A CARRIER-MEDIATED TRANSFER MODEL FOR THE ACCUMULATION OF 14-C-GAMMA-AMINOBUTYRIC ACID BY SUBCELLULAR BRAIN PARTICLES.
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Aminobutyrates↗
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[BLOCKING ACTION OF GAMMA-AMINOBUTYRIC ACID ON CENTRAL SYNAPSES IN INSECTS].
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Aminobutyrates↗
Involvement of gamma-aminobutyric acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal cortex.
The present study was designed to examine the possible involvement of gamma-aminobutyric acid (GABA) neurotransmission in the mechanism of phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP)-induced dopamine release in the medial prefrontal cortex, using in vivo microdialysis in awake, freely moving rats. Local perfusion via the dialysis probe into the medial prefrontal cortex with PCP (100 and 500 microM) and dizocilpine ((+)-5-methyl-10,11-dihydroxy-5-H-dibenzo(a,d)cyclo-heptan-5,10-im ine; MK-801, 10 and 50 microM), a selective non-competitive NMDA receptor antagonist, was found to increase extracellular dopamine levels. Co-perfusion with NMDA (1 mM) or the GABAA receptor agonist muscimol (50 microM) attenuated the effects of PCP (500 microM) and MK-801 (50 microM) on extracellular dopamine levels. The dopamine reuptake inhibitor nomifensine (50 microM) also produced an increase in extracellular dopamine levels in the medial prefrontal cortex, but this effect was not affected by co-perfusion with muscimol (50 microM). On the other hand, local perfusion with PCP (100 and 500 microM) and MK-801 (10 and 50 microM), but not nomifensine (50 microM), reduced extracellular GABA levels in the medial prefrontal cortex. Co-perfusion with NMDA (1 mM) reduced the effects of PCP (500 microM) and MK-801 (50 microM) on extracellular GABA levels. These results suggest that PCP may facilitate dopamine release in the medial prefrontal cortex, at least in part, by the inhibition of GABA release via the antagonism of NMDA receptors.
Animals↗
Augmentation by chlordiazepoxide of the inhibitory effects of taurine, beta-alanine and gamma-aminobutyric acid on spike discharges in guinea-pig cerebellar slices.
1. Chlordiazepoxide (Cdp, 1 to 100 micrometer) enhanced the inhibitory action of externally applied gamma-aminobutyric acid (GABA) upon spontaneous spike discharges in guinea-pig cerebellar slices; the actions of externally applied beta-alanine and taurine, but not externally applied glycine, were also enhanced by Cdp. 2. It was suggested the Cdp might exert its action by enhancing the increase of membrane permeability to K+ induced by the amino acid, but not to Cl-. 3. Cdp (5 to 100 micrometer) reversed the antagonism of picrotoxin to the inhibitory action of externally applied GABA and also the antagonism of strychnine to the actions of externally applied beta-alanine and taurine. 4. The inhibition of the spontaneous spike discharges of Purkinje cells, evoked by electrical stimulation of the slice, was also enhanced by Cdp (10 to 100 micrometer). 5. The blocking action of picrotoxin (10 to 20 micrometer) on the stimulus-evoked inhibition of spike discharges was reversed by Cdp (10 micrometer). 6. In a similar manner, strychnine (10 or 20 micrometer) was also found to block the stimulus-evoked inhibition of spike discharges. It is suggested that in the cerebellum strychnine-sensitive amino acid(s) may be involved in synaptic transmission. Strychnine blockade was also reversed by Cdp (10 micrometer).
Action Potentials↗
Further investigations into the pathophysiology of MPTP-induced parkinsonism in the primate: an intracerebral microdialysis study of gamma-aminobutyric acid in the lateral segment of the globus pallidus.
The technique of intracerebral microdialysis has been employed to examine the extracellular level of gamma-aminobutyric acid (GABA) within the lateral segment of the globus pallidus of two cynomolgus monkeys, before and after the induction of parkinsonism with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Microdialysis probes were acutely implanted through indwelling cannulae positioned at several sites above the lentiform nuclei in the conscious primates, and the basal and potassium (100 mM) evoked amino acid levels were monitored for 3 h. These procedures were repeated at fresh sites within the lateral globus pallidus following the induction of parkinsonism with MPTP. The levels of a number of amino acids, including Asn, Ala, Gln, Ser, and Tau were unchanged following MPTP treatment, whereas both the basal and K(+)-evoked release of GABA was consistently increased. This observation represents further corroboration of the evidence for increased GABAergic input to the lateral globus pallidus in MPTP-induced parkinsonism.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Gamma-aminobutyric acid enhancement of halothane binding in rat cerebellum.
Quantitative autoradiography of 14C-halothane direct photolabeled rat cerebellum sections was performed in the presence of increasing concentrations of gamma-aminobutyric acid (GABA) or glutamate to test the hypothesis that a coupled binding equilibrium between the anesthetic and neurotransmitter exists. The results show that halothane binding was enhanced in the presence of GABA by approximately 50% in the molecular layer and to a lesser extent in the granular layer, with no change in the myelin layer. Glutamate, however, did not enhance halothane binding in any layer. These data confirm the presence of coupling, and thus suggest a direct interaction of halothane with a GABA binding protein.
Animals↗
Preloading in vivo: a rapid and reliable method for measuring gamma-aminobutyric acid and glutamate fluxes by microdialysis.
In vivo microdialysis was used in conjunction with a novel dual-label preloading method, to monitor changes in extracellular levels of gamma-aminobutyric acid (GABA) and glutamate in the striatum of conscious, unrestrained rats. [3H]GABA and [14C]glutamate were applied in the dialysis stream for a preloading period of 30 min, after which dialysis perfusion was continued for up to 6 h, and dialysate samples were collected for scintillation counting. Veratridine (Vtd: 100 microM in the dialysate) caused significant rises in both 3H and 14C content measured in the dialysates, the majority of which remained associated with the preload GABA and glutamate, respectively. The Vtd-stimulated release of GABA and glutamate measured in this way was blocked by tetrodotoxin and was Ca2+ dependent. Thus, by reproducing results obtained using other techniques, we have shown that the preloading method provides a quick and reliable method for measuring the effects of drugs on the release of neurotransmitter GABA and glutamate in vivo by dyalisis. It should enable sample times as low as 1 min to be used, thus allowing resolution of transient stimulated responses taking place over a time course of minutes.
Animals↗
Effect of adrenalectomy on gamma-aminobutyric acid concentrations in the central nervous system.
Pyridoxal-5'-phosphate (PLP) plays a crucial role in regulating the steady-state levels of gamma-aminobutyric acid (GABA) in CNS. Adrenalectomy resulted in decreased conversion of dietary vitamin B6 to PLP. As a consequence of this, GABA levels in cerebral cortex decrease, since synthesis of GABA is determined by glutamate decarboxylase, a PLP-dependent enzyme. Feeding diet supplemented with vitamin B6 elevated the GABA levels in adrenalectomized animals, because of increased availability of the coenzyme for apodecarboxylase. The data suggest a role for corticosteroids in maintaining GABA levels, through their effects on PLP formation.
Adrenalectomy↗
Effect of isoflurane on release and uptake of gamma-aminobutyric acid from rat cortical synaptosomes.
We have studied the effect of isoflurane on potassium-evoked release and high-affinity uptake of gamma-aminobutyric acid (GABA) in rat cortical synaptosomes. Isoflurane 1.5% and 3% increased calcium-dependent release by 38% and 36% of control values, respectively (P < 0.05). Calcium-independent release was reduced correspondingly by 24% and 26% (P < 0.05). High-affinity uptake of GABA was not affected by isoflurane. The findings of increased synaptic GABA release combined with unaltered uptake suggest that isoflurane increases GABA in the synaptic cleft and thus may enhance inhibition.
Anesthetics, Inhalation↗
Neurons in cat lateral geniculate nucleus that concentrate exogenous [3H]-gamma-aminobutyric acid (GABA).
About one-quarter of the neurons in the A-laminae of the cat lateral geniculate selectively accumulate exogenous [3H]-gamma-aminobutyric acid (GABA), its analog, [3H]-2,4-diaminobutyric acid (DABA), and the GABA agonist, [3H] muscimol. These neurons are small (12-18 micrometers diameter) and lack a laminar body, which suggests that they correspond to the class III cell identified in Golgi material. GABA and DABA are also accumulated by F-terminals which are post-synaptic to retinal terminals and presynaptic to relay cell dendrites. It is suggested that GABA may be the transmitter for these small neurons which appear to mediate by means of local circuits a feed-forward inhibition onto the relay cells.
Animals↗
Double-label analyses of somatostatin's coexistence with enkephalin and gamma-aminobutyric acid in amacrine cells of the chicken retina.
Double-label analyses were performed to investigate somatostatin's coexistence with either enkephalin or gamma-aminobutyric acid (GABA) in amacrine cells of the chicken retina. Double-label immunocytochemistry revealed that although some amacrine cells labelled only for somatostatin or enkephalin, approx. 81% and 85% of somatostatin-immunopositive cells in the center and periphery of the retina, respectively, were also enkephalin-immunoreactive. Somatostatin-immunocytochemistry combined with autoradiography of high-affinity [3H]GABA uptake revealed that approx. 18% of somatostatin-immunoreactive amacrine cells exhibit high-affinity uptake of [3H]GABA.
Animals↗
Effect of diphenylhydantoin on gamma aminobutyric acid (GABA) and succinate activity in rat Purkinje cells.
A study has been made of the effect of diphenylhydantoin (DPH) upon the levels of gamma aminobutyric acid (GABA) and succinic dehydrogenase in rat Purkinje cells. DPH was administered over 26 days in chronic experiments using controls receiving the same injection vehicle without DPH. Animals in this group received daily 1.25 mg/kg body weight, 12.5 mg/kg body weight, and 50 mg/kg body weight DPH. Acute experiments were carried out over the course of not more than four days, three groups of animals receiving 75 mg/kg body weight, 87.5 mg/kg body weight, and 100 mg/kg body weight DPH. No effect upon succinic dehydrogenase could be demonstrated at any dose level. There was a significant progressive loss of GABA with increasing dosage of DPH.
Aminobutyrates↗
[Catabolism of labelled alpha-ketoglutarate, succinate, aspartate and gamma-aminobutyric acid in nerve tissue; the effect of pyridoxal-5'-phosphate in vitro].
Proceeding from estimation of the 14CO2 release from [5-14C]alpha-ketoglutarate, [1-14C] gamma-aminobutyric acid (GABA), [1,4-14C] succinate and [4-14C] aspartate (0.4-1 mM) during their incubation with homogenates of different brain areas with regard for the label position and stereospecificity of decarboxylation of citrate formed due to the metabolism, the relative intensity of their catabolism is determined: [1,4-14C] succinate much greater than [4-14C]aspartate greater than [5-14C] alpha-ketoglutarate much greater than [1-14C]GABA. The label release with catabolism of [1-14C] alpha-ketoglutarate considerably exceeds the intensity of decarboxylation of the above enumerated substrates. In all cases the maximum release of 14CO2 has been registered in the cortex homogenates, the minimum--in the medulla homogenates, and only under long-term incubation with high concentration of GABA (50 mM) maximum catabolism was registered in the medulla. Preincubation of nervous tissue with pyridoxal-5'-phosphate (40 microM) results in significant acceleration of catabolism of [1-14C] alpha-ketoglutarate, [5-14C] alpha-ketoglutarate and [4-14C] aspartate with an inconsiderable increase of catabolism of the rest of labelled substrates.
Animals↗
gamma-Aminobutyric acid (GABA) enhances glutamate cytotoxicity in a cerebellar cell line.
A temperature-sensitive rat cerebellar cell line SC9 has been used to study the role of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in glutamate cytotoxicity. GABA increases glutamate toxicity in a dose-dependent fashion, but NMDA and kainic acid were not toxic in the presence or absence of GABA. The specificity of this cytotoxicity was further indicated by the NMDA-selective antagonist 2-amino-7-phosphonoheptanoic acid (APV), which does not block glutamate effect. These observations, as well as binding experiments with 3H-glutamate, suggest that glutamate cytotoxicity in these cells depends on quisqualate-selective uptake sites of the amino acid. The study may open therefore a novel pathway for understanding the cytotoxic effect of excitatory amino acids in brain structures that are enriched with GABA and glutamate uptake sites.
Animals↗
Chronic diazepam treatment in rats causes long-lasting changes in central [3H]-5-hydroxytryptamine and [14C]-gamma-aminobutyric acid release.
The effects of chronic diazepam administration to rats on the central release of [3H]-5-hydroxytryptamine ([3H]-5-HT) and [14C]-gamma-aminobutyric acid ([14C]-GABA, ex vivo) were examined. Chronic (5 and 21 days) administration of diazepam (4 mg kg-1 i.p. daily for 21 days) reduced the K-evoked (20 mM KCl) release of [3H]-5-HT from frontal cortex by approximately 50%. Remarkably, this decrease was still present 1 week after diazepam withdrawal. Chronic diazepam treatment did not significantly affect hippocampal [3H]-5-HT release but after 21 days the K-evoked release of [14C]-GABA was more than doubled and remained elevated 30 h after withdrawal; it returned to control levels after 1 week, and decreased below control levels after 2 weeks. This study indicates that chronic diazepam treatment produces striking changes in transmitter release in rats that persist long after treatment has ceased.
Animals↗
Evidence for the inhibitory neurotransmitter gamma-aminobutyric acid in aspiny and sparsely spiny nonpyramidal neurons of the turtle dorsal cortex.
In order to learn more about the anatomical substrate for gamma-aminobutyric acid (GABA)-mediated inhibition in cortical structures, the intrinsic neuronal organization of turtle dorsal cortex was studied by using Golgi impregnation, immunohistochemical localization of GABA and its synthetic enzyme glutamic acid decarboxylase (GAD), and histochemical localization of the presynaptic GABA-degrading enzyme GABA-transaminase (GABA-T). GABAergic markers are found in neurons identical in morphology and distribution to Golgi-impregnated aspiny and sparsely spiny nonpyramidal neurons with locally arborizing axons and appear to label most if not all of the nonpyramidal neurons. In addition, the GABAergic markers are found in punctate structures in a distribution characteristic of presumed inhibitory terminals. The spine-laden pyramidal neurons, the principal projecting cell type in the dorsal cortex, are devoid of labelling for GABAergic markers but are surrounded by presumed GABAergic terminals. The data complement previous physiological and ultrastructural studies that implicate aspiny and sparsely spiny nonpyramidal neurons as mediators of intrinsic inhibition of pyramidal neurons in turtle cortex. The results also suggest similarities in the functional organization of intrinsic inhibitory elements in turtle and mammalian cortex.
4-Aminobutyrate Transaminase↗
Alteration of metabolism of retinal taurine following prolonged light and dark adaptation: a quantitative comparison with gamma-aminobutyric acid (GABA).
Alteration of metabolism of taurine in prolonged light- and dark-adapted frog retinae were studied in comparison with that of gamma-aminobutyric acid (GABA) and the following results were obtained. (1) Statistically significant alterations in retinal taurine, an increase in dark-adapted, and a decrease in light-adapted states, respectively, occurred when frogs were adapted continuously to light or dark for more than 3 weeks. Under the same experimental conditions, no alteration in retinal GABA was noted. (2) At 3 weeks and thereafter, a significant increase of retinal cysteine sulfinic acid decarboxylase (CSD; EC 4.1.1.12) activity, an enzyme involved in the biosynthetic pathway of taurine, also occurred in the dark, whereas the activity in the light-adapted retina was reduced. On the other hand, the retinal activity of L-glutamate decarboxylase (GAD; EC 1.1.1.15), the rate-limiting enzyme of GABA biosynthesis, was not altered in dark- as well as light-adapted state. Similarly, retinal GABA-transaminase (GABA-T; EC 2.6.1.19)-succinic semialdehyde dehydrogenase (SSADH; EC 1.2.1.16) was unaltered. (3) These alterations in retinal taurine were, however, unaccompanied by any changes in factors related to transmitter actions such as evoked release, high affinity uptake, and specific binding to synaptic membranes. The above results suggest that, different from GABA as a potent candidate for inhibitory neurotransmitter, retinal taurine may act as neuromodulator and/or may play an important role as a basic factor for maintaining cellular integrity under certain pathophysiological conditions.
4-Aminobutyrate Transaminase↗
An increase in glutamate release follows a decrease in gamma aminobutyric acid and the pubertal increase in luteinizing hormone releasing hormone release in the female rhesus monkeys.
Previously we have shown that release of gamma-aminobutyric acid (GABA) in the stalk-median eminence (S-ME) is high in prepubertal monkeys and that a decrease in GABA release triggers the onset of puberty. However, it is still unclear how disinhibition of the luteinizing hormone releasing hormone (LHRH) neuronal system from GABA input is followed (or accompanied) by an increase in stimulatory signals, such as glutamatergic input to LHRH neurons. To clarify the temporal relationship between the reduction of the GABAergic inhibitory signal and the enhancement of the glutamatergic stimulatory signal in the control of LHRH release at the onset of puberty, we conducted two experiments using a push-pull perfusion method. In the first experiment, we measured developmental changes in release of LHRH, GABA, and glutamate in the S-ME. LHRH levels were very low in prepubertal monkeys, increased to higher levels in early pubertal monkeys, with the highest LHRH levels occurring in mid-pubertal monkeys. As we previously observed, GABA levels were high in prepubertal monkeys and then decreased in early- and mid-pubertal monkeys. In contrast, glutamate levels were very low in prepubertal monkeys, increased dramatically in early pubertal monkeys, and then slightly decreased in mid-pubertal monkeys, although mid-pubertal levels remained much higher than prepubertal levels. In the second experiment, we measured GABA, glutamate and LHRH in the same samples obtained from prepubertal monkeys which were infused with an antisense oligodeoxynucleotide (AS) for glutamic acid decarboxylase (GAD) 67 mRNA into the S-ME. GAD67 is a catalytic enzyme for GABA synthesis from glutamate, and AS GAD67 mRNA interferes with GAD67 synthesis. Infusion of the AS GAD67 induced a decrease in GABA release, which subsequently resulted in an increase in LHRH release. Surprisingly, glutamate release also increased several hours after the decrease in GABA release, and the increased LHRH release continued. These data are interpreted to mean that a decrease in GABA synthesis by interference with GAD67 synthesis and the reduction of GABA release in the S-ME trigger an increase in LHRH release, but that a subsequent increase in glutamate release in the S-ME further contributes to the pubertal increase in LHRH release at the onset of puberty. The data further support our hypothesis that GAD plays an important role in the mechanism of the onset of puberty.
Animals↗