Glutamate And Γ-aminobutyric Acid Research Articles

Alleviation of glutamate mediated neuronal insult by piroxicam in rodent model of focal cerebral ischemia: a possible mechanism of GABA agonism.

Neurotransmitter imbalance is an inevitable outcome in cerebral ischemia that leads to neuronal death. In the present study, we evaluated the effects of piroxicam, a nonsteroidal anti-inflammatory drug (NSAID), on extracellular brain glutamate and γ-aminobutyric acid (GABA) release, survival time, and neuronal cell death. Transient focal cerebral ischemia in male Charles Foster rat led to neuronal infarction and compromised intrinsic antioxidant status. Thirty-minute preadministration of piroxicam (10 mg/kg b.w.) showed a significant (P < 0.01) reduction in cerebral infarct volume and potentiation of the intrinsic antioxidant status. High-performance liquid chromatography of brain cortex and striatum revealed changes in extracellular concentrations of neurotransmitters which were found to be 0.519 ± 0.44 pmole/mg (GABA); 1.18 ± 0.28 pmole/mg (glutamate), and 0.63 ± 0.21 pmole/mg (serotonin), respectively. Hydroxyl radical (·OH) adduct of salicylate in the frontal cortex and striatum in control, untreated, and treated groups was found to be 0.261 ± 0.06, 0.68 ± 0.52, and 0.401 ± 0.68 pmole/mg, respectively. After stroke, the extracellular level of glutamate in rat brain increases continuously as compared to that of control group. However, piroxicam administration in stroke rat significantly reduced (P < 0.05) elevated extracellular cerebral glutamate. This indicates that piroxicam attenuates extracellular glutamate release and also reduces neuronal cell death due to reduction in oxidative stress in cerebral ischemia. Our results also indicate a consequent increase of extracellular GABA in brain regions administered with piroxicam, which hints that piroxicam alleviates glutamate excitotoxicity possibly by GABA agonism.

Glutamate and GABA contributions to medial prefrontal cortical activity to emotion: Implications for mood disorders

The dorsomedial prefrontal cortex (MdPFC) and anterior cingulate cortices (ACC) play a critical role in implicit emotion regulation; however the understanding of the specific neurotransmitters that mediate such role is lacking. In this study, we examined relationships between MdPFC concentrations of two neurotransmitters, glutamate and γ-amino butyric acid (GABA), and BOLD activity in ACC during performance of an implicit facial emotion-processing task. Twenty healthy volunteers, aged 20–35 years, were scanned while performing an implicit facial emotion-processing task, whereby presented facial expressions changed from neutral to one of the four emotions: happy, anger, fear, or sad. Glutamate concentrations were measured before and after the emotion-processing task in right MdPFC using magnetic resonance spectroscopy (MRS). GABA concentrations were measured in bilateral MdPFC after the emotion-processing task. Multiple regression models were run to determine the relative contribution of glutamate and GABA concentration, age, and gender to BOLD signal in ACC to each of the four emotions. Multiple regression analyses revealed a significant negative correlation between MdPFC GABA concentration and BOLD signal in subgenual ACC (p<0.05, corrected) to sad versus shape contrast. For the anger versus shape contrast, there was a significant negative correlation between age and BOLD signal in pregenual ACC (p<0.05, corrected) and a positive correlation between MdPFC glutamate concentration (pre-task) and BOLD signal in pregenual ACC (p<0.05, corrected). Our findings are the first to provide insight into relationships between MdPFC neurotransmitter concentrations and ACC BOLD signal, and could further understanding of molecular mechanisms underlying emotion processing in healthy and mood-disordered individuals.

The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens.

Alpha7 and α4β2 nicotinic acetylcholine receptor (nAChR) agonists have been shown to improve cognition in various animal models of cognitive impairment and are of interest as treatments for schizophrenia, Alzheimer's disease, and other cognitive disorders. Increased release of dopamine (DA), acetylcholine (ACh), glutamate (Glu), and γ-aminobutyric acid (GABA) in cerebral cortex, hippocampus, and nucleus accumbens (NAC) has been suggested to contribute to their beneficial effects on cognition. Using in vivo microdialysis, we found that EVP-6124 [(R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide], a high-affinity α7 nAChR partial agonist, at 0.1mg/kg, s.c., increased DA efflux in the medial prefrontal cortex (mPFC) and NAC. EVP-6124, 0.1 and 0.3mg/kg, also increased efflux of ACh in the mPFC but not in the NAC. Similarly, EVP-6124, 0.1mg/kg, but not 0.03 and 0.3mg/kg, significantly increased mPFC Glu efflux. Thus, EVP-6124 produced an inverted U-shaped curve for DA and Glu release, as previously reported for other α7 nAChR agonists. The three doses of EVP-6124 did not produce a significant effect on GABA efflux in either region. Pretreatment with the selective α7 nAChR antagonist, methyllycaconitine (MLA, 1.0mg/kg), significantly blocked cortical DA and Glu efflux induced by EVP-6124 (0.1mg/kg), suggesting that the effects of EVP-6124 on these neurotransmitters were due to α7 nAChR agonism. MLA only partially blocked the effects of EVP-6124 on ACh efflux in the mPFC. These results suggest increased cortical DA, ACh, and Glu release, which may contribute to the ability of the α7 nAChR agonist, EVP-6124, to treat cognitive impairment and possibly other dimensions of psychopathology.

Large Conductance Calcium-Activated Potassium Channels: Their Expression and Modulation of Glutamate Release from Nerve Terminals Isolated from Rat Trigeminal Caudal Nucleus and Cerebral Cortex

Large conductance, calcium-activated potassium channels [big potassium (BK) channel] consist of a tetramer of pore-forming α-subunit and distinct accessory β-subunits (β1-4) that modify the channel's properties. In this study, we analyzed the effects of BK channel activators and blockers on glutamate and γ-aminobutyric acid (GABA) release from synaptosomes isolated from the cerebral cortices or trigeminal caudal nuclei (TCN) of rats. Real-time polymerase chain reaction was used to characterize BK channel α and β(1-4) subunit expression in the cortex and in the trigeminal ganglia (TG), whose neurons project primary terminal afferents into the TCN. Immunocytochemistry was used to localize these subunits on cortical and TCN synaptosomes. The BK channels regulating [(3)H]D-aspartate release from primary afferent nerve terminals projecting into the TCN displayed limited sensitivity to iberiotoxin, whereas those expressed on cortical synaptosomes were highly sensitive to this toxin. BK channels did not appear to be present on GABAergic nerve terminals from the TCN since [(3)H]-γ-aminobutyric acid release in this model was unaffected by BK channel activators or blockers. Gene expression studies revealed expression levels of the α subunit in the TG that were only 31.2 ± 2.1% of those found in cortical tissues. The β4 subunit was the accessory subunit expressed most abundantly in both the cortex and TG. Levels of β1 and β2 were low in both these areas although β2 expression in the TG was higher than that found in the cortex. Immunocytochemistry experiments showed that co-localization of α and β4 subunits (the accessory subunit most abundantly expressed in both brain areas) was more common in TCN synaptosomes than in cortical synaptosomes. On the basis of these findings, it is reasonable to hypothesize that BK channels expressed on glutamatergic terminals in the TCN and cortex have distinct pharmacological profiles, which probably reflect different α and β subunit combinations. Channels in the cortex seem to be composed mainly of α subunits and to a lesser degree by α and β4 subunits, whereas in the TG the α + β4 combination seems to prevail (although α and/or α + β2 channels cannot be excluded). In light of the BK channels' selective control of excitatory transmission and their pharmacological diversity, their effects on primary glutamatergic afferents projecting to TCN represent a potential target for drug therapy of migraines and other types of orofacial pain.

Schizophrenia: mechanism of action of current and novel treatments.

Article Abstract Click to enlarge page Antipsychotics are effective for managing the positive symptoms of schizophrenia. When prescribing these agents, clinicians should consider pharmacokinetics, pharmacodynamics, and the interaction between the drug and the individual patient's unique genetics, age, disease variables, and environment. All antipsychotics are D2 receptor-antagonists; however, only 1 of the 6 dopamine pathways in the brain is implicated in psychosis. Dopamine blockade in the other pathways can cause a wide range of side effects, and unfortunately, a medication cannot target only 1 dopamine pathway. Therefore, other strategies, such as agents that also act at other neurotransmitter systems, could be used to balance D2 blockade in the other 5 pathways. Aiming at a novel treatment target, N-methyl-d-aspartate (NMDA) receptors, may also help to mediate the downstream release of dopamine as well as other neurotransmitters, such as glutamate and γ-aminobutyric acid (GABA), which are thought to be involved in the pathophysiology of schizophrenia. Because noncompetitive NMDA receptor agonists, such as ketamine and phencyclidine (PCP), induce schizophrenia-like positive, negative, and cognitive symptoms, dysfunctional NMDA receptor-mediated neurotransmission in the glutamate pathway may underlie the pathogenesis of schizophrenia. From the Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks; the Department of Psychiatry, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead; and Behavior Health Services, North Shore-Long Island Jewish Health System, New Hyde Park, New York (Dr Kane); and the Recognition and Prevention Program (RAP), The Zucker Hillside Hospital, Glen Oaks; the Department of Psychiatry and Molecular Medicine, Hofstra-North Shore-Long Island Jewish School of Medicine, Hempstead; and the Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York (Dr Correll).†‹

CXCL12 chemokine and its receptors as major players in the interactions between immune and nervous systems

The chemokine CXCL12/stromal cell-derived factor 1 alpha has first been described in the immune system where it functions include chemotaxis for lymphocytes and macrophages, migration of hematopoietic cells from fetal liver to bone marrow and the formation of large blood vessels. Among other chemokines, CXCL12 has recently attracted much attention in the brain as it has been shown that it can be produced not only by glial cells but also by neurons. In addition, its receptors CXCR4 and CXCR7, which are belonging to the G protein-coupled receptors family, are abundantly expressed in diverse brain area, CXCR4 being a major co-receptor for human immunodeficiency virus 1 entry. This chemokine system has been shown to play important roles in brain plasticity processes occurring during development but also in the physiology of the brain in normal and pathological conditions. For example, in neurons, CXCR4 stimulation has been shown regulate the synaptic release of glutamate and γ-aminobutyric acid (GABA). It can also act post-synaptically by activating a G protein activated inward rectifier K+ (GIRK), a voltage-gated K channel Kv2.1 associated to neuronal survival, and by increasing high voltage activated Ca2+ currents. In addition, it has been recently evidenced that there are several cross-talks between the CXCL12/CXCR4–7 system and other neurotransmitter systems in the brain (such as GABA, glutamate, opioids, and cannabinoids). Overall, this chemokine system could be one of the key players of the neuro-immune interface that participates in shaping the brain in response to changes in the environment.

Environmental remodelling of GABAergic and glutamatergic neurotransmission: Rise of the anoxia-tolerant turtle brain

Climate cooling over the past one hundred thousand years has resulted in seasonal ice cover at northern and southern latitudes that has selected for hypoxia and anoxia tolerance in some species, such as freshwater turtles. At the northern reaches of their range, North American freshwater turtles spend 4 months or more buried in the mud bottom of ice covered lakes and ponds. From a comparative perspective this gives us the opportunity to understand how an extremely oxygen-sensitive organ, such as the vertebrate brain, can function without oxygen for long periods. Brain function is based on complex excitatory (on) and inhibitory (off) circuits involving the major neurotransmitters glutamate and, γ-aminobutyric acid (GABA) respectively. When a mammalian brain becomes anoxic, glutamate levels rise within minutes resulting in excitotoxic cell death which does not occur in anoxic turtle brain. The response in turtle brain has been remodelled – GABA levels rise rapidly resulting in large inhibitory GABA receptor currents and inhibition of glutamate receptor function that together depress neuronal activity.

Gabapentin

Gabapentin

Maternal behaviour and lamb survival: from neuroendocrinology to practical application

Parental care promotes offspring survival and, for livestock species, this care is provided solely by the mother. Maternal behaviour in the sheep has been exceptionally well-studied compared with other species and many of the underpinning biological processes leading to the expression of maternal care are known. In this review the current state of play with regard to the biology of maternal care will be reviewed, and its application to provide practical solutions to reduce lamb mortality considered. For maternal care to be elicited at birth the ewe requires elevated circulating oestradiol in late gestation, which stimulates the expression of oxytocin receptors in both peripheral and central areas (particularly the hypothalamic and limbic areas of the brain). At birth stretching of the vaginocervical canal elicits a spinal reflex which triggers the release of oxytocin primarily from neurones within the paraventricular nucleus of the hypothalamus. Oxytocin release causes an increase in the neurotransmitters noradrenaline, acetylcholine, glutamate and γ-aminobutyric acid (GABA) in the olfactory bulb, and other brain regions important for maternal behaviour. Finally, sensory cues provided by the lamb, in particular the amniotic fluids surrounding it, lead to the expression of maternal behaviours (licking, low-pitched bleats, acceptance of the lamb at the udder and suckling). This allows the expression of the two facets of maternal behaviour in the ewe: nurturance of the young and maternal selectivity, whereby a specific olfactory memory for the ewes own lamb is formed and the expression of maternal care is restricted to this lamb. Variation in the expression of maternal care has been demonstrated in primiparous ewes compared with multiparous, in different sheep genotypes, with undernutrition, stress in pregnancy, following a difficult delivery, and may occur with variation in ewe temperament. An understanding of the importance of the timing of various events in late pregnancy and during parturition, as well as the factors that can disrupt these events, can help to design management activities to minimise risks to the successful onset of maternal behaviour. Management practices that work with the biology of the ewe will be the most successful in ensuring that maternal care is expressed, so improving the welfare of the ewe and lamb, and the profitability of the farm.

High-frequency stimulation of nucleus accumbens changes in dopaminergic reward circuit.

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is a potential remedial therapy for drug craving and relapse, but the mechanism is poorly understood. We investigated changes in neurotransmitter levels during high frequency stimulation (HFS) of the unilateral NAc on morphine-induced rats. Sixty adult Wistar rats were randomized into five groups: the control group (administration of saline), the morphine-only group (systematic administration of morphine without electrode implantation), the morphine-sham-stimulation group (systematic administration of morphine with electrode implantation but not given stimulation), the morphine-stimulation group (systematic administration of morphine with electrode implantation and stimulation) and the saline-stimulation group (administration of saline with electrode implantation and stimulation). The stimulation electrode was stereotaxically implanted into the core of unilateral NAc and microdialysis probes were unilaterally lowered into the ipsilateral ventral tegmental area (VTA), NAc, and ventral pallidum (VP). Samples from microdialysis probes in the ipsilateral VTA, NAc, and VP were analyzed for glutamate (Glu) and γ-aminobutyric acid (GABA) by high-performance liquid chromatography (HPLC). The levels of Glu were increased in the ipsilateral NAc and VP of morphine-only group versus control group, whereas Glu levels were not significantly changed in the ipsilateral VTA. Furthermore, the levels of GABA decreased significantly in the ipsilateral NAc, VP, and VTA of morphine-only group when compared with control group. The profiles of increased Glu and reduced GABA in morphine-induced rats suggest that the presence of increased excitatory neurotransmission in these brain regions. The concentrations of the Glu significantly decreased while the levels of GABA increased in ipsilateral VTA, NAc, and VP in the morphine-stimulation group compared with the morphine-only group. No significant changes were seen in the morphine-sham stimulation group compared with the morphine-only group. These findings indicated that unilateral NAc stimulation inhibits the morphine-induced rats associated hyperactivation of excitatory neurotransmission in the mesocorticolimbic reward circuit.

Transporter‐mediated replacement of extracellular glutamate for GABA in the developing murine neocortex

During early development, cortical neurons migrate from their places of origin to their final destinations where they differentiate and establish synaptic connections. During corticogenesis, radially migrating cells move from deeper zone to the marginal zone, but they do not invade the latter. This "stop" function of the marginal zone is mediated by a number of factors, including glutamate and γ-aminobutyric acid (GABA), two main neurotransmitters in the central nervous system. In the marginal zone, GABA has been shown to be released via GABA transporters (GAT)-2/3, whereas glutamate transporters (EAATs) operate in the uptake mode. In this study, GABAergic postsynaptic currents (GPSCs) were recorded from Cajal-Retzius cells in the marginal zone of murine neonatal neocortex using a whole-cell patch-clamp technique. Minimal electrical stimulation was applied to elicit evoked GPSCs using a paired-pulse protocol. EAAT blockade with dl-threo-b-benzyloxyaspartic acid (dl-TBOA), a specific non-transportable EAAT antagonist, abolishes constitutive GAT-2/3-mediated GABA release. In contrast to dl-TBOA, d-aspartate, an EAAT substrate, fails to block GAT-2/3-mediated GABA release. SNAP-5114, a specific GAT-2/3 antagonist, induced an elevation of intracellular sodium concentration ([Na(+) ]i ) under resting conditions and in the presence of d-aspartate, indicating that GAT-2/3 operates in reverse mode. In the presence of dl-TBOA, however, SNAP-5114 elicited a [Na(+) ]i decrease, demonstrating that GAT-2/3 operates in uptake mode. We conclude that EAATs via intracellular Na(+) signaling and/or cell depolarization can govern the strength/direction of GAT-mediated GABA transport.

A comparison of random forest regression and multiple linear regression for prediction in neuroscience

BackgroundRegression is a common statistical tool for prediction in neuroscience. However, linear regression is by far the most common form of regression used, with regression trees receiving comparatively little attention. New methodIn this study, the results of conventional multiple linear regression (MLR) were compared with those of random forest regression (RFR), in the prediction of the concentrations of 9 neurochemicals in the vestibular nucleus complex and cerebellum that are part of the l-arginine biochemical pathway (agmatine, putrescine, spermidine, spermine, l-arginine, l-ornithine, l-citrulline, glutamate and γ-aminobutyric acid (GABA)). ResultsThe R2 values for the MLRs were higher than the proportion of variance explained values for the RFRs: 6/9 of them were ≥0.70 compared to 4/9 for RFRs. Even the variables that had the lowest R2 values for the MLRs, e.g. ornithine (0.50) and glutamate (0.61), had much lower proportion of variance explained values for the RFRs (0.27 and 0.49, respectively). The RSE values for the MLRs were lower than those for the RFRs in all but two cases. Comparison with existing methodsIn general, MLRs seemed to be superior to the RFRs in terms of predictive value and error. ConclusionIn the case of this data set, MLR appeared to be superior to RFR in terms of its explanatory value and error. This result suggests that MLR may have advantages over RFR for prediction in neuroscience with this kind of data set, but that RFR can still have good predictive value in some cases.

Influence of Jianpizhidong decoction on the behavioral record an bilateral striatal amino acid neurotransmitters in mice with Tourette syndrome disease

Objective To study the influences of Jianpizhidong decoction(JPZDD) on bilateral striatal amino acid neurotransmitters in mice with Tourette Syndrome(TS) disease and discuss the mechanism of JPZDD. Methods Thirty mice were injected 3, 3-iminodipropionitrile (IDPN) with 350 mg·kg-1 once a day for 7 consecutive days except ten mice of the blank control group which were injected with saline. TS mice were randomly divided into three groups: TS model group, JPZDD group(the Chinese herbal group), Tiapride group(the western medicine group). The TS model group and the blank control group were gavaged with saline(0.9%)at 20 ml·Kg-1, the Tiapride group with Tiapride at 50 mg·kg-1, and JPZDD group with JPZDD at 20 g·kg-1, respectively, once a day for six weeks .Then behavioral recordings were conducted , and the content of glumatic acid(Glu) and γ-aminobutyric acid (GABA)in the bilateral striatum of the mice were detected by using HPLC. Results Behavioral recording indicated that there were significant differences in the Chinese herbal group and the Tiapride group before(1.90±1.80, 2.05±1.40) and after(1.15±1.67, 1.00±1.08) treatment(P 0.05). The ratio of Glu and GABA were lower in the JPZDD, the Tiapride and the model groups than that in the blank control group, but there were no statistical differences between these groups(P>0.05). Conclusion JPZDD can regulate the content of Glu and GABA in the striatum, and keep the dynamic equilibrium, which might be its pharmacodynamic mechanisms for treating TS. Key words: Jianpizhidong decoction; TS model; Glu; GABA; Striatum; Mice

Comparison of concentrations of γ-aminobutyric acid and glutamate in cerebrospinal fluid of dogs with idiopathic epilepsy with and without seizure-related magnetic resonance imaging hyperintense areas in the limbic system

To investigate differences in CSF concentrations of excitatory and inhibitory neurotransmitters in dogs with and without T2-weighted (T2W) MRI hyperintense areas in the limbic system. Archived CSF samples and stored brain MRI images of 5 healthy research dogs (group 1), 8 dogs with idiopathic epilepsy (IE) with no abnormal MRI findings (group 2), and 4 dogs with IE with hyperintense areas in the limbic system detected by means of T2W MRI (group 3). Archived CSF samples and stored MRI images obtained from all dogs were evaluated. Dogs in groups 2 and 3 were matched on the basis of age and breed. High-performance liquid chromatography was used to evaluate glutamate and γ-aminobutyric acid (GABA) concentrations in CSF samples. Glutamate concentrations were higher in CSF of both groups of dogs with IE than in healthy dogs. However, glutamate concentrations in CSF were not significantly higher in dogs with IE and with hyperintense areas than in dogs with IE but no abnormal MRI findings. Concentrations of GABA in CSF were higher in group 3 than in group 2 and in group 2 than in group 1. No significant difference was evident between glutamate concentrations in CSF of dogs with IE and with and without hyperintense areas detected by means of T2W MRI. However, glutamate concentrations typically were higher in CSF of dogs with IE and MRI hyperintense areas. Future studies with larger sample sizes should be conducted to confirm this finding and to determine the clinical importance of high glutamate concentrations in CSF of dogs with IE.

Neurocognitive endophenotypes in schizophrenia: Modulation by nicotinic receptor systems

Cigarette smoking is the leading preventable cause of death in the Western world, with a considerably higher prevalence observed in schizophrenia compared to the general population. Despite the negative health consequences of smoking heavily, it has been proposed that individuals with schizophrenia may maintain smoking behaviors to remediate symptoms associated with the disorder. Neurocognitive deficits are a core feature of schizophrenia and are present in approximately 80% of patients. Further, these deficits constitute an endophenotype of schizophrenia, as they are stable across disease phases, and are heritable. The neurocognitive deficits that are present in schizophrenia are especially debilitating, since they are associated with poor clinical and functional outcomes and community integration. Interestingly, these deficits may also constitute a vulnerability factor towards the initiation and maintenance of tobacco use. Contributing to the potential shared vulnerability between schizophrenia and tobacco dependence is a dysregulation of the nicotinic acetylcholine receptor (nAChR) system. Pre-clinical evidence has shown that nicotine affects several neurotransmitter systems, including dopamine (DA), glutamate, and γ-aminobutyric acid (GABA), and certain neuropsychological deficits associated with these neurotransmitters (reaction time, spatial working memory, sustained attention, and sensory gating) are improved after nicotine administration in patients with schizophrenia. These positive effects on neurocognition appear to be more pronounced in smokers with schizophrenia, and may be an important mechanism that explains the co-morbidity of schizophrenia and tobacco dependence.

Cocaine self-administration differentially modulates the expression of endogenous cannabinoid system-related proteins in the hippocampus of Lewis vs. Fischer 344 rats

The endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) are modulators of glutamate and γ-aminobutyric acid (GABA), two transmitters involved in cocaine addiction. However, little is known on the effects of cocaine on the enzymes that produce and degrade endocannabinoids. The present work addresses the effects of cocaine self-administration on the immunohistochemical expression of endocannabinoid signalling (ECS)-related proteins in the hippocampus. The study has been performed on two different strains of rats, Lewis (Lew) and Fischer 344 (F344), which are characterized for displaying a differential sensitivity to cocaine, thus making them suitable in the study of vulnerability to drug addiction. Both strains showed differences in the expression of ECS-related proteins in the hippocampus, i.e. Lew rats exhibited lower CB1 expression but higher CB2 expression than F344 rats. After setting similar cocaine self-administration, both strains showed clear differences in the expression of ECS-related proteins, which were differentially restricted to either the 2-AG or anandamide signalling pathways in a self-administration training/drug-dependent manner. The decreases observed in CB1 expression and N-acyl phosphatidylethanolamine phospholipase D:fatty acid amino hydrolase ratio after saline self-administration were enhanced only in cocaine self-administered Lew rats. CB2 expression increase and diacylglycerol lipase α:monoacylglycerol lipase ratio decrease detected after saline self-administration were blocked only in cocaine self-administered F344 rats. These findings indicate that cocaine may regulate hippocampal GABA/glutamate synapses by directly modulating endocannabinoid production/degradation enzymes and that these actions are strain-dependent. This differential response suggests that the endogenous cannabinoid system might contribute to genotype/strain differences on the sensitivity to self-administration training and cocaine addiction.

The "Stop" and "Go" of Nicotine Dependence: Role of GABA and Glutamate

Nicotine plays an important role in the initiation and maintenance of tobacco smoking. Importantly, chronic nicotine exposure alters the function of brain reward systems, resulting in the development of a nicotine-dependent state. This nicotine-dependent state is associated with aversive affective and somatic signs upon abstinence from smoking, often leading to relapse in abstinent smokers. This article reviews the role of the major excitatory and inhibitory neurotransmitters glutamate and γ-aminobutyric acid (GABA), respectively, in both the reinforcing effects of nicotine and development of nicotine dependence. Evidence suggests that blockade of glutamatergic neurotransmission attenuates both nicotine intake and nicotine seeking. In contrast, both nicotine intake and nicotine seeking are attenuated when GABA neurotransmission is facilitated. In conclusion, medications that either attenuate/negatively modulate glutamatergic neurotransmission or facilitate/positively modulate GABA neurotransmission may be useful for promoting smoking cessation in humans.

Ethanol-induced alterations of amino acids measured by in vivo microdialysis in rats: a meta-analysis.

PurposeIn recent years in vivo microdialysis has become an important method in research studies investigating the alterations of neurotransmitters in the extracellular fluid of the brain. Based on the major involvement of glutamate and γ-aminobutyric acid (GABA) in mediating a variety of alcohol effects in the mammalian brain, numerous microdialysis studies have focused on the dynamical behavior of these systems in response to alcohol.MethodsHere we performed multiple meta-analyses on published datasets from the rat brain: (i) we studied basal extracellular concentrations of glutamate and GABA in brain regions that belong to a neurocircuitry involved in neuropsychiatric diseases, especially in alcoholism (Noori et al., Addict Biol 17:827-864, 2012); (ii) we examined the effect of acute ethanol administration on glutamate and GABA levels within this network and (iii) we studied alcohol withdrawal-induced alterations in glutamate and GABA levels within this neurocircuitry.ResultsFor extraction of basal concentrations of these neurotransmitters, datasets of 6932 rats were analyzed and the absolute basal glutamate and GABA levels were estimated for 18 different brain sites. In response to different doses of acute ethanol administration, datasets of 529 rats were analyzed and a non-linear dose response (glutamate and GABA release) relationship was observed in several brain sites. Specifically, glutamate in the nucleus accumbens shows a decreasing logarithmic dose response curve. Finally, regression analysis of 11 published reports employing brain microdialysis experiments in 104 alcohol-dependent rats reveals very consistent augmented extracellular glutamate and GABA levels in various brain sites that correlate with the intensity of the withdrawal response were identified.ConclusionsIn summary, our results provide standardized basal values for future experimental and in silico studies on neurotransmitter release in the rat brain and may be helpful to understand the effect of ethanol on neurotransmitter release. Furthermore, this study illustrates the benefit of meta-analyses using the generalization of a wide range of preclinical data.

Analysis of Glutamate, GABA, Noradrenaline, Dopamine, Serotonin, and Metabolites Using Microbore UHPLC with Electrochemical Detection

The applicability of microbore ultrahigh performance liquid chromatography (UHPLC) with electrochemical detection for offline analysis of a number of well-known neurotransmitters in less than 10 μL microdialysis fractions is described. Two methods are presented for the analysis of monoamine or amino acid neurotransmitters, using the same UHPLC instrument. Speed of analysis of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and the metabolites homovanillic acid (HVA), 5-hydroxyindole aceticacid (5-HIAA), and 3,4-dihydroxyphenylacetic acid (DOPAC) was predominated by the retention behavior of NA, the nonideal behavior of matrix components, and the loss in signal of 5-HT. This method was optimized to meet the requirements for detection sensitivity and minimizing the size of collected fractions, which determines temporal resolution in microdialysis. The amino acid neurotransmitters glutamate (Glu) and γ-aminobutyric acid (GABA) were analyzed after an automated derivatization procedure. Under optimized conditions, Glu was resolved from a number of early eluting system peaks, while the total runtime was decreased to 15 min by a 4-fold increase of the flow rate under UHPLC conditions. The detection limit for Glu and GABA was 10 nmol/L (15 fmol in 1.5 μL); the monoamine neurotransmitters had a detection limit between 32 and 83 pmol/L (0.16-0.42 fmol in 5 μL) in standard solutions. Using UHPLC, the analysis times varied from 15 min to less than 2 min depending on the complexity of the samples and the substances to be analyzed.

Effect of Kai Xin San on Learning and Memory in a Rat Model of Paradoxical Sleep Deprivation

The present study aimed to evaluate the effect of kai xin san (KXS, at doses of 500, 250, and 125 mg/kg body weight per day), a well-known traditional Chinese medicine, on learning and memory in paradoxical sleep deprivation (PSD)-induced cognition deficit rats. Two behavior tests (the Open Field test and the Morris water maze task) were used for testing the effects of KXS on a PSD-induced learning and memory deficit model. Furthermore, its effect on the glutamic acid (GLU) and γ-amino-butyric acid (GABA) levels in the brain tissue, brain-derived neurotrophic factor (BDNF), cyclic AMP response element binding protein (CREB), and phosphorylated-CREB (p-CREB) expression in the hippocampus was also tested. KXS exerted the greatest cognition against the 48 h PSD-induced cognitive deficit and these effects may be mediated by decreasing the GLU and GABA levels and increasing the levels of BDNF, CREB, and p-CREB. This study indicates that the effect of KXS on learning and memory in a rat model of PSD could be associated with the modulation of neurotransmitter levels and the expression of some genes in the brain that contribute to memory functions.