NMDA

Ethnopharmacological relevance: Before modern anticonvulsive drugs were developed people in central Europe used herbal remedies to treat epilepsy. Hundreds of different plants for this indication can be found in German herbals of the 16th and 17th centuries. Here we compile these plants and discuss their use from a pharmacological perspective. Materials and methods: Nine of the most important European herbals of the 16th and 17th century including Bock (1577), Fuchs (1543), Mattioli (1590), Lonicerus (1660, 1770), Brunfels (1532), Zwinger (1696), and Tabernaemontanus (1591, 1678) were searched for terms related to epilepsy, and plants and recipes described for its treatment were documented. We then searched scientific literature for pharmacological evidence of their effectiveness. Additionally the overlapping of these remedies with those in De Materia Medica by the Greek physician Dioscorides was studied. Results: Two hundred twenty one plants were identified in the herbals to be used in the context of epilepsy. In vitro and/or in vivo pharmacological data somehow related to the indication epilepsy was found for less than 5% of these plants. Less than 7% of epilepsy remedies are in common with De Materia Medica. Conclusions: Numerous plants were used to treat epilepsy in the 16th and 17th centuries. However, few of these plants have been investigated with respect to pharmacological activity on epilepsy related targets.

The medial temporal lobe, including the entorhinal cortex, the amygdala and the hippocampus, has an important role in learning and memory, and its circuits exhibit synaptic plasticity (long-term potentiation [LTP]). The entorhinal cortex is positioned to exert a potent influence on the amygdala and the hippocampus given its extensive monosynaptic projections to both areas. We therefore studied the effects of activation of the entorhinal cortex with simultaneous recording of LTP in the hippocampus and amygdala in the anesthetized rat. Burst stimulation of the lateral entorhinal cortex induced LTP simultaneously in the basal amygdaloid nucleus and in the dentate gyrus. However, the mechanisms involved in the induction of LTP in the two areas differed. The Nmethyl-D-aspartate receptor antagonist 3-[(؎)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid delivered 1 h before LTP induction (10 mg/kg, i.p.), blocked LTP in the dentate gyrus but not in the amygdala. In addition we found that the basal amygdala as well as the dentate gyrus sustained latephase LTP (10 h) which may participate in memory encoding and/or modulation processes. Overall, the results suggest a coordinating role for the entorhinal cortex by simultaneously modulating activity and plasticity in these structures, albeit through different mechanisms. Interactive encoding of this sort is believed to endow memories with a different, more integrative, quality than when either pathway is activated alone.

A major component of consolidation theory holds that protein synthesis is required to produce the synaptic modification needed for long-term memory storage. Protein synthesis inhibitors have played a pivotal role in the development of this theory. However, these commonly used drugs have unintended effects that have prompted some to reevaluate the role of protein synthesis in memory consolidation.

This review addresses the use of high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) as affinity separation methods to characterise drugs or potential drugs-bio-polymer interactions. Targets for the development of new drugs such as enzymes (IMERs), receptors, and membrane proteins were immobilized on solid supports. After the insertion in the HPLC system, these immobilized bio-polymers were used for the determination of binding constants of specific ligands, substrates and inhibitors of pharmaceutical interest, by frontal analyses and zonal elution methods. The most used bio-polymer immobilization techniques and methods for assessing the amount of active immobilized protein are reported. Examples of increased stability of immobilized enzymes with reduced amount of used protein were shown and the advantages in terms of recovery for reuse, reproducibility and on-line high-throughput screening for potential ligands are evidenced. Dealing with the acquisition of relevant pharmacokinetic data, examples concerning human serum albumin binding studies are reviewed. In particular, papers are reported in which the serum carrier has been studied to monitor the enantioselective binding of chiral drugs and the mutual interaction between co-administered drugs by CE and HPLC. Finally CE, as merging techniques with very promising and interesting application of microscale analysis of drugs' binding parameters to immobilized bio-polymers is examined.

Enzymatically derived NO and extracellular ATP are receiving greater attention due to their role as messengers in the CNS during different physiological and pathological processes. Ionotropic (P2XR) and metabotropic (P2YR) purinergic receptors mediate ATP effects and are present throughout the body. Particularly P2XR are crucial for brain plasticity mechanisms, and are involved in the pathogenesis of different CNS illnesses. NO does not have a specific receptor and its actions are directly dependent on the production on demand by different nitric oxide synthase isoforms. NO synthesizing enzymes are present virtually in all tissues, and NO influences multifarious physiological and pathological functions. Interestingly, various are the tissue and organs modulated by both ATP and NO, such as the immune, brain and vascular systems. Moreover, direct interactions between purinergic and nitrergic mechanisms outside the CNS are well documented, with several studies also indicating that ATP and NO do participate to the same CNS functions. In the past few years, further experimental evidence supported the physiological and pathological relevance of ATP and NO direct interactions in the CNS. The aim of the present review is to provide an account of the available information on the interplay between purinergic and nitrergic systems, focussing on the CNS. The already established relevance of ATP and NO in different pathological processes would predict that the knowledge of ATP/NO cross-talk mechanisms would support pharmacological approaches toward the development of novel ATP/NO combined pharmacological agents. #

Ascorbate (vitamin C) is a vital antioxidant molecule in the brain. However, it also has a number of other important functions, participating as a co-factor in several enzyme reactions including catecholamine synthesis, collagen production and regulation of HIF-1α. Ascorbate is transported into the brain and neurons via the Sodium-dependent Vitamin C Transporter-2 (SVCT2), which causes accumulation of ascorbate within cells against a concentration gradient. Dehydroascorbic acid, the oxidized form of ascorbate, is transported via glucose transporters of the GLUT family. Once in cells, it is rapidly reduced to ascorbate. The highest concentrations of ascorbate in the body are found in the brain and neuroendocrine tissues such as adrenal, although the brain is the most difficult organ to deplete of ascorbate. Combined with regional asymmetry in ascorbate distribution within different brain areas, these facts suggest an important role for ascorbate in the brain. Ascorbate is proposed as a neuromodulator of glutamatergic, dopaminergic, cholinergic and GABAergic transmission and related behaviors. Neurodegenerative diseases typically involve high levels of oxidative stress and thus ascorbate has been posited to have potential therapeutic roles against ischemic stroke, Alzheimer's disease, Parkinson's disease and Huntingdon's disease.

A B S T R A C T Peptide and protein (P/P) drugs have been identified as showing great promises for the treatment of various neurodegenerative diseases. A major challenge in this regard, however, is the delivery of P/P drugs over the blood-brain barrier (BBB). Intense research over the last 25 years has enabled a better understanding of the cellular and molecular transport mechanisms at the BBB, and several strategies for enhanced P/P drug delivery over the BBB have been developed and tested in preclinical and clinicalexperimental research. Among them, technology-based approaches (comprising functionalized nanocarriers and liposomes) and pharmacological strategies (such as the use of carrier systems and chimeric peptide technology) appear to be the most promising ones. This review combines a comprehensive overview on the current understanding of the transport mechanisms at the BBB with promising selected strategies published so far that can be applied to facilitate enhanced P/P drug delivery over the BBB. ß

The mitochondria have several important functions in the cell. A mitochondrial dysfunction causes an abatement in ATP production, oxidative damage and the induction of apoptosis, all of which are involved in the pathogenesis of numerous disorders. This review focuses on mitochondrial dysfunctions and discusses their consequences and potential roles in the pathomechanism of neurodegenerative disorders. Other pathogenetic factors are also briefly surveyed. The second part of the review deals with the kynurenine metabolic pathway, its alterations and their potential association with cellular energy impairment in certain neurodegenerative diseases.

Development represents a critical moment for shaping adult behavior and may set the stage to disease vulnerability later in life. There is now compelling evidence that stressful experiences during gestation or early in life can lead to enhanced susceptibility for mental illness. In this paper we review the data from experimental studies aimed at investigating behavioral, hormonal, functional and molecular consequences of exposure to stressful events during prenatal or early postnatal life that might contribute to later psychopathology. The use of the newest methodology in the field and the intensive efforts produced by researchers have opened the possibility to reveal the complex, finely tuned and previously unappreciated sets of molecular interactions between different factors that are critical for neurodevelopment thus leading to important discoveries regarding perinatal life. The major focus of our work has been to revise and discuss data from animal studies supporting the role of neuronal plasticity in the long-term effects produced by developmental adversities on brain function as well as the possible implications for disease vulnerability. We believe these studies might prove useful for the identification of novel targets for more effective pharmacological treatments of mental illnesses. # Abbreviations: ABN-LG, arched-back nursing and licking/grooming; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; BDNF, brain derived neurotrophic factor; FGF-2, basic fibroblast growth factor; HPA, hypothalamus-

Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of selfmonitoring, leading to a mechanistic explanation for firstrank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia.

Modifications of neuronal circuits allow the brain to adapt and change with experience. This plasticity manifests during development and throughout life, and can be remarkably long lasting. Evidence has linked activity-regulated gene expression to the long-term structural and electrophysiological adaptations that take place during developmental critical periods, learning and memory, and alterations to sensory map representations in the adult. In all these cases, the cellular response to neuronal activity integrates multiple tightly coordinated mechanisms to precisely orchestrate long-lasting, functional and structural changes in brain circuits. Experience-dependent plasticity is triggered when neuronal excitation activates cellular signaling pathways from the synapse to the nucleus that initiate new programs of gene expression. The protein products of activity-regulated genes then work via a diverse array of cellular mechanisms to modify neuronal functional properties. Synaptic stre...

Occurring both peripherally and centrally, the kynurenine pathway (KP) -an alternative pathway to 5-HT synthesis from tryptophan (TRP) -could be of particular value to better understand the link between peripheral changes of circulating levels of glucocorticoids (GC)/proinflammatory cytokines and altered neurotransmission observed in depressed patients. Indeed, it is activated by these mediators of stress and can produce several neuroactive compounds like quinolinic acid (QUIN) and kynurenic acid (KYNA) that can respectively increase and decrease glutamate concentration in brain. In order to characterize the role of both the peripheral and cerebral KP in the pathophysiology of depressive disorders, we used the Unpredictable Chronic Mild Stress (UCMS) to induce a depressive-like syndrome and we then measured the level of relevant TRP-KYN pathway metabolites: KYN, 3-hydroxykynurenine (3HK; precursor of QUIN) and KYNA. We also measured TRP-5HT pathway metabolites: TRP, 5-HT, 5-HIAA. We showed that UCMS increased TRP catabolism along the KP in the periphery. 5-HT and KYN were found to be strongly negatively correlated in all brain structures of control mice and of UCMS mice except in the hippocampus. More importantly we found that KYN was preferentially metabolized along the QUIN pathway at the subcortical level (amygdala/striatum) whereas, at the cortical level (cingulate cortex), the QUIN pathway was reduced. Considering the role of these metabolites on the glutamatergic neurotransmission, we propose that such KP alterations could participate to the cortical/subcortical glutamatergic alterations reported in depressed patients.

The safe use of grasspea (Lathyrus sativus) and allied species (L. cicera, L. clymenum and L. ochrus) requires a better understanding of the factors that are involved in the development of neurolathyrism. A suitable animal model is needed. The nutritional quality, seed chemical composition, the role of malnutrition, synergistic action of antinutritional factors, the toxicity of both seed and forage to animals, metabolism and tissue distribution of the toxic amino acid beta-N-oxalyl-alpha,beta-L-diaminopropionic acid (ODAP) in mammals are reviewed. Malnutrition is not necessary for the development of neurolathyrism, however, the supply of sulfur amino acids by Lathyrus spp. is limited by the combined action of several antinutritional factors and the low inherent levels in the seeds. Metabolism or excretion of ODAP and clearance from the central nervous system appear to function well under normal circumstances, while species differences exist. Interruptions to these processes and excessive concurrent demands for reduced sulfur amino acids are likely to be conducive to the onset of neurotoxicity.

Endocannabinoids are endogenous agonists of cannabinoid receptors, and comprise amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol are the best-studied members of this class of lipid mediators, and it is now widely accepted that their in vivo concentration and biological activity are largely dependent on a ''metabolic control.'' Therefore, the proteins that synthesize, transport and degrade endocannabinoids, and that together with the target receptors form the so-called ''endocannabinoid system,'' are the focus of intense research. This new system will be presented in this review, in order to put in a better perspective the impact of its modulation on Huntington's disease. In particular, the effect of agonists/antagonists of endocannabinoid receptors, or of inhibitors of endocannabinoid metabolism, will be discussed in the context of onset and progression of Huntington's disease, and will be compared with other neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, and amyotropic lateral sclerosis. Also the plastic changes of endocannabinoids in multiple sclerosis will be reviewed, as a paradigm of their impact in neuroinflammatory disorders. #

Several selective antagonists for adenosine A 2A receptors (A 2A R) are currently under evaluation in clinical trials (phases I to III) to treat Parkinson's disease, and they will probably soon reach the market. The usefulness of these antagonists has been deduced from studies demonstrating functional interactions between dopamine D 2 and adenosine A 2A receptors in the basal ganglia. At present it is believed that A 2A R antagonists can be used in combination with the dopamine precursor L-DOPA to minimize the motor symptoms of Parkinson's patients. However, a considerable body of data indicates that in addition to ameliorating motor symptoms, adenosine A 2A R antagonists may also prevent neurodegeneration. Despite these promising indications, one further issue must be considered in order to develop fully optimized anti-parkinsonian drug therapy, namely the existence of receptor (hetero)dimers/oligomers of G protein-coupled receptors, a topic currently the focus of intense debate within the scientific community. Dopamine D 2 receptors (D 2 Rs) expressed in the striatum are known to form heteromers with A 2A adenosine receptors. Thus, the development of heteromer-specific A 2A receptor antagonists represents a promising strategy for the identification of more selective and safer drugs.

This review focuses on the remodeling of brain circuitry associated with epilepsy, particularly in excitatory glutamate and inhibitory GABA systems, including alterations in synaptic efficacy, growth of new connections, and loss of existing connections. From recent studies on the kindling and status epilepticus models, which have been used most extensively to investigate temporal lobe epilepsy, it is now clear that the brain reorganizes itself in response to excess neural activation, such as seizure activity. The contributing factors to this reorganization include activation of glutamate receptors, second messengers, immediate early genes, transcription factors, neurotrophic factors, axon guidance molecules, protein synthesis, neurogenesis, and synaptogenesis. Some of the resulting changes may, in turn, contribute to the permanent alterations in seizure susceptibility. There is increasing evidence that neurogenesis and synaptogenesis can appear not only in the mossy fiber pathway in the hippocampus but also in other limbic structures. Neuronal loss, induced by prolonged seizure activity, may also contribute to circuit restructuring, particularly in the status epilepticus model. However, it is unlikely that any one structure, plastic system, neurotrophin, or downstream effector pathway is uniquely critical for epileptogenesis. The sensitivity of neural systems to the modulation of inhibition makes a disinhibition hypothesis compelling for both the triggering stage of the epileptic response and the long-term changes that promote the epileptic state. Loss of selective types of interneurons, alteration of GABA receptor configuration, and/or decrease in dendritic inhibition could contribute to the development of spontaneous seizures.

Major depression and chronic pain are significant health problems that seriously impact the quality of life of affected individuals. These diseases that individually are difficult to treat often co-exist, thereby compounding the patient's disability and impairment as well as the challenge of successful treatment. The development of efficacious treatments for these comorbid disorders requires a more comprehensive understanding of their linked associations through common neuromodulators, such as tumor necrosis factor-α (TNFα), and various neurotransmitters, as well as common neuroanatomical pathways and structures, including the hippocampal brain region. This review discusses the interaction between depression and chronic pain, emphasizing the fundamental role of the hippocampus in the development and maintenance of both disorders. The focus of this review addresses the hypothesis that hippocampal expressed TNFα serves as a therapeutic target for management of chronic pain and maj...

Neurodegenerative diseases constitute a worldwide health problem. Metals like iron and copper are essential for life, but they are also involved in several neurodegenerative mechanisms such as protein aggregation, free radical generation and oxidative stress.

Evidence for an important link between sensitization of midbrain dopamine (DA) neuron reactivity and enhanced self-administration of amphetamine and cocaine has been reported. To the extent that exposure to nicotine also sensitizes nucleus accumbens DA reactivity, it is likely that it will also impact subsequent drug taking. It is thus necessary to gain an understanding of the long-term effects of exposure to nicotine on nicotinic acetylcholine receptors (nAChRs), neuronal excitability and behavior. A review of the literature is presented in which different regimens of nicotine exposure are assessed for their effects on upregulation of nAChRs, induction of LTP in interconnected midbrain nuclei and development of long-lasting locomotor and DA sensitization. Exposure to nicotine upregulates nAChRs and nAChR currents and produces LTP of excitatory inputs to midbrain DA neurons. These effects appear in the hours to days following exposure. Exposure to nicotine also leads to long-lasting sensitization of nicotine's nucleus accumbens DA and locomotor activating effects. These effects appear days to weeks after drug exposure. A model is proposed in which nicotine exposure regimens that produce transient nAChR upregulation and LTP consequently produce long-lasting sensitization of midbrain DA neuron reactivity and nicotine-induced behaviors. These neuroadaptations are proposed to constitute critical components of the mechanisms underlying the initiation, maintenance and escalation of drug use.

The corticostriatal pathway provides most of the excitatory glutamatergic input into the striatum and it plays an important role in the development of the phenotype of Huntington's disease (HD). This review summarizes results obtained from genetic HD mouse models concerning various alterations in this pathway. Evidence indicates that dysfunctions of striatal circuits and cortical neurons that make up the corticostriatal pathway occur during the development of the HD phenotype, well before there is significant neuronal cell loss. Morphological changes in the striatum are probably primed initially by alterations in the intrinsic functional properties of striatal medium-sized spiny neurons. Some of these alterations, including increased sensitivity of N-methyl-d-aspartate receptors in subpopulations of neurons, might be constitutively present but ultimately require abnormalities in the corticostriatal inputs for the phenotype to be expressed. Dysfunctions of the corticostriatal pathway are complex and there are multiple changes as demonstrated by significant age-related transient and more chronic interactions with the disease state. There also is growing evidence for changes in cortical microcircuits that interact to induce dysfunctions of the corticostriatal pathway. The conclusions of this review emphasize, first, the general role of neuronal circuits in the expression of the HD phenotype and, second, that both cortical and striatal circuits must be included in attempts to establish a framework for more rational therapeutic strategies in HD. Finally, as changes in cortical and striatal circuitry are complex and in some cases biphasic, therapeutic interventions should be regionally specific and take into account the temporal progression of the phenotype.

Cannabinoids recently have been shown to control the cell survival/death decision. Thus, cannabinoids induce growth arrest or apoptosis in a number of transformed neural and non-neural cells in culture. In addition, cannabinoid administration induces regression of malignant gliomas in rodents by a mechanism that may involve sustained ceramide generation and extracellular signal-regulated kinase activation. In contrast, most of the experimental evidence indicates that cannabinoids may protect normal neurons from toxic insults, such as glutamatergic overstimulation, ischaemia, and oxidative damage. Regarding immune cells, low doses of cannabinoids may enhance proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis. The potential therapeutic applications of these findings are discussed. D

Adolescence is a period of significant neurobiological change that occurs as individuals transition from childhood to adulthood. Because the nervous system is in a relatively labile state during this stage of development, it may be especially sensitive to experience-induced plasticity. One such experience that is relatively common to adolescents is the exposure to drugs of abuse, particularly alcohol and psychostimulants. In this review, we highlight recent findings on the long-lasting effects of exposure to these drugs during adolescence in humans as well as in animal models. Whenever possible, our focus is on studies that use comparison groups of adolescent-and adult-exposed subjects as this is a more direct test of the hypothesis that adolescence represents a period of enhanced vulnerability to the effects of drug-induced plasticity. Lastly, we suggest areas of future investigation that are needed and methodological concerns that should be addressed.

Objectives –  Parkinson’s disease (PD) may be associated with increased energy metabolism in overactive regions of the basal ganglia. Therefore, we hypothesized that treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist memantine would decrease regional cerebral blood flow (rCBF) and oxygen metabolism in the basal ganglia of patients with early-stage PD.Methods –  Quantitative positron emission tomography (PET) recordings were obtained with [15O]water and [15O]oxygen in 10 patients, scanned first in a baseline condition, and again 6 weeks after treatment with a daily dose of 20 mg memantine. Dynamic PET data were analyzed using volume of interest and voxel-based approaches.Results –  The treatment evoked rCBF decreases in basal ganglia, and in several frontal cortical areas. The regional cerebral metabolic rate of oxygen (rCMRO2) did not decrease in any of the a priori defined regions, and consequently the oxygen extraction fraction was increased in these regions. Two peaks of significantly decreased rCMRO2 were detected near the frontal poles in both hemispheres, using a posteriori voxel-based analysis.Conclusions –  Although we did not find the predicted decrease in basal ganglia oxygen consumption, our data suggest that treatment with memantine actively modulates neuronal activity and/or hemodynamic response in basal ganglia of PD patients. This finding may be relevant to the putative neuroprotective properties of NMDAR antagonists.

The new '5-HT' hypothesis of depression: Cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression This paper reviews the body of evidence that not only tryptophan and consequent 5-HT depletion, but also induction of indoleamine 2,3-dioxygenase (IDO) and the detrimental effects of tryptophan catabolites (TRYCATs) play a role in the pathophysiology of depression. IDO is induced by interferon (IFN)γ, interleukin-6 and tumor necrosis factor-α, lipopolysaccharides and oxidative stress, factors that play a role in the pathophysiology of depression. TRYCATs, like kynurenine and quinolinic acid, are depressogenic and anxiogenic; activate oxidative pathways; cause mitochondrial dysfunctions; and have neuroexcitatory and neurotoxic effects that may lead to neurodegeneration. The TRYCAT pathway is also activated following induction of tryptophan 2,3-dioxygenase (TDO) by glucocorticoids, which are elevated in depression. There is evidence that activation of IDO reduces plasma tryptophan and increases TRYCAT synthesis in depressive states and that TDO activation may play a role as well. The development of depressive symptoms during IFNαbased immunotherapy is strongly associated with IDO activation, increased production of detrimental TRYCATs and lowered levels of tryptophan. Women show greater IDO activation and TRYCAT production following immune challenge than men. In the early puerperium, IDO activation and TRYCAT production are associated with the development of affective symptoms. Clinical depression is accompanied by lowered levels of neuroprotective TRYCATs or increased levels or neurotoxic TRYCATs, and lowered plasma tryptophan, which is associated with indices of immune activation and glucocorticoid hypersecretion. Lowered tryptophan and increased TRYCATs induce T cell unresponsiveness and therefore may exert a negative feedback on the primary inflammatory response in depression. It is concluded that activation of the TRYCAT pathway by IDO and TDO may be associated with the development of depressive symptoms through tryptophan depletion and the detrimental effects of TRYCATs. Therefore, the TRYCAT pathway should be a new drug target in depression. Direct inhibitors of IDO are less likely to be useful drugs than agents, such as kynurenine hydroxylase inhibitors; drugs which block the primary immune response; compounds that increase the protective effects of kynurenic acid; and specific antioxidants that target IDO activation, the immune and oxidative pathways, and 5-HT as well.

One of the most consistent genetic findings to have emerged from bipolar disorder genome wide association studies (GWAS) is with CACNA1C, a gene that codes for the α(1C) subunit of the Ca(v)1.2 voltage-dependent L-type calcium channel (LTCC). Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders, as well as changes in brain function and structure in control subjects who have no diagnosable psychiatric illness. These data are consistent with a continuum of shared neurobiological vulnerability between diverse-Diagnostic and Statistical Manual (DSM) defined-neuropsychiatric diseases. While involved in numerous cellular functions, Ca(v)1.2 is most frequently implicated in coupling of cell membrane depolarization to transient increase of the membrane permeability for calcium, leading to activation and, potentially, changes in intracellular signaling pathway activity, gene transcription, and synaptic plasticity. Ca(v)1.2 is involv...

Animals made dependent via an ethanol (ETOH)-containing liquid diet (6% v/v) for 14 days were subjected to a contextual fear conditioning paradigm 3 days after the last consumption day. After conditioning, rats were subjected to four extinction trials by exposing the animals to the conditioned context and their freezing was evaluated for each trial. Immediately after the first extinction trial, animals were injected with D-cycloserine (DCS) 5 mg/kg i.p., a dose that did not influence the extinction in control rats. Spontaneous recovery of learned fear was tested seven days after the last extinction trial. The following day, animals were subjected to a reacquisition or a reinstatement procedure and their freezing responses evaluated 24 h later. The present study shows that: 1. discontinuation from chronic ETOH administration facilitated the formation of a new fear memory concomitant with a marked resistance to being extinguished, 2. administration of DCS (5 mg/kg) facilitated the extinction process only in ETOH withdrawn rats, 3. both reinstatement and reacquisition procedures restored the increased freezing in ETOH withdrawn animals after extinction, 4. DCS administered immediately after the first extinction trial prevented the increase in freezing following both reacquisition and reinstatement. The enhanced sensitivity to the facilitatory effect of DCS in ETOH withdrawn animals may be mediated by adaptive changes in N-methyl-D-aspartate (NMDA) receptor provoked by ETOH dependence.

The present study was done to determine if estrogen interacts with excitatory and / or inhibitory amino acid neurotransmitters to alter neuronal excitability within the parabrachial nucleus (PBN) and modulate autonomic tone. First, the role of estrogen in modulating autonomic tone was investigated in male rats anesthetized with Inactin (100 mg / kg). Animals were instrumented to record blood pressure, heart rate, vagal parasympathetic and renal sympathetic nerve activities as well as baroreflex sensitivity. Direct, bilateral injection of 17b-estradiol (0.5 mM; 200 nl / side) into the PBN resulted in a significant decrease in blood pressure (1764 mmHg), sympathetic tone (2065%) and heart rate (2265 beats / min) while increasing parasympathetic tone (3464%) 30 min post-injection. These estrogeninduced effects were completely blocked by the co-injection of estrogen with the estrogen receptor antagonist, ICI 182,780 (20 mM; 200 nl / side). Co-injection of the NMDA receptor antagonist, (6)-3-(2-carboxypiperazine-4-yl) propyl-1-phosphonic acid (CPP; 10 mM; 200 nl / side), with estradiol resulted in complete blockade of the estrogen-induced decrease in heart rate and increase in parasympathetic tone only. Co-injection of estradiol with the GABA receptor antagonist, (1)-bicuculline (0.1 mM; 200 nl / side), resulted in complete blockade A of the estrogen-induced decrease in blood pressure and sympathetic nerve activity only. These results suggest that estrogen acts on estrogen receptors on neurons in the PBN to modulate GABA -receptor mediated inhibitory neurotransmission to alter sympathetic tone A and blood pressure and on neurons in a separate, parallel pathway to modulate NMDA-receptor mediated neurotransmission to alter parasympathetic tone and heart rate. 

The aim of this critical review is to address that the study of cognition and antipsychotics is not always driven by logic and that research into real pro-cognitive drug treatments must be guided by a better understanding of the biochemical mechanisms underlying cognitive processes and deficits. Many studies have established that typical neuroleptic drugs do not improve cognitive impairment. Atypical antipsychotics improve cognition, but the pattern of improvement differs from drug to drug. Diminished cholinergic activity has been associated with memory impairments. Why atypical drugs improve aspects of cognition might lie in their ability to increase dopamine and acetylcholine in the prefrontal cortex. An optimum amount of dopamine activity in the prefrontal cortex is critical for cognitive functioning. Another mechanism is related to procedural learning, and would explain the quality of the practice during repeated evaluations with atypical antipsychotics due to a more balanced bl...

The superfamily of G-protein-coupled receptors (GPCRs) could be subclassified into 7 families (A, B, large N-terminal family B-7 transmembrane helix, C, Frizzled/Smoothened, taste 2, and vomeronasal 1 receptors) among mammalian species. Cloning and functional studies of GPCRs have revealed that the superfamily of GPCRs comprises receptors for chemically diverse native ligands including (1) endogenous compounds like amines, peptides, and Wnt proteins (i.e., secreted proteins activating Frizzled receptors); (2) endogenous cell surface adhesion molecules; and (3) photons and exogenous compounds like odorants. The combined use of site-directed mutagenesis and molecular modeling approaches have provided detailed insight into molecular mechanisms of ligand binding, receptor folding, receptor activation, G-protein coupling, and regulation of GPCRs. The vast majority of family A, B, C, vomeronasal 1, and taste 2 receptors are able to transduce signals into cells through G-protein coupling. However, G-protein-independent signaling mechanisms have also been reported for many GPCRs. Specific interaction motifs in the intracellular parts of these receptors allow them to interact with scaffold proteins. Protein engineering techniques have provided information on molecular mechanisms of GPCR-accessory protein, GPCR-GPCR, and GPCR-scaffold protein interactions. Site-directed mutagenesis and molecular dynamics simulations have revealed that the inactive state conformations are stabilized by specific interhelical and intrahelical salt bridge interactions and hydrophobic-type interactions. Constitutively activating mutations or agonist binding disrupts such constraining interactions leading to receptor conformations that associates with and activate G-proteins. .no (K. Kristiansen).

Glutamate excitotoxicity is associated with a wide range of neurodegenerative disorders and also seems to be involved in the pathology of demyelinating disorders such as multiple sclerosis (MS). Cuprizoneinduced toxic demyelination shows clear characteristics of MS such as demyelination and axonal damage without the involvement of the innate immune system. In this study, we have evaluated glutamate signaling during cuprizone-induced demyelination in the white and gray matter of mouse brain by studying the expression of ionotropic and metabotropic glutamate-receptors and -transporters by Affymetrix gene array analysis, followed by real-time PCR and western blot analysis. Cellular localization of glutamate transporters was investigated by fluorescence double-labeling experiments. Comparing white and gray matter areas, the expression of glutamate receptors was region-specific. Among NMDA receptor subunits, NR2A was up-regulated in the demyelinated corpus callosum (CC), whereas the metabotropic glutamate receptor mGluR2 was down-regulated in demyelinated gray matter. Glutamate-aspartate transporter (GLAST) co-localizing with GFAP + astrocytes was increased in both demyelinated CC and telencephalic cortex, whereas Slc1a4 transporter was up-regulated only in CC. Our data indicate that cuprizone treatment affects glutamate-receptors and -transporters differently in gray and white matter brain areas revealing particularly regulation of GLAST and Slc1a4 compared with other genes. This might have an important influence on brain-region selective sensitivity to neurotoxic compounds and the progression of demyelination as has been reported for MS and other demyelinating neurological diseases.

Localized cell and drug delivery to the cochlea and central auditory pathway can improve the safety and performance of implanted auditory prostheses (APs). While generally successful, these devices have a number of limitations and adverse effects including limited tonal and dynamic ranges, channel interactions, unwanted stimulation of non-auditory nerves, immune rejection, and infections including meningitis. Many of these limitations are associated with the tissue reactions to implanted auditory prosthetic devices and the gradual degeneration of the auditory system following deafness. Strategies to reduce the insertion trauma, degeneration of target neurons, fibrous and bony tissue encapsulation, and immune activation can improve the viability of tissue required for AP function as well as improve the resolution of stimulation for reduced channel interaction and improved place-pitch and level discrimination. Many pharmaceutical compounds have been identified that promote the viability of auditory tissue and prevent inflammation and infection. Cell delivery and gene therapy have provided promising results for treating hearing loss and reversing degeneration. Currently, many clinical and experimental methods can produce extremely localized and sustained drug delivery to address AP limitations. These methods provide better control over drug concentrations while eliminating the adverse effects of systemic delivery. Many of these drug delivery techniques can be integrated into modern auditory prosthetic devices to optimize the tissue response to the implanted device and reduce the risk of infection or rejection. Together, these methods and pharmaceutical agents can be used to optimize the tissuedevice interface for improved AP safety and effectiveness.

Nitric oxide (NO) is involved in many physiological processes and several lines of evidence have indicated that NO plays a complex and diverse role in the modulation of pain. Nitric oxide is an important neurotransmitter involved in the nociceptive process and, in the dorsal horn of the spinal cord, it contributes to the development of central sensitization. On the other hand, experimental data have also demonstrated that NO inhibits nociception in the peripheral and also in the central nervous system. In addition, it has been shown that nitric oxide mediates the analgesic effect of opioids and other analgesic substances. The information included in the present review aims to present and analyze data about the dual effect of NO on pain transmission and control, the molecular mechanisms involved in these effects and also the potential use of nitric oxide in pain therapy.

Glycinergic membrane responses have been described in cortical plate neurons (CPn) and Cajal-Retzius cells (CRc) during early neocortical development. In order to elucidate the functional properties and molecular identity of glycine receptors in these two neuronal cell types, we performed whole-cell patch-clamp recordings and subsequent single-cell multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) analyses on visually identified neurons in tangential and coronal slices as well as in situ hybridizations of coronal slices from neonatal rat cerebral cortex (postnatal days 0-4). In both CPn and CRc the glycinergic agonists glycine, ␤-alanine and taurine induced inward currents with larger current densities in CRc. The functional properties of these currents were similar between CPn and CRc. In both cell types the glycine receptor showed a higher affinity for glycine than for the glycinergic agonists ␤-alanine and taurine. The glycinergic responses of both cells were blocked by the glycinergic antagonist strychnine and were unaffected by the GABAergic antagonist bicuculline (100 M), the N-methyl-D-aspartic acid receptor antagonist (؎)-2-amino-5-phosphonopentatonic acid (60 M) and by picrotoxin (30 M), an antagonist of ␣ homomeric glycine receptors. Single-cell multiplex RT-PCR revealed the expression of glycine receptor ␣ 2 and ␤ subunits in CPn and CRc, while no ␣ 1 and ␣ 3 subunits were observed. In situ hybridization histochemistry showed the expression of mRNAs for ␣ 2 and ␤ subunits within the cortical plate and in large neurons of the marginal zone, while there were no signals for ␣ 1 and ␣ 3 subunits. In summary, these results suggest that CPn and CRc express glycine receptors with similar functional and pharmacological properties. The correlation of pharmacological properties and mRNA expression suggests that the glycine receptors in both cell types may consist of ␣ 2 /␤ heteromeric receptors.

Homocysteine (Hcy) has been implicated as a risk factor for vascular disease as well as brain atrophy. There is evidence to implicate Hcy in increased oxidative stress, DNA damage, the triggering of apoptosis and excitotoxicity, all important mechanisms in neurodegeneration. Hcy is also prothrombotic and proatherogenic, and causes damage to the vessel wall. It is related to brain atrophy in older individuals, and possibly to white matter hyperintensities (WMH) in the brain. Epidemiological evidence and longitudinal data support Hcy as a risk factor for cognitive impairment and Alzheimer's Disease (AD). This may be due to cerebrovascular as well as direct neurotoxic mechanisms. Its role in Parkinson Disease (PD) is less well supported. High Hcy has been suggested as a mediating factor in alcohol-related brain atrophy. The high prevalence of hyperhomocysteinemia in the population and its easy treatability make Hcy an interesting amino acid for future intervention studies in the prevention of degenerative brain disorders. Intervention studies are necessary to confirm its aetiological role. D

Tinnitus is a frequent condition without consistently effective remediation. Mr V. was a 64 year old man with Behcet's disease, a generalized systemic relapsing vasculitis. Tinnitus appeared in 1998 and he had been both aware and distressed by his tinnitus 80% of his awake time. After his last colonoscopic examination, he mentioned a transient interruption of his tinnitus. Mr V. only received propofol, an anesthesic drug that selectively down-regulates glutamatergic synaptic transmission. Amantadine, another glutamate antagonist, was later prescribed and durably suppressed tinnitus. Systematically inquiry about post-anesthesia effects on tinnitus may help decide if amantadine may be tried on an individual basis.Tinnitus is a frequent condition without consistently effective remediation. Mr V. was a 64 year old man with Behcet's disease, a generalized systemic relapsing vasculitis. Tinnitus appeared in 1998 and he had been both aware and distressed by his tinnitus 80% of his awake time. After his last colonoscopic examination, he mentioned a transient interruption of his tinnitus. Mr V. only received propofol, an anesthesic drug that selectively down-regulates glutamatergic synaptic transmission. Amantadine, another glutamate antagonist, was later prescribed and durably suppressed tinnitus. Systematically inquiry about post-anesthesia effects on tinnitus may help decide if amantadine may be tried on an individual basis.

Hedonism and pleasure are one of the main goals of human life. Pleasure can be accepted as a reward for the brain, while the major reward neurotransmitters are dopamine, norepinephrine, oxytocin and gluta-mate. Boost of dopamine in the "hedonic hot spots" creates euphoria, delight, pleasure, contentment and is associated with happiness. The reward circuitry and pleasure centers in the brain involve the ventral teg-mental area (VTA), nucleus accumbens (NA), substantia nigra (SN), ventral pallidum, insula, lateral thala-mus, cingulate cortex, hippocampus, amygdala, medial prefrontal cortex and orbitofrontal cortex. Pleasure is a learned enjoyable phenomenon and pursuing the pleasure principle is one of the crucial goals of human life. However, to some extent of pleasure, due to the release of dopamine and glutamate and the activation of D1-like excitatory dopamine receptors and NMDA receptors, may induce different forms of psychological addiction. Sexual motivation, sexual drive and orgasm also use the same reward circuitry and similar neuro-chemicals in the brain. The experience of "getting high on dopamine" has been one of the primary longstanding goals for human beings, as well as for other higher primates and animals during the normal course of evolution. Today, it is known that pleasure and sexual hedonism may even alter synaptic plasticity , and may influence a variety of psychological responses and the personality of individuals, as Sigmund Freud had pointed out a century ago.

Rationale: Valproic acid (VPA) is a psychoactive drug currently used for the treatment of epilepsy. Recently it has been introduced in psychiatry for the treatment of bipolar disorders, aggression, impulsivity, and resistant schizophrenia, although the mechanism by which VPA acts on these psychiatric diseases remains still unknown. Objectives: The aim of this study was to analyze the distinct effects of sodium-(Na-) and magnesium-valproate (Mg-VPA) in pyramidal neurons of the medial prefrontal cortex (mPFC) and their interactions with gamma-aminobutyric acid (GABA) and excitatory amino acid responses. Materials and methods: In vivo electrophysiology and microiontophoresis techniques were used to attend these goals. Results: Both VPA salts decreased spontaneous neuronal firing activity in greater than 60% of recorded pyramidal neurons as well as potentiated GABA inhibitions. When injected at equal concentrations and currents, Mg-VPA blocked the excitatory responses induced by Nmethyl-D-aspartate (NMDA) more frequently than Na-VPA. Both VPA salts equally blocked the excitatory responses of quisqualate and kainate. Conclusions: These data suggest that VPA salts significantly modulate the activity of excitatory amino acid at mPFC pyramidal neurons and this mechanism should explain the therapeutic effects of valproate in psychiatric diseases involving NMDA, AMPA, and kainate receptors at the mPFC level.

Astrocytes do not merely serve as the supporting cast and scenery against which starring roles would be played by neurons. Rather, these glial cells are intimately involved in many of the brain's functions by responding to neuronal activity and modulating it. Such interplay between two principle neural cells, neurons and astrocytes, is evidenced in bi-directional glutamatergic astrocyte-neuron signaling. A key feature in this signaling pathway is astrocytic excitability based on variations of cytosolic Ca 2+ . It enables astrocytes, through the activation of their glutamatergic receptors, to respond to the same signal used by nearby neurons in synaptic transmission. Furthermore, increases in cytosolic Ca 2+ in astrocytes can subsequently lead to Ca 2+ -dependent exocytotic secretion of gliotransmitter glutamate that in turn can signal to adjacent neurons. Astrocytic secretory machinery includes an assortment of exocytotic proteins which governs a merger of secretory vesicles to the plasma membrane. A cumulative knowledge on astrocytic excitability will aid better understanding of operating procedures in the brain in health and disease.