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At least 37 records · Page 2Linked to original sources

PubMed2003

GABA(B1a), GABA(B1b) AND GABA(B2) mRNA variants expression in hippocampus resected from patients with temporal lobe epilepsy.

The aim of this study was to investigate the mRNA expression of the two GABA(B1) receptor isoforms and the GABA(B2) subunit, in human postmortem control hippocampal sections and in sections resected from epilepsy patients using quantitative in situ hybridisation autoradiography. Utilising human control hippocampal sections it was shown that the oligonucleotides employed were specific to the receptor. Hippocampal slices from surgical specimens obtained from patients with hippocampal sclerosis and temporal lobe epilepsy were compared with neurologically normal postmortem control subjects for neuropathology and GABA(B) mRNA expression. Neuronal loss was observed in most of the hippocampal subregions, but in the subiculum no significant difference was detected. The localisation of GABA(B1a) and GABA(B1b) isoform mRNAs in human control hippocampal sections supported and extended earlier studies using the GABA(B1) pan probe, which does not distinguish between the two GABA(B1) isoforms. Moreover, the GABA(B2) mRNA location confirmed the heterodimerisation of the receptor. Thus, although there was an apparent correlation between GABA(B1b) and GABA(B2), GABA(B1a) exhibited no such relationship. GABA(B1b) and GABA(B2) showed a similar intensity of expression whilst GABA(B1a) displayed a lower hybridisation signal. Comparison of the expression of the three mRNAs between control and epileptic subjects showed significant decreases or increases in different hippocampal subregions.GABA(B) isoforms and subunit mRNA expression per remaining neuron was significantly increased in the hilus and dentate gyrus. These results demonstrate that altered GABA(B) receptor mRNA expression occurs in human TLE; possibly the observed changes may also serve to counteract ongoing hyperexcitability.

Adult↗

PubMed2006

GABA(B) receptors in the centromedian/parafascicular thalamic nuclear complex: an ultrastructural analysis of GABA(B)R1 and GABA(B)R2 in the monkey thalamus.

Strong gamma-aminobutyric acid type B (GABA(B)) receptor binding has been shown throughout the thalamus, but the distribution of the two GABA(B) receptor subunits, GABA(B) receptor subunit 1 (GABA(B)R1) and GABA(B) receptor subunit 2 (GABA(B)R2), remains poorly characterized. In primates, the caudal intralaminar nuclei, centromedian and parafascicular (CM/PF), are an integral part of basal ganglia circuits and a main source of inputs to the striatum. In this study, we analyzed the subcellular and subsynaptic distribution of GABA(B) receptor subunits by using light and electron microscopic immunocytochemical techniques. Quantitative immunoperoxidase and immunogold analysis showed that both subunits display a similar pattern of distribution in CM/PF, being expressed largely at extrasynaptic and perisynaptic sites in neuronal cell bodies, dendrites, and axon-like processes and less abundantly in axon terminals. Postsynaptic GABA(B)R1 labeling was found mostly on the plasma membrane (70-80%), whereas GABA(B)R2 was more evenly distributed between the plasma membrane and intracellular compartments of CM/PF neurons. A few axon terminals forming symmetric and asymmetric synapses were also labeled for GABA(B)R1 and GABA(B)R2, but the bulk of presynaptic labeling was expressed in small axon-like processes. About 20% of presynaptic vesicle-containing dendrites of local circuit neurons displayed GABA(B)R1/R2 immunoreactivity. Vesicular glutamate transporters (vGluT1)-containing terminals forming asymmetric synapses expressed GABA(B)R1 and/or displayed postsynaptic GABA(B)R1 at the edges of their asymmetric specialization. Overall, these findings provide evidence for multiple sites where GABA(B) receptors could modulate GABAergic and glutamatergic transmission in the primate CM/PF complex.

Animals↗

PubMedDate not supplied

Plasma GABA, GABA-like activity and the brain GABA-benzodiazepine receptor complex in rats with chronic hepatic encephalopathy.

Plasma gamma-aminobutyric acid (GABA)-like activity, plasma GABA and the brain GABA-benzodiazepine receptor complex were studied in rats with chronic hepatic encephalopathy. Portal vein ligation (after prior subcutaneous transposition of the spleen) results in complete portal bypass of splanchnic blood. In addition, significant hepatocellular damage was superimposed on this model of portosystemic shunting by ligation of the common bile duct. Plasma GABA-like activity (determined by radioreceptor assay) and true plasma GABA concentrations (determined by high-performance liquid chromatography) were found to be significantly increased in both portal vein-ligated and portal vein and bile duct-ligated rats, compared with controls. However, plasma GABA-like activity was consistently greater than the concentration of true GABA in the plasma of all rats. This suggested the presence of a GABA-like factor in plasma that can inhibit [3H]GABA binding, but is not GABA itself. The concentration of this GABA-like factor was significantly increased in the plasma of rats with chronic hepatic encephalopathy. Despite the significant increase in plasma GABA-like activity and plasma GABA concentrations, there was no alteration in the affinity or density of the physiologically relevant, low-affinity brain GABA binding site in the rats with portal vein ligation, with or without bile duct ligation. There was also no significant alteration in brain benzodiazepine binding in these rats. GABA enhancement of benzodiazepine binding was unchanged in the portal vein-ligated rats. However, the maximal enhancement of benzodiazepine binding was decreased in the rats with portal vein and bile duct ligation. There appears to be no substantial evidence that brain GABAergic neurotransmission is increased in these models of chronic hepatic encephalopathy.

Animals↗

PubMed2002

Recombinant GABA(B) receptors formed from GABA(B1) and GABA(B2) subunits selectively inhibit N-type Ca(2+) channels in NG108-15 cells.

Efficient transfection of NG108-15 cells with GABA(B) receptor subunits was achieved using polyethylenimine. Baclofen modulated high voltage-activated Ca(2+) current in differentiated cells transfected with GABA(B1) and GABA(B2) receptor subunits or with the GABA(B2) subunit alone, but not with the GABA(B1) subunit alone. Characteristics of the current modulation were very similar for cells transfected with GABA(B1/2) and GABA(B2) subunits. Using antisense oligonucleotides against GABA(B1) subunits and also western immunoblotting, we are able to show that NG108-15 cells contain endogenous GABA(B1) subunits. Therefore, functional receptors can be formed by the combination of native GABA(B1) subunits with transfected GABA(B2) subunits, in agreement with the proposed heteromeric structure of GABA(B) receptors. Finally, we used selective channel blockers to identify the subtypes of Ca(2+) channels that are modulated by GABA(B) receptors. In fact, in differentiated NG108-15 cells, the recombinant GABA(B) receptors couple only to N-type Ca(2+) channels.

Animals↗

PubMed2004

Characterization of GABA(B) receptors involved in inhibition of motility associated with acetylcholine release in the dog small intestine: possible existence of a heterodimer of GABA(B1) and GABA(B2) subunits.

Characterization of the gamma-aminobutyric acid (GABA)(B) receptor involved in the motility of dog small intestine was analyzed by application of the microdialysis method to the small intestine of the whole body of the dog. The reverse transcription-polymerase chain reaction (RT-PCR) was used. Intraarterial administration of muscimol induced acceleration of motility associated with acetylcholine (ACh) release, these responses being antagonized by bicuculline. Intraarterial administration of baclofen induced inhibition of motility associated with ACh release, these responses being antagonized by CGP62349. GABA induced inhibition of motility associated with decrease in ACh release. CGP62349 alone induced acceleration of motility associated with increase in ACh release. RT-PCR revealed the presence of mRNAs for both subunits of GABA(B) receptor, GABA(B1) and GABA(B2), in the dog small intestine, although GABA(B1) subunits were 6 isoforms of GABA(B1) (GABA(B1(a)) - GABA(B1(g))), except GABA(B1(d)). Thus, the GABA(B) receptor located at cholinergic neurons as a heterodimer with subunits of GABA(B1) and GABA(B2) in the dog small intestine operates predominantly relative to the GABA(A) receptor in physiological motility.

Acetylcholine↗

PubMed2001

GABA transaminase inhibition induces spontaneous and enhances depolarization-evoked GABA efflux via reversal of the GABA transporter.

The GABA transporter can reverse with depolarization, causing nonvesicular GABA release. However, this is thought to occur only under pathological conditions. Patch-clamp recordings were made from rat hippocampal neurons in primary cell cultures. Inhibition of GABA transaminase with the anticonvulsant gamma-vinyl GABA (vigabatrin; 0.05-100 microm) resulted in a large leak current that was blocked by bicuculline (50 microm). This leak current occurred in the absence of extracellular calcium and was blocked by the GABA transporter antagonist SKF-89976a (5 microm). These results indicate that vigabatrin induces spontaneous GABA efflux from neighboring cells via reversal of GABA transporters, subsequently leading to the stimulation of GABA(A) receptors on the recorded neuron. The leak current increased slowly over 4 d of treatment with 100 microm vigabatrin, at which time it reached an equivalent conductance of 9.0 +/- 4.9 nS. Blockade of glutamic acid decarboxylase with semicarbazide (2 mm) decreased the leak current that was induced by vigabatrin by 47%. In untreated cells, carrier-mediated GABA efflux did not occur spontaneously but was induced by an increase in [K(+)](o) from 3 to as little as 6 mm. Vigabatrin enhanced this depolarization-evoked nonvesicular GABA release and also enhanced the heteroexchange release of GABA induced by nipecotate. Thus, the GABA transporter normally operates near its equilibrium and can be easily induced to reverse by an increase in cytosolic [GABA] or mild depolarization. We propose that this transporter-mediated nonvesicular GABA release plays an important role in neuronal inhibition under both physiological and pathophysiological conditions and is the target of some anticonvulsants.

4-Aminobutyrate Transaminase↗

PubMed1974

Biological actions in vivo and in vitro of two gamma-aminobutyric acid (GABA) analogues: beta-chloro GABA and beta-phenyl GABA.

1 The synthesis of two analogues of gamma-aminobutyric acid (GABA), beta-chloro GABA and beta-phenyl GABA is described.2 The activity of brain GABA aminotransferase was inhibited by beta-chloro GABA (5.7 x 10(-5)M) and beta-phenyl GABA (4.6 x 10(-3)M) in a competitive manner with GABA.3 beta-Chloro GABA exhibited 50% of the inhibitory activity of GABA in blocking the discharge of the crayfish stretch receptor neurone; beta-phenyl GABA had no detectable effect.4 Injection of beta-phenyl GABA (200 mg/kg) into normal or epileptic cats (cobalt) caused the appearance of synchronized slow-wave EEG activity.5 Administration of beta-chloro GABA (200 mg/kg) to epileptic cats (cobalt) produced a temporary diminution or abolition of epileptic discharges while causing no alteration in normal EEG activity.6 beta-Chloro GABA and beta-phenyl GABA had no effect on the concentrations of catecholamines or of amino acids in mouse brain.7 The results suggest that both beta-chloro GABA and beta-phenyl GABA may pass the blood-brain barrier.

Amino Acids↗

PubMed1981

Effect of homo-beta-proline and other heterocyclic GABA analogues on GABA uptake in neurons and astroglial cells and on GABA receptor binding.

Two groups of GABA (gamma-aminobutyric acid) analogues, one comprising derivatives of beta-proline and the other compounds structurally related to nipecotic acid, were investigated as potential inhibitors of high-affinity GABA transport in neurons and glial cells, as well as displacers of GABA receptor binding. In addition to cis-4-hydroxynipecotic acid, which is known as a potent inhibitor of GABA uptake, homo-beta-proline was the only compound which proved to be a potent inhibitor of glial as well as neuronal GABA uptake. IC50 values for GABA uptake into glial cells and brain cortex "prisms" were 20 and 75 micro M, respectively, and the IC50 value obtained for GABA uptake into cultured neurons was 10 micro M. A kinetic analysis of the action of homo-beta-proline on GABA uptake into cultured astrocytes and neurons showed that this compound acts as a competitive inhibitor of GABA uptake in both cell types. From the apparent Km values, Ki values for homo-beta-proline of 16 and 6 micro M could be calculated for glial and neuronal uptake, respectively. This mechanism of action strongly suggests that homo-beta-proline interacts with the GABA carriers. Furthermore, homo-beta-proline also displaced GABA from its receptor with an IC50 value of 0.3 micro M. The cis-4-hydroxynipecotic acid analogues, cis- and trans-4-mercaptonipecotic acid, had no inhibitory effect on glial or neuronal GABA uptake. Other SH reagents, PCMB, NEM and DTNB, were shown to be relatively weak inhibitors of GABA uptake into cultured astrocytes, suggesting that SH groups are not directly involved in the interaction between GABA and its transport carrier.

Animals↗

PubMed1992

Restraining action of GABA on estradiol-induced LH surge in the rat: GABA activity in brain nuclei and effects of GABA mimetics in the medial preoptic nucleus.

The relationship between GABA dynamics and LH release was studied on day 2 after subcutaneous estrogen implant in short-term ovariectomized rats. GABA accumulation, used as an index of GABA turnover, was determined in the medial preoptic nucleus (MPN), medial (MS) and lateral (LS) septal nuclei, median eminence-mediobasal hypothalamus (MBH) and locus ceruleus (LC). Measurements of GABA were performed at two different times of day (11.00 and 15.00 h), 3 h after intraperitoneal administration of gamma-vinyl-GABA (GVG), an irreversible inhibitor of GABA transaminase. Either morning or afternoon ovariectomized rats (OVX) showed a significant increase in GABA accumulation after GVG treatment in all the areas studied. Estrogen-treated OVX rats showed in the morning a lower GABA accumulation in the MPN, MBH and LC, and GABA levels remained unchanged in the LS and MS. In the afternoon, the MPN and LS showed a lower rate of GABA accumulation whereas in the MBH and LC the GABA increase was not observed. In contrast the MS showed a rate of GABA accumulation similar as in the OVX rats. Local administration in the MPN of 20 micrograms GVG, or GABA-A receptor stimulation by muscimol (50 ng), prior to the increase in plasma LH levels, prevented the occurrence of the estradiol-induced LH surge. The effect of muscimol was reversed by bicuculline (30 ng), a GABA-A receptor antagonist. Bicuculline in low doses lacked effect by itself. In conclusion, these results strongly suggest that a decreased GABAergic activity in MPN, MBH and LC precedes the estradiol-evoked LH surges in ovariectomized rats. Moreover, that in septal nuclei, a low GABAergic activity takes place well before the occurrence of plasma LH increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

The rate of turnover of cortical GABA from [1-13C]glucose is reduced in rats treated with the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA).

Brain GABA levels rise and plateau following prolonged administration of the irreversible GABA-transaminase inhibitor vigabatrin (gamma-vinylGABA). Recently it has been shown that increased GABA levels reduces GAD67 protein, one of two major isoforms of glutamic acid decarboxylase (GAD). The effects of GABA elevation on GABA synthesis were assessed in vivo using 1H and 13C-edited NMR spectroscopy. Rates of turnover of cortical glutamate and GABA from intravenously administered [1-13C]glucose were measured in alpha-chloralose anesthetized rats 24 hours after receiving vigabatrin (500 mg/kg, i.p.) and in non-treated controls. GABA concentration was increased 2-fold at 24 hours (from 1.3 +/- 0.4 to 2.7 +/- 0.9 mumol/g) and GABA-T activity was inhibited by 60%. Tricarboxylic acid cycle flux was not affected by vigabatrin treatment compared to non-treated rats (0.47 +/- 0.19 versus 0.52 +/- 0.18 mumol/g, respectively). GABA-C2 fractional enrichment (FE) measured in acid extracts rose more slowly in vigabatrin-treated compared to non-treated rats, reaching > 90% of the glutamate FE after 3 hours. In contrast, GABA FE > or = glutamate FE in non-treated rats. A metabolic model consisting of a single glutamate pool failed to account for the rapid labeling of GABA from glutamate. Metabolic modelling analysis based on two (non-communicating) glutamate pools revealed a approximately 70% decrease in the rate of GABA synthesis following vigabatrin-treatment, from 0.14 (non-treated) to 0.04 mumol/g/min (vigabatrin-treated). These findings, in conjunction with the previously reported differential effects of elevated GABA on the GAD isoforms, suggests that GAD67 may account for a major fraction of cortical GABA synthesis in the alpha-chloralose anesthetized rat brain in vivo.

4-Aminobutyrate Transaminase↗

PubMed1988

Effect of ethanol on gamma-vinyl GABA-induced GABA accumulation in the substantia nigra and on synaptosomal GABA content in six rat brain regions.

Two recently developed methods for estimating changes in presynaptic gamma-aminobutyric acid (GABA) homeostasis were used for the first time to evaluate the effects of acute and chronic ethanol treatments on GABA utilization. GABA accumulation in the left substantia nigra zona reticulata (SNR) following unilateral microinjection of gamma-vinyl GABA (GVG; 5 micrograms) was linear for at least 180 min while GABA concentrations in the uninjected right SNR did not change over this period. Net GABA accumulation (left minus right SNR) also increased linearly over this interval. Intraperitoneal (i.p.) administration of ethanol (0.3, 1 or 3 g/kg) 15 min after GVG microinjection did not significantly change either the rate of GABA accumulation in left SNR, the net GABA accumulated or the concentration of GABA in the uninjected right SNR relative to saline injected controls over the 45-min test interval. Likewise, GABA accumulation in the left SNR or steady-state GABA concentrations in the right SNR of chronically intoxicated rats or physically dependent animals withdrawn from ethanol for 12 h did not change significantly from that dextrose-fed controls. In a separate study, the effects of acute and chronic ethanol treatments on the concentration of GABA in synaptosomes isolated from the frontal cortex, hippocampus, tectum, striatum, cerebellum or brainstem were determined. Thirty min after acute treatment with ethanol (0.5, 1, 2 or 4 g/kg, i.p.) the concentration of GABA in synaptosomes from any of these brain regions was not significantly altered. Furthermore, chronic ethanol treatment sufficient to induce physical dependence and a severe ethanol withdrawal syndrome also did not significantly modify synaptosomal GABA concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminocaproates↗

PubMed2001

Distribution of GABA(B(1a)), GABA(B(1b)) and GABA(B2) receptor protein in cerebral cortex and thalamus of adult rats.

The distribution of GABA(B) receptor subunits GABA(B(1a)), GABA(B(1b)) and GABA(B2), has been examined in the cerebral cortex and thalamus of adult rats using an immunocytochemical technique. GABA(B(1a)) and GABA(B(1b)) subunits co-localized with GABA(B2) in the cortex, where afferent thalamic GABAergic axons project to pyramidal neurones. The expression patterns of GABA(B(1a)), GABA(B(1b)) and GABA(B2) were similar throughout the thalamus. The data suggest that the GABA(B(1b)) subunit might be the presynaptic isoform in the thalamo-cortical pathway with the GABA(B(1a)) subunit possibly present at postsynaptic sites on cell bodies. This contrasts with our previous data, obtained in cerebellum and spinal cord which indicate opposite locations. Thus, it seems unlikely that functional role along with cellular location can be assigned in a general manner to specific GABA(B) receptor subunit splice variants.

Age Factors↗

PubMed2003

Subcellular localization of metabotropic GABA(B) receptor subunits GABA(B1a/b) and GABA(B2) in the rat hippocampus.

Metabotropic GABA(B) receptors mediate slow inhibitory effects presynaptically and postsynaptically. Using preembedding immunohistochemical methods combined with quantitative analysis of GABA(B) receptor subunit immunoreactivity, this study provides a detailed description of the cellular and subcellular localization of GABA(B1a/b) and GABA(B2) in the rat hippocampus. At the light microscopic level, an overlapping distribution of GABA(B1a/b) and GABA(B2) was revealed in the dendritic layers of the hippocampus. In addition, expression of the GABA(B1a/b) subunit was found in somata of CA1 pyramidal cells and of a subset of GABAergic interneurons. At the electron microscopic level, immunoreactivity for both subunits was observed on presynaptic and, more abundantly, on postsynaptic elements. Presynaptically, subunits were mainly detected in the extrasynaptic membrane and occasionally over the presynaptic membrane specialization of putative glutamatergic and, to a lesser extent, GABAergic axon terminals. Postsynaptically, the majority of GABA(B) receptor subunits were localized to the extrasynaptic plasma membrane of spines and dendritic shafts of principal cells and shafts of interneuron dendrites. Quantitative analysis revealed enrichment of GABA(B1a/b) around putative glutamatergic synapses on spines and an even distribution on dendritic shafts of pyramidal cells contacted by GABAergic boutons. The association of GABA(B) receptors with glutamatergic synapses at both presynaptic and postsynaptic sides indicates their intimate involvement in the modulation of glutamatergic neurotransmission. The dominant extrasynaptic localization of GABA(B) receptor subunits suggests that their activation is dependent on spillover of GABA requiring simultaneous activity of populations of GABAergic cells as it occurs during population oscillations or epileptic seizures.

Animals↗

PubMed1991

Immunocytochemical identification of GABA in astrocytes located in white matter after inhibition of GABA-transaminase with gamma-acetylenic GABA.

Several lines of evidence suggest that astrocytes contribute to the uptake and degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Recent immunohistochemical studies have shown that GABA-like immunoreactivity can be demonstrated in astrocytes in the grey matter of the rat's brainstem. The present study investigates whether GABA is also present in astrocytes located in the white matter. Adult rats were given gamma-acetylenic GABA (GAG), which inhibits the GABA-degratory enzyme GABA-alpha-ketoglutaric acid aminotransferase, and tissue sections from the cerebral cortex and brainstem were processed for GABA immunohistochemistry using an antiserum to GABA. Light microscopic examination of the sections showed numerous small GABA-immunoreactive cells in fibre tracts as well as in nuclear regions. Electron microscopic examination of the immunoreactive cells showed that they were fibrous astrocytes. The results provide evidence that the large increase in GABA in fibre tracts found in biochemical studies of rats injected with GAG is due to an increase in astrocytic GABA and suggest that fibrous astrocytes regulate GABA levels in the extracellular space of white matter.

4-Aminobutyrate Transaminase↗

PubMed2006

Deletion of the GABA(A) receptor alpha1 subunit increases tonic GABA(A) receptor current: a role for GABA uptake transporters.

The loss of more than half the number of GABA(A) receptors yet lack of pronounced phenotype in mice lacking the gene for the GABA(A) alpha1 subunit is somewhat paradoxical. We explored the role of tonic GABA(A) receptor-mediated current as a target of compensatory regulation in the alpha1 knock-out (-/-) mice. A 62% increase of tonic current was observed in the cerebellar granule cells (CGCs) of alpha1-/- compared with wild-type (+/+) mice along with a 67% increase of baseline current variance. Examination of whole-cell currents evoked by low concentrations of GABA and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol suggested no upregulation of alpha6 and delta subunit-containing GABA(A) receptors in the alpha1-/-, confirming previous biochemical studies. Single-channel current openings were on average 32% shorter in the alpha1-/- neurons. Single-channel conductance and frequency of opening were not different between genotypes. Tonic current induced by application of the GABA transporter GAT-1 blocker NO711 (1-[2([(diphenylmethylene)imino]oxy)ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride) was significantly larger in the alpha1-/-, suggesting an increase of ambient GABA concentration. Experiments done with a known concentration of extracellular GABA complemented by a series of biochemical experiments revealed a reduction of GAT activity in alpha1-/- without an identifiable reduction of GAT-1 or GAT-3 protein. We report increased tonic GABA(A) receptor-mediated current in the alpha1-/- CGCs as a novel compensatory mechanism. Our data establish a role for GABA transporters as regulators of neuronal excitability in this and relevant models and examine other tonic conductance-regulating mechanisms responsible for the adaptive response of the cerebellar network to a deletion of a major synaptic GABA(A) receptor subunit.

Animals↗

PubMed1993

Inhibition of luteinizing hormone secretion in ovariectomized ewes during the breeding season by gamma-aminobutyric acid (GABA) is mediated by GABA-A receptors, but not GABA-B receptors.

We have investigated the effects of agonists and antagonists to gamma-aminobutyric acid-A (GABA-A) and GABA-B receptors microinjected (1 microliters) into the preoptic area (POA) on LH in ovariectomized (OVX) ewes with or without estrogen (E) treatment during the breeding season. Guide tubes were placed into the preoptic area of OVX ewes using lateral ventriculograms for localization of the target area. Doses of 10 micrograms of the GABA agonists muscimol (GABA-A) and baclofen (GABA-B) or the GABA antagonists bicuculline (GABA-A) and phaclofen (GABA-B) were injected into the POA of tame conscious animals. Jugular venous blood was collected at 10-min intervals for 3 h, the injection of GABA drug or vehicle was given, and samples were collected for a further 3 h. The plasma samples were assayed for LH. On completion of the experiments, the brains were sectioned to locate the site of injection. In the first year, 17 ewes were used, of which 16 had correct guide tube placement. In OVX sheep, both muscimol and bicuculline injections caused suppression of plasma LH concentrations, with a cessation of pulses in many instances. When OVX sheep were treated with 1.0-cm Silastic implants (sc) of E for at least 7 days, there was a decrease in LH interpulse interval. In these sheep, muscimol and bicuculline injections had effects on plasma LH concentrations similar to those in OVX sheep. In addition, bicuculline was injected into the POA of OVX ewes treated with 2.0-cm E implants. Despite E treatment resulting in reduced plasma LH levels, due to an increase in the interpulse interval, bicuculline injection further suppressed plasma LH levels. Neither baclofen nor phaclofen injection had any effect on plasma LH secretion in either OVX ewes or OVX ewes given 1.0-cm E implants. In the second year, eight sheep were used, all of which had correct guide tube placement. These sheep were treated with 2.0-cm E implants and injected with phaclofen. Phaclofen had no effect on LH secretion. These results suggest that GnRH secretion is regulated by GA-BAergic neurons at the level of the GnRH cell bodies in the POA and that during the breeding season, this is effected by GABA-A and not GABA-B receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1984

Enzymes of cerebral GABA metabolism and synaptosomal GABA uptake in acute liver failure in the rabbit: evidence for decreased cerebral GABA-transaminase activity.

Measurements of the activities of the two key enzymes in cerebral GABA metabolism--glutamate decarboxylase (GAD) and GABA-transaminase (GABA-T)--were performed in normal rabbits and in rabbits with hepatic encephalopathy due to galactosamine-induced liver failure. Furthermore the uptake of GABA by synaptosomes was studied. Hepatic encephalopathy was associated with a marked decrease in the activity of GABA-T. This decrease in activity was already apparent in galactosamine-treated rabbits before the onset of hepatic encephalopathy. Sera and serum ultrafiltrates of rabbits with hepatic encephalopathy but not of normal rabbits or of rabbits with uremic encephalopathy were shown to inhibit GABA-T activity in vitro. Cerebral GAD activity and synaptosomal GABA uptake in rabbits with hepatic encephalopathy and in untreated animals were not different. These later findings indicate that hepatic encephalopathy is not associated with alterations of presynaptic GABA nerve terminals in the central nervous system. The demonstration of a decrease in cortical GABA-T activity provides indirect evidence for decreased GABA turnover in the brains of rabbits with hepatic encephalopathy and thus is compatible with augmented GABA-ergic inhibitory neurotransmission contributing to the neural inhibition of hepatic encephalopathy.

4-Aminobutyrate Transaminase↗

PubMed1980

Effects of intraventricular gamma-acetylenic-GABA on GABA concentrations, GABA-T and GAD in several areas of the chick brain.

The great interest in new compounds able to increase GABA concentration in the brain as potential antiepileptic drugs has led to the synthesis of powerful inhibitors of GABA transaminase (GABA-T) e.g. gamma-acetylenic GABA (GAG) and gamma-vinyl-GABA. Present experiments were aimed to study behavioral, electrocortical and biochemical effects of GAG after its intraventricular injection. It has been shown that in chicks the microinjection of GAG into the third cerebral ventricle produced a biphasic behavioral and electrocortical syndrome : an initial phase of behavioral and electrocortical sleep followed by a paradoxycal increase in motor activity and a very intense behavioral and ECoG arousal pattern. In addition intraventricular GAG (0.8 mumol) produced a significant increase 1 and 2 h later in GABA concentration in the diencephalon and brain-stem whereas no changes occurred in other brain areas e.g. cerebral hemispheres, optic lobes. Higher doses (1.6 mumol), produced after 1 h, concomitantly to the increased GABA concentration, a significant GABA-T inhibition and a profound inhibition of glutamate-decarboxylase in the diencephalon and brain-stem. Present experiments may explain the paradoxical behavioral, motor and electrocortical stimulation observed at the time of GABA increase concentration and suggest that a small functional neuronal pool of GABA, more than the whole absolute levels of GABA in a given area of the brain, seems to be involved in the control of GABAergic mediated inhibitory mechanisms.

4-Aminobutyrate Transaminase↗