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PubMed1993

N-methyl-D-aspartate releases gamma-aminobutyric acid from rat striatum in vivo: a microdialysis study using a novel preloading method.

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 due to N-methyl-D-aspartate (NMDA) infusion in the striatum of conscious, unrestrained rats. [14C]GABA and [3H]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 analysis by liquid scintillation spectrometry. NMDA (300 microM in the dialysate) caused significant rises in both 14C and 3H content measured in the dialysates, the majority of which remained associated with the preloaded GABA and glutamate, respectively. The NMDA-evoked release of both GABA and glutamate was blocked by the specific NMDA receptor antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP), indicating that the response was receptor mediated. The NMDA-stimulated release of glutamate was also totally abolished by concomitant application of the adenosine agonist 2-chloroadenosine or by prior frontal decortication. However, these two treatments caused little change in NMDA-evoked GABA release. These results show that NMDA causes release of GABA from the striatum in vivo by an NMDA receptor-mediated mechanism and that the majority of this release is not secondary to glutamate release from terminals of the corticostriate pathway. In addition, they confirm the results of previous studies investigating the effect of NMDA on endogenous glutamate release.

Animals↗
PubMed1984

Novel inhibitors of gamma-aminobutyric acid (GABA) uptake: anticonvulsant actions in rats and mice.

SK&F 89976A [N-(4,4-diphenyl-3-butenyl)-nipecotic acid] and SK&F 100330A [N-(4,4-diphenyl-3-butenyl)-guvacine] represent a new series of potent, orally active inhibitors of gamma-aminobutyric acid (GABA) uptake. In vitro studies with synaptosome-rich (P2) fractions of rat brain indicated that these compounds were approximately 20 times more potent than the parent amino acids as inhibitors of [3H]GABA uptake. They did not inhibit [3H] muscimol binding at nanomolar concentrations. The present studies demonstrated that these compounds were also potent anticonvulsants when administered either orally or i.p. to rats. Both compounds attenuated the forelimb extensor component of bicuculline-induced convulsions, but had no effect on strychnine-induced convulsions, indicating that they were acting through a GABAergic mechanism in vivo. Two animal models which are known to be indicative of anticonvulsant efficacy in man are inhibition of maximal electroshock seizures (MES) and inhibition of pentylenetetrazol (PTZ) convulsions in either rats or mice. SK&F 89976A, SK&F 100330A and several related compounds were potent inhibitors of PTZ convulsions in rats. SK&F 100330A also inhibited MES convulsions in rats. In contrast, neither compound inhibited MES or electroshock seizure threshold in mice, and whereas both compounds inhibited the tonic phase of PTZ convulsions in approximately 50% of the mice tested, this inhibition was not dose-related. Thus, the rat appears to be a more suitable species for further testing of these compounds. These studies indicate that the family of compounds represented by SK&F 89976A and SK&F 100330A may have clinically relevant anticonvulsant activity.

Animals↗
PubMed1995

Carbachol, glycine and gamma aminobutyric acid also activate cardiovascular neurons of pontomedulla responsive to glutamate.

Thirty-three cats under intraperitoneal chloralose (40 mg/kg) and urethane (400 mg/kg) anesthesia were used to explore the effect of microinjections (100 nl) of carbachol (CCh, 0.5 M), a cholinergic analogue, glycine (Gly, 1 M) and gamma aminobutyric acid (GABA, 0.4 M) on the cardiovascular-reactive sites in the pontomedulla that responded to microinjection of monosodium glutamate (Glu, 0.25 M, 100 nl) resulting in changes of systemic arterial pressure (SAP). Brain sites under exploration included gigantocellular tegmental field and lateral tegmental field (FTG-FTL), the dorsomedial (DM) and ventrolateral (VLM) medulla which produced pressor responses; caudal VLM (CVLM) and paramedian reticular nucleus (PRN) which produced depressor responses. It was found that CCh produced significant fall of SAP in DM and VLM while the rise of SAP in the same site by Glu. CCh produced SAP decrease in CVLM similar to Glu. GABA significantly caused a slight to moderate increase of SAP in FTG-FTL, DM and VLM, and decrease of SAP in CVLM, all in direction similar to that of Glu. Gly produced significant and marked increase of SAP in DM and VLM similar to Glu both in magnitude and duration. Gly produced increase of SAP in CVLM but the fall of SAP by Glu. PRN was relatively non-reactive except a few microinjections of CCh which produced hypotension. In conclusion, the cardiovascular-reactive sites in the pontomedulla that respond to Glu may also react to other chemicals or neurotransmitters. It is highly possible that multiple receptors of different nature co-exist in neurons of some cardiovascular regions in the pontomedulla.

Animals↗
PubMed1980

[Effect of gamma-aminobutyric acid and gamma-hydroxybutyric acid on the rate of 14C-leucine incorporation into proteins of the gastric mucosa and hypothalamus].

In experimental peptic ulcer the rate of labeled 14C-leucine inclusion in gastric mucosa proteins was decreased. Gamma-aminobutyric acid (GABA) and gamma-oxybutyric acid (GOBA) potentiated the inclusion of amino acids in gastric tissue and hypothalamus proteins, promoted the increased intensity of the trophic processes and exhibited an antiulcerous effect. Studies on 14C-GABA distribution in different organs of rats showed that the largest amount of the acid was detected in the liver and stomach, with a comparatively less amount being found in the hypothalamus.

Animals↗
PubMed1996

Testicular gamma-aminobutyric acid and circulating androgens in Syrian and Djungarian hamsters during sexual development.

Several factors, besides luteinizing hormone (LH), participate in the modulation of testicular function. A number of neurotransmitters are reported to be involved in this process, including a stimulatory action of gamma-aminobutyric acid (GABA) on steroidogenesis in the rat testis. The purpose of this study was to investigate the testicular pattern of GABA and glutamic acid, one of its main precursors, during sexual maturation in two seasonally breeding species: Syrian (golden) and Djungarian hamsters. Plasma androgen levels were also measured. The animals were maintained under long-day photoperiod (16:8, L:D) and were killed at 23, 30, 36, 46, 60, and 90 days of age. A different pattern of developmental changes in body and testicular weight was observed in these two species. GABA was present in the testes at all ages studied. GABA concentration and content showed a sharp elevation in the prepubertal period in golden as well as Djungarian hamsters. However, glutamic acid concentrations remained nearly constant during development in both species. Glutamic acid content increased gradually with age in the golden hamster, while a marked peak at 36 days of age was detected in the Djungarian hamster. Plasma testosterone and dihydrotestosterone levels were maximal at pubertal age in both species. The plasma levels of 5 alpha-androstane-3 alpha, 17 beta-diol increased significantly at 30 days of age in the golden hamster while in Djungarian hamsters this steroid remained unchanged. These results suggest that glutamic acid may serve as a precursor for GABA biosynthesis in the testis. In addition, changes in testicular GABA and plasma androgen levels might reflect a modulatory effect of this neurotransmitter in the acquisition of steroidogenic capability during development.

Androgens↗
PubMed1978

Opiate receptor agonists as modulators of gamma-aminobutyric acid turnover in the nucleus caudatus, globus pallidus and substantia nigra of the rat.

The injection of various doses of morphine, subcutaneously, or of beta-endorphin, intraventricularly, changes the turnover rate of gamma-aminobutyric acid (TRGABA) in the substantia nigra, globus pallidus and nucleus caudatus. The TRGABA decreases in N. caudatus but increases in globus pallidus and substantia nigra. These changes are dose related and can be inhibited by naltrexone. The increased TRGABA in globus pallidus elicited by these opioid receptor agonists may be associated with catalepsy since muscimol, a specific GABA receptor agonist, injected into the globus pallidus causes a dose-related catalepsy. Since this GABA receptor agonist injected into the substantia nigra fails to cause catalepsy, one can exclude that the increase in the TRGABA of substantia nigra elicited by opiate receptor agonists is operative in mediating the catalepsy elicited by opioids.

Animals↗
PubMed1975

The gamma-aminobutyric acid system in rat cerebellum during cannabinoid-induced cataleptoid state.

Repeated, but not single, intraperitoneal injections of delta1,6-tetrahydrocannabinol (delta1,6-THC) 20 mg/kg to rats administered daily for two weeks, produced increased gamma-aminobutyric acid (GABA) concentration and decreased glutamic acid decarboxylase (GAD) activity in the cerebellum, as well as enhancement of [3H]-GABA uptake by cerebellar crude synaptosomes. It seems that the motor impairment elicited by delta1,6-THC was not associated with the GABA system, but presumably might be related to changes in brain excitability.

Aminobutyrates↗
PubMed1989

Changes in [3H]nitrendipine binding and gamma-aminobutyric acid release in rat hippocampus following repeated morphine administration.

An antagonistic effect of calcium on the action of morphine was studied in rat hippocampal slices. The effect of repeated administration of morphine on gamma-aminobutyric acid (GABA) release and binding of [3H]nitrendipine, a calcium antagonist, was also examined. (1) In rat brain hippocampal slices, morphine enlarged the amplitude of the field potentials evoked in pyramidal neurons, disinhibiting them through basket cells. When the calcium concentration was elevated, potentiation of the field potentials by morphine was reduced. Decrease of the calcium concentration, on the other hand, enhanced the potentiating effect of morphine. Following repeated administration of morphine, its enhancing effect on the field potentials in slices was not observed. (2) In hippocampal membrane fractions obtained from rats repeatedly treated with morphine, enhancement of [3H]nitrendipine binding was observed. (3) In hippocampal slice preparations from rats receiving morphine repeatedly, K+ (45 mM)-stimulated [3H]GABA efflux was enhanced. The above results indicate that morphine antagonizes calcium, thereby reducing the release of transmitters. Furthermore, increase in calcium channels following repeated treatment of rats with morphine may explain the mechanism underlying development of tolerance.

Action Potentials↗
PubMed1971

Localization of the sites of gamma-aminobutyric acid (GABA) uptake in lobster nerve-muscle preparations.

The principal sites of gamma-aminobutyric acid (GABA) uptake in lobster nerve-muscle preparations have been determined with radioautographic techniques after binding of the amino acid to proteins by aldehyde fixation. Semiquantitative studies showed that about 30% of the radioactive GABA taken into the tissue was bound to protein by fixation. Both light and electron micrographs showed dense accumulations of label over Schwann and connective tissue cell cytoplasm; muscle was lightly labeled, but axons and terminals were almost devoid of label. The possible role of Schwann and connective tissue cells in the inactivation of GABA released from inhibitory axons is discussed.

Aldehydes↗
PubMed1997

gamma-Aminobutyric acid (GABA) induces the acrosome reaction in human spermatozoa.

The sperm acrosome reaction takes place in response to progesterone and zona pellucida. Progesterone may act on more than one type of surface receptor, of which one is a gamma-aminobutyric acid (GABA) type A-like receptor. Although there is direct evidence of GABA initiation of mouse sperm acrosome reaction, there are conflicting results regarding GABA-induced exocytosis in human spermatozoa. We have examined whether GABA would initiate exocytosis in human spermatozoa using the chlortetracycline assay and a zona-free hamster oocyte test. Human spermatozoa preincubated for > or = 3 h in Biggers-Whitten-Whittingham medium with 0.35% bovine serum albumin underwent acrosome reactions in response to GABA, with maximal responses in spermatozoa preincubated for 9 h. The effect was concentration-dependent. Preincubated spermatozoa treated with GABA were able to fertilize a higher proportion of zona-free oocytes, with a higher number of spermatozoa penetrating each oocyte. Exposure of preincubated spermatozoa to GABA and progesterone together resulted in a higher proportion of acrosome reactions than when each agonist was used alone. The effect of GABA was mediated by the influx of extracellular Ca2+ because inclusion of EGTA or the Ca2+ channel antagonist La3+ prevented GABA-induced acrosome reactions. These results indicate that GABA can initiate exocytosis in capacitated human spermatozoa and open up possibilities for studies of signalling mechanisms activated upon occupancy of the GABAA receptor present on the sperm surface.

Acrosome↗
PubMed1991

Release of gamma-[3H]aminobutyric acid from synaptosomes: effect of external cations and of ouabain.

In the present study we have investigated the effect of cations and ouabain on Ca(2+)-independent and Ca(2+)-dependent release of gamma-[3H]aminobutyric acid ([3H]GABA) from sheep brain synaptosomes. The presence of Na+ in the external medium is essential for the Ca(2+)-independent release induced by K+ or ouabain. Thus, in the absence of Ca2+, ouabain or K+ causes the release of [3H]GABA provided that Na+ is present in the external medium. Under K(+)-depolarizing conditions, in a Na+ medium, either ouabain or Ca2+ further increases the [3H]GABA release induced by depolarization, but their effects are not additive. The presence of external Na+ is not required for the Ca(2+)-dependent release of [3H]GABA due to K+ depolarization, and this release, which occurs in a choline medium, is not modified by ouabain. Under these conditions (choline medium) K(+)-depolarization dependent release is absolutely dependent on external Ca2+, which suggests that this release of [3H]GABA occurs only by exocytosis, without the carrier-mediated efflux which normally co-exists with exocytosis due to K(+)-depolarization in a Na+ medium. It is likely that the release induced by ouabain or K+ involves the membrane carrier which responds to changes in membrane potential.

Animals↗
PubMed1984

gamma-Aminobutyric acid acts at axon terminals of turtle photoreceptors: difference in sensitivity among cell types.

It has been proposed that horizontal cells of the vertebrate retina have a negative feedback synapse with cone photoreceptors. gamma-Aminobutyric acid (GABA) has been suggested to be a neurotransmitter of monophasic horizontal cells (a subtype of horizontal cells), which have direct connections with red-sensitive and green-sensitive cones. We have examined the feedback hypothesis by measuring the GABA sensitivity of photoreceptors. To eliminate interaction with other cells, we dissociated photoreceptors from the turtle retina enzymatically. The subtype of photoreceptors was identified unequivocally on the bases of the shape of the cell and the color of the oil droplets, which are known to correlate with the spectral sensitivity. Cells were voltage-clamped using "Giga-ohm sealed" suction pipettes in the whole-cell recording configuration, and membrane currents were measured in response to GABA applied ionophoretically at various positions on the cell. It was found that red-sensitive and green-sensitive cones were highly sensitive to GABA and that the sensitivity was localized at the axon terminals. GABA-sensitivity in blue-sensitive cones and in rods was very low. GABA-induced current reversed its polarity near the equilibrium potential of chloride, suggesting that GABA increased chloride conductance. Thus, our findings are consistent with the negative feedback hypothesis.

Animals↗
PubMed1982

gamma-Aminobutyric acid (GABA) receptor stimulation. I. Neuropharmacological profiles of progabide (SL 76002) and SL 75102, with emphasis on their anticonvulsant spectra.

Progabide (4-([(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)-methylene]amino) butanamide) is a gamma-aminobutyric acid (GABA) receptor agonist which readily enters the brain. In the body, progabide is metabolized to three active metabolites: SL 75102, gabamide and GABA. Progabide and SL 75102 readily enter the brain and GABA and gabamide are also formed within this organ. Both progabide and SL 75102 exhibit a broad spectrum of anticonvulsant activities against seizures which involve GABA-mediated events (bicuculline, picrotoxinin and pentylenetetrazol) or which are apparently independent of GABAergic mechanisms (penicillin, strychnine, electroshock and audiogenic seizures). These data support the hypothesis that direct GABA receptor stimulation is an effective means of controlling convulsions of various origins. Progabide and SL 75102 have relatively minor secondary effects in comparison to commonly used antiepileptics. Myorelaxation occurs, but only at doses higher than the ED50 values in convulsant tests. Furthermore, these compounds are not sedative. Finally, these GABA agonists have a complex action in the extrapyramidal system. Anticonvulsant doses are antagonistic to dopamine receptor-mediated behaviors, whereas much lower doses seem to facilitate the effects of dopaminergic transmission.

Animals↗
PubMed2006

beta-Alanine and gamma-aminobutyric acid in chronic fatigue syndrome.

BACKGROUND: Due to the occurrence of sleep disturbances and fatigue in chronic fatigue syndrome (CFS), an investigation was performed to examine if there is an abnormal excretion of gamma-aminobutyric acid (GABA) and/or its structural analogue beta-alanine in the urine from CFS patients. Both GABA and beta-alanine are inhibitory neurotransmitters in the mammalian central nervous system. METHODS: The 24 h urine excretion of GABA and beta-alanine was determined by isotope dilution gas chromatography mass spectrometry in 33 CFS patients and 43 healthy controls. The degree of symptoms in both patients and controls was measured by grading of three typical CFS symptoms using a Visual Analogue Scale. RESULTS: Men had a significantly higher excretion of both beta-alanine and GABA than women. Comparing CFS patients with healthy controls showed no significant difference in excretion of neither beta-alanine nor GABA. No correlation was found between the excretion of beta-alanine or GABA and any of the three characteristic CFS symptoms measured. However, two female and two male CFS patients excreted considerably higher amounts of beta-alanine in their 24 h urine samples than control subjects. CONCLUSIONS: Increased excretion of beta-alanine was found in a subgroup of CFS patients, indicating that there may be a link between CFS and beta-alanine in some CFS patients.

Adult↗
PubMed1973

On the pharmacology of the gamma-aminobutyric acid receptors on the cuneo-thalamic relay cells of the cat.

1. gamma-Aminobutyric acid (GABA) and glycine applied by iontophoresis were equipotent depressants of cuneo-thalamic relay neurones isolated from the middle third of the cuneate nucleus of cats either decerebrated or anaesthetized with sodium pentobarbitone.2. Glycine 13+/-2 nA and GABA 20+/-2 nA were equipotent depressors of hair cells (n=22) and, bicuculline applied by iontophoresis caused a parallel shift to the right of the GABA but not the glycine log-current response curves. The GABA equipotent dose-ratio was 2.0+/-0.2 for bicuculline currents of approximately 144 nA lasting about 11 min in cells excited either transynaptically by peripheral stimulation or postsynaptically by glutamate.3. Although a maximal bicuculline current seldom caused a significant shift of the glycine-log current response curve, many of our records show the onset of the glycine response to be slowed by doses in excess of 84 nA.4. Bicuculline also antagonized depressions by beta-guanidinopropionic acid, and delta-aminovaleric acid which mimicked the action of GABA.5. When tested on the same neurone, bicuculline and picrotoxin applied by iontophoresis were equipotent and their effects appear to be additive.6. The GABA sensitivity was not modified by repetitive (5 or 6) doses of i.v. bicuculline (0.2 mg/kg).7. The antagonism of GABA by bicuculline and picrotoxin appears to be of sufficient specificity to enable the separate roles of GABA and glycine as putative inhibitory transmitters of cuneo-thalamic relay cells to be determined.

Alkaloids↗
PubMed1990

GABAergic growth cones: release of endogenous gamma-aminobutyric acid precedes the expression of synaptic vesicle antigens.

Growth cone fractions isolated from neonatal [postnatal day 3 (P3)] rat forebrain contain GABAergic growth cones as demonstrated by immunofluorescence staining with monospecific antibodies to gamma-aminobutyric acid (GABA). HPLC analysis shows that GABAergic growth cones release this endogenous GABA when stimulated with high K+. Endogenous GABA release is Ca2(+)-independent and, in this respect, similar to that seen previously with [3H]GABA. Isolated growth cone fractions also exhibit a K(+)-stimulated, Ca2(+)-independent release of endogenous taurine. None of the other amino acids shown to be present in isolated growth cone fractions were released, including glutamate, aspartate, and glycine. A population of dissociated cerebral cortical neurones prepared from P1 rat forebrain were GABA-immunoreactive after 1 day in culture. The cell body, neurites, and growth cones of these neurones were all stained with GABA antibodies. At this time in culture, neurones did not stain with either of two antibodies to synaptic vesicle antigens, i.e., p65 and synaptophysin. Growth cones isolated from P3 rat forebrain were also not immunoreactive with these antibodies. After about 8 days in culture, when neurones had established extensive networks of long, varicose axons and elaborately branched dendrites, many neurones and their neurites were immunoreactive for GABA antibodies. At this time in culture, p65 and synaptophysin antibodies did stain neuronal cell bodies and particularly their varicose axons. Dendrites were not stained with synaptic vesicle antibodies. These results suggest that GABAergic neurones synthesize GABA during neurite outgrowth and that GABA is present in, and can be released from, the growth cones of these neurones. The presence of GABA in GABAergic growth cones is not associated with synaptic vesicles, which explains the Ca2+ independency of both endogenous and [3H]GABA release from these growth cones.

Animals↗
PubMed1986

Mutual inhibition kinetic analysis of gamma-aminobutyric acid, taurine, and beta-alanine high-affinity transport into neurons and astrocytes: evidence for similarity between the taurine and beta-alanine carriers in both cell types.

The transport kinetics of gamma-aminobutyric acid (GABA), taurine, and beta-alanine in addition to the mutual inhibition patterns of these compounds were investigated in cultures of neurons and astrocytes derived from mouse cerebral cortex. A high-affinity uptake system for each amino acid was demonstrated both in neurons (Km GABA = 24.9 +/- 1.7 microM; Km Tau = 20.0 +/- 3.3 microM; Km beta-Ala = 73.0 +/- 3.6 microM) and astrocytes (Km GABA = 31.4 +/- 2.9 microM, Km Tau = 24.7 +/- 1.3 microM; Km beta-Ala = 70.8 +/- 3.6 microM). The maximal uptake rates (Vmax) determined were such that, in neurons, Vmax GABA greater than Vmax beta-Ala = Vmax Tau, whereas in astrocytes, Vmax beta-Ala greater than Vmax Tau = Vmax GABA. Taurine was found to inhibit beta-alanine uptake into neurons and astrocytes in a competitive manner, with Ki values of 217 microM in neurons and 24 microM in astrocytes. beta-Alanine was shown to inhibit taurine uptake in neurons and astrocytes, also in a competitive manner, with Ki values of 72 microM in neurons and 71 microM in astrocytes. However, beta-alanine was found to be a weak noncompetitive inhibitor of neuronal and astrocytic GABA uptake, whereas in reverse experiments, GABA displayed weak noncompetitive inhibition of neuronal and astrocytic uptake of beta-alanine. Likewise, taurine was a weak noncompetitive inhibitor of GABA uptake in neurons and similarly, GABA was a weak noncompetitive inhibitor of taurine uptake into neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗