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PubMed1988

Determination of gamma-aminobutyric acid and associated amino acids in mouse brain by liquid chromatography.

A rapid method is described for the analysis of amino acids containing in mouse brain by high performance liquid chromatography equipped with a fluorescence detector. Pre-column o-phthalaldehyde-2-mercaptoethanol derivatives of the amino acids were injected onto an ODS C-18 column. 5-Amino-n-valeric acid, a non-endogenous amino acid, was used as an internal standard. Separation and elution of amino acid derivatives were achieved by varying the ratio of organic phase by a step gradient. Significant increases in gamma-aminobutyric acid, glutamine and glycine levels in the brain were detected 2 h after injection of 800 mg/kg valproic acid (VPA). A high dose administration of VPA was correlated with Reye's syndrome.

Amino Acids↗
PubMed1999

[3H] gamma-aminobutyric acid transport in rat substantia nigra pars reticulata synaptosomes: pharmacological characterization and phorbol ester-induced inhibition.

In synaptosomes from rat substantia nigra pars reticulata, [3H] gamma-aminobutyric acid (GABA) uptake was inhibited by GABA, (+/-)-nipecotic acid, beta-alanine and SKF 89976-A. Inhibition was concentration-dependent and monophasic, with IC50 values that agree with those reported for the cloned rat GABA transporter GAT-1. [3H]GABA uptake was modestly, but significantly, reduced (21 +/- 3% inhibition) by 100 nM phorbol 12-tetradecanoyl-13-acetate (TPA), an activator of protein kinase C (PKC). The inhibitory action of TPA was reversed by the PKC inhibitor staurosporine (100 nM). Saturation analysis revealed that TPA reduced the maximum capacity of transport with no change in the affinity for GABA. [3H]GABA uptake was unaffected by either forskolin (10 microM) or 8-bromo-cAMP (500 microM). These results indicate that SNr GABAergic afferents express the GAT-1 transporter whose activity can be regulated by a PKC-mediated mechanism.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1983

Possible involvement of humoral regulation in the effects of elevated cerebral 4-aminobutyric acid levels on the polyamine metabolism in brain.

It has been reported in several recent studies that the manipulation of cerebral 4-aminobutyric acid (GABA) level results in unexpected changes in the cerebral polyamine metabolism in vivo. The mechanisms behind these interactions have remained unknown. The present results show that the changes in polyamine metabolism are not limited to the brain, but are observable also in the liver, which served as a peripheral reference tissue. Different types of responses in the activities of the polyamine-synthesizing enzymes, ornithine decarboxylase and adenosylmethionine decarboxylase, were observed after increasing the cerebral GABA concentration of mice with varying doses of two GABA transaminase inhibitors, gabaculine and ethanolamine-O-sulphate. The time course of the significant changes in the enzyme activities showed significant correlation between the brain and liver. The possibility of direct effects of the drugs on liver was excluded by injecting them intracerebroventricularly, and by performing control experiments with equal doses given peripherally. It is concluded that the observed changes in the polyamine metabolism of liver are produced through centrally mediated humoral regulation, and that the corresponding changes in the brain are obviously due to the same factor or factors, since they are significantly correlated to the changes in liver.

4-Aminobutyrate Transaminase↗
PubMed1981

Competitive inhibition of gamma-aminobutyric acid receptor binding by N-2-hydroxyethylpiperazine-N'-2-e-ethanesulfonic acid and related buffers.

Several Good buffers (MOPS, ACES, BES, HEPES, ADA, and PIPES) competitively inhibited both high-affinity and low-affinity [3H]gamma-aminobutyric acid receptor binding to rat brain synaptic membranes. The most potent inhibitor was MOPS, which had Ki values of 180 nM and 79 nM for the high- and low-affinity binding sites, respectively. HEPES had Ki values of 2.25 mM and 115 microM. The buffers had no appreciable effect on sodium-dependent GABA binding or on gamma-aminobutyrate aminotransferase activity. Surprisingly, the buffers were extremely ineffectual as inhibitors of either high- or low-affinity [3H]muscimol binding. Indeed, they were of the order of 10(5) times less effective in this case than against [3H]GABA binding. These results clearly show (a) that the use of such buffers as MOPS or HEPES should be avoided in studying the interaction of GABA with its receptor, and (b) the binding sites of [3H]GABA and [3H]muscimol are not identical.

4-Aminobutyrate Transaminase↗
PubMed1985

Improved method for isolating synaptosomes from 11 regions of one rat brain: electron microscopic and biochemical characterization and use in the study of drug effects on nerve terminal gamma-aminobutyric acid in vivo.

A procedure is described for the rapid preparation of nerve ending particles (synaptosomes) from 11 regions of one rat brain. The synaptosomal fractions have been characterized by electron microscopy and determination of four marker enzymes, i.e., glutamate decarboxylase (GAD), acetylcholinesterase, succinate dehydrogenase, and glycerol 3-phosphate dehydrogenase. Comparison with a much lengthier standard (Ficoll-sucrose) preparation showed that the synaptosomal yield of the new procedure was substantially better as judged by both morphological evaluation and protein recovery. The improved synaptosome preparation was used for determination of regional gamma-aminobutyric acid (GABA) levels in synaptosomal fractions. The postmortem increase in GABA level during removal and dissection of brain tissue and homogenization and fractionation procedures could be minimized by rapid processing of the tissue at low temperatures and inclusion of the GAD inhibitor 3-mercaptopropionic acid (3-MP; 1 mM) in the homogenizing medium. The addition of GABA (0.2 mM) to the homogenizing medium did not alter the GABA levels in the synaptosomes, indicating that no significant redistribution of GABA occurred during subcellular fractionation in sodium-free media. Synaptosomal GABA levels determined in the 11 rat brain areas showed the same regional distribution as the GABA-synthesizing enzyme GAD. On the basis of these findings, it was suggested that the synaptosome preparation could be used to evaluate the in vivo effects of drugs on nerve terminal GABA. Treatment of rats with a convulsant dose of 3-MP (50 mg/kg i.p.) 3 min before decapitation significantly lowered synaptosomal GABA levels in olfactory bulb, hippocampus, thalamus, tectum, and cerebellum. The 3-MP-induced seizures and reduction of GABA levels could be prevented by administration of valproic acid (200 mg/kg i.p.) 15 min before the 3-MP injection. The data indicate that the improved synaptosome preparation offers a convenient method of preparing highly purified synaptosomes from a large number of small tissue samples and can provide useful information on the in vivo effects of drugs on regional GABA levels in nerve terminals.

3-Mercaptopropionic Acid↗
PubMed1989

Release of gamma-[3H]aminobutyric acid (GABA) from electrically stimulated rat cortical slices and its modulation by GABAB autoreceptors.

Slices of rat temporo-parietal cortex were prelabeled with gamma-[3H]aminobutyric acid ([3H]GABA), in the presence of the glial GABA uptake inhibitor beta-alanine. The slices were then superfused with a medium containing the GABA transaminase inhibitor aminooxyacetic acid and stimulated electrically (5 min, 2 msec, 36 mA at 5 or 10 Hz), in the presence of the neuronal GABA reuptake inhibitor SK&F 89976A [N-(4,4-diphenyl-3-butenyl)-nipecotic acid] and of beta-alanine. Representative experiments showed that the tritium released could be accounted for almost entirely by authentic [3H]GABA. The electrically evoked overflow of [3H]GABA was tetrodotoxin sensitive and largely calcium-dependent. Exogenous GABA, added to the superfusion medium at 3 to 30 microM, reduced in a concentration-dependent manner the electrically evoked (5 Hz) release of [3H]GABA. The GABAB receptor agonist (-)-baclofen, but not the GABAA receptor agonist muscimol, mimicked GABA and produced a concentration-inhibition curve almost superimposable to that of the natural transmitter. The effects of GABA and of (-)-baclofen were much more pronounced at 5 than at 10 Hz. The GABA-induced inhibition of [3H]GABA release was sensitive to the novel GABAB receptor antagonist beta-(p-chlorophenyl)-3-amino propyl phosphonic acid which, by itself, increased the [3H]GABA overflow. The inhibitory effect of GABA was not counteracted by the GABAA receptor antagonists bicuculline or SR 95531 [2-(3'-carbethoxy-2'-propenyl)-3-amino-6-paramethoxy-phenyl-pyr idazinium bromide]. The results are compatible with the presence in the rat cerebral cortex of autoreceptors mediating inhibition of GABA release and belonging to the GABAB type. These autoreceptors may be activated tonically under physiological conditions.

Animals↗
PubMed2006

Gamma-aminobutyric acid (GABA) and cell proliferation: focus on cancer cells.

In addition to its role in the adult mammalian nervous system as an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) is involved in the proliferation, differentiation, and migration of several kinds of cells including cancer cells. GABA is synthesized predominantly from glutamate by glutamate decarboxylase and exerts its effects via ionotropic GABA(A) receptors and/or metabotropic GABA(B) receptors. In this review, the current state of knowledge regarding the role of the GABAergic system in peripheral nonneuronal cell proliferation is described, and recent advances in elucidation of the mechanisms leading to cell proliferation are discussed.

Animals↗
PubMed1993

Autoradiographic analysis of the uptake of [3H]dopamine, [3H]angiotensin II and [3H]gamma aminobutyric acid by the chicken thrombocyte.

The ability of chicken thrombocytes to take up and store transmitters of different categories, such as dopamine, angiotensin II and gamma aminobutyric acid (GABA), was examined by electron microscope autoradiography. Chicken thrombocytes selectively took up [3H]dopamine, which was stored in large vacuoles with peripherally situated electron-dense granules. Exogenous [3H]angiotensin II was also taken up by chicken thrombocytes. This accumulated in the same large vacuoles in which [3H]dopamine was stored. No active uptake of exogenous [3H]GABA was detected. The results indicate that chicken thrombocytes take up exogenous dopamine and angiotensin II which both appear to be stored in the same vacuoles, the amine storage organelles.

Angiotensin II↗
PubMed1979

The neuropharmacology of a novel gamma-aminobutyric acid analog, kojic amine.

Kojic amine (KA; 2-aminomethyl-5-hydroxy-4H-pyran-4-one), a compound which shares some structural features with gamma-aminobutyric acid (GABA) and muscimol, has been examined in a variety of test systems for GABAmimetic activity. In several in vitro central nervous system receptor binding assays employing rat brain membrane preparations, KA exhibited selective activity to displace 3H-muscimol but with a relatively high IC50 of 4.4 muM. KA did not alter the binding of 3H-diazepam. Iontophoretically applied KA exerted a pronounced (comparable to GABA on the basis of ejection currents)i inhibition of the firing of cerebellar Purkinje cells and spontaneously active or glutamate-activated neurons in the cerebral cortex. The inhibitory effects of KA, which were longer lasting than those of GABA, were antagonized by bicuculline and enhanced in the presence of 2,4-diaminobutyric acid. On the isolated amphibian (Bufo marinus) spinal cord, KA was less than 1/3 as potent as GABA in depolarizing primary afferent terminals. In this preparation KA caused a marked decrease in the dorsal and ventral root potentials evoked by electrical stimulation of an adjacent or corresponding dorsal root. KA is a poor substrate for GABA uptake systems into rat brain synaptosomes, has no effect on GABA release in vitro, and does not inhibit GABA transaminase activity. Altogether, these data suggest that KA does have some GABAmimetic actions (which are perhaps restricted to hyperpolarizing post-synaptic GABA receptors) but also exerts other pharmacological effects as well.

4-Aminobutyrate Transaminase↗
PubMed1994

[Effects of gamma-aminobutyric acid and bicuculline on the spontaneous discharge of the nucleus paragigantocellularis lateralis neurons in brainstem slices in rat].

The effects of iontophoretic application of gamma-aminobutyric acid (GABA) and its antagonist, bicuculline (BIC) on the spontaneous discharge of paragigantocellularis lateralis (PGCL) neurons and the influence of BIC on the effects of GABA were studied in brainstem slice in rat with multibarrel microelectrode techniques. Both GABA and BIC showed three types of effects, i.e., excitatory, inhibitory and unaffected; the percentage of each is 56.10%, 31.70%, 12.20% (for GABA) and 66.67%, 5.88%, 27.45% (for BIC) of the tested neurons, respectively. The inhibitory effect of GABA and excitatory effect of BIC are dose-dependent. In most of the neurons tested the response to GABA could be blocked by BIC. The results at cellular level suggest that there is endogenous GABA in PGCL and that there exists GABAA receptors on some of the PGCL neurons.

Animals↗
PubMed1985

The development of the dorsal root potential and the responsiveness of primary afferent fibers to gamma-aminobutyric acid in the spinal cord of rat fetuses.

The development of the dorsal root potential (DRP) and the responsiveness of primary afferent fibers to gamma-aminobutyric acid (GABA) were investigated in the isolated spinal cord of rat fetuses. At embryonic day 15.5, stimulation of the lumbar dorsal root was first effective in eliciting the DRP, which was not inhibited by bicuculline. A bicuculline-sensitive component of the DRP appeared at embryonic day 17.5. GABA (10 microM to 1 mM) caused a dose-dependent depolarization of the primary afferent fibers from embryonic day 13.5. The amplitude of the depolarization gradually increased with age until embryonic day 17.5 and was maintained thereafter. If the bicuculline-sensitive DRP solely reflects GABAergic activity, it is suggested that GABAergic activity develops at embryonic day 17.5 and the development of the responsiveness of primary afferent fibers to GABA precedes the functional onset of GABAergic neurons.

Animals↗
PubMed2000

gamma-aminobutyric acid- and glycine-immunoreactive neurons postsynaptic to substance P-immunoreactive axon terminals in the superficial layers of the rat medullary dorsal horn.

gamma-Aminobutyric acid (GABA)ergic and glycinergic neurons were examined light- and electron-microscopically in laminae I and II of the medullary dorsal horn (MDH, i.e. spinal trigeminal nucleus caudalis in the rat). The majority of GABA- and glycine (Gly)-immunoreactive (-ir) neurons showed both GABA- and Gly-immunoreactivities (-IRs). Noxious stimulation (subcutaneous injection of formalin into perioral regions) induced Fos-IR in some of GABA- and Gly-ir neurons. GABA- and Gly-ir neuronal profiles were postsynaptic to substance P-ir axon terminals. These results suggest that nociceptive information being carried by primary afferent SP-fibers may be relayed directly to GABAergic and glycinergic neurons in laminae I and II of the MDH.

Animals↗
PubMed1998

Behavioral effects of vigabatrin correlated with whole brain gamma-aminobutyric acid metabolism in audiogenic sensitive rats.

The present study evaluates dose-dependent behavioral effects of acutely or subacutely administered single doses of vigabatrin (gamma-vinyl gamma-aminobutyric acid, gamma-vinyl GABA, CAS 60643-86-9) in audiogenic sensitive rats, in correlation with whole brain GABA metabolism. There was a discrepancy in timing between behaviorally observed maximal antiepileptic protection (4 h after i.p. administration of gamma-vinyl GABA) and on the other hand maximal inhibition of GABA-transaminase activity and maximal increase of whole brain GABA content (24 h after i.p. administration of gamma-vinyl GABA). This suggests that the antiepileptic properties of gamma-vinyl GABA not only depend on GABA-ergic neurotransmission. A possible explanation is a gamma-vinyl GABA-induced decrease of excitatory amino acids or increased glycine concentrations in the brain.

4-Aminobutyrate Transaminase↗
PubMed1980

Adenosine inhibition of gamma-aminobutyric acid release from slices of rat cerebral cortex.

1 The effect of purine compounds on the potassium-evoked release of 14C-labelled gamma-aminobutyric acid (GABA) has been studied in 400 micrometers slices of rat cerebral cortex in vitro. 2 Adenosine and adenosine 5' monophosphate (AMP) inhibited the release of GABA at 10(-5) to 10(-3) M. Adenosine triphosphate (ATP) produced a significant inhibition of release only at 10(-3) M. 3 Theophylline 10(-4) or 10(-3) M reduced the inhibitory effect of adenosine, but did not change basal release of GABA. 4 Dipyridamole 10(-5) M itself reduced evoked GABA release, but did not prevent the inhibitory effect of adenosine, implying that adenosine was acting at an extracellularly directed receptor. 5 Calcium removal or antagonism by verapamil reduced the evoked release of GABA, but adenosine did not produce any further reduction of the calcium-independent release. This may indicate that the inhibitory effect of adenosine on GABA release results from interference with calcium influx or availability within the terminals.

Adenosine↗
PubMed1986

Non involvement of gamma-aminobutyric acid in catechol-induced seizures.

The effects of certain anticonvulsant agents, namely, valproate, diazepam and phenobarbitone were investigated on catechol-induced spontaneous and evoked convulsions, in anaesthetized rats and mice. Valproate and diazepam significantly reduced the intensity of spontaneous convulsions and the frequency of occurrence of the longer-latency components (M2 and M3) of the evoked muscle response. Phenobarbitone significantly reduced spontaneous convulsions and the M3 component of the evoked muscle response. None of the drugs affected the short latency M1 component indicating a supra-spinal site of action of these drugs. Agents which modify gamma-aminobutyric acid (GABA)-mediated transmission were without effect on the frequency of occurrence of M1, M2 or M3. The results suggest that the convulsant action of catechol is not dependent on antagonism of GABA-mediated inhibition.

Animals↗
PubMed2002

Involvement of gamma-aminobutyric acid (GABA) B receptors in the hypotensive effect of systemically administered GABA in spontaneously hypertensive rats.

We investigated the effects of intraduodenally (i.d.) administered gamma-aminobutyric acid (GABA) on blood pressure (BP) in anesthetized spontaneously hypertensive rats (SHR) and the mechanism underlying this effect, especially the type of GABA receptor involved in the depressive effect of this amino acid. GABA (0.3 to 300 mg/kg, i.d.) caused a dose-related decrease in the BP of 9.20 +/- 3.96 to 35.0 +/- 5.34 mmHg (mean +/- S.E.M.) that lasted for 30 to 50 min. The minimum effective i.d. dose of GABA was 0.3 to 1.0 mg/kg. Results pertaining to the mechanism underlying the GABA-induced effects on BP were as follows: a) GABA did not alter the BP-related effects of exogenous noradrenaline and acetylcholine; b) pretreatment with hexamethonium decreased the GABA-induced fall in BP, and GABA tended to reduce the pressor response associated with injection of dimethyl phenylpiperazinium; and c) pretreatment with 2-hydroxysaclofen markedly reduced the GABA-induced drop in BP, whereas pretreatment with bicuculline did not. In conclusion, in SHR, low-dose (0.3 to 1.0 mg/kg, i.d.) GABA had a hypotensive effect, which may result from attenuation of sympathetic transmission through the activation of GABA(B) receptors at presynaptic or ganglionic sites.

Animals↗
PubMed1981

Compartments of labeled and endogenous gamma-aminobutyric acid giving rise to release evoked by potassium or veratridine in rat cortical slices.

To establish compartments involved in depolarization-induced release of gamma-aminobutyric acid (GABA) in rat brain slices, the amount of exogenous labeled and endogenous GABA released and retained was followed during 48 min exposure to 50 mM-K+ or to 50 microM-veratridine. Endogenous GABA was measured with high performance liquid chromatography. The presence of 10 microM-aminooxyacetic acid throughout prevented both the metabolism of GABA and the formation of endogenous GABA due to depolarization. During superfusion with 50 mM-K+ and 2.6 nM-Ca2+ the efflux of labeled and endogenous GABA after an initial large increase declined to 10% of the highest value with constant and identical rates. Kinetic analysis of efflux showed that 10% of endogenous and 25% of labeled GABA present is available for release by high K+ and Ca2+. In the absence of Ca2+, release by high K+ of both labeled and endogenous GABA was nearly suppressed. Veratridine, unlike high K+, caused an efflux which declined with an initial fast and late very slow phase. The slow efflux by veratridine was doubled in the absence of Ca2+. Exposure to veratridine in the absence of Ca2+ during 120 min released nearly 70% of labeled and endogenous GABA present. Results suggest that only about 0.25 mumol . g-1 endogenous GABA is the source of physiological Ca2+-dependent release, while much of the remaining GABA present is released only under unphysiological conditions.

Animals↗
PubMed1988

Levels of total gamma-aminobutyric acid (GABA), free GABA and homocarnosine in cerebrospinal fluid of epileptic patients before and during gamma-vinyl-GABA (vigabatrin) treatment.

Levels of total gamma-aminobutyric acid (TGABA), free GABA (FGABA), and homocarnosine (HC) were studied in CSF taken from 12 controls and 28 patients with drug-refractory epilepsy before and during 7 months of gamma-vinyl-GABA (GVG) administration. At baseline TGABA and FGABA in CSF of epileptic patients did not differ from that of the controls. In epileptic patients HC was 127% of that in controls. During GVG treatment TGABA was 283%, FGABA 197%, and HC 310% of the levels at baseline in the same patients. The patients who had over 50% reduction in seizure frequency during GVG (responders, 46% of the study population) at baseline had higher TGABA and HC in CSF than patients with less than 50% reduction in seizures (non-responders). During GVG the responders and nonresponders had similar levels of different GABAergic markers. The present study shows that in man GVG treatment effectively suppresses seizures in nearly half of the epileptic patients who had previously been drug-refractory. The elevated levels of GABAergic markers in CSF are not, however, necessarily related to good seizure control during GVG.

Adolescent↗