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At least 757 records · Page 42Linked to original sources
PubMed1989

Release and effect of gamma-aminobutyric acid (GABA) on rat pineal melatonin production in vitro.

1. 3H-gamma-Aminobutyric acid (GABA) release elicited by a depolarizing K+ stimulus or by noradrenergic transmitter was examined in rat pineals in vitro. 2. The release of 3H-GABA was detectable at a 20 mM K+ concentration in medium and increased steadily up to 80 mM K+. 3. In a Ca2+-free medium 3H-GABA release elicited by 30 mM K+, but not that elicited by 50 mM K+, became blunted. 4. Norepinephrine (NE; 10(-6)-10(-4) M) stimulated 3H-GABA release from rat pineal explants in a dose-dependent manner. 5. The activity of 10(-5) M NE on pineal GABA release was suppressed by equimolecular amounts of prazosin or phentolamine (alpha 1- and alpha 1/alpha 2-adrenoceptor blockers, respectively) and was unaffected by propranolol (beta-adrenoceptor blocker). 6. The alpha 1-adrenoceptor agonist phenylephrine (10(-7)-10(-5) M) and the beta-adrenoceptor agonist isoproterenol (10(-5) M) mimicked the GABA releasing activity of NE, while 10(-7) M isoproterenol failed to affect it; the alpha 2-adrenoceptor agonist clonidine (10(-7)-10(-5) M) did not modify 3H-GABA release. 7. The addition of 10(-4) M GABA or of the GABA transaminase inhibitor gamma-acetylenic GABA or aminooxyacetic acid inhibited the melatonin content and/or release to the medium in rat pineal organotypic cultures. 8. GABA at concentrations of 10(-5) M or greater partially inhibited the NE-induced increase in melatonin production by pineal explants. 9. The depressant effect of GABA on melatonin production was inhibited by the GABA type A receptor antagonist bicuculline; bicuculline alone increased the pineal melatonin content. Baclofen, a GABA type B receptor agonist, did not affect the pineal melatonin content or release. 10. The decrease in serotonin (5-HT) content of rat pineal explants brought about by NE was not modified by GABA; GABA by itself increased 5-HT levels. 11. These results indicate that (a) GABA is released from rat pineals by a depolarizing stimulus of K+ through a mechanism which is partially Ca2+ dependent; (b) NE releases rat pineal GABA via interaction with alpha 1-adrenoceptors; (c) GABA inhibits melatonin production in vitro via interaction with GABA type A receptor sites; and (d) GABA's effect on NE-induced melatonin release does not correlate with the lack of effect on the NE-induced decrease in pineal 5-HT content.

Animals↗
PubMed1994

Rapid assay for gamma-aminobutyric acid in mouse brain synaptosomes using gas chromatography-mass spectrometry.

A sensitive and efficient assay for gamma-aminobutyric acid (GABA) was applied to fresh mouse whole brain synaptosomes where the extracted GABA was analyzed as its di(tert.-butyl(dimethylsilyl)) derivative by gas chromatography-mass spectrometry (GC-MS) using GABA-d6 as an internal standard. Endogenous levels of 20.01 +/- 0.75 nmol GABA/mg protein were found. The method is characterized by a detection limit of about 10 fmol injected GABA derivative and coefficients of intra-day and inter-day variation of 0.95% and 7.7%, respectively. The rate of synaptosomal GABA synthesis was used to determine the activity of glutamate decarboxylase (GAD) as 314.9 +/- 9.0 nmol GABA/mg protein/h. Both GABA levels and GAD activity were significantly elevated by therapeutic doses of the antiepileptic drug valproic acid.

Acetamides↗
PubMed1998

Alcoholism abolishes the gamma-aminobutyric acid (GABA)ergic control of GH secretion in humans.

In order to establish possible alterations in the gamma-aminobutyric acid (GABA)ergic control of growth hormone (GH) secretion in alcoholics, 800 mg sodium valproate (a drug enhancing endogenous GABA activity), 10 mg baclofen (a GABA(B) receptor agonist) or a placebo were given orally to nine normal men (age 38-48 years) and nine 2-4-week-abstinent alcoholics (age 35-50 years; duration of alcohol consumption 3-6 years). Blood samples for GH assay were taken every 30 min for the next 150 min. Both drugs induced a significant increment in serum GH levels in the normal controls; mean peak was 7.2 and 3.27 times higher than baseline after sodium valproate and baclofen, respectively. In contrast, GH secretion in alcoholic patients did not change after baclofen or sodium valproate administration. Placebo administration did not modify GH secretion in any subject. In concurrence with previous reports showing alterations of GABAergic neurotransmission in the central nervous system of patients affected by alcoholism, these data show the loss of the GABAergic mechanism(s) underlying the GH response to sodium valproate and/or baclofen action in alcoholism.

Adult↗
PubMed1982

Modulatory role of gamma-aminobutyric acid (GABA) in the regulation of gonadotropin secretion in patients with chronic renal failure.

The role of gamma-aminobutyric acid (GABA) in the regulation of gonadotropin secretion in renal failure, was studied in 5 patients with chronic renal failure who were on maintenance dialysis. Di-n-propylacetic acid (valproic acid-VA), a GABA-transaminase inhibitor which has been shown to increase brain GABA levels, was used in the study. VA produced no significant change in the basal serum LH and FSH concentrations, or in E2 or T concentrations in the renal failure patients, or the E2 and P concentrations in normal controls, but augmented the delta LH (maximum increment above baseline) and delta FSH response to LH-RH. delta LH rose from 30.4 +/- 12.7 mIU/ml (mean +/- SD) to 41.1 +/- 16.8 mIU/ml (p less than 0.01) after VA, while delta FSH rose from 2.8 +/- 1.8 mIU/ml to 3.8 +/- 1.6 mIU/ml (p less than 0.05). The findings support a modulatory role for GABA in gonadotropin secretion in chronic renal failure.

Adult↗
PubMed1991

Role of dendritic dopamine of the substantia nigra in the modulation of nigrocollicular gamma-aminobutyric acid release: in vivo studies in the rat.

The release of gamma-[3H]aminobutyric acid ([3H]GABA) newly synthesized from [3H]glutamine was estimated in the superior colliculus of ketamine-anesthetized rats superfused via a push-pull cannula. A significant amount of [3H]GABA was spontaneously released in the superior colliculus (582 +/- 49 pCi/10 min). A major part of the large K(+)-evoked increase of the [3H]GABA release was Ca2+ dependent. When neuronal activity of the substantia nigra was enhanced by nigral application of K+ (30 mM) or bicuculline (10(-4) M), a persistent increase of the collicular [3H]GABA release was observed (60 and 80%, respectively). Conversely, when nigral activity was reduced by nigral application of GABA (10(-4) M) or superfusion with a Ca(2+)-free medium, a sustained decrease of the collicular [3H]GABA release was observed (-30 and -40%, respectively). Following the nigral application of a selective D2-receptor agonist. RU 24926 (10(-6) M), for 30 min in 6-hydroxydopamine-lesioned rats, a phasic increase (60%) of the collicular [3H]GABA release was detected. This effect could result from an activation of nigrocollicular GABAergic neurons by D2-receptor stimulation, because nigral activity and collicular release of [3H]GABA changed in a parallel direction.

Animals↗
PubMedDate not supplied

Effect of hydralazine-induced hypotension on glutamate, gamma-aminobutyric acid and some other amino acid levels in medullary regions of the rat.

Concentrations of glutamate, gamma-aminobutyric acid (GABA), glycine, beta-alanine and taurine were measured in microdissected areas of the rostral ventrolateral medulla (RVL), nucleus tractus solitarii (NTS) and caudal ventrolateral medulla (CVL) of the rat, and the effects of hydralazine-induced hypotension on the concentrations of amino acids were examined. All five amino acids were ubiquitously present in these brainstem regions. Hydralazine-induced hypotension increased glutamate levels in the NTS and CVL regions, but decreased GABA levels in all the regions studied. The level of glycine was decreased in the RVL region after hydralazine. Hydralazine decreased beta-alanine levels in the NTS and CVL regions. Electrical stimulation of slices containing the RVL region decreased glutamate levels but increased GABA levels in tissues. These results are compatible with the hypothesis that glutamate and GABA systems in these brainstem areas are related to blood pressure regulation.

Amino Acids↗
PubMed2000

Two novel residues in M2 of the gamma-aminobutyric acid type A receptor affecting gating by GABA and picrotoxin affinity.

An amino acid residue was found in M2 of gamma-aminobutyric acid (GABA) type A receptors that has profound effects on the binding of picrotoxin to the receptor and therefore may form part of its binding pocket. In addition, it strongly affects channel gating. The residue is located N-terminally to residues suggested so far to be important for channel gating. Point mutated alpha1beta(3) receptors were expressed in Xenopus oocytes and analyzed using the electrophysiological techniques. Coexpression of the alpha(1) subunit with the mutated beta(3) subunit beta(3)L253F led to spontaneous picrotoxin-sensitive currents in the absence of GABA. Nanomolar concentrations of GABA further promoted channel opening. Upon washout of picrotoxin, a huge transient inward current was observed. The reversal potential of the inward current was indicative of a chloride ion selectivity. The amplitude of the inward current was strongly dependent on the picrotoxin concentration and on the duration of its application. There was more than a 100-fold decrease in picrotoxin affinity. A kinetic model is presented that mimics the gating behavior of the mutant receptor. The point mutation in the neighboring residue beta(3)A252V resulted in receptors that displayed an about 6-fold increased apparent affinity to GABA and an about 10-fold reduced sensitivity to picrotoxin.

Amino Acid Sequence↗
PubMed1983

Electrical stimulation of the stratum radiatum increases the release and neosynthesis of aspartate, glutamate, and gamma-aminobutyric acid in rat hippocampal slices.

The release of endogenous aspartic, glutamic, and gamma-aminobutyric acids (Asp, Glu, GABA, respectively) was measured in the effluent from superfused hippocampal slices using a new and sensitive mass spectrometric method. The stimulation of the stratum radiatum of the rat dorsal hippocampus caused a Ca2+-dependent increase in the release of these amino acids. This release was accompanied by an increase in the incorporation of [13C2] from [13C]glucose into Asp, Glu, and GABA, suggesting an increase in their neosynthesis. The removal of Ca2+ from the superfusion fluid brought about a marked decrease in Asp and Glu release at rest, and prevented their stimulation-evoked release and the appearance of population spikes. The results support the hypothesis that Asp and Glu are excitatory neurotransmitters in intrinsic hippocampal circuits and are possibly released from the Schaffer collaterals and commissural fibres. The increase in GABA release and neosynthesis during stimulation of the stratum radiatum could be related to recurrent inhibition evoked by transsynaptic stimulation of the pyramidal cells.

Animals↗
PubMed1987

Conversion of 4-aminobutyraldehyde to gamma-aminobutyric acid in retina.

4-Aminobutyraldehyde (ABAL) was shown to be converted to gamma-aminobutyric acid (GABA) in the rat retina in vivo as well as in vitro. The results suggest that ABAL can easily cross the blood-retinal barrier and be rapidly oxidized to GABA in the retina. The conversion of ABAL to GABA also occurred in retinas treated with kainic acid, which greatly reduced glutamic acid decarboxylase (GAD) activity. Therefore, it is suggested that the conversion in the retina is independent of the GAD pathway and may occur not only in GABAergic neurons but also in glia or photoreceptor cells.

Aldehydes↗
PubMed1985

Dopamine inhibits calcium-independent gamma-[3H]aminobutyric acid release induced by kainate and high K+ in the fish retina.

Kainic acid (KA) at micromolar concentrations stimulated the release of gamma-[3H]aminobutyric acid [( 3H]GABA) from a particulate fraction of the carp (Cyprinus carpio) retina. The KA action was dose-dependent but Ca2+-independent. A similar response was elicited by another glutamate receptor agonist, quisqualic acid, and high K+, but not by an aspartate agonist, N-methyl-D-aspartic acid. The stimulatory action of KA on the [3H]GABA release was selectively blocked by the KA blockers gamma-D-glutamylglycine and cis-2,3-piperidine dicarboxylic acid. Dopamine (DA), which is contained in DA interplexiform cells in the carp retina, inhibited the [3H]GABA release induced by KA and high K+ in a dose-dependent manner. 5-Hydroxytryptamine and two well-known GABA antagonists, bicuculline (Bic) and picrotoxin (Pic), also mimicked the DA effect on the GABA release at a comparable concentration. This inhibitory effect of DA as well as Bic and Pic on the [3H]GABA release evoked by KA was clearly antagonized by a DA blocker, haloperidol. The action of these agents (KA, DA, GABA antagonist) belonging to three different receptor categories on the GABAergic neurons (possibly external horizontal cells; H1 cells) is discussed in relation to other electrophysiological studies on the lateral spread of S-potentials between H1 cells.

Animals↗
PubMed2003

Theoretical research on structures of gamma-aminobutyric acid and glutamic acid in aqueous conditions.

Even though glutamic acid contains only one more carboxyl group than gamma-aminobutyric acid (GABA), these neurotransmitters are recognized by their own specific receptors. To understand the ligand-recognition mechanism of the receptors, we must determine the geometric and electronic structures of GABA and glutamic acid in aqueous conditions using the ab initio calculation. The results of the present study showed that the stable structure of GABA was the extended form, and it attracted both cations and anions. Glutamic acid only attracted cations and was stabilized in four forms in aqueous conditions: Type 1 (an extended form), Type 2 (a rounded form), and Types 3 and 4 (twisted forms of Type 1). The former two types had low energy and the energy barrier between them was estimated to be small. These results showed that most free glutamic acid is present as Type 1, Type 2, and transient forms. The present results therefore suggest that the flexibility of the geometric structures of ligands should be taken into account when we attempt to elucidate the mechanism of recognition between ligands and receptors, in addition to the physicochemical characteristics of ligands and receptors.

Glutamic Acid↗
PubMed1984

High specific gamma-aminobutyric acid binding to membranes of the human ovary.

The concentration of gamma-aminobutyric acid (GABA) in the human ovary and the capacity of a membrane preparation from the same organ to bind [3H]GABA specifically were examined. The GABA concentration in the ovary was found to be 214 +/- 66 nmol/g frozen tissue (mean +/- SEM of six independent determinations). Moreover, a single population of high-affinity GABA binding sites has been identified in the ovarian membranes. The apparent dissociation constant (Kd) and maximum binding capacity (Bmax) were 38.3 nM and 676 fmol/mg protein, respectively. The specific binding of [3H]GABA was displaced by muscimol, unlabelled GABA, or (+)bicuculline, but was unaffected by (+/-)baclofen and picrotoxin. The present results show that GABA and an extremely high density of GABAA receptor binding sites are present in the human ovary, indicating a physiological significance of this amino acid in the female reproductive system.

Adult↗
PubMed1985

Orally active and potent inhibitors of gamma-aminobutyric acid uptake.

3-Pyrrolidineacetic acid (1a), certain piperidinecarboxylic acids--i.e., 3-piperidinecarboxylic acid (2a), 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (3a), and cis-4-hydroxy-3-piperidinecarboxylic acid (4a)--cis-3-aminocyclohexanecarboxylic acid (5a, cis-3-ACHC), and gamma-aminobutyric acid (6a, GABA) itself are among the most potent inhibitors of [3H]GABA uptake by neurons and glia in vitro. These hydrophilic amino acids, however, do not readily enter the central nervous system in pharmacologically significant amounts following peripheral administration. We now report that N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid (2b) is a specific GABA-uptake inhibitor that is more potent, more lipophilic and, in limited testing, as selective as 2a. Similar results were obtained with the N-(4,4-diphenyl-3-butenyl) derivatives of 1a, 3a, and 4a. By contrast, N-(4,4-diphenyl-3-butenyl) derivatives of 5a and 6a were not more potent than the parent amino acids and appear to inhibit GABA uptake, at least in part, by a nonselective mechanism of action. The N-(4,4-diphenyl-3-butenyl)amino acids 1b-4b exhibit anticonvulsant activity in rodents following oral or intraperitoneal administration [Yunger, L.M.; et al. J. Pharmacol. Exp. Ther. 1984, 228, 109].

4-Aminobutyrate Transaminase↗
PubMed1990

Fine distribution of gamma-aminobutyric acid, aspartate and glutamate in human dentate nucleus.

The fine distribution of gamma-aminobutyric acid (GABA), aspartate and glutamate in the lateral and medial part of the human dentate nucleus was biochemically determined after microdissection of the grey and the white matter. The mean GABA concentrations of the lateral and medial grey matter were largely similar. The topographical distribution, however showed a higher concentration in the caudal part of the lateral grey than in other parts of dentate nucleus. In the medial section the GABA concentration was the lowest in the white matter. The surrounding white matter showed the highest GABA concentration on the caudal side of the lateral part of the dentate nucleus. Aspartate concentration was the highest in the lateral grey matter. On the ventral caudal side of the dentate nucleus the aspartate concentration was much higher compared to other parts of the surrounding white matter. Glutamate roughly showed a similar distribution pattern compared to aspartate, although no specific pattern in the surrounding white matter could be found. The results suggest specific entry and ending patterns for functionally verified afferent fibers to the dentate nucleus in man.

Aged↗
PubMed1992

NNC-711, a novel potent and selective gamma-aminobutyric acid uptake inhibitor: pharmacological characterization.

NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride) is a novel, potent and selective gamma-aminobutyric acid (GABA) uptake inhibitor. NNC-711 inhibited synaptosomal (IC50 = 47 nM), neuronal (IC50 = 1238 nM) and glial (IC50 = 636 nM) GABA uptake in vitro NNC-711 lacked affinity for other neurotransmitter receptor binding sites, uptake sites and ion channels examined in vitro. In vivo, NNC-711 was a potent anticonvulsant compound against rodent seizures induced by methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (ED50 (clonic) = 1.2 mg/kg i.p.), pentylenetetrazole (PTZ) (ED50 (tonic) = 0.72 mg/kg i.p., mouse; and ED50 (tonic) = 1.7 mg/kg, rat), or audiogenic (ED50 (clonic and tonic) = 0.23 mg/kg i.p.). At higher doses NNC-711 produced behavioral side effects characterized by inhibition of traction (ED50 = 23 mg/kg i.p.), rotarod (ED50 = 10 mg/kg i.p.) and exploratory locomotor activity (ED50 = 45 mg/kg i.p.) in the mouse. Following acute (3-h) in vivo pretreatment with NNC-711, behavioral tolerance developed to its motor impairing side effects (inhibition of traction, rotarod or exploratory locomotor activity) without corresponding tolerance to the anticonvulsant effects. These data suggest that NNC-711 will be useful for future in vitro and in vivo experiments to elucidate the role of the GABA uptake carrier in the central nervous system.

Animals↗
PubMed1978

gamma-Aminobutyric acid receptors visualized in spinal cord cultures by [3H]muscimol autoradiography.

gamma-Aminobutyric acid (GABA) receptors were visualized in mouse spinal cord explant cultures by [3H]muscimol autoradiography over certain small neurons of the dorsal horn grey matter, in the interneuronal neuropil of dorsal and ventral horns, and (rarely) in small clusters on processes of anterior horn cells. Specificity was indicated in control experiments by inhibition of binding by [3H]muscimol after pretreatment with GABA or a GABA analogue, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, isoxazole 16), or with receptor antagonists bicuculline and picrotoxin. Unlabeled muscimol exchanged effectively with [3H]muscimol and produced autoradiographic label in locations indistinguishable from those found in experiments with [3H]muscimol alone. Pretreatment with the GABA uptake and transport inhibitors (-)-nipecotic acid and guvacine did not affect binding with [3H]muscimol. These experiments indicate that explant culture systems can be used for demonstration of functional receptors.

Animals↗
PubMed1989

[Effects of noradrenaline,glycine, gamma-aminobutyric acid and L-glutamic acid on spinal field potentials in the rat].

Noradrenaline (NE), glucine (GLY), gamma-aminobutyric acid (GABA) and L-glutamic acid (L-GLU) were locally applied to the dorsal surface of lumbar spinal cord on anesthetized and immobilized rats and their effects on segmental (SP) and descending (DP) spinal field potentials were examined. Both waves N and P of SP and DP were reduced markedly in amplitudes following local application of NE. A significant decrease in amplitude of wave N and a remarkable increase in wave P in both SP and DP were shown during the application of GLY, GABA and L-GLU. The results suggest that these neurotransmitters may be involved in the generation of waves N and P, particularly affecting the activities of interneurons in the spinal dorsal horn.

Animals↗