Effect of aminooxyacetic acid, thiosemicarbazide and haloperidol on the metabolism and half-lives of glutamate and GABA in rat brain

The activity of the enzymes glutamate decarboxylase (GAD) and GABA-2-oxoglutarate transaminase (GABA-T), the endogenous GABA and glutamate levels and the half-lives ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ values) of radioactive GABA and glutamate have been measured in the brains of untreated rats and in those injected with aminooxyacetic acid (AOAA), thiosemicarbazide (TSC) and haloperidol. The effect of the drugs in vitro on a purified preparation of glutamate dehydrogenase (GDH) was also measured.AOAA profoundly inhibited GABA-T, did not inhibit GAD and in in vitro experiments activated GDH. Brain glutamate levels were unaffected by the drug as was the half-life for glutamate. Brain GABA levels were elevated after AOAA and the rate of disappearance of radioactive GABA slowed.TSC did not significantly alter either GABA or glutamate brain levels but did significantly inhibit GAD and GDH activities. In addition, TSC had no effect on the half-life of either GABA or glutamate.Haloperidol was an effective inhibitor of GDH in vitro and reduced brain glutamate concentrations in vivo. Moreover, the rate of disappearance of radioactive GABA was increased whereas that of glutamate was decreased. The drug had no effect on GAD and GABA-T activities or on brain levels of GABA.It is suggested that the behavioural effects of haloperidol might in part be due to actions on the metabolism of GABA and glutamate. Interaction of TSC with glutamate metabolism might be a factor in seizure-provoking activity of the drug.     

Effect of 2-pyrrolidone on the concentration of GABA in rat tissues

The effects of 2-pyrrolidone, a cyclic lactam of GABA, were studied on blood and organ levels of 2-pyrrolidone, GABA, glutamic acid, glutamate decarboxylase (GAD) and GABA-transaminase (GABA-T). When administered i.p., the only significant effects observed were increases of brain and liver 2-pyrrolidone. In contrast, regular oral administration for 7 months produced significant increases of GABA and glutamic acid in brain and of glutamic acid alone in liver while GAD decreased in brain and increased in liver; GABA-T was unchanged. A new method for the synthesis of radioactive 2-pyrrolidone was set up and the enzymatic conversion of 2-pyrrolidone to GABA was measured by an original procedure. The results obtained in vitro by this method on the conversion of 2-pyrrolidone to GABA catalyzed by tissue slices, together with the observed inhibition of the GABA-dependent oxygen consumption by 2-pyrrolidone, partially explain the effects of the oral administration.     

Effect of the convulsive agent 3-mercaptopropionic acid on the levels of GABA, other amino acids and glutamate decarboxylase in different regions of the rat brain

Intraperitoneal injection of 3-mercaptopropionic acid into rats caused severe convulsions which started after about 7 min. Of the amino acids examined only the level of GABA changed after 4 min and immediately before (6.5–7 min) the convulsions started. The decrease in GABA concentration detected immediately before the onset of convulsions was about 35 per cent in the cerebral cortex, corpus striatum and cerebellum, 30 per cent in pons-medulla and 20% in hippocampus. Concomitant with the fall in GABA there was a large, reversible inhibition of glutamate decarboxylase activity in the brain. The uptake of GABA into synaptosomes isolated after injection of the convulsive agent was not reduced, and the uptake of GABA into synaptosomes was not inhibited by high concentrations of 3-mercaptopropionic acid added in vitro. During convulsions levels of aspartate and taurine decreased significantly in all the brain regions investigated. A small increase in glutamine was detected in pons-medulla and in cerebellum. Major changes in the concentrations of other amino acids such as glutamate, alanine, serine and glycine were found only in corpus striatum.     

Effects of acute and continuous pentobarbital administration on the gamma-aminobutyric acid system

Effects of acute anesthetic doses and chronic administration of pentobarbital on γ-aminobutyric acid (GABA) and glutamic acid levels in mouse brain have been investigated. Acute administration of pentobarbital caused an increase in the brain level of GABA which was associated with pentobarbital-induced narcosis. This was further substantiated by the finding that pentobarbital-induced sleeping time was prolonged when brain GABA level was elevated by the administration of either amino-oxyacetic acid (AOAA), an inhibitor of GABA-2-oxoglutarate aminotransferase (GABA-T), or glutamate, the precursor of GABA. In addition, the activity of l-glutamate-1-carboxylase (GAD) measured during pentobarbital-induced narcosis was higher than that of the control group. On the other hand, chronic administration of pentobarbital resulted in a decrease of both GABA and glutamate levels. There was a concomitant 30 per cent decrease in the activity of GAD. This was confirmed by the finding that the rate of brain GABA accumulation induced by AOAA administration in tolerant mice was slower than that of the non-tolerant animals. Brain GABA remained at significantly lower levels after an abrupt withdrawal from pentobarbital; however, brain glutamate levels showed no significant difference as compared to the control group. It appears that the GABA system in the central nervous system may be involved in barbiturate narcosis and further linked with the development of tolerance to barbiturate.     

Reduced inhibition of cortical glutamate and GABA release by halothane in mice lacking the K+ channel, TREK-1

BACKGROUND AND PURPOSE: Deletion of TREK-1, a two-pore domain K(+) channel (K(2P)) activated by volatile anaesthetics, reduces volatile anaesthetic potency in mice, consistent with a role for TREK-1 as an anaesthetic target. We used TREK-1 knockout mice to examine the presynaptic function of TREK-1 in transmitter release and its role in the selective inhibition of glutamate vs GABA release by volatile anaesthetics. EXPERIMENTAL APPROACH: The effects of halothane on 4-aminopyridine-evoked and basal [(3)H]glutamate and [(14)C]GABA release from cerebrocortical nerve terminals isolated from TREK-1 knockout (KO) and littermate wild-type (WT) mice were compared. TREK-1 was quantified by immunoblotting of nerve terminal preparations. KEY RESULTS: Deletion of TREK-1 significantly reduced the potency of halothane inhibition of 4-aminopyridine-evoked release of both glutamate and GABA without affecting control evoked release or the selective inhibition of glutamate vs GABA release. TREK-1 deletion also reduced halothane inhibition of basal glutamate release, but did not affect basal GABA release. CONCLUSIONS AND IMPLICATIONS: The reduced sensitivity of glutamate and GABA release to inhibition by halothane in TREK-1 KO nerve terminals correlates with the reduced anaesthetic potency of halothane in TREK-1 KO mice observed in vivo. A presynaptic role for TREK-1 was supported by the enrichment of TREK-1 in isolated nerve terminals determined by immunoblotting. This study represents the first evidence for a link between an anaesthetic-sensitive 2-pore domain K(+) channel and presynaptic function, and provides further support for presynaptic mechanisms in determining volatile anaesthetic action.     

N-demethylation of methyl and dimethyl derivatives of phenytoin and their anticonvulsant activities in mice

Anticonvulsant activities of 3-methylphenytoin (3-MP) and 1,3-dimethylphenytoin (1,3-DMP) were observed to peak 3 hr after i.p. administration of the drugs dissolved in dimethylsulphoxide (DMSO), while maximal activity was obtained within 15 min with phenytoin. HPLC was employed to monitor the plasma concentrations of all three compounds at various time intervals after injecting 3-MP or 1,3-DMP. In both cases, phenytoin appeared in the plasma, gradually reaching 14-15 micrograms/ml in 3 hr. The time course of increase in plasma phenytoin levels correlated with that of anticonvulsant activities. It was also found that 1,3-DMP gave rise to a major unidentified metabolite as well as 3-MP and phenytoin. This unidentified metabolite eluted only half a minute in front of 3-MP in the HPLC. Mice injected with high doses of 3-MP (100 mg/kg) in DMSO exhibited severe epileptiform activities. Phenobarbital, diazepam and clonazepam were found to protect against such seizures, but not phenytoin, carbamazepine and valproic acid. This shows that 3-MP is at least a pro-convulsant, taking into account that its effects might have been enhanced by DMSO. Unlike phenytoin, 3-MP lacked the ability to inhibit synaptosomal uptakes of both glutamate and GABA. This difference may be related to the fact that phenytoin, but not 3-MP, possesses potent anticonvulsant activity.     

Cleft palate by picrotoxin or 3-MP and palatal shelf elevation in GABA-deficient mice

gamma-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian central nervous system. Gene targeting of GABA-synthetic glutamic acid decarboxylase (GAD) 67 and GABAA receptor beta(3) subunit induces cleft palate in the mouse. These findings appear to contradict previous pharmacological investigations using benzodiazepines and GABA itself, which indicate that GABA suppresses palatogenesis. Therefore, the effects of picrotoxin and 3-mercaptopropionic acid (3-MP) on palate formation were investigated in the present study. Picrotoxin and 3-MP impair GABA functions by blocking the GABA receptor and synthesis, respectively. Pregnant mice in the critical period [Embryonic Day (E) 11-15] of palatogenesis were administered these substances by subcutaneous injection or continuous infusion at subconvulsive doses, and their fetuses at E17-18 were investigated. A complete cleft in the secondary palate was observed in 15% of 333 embryos in 28 litters. In the remaining fetuses, a complete cleft palate was not observed, but microscopic examination of serial sections revealed partial defects of the palate. Furthermore, rescue from cleft palate in GAD67-deficient mice was attempted by GABA infusion. Horizontal elevation of palatal shelves, which is not observed in nontreated mice, did occur after the infusion in all 14 GABA-infused GAD67-deficient fetuses, although cleft palate still persisted. These results indicate that GABA is required for palatogenesis and is consistent with findings in gene knockout mice.     

Effects of diazepam on extracellular brain neurotransmitters in pilocarpine-induced seizures in rats.

The present study was undertaken to gain insights into the mechanism of action of diazepam in focally-evoked pilocarpine-induced seizures by concomitantly assessing the changes produced in the extracellular levels of glutamate, GABA (gamma-aminobutyric acid) and dopamine. In vivo microdialysis, coupled to continuous monitoring of electrocorticographic (ECoG) recordings, was performed in freely moving rats. Intrahippocampal perfusion with 10 mM pilocarpine (40 min, 2 microl/min) produced limbic seizures. A single dose of intraperitoneal diazepam (5 mg/kg) was administered 2 h after pilocarpine perfusion was started. Dialysates were sampled both from hippocampus and cerebellum and analysed by microbore liquid chromatography. Diazepam produced instant inhibition of behavioural and ECoG seizure activity. Pilocarpine-induced increases in the extracellular levels of glutamate and dopamine in hippocampus were promptly reduced by diazepam. No concurrent alterations in pilocarpine-induced increases in the extracellular levels of GABA in either hippocampus or cerebellum were seen. Pilocarpine enhanced cerebellar glutamate levels only transiently and levels returned to baseline before diazepam administration. No further changes in cerebellar glutamate levels were observed with diazepam. Our findings suggest that the anti-convulsant action of diazepam against pilocarpine-induced seizures is associated with a prompt attenuation of extracellular hippocampal glutamate overflow without concurrent alteration of pilocarpine-induced increases in endogenous GABA levels. Diazepam also significantly decreased pilocarpine-induced increases in extracellular dopamine levels within the hippocampus. No immediate alterations of the basal levels of the neurotransmitters monitored were observed with diazepam.     

Cardiovascular effects of 3-mercaptopropionic acid and levels of GABA in regions of the brain of guinea-pigs

3-Mercaptopropionic acid (3-MP), an inhibitor of the synthesis of gamma-aminobutyric acid (GABA), was administered to anesthetized rats and guinea-pigs in order to examine the relationship between the effect of this agent on regional levels of GABA in the brain and cardiovascular function. After a latent period, 3-mercaptopropionic acid (0.16 ml/kg, i.p.) produced initial increases in blood pressure and heart rate in rats followed by vagal bradycardia and hypotension. Guinea-pigs treated with 3-mercaptopropionic acid developed one of three patterns of cardiovascular changes. The type I response consisted of a period of sympathetically-mediated hypertension and tachycardia followed by vagal bradycardia. Type II animals exhibited increased arterial pressure and heart rate, but no vagal activation. Type III and control animals exhibited no significant cardiovascular changes following administration of 3-mercaptopropionic acid or appropriate vehicle. Regional levels of GABA in brain, measured at 90 min after treatment were significantly lower than control in type I and II animals in 3 of 4 areas of the brain measured, but not in type III guinea-pigs. When decreases in levels of GABA were compared to the changes in cardiovascular parameters for individual animals, the decrease in heart rate at the time of sacrifice was directly correlated with the decrease in medullary levels of GABA in type I animals. Conversely, in type II guinea-pigs, decreases in hypothalamic levels of GABA correlated inversely with heart rate at sacrifice. These results suggest that activation of cardiac sympathetic and parasympathetic nervous pathways following the administration of 3-mercaptopropionic acid may result from decreased levels of GABA in different regions of the brain.     

Studies on the relation of γ-hydroxybutyric acid (GHB) to γ-aminobutyric acid (GABA): Evidence that GABA is not the sole source for GHB in rat brain

The effects of γ-aminobutyric acid (GABA)-α-oxoglutarate aminotransferase (GABA-T) inhibitors, l-glutamic acid decarboxylase (GAD) inhibitors, and antipetit mal anticonvulsants on γ-hydroxybutyric acid (GHB) and GABA were studied. Treatment with anticonvulsants and GABA-T inhibitors resulted in an increase in steady-state brain levels of both GHB and GABA. GAD inhibitors produced markedly decreased levels of brain GABA but no change in GHB concentrations. Studies of GHB derived exclusively from GABA showed that GABA-T inhibitors which produced an elevation of steady-state levels of GHB in brain also resulted in a decrease in GABA-derived GHB. Intracere-broventricular (i.c.v.) administration of GABA, putrescine, and 1,4-butanediol all produced significant elevations in brain GHB, but GABA-T inhibitors blocked this effect of GABA and putrescine. These data suggest that there may be another source for GHB in brain in addition to GABA and raise the possibility that 1,4-butanediol may be that source.     

3-Mercaptopropionic acid: convulsant properties, effects on enzymes of the gamma-aminobutyrate system in mouse brain and antagonism by certain anticonvulsant drugs, aminooxyacetic acid and gabaculine.

Subcutaneous injection of 3-mercaptopropionic acid (MP) into mice caused severe convulsions which started after about 6 min and were paralleled by a large, reversible inhibition of glutamate decar?ylase (GAD) and activation of (GABA)-α-oxoglutarate aminotransferase (GABA-T) in the brain. The central (GABA) level, determined by a newly developed gas Chromatographic method, was not altered after administration of the CD 97 of MP (60 mg/kg) but decreased after doubling or tripling the dose. Protection against the convulsions elicited by MP could be effected by pretreatment with phenobarbital, phenytoin, diazepam, carbamazepine, sodium valproate and trimethadione but not by ethosuximide and dimethadione. The ED 50's of the respective anticonvulsants against MP were similar to those determined against picrotoxin but, except in the case of trimethadione clearly less than those against strychnine-induced convulsions. All anticonvulsants effective against the convulsions of MP reversed the activation of GABA-T and tended to antagonize the inhibition of GAD caused by MP whereas dimethadione and ethosuximide were devoid of such action. The dissociative anaesthetic ketamine, which suppressed the MP-induced convulsions only at doses approaching the anaesthetic level, also failed to antagonize the alterations in the enzyme activities. Aminooxyacetic acid (AOAA) and gabaculine ((?)-5-amino-1,3-cyclohexadiene car?yclic acid) had a dose-dependent anticonvulsant effect against MP (ED 50 27 mg/kg s. c. and 135 mg/kg i. p., respectively) but at doses which were potentially (AOAA) or absolutely (gabaculine) lethal (LD 50 40 mg/kg and 62 mg/kg, respectively). Both drugs antagonized the inhibition of GAD caused by MP, reduced the activity of GABA-T to zero and raised the central level of GABA by more than 500 per cent.The results suggest a role played by the GABA system in the convulsant action of M P and in the antiseizure activity of several clinically useful anticonvulsants as well as AOAA and gabaculine. With respect to the GABA system, MP seems to be a useful tool in studies of experimental epilepsy.     

The influence of manipulations to alter ambient GABA concentrations on the hypnotic and immobilizing actions produced by sevoflurane, propofol, and midazolam

Recent studies have suggested that extrasynaptic GABA(A) receptors, which contribute tonic conductance, are important targets for general anesthetics. We tested the hypothesis that manipulations designed to alter ambient GABA concentrations (tonic conductance) would affect hypnotic (as indicated by loss of righting reflex, LORR) and immobilizing (as indicated by loss of tail-pinch withdrawal reflex, LTWR) actions of sevoflurane, propofol, and midazolam. Two manipulations studied were 1) the genetic absence of glutamate decarboxylase (GAD) 65 gene (GAD65-/-), which purportedly reduced ambient GABA concentrations, and 2) the pharmacological manipulation of GABA uptake using GABA transporter inhibitor (NO-711). The influence of these manipulations on cellular and behavioral responses to the anesthetics was studied using behavioral and electrophysiological assays. HPLC revealed that GABA levels in GAD65-/- mice were reduced in the brain (76.7% of WT) and spinal cord (68.5% of WT). GAD65-/- mice showed a significant reduction in the duration of LORR and LTWR produced by propofol and midazolam, but not sevoflurane. NO-711 (3?mg/kg, ip) enhanced the duration of LORR and LTWR by propofol and midazolam, but not sevoflurane. Patch-clamp recordings revealed that sevoflurane (0.23?mM) slightly enhanced the amplitude of tonic GABA current in the frontal cortical neurons; however, these effects were not strong enough to alter discharge properties of cortical neurons. These results demonstrate that ambient GABA concentration is an important determinant of the hypnotic and immobilizing actions of propofol and midazolam in mice, whereas manipulations of ambient GABA concentrations minimally alter cellular and behavioral responses to sevoflurane.     

Hypophysial GABA after ether stress, dexamethasone or inhibition of GABA catabolism

Ether stress (2 X 2 min within 15 min) and dexamethasone treatment (1 mg/kg IP; 1, 3 and 12 hours before sacrifice), the procedures supposed to increase the activity of glutamate decarboxylase (GAD) in the hypothalamus, fail to affect the concentration of GABA in the rat hypophysis. Five and/or ten minutes post-mortem an increased GABA level in the hypothalamus and cingulate cortex, and a decreased GABA concentration in the hypophysis was found. Three and four hours after the IP administration of 1-cycloserine (50 mg/kg) and 1-glutamic acid-gamma-hydrazide (160 mg/kg) respectively (both drugs are inhibitors of GABA catabolism) the concentration of GABA raised in all the regions examined. On the basis of studies in the whole gland it might be concluded that the concentration of GABA in the hypophysis depends more on GABA release from extrahypophysial tissue and GABA degradation in the hypophysis than on the extrahypophysial GABA synthesis. Also on the basis of post-mortem studies in the whole gland no indication for the appearance of GABA synthesis in hypophysis could be found.     

γ-Aminobutyric acid metabolism in rat brain following chronic oral administration of ethanolamine O-sulphate

Chronic, oral EOS¹ administration resulted in a marked inhibition of rat whole-brain GABA-T activity and a significant increase in brain GABA concentrations. The maximum degree of GABA-T inhibition attained was 83 per cent, when GABA levels were 200 per cent of control values. A fixed dose of EOS produced a steady fall in GABA-T activity over the first 7 days of administration, when enzyme activity appeared to stabilize at 20–25 per cent of control values. Concurrently, GABA levels rose to a steady maximum value of approximately 240 per cent of control values. These changes were accompanied by significant reductions in whole-brain GAD activity. Chronic EOS also produced small but significant increases in brain content of alanine and taurine. No behavioural changes were seen following chronic EOS administration.     

Immunohistochemical study on GABAergic system in salivary glands

Gamma-aminobutyric acid (GABA) and its receptors are found in the central nervous system and several peripheral tissues. The purpose of this study was to determine the expression and distribution of GABA and glutamate decarboxylase (GAD), a GABA biosynthetic enzyme, in rat salivary gland. Western blot and real time quantitative RT-PCR revealed that GAD67 was the major isoform of GAD in the salivary glands. Furthermore, both GABA and GAD were detected around the acinar cells in the submandibular glands by immunohistochemical analysis. When both sympathetic and parasympathetic nerves related to the submandibular glands were denervated, the immunoreactivities of GABA and GAD were dramatically depressed, and levels of GAD67 and GABA significantly decreased. However, no morphological changes in the glands were observed after denervation. These results indicate that GAD67 is present around acinar cells in the salivary glands, and suggest that the GABAergic system in the glands is closely related to the autonomic nervous system.     

Development of tolerance to the effects of vigabatrin (gamma-vinyl-GABA) on GABA release from rat cerebral cortex, spinal cord and retina.

1. The effects of acute and chronic vigabatrin (gamma-vinyl-GABA) (GVG) administration on gamma-aminobutyric acid (GABA) levels and release in rat cortical slices, spinal cord slices and retinas were studied. 2. GVG (250 mgkg-1 i.p.) administered to rats 18 h before death (acute administration) produced an almost 3 fold increase in GABA levels of the cortex and spinal cord and a 6 fold increase in retinal GABA. The levels of glutamate, aspartate, glycine and taurine were unaffected. 3. When GVG (250 mgkg-1 i.p.) was administered daily for 17 days (chronic administration) a similar (almost 3 fold) increase in cortical GABA occurred but the increases in spinal and retinal GABA were reduced by approximately 40%. 4. Acute administration of GVG strikingly increased the potassium-evoked release (KCl 50 mM) of GABA from all three tissues. This enhanced evoked release was reduced by about 50% in tissues taken from rats that had been chronically treated with GVG. 5. Acute administration of GVG reduced GABA-transaminase (GABA-T) activity by approximately 80% in cortex and cord and by 98% in the retina. Following the chronic administration of GVG, there was a trend for GABA-T activities to recover (significant only in cortex). Acute administration of GVG had no effect on glutamic acid decarboxylase (GAD) activity in cortex or spinal cord. However, chronic treatment resulted in significant decreases in GAD activity in both the cortex and cord (35% and 50% reduction respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered time course of changes in the hippocampal concentration of excitatory and inhibitory amino acids during kainate-induced epilepsy

The temporal sequence of electrophysiological and biochemical correlates of epilepsy induced by systemic injection of kainic acid (15 mg/kg i.p.) was investigated in male rats. A significant decrease in the hippocampal concentration of glutamate and aspartate was observed 20 min after the injection. These decreases preceded both electrographic and behavioral manifestations of epilepsy, thus suggesting a causal relationship between acidic amino acid changes and the genesis of kainate-induced hyperactivity. About 30-45 min after kainate injection, a decrease in glutamate, aspartate, glycine and taurine and no change in GABA concentration were observed. Bioelectrical activity, recorded in the regio inferior (CA3) of the hippocampus or in the fascia dentata revealed the presence of high frequency bursts separated by a long-lasting depression of discharge. About 55-75 min after the injection, the number of spikes in each burst increased and the duration and frequency of interictal pauses decreased. This stage was characterized by a decrease in glutamate and aspartate, restoration to normal of glutamine, glycine and taurine and a decrease in GABA.     

The metabotropic glutamate receptor 7 (mGluR7) allosteric agonist AMN082 modulates nucleus accumbens GABA and glutamate, but not dopamine, in rats

The group III metabotropic glutamate receptor 7 (mGluR7) has been implicated in many neurological and psychiatric diseases, including drug addiction. However, it is unclear whether and how mGluR7 modulates nucleus accumbens (NAc) dopamine (DA), L-glutamate or gamma-aminobutyric acid (GABA), important neurotransmitters believed to be involved in such neuropsychiatric diseases. In the present study, we found that systemic or intra-NAc administration of the mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082) dose-dependently lowered NAc extracellular GABA and increased extracellular glutamate, but had no effect on extracellular DA levels. Such effects were blocked by (R,S)-alpha-methylserine-O-phosphate (MSOP), a group III mGluR antagonist. Intra-NAc perfusion of tetrodotoxin (TTX) blocked the AMN082-induced increases in glutamate, but failed to block the AMN082-induced reduction in GABA, suggesting vesicular glutamate and non-vesicular GABA origins for these effects. In addition, blockade of NAc GABAB receptors by 2-hydroxy-saclofen itself elevated NAc extracellular glutamate. Intra-NAc perfusion of 2-hydroxy-saclofen not only abolished the enhanced extracellular glutamate normally produced by AMN082, but also decreased extracellular glutamate in a TTX-resistant manner. We interpret these findings to suggest that the increase in glutamate is secondary to the decrease in GABA, which overcomes mGluR7 activation-induced inhibition of non-vesicular glutamate release. In contrast to its modulatory effect on GABA and glutamate, the mGluR7 receptor does not appear to modulate NAc DA release.     

Effects of L-DOPA on GABA metabolism in chick brain and retina

The effects of an oral subacute treatment with l-DOPA on GAD, GABA and GABA-T in chick n. basalis (homologous to the mammalian striatum), brain hemispheres, brain-stem and retina were studied. A significant increase in n. basalis GAD activity associated with an increase in GABA content and decrease of GABA-T activity was shown to occur. Similar effects were observed in the brain-stem except for GABA-T which was stimulated. In contrast, in brain hemispheres, l-DOPA produced a decrease in GAD and GABA-T activity. No changes, however, were observed in GAD activity at the retinal level, whereas GABA-T activity was significantly decreased and GABA content increased. In conclusion, the present experiments show that in some areas of the brain the administration of l-DOPA is able to affect GABA turnover.     

GABA(B) receptor-mediated presynaptic inhibition of glutamatergic and GABAergic transmission in the basolateral amygdala

The information processing at central synapses is mediated not only by homosynaptic transmission with direct synaptic connections but also by heterosynaptic interactions between distinct synaptic inputs. Using rat brain slices and whole-cell recordings this study aimed to examine the roles of GABA(B) receptors in synaptic interactions in the basolateral amygdala (BLA), a critical brain structure related to fear and anxiety. Stimulation in the BLA produced non-NMDA type glutamate receptor antagonist-sensitive excitatory postsynaptic currents (EPSCs) and bicuculline-sensitive inhibitory postsynaptic currents (IPSCs) in the BLA neurons. The GABA(B) receptor agonist baclofen markedly inhibited both EPSCs and IPSCs in a concentration-dependent manner, and the baclofen-induced inhibition was selectively abolished by the GABA(B) receptor antagonist CGP55845A. The paired-pulse ratio of EPSC and IPSC amplitude was increased by baclofen. The effect of baclofen was mimicked by lowering the external Ca2+ concentration but not by glutamate- and GABA(A)-receptor antagonists. The frequency but not the mean amplitude of miniature EPSCs and IPSCs was decreased by baclofen. The findings suggest that activation of GABA(B) receptors by baclofen reduces the strength of excitatory and inhibitory transmission in the BLA by a presynaptic mechanism. Repetitive conditioning stimulation applied to GABAergic synaptic inputs exerted an inhibitory action on glutamatergic excitatory transmission, and the stimulation-induced inhibition was abolished by CGP55845A. Furthermore, the paired-pulse ratio of EPSCs was increased during the stimulation-induced inhibition. The results in this study provide evidence that synaptic activation of GABA(B) heteroreceptors elicits presynaptic inhibition of glutamatergic excitatory transmission in the BLA.