Glutamate And Γ-aminobutyric Acid Research Articles

Age-related changes in arginine and its metabolites in memory-associated brain structures

l-arginine is metabolised by nitric oxide synthase (NOS) and arginase to form l-citrulline and nitric oxide, and l-ornithine and urea, respectively. The present study investigated NOS and arginase activities, and the levels of l-arginine, l-citrulline and l-ornithine, as well as glutamate and γ-aminobutyric acid (GABA), in memory-related brain structures in 4, 12 and 24 months old rats. Significantly increased NOS and arginase activities with age were found across the CA1, CA2/3 and dentate gyrus (DG) sub-regions of the hippocampus and the prefrontal, entorhinal, perirhinal, postrhinal and temporal cortices in a region-specific manner. For l-arginine, there were age-related increases in CA1 and the perirhinal and temporal cortices, and decreases in the entorhinal and postrhinal cortices. l-citrulline levels were decreased with age in the prefrontal, postrhinal and temporal cortices. There were age-related decreases in l-citrulline/ l-arginine molar ratio in CA1 and CA2/3 and the prefrontal and temporal cortices, but an increase in the entorhinal cortex (EC). Increased l-ornithine levels and l-ornithine/ l-arginine molar ratios with age were found in most of the brain regions examined. Glutamate levels were significantly decreased with age in the prefrontal, entorhinal, perirhinal and temporal cortices, whereas GABA level was largely unchanged except for age-related increase in CA1. There were significantly decreased glutamate/GABA molar ratios with age in six brain regions. Correlational analyses revealed no inverse relationship between NOS and arginase activities, and no positive correlations between the activities of the two enzymes and the tissue concentrations of their products. Interestingly, there were significant positive correlations between glutamate and GABA, and l-arginine and its metabolites in many brain regions. These results demonstrate that the aging process has dramatic effects on the NOS and arginase metabolic pathways of l-arginine and the glutamatergic neurotransmitter system. Since l-arginine metabolism is complex, there is a need to determine its metabolomic profile in vivo in the future.

Associations between anterior cingulate cortex glutamate and γ-aminobutyric acid concentrations and the harm avoidance temperament

Converging lines of evidence have suggested that the personality traits might have neurobiological underpinnings. The anterior cingulate cortex (ACC) has been implicated to play an important role in the human fear and anxiety. Functional and structural characteristics of ACC have been suggested to be associated with the harm avoidance (HA) temperament, one of the important temperament dimensions. Therefore, we aimed to investigate correlations between neurometabolite concentrations in ACC, specifically glutamate and γ-aminobutyric acid (GABA), which are major excitatory and inhibitory neurotransmitters, respectively, and HA scores. Neurometabolite concentrations were measured using high resolution single voxel proton magnetic resonance spectroscopy ( 1H-MRS), and the HA temperament was evaluated using the Temperament and Character Inventory (TCI). Correlations between HA scores from 37 participants (21 men/16 women, age of 30.3 ± 7.0) and glutamate and GABA concentrations in the mid-ACC region were evaluated. HA scores correlated negatively with glutamate concentrations in ACC (partial correlation, R = −0.54, df = 33, P = 0.001) and positively with GABA concentrations in ACC (partial correlation, R = 0.48, df = 30, P = 0.005). These findings suggest that glutamate and GABA concentrations in ACC are closely related to levels of the HA temperament in healthy subjects.

The Excitatory Peptide Kisspeptin Restores the Luteinizing Hormone Surge and Modulates Amino Acid Neurotransmission in the Medial Preoptic Area of Middle-Aged Rats

Reproductive success depends on a robust and appropriately timed preovulatory LH surge. The LH surge, in turn, requires ovarian steroid modulation of GnRH neuron activation by the neuropeptide kisspeptin and glutamate and gamma-aminobutyric acid (GABA) neurotransmission in the medial preoptic area (mPOA). Middle-aged females exhibit reduced excitation of GnRH neurons and attenuated LH surges under estrogen-positive feedback conditions, in part, due to increased GABA and decreased glutamate neurotransmission in the mPOA. This study tested the hypothesis that altered kisspeptin regulation by ovarian steroids plays a role in age-related LH surge dysfunction. We demonstrate that middle-aged rats exhibiting delayed and attenuated LH surges have reduced levels of Kiss1 mRNA in the anterior hypothalamus under estrogen-positive feedback conditions. Kisspeptin application directly into the mPOA rescues total LH release and the LH surge amplitude in middle-aged rats and increases glutamate and decreases GABA release to levels seen in the mPOA of young females. Moreover, the N-methyl-D-aspartate receptor antagonist MK801 blocks kisspeptin reinstatement of the LH surge. These observations suggest that age-related LH surge dysfunction results, in part, from reduced kisspeptin drive under estrogen-positive feedback conditions and that kisspeptin regulates GnRH/LH release, in part, through modulation of mPOA glutamate and GABA release.

Nefiracetam and galantamine modulation of excitatory and inhibitory synaptic transmission via stimulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons

The cholinergic and glutamatergic systems are known to be downregulated in the brain of Alzheimer's disease patients. Galantamine and nefiracetam have been shown to potentiate the phasic activity of nicotinic acetylcholine receptors (nAChRs) in the brain. Stimulation of nAChRs is also known to cause release of various neurotransmitters including glutamate and γ-aminobutyric acid (GABA). We have previously reported that nefiracetam and galantamine potentiate the activity of nAChRs. Therefore, nefiracetam and galantamine are hypothesized to cause stimulations of the glutamate and GABA systems via stimulation of nAChRs. The present study was set out to test this hypothesis by measuring the effects of these drugs on spontaneous miniature excitatory postsynaptic currents (mEPSCs) and spontaneous miniature inhibitory postsynaptic currents (mIPSCs) recorded by the whole-cell patch clamp technique from rat cortical neurons in primary cultures. Acetylcholine (ACh) at 30 nM generated a steady inward current and increased the frequency of mEPSCs and mIPSCs. Nefiracetam at 10 nM plus 30 nM ACh increased the frequency of mEPSCs and mIPSCs beyond the levels increased by ACh alone. The potentiating action of nefiracetam was abolished by dihydro-β-erythroidine. None of these treatments affected the amplitude of mEPSCs or mIPSCs. Galantamine at 1 μM plus ACh did not significantly potentiate the frequency. Nefiracetam at 10 nM had no effect on neurons that did not respond to 30 nM ACh. It was concluded that the nefiracetam released glutamate via stimulation of the α4β2 nAChRs.

Neuro-Transmitters in the Central Nervous System & their Implication in Learning and Memory Processes

This review article gives an overview of a number of central neuro-transmitters, which are essential for integrating many functions in the central nervous system (CNS), such as learning, memory, sleep cycle, body movement, hormone regulation and many others. Neurons use neuro-transmitters to communicate, and a great variety of molecules are known to fit the criteria to be classified as such. A process shared by all neuro-transmitters is their release by excocytosis, and we give an outline of the molecular events and protein complexes involved in this mechanism. Synthesis, transport, inactivation, and cellular signaling can be very diverse when different neuro-transmitters are compared, and these processes are described separately for each neuro-transmitter system. Here we focus on the most well known neuro-transmitters: acetyl-choline, catechol-amines (dopamine and nor-adrenalin), indole-amine (serotonin), glutamate, and gamma-amino-butyric acid (GABA). Glutamate is the major excitatory neuro-transmitter in the brain and its actions are counter-balanced by GABA, which is the major inhibitory substance in the CNS. A balance of neuronal transmission between these two neuro-transmitters is essential to normal brain function. Acetyl-choline, serotonin and catechol-amines have a more modulatory function in the brain, being involved in many neuronal circuits. Apart from summarizing the current knowledge about the synthesis, release and receptor signaling of these transmitters, some disease states due to alteration of their normal neuro-transmission are also described.

Pre-ischemic treadmill training affects glutamate and gamma aminobutyric acid levels in the striatal dialysate of a rat model of cerebral ischemia

Aims Treadmill training has been shown to improve function in animal models and patients with cerebral ischemia. However, the neurochemical effects of this intervention on the ischemic brain have not been well studied. This study was designed to evaluate the effects of pre-ischemic treadmill training on the release of glutamate and γ-aminobutyric acid (GABA) from the striatum in a rat middle cerebral artery occlusion (MCAO) model. Main methods Rats were divided into five groups: sham control without MCAO, and 0, 1, 2 and 4 weeks pre-ischemic treadmill training. After training, cerebral ischemia was induced by MCAO for 120 min, followed by reperfusion. Microdialysis was used to collect dialysates from the striatum immediately before ischemia, and at 40, 80 and 120 min after ischemia, as well as at 40, 80, 120, 160, 200 and 240 min after reperfusion. Key findings Pre-ischemic treadmill training decreased glutamate release and increased GABA release during the acute phase of cerebral ischemia/reperfusion. Treadmill training for at least 2 weeks produced statistically significant changes in GABA/glutamate release. Significance The present study suggests that treadmill training inhibits the excessive release of glutamate, by stimulating GABA release during the acute phase of cerebral ischemia. This may be one of the important mechanisms to protect the striatal neurons from ischemic damage.

Improved high-performance liquid chromatographic method for GABA and glutamate determination in regions of the rodent brain

A C18 reversed-phase column and isocratic fluorescence HPLC method for the simultaneous detection of glutamate and γ-aminobutyric acid (GABA) is described. In this article a fast and more efficient method for the extraction of these neurotransmitters in rat brain tissue is also presented. The supernatant was derivatized with o-phthalaldehyde (OPA) and analyzed by HPLC with fluorescence detection. Intraday reproducibility was 97.0% and 96.7% and interday reproducibility was 97.1% and 93.7% for GABA and glutamate, respectively. Recovery assays indicate that the accuracy of the method for GABA is 99.6±2.3% and for glutamate is 101.9±1.8%. In addition, the time consumed to run a sample is lower than that described by other authors. Mean elution time was 3.10min and 8.22min for glutamate and GABA, respectively. Thus, in a total runtime of less than 9min both neurotransmitters were detected. Moreover, when compared to the current methods, the extraction solution used here allowed a high drawing out of the neurotransmitters, glutamate and GABA, from the hippocampus, thalamus and prefrontal cortex of the rat brain.

Level of Heat Shock Protein 70 in the Brain after Seizure Induction in Normo- and Hyperglycemic rats: Relationship to Neurotransmitters Level

Although heat shock protein 70 (Hsp70) has been suggested to be a stress marker or to play a protective role in brain injury, the relevance of its expression in epilepsy and hyperglycemia is unclear. The aim of this study was to evaluate the level of Hsp70 in the rat hippocampus following pilocarpine induced seizure in normo- and hyperglycemic rat and its relation to glutamate and γamino-butyric acid (GABA) level. This study was carried out on 40 adult male albino rats divided into two main groups 20 rats per each; Group I: induction of seizures in normal rats; Ia: 10 control rats were injected with intraperitoneal (i.p.) saline. Ib: 10 rats were injected with pilocarpine (310-320mg/kg,ip) for seizure induction. Group II: induction of seizures in diabetic rats; 20 rats were rendered diabetic for one month by the injection of streptozotocin. Then they were subdivided into 2 subgroups; Group II a: 10 diabetic rats were injected with i.p. saline. Group II b: 10 diabetic rats were injected with i.p. pilocarpine. Development ofdiabetes was confirmed bymeasuring blood glucose levels in blood samples taken from tail vein.At the end of experimental period rats were sacrificed and the hippocampi were bilaterally dissected and handled to estimate levels of Hsp70, glutamate and GABA concentration. The results revealed significant increase in Hsp70 concentration in hippocampus after experimental seizures, Hyperglycemia alone was not associated with significant change in Hsp70 level in group IIa compared to control. Nosignificant difference in Hsp 70 level was found between hyperglycemic rats with and without seizure induction. Levels of glutamate and GABA were not changed significantly after pilocarpine administration. Hyperglycemia followed by seizure induction was associated with significant increase in glutamate and decrease in GABA level. On the other hand, hyperglycemia alone failed to exert any significant change in NTlevels. The current study therefore, suggested that Hsp70 could play a role in neuroprotection during an epileptogenic state as evidenced by low scores of seizure in rats and levels of NT; in addition, Hyperglycemia is associated with impairment of Hsp70 expression; therefore, the neurons were more vulnerable to the damaging effect of pilocarpine as showed in severe seizure attacks and significant changes in NT level.

Change of Extracellular Glutamate and Gamma-Aminobutyric Acid in Substantia Nigra and Globus Pallidus during Electrical Stimulation of Subthalamic Nucleus in Epileptic Rats

Objective: To study the neurochemical change during high-frequency stimulation of the subthalamic nucleus in epileptic rats. Methods: Two animal groups – 12 rats with epilepsy induced by the systemic administration of kainic acid and 12 normal rats – were used. Concentric bipolar electrodes were stereotaxically implanted in the unilateral subthalamic nucleus (STN), stimulated by high frequencies of 130 and 260 Hz in each group. The microdialysis probes were unilaterally lowered into the globus pallidus (GP) and the substantia nigra pars reticulata (SNr). The concentrations of glutamate (Glu) and γ-aminobutyric acid (GABA) in dialysate samples were determined by high-performance liquid chromatography. Results: Electrical stimulation of the STN induced increases in GABA content in the SNr of each group, while GABA remained stable in the GP. The extracellular GABA level in the epileptic group was significantly higher than that of the normal group. In addition, the frequency of 130 Hz provoked the maximum increase in Glu contents both in the GP and SNr, whereas 260 Hz had less effect. Conclusions: This study demonstrates the neurochemical modifications in STN targets during electrical STN stimulation and shows that different frequencies of high-frequency stimulation have different effects on the neurotransmitters.

Astroglia: Not Just Glue

Astroglia: Not Just Glue

Asenapine Increases Dopamine, Norepinephrine, and Acetylcholine Efflux in the Rat Medial Prefrontal Cortex and Hippocampus

Atypical antipsychotic drugs, which are more potent direct acting antagonists of brain serotonin (5-HT)(2A) than dopamine (DA) D(2) receptors, preferentially enhance DA and acetylcholine (ACh) efflux in the rat medial prefrontal cortex (mPFC) and hippocampus (HIP), compared with the nucleus accumbens (NAc). These effects may contribute to their ability, albeit limited, to improve cognitive function and negative symptoms in patients with schizophrenia. Asenapine (ASE), a new multireceptor antagonist currently in development for the treatment of schizophrenia and bipolar disorder, has complex serotonergic properties based upon relatively high affinity for multiple serotonin (5-HT) receptors, particularly 5-HT(2A) and 5-HT(2C) receptors. In the current study, the effects of ASE on DA, norepinephrine (NE), 5-HT, ACh, glutamate, and gamma-aminobutyric acid (GABA) efflux in rat mPFC, HIP, and NAc were investigated with microdialysis in awake, freely moving rats. ASE at 0.05, 0.1, and 0.5 mg/kg (s.c.), but not 0.01 mg/kg, significantly increased DA efflux in the mPFC and HIP. Only the 0.5 mg/kg dose enhanced DA efflux in the NAc. ASE, at 0.1 and 0.5 mg/kg, significantly increased ACh efflux in the mPFC, but only the 0.5 mg/kg dose of ASE increased HIP ACh efflux. ASE did not increase ACh efflux in the NAc at any of the doses tested. The effect of ASE (0.1 mg/kg) on DA and ACh efflux was blocked by pretreatment with WAY100635, a 5-HT(1A) antagonist/D(4) agonist, suggesting involvement of indirect 5-HT(1A) agonism in both the actions. ASE, at 0.1 mg/kg, increased NE, but not 5-HT, efflux in the mPFC and HIP. ASE, at 0.1 mg/kg (s.c.), had no effect on glutamate and GABA efflux in either the mPFC or NAc. These findings indicate that ASE is similar to clozapine and other atypical antipsychotic drugs in preferentially increasing the efflux of DA, NE, and ACh in the mPFC and HIP compared with the NAC, and suggests that, like these agents, it may also improve cognitive function and negative symptoms in patients with schizophrenia.

Induction of GABAergic Postsynaptic Differentiation by α-Neurexins

Beta-neurexin and neuroligin cell adhesion molecules contribute to synapse development in the brain. The longer alpha-neurexins function at both glutamate and gamma-aminobutyric acid (GABA) synapses in coupling to presynaptic calcium channels. Binding of alpha-neurexins to neuroligins was recently reported, but the role of the alpha-neurexins in synapse development has not been well studied. Here we report that in COS cell neuron coculture assays, all three alpha-neurexins induce clustering of the GABAergic postsynaptic scaffolding protein gephyrin and neuroligin 2 but not of the glutamatergic postsynaptic scaffolding protein PSD-95 or neuroligin 1/3/4. alpha-Neurexins also induce clustering of the GABA(A) receptor gamma2 subunit. This synapse promoting activity of alpha-neurexins is mediated by the sixth LNS (laminin neurexin sex hormone-binding protein) domain and negatively modulated by upstream sequences. Although inserts at splice site 4 (S4) in beta-neurexins promote greater clustering activity for GABA than glutamate proteins in coculture assay, alpha-neurexin-specific sequences confer complete specificity for GABA proteins. We further report a developmental increase in the ratio of -S4 to +S4 forms of neurexins correlating with an increase in glutamate relative to GABA synaptogenesis and activity regulation of splicing at S4. Thus, +S4 beta-neurexins and, even more selectively, alpha-neurexins may be mediators of GABAergic synaptic protein recruitment and stabilization.

Vulnerability to Seizures Induced by Potassium Dyshomeostasis in the Hippocampus in Aged Rats

Neurological diseases such as ischemia and dementia increase with aging, while whether seizure susceptibility increases with aging remains debatable. Seizure activity frequently originates in the hippocampus and is linked to excess of extracellular glutamate. To analyze seizure susceptibility in aged rats, the response of hippocampus excited excessively was evaluated based on extracellular concentrations of neurotransmitters and epileptic behavior. In 8-week-old and 90–100-week-old rats, which exhibited normal passive avoidance behavior, the hippocampus was stimulated with 50–100 mM KCl using in vivo microdialysis. The basal concentrations of extracellular glutamate and γ-amino butyric acid (GABA) were almost the same between young and aged rats. The changes in their concentrations after stimulation with 50–100 mM KCl were not also appreciably different between them. However, seizures, i.e. ,m yoclonic jerks, were observed only in aged rats during the stimulation. These results suggest that aged rats are vulnerable to seizures induced by dyshomeostasis of potassium and chloride ions in the hippocampal extracellular fluid. Homeostasis of electrolytes in the hippocampal extracellular fluid seems to be important in preventing seizure activity in the elderly.

Activation of Kainate GLUK5 Transmission Rescues Kindling-Induced Impairment of LTP in the Rat Lateral Amygdala

The amygdala is a component of the limbic system that plays a central role in emotional behavior and certain psychiatric diseases. Pathophysiological alterations of neuronal excitability in the amygdala are characteristic features of temporal lobe epilepsy and certain (epilepsy accompanying) psychiatric illnesses such as anxiety and depressive disorders. The role of kainate receptors in the activity of synaptic networks, in brain function, and diseases is still poorly understood. Various kainate receptor subtypes have been shown to contribute to synaptic transmission and modulate presynaptic release of glutamate and gamma-aminobutyric acid (GABA). Several lines of evidence point to the importance of GLU(K5) kainate receptors in epilepsy. In this study we investigated the role of specific GLU(K5) kainate receptor in the lateral nucleus of the amygdala (LA). The cellular mechanisms for emotional learning in the amygdala are believed to be the result of changes in synaptic transmission efficacy, similar to long-term potentiation (LTP). Here, we used both field potential and intracellular recordings in horizontal rat amygdala slices, and showed that LTP in the LA, induced by high-frequency stimulation of afferents running within LA, is impaired 48 h after the last induced seizure. This kindling-induced impairment was reversed by the specific kainate GLU(K5) agonist ATPA. Partial blockade of GABAergic transmission with the specific GABA(A) receptor antagonist SR95531 also significantly facilitated the induction of early LA-LTP, but only partially abolished the kindling-induced impairment of LA-LTP. This study shows that the stimulation of the GLU(K5) kainate receptor subtype rescues the kindling-induced impairment of LA-LTP at least within 48 h after the last seizure. Therefore, GLU(K5) kainate receptor subunits are involved in kindling-induced plasticity changes in the amygdala.

Differential presynaptic actions of pyrethroid insecticides on glutamatergic and GABAergic neurons in the hippocampus

This study was designed to investigate the effects of several pyrethroids on the extracellular level of glutamate and γ-aminobutyric acid (GABA) in the hippocampus of rats measured using microdialysis following systemic (i.p.) administration. Pyrethroids, allethrin (type I), cyhalothrin (type II) and deltamethrin (type II), were found to have differential effects on glutamatergic and GABAergic neurons in the hippocampus. Allethrin had an interesting dual effect, increasing glutamate release with low doses (10 and 20 mg/kg) to about 175–150% and decreasing glutamate release with high dose (60 mg/kg) to about 50% of baseline. Cyhalothrin (10, 20 and 60 mg/kg) inhibited the release of glutamate dose-dependently to about 60–30% of baseline. The extracellular level of GABA was decreased to about 50% of baseline by 10 and 20 mg/kg allethrin. The high dose of allethrin (60 mg/kg) and all doses of cyhalothrin (10, 20 and 60 mg/kg) increased the extracellular level of GABA while decreasing the level of glutamate. Deltamethrin dose-dependently increased extracellular glutamate levels to about 190–275% of baseline while decreasing the level of GABA. Local infusion of TTX (1 μM), a Na + channel blocker, completely prevented the effect of allethrin (10, 20 and 60 mg/kg), cyhalothrin (20 and 60 mg/kg) and deltamethrin (20 mg/kg) on glutamate and GABA release, but only partially blocked the effects of 60 mg/kg deltamethrin. The effect of deltamethrin (60 mg/kg) on glutamate release was completely prevented by local infusion of nimodipine (10 μM), an L-type Ca 2+ channel blocker. Collectively, results from this study suggest that the excitatory glutamatergic neurons in the hippocampus are modulated by inhibitory GABA-releasing interneurons and that other mechanisms, beside sodium channels, may be involved with the neurotoxic action of pyrethroids.

Mitochondrial transport proteins of the brain

In this study, cellular distribution and activity of glutamate and gamma-aminobutyric acid (GABA) transport as well as oxoglutarate transport across brain mitochondrial membranes were investigated. A goal was to establish cell-type-specific expression of key transporters and enzymes involved in neurotransmitter metabolism in order to estimate neurotransmitter and metabolite traffic between neurons and astrocytes. Two methods were used to isolate brain mitochondria. One method excludes synaptosomes and the organelles may therefore be enriched in astrocytic mitochondria. The other method isolates mitochondria derived from all regions of the brain. Immunological and enzymatic methods were used to measure enzymes and carriers in the different preparations, in addition to studying transport kinetics. Immunohistochemistry was also employed using brain slices to confirm cell type specificity of enzymes and carriers. The data suggest that the aspartate/glutamate carriers (AGC) are expressed predominantly in neurons, not astrocytes, and that one of two glutamate/hydroxyl carriers is expressed predominantly in astrocytes. The GABA carrier and the oxoglutarate carrier appear to be equally distributed in astrocytes and neurons. As expected, pyruvate carboxylase and branched-chain aminotransferase were predominantly astrocytic. Insofar as the aspartate/glutamate exchange carriers are required for the malate/aspartate shuttle and for reoxidation of cytosolic NADH, the data suggest a compartmentation of glucose metabolism in which astrocytes catalyze glycolytic conversion of glucose to lactate, whereas neurons are capable of oxidizing both lactate and glucose to CO(2) + H(2)O.

Effect of ocular hypertension on retinal GABAergic activity

Glutamate and γ-aminobutyric acid (GABA) are major excitatory and inhibitory retinal neurotransmitters. The balance between these signals is a key principle of organization at retinal level. Although glutamate-induced excitotoxicity could mediate retinal ganglion cell death in glaucoma, the GABAergic system was not previously examined in this disease. The aim of this work was to study the retinal GABAergic activity in eyes with ocular hypertension induced by hyaluronic acid (HA). For this purpose, weekly injections of HA were performed unilaterally in the rat anterior chamber, whereas the contralateral eye was injected with saline solution. At 3 weeks of treatment with HA, GABA turnover rate, glutamic acid decarboxylase activity, and both glutamate- and high K +-induced GABA release significantly decreased, whereas GABA uptake increased in HA-treated eyes. The binding of t-butylbicyclophosphorothionate (TBPS) to GABA A/benzodiazepine Cl − channels significantly increased in eyes injected with HA as compared with vehicle-injected eyes. Changes in GABA uptake and TBPS binding persisted at 6 weeks of treatment with HA. These results indicate a dysfunction of the retinal GABAergic activity in hypertensive eyes, which could suggest the involvement of GABA in glaucomatous neuropathy.

Quantal Release of ATP in Mouse Cortex

Transient currents occur at rest in cortical neurones that reflect the quantal release of transmitters such as glutamate and γ-aminobutyric acid (GABA). We found a bimodal amplitude distribution for spontaneously occurring inward currents recorded from mouse pyramidal neurones in situ, in acutely isolated brain slices superfused with picrotoxin. Larger events were blocked by glutamate receptor (AMPA, kainate) antagonists; smaller events were partially inhibited by P2X receptor antagonists suramin and PPADS. The decay of the larger events was selectively prolonged by cyclothiazide. Stimulation of single intracortical axons elicited quantal glutamate-mediated currents and also quantal currents with amplitudes corresponding to the smaller spontaneous inward currents. It is likely that the lower amplitude spontaneous events reflect packaged ATP release. This occurs with a lower probability than that of glutamate, and evokes unitary currents about half the amplitude of those mediated through AMPA receptors. Furthermore, the packets of ATP appear to be released from vesicle in a subset of glutamate-containing terminals.

Reduced Prefrontal Glutamate/Glutamine and γ-Aminobutyric Acid Levels in Major Depression Determined Using Proton Magnetic Resonance Spectroscopy

Increasing evidence indicates that major depressive disorder (MDD) is associated with altered function of the major excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. A recently developed magnetic resonance spectroscopy method allows for reliable measurement of glutamate/glutamine (Glx) and GABA concentrations in prefrontal brain regions that have been implicated in the pathophysiologic mechanisms of MDD by studies using other neuroimaging and postmortem techniques. To measure Glx and GABA levels in 2 regions of the prefrontal brain tissue in unmedicated adults with MDD. Cross-sectional study for association. Psychiatric outpatient clinic. Twenty unmedicated, depressed patients with MDD and 20 age- and sex-matched controls. Intervention Participants underwent scanning using a 3-T whole-body scanner with a transmit-receive head coil, providing a homogeneous radiofrequency field and the capability of obtaining spectroscopic measurements in a dorsomedial/dorsal anterolateral prefrontal region of interest (ROI) and a ventromedial prefrontal ROI. Glx and GABA levels derived from magnetic resonance spectroscopy signals. Depressed patients had reduced Glx levels in both ROIs. The GABA levels were reduced in the dorsomedial/dorsal anterolateral prefrontal ROI. Levels of GABA and Glx were positively correlated in both ROIs. For the first time, GABA and Glx concentrations were compared between unmedicated depressed adults and controls in prefrontal ROIs. The abnormal reductions in Glx and GABA concentrations found in the MDD sample were compatible with findings from postmortem histopathologic studies, indicating that glial cell density is reduced in the same areas in MDD.

Extracellular glutamate and GABA in the ventral tegmental area of alcohol-preferring AA and alcohol-avoiding ANA rats treated repeatedly with morphine

Glutamate and γ-amino-butyric acid (GABA) have been implicated in neuronal plasticity related to behavioral sensitization. In the present study, we examined morphine-induced changes in the extracellular concentrations of glutamate and GABA in the ventral tegmental area in alcohol-preferring Alko Alcohol (AA) and alcohol-avoiding Alko Non-Alcohol (ANA) rats that have previously been shown to differ in morphine-induced sensitization. The rats were given escalating doses (5–20 mg/kg) of morphine every other day for five days. This treatment produced behavioral sensitization to locomotor effects of morphine in AA, but not in ANA rats, when challenged with an additional injection of morphine (10 mg/kg) 10 days later. Morphine also increased the levels of glutamate in the ventral tegmental area only in AA rats, while no significant changes were found in the extracellular concentrations of GABA between the lines. Challenging the morphine-treated AA rats with ethanol (1.5 g/kg) did not modify the levels of glutamate or GABA. No changes in the concentrations of glutamate or GABA were seen in saline-treated AA and ANA rats after morphine challenge. These results render increased glutamate transmission in the ventral tegmental area a potential contributor to the higher susceptibility of AA rats to morphine-induced behavioral and neurochemical effects relative to ANA rats.