NEUROCHEMICAL PROCESSES

DR O.B. ESAN
CONSULTANT PSYCHIATRIST
UNIVERSITY COLLEGE HOSPITAL, IBADAN
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LEARNING OBJECTIVES

 To understand
1. Neurotransmitters synthesis, storage, release and function.

2. Basic pharmacology of NTs

3. Effects of psychotropic drugs on neurotransmission

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OUTLINE

•What are Neurotransmitters

•Properties of a Neurotransmitters

•Neurotransmission

•Classification of Neurotransmitters

•Selected Neurotransmitters-Overview
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WHAT ARE NEUROTRANSMITTERS

• Neurotransmitters (NT) are endogenous chemicals that

transmit signals from a neuron to a target cell across a
synapse.
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• Release of NT usually follows arrival of an action potential

at the synapse.

• Release may also follow graded electrical potentials.

• NTs are synthesized from precursors, such as A/acids

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PROPERTIES OF A NT

1. Should be synthesized in the presynaptic neuron

2. Presynaptic terminal should contain a store of the

substance.

3. Should be localized to vesicles in the presynaptic

neuron

4. Released from the presynaptic neuron under

physiological conditions.

5. Applying the substance to a postsynaptic cell should

mimic the effects
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PROPERTIES OF A NT

6. Rapidly removed from the synaptic cleft by uptake or

degradation.

7. A drug known to block a NT should mimic this

transmitter when applied exogenously.

8. Presence of receptor on the post-synaptic neuron.

9. Binding to the receptor elicits a biological response.

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NEUROMODULATOR

• Are not NTs

• Alter the sensitivity of the synaptic membranes to

transmitter stimulation or inhibition

• Are frequently peptides

• Can act at very low concentration but have very long

duration
 NEUROTRANSMISSION

• Describes how communication occurs via chemicals i.e. NT

• NT is passed from presynaptic to postsynaptic neuron

• Receptor sites are sensitive to a particular transmitter

• Excitation or inhibition of postsynaptic neuron

• If threshold is reached, the signal is passed along.

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CLASSIFICATION OF NTS

• There are many ways to classify NTs.

• 2 common ways to classify NT
1 Chemical Classification of NTs

2 Functional Classification of NT
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CHEMICAL CLASSIFICATION OF NTS

1. Acetylcholine

2. Biogenic Amines
A.Catecholamines: Dopamine, Norepinephrine (NE), and
Epinephrine

B. Indolamines : Serotonin and histamine

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3. Amino Acids
• GABA—Gamma -amino butyric acid
• Glycine
• Aspartate
• Glutamate
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4. Neuropeptides
• Substance P ,Endorphins and Encephalin
• Somatostatin, gastrin, cholecystokinin, oxytocin,
vasopressin, Luteinizing hormone releasing hormone
(LHRH)
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• 5. Purines
• Adenosine
• ATP(Adenosine triphosphate)

• 6. Gases and Lipids

• Nitric Oxide (NO)
• Carbonmonooxide (CO)
• Cannabinoids
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FUNCTIONAL CLASSIFICATION OF NTS

1. Excitatory NT
2. Inhibitory NT
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 EXCITATORY VS INHIBITORY NT
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MORE ABOUT NTS.......

• The major NTs of the brain are Glutamic acid and GABA.

• In the brain, the monoamines & acetylcholine perform specialized

modulating functions.

• Peptides perform specialized functions in the hypothalamus brain.

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MORE ABOUT NTS.......

• Although there are many NTs in the CNS, the PNS has only two: Ach
and NE

• There are many brain NTs- Because the fnxs performed by brain NTs
are not as uniform.

• Some (like glutamate) are excitatory, whereas others (like GABA)

are primarily inhibitory.
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MORE ABOUT NTS.......

• In many cases it is the receptor which determines

whether the transmitter is excitatory or inhibitory.

• Receptors determine whether a NT acts rapidly or

slowly

• Rapidly by direct action on an ion channel (e.g.

nicotinic Ach receptors)

• Slowly, by a second-messenger system that allows for

synaptic plasticity (e.g., muscarinic Ach receptors).
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MORE ABOUT NTS.......
• Speed & mechanism of NT inactivation after the signal has been sent is
a factor in whether an NT acts rapidly or not .

• Many costs & benefits in synthesizing, transporting & recycling various

NT in the brain
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NEUROTRANSMITTERS RELEVANT TO
PSYCHIATRY
• Serotonin (5-HT)
• mood regulation, sleep, appetite, and social behavior.
• Dysregulation is linked to depression, anxiety, and OCD.

• Dopamine (DA)
• Associated with reward, motivation, pleasure, and motor control.
• Imbalances are linked to schizophrenia, Parkinson's disease, and addiction.

• Norepinephrine (NE)
• Plays a role in arousal, alertness, and the stress response.
• Linked to mood disorders such as depression and anxiety.
• Gamma-Aminobutyric Acid (GABA)
• The primary inhibitory neurotransmitter in the brain.
• Involved in anxiety regulation and implicated in anxiety disorders, epilepsy

• Glutamate
• The primary excitatory neurotransmitter.
Plays a role in learning and memory

• Acetylcholine (ACh)
• Involved in learning, memory, and attention.
• Dysfunctions are linked to Alzheimer's disease and other cognitive disorders.
• Endorphins
• Act as natural painkillers ;involved in the body's reward system.
• Linked to mood, emotional states, and experience of pain and
stress.

• Histamine
• Involved in the sleep-wake cycle, appetite regulation, and
immune response.
• Dysregulation can impact sleep disorders and allergies.
SEROTONIN

• Serotonin is synthesized from the amino acid tryptophan.

• Two key enzymes, tryptophan hydroxylase and aromatic L-amino acid

decarboxylase, facilitate the conversion of tryptophan to serotonin.
SEROTONIN

• Serotonin receptors subtypes : 7 families (5-HT1 to 5-HT7).

• 5-HT1: Inhibitory, reduces cAMP, regulates mood/anxiety.

• 5-HT2: Excitatory, increases calcium, affects mood/cognition.

• 5-HT3: Ligand-gated, fast transmission, nausea/anxiety.

• 5-HT4-7: Modulate processes like motility, memory.

• Serotonin receptors are pre- and post-synaptic.

• Presynaptic: Regulate neurotransmitter release via feedback.

• Postsynaptic: Mediate effects on target cells

SEROTONIN

• Serotonin plays a crucial role in mood regulation, anxiety, and other psychiatric
conditions.

• Selective Serotonin Reuptake Inhibitors (SSRIs) increase serotonin levels by

blocking its reuptake, used to treat depression and anxiety disorders.

• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) e.g Velanfaxine inhibit

the reuptake of both serotonin and norepinephrine, enhancing their levels to
treat depression and anxiety.

• 5-HT1A Agonists: Drugs like buspirone act as partial agonists at 5-HT1A

receptors, primarily used to treat generalized anxiety disorder.

• 5-HT2 Antagonists: Antipsychotic drugs like risperidone and olanzapine block 5-

HT2A receptor.
DOPAMINE

• Dopamine synthesis begins with the amino acid tyrosine in

dopaminergic neurons.

• Key enzymes in synthesis include tyrosine hydroxylase, which

converts tyrosine to L-DOPA.

• DOPA decarboxylase converts L-DOPA to dopamine.

• Dopamine is stored in synaptic vesicles.

• Dopamine release is calcium-dependent and occurs through

exocytosis.

• In the synaptic cleft, dopamine binds to receptors on post-synaptic

neurons or is reuptaken by Dopamine transporter (DAT)
DOPAMINE RECEPTORS

• Dopamine receptors are divided into two families: D1-like and D2-like
receptors.

• D1-like receptors (D1, D5 have excitatory effects.

• D2-like receptors (D2, D3, D4) generally have inhibitory effects.

• Pre-synaptic D2 receptors act as autoreceptors regulating dopamine

release and synthesis
• In the CNS, dopamine is involved in reward, motivation, motor control, and
mood regulation.

• Dysregulation of dopamine is linked disorders such as Parkinson's disease,

schizophrenia, and addiction.

• Antipsychotics target D2 receptors to reduce dopaminergic activity, which is

beneficial for treating schizophrenia.

• Dopamine agonists stimulate dopamine receptors and are used in treating

Parkinson's disease..
• Reuptake inhibitors inhibit DAT, increasing dopamine levels in the
synaptic cleft, and are used in some antidepressants and
psychostimulants.

• MAO inhibitors prevent the breakdown of dopamine, increasing its

availability and are used in the treatment of depression and
Parkinson's disease.

• Dopamine influences psychological processes including motivation

and pleasure.

• Various drugs manipulate dopamine levels, highlighting its

importance in health and disease
NOREPINEPHRINE (NE)

• Norepinephrine (NE) is synthesized from the amino acid

tyrosine.

• Tyrosine is converted to L-DOPA by the enzyme tyrosine

hydroxylase, the rate-limiting step in NE synthesis.

• L-DOPA is decarboxylated to dopamine.

• Dopamine is transported into synaptic vesicles and

converted to NE by dopamine β-hydroxylase.
NOREPINEPHRINE (NE)

• In the central nervous system (CNS), NE regulates mood, arousal,

attention, and stress response.

• In the peripheral nervous system (PNS), NE acts in the sympathetic

nervous system, influencing heart rate and blood pressure .

NOREPINEPHRINE (NE)

• NE acts on alpha (α) and beta (β) adrenergic receptors.

• Alpha-1 (α1) receptors are involved in vasoconstriction and increasing

peripheral resistance.

• Alpha-2 (α2) receptors act as autoreceptors, inhibiting NE release via negative

feedback.

• Beta-1 (β1) receptors are located in the heart and increase heart rate and
contractility.

• Beta-2 (β2) receptors cause bronchodilation and vasodilation in smooth

muscles.

• Beta-3 (β3) receptors are involved in lipolysis in adipose tissue.

NOREPINEPHRINE (NE)

• NE's actions are terminated by reuptake via the norepinephrine

transporter (NET).
• NE is degraded by enzymes like monoamine oxidase (MAO) and
catechol-O-methyltransferase (COMT).
• Antidepressants like SNRIs and TCAs inhibit NE reuptake, enhancing
mood and arousal.
• Beta blockers reduce NE's cardiovascular effects by blocking beta-
adrenergic receptors.
• Alpha-2 agonists like clonidine activate α2 receptors, reducing NE
release and managing hypertension .
GABA

• GABA is the main inhibitory neurotransmitter in the

central nervous system (CNS).

• Synthesized from glutamate via the enzyme glutamate

decarboxylase (GAD).

• GABA is released into the synaptic cleft in response to an

action potential, triggered by calcium ion influx.
GABA

• GABA reduces neuronal excitability throughout the nervous system.

• Thus GABA prevents over-excitation, which can lead to conditions

like seizures.

• Also plays a crucial role in regulating muscle tone.

• GABA is involved in mood regulation, anxiety, and sleep.

GABA

• GABA_A Receptors: These are ionotropic receptors forming chloride ion channels and are
fast-acting, involved in rapid inhibitory synaptic transmission.

• GABA_A Receptor Action: GABA binding opens Cl^- ion channels, causing hyperpolarization
and reducing the likelihood of neuron firing.

• GABA_B Receptors: These are metabotropic receptors coupled to G-proteins, mediating

slower, prolonged inhibitory effects.

• GABA_B Receptor Action: Activation leads to potassium channel opening, calcium channel
inhibition, hyperpolarization, and reduced neurotransmitter release.
GABA

• Benzodiazepines are positive allosteric modulators of GABA_A

receptors, enhancing GABA's inhibitory effects.

• Barbiturates enhance GABA_A receptor activity

• Baclofen is a GABA_B receptor agonist used as a muscle relaxant.

• Anxiolytics and Hypnotics Benzodiazepines are used to reduce

anxiety and promote sleep by enhancing GABA's effects.
GABA

• Gabapentin and Pregabalin: used to treat neuropathic

pain and epilepsy, modulating GABAergic
neurotransmission.

• Clinical Importance: GABAergic modulation is crucial in

treating conditions ranging from anxiety to epilepsy,
highlighting GABA's role in maintaining neural balance.
 GLUTAMATE
• Glutamate is the primary excitatory neurotransmitter in the
central nervous system.

• It is synthesized from glutamine via the enzyme glutaminase.

• Glutamate can also be produced from alpha-ketoglutarate

through glutamate dehydrogenase or transamination reactions.

• It plays a crucial role in synaptic plasticity, influencing learning and

memory.
GLUTAMATE

• Glutamate receptors are divided into ionotropic and

metabotropic categories.

• Ionotropic receptors include NMDA, AMPA, and kainate

receptors, functioning as ligand-gated ion channels.
GLUTAMATE

• Excessive glutamate activation can cause excitotoxicity, leading to neuronal damage or

death.

• Excitotoxicity is linked to neurodegenerative diseases such as Alzheimer's,

Huntington's disease, and stroke.

• The regulation of glutamate is essential for preventing neurotoxicity and maintaining

neuronal health.

• NMDA receptor antagonists, like ketamine and memantine, modulate glutamate

transmission to treat depression and Alzheimer's disease.
ACETYLCHOLINE (ACH)

• ACh is crucial in both the central and peripheral nervous systems.

• Involved in muscle activation, learning, memory, and autonomic body

functions.

• ACh is synthesized from choline and acetyl-CoA by choline

acetyltransferase (ChAT).
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• Receptor Types: ACh acts on nicotinic and muscarinic receptors.

• Nicotinic Receptors (nAChRs)

• Type: Ionotropic receptors that allow the influx of Na⁺ and Ca²⁺.

• Effect: Cause depolarization and excitation of the post-synaptic

neuron.

• Location: Found at neuromuscular junctions, autonomic ganglia, and

in the CNS.

• Functions: Involved in motor control, cognitive processes, and

autonomic functions.
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• Muscarinic Receptors (mAChRs)

• Type: Metabotropic receptors linked to G-proteins.

• Subtypes: Five subtypes (M1-M5), with M1, M3, and M5 typically

excitatory, and M2, M4 inhibitory.

• Functions: Regulate heart rate, glandular secretion, and smooth

muscle contraction.

• Degradation: ACh is rapidly broken down by acetylcholinesterase

(AChE) into choline and acetate.
BASIC PHARMACOLOGY
OF ACH

• Cholinesterase Inhibitors: Drugs like donepezil and rivastigmine enhance ACh

levels, used in Alzheimer's disease.

• Anticholinergics: Drugs like atropine and scopolamine block mAChRs, used for
motion sickness and muscle spasms.

• Nicotinic Agonists/Antagonists: Nicotine stimulates both CNS and peripheral

systems; nicotinic antagonists are used during surgery for muscle paralysis.
ENDORPHINS

• Endorphins are endogenous opioid peptides

produced in the CNS and peripheral tissues.
• They play crucial roles in pain modulation, reward,
and emotional regulation.
• Synthesized from precursor proteins, primarily
proopiomelanocortin (POMC).
• POMC undergoes enzymatic cleavage to produce
peptides, including β-endorphin.
ENDORPHINS

• β-endorphin is the most potent endorphin.

• Endorphins are stored in vesicles within neurons.

• They are released into the synaptic cleft in response

to pain, stress, or exercise.

• Calcium ions regulate the release by triggering

vesicle fusion with the presynaptic membrane.
ENDORPHINS

• Opioid Agonists: Drugs like morphine and fentanyl mimic endorphins,

providing pain relief and euphoria but risk addiction and tolerance.

• Opioid Antagonists: Naloxone and naltrexone block opioid receptors,

used in treating opioid overdose and alcohol dependence.

• Antidepressants: Some, like SSNRIs, indirectly influence endorphin

levels by modulating neurotransmitter systems involved in mood
regulation.
HISTAMINE

• Histamine is synthesized from histidine via histidine

decarboxylase.
• Stored in synaptic vesicles and mast cells.
• Histaminergic neurons are primarily in the
tuberomammillary nucleus of the hypothalamus.
• These neurons project widely throughout the central
nervous system.
• Released in response to depolarization and calcium influx.
HISTAMINE

• Modulates acetylcholine, dopamine, and serotonin systems.

• H1 Receptor: Promotes arousal, reduces sleep, involved in

vasodilation.

• H2 Receptor: Regulates gastric acid secretion.

• H3 Receptor: Acts as an autoreceptor, inhibiting histamine synthesis

and release.

• H4 Receptor: Found mainly in the immune system, involved in

inflammatory responses.
• H1 Antagonists: Used to treat allergies and motion
sickness; can cause sedation.

• H2 Antagonists: Used to reduce stomach acid in

peptic ulcers.
HISTAMINE

• Psychotropic Drug Effects: Many antipsychotics have

antihistaminergic effects, particularly H1 antagonism.
• Side Effects: H1 antagonism can lead to sedation and
weight gain.
• Therapeutic Potential - H3 Antagonists: Explored for
treating cognitive deficits in schizophrenia and
Alzheimer's.
• H3 Antagonists: Enhance histamine release and modulate
other neurotransmitter systems.
NEUROPEPTIDES

• Neuropeptides are synthesized in the neuron's cell body.

• Involved in pain modulation, mood regulation, and appetite control.

• Neuropeptides alter the activity of other neurotransmitters and

receptors.

• Neuropeptides do not easily cross the blood-brain barrier, limiting

direct therapeutic use.

• May alter the synthesis and release of neuropeptides like Substance P

and neuropeptide Y.
• Antipsychotics can affect levels and activity of
neuropeptides like neurotensin.

• Opioids directly mimic endogenous neuropeptides

like endorphins, binding to opioid receptors.

• Neuropeptides play crucial roles in neural

communication and modulation.
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Summary of the Known Major Neurotransmitters

Neurotransmitter Function Effect of Deficit Effect of Surplus
Acetylcholine Excitatory: It produces muscle contractions Paralysis; Violent muscle contractions
(ACh) and is found in the motor neurons; in the A factor associated with
hippocampus, it is involved in memory Alzheimer’s disease: levels of
formation, learning and general intellectual acetylcholine are severely
function. reduced associated with memory
impairment.
Dopamine Excitatory: involved in voluntary muscle Muscle rigidity; One factor associated with
movements, attention, learning, memory, A factor associated with schizophrenia-like symptoms
and emotional arousal and rewarding Parkinson’s disease: degeneration such as hallucinations and
sensations of neurons in the substantia nigra perceptual disorders,
that produce dopamine. addiction
Serotonin Inhibitory or excitatory: involved in mood, Anxiety, mood disorders, Autism
sexual behavior, pain perception, sleep, insomnia;
eating behavior, maintaining a normal body One factor associated with
temperature and hormonal state obsessive-compulsive disorder
and depression
Endorphins Inhibitory: regulates pain perception and Body experiences pain Body may not give adequate
involved in sexuality, pregnancy, labor, and warning about pain
positive emotions associated with aerobic
exercise—the brains natural opiates.
Norepinephrine Excitatory and inhibitory: involved in One factor associated with Anxiety
increasing heartbeat, arousal, learning, depression.
memory, and eating
GABA (gamma Inhibitory: communicates messages to Destruction of GABA-producing Sleep and eating disorders
aminobutyric acid) other neurons, helping to balance and offset neurons in Huntington’s disease
excitatory messages. It is also involved in produces tremors and loss of
allergies motor control, as well as
personality changes.

Also see Table 2.1 on page 52

1/17/08
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