Increase In Extracellular GABA Research Articles

Interhemispheric regulation of the rat medial prefrontal cortical glutamate stress response: role of local GABA- and dopamine-sensitive mechanisms.

We previously reported that stressors increase medial prefrontal cortex (PFC) glutamate (GLU) levels as a result of activating callosal neurons located in the opposite hemisphere and that this PFC GLU stress response is regulated by GLU-, dopamine- (DA-), and GABA-sensitive mechanisms (Lupinsky et al. 2010). Here, we examine the possibility that PFC DA regulates the stress responsivity of callosal neurons indirectly by acting at D1 and D2 receptors located on GABA interneurons. Microdialysis combined with drug perfusion (reverse dialysis) or microinjections was used in adult male Long-Evans rats to characterize D1, D2, and GABAB receptor-mediated regulation of the PFC GABA response to tail-pinch (TP) stress. We report that TP stress reliably elicited comparable increases in extracellular GABA in the left and right PFCs. SCH23390 (D1 antagonist; 100μM perfusate concentration) perfused by reverse microdialysis attenuated the local GABA stress responses equally in the left and right PFCs. Intra-PFC raclopride perfusion (D2 antagonist; 100μM) had the opposite effect, not only potentiating the local GABA stress response but also causing a transient elevation in basal (pre-stress) GABA. Moreover, unilateral PFC raclopride microinjection (6nmol) attenuated the GLU response to TP stress in the contralateral PFC. Finally, intra-PFC baclofen perfusion (GABAB agonist; 100μM) inhibited the local GLU and GABA stress responses. Taken together, these findings implicate PFC GABA interneurons in processing stressful stimuli, showing that local D1, D2, and GABAB receptor-mediated changes in PFC GABA transmission play a crucial role in the interhemispheric regulation of GLU stress responsivity.

GABA transporter subtype 1 and GABA transporter subtype 3 modulate glutamatergic transmission via activation of presynaptic GABAB receptors in the rat globus pallidus

AbstractThe intra‐pallidal application of γ‐aminobutyric acid (GABA) transporter subtype 1 (GAT‐1) or GABA transporter subtype 3 (GAT‐3) transporter blockers [1‐(4,4‐diphenyl‐3‐butenyl)‐3‐piperidinecarboxylic acid hydrochloride (SKF 89976A) or 1‐[2‐[tris(4‐methoxyphenyl)methoxy]ethyl]‐(S)‐3‐piperidinecarboxylic acid (SNAP 5114)] reduces the activity of pallidal neurons in monkey. This effect could be mediated through the activation of presynaptic GABAB heteroreceptors in glutamatergic terminals by GABA spillover following GABA transporter (GAT) blockade. To test this hypothesis, we applied the whole‐cell recording technique to study the effects of SKF 89976A and SNAP 5114 on evoked excitatory postsynaptic currents (eEPSCs) in the presence of gabazine, a GABAA receptor antagonist, in rat globus pallidus slice preparations. Under the condition of postsynaptic GABAB receptor blockade by the intra‐cellular application of N‐(2,6‐dimethylphenylcarbamoylmethyl)‐triethylammonium bromide (OX314), bath application of SKF 89976A (10 μm) or SNAP 5114 (10 μm) decreased the amplitude of eEPSCs, without a significant effect on its holding current and whole cell input resistance. The inhibitory effect of GAT blockade on eEPSCs was blocked by (2S)‐3‐[[(1S)‐1‐(3,4‐dichlorophenyl)ethyl]amino‐2‐hydroxypropyl](phenylmethyl)phosphinic acid, a GABAB receptor antagonist. The paired‐pulse ratio of eEPSCs was increased, whereas the frequency, but not the amplitude, of miniature excitatory postsynaptic currents was reduced in the presence of either GAT blocker, demonstrating a presynaptic effect. These results suggest that synaptically released GABA can inhibit glutamatergic transmission through the activation of presynaptic GABAB heteroreceptors following GAT‐1 or GAT‐3 blockade. In conclusion, our findings demonstrate that presynaptic GABAB heteroreceptors in putative glutamatergic subthalamic afferents to the globus pallidus are sensitive to increases in extracellular GABA induced by GAT inactivation, thereby suggesting that GAT blockade represents a potential mechanism by which overactive subthalamopallidal activity may be reduced in parkinsonism.

11C]flumazenil Binding Is Increased in a Dose-Dependent Manner with Tiagabine-Induced Elevations in GABA Levels

Evidence indicates that synchronization of cortical activity at gamma-band frequencies, mediated through GABA-A receptors, is important for perceptual/cognitive processes. To study GABA signaling in vivo, we recently used a novel positron emission tomography (PET) paradigm measuring the change in binding of the benzodiazepine (BDZ) site radiotracer [11C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [11C]flumazenil binding potential (BPND) over baseline in the major functional domains of the cortex, consistent with preclinical studies showing that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands. In the current study we sought to replicate our previous results and to further validate this approach by demonstrating that the magnitude of increase in [11C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [11C]flumazenil distribution volume (VT) was measured in 18 healthy volunteers before and after GAT1 blockade with tiagabine. Two dose groups were studied (n = 9 per group; Group I: tiagabine 0.15 mg/kg; Group II: tiagabine 0.25 mg/kg). GAT1 blockade resulted in increases in mean (± SD) [11C]flumazenil VT in Group II in association cortices (6.8±0.8 mL g−1 vs. 7.3±0.4 mL g−1;p = 0.03), sensory cortices (6.7±0.8 mL g−1 vs. 7.3±0.5 mL g−1;p = 0.02) and limbic regions (5.2±0.6 mL g−1 vs. 5.7±0.3 mL g−1;p = 0.03). No change was observed at the low dose (Group I). Increased orbital frontal cortex binding of [11C]flumazenil in Group II correlated with the ability to entrain cortical networks (r = 0.67, p = 0.05) measured via EEG during a cognitive control task. These data provide a replication of our previous study demonstrating the ability to measure in vivo, with PET, acute shifts in extracellular GABA.

Manganese exposure inhibits the clearance of extracellular GABA and influences taurine homeostasis in the striatum of developing rats

Manganese (Mn) accumulation in the brain has been shown to alter the neurochemistry of the basal ganglia. Mn-induced alterations in dopamine biology are fairly well understood, but recently more evidence has emerged characterizing the role of γ-aminobutyric acid (GABA) in this dysfunction. The purpose of this study was to determine if the previously observed Mn-induced increase in extracellular GABA (GABA EC) was due to altered GABA transporter (GAT) function, and whether Mn perturbs other amino acid neurotransmitters, namely taurine and glycine (known modulators of GABA). Extracellular GABA, taurine, and glycine concentrations were collected from the striatum of control (CN) or Mn-exposed Sprague–Dawley rats using in vivo microdialysis, and the GAT inhibitor nipecotic acid (NA) was used to probe GAT function. Tissue and extracellular Mn levels were significantly increased, and the Fe:Mn ratio was decreased 36-fold in the extracellular space due to Mn-exposure. NA led to a 2-fold increase in GABA EC of CNs, a response that was attenuated by Mn. Taurine responded inversely to GABA, and a novel 10-fold increase in taurine was observed after the removal of NA in CNs. Mn blunted this response and nearly abolished extracellular taurine throughout collection. Striatal taurine transporter (Slc6a6) mRNA levels were significantly increased with Mn-exposure, and Mn significantly increased 3H-Taurine uptake after 3-min exposure in primary rat astrocytes. These data suggest that Mn increases GABA EC by inhibiting the function of GAT, and that perturbed taurine homeostasis potentially impacts neural function by jeopardizing the osmoregulatory and neuromodulatory functions of taurine in the brain.

Hyperammonemia Increases GABAergic Tone in the Cerebellum but Decreases It in the Rat Cortex

GABAA receptors modulate the function of the glutamate-nitric oxide-guanosine 3',5'-cyclic monophosphate (cGMP) pathway, which is reduced in cerebellum in hyperammonemic rats. It has been proposed that hyperammonemia-induced increases in gamma-aminobutyric acid "(GABAergic) tone" contribute to the pathogenesis of hepatic encephalopathy (HE), although this has not been assessed in vivo in animal models. We studied whether chronic hyperammonemia in rats increases GABAergic tone in the cerebellum and/or cerebral cortex and whether this increase contributes to cognitive impairment. We blocked GABAA receptors of rats with bicuculline and analyzed the function of this pathway in cerebellum and effects on learning ability. Hyperammonemia increased GABAergic tone in cerebellum but decreased it in the cerebral cortex of rats. Increased GABAergic tone in the cerebellum of rats with hyperammonemia could have been caused by increases in extracellular GABA; tetrahydrodeoxy-corticosterone (a neurosteroid that enhances GABAA receptor activation); or amounts of the alpha1, alpha6, and gamma2 subunits of GABAA receptors. The decrease in GABAergic tone observed in the cortex could have resulted from the reduced amount of GABAA receptors delta and gamma2 subunits or increased levels of pregnanolone (5-fold), which selectively reduces activation of GABAA receptors that contain alpha4 subunits (widely expressed in cortex but not in cerebellum). Treatment with bicuculline normalized GABAergic tone and restored the increase in cGMP that was induced by activation of N-methyl-D-aspartate receptors and learning ability in hyperammonemic rats. Increased GABAergic tone in the cerebellum contributes to cognitive impairment in hyperammonemic rats.

Chronic nicotine modifies the effects of morphine on extracellular striatal dopamine and ventral tegmental GABA

Previously, we have shown that 7-week oral nicotine treatment enhances morphine-induced behaviors and dopaminergic activity in the mouse brain. In this study, we further characterized the nicotine-morphine interaction in the mesolimbic and nigrostriatal dopaminergic systems, as well as in the GABAergic control of these systems. In nicotine-pretreated mice, morphine-induced dopamine release in the caudate putamen and nucleus accumbens was significantly augmented, as measured by microdialysis. Chronic nicotine treatment did not change basal extracellular concentrations of dopamine and its metabolites in the caudate putamen and nucleus accumbens, nor did it affect the rate of dopamine synthesis, as assessed by 3-hydroxybenzylhydrazine dihydrochloride-induced DOPA accumulation. GABAergic control of dopaminergic activity was studied by measuring extracellular GABA in the presence of nipecotic acid, an inhibitor of GABA uptake. Acute (0.3 mg/kg or 0.5 mg/kg i.p.) and chronic nicotine, as well as morphine (15 mg/kg s.c.) in control mice decreased nipecotic acid-induced increase in extracellular GABA in the ventral tegmental area/substantia nigra (VTA/SN). In contrast, in nicotine-treated mice, morphine increased GABA levels in the presence of nipecotic acid. We did not find any alterations in GABA(B)-receptor function after chronic nicotine treatment. Thus, our data show that chronic nicotine treatment sensitizes dopaminergic systems to morphine and affects GABAergic systems in the VTA/SN.

GABA transporter type 1 (GAT-1) uptake inhibition reduces stimulated aspartate and glutamate release in the dorsal spinal cord in vivo via different GABAergic mechanisms

Mechanisms through which the reported antinociceptive activity of GABA re-uptake inhibitors is mediated (and where on the sensory neuraxis) have not been defined. Here, microdialysis in the anaesthetised rat was used to examine the effect of selective GABA transporter type 1 (GAT-1) inhibition on basal and evoked amino acid release in the dorsal spinal cord. Reverse dialysis of the selective GAT-1 inhibitor NO-711 (10–300 μM) induced a concentration-related increase in extracellular GABA (maximal ∼threefold of basal levels) without affecting other amino acids. Employing an S2/S1 paradigm, release evoked by brief high (45 mM) K +-induced depolarisation of aspartate and glutamate, but not GABA or glycine, was found to be significantly reduced by reverse dialysis of NO-711 (300 μM). Co-administration of selective antagonists for GABA A or GABA B receptors ((+)-bicuculline (100 μM) or SCH 50911 (100 μM), respectively) prevented the GAT-1 inhibition-induced reduction of evoked aspartate. In contrast, while (+)-bicuculline also antagonised the reduction of evoked glutamate, SCH 50911 (up to 1 mM) was without effect. Inhibition of GAT-1 re-uptake was further found to play a permissive role in autoinhibitory effects on GABA release mediated through GABA A and GABA B receptors. These data demonstrate that augmentation of GABAergic neurotransmission by re-uptake inhibition activates pharmacologically distinguishable inhibitory influences on aspartate and glutamate release in the dorsal spinal cord. Thus, inhibition of spinal pro-nociceptive neurotransmitter release may contribute to the analgesic action of this drug class.

Estradiol attenuates the K+-induced increase in extracellular GABA in rat striatum

Estradiol acts rapidly and directly to inhibit L-type Ca2+ current in medium spiny neurons from striatum. Since medium spiny neurons contain gamma-aminobutyric acid (GABA), we hypothesized that estradiol inhibition of Ca2+ channel current in the cell body would result in decreased GABA release. In this study, we examined the effect of estradiol on the concentration of GABA, taurine, and glutamate in dialysate from striatum. In support of our hypothesis, the K+-evoked increase in GABA, but not taurine or glutamate, was significantly attenuated 30 min after treatment with estradiol.

The effect of acetylcholinesterase-inhibition on depolarization-induced GABA release from rat striatal slices

The severity of poisoning after intoxication with the acetylcholinesterase (AChE) inhibitor soman has been shown to be positively correlated with GABA release in rat striatum. Since most of the neurons in striatum and striatal projection regions use GABA as transmitter, it is still unclear, whether an increase of extracellular GABA in this region results from enhanced activation of these projections or is due to the local effect of AChE inhibition. In this study, the modulation of depolarization-induced increase in GABA concentration by soman was determined in the superfusate of rat striatal slices. Soman and neostigmine increased GABA concentration in the superfusate dose dependently. This increase was exerted through M-cholinoceptors as it could be blocked by atropine and enhanced by application of the muscarinic agonists pilocarpine or oxotremorine. These results clearly indicate that AChE inhibition by soman in rat striatum can directly lead to enhanced release of GABA through M-cholinoceptors.

Convergent evidence from microdialysis and presynaptic immunolabeling for the regulation of gamma-aminobutyric acid release in the globus pallidus following acute clozapine or haloperidol administration in rats.

Antipsychotic drugs (APDs) have been primarily characterized for their effects on dopaminergic terminal regions in the brain, especially within the corpus striatum. Efferent GABA pathways are the primary outflow of striatal processing via their projections to the substantia nigra and the globus pallidus (GP). In the current study, we analyzed changes in pallidal GABA function following acute APD administration by means of in vivo microdialysis, followed by immunolabeling of presynaptic GABA terminal density in the contralateral hemisphere of the same animals. Acute administration of the atypical APD, clozapine (10 or 30 mg/kg, s.c.), produced a dose-dependent decrease in extracellular GABA. A corresponding dose-dependent increase in the density of presynaptic terminal GABA immunolabeling in the GP was found. In contrast, the typical APD, haloperidol (1 or 3 mg/kg, s.c.), had no significant effects on either measure, although a non-significant increase in extracellular GABA and decrease in the density of GABA terminal immunolabeling was noted. Paw retraction tests conducted during the time of microdialysis showed that haloperidol produced a typical pattern of highly pronounced motor impairment, while clozapine showed an atypical profile of minimal catalepsy. These complementary results obtained from in vivo neurochemistry and presynaptic neurotransmitter labeling suggest that systemic clozapine suppresses neuronal GABA release within the GP. This decrease in released pallidal GABA may play a role in the low motor side-effect liability of atypical APDs.

Norepinephrine mediates glucoprivic-induced increase in GABA in the ventromedial hypothalamus of rats.

Noradrenergic mechanisms in the hypothalamus may be involved in counterregulatory responses to glucoprivic episodes. After 2-deoxy-D-glucose (2-DG; 1.2 mmol/kg iv), extracellular norepinephrine (NE) concentration in the ventromedial hypothalamus (VMN) increased in a bimodal fashion to 251 +/- 39% (P < 0.001) and 150 +/- 17% (P < 0.001) of baseline during the first 30 min. In the lateral hypothalamus (LHA), NE decreased by 30 min (61 +/- 4%, P < 0.001) and no consistent changes were measured in the paraventricular nucleus (PVN). Because the NE response in the VMN after 2-DG followed the same pattern as GABA, the interaction between NE and GABA was evaluated. In the VMN, GABA had little effect on extracellular NE concentrations but NE increased GABA concentrations 166 +/- 13%, (P < 0.01). In the presence of yohimbine (alpha(2)-adrenoceptor antagonist) the first GABA peak after 2-DG was absent, and the second GABA peak was absent in the presence of timolol (beta-adrenoceptor antagonist). These results support an interaction among noradrenergic and GABAergic systems in the VMN during glucoprivation and that increased NE mediates the increase in extracellular GABA after 2-DG.

Effects of endogenous glutamate on extracellular concentrations of GABA, dopamine, and dopamine metabolites in the prefrontal cortex of the freely moving rat: involvement of NMDA and AMPA/KA receptors.

Using microdialysis, interactions between endogenous glutamate, dopamine, and GABA were investigated in the medial prefrontal cortex of the freely moving rat. Interactions between glutamate and other neurotransmitters in the prefrontal cortex had already been studied using pharmacological agonists or antagonists of glutamate receptors. This research investigated whether glutamate itself, through the increase of its endogenous extracellular concentration, is able to modulate the extracellular concentrations of GABA and dopamine in the prefrontal cortex. Intracortical infusions of the selective glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) were used to increase the endogenous extracellular glutamate. PDC (0.5, 2, 8, 16 and 32 mM) produced a dose-related increase in dialysate glutamate in a range of 1-36 microM. At the dose of 16 mM, PDC increased dialysate glutamate from 1.25 to 28 microM. PDC also increased extracellular GABA and taurine, but not dopamine; and decreased extracellular concentrations of the dopamine metabolites DOPAC and HVA. NMDA and AMPA/KA receptor antagonists were used to investigate whether the increases of extracellular glutamate were responsible for the changes in the release of GABA, and dopamine metabolites. The NMDA antagonist had no effect on the increase of extracellular GABA, but blocked the decreases of extracellular DOPAC and HVA, produced by PDC. In contrast, the AMPA/KA antagonist blocked the increases of extracellular GABA without affecting the decreases of extracellular DOPAC and HVA produced by PDC. These results suggest that endogenous glutamate acts preferentially through NMDA receptors to decrease dopamine metabolism, and through AMPA/KA receptors to increase GABAergic activity in the medial prefrontal cortex of the awake rat.

Changes in extracellular glutamate and GABA levels in the hippocampal CA 3 and CA 1 areas and the induction of glutamic acid decarboxylase-67 in dentate granule cells of rats treated with kainic acid

For the evaluation of glutamatergic and GABAergic transmission during seizures, rat hippocampal CA 1 and CA 3 areas were separately assessed by brain microdialysis, and extracelluar glutamate and GABA were measured through the course of the seizures after a systemic administration of kainic acid (KA). The generalized convulsion started at about 1.5 h and was suppressed by diazepam at 2 h after the KA treatment. In the CA 3 area, extracellular glutamate started to increase soon after the KA injection and returned to the control level at about 1.5 h. A decrease and then slight increase of the extracellular glutamate level in CA 3 followed the diazepam injection. In the CA 1 area, in contrast, a long-lasting decrease of extracellular glutamate was observed. The extracellular GABA concentration in the CA 3 area increased immediately after the systemic administration of KA and returned to the normal level at about 3.5 h. A second increase in the extracellular GABA in this area began at about 4.5 h after the KA treatment. In the CA 1 area, an increase of extracellular GABA began at about 3.5 h after KA administration (much later than that observed in the CA 3 area) and was maintained throughout the observation. In situ hybridization showed a transient expression of glutamic acid decarboxylase (GAD)-67 mRNA in the granule cell layer of the dentate gyrus at 4 and 6 h, whereas GAD65 mRNA was unaffected. GABA immunoreactivity in the same area and mossy fibers in the CA 3 were increased most significantly at 8 h after administration of KA. The possible relation of GABA induction in mossy fibers with the delayed increase in extracellular GABA in CA 3 was discussed.

Amphetamine releases GABA in striatum of the freely moving rat: involvement of calcium and high affinity transporter mechanisms

Using microdialysis the effect was investigated of amphetamine (AMPH) infusions into the striatum on the release of GABA in the freely moving rat. AMPH (5, 10 and 20 μg/μl), infused through a microdialysis probe at the rate of 2.5 μl/min, produced a dose-related increase in extracellular concentrations of GABA. At the highest dose (20 μg/μl), AMPH increased GABA from 0.08±0.01 to 0.67±0.14 μM. Increases in extracellular GABA produced by AMPH were both calcium-dependent and high affinity GABA transporter-mediated. A medium free of calcium reduced the increase of extracellular GABA produced by AMPH by 37%. Nipecotic acid (2, 4 and 8 mM), a specific GABA re-uptake blocker, significantly attenuated increases in extracellular GABA, but not GLU, produced by AMPH (20 μg/μl). This study is the first in vivo evidence showing the release of GABA produced by AMPH through a high affinity transporter mechanism.

Activity at the GABA transporter contributes to acute cellular swelling produced by metabolic impairment in retina

The role of the GABA transporter in acute toxicity in chick retina due to metabolic inhibition was investigated by the use of several substrate (nipecotic acid, THPO) and nonsubstrate (SKF 89976A, NO711) GABA transport inhibitors. Metabolic stress-induced acute toxicity in the retina is characterized by swelling of distinct populations of retinal neurons and selective release of GABA into the medium. Inhibitor concentrations were based on that needed to attenuate 14C-GABA uptake at its approximate KM concentration by > or = 70%. Under basal conditions, substrate, but not nonsubstrate, inhibitors increased extracellular GABA, but did not cause histological swelling per se. Under conditions of glycolytic inhibition, nonsubstrate, but not substrate, inhibitors significantly attenuated acute toxicity. Metabolic stress-induced acute toxicity was not altered by the GABA agonist muscimol, nor did muscimol reverse the protective effects of nonsubstrate transport inhibitors, suggesting that an increase in extracellular GABA during metabolic stress was not a component of the acute phase of toxicity. The results indicate that during metabolic inhibition, activity at the GABA transporter contributes to acute cellular swelling.

Microdialysis study of modification of hypothalamic neurotransmitters in streptozotocin-diabetic rats.

Neurochemical changes in the ventromedial hypothalamus (VMH) after a single intravenous injection of streptozotocin were examined, using in vivo brain microdialysis under free-moving conditions. Although streptozotocin-induced diabetes produced significant decreases in extracellular concentrations of noradrenaline (NA), serotonin (5-HT), and their metabolites in the VMH, the ratios of 3-methoxy-4-hydroxyphenylglycol/NA and 5-hydroxyindoleacetic acid (5-HIAA)/5-HT were increased. Experimental diabetes led to a pronounced increase in extracellular GABA, which correlated strongly with the decrease in dialysate levels of NA, and to a smaller extent with that of 5-HT. A modification of dopamine (DA) metabolism was induced in the VMH of diabetic rats, whereas there was no change in dialysate DA levels. Daily injections of insulin were able to restore their levels to normal in the areas tested in the microdialysis study. The equal increases in dialysate 5-HT and 5-HIAA and the better restoration of the 5-HIAA/5-HT ratio after insulin therapy indicate that serotonergic activity may depend on the levels of circulating insulin more than on noradrenergic activity. Circulating NA was reduced in streptozotocin-diabetic rats, suggesting that the diabetes-induced reduction in sympathetic activity is accompanied by decreases in NA, or 5-HT, or both, in the VMH.

GABA concentrations in the striatum following repetitive cerebral ischemia

GABAergic neurons in the striatum are very sensitive to the effects of ischemia. The progressive decline in striatal GABA following transient forebrain ischemia in gerbils may be secondary to either a decreased production or an increase in reuptake mechanisms or both. The current experiment was designed to evaluate release of GABA by stimulation with K+ or inhibition of its uptake with nipecotic acid or their combination (K+ nipecotic) after repetitive forebrain ischemia in gerbils by in-vivo microdialysis on Days 1, 3, 5, and 14 following the insult. Infusion of nipecotic acid or potassium chloride, resulted in a significant increase in extracellular GABA. This response was significantly decreased in the post-ischemic animals. The synergistic effect of increased GABA concentrations by the infusion of nipecotic acid + potassium chloride seem in the controls was not evident in the post-ischemic animals. In conclusion, though there is a reduction in the extracellular GABA concentrations in the first week following an ischemic insult, restorative mechanisms are operative in the second week as seen by the increasing GABA concentrations.

The significance of extracellular GABA in the substantia nigra of the rat during seizures and anticonvulsant treatments

The effects of the anti-epileptic drugs valproic acid and gamma-vinyl-GABA j(vigabatrin) on the extracellular content of GABA was determined by microdialysis. Probes were implanted in the substantia nigra reticulata (SNR) of rats. It was found that gamma-vinyl-GABA (1000 mg/kg) induced a 4–6-fold increase in the extracellular content of GABA. This increase lasted for at least 72 h. PTZ-induced convulsions were partly antagonized by the GVG treatment. The increase of extracellular GABA after gamma-vinyl-GABA was not affected by infusion of tetrodotoxin. In contrast valproic acid (200 mg/kg), although effective in preventing pentylenetetrazol (PTZ)-induced convulsions, did not affect extracellular GABA in the SNR. PTZ-induced convulsions did not modify extracellular GABA, neither in control rats nor in valproic acid or gamma-vinyl-GABA pretreated animals. The results do not support the idea that extracellular GABA in the SNR plays a significant role in anti-convulsive treatment. However, the present data can also be interpreted that extracellular GABA, as sampled by microdialysis, is not a reliable marker for GABA release.

Short-term dopaminergic regulation of GABA release in dopamine deafferented caudate-putamen is not directly associated with glutamic acid decarboxylase gene expression

In vivo microdialysis and in situ hybridization were combined to study dopaminergic regulation of γ-amino butyric acid (GABA) neurons in rat caudate-putamen (CPu). Potassium-stimulated GABA release in CPu was elevated following a dopamine deafferentation. Local perfusion with exogenous dopamine (50 μM) for 3h via the microdialysis probe attenuated the potassium-stimulated increase in extracellular GABA in CPu. Expression of glutamic acid decarboxylase (GAD) mRNA was also increased in the dopamine deafferented CPu. However, local perfusion with dopamine had no significant attenuating effect on the increased GAD mRNA expression. These findings indicate that dopaminergic regulation of GABA neurons in the dopamine deafferented CPu includes both a short-term effect at the level of GABA release independent of changes in GAD mRNA expression and a long-term modulation at the level of GAD gene expression.

Infantile spasms, gamma-vinyl-gaba (GVG) and the EEG

The effects of the anti-epileptic drugs valproic acid and gamma-vinyl-GABA j(vigabatrin) on the extracellular content of GABA was determined by microdialysis. Probes were implanted in the substantia nigra reticulata (SNR) of rats. It was found that gamma-vinyl-GABA (1000 mg/kg) induced a 4–6-fold increase in the extracellular content of GABA. This increase lasted for at least 72 h. PTZ-induced convulsions were partly antagonized by the GVG treatment. The increase of extracellular GABA after gamma-vinyl-GABA was not affected by infusion of tetrodotoxin. In contrast valproic acid (200 mg/kg), although effective in preventing pentylenetetrazol (PTZ)-induced convulsions, did not affect extracellular GABA in the SNR. PTZ-induced convulsions did not modify extracellular GABA, neither in control rats nor in valproic acid or gamma-vinyl-GABA pretreated animals. The results do not support the idea that extracellular GABA in the SNR plays a significant role in anti-convulsive treatment. However, the present data can also be interpreted that extracellular GABA, as sampled by microdialysis, is not a reliable marker for GABA release.