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At least 19 recordsLinked to original sources
PubMed2000

gamma-Aminobutyric acid, acting through gamma -aminobutyric acid type A receptors, inhibits the biosynthesis of neurosteroids in the frog hypothalamus.

Most of the actions of neurosteroids on the central nervous system are mediated through allosteric modulation of the gamma-aminobutyric acid type A (GABA(A)) receptor, but a direct effect of GABA on the regulation of neurosteroid biosynthesis has never been investigated. In the present report, we have attempted to determine whether 3beta-hydroxysteroid dehydrogenase (3beta-HSD)-containing neurons, which secrete neurosteroids in the frog hypothalamus, also express the GABA(A) receptor, and we have investigated the effect of GABA on neurosteroid biosynthesis by frog hypothalamic explants. Double immunohistochemical labeling revealed that most 3beta-HSD-positive neurons also contain GABA(A) receptor alpha(3) and beta(2)/beta(3) subunit-like immunoreactivities. Pulse-chase experiments showed that GABA inhibited in a dose-dependent manner the conversion of tritiated pregnenolone into radioactive steroids, including 17-hydroxy-pregnenolone, progesterone, 17-hydroxy-progesterone, dehydroepiandrosterone, and dihydrotestosterone. The effect of GABA on neurosteroid biosynthesis was mimicked by the GABA(A) receptor agonist muscimol but was not affected by the GABA(B) receptor agonist baclofen. The selective GABA(A) receptor antagonists bicuculline and SR95531 reversed the inhibitory effect of GABA on neurosteroid formation. The present results indicate that steroid-producing neurons of the frog hypothalamus express the GABA(A) receptor alpha(3) and beta(2)/beta(3) subunits. Our data also demonstrate that GABA, acting on GABA(A) receptors at the hypothalamic level, inhibits the activity of several key steroidogenic enzymes, including 3beta-HSD and cytochrome P450(C17) (17alpha-hydroxylase).

Animals↗
PubMed1992

gamma-Aminobutyric acid A or C receptor? gamma-Aminobutyric acid rho 1 receptor RNA induces bicuculline-, barbiturate-, and benzodiazepine-insensitive gamma-aminobutyric acid responses in Xenopus oocytes.

Xenopus oocyte expression of the recently cloned gamma-aminobutyric acid (GABA) rho 1 receptor subunit cDNA yields a pharmacologic profile characteristic of the GABAc responses described by Johnston [Benzodiazepine/GABA Receptors and Chloride Channels. Receptor Biochemistry and Methodology (R. W. Olsen and J. C. Venter, eds), Vol. 5. Alan R. Liss, New York, 57-71 (1986)] and the responses to retinal mRNA recently reported in the Xenopus expression system [Proc. Natl. Acad. Sci. USA 88:4318-4322 (1991)]. A rationale for defining GABA rho 1 as forming a GABAc receptor is discussed.

Animals↗
PubMed1989

Entropy as a factor in the binding of gamma-aminobutyric acid and nipecotic acid to the gamma-aminobutyric acid transport system.

Nipecotic acid is one of the most potent competitive inhibitors and alternative substrates for the high-affinity gamma-aminobutyric acid transport system in neurons, but the structural basis of this potency is unclear. Because gamma-aminobutyrate is a highly flexible molecule in solution, it would be expected to lose rotational entropy upon binding to the transport system, a change which does not favor binding. Nipecotic acid, in contrast, is a much less flexible molecule, and one would expect the loss of conformational entropy upon binding to be smaller thus favoring the binding of nipecotic acid over gamma-aminobutyric acid. To investigate this possibility, the thermodynamic parameters, delta G degrees, delta H degrees, and delta S degrees, were determined for the binding of gamma-aminobutyrate and nipecotic acid to the high affinity GABA transport system in synaptosomes. In keeping with expectations, the apparent entropy change for nipecotic acid binding (112 +/- 13 J.K-1) was more favorable than the apparent entropy change for gamma-aminobutyric acid binding (61.3 +/- 6.6 J.K-1). The results suggest that restricted conformation per se is an important contributory factor to the affinity of nipecotic acid for the high-affinity transport system for gamma-aminobutyric acid.

Animals↗
PubMed1979

Changes in primary afferent depolarization after administration of gamma-acetylenic gamma aminobutyric acid (GAG), a gamma-aminobutyric acid (GABA) transaminase inhibitor.

gamma-Acetylenic gamma-aminobutyric acid (GAG), an irreversible inhibitor of GABA transaminase, increased the concentration of GABA in feline spinal cords to 239% of the control value by 225 min after its injection. After administration of GAG to spinally transected cats, the height of the segmentally evoked dorsal root potential (DRP), which is generated at one point via a GABA synapse, was increased to more than twice the control value although the area increased only slightly. However, GAG had no effect on the segmental DRP in the decerebrate cat. In contrast, the DRP evoked in decerebrate cats by electrical stimulation of the brain stem, which is probably mediated by GABA, was decreased by administration of GAG. These effects of GAG were accompanied by the development of spontaneous primary afferent depolarizations which resembled spontaneous DRPs in both spinal and decerebrate cats. The temporal and size correlation between spontaneous DRPs occurring in different spinal roots indicate they are generated by an interneuronal pathway that is released by the action of GAG. The action of GAG on the segmental DRP in the spinal but not decerebrate preparation is also most easily explained by GAG-induced effects on interneuronal pathways. These data suggest GABA transaminase inhibition does not affect the axoaxonic GABA synapse mediating the DRP.

4-Aminobutyrate Transaminase↗
PubMed1983

4-aminobutyric acid methyl ester hydrochloride, a precursor of 4-aminobutyric acid.

4-Aminobutyric methyl ester hydrochloride (GME) is able to cross the blood-brain barrier after intracardiac administration to the rat. GME has an LD50 of 1300 mg/kg in mice and 950 mg/kg in rats, exhibits an antiaggressive effect and is able to decrease isoniazid-induced convulsions in the rat. GME is hydrolyzed to 4-aminobutyric acid (GABA) by brain homogenates, acts as an inhibitor of GABA binding to crude synaptic plasma membranes, activates the release and inhibits the uptake of GABA by rat synaptosomes and acts as a competitive inhibitor of the so-called GABAse system in vitro.

Animals↗
PubMed1991

Effect of gamma-vinyl gamma-aminobutyric acid on the gamma-aminobutyric acid receptor-coupled chloride ion channel in vesicles from the brain of the rat.

The effect of gamma-vinyl GABA on the gamma-aminobutyric acid (GABA) receptor-coupled chloride ion (Cl-) channel was studied using membrane vesicles from cerebral cortex of the rat. gamma-Vinyl GABA, an antiepileptic drug, had no effect on uptake of 36Cl-, without preincubation. However, preincubation of membrane vesicles with gamma-vinyl GABA (100-1000 microM) produced a concentration-dependent decrease in net uptake of 36Cl-. No alteration was observed in basal uptake of 36Cl-. This decrease in net uptake of 36Cl- was not related to desensitization induced by endogenous GABA, which might be increased by gamma-vinyl GABA through selective, irreversible inhibition of GABA-transaminase (GABA-T). Concentration-response curves for GABA showed that preincubation with gamma-vinyl GABA inhibited GABA-stimulated uptake of 36Cl- with no change in ED50. These results indicate that gamma-vinyl GABA may act directly at the GABA/benzodiazepine ionophore complex, as a non-competitive antagonist of GABA.

4-Aminobutyrate Transaminase↗
PubMed1999

Striatal outflow of adenosine, excitatory amino acids, gamma-aminobutyric acid, and taurine in awake freely moving rats after middle cerebral artery occlusion: correlations with neurological deficit and histopathological damage.

BACKGROUND AND PURPOSE: While a number of studies have investigated transmitter outflow in anesthetized animals after middle cerebral artery occlusion (MCAO) performed by craniectomy, studies have never been performed after MCAO induced by intraluminal filament. In addition, it has been reported that after MCAO, infarct volume correlates with functional outcome and with transmitter outflow, although there are no studies that demonstrate a direct correlation between transmitter outflow and functional outcome. The purpose of the present study was to assess excitatory amino acids, gamma-aminobutyric acid, taurine, and adenosine outflow in awake rats after intraluminal MCAO and to determine whether, in the same animal, outflow was correlated with neurological outcome and histological damage. METHODS: Vertical microdialysis probes were placed in the striatum of male Wistar rats. After 24 hours, permanent MCAO was induced by the intraluminal suture technique. The transmitter concentrations in the dialysate were determined by high-performance liquid chromatography. Twenty-four hours after MCAO, neurological deficit and histological outcome were evaluated. RESULTS: All transmitters significantly increased after MCAO. Twenty-four hours after MCAO, the rats showed a severe sensorimotor deficit and massive ischemic damage in the striatum and in the cortex (9+/-2% and 25+/-6% of hemispheric volume, respectively). Significant correlations were found between the efflux of all transmitters, neurological score, and striatal infarct volume. CONCLUSIONS: In this study, for the first time, amino acid and adenosine extracellular concentrations during MCAO by the intraluminal suture technique were determined in awake and freely moving rats, and a significant correlation was found between transmitter outflow and neurological deficit. The evaluation of neurological deficit, histological damage, and transmitter outflow in the same animal may represent a useful approach for studying neuroprotective properties of new drugs/agents against focal ischemia.

Adenosine↗
PubMed1984

Distribution of glycine, gamma-aminobutyric acid, glutamate decarboxylase, and gamma-aminobutyric acid transaminase in rabbit and mudpuppy retinas.

The distributions of glycine, gamma-aminobutyric acid (GABA), glutamate decarboxylase (EC 4.1.1.15), and GABA transaminase (EC 2.6.1.19) were determined in rabbit and mudpuppy retinas. In both species, peak levels of the amino acids and the enzymes occurred in the inner plexiform layer. Glutamate decarboxylase was almost entirely confined to the inner plexiform layer. Determinations were also made of the GABA content of 107 individual putative amacrine cell somas from mudpuppy retina. About 30% of those somas were found to have high endogenous GABA levels.

4-Aminobutyrate Transaminase↗
PubMed1990

Systemic CI-966, a new gamma-aminobutyric acid uptake blocker, enhances gamma-aminobutyric acid action in CA1 pyramidal layer in situ.

A new potent, blood-brain barrier permeable gamma-aminobutyric acid (GABA) uptake blocker, 1-[2-[bis[4-(trifluoromethyl)-phenyl]methoxy]ethyl]-1,2,5,6- tetrahydro-3-pyridinecarboxylic acid (CI-966) was administered systemically by i.p. injection (5 mg/kg) in Sprague-Dawley rats under urethane anaesthesia. Twenty to thirty minutes after injection there was a highly variable, but overall significant, enhancement of the inhibition of hippocampal population spikes by GABA applied by microiontophoresis in the CA1 region. Like the effect of nipecotic acid (applied locally by iontophoresis), the potentiation by CI-966 was clearest when GABA was applied in or near the stratum pyramidale where its action normally is weakest and shows the most pronounced fading. This change in GABA potency is most simply explained by a reduction in GABA uptake.

Animals↗
PubMed1997

[Effects of L-glutamic acid, gamma-aminobutyric acid and their respective antagonists on spontaneous discharge of nucleus paragigantocellularis lateralis neurons in rats].

Using multibarrel microelectrode techniques, we studied the effects of iontophoretic application of L-glutamic acid (L-Glu), gamma-aminobutyric acid (GABA) and their respective antagonists DL-2-amino-5-phosphonovaleric acid (AP5), bicuculline (BIC) on the spontaneous discharge of the caudal half of nucleus paragigantocellularis lateralis (cPGCL) neurons (including respiratory related neurons) and the influences of AP5 and BIC on the effects of L-Glu and GABA respectively in 22 anesthetized spontaneously breathing Sprague-Dawley rats. The spontaneous discharges of all the cPGCL neurons tested were inhibited by GABA(n = 53). Most of the tested neurons were excitated by L-Glu (30/36). AP5 and BIC both showed three kinds of effects on the cPGCL neuronal spontaneous discharge; excitatory, inhibitory and no-effect. The excitatory effects of L-Glu and BIC and the inhibitory effects of GABA showed a dose-response relationship. AP5 could block partially the excitatory effect of L-Glu on a large part of neurons tested (14/19). BIC blocked, partially or completely, the inhibitory effect of GABA also on a large part of the neurons tested(18/24). The results implicate that there might exist endogenous L-Glu and GABA acting as neurotransmitters in the cPGCL area and excitatory amino acids (EAA, including NMDA and non-NMDA) and GABA-receptors on cPGCL neurons. These neurotransmitters and receptors may mediate the regulatory action of cPGCL on respiration and other functional systems.

2-Amino-5-phosphonovalerate↗
PubMed1978

Baclofen (beta-p-chlorophenyl-gamma-aminobutyric acid) enhances [3H]gamma-aminobutyric acid (3H-GABA) release from rat globus pallidus in vitro.

The rat globus pallidus has been investigated as a possible model in which to study pre-synaptic GABA mechanisms in vitro. (+/-)-Baclofen (300 micrometer-1 mM) significantly enhanced the release of radioactivity from superfused slices of rat globus pallidus prelabelled with 3H-GABA in vitro. This releasing action was specific to the (+)-isomer of baclofen: neither the (-)-isomer nor another neuronal depressant dl-alpha-epsilon-diaminopimelic acid had any significant effect. The releasing effect of baclofen appeared unrelated to the phenethylamine moiety of its structure as neither beta-phenethylamine nor dopamine evoked release of 3H-GABA from pallidal slices. Baclofen increased the efflux of radioactivity from pallidal slices prelabelled with either [3H]-beta-alanine or [3H]diaminobutyric acid in vitro. The use of specific glial and neuronal GABA uptake blocking compounds (beta-alanine and (+/-)-cis-1,3-amino-cyclohexanecarboxylic acid) did not permit resolution of the elements from which baclofen was evoking [3H]GABA release. Baclofen also inhibited uptake of [3H]GABA into pallidal slices with an IC50 value of 6 x 10(-4) m. The GABA-like properties of baclofen may be related to the (+)-isomer while non-specific neuronal depressant actions are an effect of the (-)-isomer. The potential of the (+)-isomer as an antipsychotic agent while (-)-baclofen remains the effective antispastic drug free from unwanted side-effects, is discussed.

Alanine↗