Identification of gamma-aminobutyric acid in brain by the isotope derivative method.
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Aminobutyrates↗
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Detection of glutamate and gamma-aminobutyric acid in vitreous of patients with proliferative diabetic retinopathy.
PURPOSE: To study the levels of glutamate and gamma-aminobutyric acid (GABA) in vitreous of patients with proliferative diabetic retinopathy (PDR) and to investigate their roles in retinal ischemia. METHOD: Vitreous samples were collected from 25 patients (27 eyes) with PDR and 14 patients (14 eyes) with idiopathic macular hole. Glutamate and GABA detection were performed by high-performance liquid chromatography (HPLC). RESULTS: Patients with PDR had significantly higher concentrations of glutamate and GABA than the control group. The glutamate level has a significantly positive correlation with GABA level. CONCLUSION: Detection of glutamate and GABA in vitreous provides biochemical support for the mechanism and treatment of ischemic retinal damage in patients with PDR.
Diabetic Retinopathy↗
Effect of propofol on glutamate and gamma-aminobutyric acid release from rat hippocampal synaptosomes.
To investigate the effect of propofol on the release of glutamate and gamma-aminobutyric acid (GABA) from rat hippocampal synatosomes, synaptosomes was made from hippocampus and incubated with artificial cerebrospinal fluid (aCSF). With the experiment of Ca(2+)-dependent release of glutamate and GABA, dihydrokainic acid (DHK) and nipectic acid were added into aCSF. For the observation of Ca(2+)-independent release of glutamate and GABA, no DHK, nipectic acid and Ca2+ were added from aCSF. The release of glutamate and GABA were evoked by 20 micromol/L veratridine or 30 mmol/L KCI. The concentration of glutamate and GABA in aCSF was measured by using high-performance liquid chromatography (HPLC). 30, 100 and 300 micromol/L propofol significantly inhibited veratridine-evoked Ca(2+)-dependent release of glutamate and GABA (P < 0.01 or P < 0. 05). However, propofol showed no effect on elevated KCl-evoked Ca(2+)-dependent release of glutamate and GABA (P > 0.05). Veratridine or elevated KCI evoked Ca(2+)-independent release of glutamate and GABA was not affected significantly by propofol (P > 0.05). Propofol could inhibit Ca(2+)-dependent release of glutamate and GABA. However, it has no effect on the Ca(2+)-independent release of glutamate and GABA.
Anesthetics, Intravenous↗
Induced release of gamma-aminobutyric acid by a carrier-mediated, high-affinity uptake of L-glutamate in cultured chick retina cells.
[3H]gamma-aminobutyric acid (GABA) was taken up by cultured embryonic retina cells during the initial stages of cell differentiation. The accumulated GABA was released in the bathing medium and a transient increase in the efflux of GABA was observed when cultures were pulse-stimulated (2 min) with 0.1 mM L-glutamate but not with D-glutamate. The EC50 for L-glutamate to evoke [3H]GABA release was approximately 15 microM. This value is close to the Km for high-affinity uptake of L-glutamate by retina cells. When Na+ ions were replaced by Li+ ions, L-glutamate-induced release of GABA was abolished. Moreover, L-[14C]glutamate uptake by retina cells was significantly reduced when NaCl was replaced by LiCl in the incubation medium. L-Glutamate elicited release of GABA was Ca2+ independent, and was observed when Ca2+ was replaced by Co2+ or when Mg2+ ions were increased to 10 mM concentration. D-Aspartate, which is taken up by the same high-affinity uptake mechanism as L-glutamate, induced an increase in [3H]GABA efflux comparable to L-glutamate. The addition of unlabeled GABA to the medium also promoted the release of accumulated [3H]GABA. However, GABA was twofold less effective than L-glutamate in eliciting [3H]GABA release. The addition of both GABA and L-glutamate to the incubation medium indicated that [3H]GABA efflux due to L-glutamate and GABA was additive. L-Aspartate also promoted an increase in the efflux of [3H]GABA accumulated by retina cells. However, L-aspartate effect was significantly decreased in the absence of Ca2+ or when Na+ ions were replaced by Li+. Our results indicate that at least three releasable pools of GABA are present in the chick embryo retina cells: (a) a GABA-promoted GABA release-homoexchange, (b) a Ca2+-dependent L-aspartate-promoted release, and (c) a Ca2+-independent, Na+-dependent L-glutamate-evoked release. In addition, our data strongly suggest that the L-glutamate-promoted GABA release is due to a process of exchange of L-glutamate with GABA, which may play a fundamental role in the fine control of the excitability of local circuits in the retina.
Animals↗
Effect of gonadal steroids and gamma-aminobutyric acid on LH release and dopamine expression and activity in the zona incerta in rats.
A dopaminergic system in the zona incerta stimulates LH release and may mediate the positive feedback effects of the gonadal steroids on LH release. In this study the mechanisms by which steroids might increase dopamine activity in the zona incerta were investigated. In addition, experiments were conducted to determine whether the inhibitory effects of gamma-aminobutyric acid (GABA) on LH release in the zona incerta are due to suppression of dopamine activity in this area or conversely whether the stimulatory effects of dopamine on LH release are due to suppression of a tonic inhibitory GABAergic system. Ovariectomized rats were treated s.c. with oil, 5 micrograms oestradiol benzoate or 5 micrograms oestradiol benzoate followed 48 h later by 0.5 mg progesterone, and killed 54 h after the oestradiol benzoate injection. At this time the LH concentrations were suppressed in the oestradiol benzoate group and increased in the group treated with oestradiol benzoate and progesterone. The ratio of tyrosine hydroxylase:beta-actin mRNA in the zona incerta was significantly increased by the oestradiol benzoate treatment, but the addition of progesterone resulted in values similar to those in the control group. At the same time, the progesterone treatment increased tyrosine hydroxylase activity in the zona incerta as indicated by an increase in L-dihydroxyphenylalanine (L-DOPA) accumulation after 100 mg 3-hydroxybenzylhydrazine hydrochloric acid (NSD1015) kg-1 and an increase in dopamine release as indicated by a increase in dihydroxyphenylacetic acid (DOPAC) concentrations (one of the major metabolites of dopamine). Ovariectomized rats treated with oestradiol benzoate plus progesterone were also injected i.p. with 75 mg gamma-acetylenic GABA kg-1 (a GABA transaminase inhibitor) to increase GABA concentrations in the brain. This treatment had no effect on the ratio of tyrosine hydroxylase:beta-actin mRNA but decreased L-DOPA accumulation and DOPAC concentrations in the zona incerta, indicating a post-translational inhibition of dopamine synthesis and release. Treatment of ovariectomized rats with oestradiol benzoate followed by 100 mg L-DOPA i.p. to increase dopamine concentrations in the whole brain had no effect on glutamic acid decarboxylase mRNA expression in the zona incerta, although it increased the glutamic acid decarboxylase:beta-actin mRNA ratio in other hypothalamic areas (that is, the medical preoptic area, ventromedial nucleus and arcuate nucleus). In conclusion, the steroids act to increase dopamine activity in different ways: oestrogen increases tyrosine hydroxylase mRNA expression and progesterone acts after translation to increase tyrosine hydroxylase activity and dopamine release (as indicated by increases in DOPAC concentrations). This latter effect may be due to progesterone removing a tonic GABAergic inhibition from the dopaminergic system.
3,4-Dihydroxyphenylacetic Acid↗
Cortical lesions modulate turnover rates of acetylcholine and gamma-aminobutyric acid.
Interruption of the cortico-striatal glutamatergic pathway by decoratication results in significant decreases in the turnover rates of acetylcholine TRACh and gamma-aminobutyric acid TRGABA of striatum. These data support the hypothesis that the cortical input to the striatum is excitatory and acts to modulate cholinergic and GABAergic function in this nucleus. Studies of kainate-induced lesions of the striatum also indicate that most striatal cholinergic interneurons receive a glutamatergic input and that multiple injections of kainate are required to destroy this large population of interneurons.
Acetylcholine↗
gamma-Aminobutyric acid inhibits the release of alpha-melanocyte-stimulating hormone from rat hypothalamic slices.
The effect of gamma-aminobutyric acid (GABA) on release of alpha-melanocyte-stimulating hormone (alpha-MSH) from hypothalamic neurons was investigated in vitro using the perifusion technique. Rat hypothalamic slices were continuously superfused with Krebs-Ringer medium and the release of alpha-MSH in the effluent perifusate was monitored by means of a sensitive and specific radioimmunoassay method. Infusion of 50 mM K+ for 15 min induced a transient increase of alpha-MSH release (5- to 8-fold above the spontaneous level). Infusion of the same dose of K+ for 75 min caused a brief discharge of alpha-MSH during the first 30 min followed by sustained release of the neuropeptide. The effect of GABA was investigated 27 min after the onset of KCl infusion. Application of GABA (5 x 10(-5) M) resulted in a significant and reversible inhibition of K+-induced alpha-MSH release. The GABAA agonist, muscimol (10(-4) M), produced a prolonged inhibition of K+-evoked alpha-MSH release, while the GABAB agonist, baclofen (10(-4) M), was devoid of effect on hypothalamic alpha-MSH release. Bicuculline (10(-4) M), a specific GABAA antagonist, had no effect when added alone to the medium but totally reversed the inhibitory effect of GABA on K+-induced alpha-MSH release. Taken together, these data suggest that exogenous GABA exerts an inhibitory control on alpha-MSH neurons. Our data also show that the effect of GABA on alpha-MSH release by hypothalamic neurons is mediated through GABAA-type receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Aminooxyacetic Acid↗
High-affinity transport of gamma-aminobutyric acid, glycine, taurine, L-aspartic acid, and L-glutamic acid in synaptosomal (P2) tissue: a kinetic and substrate specificity analysis.
In a cortical P2 fraction, [14C]gamma-aminobutyric acid ([14C]GABA), [14C]glycine, [14C]taurine, and [14C]glutamic and [14C]aspartic acids are transported by four separate high-affinity transport systems with L-glutamic acid and L-aspartic acid transported by a common system. GABA transport in cortical synaptosomal tissue occurs by one high-affinity system, with no second, low-affinity, transport system detectable. Only one high-affinity system is observed for the transport of aspartic/glutamic acids; as with GABA transport, no low-affinity transport is detectable. In the uptake of taurine and glycine (cerebral cortex and pons-medulla-spinal cord) both high- and low-affinity transport processes could be detected. The high-affinity GABA and high-affinity taurine transport classes exhibit some overlap, with the GABA transport system being more specific and having a much higher Vmax value. High-affinity GABA transport exhibits no overlap with either the high-affinity glycine or the high-affinity aspartic/glutamic acid transport class, and in fact they demonstrate somewhat negative correlations in inhibition profiles. The inhibition profiles of high-affinity cortical glycine transport and those of high-affinity cortical taurine and aspartic/glutamic acid transport also show no significant positive relationship. The inhibition profiles of high-affinity glycine transport in the cerebral cortex and in the pons-medulla-spinal cord show a significant positive correlation with each other; however, high-affinity glycine uptake in the pons-medulla-spinal cord is more specific than that in the cerebral cortex. The inhibition profile of high-affinity taurine transport exhibits a nonsignificant negative correlation with that of the aspartic/glutamic acid transport class.
Amino Acids↗
Inhibition by gamma-aminobutyric acid system activation of epileptic seizures in spontaneously epileptic rats.
The effects of muscimol, a gamma-aminobutyric acid (GABA)A-receptor agonist, and aminooxy-acetic acid (AOAA), an inhibitor of GABA-converting enzyme, on tonic and absence-like seizures in spontaneously epileptic rats (SER: zi/zi, tm/tm) were investigated to elucidate whether GABAergic function operates normally in these animals. Muscimol at doses of 1 and 3 mg/kg (i.p.) induced high-voltage slow waves in the cortical and hippocampal EEG of SER, although the behavioral observation suggested inhibition of absence-like seizures. Similar high-voltage slow waves were also observed in the cortical and hippocampal EEG of normal rats with muscimol (1 and 3 mg/kg). Tonic convulsions in SER were dose-dependently inhibited by muscimol. AOAA (3 and 10 mg/kg, i.v.) inhibited both tonic and absence-like seizures in SER, although there were no obvious changes in EEG pattern. The inhibitory effects of AOAA on tonic convulsions appeared more slowly and lasted longer than those on absence-like seizures. Cerebral, hippocampal and cerebellar GABA levels were significantly higher in SER than the normal Kyo:Wistar and zitter rat (zi/zi), which were both the parent strains. These findings suggest that GABA receptors and GABAergic neurons are functional in SER and that the GABA system is involved in the inhibition of both seizures.
4-Aminobutyrate Transaminase↗
Evidence for a dual effect of gamma-aminobutyric acid on thyrotropin (TSH)-releasing hormone-induced TSH release from perifused rat pituitaries.
The effects of gamma-aminobutyric acid (GABA) on the spontaneous and TRH-induced TSH release were investigated in vitro on perifused rat pituitaries. The dynamic pattern of TSH release was measured in response to a 6-min pulse of TRH (10 nM) with or without GABA addition. GABA had no effect on spontaneous TSH release but exhibited a dual effect on TSH-stimulated release according to the dose (as calculated by the induced-basal ratio): a potentiation of the TSH response to TRH at the lowest concentrations tested (less than or equal to 10 nM) and an inhibition for GABA concentrations equal or higher than 100 nM. The GABA potentiation was mimicked by muscimol (10 microM) and isoguvacine (10 nM) but not by baclofen (1 microM). Bicucullin (1 microM) or picrotoxin (1 microM) added 15 min before GABA was unable to reverse the GABA potentiation of the TSH response, although SR 95103 (1 and 10 microM), a specific GABA A antagonist, partially or totally antagonized this response. Diazepam (7 nM) was able to potentiate the TSH response by 216% when GABA was added to the system at a concentration (60 nM) which does not modify by itself the TSH response. The inhibitory effect of GABA (100 nM) was completely abolished by bicucullin (1 microM), by picrotoxin (1 microM), and by SR 95103 (1 microM). Picrotoxin not only blocked the inhibitory action of GABA but significantly (P less than 0.05) potentiated the TSH response to TRH. Our data suggest a dual GABA-ergic control of TRH-stimulated TSH release directly on the pituitary, probably mediated by two different kinds of GABA receptors: a GABA A receptor site mediating the inhibitory effect and a nonclassical GABA A receptor site of higher affinity for its stimulatory action.
Animals↗
gamma-Aminobutyric acid(A) neurotransmission and cerebral ischemia.
In this review, we present evidence for the role of gamma-aminobutyric acid (GABA) neurotransmission in cerebral ischemia-induced neuronal death. While glutamate neurotransmission has received widespread attention in this area of study, relatively few investigators have focused on the ischemia-induced alterations in inhibitory neurotransmission. We present a review of the effects of cerebral ischemia on pre and postsynaptic targets within the GABAergic synapse. Both in vitro and in vivo models of ischemia have been used to measure changes in GABA synthesis, release, reuptake, GABA(A) receptor expression and activity. Cellular events generated by ischemia that have been shown to alter GABA neurotransmission include changes in the Cl(-) gradient, reduction in ATP, increase in intracellular Ca(2+), generation of reactive oxygen species, and accumulation of arachidonic acid and eicosanoids. Neuroprotective strategies to increase GABA neurotransmission target both sides of the synapse as well, by preventing GABA reuptake and metabolism and increasing GABA(A) receptor activity with agonists and allosteric modulators. Some of these strategies are quite efficacious in animal models of cerebral ischemia, with sedation as the only unwanted side-effect. Based on promising animal data, clinical trials with GABAergic drugs are in progress for specific types of stroke. This review attempts to provide an understanding of the mechanisms by which GABA neurotransmission is sensitive to cerebral ischemia. Furthermore, we discuss how dysfunction of GABA neurotransmission may contribute to neuronal death and how neuronal death can be prevented by GABAergic drugs.
Adenosine Triphosphate↗
Inhibitory effects of quinolone antibacterial agents on gamma-aminobutyric acid binding to receptor sites in rat brain membranes.
The specific binding of 3H-labeled gamma-aminobutyric acid ([3H]GABA) to synaptic plasma membranes from rat brains was inhibited by various quinolonecarboxylic acid derivatives (quinolones), and these inhibitions were concentration dependent. The binding of [3H]muscimol to GABAA sites was also inhibited. These inhibitory potencies differed widely among the quinolones examined. The Dixon plots showed that a newly developed difluorinated quinolone, NY-198 [1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid hydrochloride], competitively inhibits the receptor bindings of [3H]GABA and [3H]muscimol. In conclusion, our findings suggest that the inhibition of GABA binding to receptors (including uptake sites) in the brain may be involved in the induction of epileptogenic neurotoxicities by quinolones.
Animals↗
Effect of 2-methyl 2-ethyl caproic acid and 2-2-dimethyl valeric acid on audiogenic seizures and brain gamma aminobutyric acid.
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Aminobutyrates↗
[Transformation of glutamic acid, putrescine and ornithine into gamma-aminobutyric acid in brain].
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Aminobutyrates↗
Potassium induced release of endogenous glutamate, gamma-aminobutyric acid (GABA) and glycine from the caudal dorsomedial medulla of the rat.
Release of endogenous glutamate, gamma-aminobutyric acid (GABA) and glycine was investigated in the caudal dorsomedial (CDM) region of the rat medulla oblongata. High potassium stimulation (50 mM) produced an increase in release of glutamate, GABA and glycine by 579.1, 303.4 and 774.5 (pmol/mg protein), respectively. The release was abolished by Ca2+ deprivation. These results indicate a possible neurotransmitter role for glutamate, GABA and glycine in the CDM medulla of the rat.
Animals↗
Endogenous release of gamma-aminobutyric acid from the medial preoptic area measured by microdialysis in the anaesthetised rat.
The characteristics of gamma-aminobutyric acid (GABA) release as monitored by microdialysis have been investigated in the chloral hydrate anaesthetised rat. The high outflow of GABA following insertion of the microdialysis probe (membrane 2 mm in length, 0.5 mm in diameter) into the medial preoptic area was found to decline to a stable baseline level after 2 h. After this time, perfusion with a medium containing 100 mM potassium ions evoked a 56-fold increase in GABA outflow. The addition of the calcium channel blocker verapamil (100 microM) to the perfusion medium induced significant 25 and 50% reductions in basal and potassium-stimulated GABA outflow, respectively. In the same animals, verapamil caused an 80% decrease in potassium-stimulated noradrenaline outflow. The glutamic acid decarboxylase inhibitors 3-mercaptopropionic acid and L-allylglycine added to the perfusion medium at a concentration of 10 mM reduced basal GABA release by approximately 50% with different time-courses of action. Ethanolamine-O-sulfate, a GABA-transaminase inhibitor, induced significant increases in basal GABA outflow 90 min after inclusion in the perfusion medium. These results demonstrate that microdialysis is a suitable technique with which to monitor extracellular levels of GABA and provide in vivo data on GABA release and degradation mechanisms.
4-Aminobutyrate Transaminase↗
Induction of c-fos mRNA expression in an in vitro hippocampal slice model of adult rats after kainate but not gamma-aminobutyric acid or bicuculline treatment.
Levels of gene expression following in vitro treatment of rat hippocampal slices with kainate, gamma-aminobutyric acid (GABA), or bicuculline were measured by the reverse transcription-coupled polymerase chain reaction method. Following a short-term exposure to kainate, c-fos gene expression was induced by 12-fold in the adult, but not the newborn, hippocampus. Under the same experimental conditions, zifl268 and brain-derived neurotrophic factor (BDNF) gene expression were unchanged. Our results also demonstrate a lack of induction of c-fos, zifl268 and BDNF after short-time treatment of either adult or newborn hippocampal slices with GABA or bicuculline. The relevance of the differential induction of gene expression in the adult and newborn in an in vitro hippocampal slice model as compared to previously described in vivo models is discussed.
Animals↗
Stimulation of prolactin and growth hormone secretion by muscimol, a gamma-aminobutyric acid agonist.
The alteration in circulating levels of PRL, GH, TSH, and cortisol was studied after the oral administration of muscimol (3-hydroxy-5-aminomethylisoxazole) to human subjects with Huntington's disease (n = 4) and chronic schizophrenia (n = 5). PRL levels rose significantly in a dose-dependent fashion within a 120-min time interval. GH rose significantly but modestly over the same time interval, whereas TSH and cortisol levels remained unchanged. Since muscimol is thought to be a potent and specific gamma-aminobutyric acid agonist, these data indicate that gamma-aminobutyric acid-mediated neural transmission may function to stimulate the release of plasma PRL and GH in human subjects.
Adult↗