47 (4): 61723. doi: 10.1016/0031-9384(90)90067-E (http://dx.doi.org/10.1016/ 0031-9384(90)90067-E). PMID 2385629 (http://www.ncbi.nlm.nih.gov/pubmed/2385629). Tewksbury JJ, Nabhan GP (July 2001). "Seed dispersal. Directed deterrence by capsaicin in chilies". Nature 412 (6845): 4034. doi: 10.1038/35086653 (http://dx.doi.org/10.1038/35086653). PMID 11473305 (http:// www.ncbi.nlm.nih.gov/pubmed/11473305). Kirifides ML, Kurnellas MP, Clark L, Bryant BP (February 2004). "Calcium responses of chicken trigeminal ganglion neurons to methyl anthranilate and capsaicin" (http://jeb.biologists.org/content/207/5/715.long). J. Exp. Biol. 207 (Pt 5): 71522. doi: 10.1242/jeb.00809 (http://dx.doi.org/10.1242/jeb.00809). PMID

Capsaicin 14747403 (http://www.ncbi.nlm.nih.gov/pubmed/14747403). Tarantula Venom, Chili Peppers Have Same "Bite," Study Finds http://news.nationalgeographic.com/news/ 2006/11/061108-tarantula-venom.html Minna M. Hamalainen, Alberto Subieta, Christopher Arpey, Timothy J. Brennan, "Differential Effect of Capsaicin Treatment on Pain-Related Behaviors After Plantar Incision," The Journal of Pain, 10,6 (2009), 637-645.

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External links
Capsaicin Technical Fact Sheet - National Pesticide Information Center (http://npic.orst.edu/factsheets/ Capsaicintech.pdf) EPA Capsaicin Reregistration Eligibility Decision Fact Sheet (http://www.epa.gov/oppsrrd1/REDs/ factsheets/4018fact.pdf) Molecule of the Month (http://www.chm.bris.ac.uk/motm/chilli/capsaicin.htm) European Commission (http://ec.europa.eu/food/fs/sc/scf/out120_en.pdf), opinion of the Scientific Committee on Food on capsaicin. Fire and Spice: The molecular basis for flavor (http://antoine.frostburg.edu/chem/senese/101/features/ capsaicin.shtml) A WikiHow article on How to Cool Chilli Pepper Burns (http://www.wikihow.com/ Cool--Burns-from-Chilli-Peppers).

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Recorder, DCDuring, DVD R W, DaemonDice, Damirgraffiti, Danger, DanielDeibler, David Johnson, DavidWestlake, Delldot, Delldot on a public computer, Delta G, Diberri, Dj Capricorn, Dmontesano, Donner60, Dr.saptarshi, ESnyder2, EdH, Edgar181, Edital, Eequor, Electric goat, Emijrp, Emurphy42, Emw, Endoman99, Eritain, Falcon8765, Favonian, Ferengi, Firsfron, Flink the blind hemophiliac, Fratrep, Fuzzform, F, GAJ, Gary King, Georgexx316, Giftlite, Golbez, Goplat, Graham87, Guitarmankev1, Gwernol, Gtz, Hairy Dude, Hazard-SJ, HelicopterBoi, Hodja Nasreddin, Hugo-cs, Hymyly, Ibuklm, Ikstau, Insomnis, JWSchmidt, Jackol, JamesMohr, Jared81, Jauhienij, Jbana, Jnc, Jncraton, Jonkerz, Josh Cherry, Julesd, Jyril, K95, KathrynLybarger, Killenheladagen, Kimchi.sg, Kingpin13, Knutux, Kpmiyapuram, Kubra, Kylowe, Lennert B, Leszek Jaczuk, Lexor, Longhair, Looie496, Lova Falk, Ltm308, Lucydong09, Luna Santin, MK8, Magnus Manske, Marc Kupper, MarcoTolo, Markus Pssel, Materialscientist, Mattycoze, Mb2012, 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Neuman, SalviaFan, Sapphic, Saric, Scarian, Scoticus, Seannyboy219, Shadowjams, ShelfSkewed, Shisha-Tom, Slowart, Smaines, Smartse, SqueakBox, St3vo, Stark1987, Subtropical-man, Subvertc, Tanevala, Tea with toast, Teles, Tgeller, TheBaur, Themfromspace, Tide rolls, Timotheus Canens, Tommy2010, Tonytross, Trainwreckwebb, Unyoyega, Verified72, Viridis Veritas, Vivio Testarossa, Vojtech.dostal, WadeSimMiser, Werson, Wicked licks, WickedSpice, WikiDao, Wormantson, X1987x, Zachjones4, Zane Russell,, 304 anonymous edits 2-Arachidonoylglycerol Source: http://en.wikipedia.org/w/index.php?oldid=557541551 Contributors: Astavats, Austinpk, Beetstra, Chem-awb, ChemNerd, ChemSpiderMan, Chemgirl131, CrowzRSA, Dcirovic, Edgar181, El Cazangero, Enix150, Jzlong, K-MUS, Kilrothi, Michal George, Panoramix303, Rhetth, Rich Farmbrough, Rjwilmsi, Roadnottaken, Shaddack, Shisha-Tom, Tanevala, WriterHound, Xasodfuih, 16 anonymous edits 2-Arachidonyl glyceryl ether Source: http://en.wikipedia.org/w/index.php?oldid=545022190 Contributors: Beetstra, Benrr101, Chem-awb, ChemSpiderMan, Chemgirl131, Cimmerian praetor, CrowzRSA, Dcirovic, Edgar181, Panoramix303, Physchim62, Rich Farmbrough, Slashme, St3vo, Tea with toast, WriterHound, 5 anonymous edits Anandamide Source: http://en.wikipedia.org/w/index.php?oldid=560167638 Contributors: .Jos, A314268, Akshatrathi294, AlexNordeen, Arcadian, Beetstra, Belizefan3000, Bendroz, Bitplane, Boghog, Cacycle, Chango369w, Chem-awb, Chemgirl131, Chempedia, Chirality, Cotard, Dcirovic, Djadvance, Doc glasgow, Drphilharmonic, Dthomsen8, Edgar181, El C, Enix150, Enomai, Eritain, Fred Bradstadt, Fvasconcellos, Gaberdine2, Gamerider, Giftlite, Gilderien, Gtz, Hertz1888, Icek, Joncolvin, Josh Parris, Jyffeh, Laminado, Lennert B, Ltnemo2000, Lumir, M7, MadSurgeon, Mahanga, MartinHarper, Max rspct, Mearlon, Mellery, Mikael Hggstrm, Mjpieters, Mykhal, Nettacog, Oatmeal batman, Olivier, Orbitalcombustion, Plastikspork, Pmallet, Reaverdrop, Redspades, RexNL, Rich Farmbrough, Rjwilmsi, Roadnottaken, Ronhirzmd, Sanders muc, Saravask, Saxbryn, Skoot13, SoCal, Sugarfish, Tanevala, Tavilis, Tea with toast, Trapezoidal, Unfree, Valera123, Van Flamm, Vjiced, Vjiced1, WriterHound, Xasodfuih, Yonskii, , 113 anonymous edits N-Arachidonoyl dopamine Source: http://en.wikipedia.org/w/index.php?oldid=554786761 Contributors: Accounting4Taste, Beetstra, Benrr101, Chem-awb, ChemNerd, Chemgirl131, Edgar181, Enix150, Nirmos, Panoramix303, PookeyMaster, Rhetth, Rich Farmbrough, Rjwilmsi, St3vo, Tea with toast, The chemistds, , 6 anonymous edits Virodhamine Source: http://en.wikipedia.org/w/index.php?oldid=545015388 Contributors: Arcadian, Beetstra, Benrr101, BlueZenith, Chem-awb, Chemgirl131, David.Throop, Drphilharmonic, Edgar181, Enix150, Natalya, Plasmic Physics, Rhetth, Rich Farmbrough, Tea with toast, WriterHound, 1 anonymous edits Oleamide Source: http://en.wikipedia.org/w/index.php?oldid=559233925 Contributors: Abductive, AxelBoldt, Beetstra, Benrr101, Chem-awb, ChemNerd, Chemgirl131, Cimmerian praetor, Drpainless, Edgar181, Ejhoekstra, Henrik, Living under a rock, Meodipt, Neoligand, Richard Taytor, Rjwilmsi, Roadnottaken, Scouse123, Skoot13, Tea with toast, WriterHound, Yikrazuul, 15 anonymous edits Palmitoylethanolamide Source: http://en.wikipedia.org/w/index.php?oldid=558760021 Contributors: AManWithNoPlan, Beetstra, Binksternet, Chemgirl131, Comatmebro, Drpainless, Drphilharmonic, Edgar181, EndoCan, Jasonwithey, Jesse V., Khazar2, Plasmic Physics, Rettitudo, Rjwilmsi, Tea with toast, Teculling, Widr, Wouterhagens, 68 anonymous edits

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O'Shea, RossBoss, Rrburke, Ryan Postlethwaite, Samboy, Sandeep.bejjam, Sayeth, Sbrools, Seans Potato Business, Seijihyouronka, Seppi333, Sharmander, Shlomke, Sifaka, SilentVocalist, Sir Nicholas de Mimsy-Porpington, Skittleys, Skizzik, Slon02, Snowolf, Sodium, Some.one.guy, Sonnejw0, Soumen sadhu, SpaceKangaroo, Spaceboy492, SteinbDJ, Stevenmitchell, Stewakyl, Strongfaithin1, Superfrumious, Tarotcards, Techelf, Teleomatic, Terry Johns, The Thing That Should Not Be, The jt, The wub, TheJJJunk, Theshibboleth, Thricecube, Tickle me gusta, Tide rolls, Tktktk, Tlesher, Tomvidar, Torzsmokus, Treybien, Tryptofish, Tunocca, Twooars, Trelio, Ugog Nizdast, Uthbrian, VGoldoni, Vanished user ikijeirw34iuaeolaseriffic, Vanv2642, Vaughan, Versus22, Viridian, Vsion, Wasted Sapience, Wavelength, West Brom 4ever, Weyes, WikHead, Wikiboyz1, William Ortiz, Wknight94, WojPob, Woodsy, Wordsmith, Wordsranch, WriterHound, XX7, Xezbeth, Xprofj, Yaramit, Yurik, Zfarhana, Zhuuu, Zill, Zonuleofzinn, kebrke, , , 720 anonymous edits Dopaminergic pathways Source: http://en.wikipedia.org/w/index.php?oldid=543469795 Contributors: Albertzeyer, Arcadian, ArcadianOnUnsecuredLoc, Bejnar, Borders999, Chris83, GregorB, Jchapple88, Mostafa Hussein, NawlinWiki, Pietro, Sannse, Tryptofish, Vaughan, WhatamIdoing, 11 anonymous edits Mesocortical pathway Source: http://en.wikipedia.org/w/index.php?oldid=542595404 Contributors: 1000Faces, Arcadian, Arjayay, Bairnfell, Brim, Bryan Derksen, Charitakis, DabMachine, Ego White Tray, Farbror Erik, Fuzzform, Kpmiyapuram, L Dopa1969, Modify, Nickwilkie, SJP, Vaughan, Ward3001, Xhaoz, 8 anonymous edits Mesolimbic pathway Source: http://en.wikipedia.org/w/index.php?oldid=559069947 Contributors: 1000Faces, Ahimsa52, Andykolandy, Arcadian, ArcadianOnUnsecuredLoc, Astavats, AzadMashari, Bomfog, Brim, Bryan Derksen, CopperKettle, DNGrimes, Fuzzform, Jonathanfu, Kpmiyapuram, Kysira, LFROTA, LetTheSunshineIn, LoVe, Looie496, Miserlou, MusicNewz, NEUROtiker, Neilc, Nickwilkie, Nmg20, Peteb4, R'n'B, Rabend, Rjwilmsi, Shisha-Tom, Sl37, Smoggyrob, Stargazer0000000, Vaughan, WhatamIdoing, Wik, Wikiauthor, 43 anonymous edits Ventral tegmental area Source: http://en.wikipedia.org/w/index.php?oldid=552749214 Contributors: Anthonyhcole, Arcadian, AxelBoldt, BD2412, Bayle Shanks, Brim, Bryan Derksen, Chinasaur, Cpt ricard, DabMachine, Drphilharmonic, Elenaschifirnet, Empyrius, Fnielsen, Gcastellanos, Gth843n, Hadal, Iamnotanorange, JeremyA, Jmcdon10, JonathanWilliford, KhunMKham, Koavf, Kpmiyapuram, LittleHow, Looie496, NifCurator1, Nucleophilic, PStrait, Peteb4, Purple Blanket, R'n'B, Saric, Updater Dan, Vaughan, Viking59, Was a bee, Wavelength, Wiccan Quagga, Wimpus, Xwdl, 57 anonymous edits Frontal lobe Source: http://en.wikipedia.org/w/index.php?oldid=559209328 Contributors: 2004-12-29T22:45Z, A314268, ABCmouse, Addshore, Alansohn, Ale jrb, Allens, Anatomist90, Angela26, Anonymaus, Anthonyhcole, Arbitrarily0, Arcadian, Ardkorjunglist, Arthena, Aunt Entropy, Bcjordan, Big Smooth, Bird, Bluefist, Booklaunch, Brighterorange, BrotherGeorge, Bryan

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Yintan, Yk Yk Yk, YnnusOiramo, Youssefsan, Zack, Zero sharp, , 605 anonymous edits Trace amine Source: http://en.wikipedia.org/w/index.php?oldid=541421533 Contributors: ASmartKid, Apd10, Arrowsmaster, BD2412, Cacycle, Chemgirl131, Closedmouth, Crystallina, Edgar181, Hu12, It Is Me Here, Jrmykrgr, M6gt2k6, Mets501, Philippe, Quantockgoblin, Scientizzle, Sole Soul, Stevereichh, Tuchomator, Xprofj, 11 anonymous edits 3-Iodothyronamine Source: http://en.wikipedia.org/w/index.php?oldid=541411976 Contributors: Arcadian, Beetstra, Chem-awb, Chemgirl131, Drphilharmonic, Edgar181, Harbinary, Jwdietrich2, Meodipt, Scientizzle, Stevereichh, 5-MeO-DMT Source: http://en.wikipedia.org/w/index.php?oldid=558050161 Contributors: ***Ria777, Aenar, Ahianx, AlleGrand, Alvis, Assassinscv, Astavats, Beetstra, Benrr101, Bobber0001, C6541, Cacycle, Casforty, Ceyockey, Ch473, Chem-awb, Chemgirl131, Chommers, DMacks, Dachannien, Danelo, David Hedlund, Dcirovic, Ddhix 2002, Deli nk, Edgar181, Eequor, Eloil, 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Shannon, Halogenated, Heah, Hede2000, James086, Jenks24, J, Kelly Martin, Lilac Soul, Louisajb, MARQUIS111, Materialscientist, Meco, Melaen, Meodipt, Mitch Ames, NTK, Nikos 1993, Ninjawailer, Nirmos, OAC, Pappa, Porkins8888, Pro bug catcher, ProxyChemist, RDBrown, Rafaelamonteiro80, Ranma9617, Raymond Keller, Rhode Island Red, Rich Farmbrough, Rich257, Rjwilmsi, Ron Delipski, STGM, Saxbryn, Sbrools, Simon Peter Hughes, Skorpion87, Sochaos, Stonemaccas, Su-no-G, Supspirit, TheBaur, Thermalite, Tillbury, Wayne Roberson, Austin, Texas, Whig, Zinnmann, , 96 anonymous edits Dimethyltryptamine Source: http://en.wikipedia.org/w/index.php?oldid=560213224 Contributors: ***Ria777, 2602:306:CEE3:AD00:49C3:337C:9462:D54A, 40ball, 4twenty42o, 62.253.64.xxx, 66.25.176.xxx, 90 Auto, 999, A bit iffy, A dullard, A purple wikiuser, ABF, AP Shinobi, ARUNKUMAR P.R, Aaron Walkhouse, Abidagus, Acather96, Achowat, AdultSwim, Aelffin, Aenar, Aeqea, Aesopos, Agrumer, Airsh0w, Aitias, Alan Rockefeller, Alansohn, AlexNordeen, AllGloryToTheHypnotoad, AlleGrand, Almo2222, Alpha19766, Amit pande, Anable, Anaxial, Andres, Anonymous anonymous, Antandrus, Anypodetos, Arbitrarily0, Arcadian, Aristotle1990, Arstchnca, Arthena, Avegab, BQmUB2010082, Backslash Forwardslash, Bdiscoe, Becritical, Beeblebrox, Beetstra, Belchfire, Ben Ben, BenKovitz, Benrt, Bento00, Beyond My Ken, Bhomas, BlackVetterr, Blakeandjustin, Blazotron, Blethering Scot, Boghog, Boing! said Zebedee, Bongwarrior, Bradenripple, Bradley.Olson, Breviksh, Brue21, Bufoman, Burpen, Byelf2007, Bytesmythe, C6541, Cacycle, Cadby Waydell Bainbrydge, Cahk, Calmer Waters, Can't sleep, clown will eat me, Capitalismojo, Captain panda, Casforty, Causa sui, Ceyockey, Charangito, ChaseAm, Ched, ChemNerd, Chemgirl131, Chemical Halo, Cheywoodward2, Chiswick Chap, Chris the speller, Chris-munch, ChrisGualtieri, Cielomobile, Clarknova, Conti, Conversion script, Cosmicgash, Creation7689, CryptoDerk, Cryptographite, DaDrought3, Dadaist6174, Dadonene89, Dan D. 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Physchim62, Quique H., RJFJR, Rajthapar, Rcorym15, Rjwilmsi, Russell E, Sbrools, Schnazola, Scientizzle, Supermood00d, Tijmz, Tkersh, Tonipares, Vogon77, Walkerma, White Ash, WiccaIrish, WriterHound, Xprofj, Zahnrad, Zoicon5, 77 anonymous edits N-Methyltryptamine Source: http://en.wikipedia.org/w/index.php?oldid=556489871 Contributors: Beetstra, Bender235, Cacycle, Chem-awb, ChemNerd, Chemgirl131, Danelo, Edgar181, Eloil, Heah, InMemoriamLuangPu, Jackjk1011, Jidanni, Malljaja, Meodipt, Morninggloryseed, Nen888, Nenwiki, Probios, R'n'B, Saxbryn, Squids and Chips, Tillbury, Use the force, Woohookitty, 7 anonymous edits Phenethylamine Source: http://en.wikipedia.org/w/index.php?oldid=557447252 Contributors: *Kat*, 00AgentBond93, Acdx, Ahoerstemeier, Aka042, Alan Liefting, Alan Rockefeller, Albmont, AlkaloidMan, Allstarecho, Ambix, ArmadniGeneral, Attys, Aurista25, Beetstra, BlueZenith, ButOnMethItIs, C.Lser, C6541, CWii, Cacycle, Calvero JP, Casconed, Casforty, Chem-awb, ChemNerd, 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Miserlou, Mixtures, Mykhal, Noctibus, Oghmoir, R'n'B, Rjwilmsi, Russell E, STGM, Sbrools, Testem, The Right Honourable, Tillbury, Todfox, Tonyrex, V8rik, WriterHound, Zachorious, Zoicon5, 85 anonymous edits 1,4-Butanediol Source: http://en.wikipedia.org/w/index.php?oldid=553780079 Contributors: AGeorgas, Albmont, Anypodetos, Apoc2400, BanyanTree, Beetstra, Benjah-bmm27, Bennybp, Brichcja, Bryan Derksen, Bryn C, C6541, Cacycle, Caerwine, Ccroberts, Chem-awb, ChemNerd, Chemgirl131, Christian75, Davemody, Dcirovic, DocScotty, Dr. Strangelove, Edgar181, EricEnfermero, Fawcett5, Firsfron, Gzornenplatz, Harbinary, HazyM, Headbomb, Itub, Jennatay, Jorgenumata, Joseph Solis in Australia, Jpers36, Kaobear, Khazar2, Klaas1978, Kst447, Louisajb, Meodipt, Mfphish, Michaelmanoff, Miserlou, Nikos 1993, Nwbeeson, Physchim62, Poccil, Puppy8800, Rada, Raffinate2, Redgolpe, Renwick, Rifleman 82, Rjwilmsi, Rob.m.baker, Rshytle, Shaddack, Silverchemist, Skyeknighton, Slashme, Smokefoot, Stone, The 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TheEgyptian, Thingg, Tim bates, Tremilux, Triona, Trusilver, Tryptofish, Twooars, TylerDurden8823, Ugen64, Useless Fodder, Uthbrian, Vineetcoolguy, Virgilio12, Vlabakje90, Vojtech.dostal, Warmfeets, Wavelength, Wawawemn, Wesley crossman, Whoop whoop pull up, Widr, Wikid77, Wimpus, Xprofj, kebrke, 339 anonymous edits Nucleus basalis of Meynert Source: http://en.wikipedia.org/w/index.php?oldid=550825785 Contributors: Cmradu, Illuminating.enigma, Khazar2, Medwikier, Nephron, Onefireuser, 2 anonymous edits Neocortex Source: http://en.wikipedia.org/w/index.php?oldid=557209497 Contributors: 4RM0, A314268, AQWIKI, Alexanderabbit, Alphathon, Arcadian, AxelBoldt, BD2412, Belizefan, Bird, Bovineone, Bryan Derksen, Can't sleep, clown will eat me, CanadianLinuxUser, Cat's Tuxedo, Ceyockey, Chris Capoccia, Colincbn, Courcelles, Cyrus.omar, DSatz, Denisarona, Diberri, Djayjp, Drphilharmonic, EncycloPetey, Encyclotadd, Fitzburgh, FlyHigh, FrozenMan, Ganymead, Gigemag76, Gleng, Gould363, Habashia, Hede2000, Israel Steinmetz, Jarble, Joebigwheel, Johnathlon, Johnuniq, Jpfagerback, Jwratner1, Ken Gallager, Kevin Murray, KryptoCleric, Ksyrie, La comadreja, LafinJack, Leptictidium, Lfrench, Looie496, M@RIX, MZMcBride, Marc Mongenet, Mmoneypenny, Mulad, Muntuwandi, NeocortexWD, NifCurator1, Nono64, Nrets, Ominus11, Patrick, Peloneous, PhineasG, Profmusic, Qvkfgmjqy, Ravi12346, Realelite, Richard Jay Morris, Rizla, RmM, Rob Hurt, RyanTMulligan, Ryu Ematsu, Sabri76, Sedate636198, Sfan00 IMG, Shirleybayer, Snhivhitavae, SoCal, Speshuldusty, Spike Wilbury, Stevenmitchell, Stevertigo, Tarcieri, Tarotcards, Theamericancliche, Tmajoor, Traveler100, Tryptofish, Verum solum, Vojtech.dostal, Volney, Vorziblix, Xenon54, Zonder, 81 anonymous edits Septal nuclei Source: http://en.wikipedia.org/w/index.php?oldid=546546737 Contributors: A314268, Arcadian, Cogpsych, Drphilharmonic, Elenaschifirnet, Eumolpo, Gleng, Harrisd5917, Jmcdon10, Mikaelcouzic, Pazda, Rob Hurt, ShelfSkewed, Stefantalpalaru, Tameamseo, Wikielwikingo, 25 anonymous edits Medial septal nucleus Source: http://en.wikipedia.org/w/index.php?oldid=434973921 Contributors: Arcadian, Bearcat, Malcolma, 1 anonymous edits Fornix of the brain Source: http://en.wikipedia.org/w/index.php?oldid=551189496 Contributors: Anatomist90, Arcadian, BerniePen, Braininfo.rprc.washington.edu, Brim, Bumm13, Capmo, CopperKettle, Dinisoe, Drizzt231, Drphilharmonic, Graoully, Handcuffed, JakobSteenberg, Jfdwolff, Jmarchn, Knowledge Seeker, Looie496, Lucifer-Psice, Lyrl, MarcoTolo, Mikael Hggstrm, Miracle Pen, NCurse, NifCurator1, Sizzlin84, Tristanb, Was a bee, 37 anonymous edits Vasoactive intestinal peptide Source: http://en.wikipedia.org/w/index.php?oldid=553683964 Contributors: Akane700, Arcadian, Bignoter, Bobjgalindo, Boghog, Brenont, Cacycle, Ceyockey, CiaranAnthony, D-rew, DarkStar7, Dcirovic, Dtrebbien, Ediacara, Ewalsh007, InvictaHOG, Jfdwolff, Mcvmccarty, Mj07x, Nakon, Naranoth, Netkinetic, Niels Olson, Nrsmoll, Prissi, R'n'B, Richardcavell, Rjwilmsi, Robodoc.at, Rogerb67, Triggtay, Whynotme1843, Widr, Wyvyrn, 33 anonymous edits Substance P Source: http://en.wikipedia.org/w/index.php?oldid=554207940 Contributors: Acdx, Adavidb, Anthonyhcole, Arcadian, Arkadiyy, BQmUB2011066, Beetstra, Bobber0001, Boghog, BrianArthurKim-GMU, CDN99, CMBJ, CWenger, Chem-awb, Chemgirl131, Chrysaor, Danio, Bibliophylax, Dcirovic, Delirium, Diberri, Drphilharmonic, Earl Moss, Ekem, Emilydia, F.chiodo, Flower-gmu, Francs2000, Fvasconcellos, Galo1969X, Gastro guy, Gt, Headbomb, Hemanshu, Interestedperson, J04n, JaGa, James McNally, Jeffq, Jeremiah, Jfdwolff, Kku, MeFaSteDo, Mijuny, Mnyakaba-GMU, Mtrnka, Naj-GMU, PFHLai, Palfrey, Paranoid, Peteb4, Pinrut, Queenabbess, R'n'B, Redmeg8, Reidtwr, Rhys, Rich Farmbrough, Rjwilmsi, Schultzbd, Seglea, Soltee, Speciate, Stevenfruitsmaak, Stillnotelf, Swithrow2546, Tarquin, Tide rolls, Tootallterri, Toyokuni3, WLU, Warut, Welumpkins, Zero sharp, 70 anonymous edits Hippocampus Source: 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Image:Atp exp.qutemol-ball.png Source: http://en.wikipedia.org/w/index.php?title=File:Atp_exp.qutemol-ball.png License: Creative Commons Attribution-ShareAlike 3.0 Unported Contributors: ALoopingIcon Image:Rossmann-fold-1g5q.png Source: http://en.wikipedia.org/w/index.php?title=File:Rossmann-fold-1g5q.png License: GNU Free Documentation License Contributors: Opabinia regalis Image:3-Iodothyronamine.svg Source: http://en.wikipedia.org/w/index.php?title=File:3-Iodothyronamine.svg License: Public Domain Contributors: Harbin file:5-MeO-DMT.svg Source: http://en.wikipedia.org/w/index.php?title=File:5-MeO-DMT.svg License: Public Domain Contributors: Harbin file:5-MeO-DMT-3d-sticks.png Source: http://en.wikipedia.org/w/index.php?title=File:5-MeO-DMT-3d-sticks.png License: Creative Commons Attribution-ShareAlike 3.0 Unported Contributors: Sbrools File:Bufo alvarius1.jpg Source: http://en.wikipedia.org/w/index.php?title=File:Bufo_alvarius1.jpg License: Public Domain Contributors: Factumquintus, Poleta33 file:Bufotenin Structural Formulae V.1.svg Source: http://en.wikipedia.org/w/index.php?title=File:Bufotenin_Structural_Formulae_V.1.svg License: Public Domain Contributors: J file:Bufotenin 27feb.gif Source: http://en.wikipedia.org/w/index.php?title=File:Bufotenin_27feb.gif License: Creative Commons Zero Contributors: ProxyChemist file:DMT.svg Source: http://en.wikipedia.org/w/index.php?title=File:DMT.svg License: Public Domain Contributors: Harbin file:Dimethyltryptamine_27feb.gif Source: http://en.wikipedia.org/w/index.php?title=File:Dimethyltryptamine_27feb.gif License: Creative Commons Zero Contributors: ProxyChemist Image:DMT biosynthetic pathway.png Source: http://en.wikipedia.org/w/index.php?title=File:DMT_biosynthetic_pathway.png License: Public Domain Contributors: --Doctorcito (talk). 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