Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “AMINOBUTYRIC ACID”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 883 records · Page 49Linked to original sources
PubMed2003

Cyclothiazide potently inhibits gamma-aminobutyric acid type A receptors in addition to enhancing glutamate responses.

Ionotropic glutamate and gamma-aminobutyric acid type A (GABAA) receptors mediate critical excitatory and inhibitory actions in the brain. Cyclothiazide (CTZ) is well known for its effect of enhancing glutamatergic transmission and is widely used as a blocker for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor desensitization. Here, we report that in addition to its action on AMPA receptors, CTZ also exerts a powerful but opposite effect on GABAA receptors. We found that CTZ reversibly inhibited both evoked and spontaneous inhibitory postsynaptic currents, as well as GABA application-induced membrane currents, in a dose-dependent manner. Single-channel analyses revealed further that CTZ greatly reduced the open probability of GABAA receptor channels. These results demonstrate that CTZ interacts with both glutamate and GABAA receptors and shifts the excitation-inhibition balance in the brain by two independent mechanisms. Understanding the molecular mechanism of this double-faceted drug-receptor interaction may help in designing new therapies for neurological diseases.

Animals↗
PubMed1993

Noradrenergic modulation of gamma-aminobutyric acid outflow from the human cerebral cortex.

The noradrenergic modulation of endogenous gamma-aminobutyric acid (GABA) outflow from slices and synaptosomes prepared from human cerebral cortex biopsies has been studied. GABA outflow was responsive to depolarizing stimuli such as ouabain and high potassium. Basal GABA outflow in slices, but not in synaptosomes, appeared to be largely dependent upon neuronal activity, being prevented by tetrodotoxin (TTX). 10 mM K(+)-evoked outflow in synaptosomes also proved to be TTX sensitive. Norepinephrine (NE) concentration dependently increased basal GABA outflow both in slices and synaptosomes. This effect was alpha 1-adrenoreceptor-mediated because it was prevented by a selective antagonist of the alpha 1-adrenoreceptor class (prazosin) but not by the alpha 2 antagonist idazoxan. However, an alpha 2-mediated inhibitory modulation was also present in the preparations used, since (1) in slices, NE significantly inhibited GABA outflow in the presence of prazosin; (2) in synaptosomes, NE significantly inhibited 10 mM K(+)-evoked outflow in the presence of prazosin. Both of these effects were prevented by idazoxan. No beta-adrenoreceptor modulation could be demonstrated. A comparison between species was also conducted. The response to ouabain and to TTX proved similar in human, rat and guinea-pig cerebral cortex. In the most simple tissue preparation used (synaptosomes), a close similarity between the three species could be observed. In all species, NE stimulated basal GABA outflow, an effect prevented by prazosin. This suggests a predominant alpha 1-adrenoreceptor-mediated stimulatory effect. In a more complex preparation (slices), differences between species could be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1999

Comparison of gamma-aminobutyric acid effects in different parts of the cat ileum.

The effects of gamma-aminobutyric acid (GABA) and those of a GABA(A) (muscimol) and a GABA(B) (baclofen) receptor agonists were determined on the spontaneous activity of longitudinally or circularly oriented preparations (segments) isolated from terminal, proximal and distal parts of the cat ileum. GABA applied at 1 microM to 2 mM caused dose-dependent biphasic changes (relaxation and contraction) in spontaneous activity of the longitudinal and circular layers in the terminal and distal parts of the cat ileum and monophasic changes (contraction) in the proximal part. The potency of GABA to elicit relaxant and/or contractile effects in different parts of the ileum showed a proximal-to-terminal increasing pattern. In the longitudinal layer of the distal and terminal ileum, muscimol (100 microM) mimicked the relaxation phase of the GABA effect, while baclofen (100 microM) simulated the contractile phase. Bicuculline, atropine and tetrodotoxin abolished GABA- and muscimol-induced relaxation and suppressed, but failed to prevent GABA- and baclofen-induced contractions. In addition, 2-hydroxysaclofen antagonized the baclofen-induced contractile effect, reduced the GABA-induced contractile phase but failed to prevent GABA- and muscimol-induced relaxation. In the circular layer of the same regions, muscimol mimicked the biphasic GABA effects, while baclofen was without effect. Bicuculline, atropine and tetrodotoxin completely prevented the GABA- and muscimol effects, while 2-hydroxysaclofen failed to antagonize them. In the longitudinal and circular layers of the proximal ileum, muscimol (100 microM) exerted a 'GABA-like' transient contractile effect, while baclofen (100 microM) did not elicit any response. Bicuculline, atropine and tetrodotoxin antagonized the GABA- and muscimol-induced contractile responses of longitudinal and circular layers, while 2-hydroxysaclofen was ineffective. The results suggested that the inhibitory and/or excitatory action of GABA on cholinergic transmission in different regions of cat ileum varies along an increasing gradient towards the terminal ileum and is mediated by GABA(A) and GABA(B) receptors in the terminal and distal ileum and by GABA(A) receptors in the proximal ileum.

Acetylcholinesterase↗
PubMed1987

gamma-Aminobutyric acid production in small and large intestine of normal and germ-free Wistar rats. Influence of food intake and intestinal flora.

In recent hypotheses concerning the pathogenesis of hepatic encephalopathy, gamma-aminobutyric acid (GABA) is claimed to be produced by the colonic flora, although enzymes necessary to generate GABA have been reported to be present in intestinal mucosa. In this study, using normal and germ-free Wistar rats, we determined GABA levels and amino-grams of arterial blood and of venous effluent from small and large bowel. The data indicate that large and small intestinal mucosa significantly contribute to GABA production. In the fasted state GABA concentrations are greater in the venous effluent of the small bowel than in the venous effluent of the large bowel. Feeding increases the arterioportal differences, and uptake in the small bowel is still significantly higher than in the large bowel. This process is not, or can only be to a minor degree, bacterially mediated, because GABA production in the gut both in the fed and fasted state is of similar magnitude in germ-free and normal animals. gamma-Aminobutyric acid release correlates significantly with glutamine uptake in the small bowel of fasted rats. Only a small fraction of the glutamine taken up is needed to account for GABA release, so that conclusions concerning which amino acids may serve as precursors of GABA cannot be drawn. Further studies are needed to delineate the metabolic pathways leading to GABA synthesis.

Aminobutyrates↗
PubMed1997

Inhibition of [3H] gamma-aminobutyric acid release by kainate receptor activation in rat hippocampal synaptosomes.

We studied the modulation of gamma-aminobutyric acid (GABA) release by activation of kainate receptor in rat whole hippocampal synaptosomes. Kainate (10-300 microM) inhibited [3H]GABA release in a concentration-dependent manner with an EC50 of 25 microM. This effect of kainate (30 microM) was prevented by the ionotropic non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) and by the selective kainate receptor antagonist 5-nitro-6,7,8,9-tetrahydrobenzo(g)indole-2,3-dione-3-oxime (NS-102, 10 microM), but not by the selective non-competitive AMPA receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5 H-2,3-benzodiazepine (GYKI 52466, 100 microM). Other kainate receptor agonists, such as domoic acid (0.3-10 microM) and (2S,4R)-4-methylglutamic acid (MGA, 0.3-3 microM), also inhibited [3H]GABA release in a concentration-dependent manner with EC50 values of 4.0 microM and 0.90 microM, respectively, whereas alpha-amino-3-hydroxy-5-methyl-4-oxazolepropionate (AMPA, 10-100 microM) was devoid of effect. These inhibitory effects of both domoic acid (3 microM) and MGA (1 microM) were antagonized by CNQX (10 microM). These results indicate that GABA release can be modulated directly by presynaptic high-affinity kainate heteroreceptors.

Animals↗
PubMed1987

gamma-Aminobutyric acid antagonists stimulate vasopressin release from organ-cultured hypothalamo-neurohypophyseal explants.

gamma-Aminobutyric acid (GABA) has been identified in axon terminals innervating neurons of the supraoptic nucleus and has been shown to inhibit the electrical activity of supraoptic neurons when applied iontophoretically. This study examines the effects of GABA and GABA antagonists on vasopressin (VP) release from organ-cultured explants of the hypothalamo-neurohypophyseal system (HNS). The GABA antagonists bicuculline and picrotoxin stimulated VP release in a concentration-dependent manner. These observations suggest that VP release by HNS explants is tonically inhibited by GABA. Exposure of HNS explants to GABA (10(-8)-10(-3) M) did not consistently alter basal VP release. This was true even when penicillin, which can block GABA-activated chloride channels, was omitted from the medium. Similarly, nipecotic acid, an agent that potentiates GABA activity by inhibiting GABA uptake, did not alter basal VP release; stimulation of VP release by acetylcholine and increases in osmolality was not diminished by the addition of 10(-5) M GABA. The failure of exogenous GABA to modify basal and stimulated VP release suggests that GABAergic inhibition of VP release is maximally activated by endogenously released GABA in cultured HNS explants. This is consistent with evidence for a local source of GABA in the supraoptic nucleus and suggests that one role of GABA in the regulation of VP release is that of a potent local inhibitory neurotransmitter.

Acetylcholine↗
PubMed2004

Four amino acids in the alpha subunits determine the gamma-aminobutyric acid sensitivities of GABAA receptor subtypes.

GABA(A) receptors, mediators of fast inhibitory neurotransmission, are heteropentameric assemblies from a large array of subunits. Differences in the sensitivity of receptor subtypes to endogenous GABA may permit subunit-dependent finely tuned responsiveness to the same GABAergic inputs. Using both radioligand binding and electrophysiology combined with mutagenesis, we identified a domain of four amino acids within the alpha subunits that mediates the distinct sensitivities to GABA allowing their selective switch between alphabeta3gamma2 combinations. Replacing this domain in alpha3 by the corresponding segments of alpha1-alpha5 resulted in mutant receptors displaying the GABA EC(50) values of the respective wild-type receptors. Vice versa, the alpha3 motif forced the low sensitivity to GABA of alpha3 upon alpha1beta3gamma2, alpha4beta3gamma2, and alpha5beta3gamma2. Binding of the GABA agonist [(3)H]muscimol was not affected by the exchange of the motif between alpha1 and alpha3 subunits. Thus, the equilibrium binding pocket is maintained upon replacement of the four amino acids. Taken together our data suggest that the identified motifs contribute to a structure involved in the transduction of the binding signal rather than to the binding itself.

Amino Acid Motifs↗
PubMed1985

gamma-Aminobutyric-acid- and pentobarbitone-gated chloride currents in internally perfused frog sensory neurones.

gamma-Aminobutyric-acid- (GABA) and pentobarbitone-induced Cl- currents (ICl) were studied in isolated frog sensory neurones after suppression of Na+, K+ and Ca2+ currents using a suction-pipette technique combining internal perfusion with voltage clamp. All GABA-sensitive neurones responded to pentobarbitone. Both GABA- and pentobarbitone-induced ICl reversed at the Cl- equilibrium potential (ECl). The dose-response curve for maxima of GABA-induced ICl was sigmoidal with a mean concentration producing a half-maximum response, Ka of 2 X 10(-5) M at a Hill coefficient of 1.8. In the presence of pentobarbitone, the GABA dose-response curve shifted to the left without affecting the saturating maximum current. At high concentrations, both GABA and pentobarbitone could also potentiate the pentobarbitone- and GABA-induced ICl respectively, while pre-treatment with one of the two markedly attenuated currents induced by the other, indicating a 'cross-desensitization'. In the presence of pentobarbitone, the augmented response was voltage dependent and this augmentation was much greater in the inward-current direction than outward. In producing ICl, pentobarbitone and its stereoisomers were potent in the order of (-) isomer greater than (+/-) racemic mixture greater than (+) isomer. A stereospecific facilitatory action of pentobarbitone on GABA responses was also found in the same order. Responses to GABA, homotaurine, taurine, beta-alanine, 5-aminovaleric acid, (+)- and (-)-gamma-amino-beta-hydroxybutyric acid and muscimol were equally enhanced by pentobarbitone, though its action on glycine-induced ICl was less effective. Picrotoxin inhibited the GABA- and pentobarbitone-induced ICl from either side of membrane, while internal application of GABA and pentobarbitone did not exert any effect. It was concluded that pentobarbitone binds to the 'barbiturate receptors' located close to the GABA receptor-Cl- channel complex, and directly affects the GABA-GABA receptor interactions rather than the ionic channels.

Action Potentials↗
PubMed1998

Mutations of gamma-aminobutyric acid and glycine receptors change alcohol cutoff: evidence for an alcohol receptor?

Alcohols in the homologous series of n-alcohols increase in central nervous system depressant potency with increasing chain length until a "cutoff" is reached, after which further increases in molecular size no longer increase alcohol potency. A similar phenomenon has been observed in the regulation of ligand-gated ion channels by alcohols. Different ligand-gated ion channels exhibit radically different cutoff points, suggesting the existence of discrete alcohol binding pockets of variable size on these membrane proteins. The identification of amino acid residues that determine the alcohol cutoff may, therefore, provide information about the location of alcohol binding sites. Alcohol regulation of the glycine receptor is critically dependent on specific amino acid residues in transmembrane domains 2 and 3 of the alpha subunit. We now demonstrate that these residues in the glycine alpha1 and the gamma-aminobutyric acid rho1 receptors also control alcohol cutoff. By mutation of Ser-267 to Gln, it was possible to decrease the cutoff in the glycine alpha1 receptor, whereas mutation of Ile-307 and/or Trp-328 in the gamma-aminobutyric acid rho1 receptor to smaller residues increased the cutoff. These results support the existence of alcohol binding pockets in these membrane proteins and suggest that the amino acid residues present at these positions can control the size of the alcohol binding cavity.

Alcohols↗
PubMed1985

Interactions of gamma-aminobutyric acid (GABA), pentobarbital, and homopantothenic acid (HOPA) on internally perfused frog sensory neurons.

Augmentatory actions among Cl- currents (ICl) induced by gamma-aminobutyric acid (GABA), pentobarbital (PB), and homopantothenic acid (HOPA) were investigated in isolated frog sensory neurons after suppression of Na+, K+, and Ca2+ currents using a suction pipette technique which combines internal perfusion with voltage clamp. GABA-sensitive neurons responded to both PB and HOPA, and the responses behaved as a simple Cl- electrode and reversed at the Cl- equilibrium potential (ECl). The dose-response curve for GABA-induced Cl- conductance was sigmoidal with the GABA concentration producing a half-maximum response (4.2 X 10(-5) M). Both GABA and HOPA dose-response curves shifted to the left in the presence of PB, though the facilitatory action of PB on GABA- and HOPA-induced ICl was more effective in the former. There was a significant facilitatory interaction between GABA- and HOPA-induced ICl. It is concluded that HOPA affects the GABA-GABA or PB-PB receptor interactions.

Animals↗
PubMed1999

Simultaneous determination of gamma-aminobutyric acid and glutamic acid in the brain of 3-mercaptopropionic acid-treated rats using liquid chromatography-atmospheric pressure chemical ionization mass spectrometry.

The measurement of gamma-aminobutyric acid (GABA) and glutamic acid (Glu) in the whole brain and in various regions of the brain in 3-mercaptopropionic acid (3-MPA)-treated rats has been developed using liquid chromatography-mass spectrometry with an atmospheric pressure ionization interface system. The recoveries of these compounds were 94.90+/-4.18% for GABA, 95.60+/-2.86% for Glu after ion-exchange treatment. The detection limits for GABA and Glu were 2.5+/-0.3 microg/ml and 5.0+/-0.8 microg/ml, respectively, when 20 microl sample were injected. GABA concentration in the whole brain decreased gradually to 5 min and reached 63% of normal value after administration of 3-MPA, and the concentration increased gradually thereafter until 60 min. Conversely, the concentration of Glu in the whole brain increased gradually to 10 min and reached 154% of normal value, and after that decreased gradually and reached almost normal level at 60 min after administration of 3-MPA. GABA concentration in various regions of brain decreased to 5 min in all regions after administration of 3-MPA, and reached normal levels at 60 min as in the whole brain. This method was found to be useful for studies of metabolism of GABA and Glu in biological samples.

3-Mercaptopropionic Acid↗
PubMed2003

Hyperalgesic effects of gamma-aminobutyric acid transporter I in mice.

The present study focused on the involvement of gamma-aminobutyric acid transporter I (GAT1) in pain. We found that GABA uptake was increased in mouse spinal cord at 20 min and 120 min after formalin injection and in mouse brain at 120 min, but not 20 min, after formalin injection. In addition, the antinociceptive effects of GAT1-selective inhibitors were examined using assays of thermal (tail-flick) and chemical (formalin and acetic acid) nociception in C57BL/6J mice. The GAT1-selective inhibitors, ethyl nipecotate and NO-711, exhibited significant antinociceptive effects in these nociceptive assays. To study further the effects of GAT1 on pain, we used two kinds of GAT1-overexpressing transgenic mice (under the control of a CMV promoter or a NSE promoter) to examine the nociceptive responses in these mice. In the thermal, formalin, and acetic acid assays, both kinds of transgenic mice displayed significant hyperalgesia after nociceptive stimuli. In addition, the micro opioid receptor antagonist naloxone had no influence on nociceptive responses in wild-type and transgenic mice. The results indicate that GAT1 is involved in the regulation of pain processes, and point to the possibility of developing analgesic drugs that target GAT1 other than opioid receptors.

Analgesics, Opioid↗
PubMed1985

Absence of modifications in gamma-aminobutyric acid metabolism after repeated generalized seizures in amygdala-kindled rats.

Alterations in gamma-aminobutyric acid (GABA) metabolism have been investigated in the kindling model of epilepsy. Numerous generalized seizures were induced by amygdala-kindling stimulations in rats. One week after the last stimulation, there were no changes in GABA levels nor in the activity of enzymes responsible for the synthesis (glutamic acid decarboxylase) and catabolism (GABA transaminase and succinyl semialdehyde dehydrogenase). These results do not exclude other changes in GABA function as modifications of transport or receptors.

4-Aminobutyrate Transaminase↗
PubMed1977

Influence of neuroglial transport on the action of gamma-aminobutyric acid on mammalian ganglion cells.

1 The effect of inhibiting the transport of gamma-aminobutyric acid (GABA) by neuroglial cells on the depolarizing action of exogenous amino acids on isolated superior cervical ganglia of the rat was studied. 1 Transport (measured by uptake of [3H]-GABA) was inhibited by (a) reducing external [na+] from 143 to 2mM and (b) administering alternative carrier-sbustrates, 3-amino-n-butyric acid (beta-amino-butyric acid, BABA) and (+/-)-nipecotic acid at a concentration of 1 mM. 3 All three procedures enhanced the depolarization produced by low concentrations of GABA (less than or equal to 10 muM) but did not alter the maximum response, nor the response to 3-aminopropanesulphonic acid (a gabamimetic with low affinity for the neuroglial carrier). 4 It is concluded that the neuroglial uptake process can limit the action of exogenous GABA upon neurones, by reducing the interstitial GABA concentration.

Alkanesulfonates↗
PubMed1982

Metabolism and brain uptake of gamma-aminobutyric acid in galactosamine-induced hepatic encephalopathy in rats.

Kinetic studies of [3H]gamma-aminobutyric acid ([3H]GABA) after an intravenous injection were performed in normal rats and in rats with severe degree of hepatic encephalopathy due to fulminant hepatic failure induced by galactosamine. Moreover, plasma and brain GABA levels, and GABA and glutamic acid decarboxylase activity were studied in some brain areas. After intravenous injection, [3H]GABA disappeared very rapidly in the blood of normal rats, with a prompt increase of 3H metabolites. In comatose rats, a delayed disappearance of [3H]GABA was parallelled by a lower amount of metabolites, indirectly indicating a peripheral decrease of GABA-transaminase activity. The amount of [3H]GABA in brain was lightly but constantly lower in comatose rats than in controls, indicating that the change in permeability of the blood-brain barrier in hepatic encephalopathy does not affect the [3H]GABA uptake of the brain. Furthermore, the assay of endogenous GABA in blood, whole brain, and brain areas did not show any significant difference in any of the two groups. The finding that glutamic acid decarboxylase activity in brain was reduced, together with the indirect evidence of a reduction in GABA-transaminase, may account for the steady state of GABA in hepatic encephalopathy. However, the reduction in glutamic acid decarboxylase activity is in favor of a functional derangement at the GABA-ergic nerve terminals in this pathological condition.

Animals↗
PubMed1987

Localization of sites in periventricular forebrain mediating cardiovascular effects of gamma-aminobutyric acid agonists and antagonists in anesthetized cats.

Previous studies have shown that injection of gamma-aminobutyric acid (GABA) antagonists such as bicuculline methiodide (BMI) into the forebrain (i.e., lateral and third) ventricular system elicits neurally mediated increases in blood pressure and heart rate and inhibits baroreflex bradycardia in anesthetized cats. Similar administration of muscimol, a GABA agonist, blocks or reverses the effects of BMI but has no effect on blood pressure or heart rate in untreated animals. These findings suggest that GABAergic inhibition may tonically suppress a forebrain mechanism capable of modifying autonomic outflow to the cardiovascular system. In the present study, we used a technique designed to restrict the distribution of intraventricularly administered drugs to varying degrees in order to better localize the relevant sites of drug action. Our findings show that BMI increases heart rate and blood pressure and that muscimol counters these changes by acting at a site that is accessible from the intermediate (as opposed to the rostral or caudal) region of the third ventricle. In contrast, these agents influence baroreflex bradycardia by acting at more rostral periventricular sites. These findings are consistent with the notion that the GABAergic mechanisms involved in the cardiovascular effects resulting from intraventricular administration of BMI and muscimol are located in the periventricular hypothalamus.

Animals↗
PubMed1982

Effects of gamma aminobutyric acid (GABA) and muscimol on endocrine pancreatic function in man.

The high concentrations of gamma aminobutyric acid (GABA) in the pancreatic islets and the neurotransmitter role played by this amino acid in the central nervous system, make it plausible that GABA also intervenes in the control of endocrine pancreatic function. In 12 normal subjects, a single oral dose of 5 or 10 g GABA, as compared to placebo, caused a significant (p less than 0.01) and dose-dependent (p less than 0.01) increase of plasma levels of immunoreactive insulin, C peptide and glucagon, without affecting plasma glucose concentration. By contrast, in 15 additional subjects, a single oral dose of 5 mg muscimol, a specific GABA receptor agonist, did not consistently influence the above parameters. Although the lack of effects of muscimol might indicate that the action of GABA is not mediated through specific receptors, the results with GABA suggest that this amino acid plays a specific role in the regulation of endocrine pancreatic function.

Adolescent↗
PubMed1982

Drugs that increase gamma-aminobutyric acid transmission protect against the high pressure neurological syndrome.

1 The effects on the high pressure neurological syndrome (HPNS) of drugs which facilitate gamma-aminobutyric acid (GABA) transmission were investigated. Threshold pressures for the onset of the behavioural signs of the HPNS in mice--tremors and convulsions were established. 2 Flurazepam hydrochloride 20 and 10 mg/kg and sodium valproate 800 and 400 mg/kg substantially raised the threshold pressures for both tremor and convulsions. 3 Amino-oxyacetic acid 35 and 25 mg/kg and diaminobutyric acid 600 mg/kg also significantly increased the thresholds. Muscimol 1 mg/kg (and 150 ng i.c.v.) was ineffective at non-toxic doses. 4 These effects paralleled the drugs' ability to raise the convulsion threshold to intravenous infusion of bicuculline in mice. 5 These results demonstrate that drugs with actions more selective than those of the general anaesthetics are effective against the HPNS. It is also possible that there is a GABAergic component to the effects of general anaesthetics on the HPNS.

Anesthetics↗