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PubMed1998

The effects of ethanol and gamma aminobutyric acid alone and in combination on hepatic regenerative activity in the rat.

BACKGROUND/AIMS: Both ethanol and gamma aminobutyric acid (GABA) have been reported to inhibit hepatic regenerative activity in the rat. Because alcoholic beverages contain appreciable amounts of GABA, we documented whether the inhibitory effects of alcohol on the liver are derived from ethanol alone or the combination of ethanol plus GABA. METHODS: Adult male Sprague-Dawley rats (n=6/group) were treated with either ethanol (3 g/kg), GABA (500 mg/kg) or ethanol plus GABA (3 kg and 500 mg/kg, respectively), beginning 1 h prior to a 70% partial hepatectomy and continued every 4 h thereafter for a total of 24 h. Rats were then sacrificed and hepatic regenerative activity was documented by 3H-thymidine incorporation into hepatic DNA. RESULTS: DNA synthesis was significantly inhibited by ethanol (-37%, p<0.005) and GABA (-19%, p<0.05). Maximum inhibition was achieved with the combination of ethanol plus GABA (-52%, p<0.001). To determine whether the additive effects of ethanol plus GABA were mediated by ethanol-induced enhancement of hepatic GABA(A) receptor activity, additional rats (n=6/group) receiving the combination of ethanol plus GABA were pre-treated with a single injection of either ciprofloxacin (50 mg/kg), a GABA(A) receptor antagonist, or an equal volume of saline. In these experiments, ciprofloxacin pre-treatment prevented the inhibitory effects of the ethanol plus GABA combination. CONCLUSIONS: The results of this study indicate that the combination of ethanol plus GABA has a greater inhibitory effect on hepatic DNA synthesis following partial hepatectomy than ethanol alone. The clinical implication of this finding is that, when standardized for ethanol content, not all alcoholic beverages would be expected to have the same inhibitory effect on hepatic regeneration.

Animals↗
PubMed2000

Ca(2+) regulation of the carrier-mediated gamma-aminobutyric acid release from isolated synaptic plasma membrane vesicles.

The regulation of the carrier-mediated gamma-aminobutyric acid (GABA) efflux was studied in isolated synaptic plasma membrane (SPM) vesicles, which are particularly useful to study neurotransmitter release without interference of the exocytotic machinery. We investigated the effect of micromolar intravesicular Ca(2+) on the GABA release from SPM vesicles under conditions of basal release (superfusion with 150 mM NaCl), homoexchange (superfusion with 500 microM GABA) and K(+) depolarization-induced release (superfusion with 150 mM KCl). We observed that, in the presence of intravesicular Ca(2+) (10 microM), the maximal velocity (J(max)) of K(+) depolarization-induced GABA release is decreased by about 64%, and this effect was abolished in the presence of the channel blocker, La(3+). In contrast, the other mechanisms were not significantly altered by these cations. In agreement with our earlier results, inhibition of GABA uptake by intravesicular Ca(2+) was also observed by determining the kinetic parameters (K(0.5) and J(max)) of influx into the SPM vesicles. Under these conditions, the J(max) of GABA uptake was 17.4 pmol/s per mg protein, whereas in control experiments (absence of Ca(2+)), this value achieved 25.5 pmol/s per mg protein. The inhibitory effect of Ca(2+) on translocation of GABA across SPM appears to be mediated by calcium/calmodulin activation of protein phosphatase 2B (calcineurin), since it was completely relieved by W7 (calmodulin antagonist) and by cyclosporin A (calcineurin inhibitor). These results show that the GABA transport system, operating either in forward or backward directions, requires phosphorylation of internally localized calcineurin-sensitive sites to achieve maximal net translocation velocity.

Animals↗
PubMed2001

gamma-Aminobutyric acid transporters in the cat periaqueductal gray: a light and electron microscopic immunocytochemical study.

The gamma-aminobutyric acid (GABA) plasma membrane transporters (GATs) mediate GABA uptake into presynaptic axon terminals and glial processes, thus contributing to the regulation of the magnitude and duration of the action of GABA at the synaptic cleft. The aim of the present study was to investigate the expression of three high-affinity GABA transporters (GAT-1, GAT-2, and GAT-3) in the periaqueductal gray matter (PAG) of adult cats by using immunocytochemistry with affinity-purified antibodies. Light microscopic observations revealed GAT-1 immunoreactivity in punctate structures, particularly dense in the lateral portion of the dorsolateral PAG column. Weak GAT-2-immunopositive puncta were homogeneously distributed in the PAG. GAT-3 immunoreactivity was detected in each column of the PAG but was more intense in the dorsolateral PAG column and around the aqueduct. Electron microscopic studies showed GAT-1 immunoreactivity in distal astroglial processes, in unmyelinated and small myelinated axons, and in axon terminals making symmetric synapses on both PAG neurons and dendrites. GAT-2 immunoreactivity was present mostly in the form of patches of different sizes in the cytoplasm of neuronal elements like the perikarya and dendrites of PAG neurons, in myelinated and unmyelinated axons, and in the axon terminals forming both symmetric and asymmetric synapses. Labeling was also observed in nonneuronal elements. Astrocytic cell bodies and their distal processes as well as the ependymal cells lining the wall of the aqueduct showed patches of GAT-2 immunoreactivity. Electron microscopic observation revealed GAT-3 immunoreactivity exclusively in distal astrocytic processes adjacent to the somata of PAG neurons and in axon terminals making both symmetric and asymmetric synapses. The present results suggest that three types of termination systems of GABAergic transmission are present in the cat periaqueductal gray matter.

Animals↗
PubMed2004

Effect of androgens on sexual differentiation of pituitary gamma-aminobutyric acid receptor subunit GABA(B) expression.

Previous work demonstrated a sexually dimorphic ontogenic expression of gamma-aminobutyric acid receptors (GABA(B)R) in rat pituitary. As sex steroids determine sex-specific expression patterns, we now studied the effect of sex hormones on pituitary GABA(B)R expression. GABA(B)R subunits, measured by Western blot and by semi-quantitative RT-PCR and luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone measured by RIA were determined in two experimental designs: First experimental design: 8- and 15-day-old females (8F, 15F); 8F and 15F treated with 100 mug testosterone propionate (TP) on day 1 of life (8F100TP, 15F100TP), 8- and 15-day-old males (8M, 15M) and 8M and 15M castrated on day 1 (8MC, 15MC). Second experimental design: 8-day-old female and male animals: 8F, 8F100TP, 8F treated with 1 mug/day TP on days 1-4 (8F1TP), 8F treated with the androgen antagonist Flutamide (Flut: 2.5 mg/100 g BW of pregnant mother on days E17-E23) (8F-Flut), 8M, 8MC, 8M treated with Flut as above (8M-Flut) and 8MC-Flut. In these animals, in addition, GABA, glutamate, aspartate and taurine were measured by HPLC in hypothalami and cortex. In the first set of experiments, GABA(B1)R mRNA/protein expression was higher in 8F than in 15F, 8M or 15M. In 8F100TP, GABA(B1)R mRNA/protein decreased to male levels. TP treatment did not alter GABA(B1)R expression in 15F. There was no difference in GABA(B1)R expression between 8M and 15M and neonatal castration did not modify its expression. In the second set of experiments, TP (1 mug) or Flut did not modify GABA(B1)R in 8F, while 100 microg TP continued to decrease GABA(B1)R expression. In 8M, Flut, alone or with castration, increased GABA(B1)R mRNA/protein expression to 8F. Hypothalamic GABA content followed the same pattern as pituitary GABA(B)R expression in 8-day-old animals, suggesting a cross-regulation. With regard to hormonal levels, 100 microg, but not 1 microg TP altered gonadotropins at 8 days, although both treatments effectively androgenized females as evidenced by lack of cycling. We conclude that androgens, acting pre- and postnatally, decrease pituitary GABA(B)R subunit expression.

Analysis of Variance↗
PubMed2001

The noradrenergic inhibition of an apamin-sensitive, small-conductance Ca2+-activated K+ channel in hypothalamic gamma-aminobutyric acid neurons: pharmacology, estrogen sensitivity, and relevance to the control of the reproductive axis.

The present study sought to determine whether small-conductance, Ca2+-activated K+ currents underlie the afterhyperpolarization (AHP) in neurons of the preoptic area (POA), a brain region important in controlling reproduction. We used an ovariectomized, female guinea pig model to test two hypotheses: 1) the current associated with the AHP (I(AHP)) regulates the firing rate of POA neurons and 2) amine neurotransmitters modulate it in a gonadal steroid-sensitive manner. Intracellular recordings followed by combined histofluorescence/in situ hybridization for glutamic acid decarboxylase, 65-kDa isomer, revealed that POA neurons, including gamma-aminobutyric acid (GABA)ergic neurons, exhibited an AHP and spike frequency adaptation. The corresponding I(AHP) was sensitive to antagonism by CdCl2 (200 microM), apamin (0.3-1 microM), and dequalinium (3 microM). The beta-adrenergic receptor agonist isoproterenol inhibited the I(AHP) in a dose-dependent, timolol-sensitive fashion. In addition, the alpha1-adrenergic receptor agonist methoxamine dose dependently inhibited the I(AHP) in a prazosin-sensitive manner and increased neuronal firing rate. Twenty-four-hour pretreatment with estradiol benzoate (EB; 25 microg, s.c.) markedly potentiated the inhibitory effect of methoxamine on the I(AHP), whereas that for isoproterenol was unaffected. Similarly, bath application of 17beta-estradiol (100 nM; 15-20 min) mimicked the effect of EB on the methoxamine-induced inhibition of the I(AHP). Thus, POA GABAergic neurons express an apamin-sensitive channel that mediates, at least in part, the I(AHP), and tempers the excitability of these cells. Furthermore, these studies demonstrate that estrogen enhances the alpha1-adrenergic receptor-mediated inhibition of this current.

Animals↗
PubMed1979

Gamma-aminobutyric acid pathways in the cerebellum studied by retrograde and anterograde transport of glutamic acid decarboxylase antibody after in vivo injections.

Injections of characterized antibody against glutamic acid decarboxylase (GAD), the enzyme responsible for the synthesis of gamma-aminobutyric acid (GABA), were made into the cerebellum. Small cortical injections of anti-GAD antibody produced labeled stellate, basket, Purkinje, and Golgi cells and their processes at the injection site. Anterograde transport of GAD antigen-antibody complexes in Purkinje cell axons caused intense labelling of terminals in deep cerebellar and several vestibular nuclei. Small groups of mossy fiber rosettes labeled and produced retrograde labeling and GAD immunoreactivity in a small number of pleomorphic neurons in the deep cerebellar nuclei. Injections into the dentate nucleus produced retrograde labeling in Purkinje cell bodies and anterograde label in a small number of mossy fiber rosettes. All projections conformed to previously reported topographic distributions of corticonuclear and nucleocortical cerebellar pathways. These findings confirm the GABA content of most Purkinje cell-deep nuclei connections and provide new evidence for a GABA component in part of the nucleocortical pathway in the cerebellum. Immunocytochemical controls for specificity were conducted by injections of preimmune rabbit serum as a substitute for GAD antibody. Only nonspecific labeling was obtained in these cases. Colchicine caused a cumulative enhancement of GAD immunoreactivity in all cases. The present studies indicate that the method of in vivo antibody injections can be utilized to study chemically specific connections in nervous tissue.

Animals↗
PubMed1995

L-glutamate and gamma-aminobutyric acid uptake in synaptosomes from the cerebral cortex of dogs with congenital chronic hepatic encephalopathy.

High affinity [3H]gamma-aminobutyric acid (GABA) and [3H]L-glutamate uptake were determined in synaptosomes prepared from the cerebral cortex of dogs with congenital hepatic encephalopathy and control dogs. The Km value for GABA uptake was increased by 35% but there was a concomitant 34% increase in Vmax suggesting that GABA uptake capacity was not changed in HE dogs. In contrast, mean Vmax for glutamate uptake in HE dogs was 85% greater than mean Vmax in control dogs; mean Km was increased by 25% in HE dogs. Therefore, overall synaptosomal high affinity glutamate uptake capacity was increased in HE dogs compared to controls.

Ammonia↗
PubMed1988

Kinetic characterization of inhibition of gamma-aminobutyric acid uptake into cultured neurons and astrocytes by 4,4-diphenyl-3-butenyl derivatives of nipecotic acid and guvacine.

The effects of N-(4,4-diphenyl-3-butenyl) derivatives of nipecotic acid (SKF-89976-A and SKF-100844-A) and guvacine (SKF-100330-A) on neuronal and astroglial gamma-aminobutyric acid (GABA) uptake were investigated. In addition, the uptake of SKF-89976-A was studied using the tritiated compound. All of the compounds were found to be competitive inhibitors of GABA uptake irrespective of the cell type, with Ki values similar to or lower than those of the parent amino acids. Moreover, none of the compounds exhibited selectivity with regard to inhibition of neuronal and glial GABA uptake. In spite of the competitive nature of SKF-89976-A, the compound was not transported by the GABA carriers in the two cell types, because no saturable uptake could be demonstrated.

Animals↗
PubMed1995

Differential effects of phenytoin and sodium valproate on seizure-induced changes in gamma-aminobutyric acid and glutamate release in vivo.

The effects of intraperitoneal administration of the anticonvulsants phenytoin and sodium valproate were compared with ethosuximide on maximal electroshock seizure-related changes in rat hippocampal gamma-aminobutyric acid (GABA) and glutamate release in vivo as measured by microdialysis. There were immediate increases in GABA and glutamate in the 5 min post-ictal period, followed by a sustained reduction in GABA levels. Glutamate levels, however, were subsequently reduced until 20 min post-ictal before gradually increasing above basal. All animals displayed tonic hind-limb extension that was blocked by phenytoin (20 mg/kg) and sodium valproate (400 mg/kg) but not ethosuximide (150 mg/kg). Phenytoin attenuated the immediate post-ictal increase observed in glutamate whilst sodium valproate enhanced GABA release and prevented its secondary post-ictal inhibition. Ethosuximide was without effect on the post-ictal changes. These are the first data to show detailed seizure-induced amino acid changes and the in vivo effects of anticonvulsants on them in the seizure model.

Animals↗
PubMedDate not supplied

Valproate effect on gamma-aminobutyric acid release in pars reticulata of substantia nigra: combination of push-pull perfusion and fluorescence histochemistry.

To study further the previously demonstrated suppressive in vivo effect of sodium valproate (VPA) on gamma-aminobutyric acid (GABA) release in the preoptic area, we examined GABA neurotransmission in substantia nigra (SN), using the push-pull cannula technique in freely moving ovariectomized rats. To clarify whether the area in the substantia nigra that is actually perfused is pars reticulata, known to receive rich GABAergic input from striatum, we used the retrograde fluorescence tracer fast blue (FB) after each perfusion experiment, applying the tracer through the push-pull cannula. Nigral perfusion with VPA caused significant suppression of local GABA release. This effect was more marked in a subgroup of animals showing retrograde labeled cell bodies in striatum, i.e., animals with a tracer application site and therefore also a perfusion site precisely in pars reticulata. Our data suggest that VPA inhibits GABA release in rat SN as it does in the preoptic area, which may be in agreement with our hypothesis of enhanced GABAergic neurotransmission by VPA, causing suppression of presynaptic GABA release through negative feedback actions on the GABA autoreceptor complex. Furthermore, the combination of push-pull cannula technique and retrograde fluorescence tracer application appears to be an important tool to prove afferent connections of the area actually perfused in neuronal networks.

Amidines↗
PubMed1984

The effects of acetylcholine, carbamylcholine and gamma-aminobutyric acid on uropod motoneurons in the crayfish Procambarus clarkii and Cambaroides japonicus.

The effects of acetylcholine (ACh), carbamylcholine and gamma-aminobutyric acid (GABA) on the spike activity of uropod motoneurons were investigated electrophysiologically in the crayfish Procambarus clarkii Girard and Cambaroides japonicus de Haan. High concentrations of ACh were required to bring about an increase in the spike discharge of uropod motoneurons while carbamylcholine, which is not destroyed by cholinesterase, caused a marked increase in the motoneuron spike discharge even in low concentrations. Application of GABA in concentrations of 10(-5)-10(-2) M caused the decrease in the spike discharge of uropod motoneurons. Under the condition that the synaptic transmission onto uropod motoneurons was blocked by perfusing EGTA containing Ca2+-free saline with high-Mg2+, ACh increased the spike discharge of uropod motoneurons whereas GABA decreased it. The results suggested that ACh and GABA function as excitatory and inhibitory transmitters, respectively, in the crayfish central nervous system.

Acetylcholine↗
PubMed1986

Uptake of gamma-aminobutyric acid by brain tissue preparations: a reevaluation.

The kinetic constants Km and Vmax for the uptake of gamma-aminobutyric acid (GABA) by various preparations from rat cerebral cortex were determined by means of Eadie-Hofstee plots and computer analysis. The Km values were much greater in 0.1-mm slices than in synaptosomal preparations, and the Km value increased further with the thickness of the slices. The apparent high Km values in slices were probably due to depletion of the GABA concentration in the extracellular fluid as the exogenous GABA ran the gauntlet of competing uptake sites on its way to sites deep within the slice, thereby bringing about a requirement for higher GABA concentrations in the incubation medium in order to maintain the internal GABA levels at the "Km level." Evidence was obtained for three GABA uptake systems with Km values (in synaptosomes) of 1.1 microM, 43 microM, and 3.9 mM, respectively. In contrast, only two uptake systems for D-aspartate were detected, with Km values of 1.8 microM and 1.8 mM, respectively. The implications of the findings in the study with respect to previous data in the literature are discussed.

Amino Acids↗