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At least 523 records · Page 29Linked to original sources
PubMed1990

Administration of vigabatrin (gamma-vinyl-gamma-aminobutyric acid) affects the levels of both inhibitory and excitatory amino acids in rat cerebrospinal fluid.

The effect of vigabatrin (gamma-vinyl-gamma-aminobutyric acid), a new anticonvulsant drug, on the transmitter amino acids in rat cisternal CSF was studied. CSF was collected through a permanently implanted polyethylene cannula from freely moving rats at 5, 24, 48, and 96 h after administration of 1,000 mg/kg of vigabatrin. The free gamma-aminobutyric acid (GABA) level was elevated maximally (13.5-fold; p less than 0.01) at 24 h after injection. The homocarnosine (GABA-histidine) level also was increased (123%; p less than 0.01) at 24 h after injection, and its concentration remained at the same level for the next 3 days. Glycine and taurine concentrations had increased [31% (p less than 0.05) and 63% (p less than 0.01), respectively] at 5 h after injection. It is interesting that the levels of glutamate and aspartate increased [330% (p less than 0.05) and 421% (p less than 0.01), respectively] at 96 h after injection, the time when the free GABA level had returned to the baseline concentration and the vigabatrin level was 3% of the maximal concentration. The present study indicates that a single dose of vigabatrin in rats elevates levels of both the inhibitory and excitatory amino acids in CSF. However, the temporal profile of observed changes in relation to vigabatrin injection shows that neither the long-lasting elevation of GABA content nor the increase in glutamate and aspartate levels correlates with the level of vigabatrin in CSF. These findings suggest that the excitatory mechanisms are also augmented following acute administration of vigabatrin, especially when the content of GABA had decreased to the baseline level and the level of vigabatrin was low.

Amino Acids↗
PubMed1993

Characterization of bicuculline/baclofen-insensitive (rho-like) gamma-aminobutyric acid receptors expressed in Xenopus oocytes. II. Pharmacology of gamma-aminobutyric acidA and gamma-aminobutyric acidB receptor agonists and antagonists.

Poly(A)+ RNA from mammalian retina expresses bicuculline/baclofen-insensitive gamma-aminobutyric acid (GABA) receptors in Xenopus oocytes with properties similar to those of homooligomeric GABA rho 1 receptors. The pharmacological profile of these rho-like receptors was extended by measuring sensitivities to various GABAA and GABAB receptor ligands. For direct comparison the same compounds were also assayed with GABAA receptors expressed by rat brain RNA. The potency sequence for heterocyclic GABA analogues at the GABA rho-like receptors was GABA (1.3) > muscimol (2.3) > isoguvacine (100) (approximate EC50 in parentheses; all EC50 and Kb values given in microM). Both muscimol and isoguvacine were partial agonists at the rho-like receptors. 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol (Kb congruent to 32), piperidine-4-sulfonic acid (Kb congruent to 85), and isonipecotic acid (Kb congruent to 1000) acted primarily as competitive antagonists, showing little or no activity as agonists. The sulfonic acid GABA analogue 3-aminopropanesulfonic acid was also a competitive antagonist (Kb congruent to 20). Conformationally restricted GABA analogues trans- and cis-4-aminocrotonic acid (TACA and CACA) were agonists at the rho-like receptors. TACA (EC50 congruent to 0.6) had twice the potency of GABA and was 125 times more potent than CACA (EC50 congruent to 75). Z-3-(Amidinothio)propenoic acid, an isothiouronium analogue of GABA, had little activity as an agonist but instead acted as a competitive antagonist (Kb congruent to 20). At concentrations of > 100 microM, bicuculline did have some weak competitive inhibitory effects on the GABA rho-like receptors (Kb congruent to 6000), but it was at least 5000 times more potent at GABAA receptors. Strychnine (Kb congruent to 70) and SR-95531 (Kb congruent to 35) also were competitive inhibitors of the rho-like receptors but were, respectively, 20 and 240 times more potent at GABAA receptors. The GABAB receptor ligands baclofen, phaclofen, and saclofen (1-100 microM) had no appreciable effects on the rho-like receptors. In contrast, 3-aminopropylphosphonic acid, the phosphonic acid analogue of GABA, acted as a competitive antagonist (Kb congruent to 10), and 3-aminopropylphosphinic acid and 3-aminopropyl(methyl)-phosphinic acid were moderately potent antagonists (Kb congruent to 1.7 and 0.8, respectively). delta-Aminovaleric acid was also an antagonist (Kb congruent to 20), whereas 4-aminobutylphosphonic acid, the phosphonic acid analogue of delta-aminovaleric acid, was only a weak inhibitor (Kb congruent to 600).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1971

The release of gamma-aminobutyric acid during inhibition in the cat visual cortex.

1. The release of gamma-aminobutyric acid (GABA) from the surface of the posterior lateral gyrus of the cerebral cortex was measured by a sensitive enzymic fluorimetric assay procedure. Experiments were performed with anaesthetized cats during resting conditions and during cortical inhibition produced by electrical stimulation of the brain surface or of the lateral geniculate nucleus (l.g.n.).2. The average resting release of endogenous GABA was 0.20 n-mole/ 7 min.cm(2) cortex; this was increased during stimulation of both the cortical surface (2.9 times resting release during monopolar stimulation and 7.4 times resting release during bipolar stimulation) and the l.g.n. (5.7 times resting release).3. Removal of calcium ions from the collection fluid did not affect the resting release of endogenous GABA but prevented the increase in GABA release normally evoked by stimulation of the cortical surface.4. The stimulus parameters used to increase the release of GABA also inhibited the glutamate-induced firing of single cells in the visual cortex and this inhibition was abolished in the absence of calcium ions.5. In three experiments the total amino acid content of cortical samples was examined using an amino acid analyser. With the exception of GABA, there were no significant differences between the rates of release of any other detected amino acids during periods with and without electrical stimulation of the cortex.6. It is suggested that since the release of GABA observed during inhibitory stimulation of the cortex is calcium-dependent and specific, it may originate from inhibitory nerve terminals in the cortex. The present findings support the view that GABA is a central inhibitory neurotransmitter.

Action Potentials↗
PubMed1984

Changes in the amino acid content of nerve endings (synaptosomes) induced by drugs that alter the metabolism of glutamate and gamma-aminobutyric acid.

The study was centered on the changes in the amino acid content of nerve endings (synaptosomes) induced by drugs that alter the metabolism of glutamate or gamma-aminobutyric acid (GABA), and that possess convulsant or anticonvulsant properties. The onset of seizures induced by various convulsant agents was associated with a decreased content of GABA and an increased content of glutamate in synaptosomes. The concurrent administration of pyridoxine prevented both the biochemical changes and the convulsions. The administration of gabaculine to mice resulted in large increases in the GABA content of synaptosomes that were counteracted by decreases in glutamate, glutamine, and aspartate levels such that the total content of the four amino acids remained unchanged. The administration of aminooxyacetic acid (0.91 mmol/kg) resulted initially in seizure activity, but subsequently in an anticonvulsant action. No simple relationship existed between the excitable state of the brain induced by aminooxyacetic acid and the changes in the synaptosomal levels of any of the amino acid transmitters. A hypothesis was, however, formulated that explained the convulsant-cum-anticonvulsant action of aminooxyacetic acid on the basis of compartmentation of GABA within the nerve endings.

Amino Acids↗
PubMed1992

Glutamate and gamma-aminobutyric acid neurotransmitter systems in the acute phase of maple syrup urine disease and citrullinemia encephalopathies in newborn calves.

Cerebral cortex tissue was obtained at autopsy from neonatal Poll Hereford calves with clinically confirmed maple syrup urine disease (MSUD), neonatal Holstein-Friesian calves with clinically confirmed citrullinemia, and matched controls. From this, synaptosomes were prepared for studies of neurotransmitter amino acid uptake and stimulus-induced release, and synaptic plasma membranes were obtained for studies of associated postsynaptic receptor binding sites. As well as having abnormal brain tissue concentrations of the pathognomic plasma amino acids (markedly increased levels of the branched-chain compounds valine, isoleucine, and leucine in MSUD; marked elevation of citrulline levels in citrullinemia), both groups of diseased animals showed reduced brain tissue concentrations of each of the transmitter amino acids glutamate, aspartate, and gamma-aminobutyric acid (GABA). Nontransmitter amino acids were generally unaffected in either disease. Citrullinemic calves showed a marked increase in brain glutamine concentration; in calves with MSUD, the glutamine concentration was raised, but to a much lesser extent. The Na(+)-dependent synaptosomal uptake of both glutamate and GABA was markedly reduced (to less than 50% of control values in both cases) in citrullinemic calves but was unaltered in calves with MSUD. Whereas synaptosomes from normal calves showed the expected stimulus-coupled release of transmitter amino acids, especially glutamate and aspartate, and no response to stimulus of nontransmitter amino acids, there was no increased release of transmitter amino acids in response to depolarization in synaptosomes from citrullinemic calves.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Reaction↗
PubMed2000

Transgenic mice overexpressing gamma-aminobutyric acid transporter subtype I develop obesity.

Transgenic mice ubiquitously overexpressing murine gamma-aminobutyric acid transporter subtype I were created. Unexpectedly, these mice markedly exhibited heritable obesity, which features significantly increased body weight and fat deposition. Behavioral examination revealed that transgenic mice have slightly reduced spontaneous locomotive capacity and altered feeding pattern. This preliminary finding indicates that the inappropriate level of gamma-aminobutyric acid transporters may be directly or indirectly involved in the pathogenic mechanism underlying certain types of obesity.

Animals↗
PubMed1981

Involvement of diamine oxidase in catabolism of 14C-putrescine in mice in vivo with special reference to the formation of gamma-aminobutyric acid.

Tissues of mice killed 2.5 or 30 min after injection of 14C-putrescine, contained 14C-gamma-aminobutyric acid, an unidentified 14C-compound, and unchanged 14C-putrescine. In mice pretreated with aminoguanidine, a powerful inhibitor of diamine oxidase, and then with 14C-putrescine, tissue levels of the radioactive catabolites, gamma-aminobutyric acid and the unidentified compound were markedly reduced. The data suggest that diamine oxidase is involved in the first step of putrescine metabolism and that intestine is the main site for this step. This and other aspects of putrescine metabolism are discussed.

Amine Oxidase (Copper-Containing)↗
PubMed2001

[Determination of 4-aminobutyric acid in pumpkin powder by high performance liquid chromatography].

A method for the separation and determination of the 4-aminobutyric acid in pumpkin powder by high performance liquid chromatography (HPLC) with post-column derivatization and fluorescence detection is described. The operating conditions were cation exchange resin column (30 cm x 0.4 cm i.d.) with gradient elution of buffer solutions A [19.6 g sodium citrate dihydrate and 1.0 g phenol dissolved in 1 L water, pH(3.15 +/- 0.02)] and B [21.0 g sodium nitrate and 1.5 g boric acid dissolved in 1 L water, pH(9.70 +/- 0.02)] as mobile phase at a flow rate of 0.5 mL/min, and a column temperature of 62 degrees C, with detection wavelength lambda ex = 338 nm, lambda em = 425 nm. The retention time of 4-aminobutyric acid was 34.77 minutes. The average recovery was 99% and the coefficient of variation was 1.35%. This method is simple, rapid and sensitive.

Cation Exchange Resins↗
PubMed2005

Classic benzodiazepines modulate the open-close equilibrium in alpha1beta2gamma2L gamma-aminobutyric acid type A receptors.

BACKGROUND: Classic benzodiazepine agonists induce their clinical effects by binding to a site on gamma-aminobutyric acid type A (GABAA) receptors and enhancing receptor activity. There are conflicting data regarding whether the benzodiazepine site is allosterically coupled to gamma-aminobutyric acid binding versus the channel open-close (gating) equilibrium. The authors tested the hypothesis that benzodiazepine site ligands modulate alpha1beta2gamma2L GABAA receptor gating both in the absence of orthosteric agonists and when the orthosteric sites are occupied. METHODS: GABAA receptors were recombinantly expressed in Xenopus oocytes and studied using two-microelectrode voltage clamp electrophysiology. To test gating effects in the absence of orthosteric agonist, the authors used spontaneously active GABAA receptors containing a leucine-to-threonine mutation at residue 264 on the alpha1 subunit. To examine effects on gating when orthosteric sites were fully occupied, they activated wild-type receptors with high concentrations of a partial agonist, piperidine-4-sulfonic acid. RESULTS: In the absence of orthosteric agonists, the channel activity of alpha1L264Tbeta2gamma2L receptors was increased by diazepam and midazolam and reduced by the inverse benzodiazepine agonist FG7142. Flumazenil displayed very weak agonism and blocked midazolam from further activating mutant channels. In wild-type receptors activated with saturating concentrations of piperidine-4-sulfonic acid, midazolam increased maximal efficacy. CONCLUSIONS: Independent of orthosteric site occupancy, classic benzodiazepines modulate the gating equilibrium in alpha1beta2gamma2L GABAA receptors and are therefore allosteric coagonists. A Monod-Wyman-Changeux coagonist gating model quantitatively predicts these effects, suggesting that benzodiazepines minimally alter orthosteric ligand binding.

Algorithms↗
PubMed2006

Additive effects of sevoflurane and propofol on gamma-aminobutyric acid receptor function.

BACKGROUND: Previous studies have shown that propofol and sevoflurane enhance the function of gamma-aminobutyric acid type A (GABAA) receptors. However, it is not known whether these two drugs modulate the same molecular pathways. In addition, little is known about receptor function in the presence of both propofol and sevoflurane. The aim of this study was to better understand the interactions of propofol and sevoflurane with the GABAA receptor. METHODS: Wild-type alpha1, beta(2), gamma(2s) GABA(A) receptor subunit complementary DNAs were transfected into human embryonic kidney cells grown on glass coverslips using a calcium phosphate transfection method. After transfection (36-72 h), cells were whole cell patch clamped and exposed to combinations of the following: 0.3-1,000 microm gamma-aminobutyric acid (GABA), 0-10 microm propofol, and 0-1,650 microm sevoflurane. Chemicals were delivered to the cells using two 10-channel infusion pumps and a rapid solution exchanger. RESULTS: Both propofol and sevoflurane alone enhanced the amplitude of GABA(A) receptor responses to submaximal concentrations of GABA in a dose-dependent manner. The enhancement was underpinned by an increase in the apparent affinity of the receptor for GABA. Coapplication of both anesthetics further enhanced the apparent affinity of the receptor for GABA. CONCLUSIONS: Response surface modeling of the potentiation of GABA responses (0.3-1,000 microm) by sevoflurane and propofol revealed that the two anesthetics modulated receptor function in an additive manner. These results are consistent with recent mutagenesis studies, suggesting that these two drugs have separate binding sites and converging pathways of action on the GABAA receptor.

Anesthesia, General↗
PubMed1998

Oleamide potentiates benzodiazepine-sensitive gamma-aminobutyric acid receptor activity but does not alter minimum alveolar anesthetic concentration.

UNLABELLED: A naturally occurring brain lipid, cis-9,10-octadeceamide--oleamide (OA), is found in increased concentrations in the cerebrospinal fluid of sleep-deprived cats, which suggests that it may be an endogenous sleep-inducing substance. We studied the effects of this fatty-acid derivative on the function of cloned gamma-aminobutyric acid (GABA(A)) receptors expressed in Xenopus oocytes. Oocytes were injected with cRNA synthesized in vitro to express simple GABA(A) receptors (alpha1beta1, alpha3beta1, alpha5beta1, and alpha1beta2 subunit combinations) and receptors in which the GABA-induced chloride currents were potentiated in the presence of benzodiazepines (alpha1beta1gamma2s and alpha1beta2gamma2s subunit combinations). OA only produced significant potentiation of the peak Cl- current when applied with GABA to benzodiazepine-sensitive GABA(A) receptors. The peak currents of the simple GABA(A) receptors in the presence of OA were either unaffected or slightly inhibited by OA, but the overall mean currents were not significantly altered. Oleic acid was also capable of potentiating benzodiazepine-sensitive GABA(A) receptor function. The function of other ligand-gated ion channels, such as the N-methyl-D-aspartate receptor (NR1 + NR2A or 2C) and the 5-HT3 receptor expressed in Xenopus oocytes, were unaffected by OA. Sprague-Dawley rats receiving intraperitoneal injections of oleamide (10, 20, or 100 mg/kg) showed no change in the minimum alveolar anesthetic concentration (MAC) of desflurane required to abolish movement in response to noxious (tail clamp) stimulation (control MAC 6.48% +/- 1.28% atm; 100 mg/kg OA MAC 7.05% +/- 0.42% atm). These results reinforce the view that oleyl compounds may be natural modulators of inhibitory ion channel function, but that these effects contribute little to the central nervous system depression produced by volatile anesthetics as measured by MAC. IMPLICATIONS: The putative sleep-inducing substance, oleamide, potentiates benzodiazepine-sensitive gamma-aminobutyric acid receptor function but does not alter desflurane minimum alveolar anesthetic concentration in rats.

Anesthetics, Inhalation↗
PubMed1983

[Blocking effect of furosemide on the chloride permeability of mollusk neuron membranes induced by acetylcholine and gamma-aminobutyric acid].

Furosemide (2.10(-4) to 1.10(-3) g/ml) was shown to prevent the increase of chloride conductance induced in isolated neurons of freshwater mollusc Planorbarius corneus by ionophoretic application of acetylcholine, suberyldicholine or gamma-aminobutyric acid. Furosemide caused no shift in the reversal potential of the chloride-dependent responses if the experiments were carried out employing microelectrode filled with potassium sulphate. When potassium chloride-filled microelectrodes were used, the reversal potential became less negative in the presence of furosemide. This effect seems to be due to the blocking of the active transport of chloride by furosemide. Neither sodium-dependent, nor potassium-dependent responses induced by cholinoreceptor activation were influenced by furosemide. Furosemide was found to diminish both the amplitude and the rate of chloride-dependent responses. The lack of selectivity with respect to acetylcholine or gamma-aminobutyric acid suggests that furosemide blocks the chloride channels of chemoceptive membrane which are probably common to acetylcholine and gamma-aminobutyric acid and does not affect their receptors.

Acetylcholine↗
PubMed1984

Effects of intraventricular injections of gamma-aminobutyric acid and related substances on feeding behavior in satiated sheep.

Feed intake was measured following injections of gamma-aminobutyric acid (GABA), muscimol (a GABA agonist), and picrotoxin (a GABA antagonist) into the lateral ventricles of satiated sheep. Doses ranging from 0.20 to 3200 nmol of GABA did not affect feeding behavior at 15, 30, 60, and 120 min postinjection. A dose of 160 nmol of muscimol induced a marked increase in feeding, comparable to that provoked by an injection of 78 mumol of pentobarbital. Muscimol-induced feeding was blocked effectively by a preinjection of picrotoxin. These observations implicate that neurons sensitive to gamma-aminobutyric acid may be involved in the control of feeding behavior in ruminants.

Animals↗
PubMed1983

Inhibition by Diazepam and γ-Aminobutyric Acid of Depolarization-Induced Release of [¹⁴C]Cysteine Sulfinate and [³H]Glutamate in Rat Hippocampal Slices.

Effects of diazepam and γ-aminobutyric acid-related compounds on the release of [¹⁴C]cysteine sulfinate and [³H]glutamate from preloaded hippocampal slices of rat brain were examined by a superfusion method. Diazepam markedly inhibited the release of cysteine sulfinate and glutamate evoked either by high K⁺ or veratridine without affecting that of other neurotransmitter candidates, e.g., γ-aminobutyric acid, acetylcholine, noradrenaline, and dopamine; IC₅₀ values for the release of cysteine sulfinate and glutamate were about 20 and 7 μM, respectively. γ-Aminobutyric acid (1 to 10 μM) and muscimol (100 μM) significantly reduced high K⁺-stimulated release of glutamate. Bicuculline, which had no effect on the release at a concentration of 50 μM by itself, antagonized the inhibitory effects of diazepam and γ-aminobutyric acid on glutamate release. Similar results were obtained with the release of cysteine sulfinate except that a high concentration (100 μM) of γ-aminobutyric acid was required for the inhibition. These results indicate the modulation by γ-aminobutyric acid innervation of the release of excitatory amino acids in rat hippocampal formation, and also suggest that some of the pharmacological effects of diazepam may be a consequence of inhibition of excitatory amino acid transmission.

Animals↗
PubMed1993

Effects of gabapentin on release of gamma-aminobutyric acid from slices of rat neostriatum.

The gamma-aminobutyric acid (GABA) analogue gabapentin (CAS 60142-96-3) has a strong anticonvulsant activity in patients, but its mechanism of action is unknown. In the present study, the effect of gabapentin was tested on the release of [3H]GABA from neostriatal slices incubated in vitro. Gabapentin displayed a bell-shaped concentration-response curve. When used at the therapeutically relevant concentration of 1 mumol/l, it nearly doubled the release of [3H]GABA, while it was without effects at concentrations of 0.1 and 10 mumol/l, respectively. The enhancing effect was blocked by the GABAA receptor antagonists picrotoxin (5 mumol/l) and bicucullin (100 mumol/l). When the slices were pre-incubated with the agonist muscimol (1 mumol/l) to occupy the GABAA receptors, 1 mumol/l gabapentin no longer enhanced the release of [3H]GABA. It is concluded that gabapentin can enhance the release of [3H]GABA, when used at a therapeutically relevant concentration. GABAA receptors are involved in this effect which may contribute to the agent's anticonvulsant activity.

Acetates↗
PubMed1982

A possible role of gamma-aminobutyric acid in the control of the endocrine pancreas.

This study examines the effect of baclofen, a specific gamma-aminobutyric acid analog which crosses the blood-brain barrier freely, upon insulin, glucagon, and GH responses to iv glucose in normal man. Normal subjects received two consecutive iv glucose tolerance tests (0.33 g/kg) before and after the acute oral administration of 5, or 10 or 20 mg baclofen, respectively, (10 subjects for each group). The dose of baclofen was divided and given 8 and 1 h before the performance of the posttreatment test. A fourth group of normal subjects served as placebo group (8 subjects). The highest dose of baclofen significantly increased insulin responses to glucose and raised basal glucagon levels (P less than 0.01). No significant change occurred with the other doses. Baclofen produced a dose-related increase in basal GH levels; a 10-fold increase was observed with the 20-mg dose. However, glucose-induced glucagon and GH suppression were not affected by baclofen. Despite the increased hormonal secretions, glucose tolerance did not change after baclofen. These results seem to indicate that gamma-aminobutyric acid may play a role in the neuroendocrine control of the pancreatic islets.

Administration, Oral↗