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PubMed1991

Gamma-aminobutyric acid induces feeding behaviour in the marine mollusc, Clione limacina.

The effects of gamma-aminobutyric acid (GABA) on the behaviour of the marine pteropod mollusc Clione limacina were studied. In intact molluscs, injection of GABA evoked the consummatory stage of feeding behaviour, i.e. protracting the tentacles, opening the mouth, catching and swallowing prey, as well as some acceleration of locomotion. In the isolated CNS, GABA (10(-5)-10(-4) M) strongly activated the feeding rhythm generator, excited the cerebral motoneurons innervating tentacle muscles (TenMNs), and accelerated locomotor rhythm. A direct excitatory action of GABA (10(-8) M) upon TenMNs was demonstrated on isolated cells extracted from cerebral ganglia. It is concluded that GABA plays an important role in activation of various neuronal networks (organization of 'functional synergy') responsible for the consummatory stage of feeding behaviour.

Animals↗

PubMed1982

Low CSF gamma-aminobutyric acid levels in Parkinson's Disease. Effect of levodopa and carbidopa.

Levels of gamma-aminobutyric acid (GABA) in CSF were measured in patients with Parkinson's disease (n = 14) and sex-matched controls (n = 14). One patient underwent a spinal tap before and after treatment. The mean (+/- SD) CSF GABA levels were 200 +/- 70 pmole/mL in controls and 121 +/- 52 pmole/mL in patients with Parkinson's disease. In the untreated patients with Parkinson's disease, the CSF GABA level was 95 +/- 31 pmole/mL (n = 7) and in those who were treated with levodopa and carbidopa the level was 144 +/- 53 pmole/mL (n = 8). No significant difference was seen in plasma GABA levels between the controls and patients with Parkinson's disease. The decreased GABA level in CSF, which was elevated by levodopa, supports the concept that in Parkinson's disease, the GABA-dopamine interaction in the substantia nigra may be an important compensatory mechanism counteracting the dopamine neuronal loss.

Aged↗

PubMed1994

[Alteration of gamma-aminobutyric acid in streptozotocin-induced diabetic rat retina].

To elucidate possible alteration of gamma-aminobutyric acid (GABA) in the diabetic retina, the distribution and determination of GABA was analyzed in streptozotocin-induced diabetic and normal rats after electroretinogram (ERG) recording. Immunoreactivity of GABA was found in the inner nuclear layer, inner plexiform layer, and ganglion cell layer in normal and diabetic rats. In the inner nuclear layer, strong immunoreactivity of GABA was found in amacrine-like cells. In diabetic retinas, GABA immunoreactivity was higher than in normal retinas. The contents of GABA increased began 1 week after occurrence of diabetes mellitus, attained a maximum at 2 months, and maintained this amount for 5 months. The latencies of oscillatory potentials of ERG were prolonged beginning 1 month after occurrence. These results suggest that increase of GABA in the amacrine cells of diabetic retinas may be related with the abnormality of oscillatory potentials.

Action Potentials↗

PubMed1994

Cloning, expression, and localization of a mouse retinal gamma-aminobutyric acid transporter.

PURPOSE: To isolate a cDNA clone encoding a high-affinity gamma-aminobutyric acid (GABA) transporter from mouse retina, to examine its biochemical and pharmacologic properties, and to determine the sites of its mRNA expression in retinal cells. METHODS: A mouse retinal cDNA library was screened using a fragment of a rat brain GABA transporter (GAT-1) cDNA as a probe. One homologous clone, mouse retinal GAT-1, was chosen for further characterization. RNA transcribed from mouse retinal GAT-1 was microinjected into Xenopus oocytes, and pharmacologic properties of the expressed transporter were determined. Sites of mouse retinal GAT-1 mRNA expression were examined by in situ hybridization. RESULTS: The protein sequence deduced from the DNA sequence of mouse retinal GAT-1 cDNA was virtually identical to that of the rat and the mouse brain GAT-1. RNA transcribed from this clone induced a [3H]-GABA uptake activity in microinjected Xenopus oocytes that was both sodium and chloride dependent. The apparent Km and Vmax for the GABA uptake were 8.3 microM and 40.0 pmol/egg per hour, respectively. The mouse retinal GAT-1 induced GABA uptake was inhibited by L-diaminobutyric acid, guvacine, cis-4-hydroxynipecotic acid, nipecotic acid, and 4,5,6,7-tetrahydroisoxazolo [4,5c]-pyridin-3-ol with IC50 values of 320, 79, 71, 7.1, and 200 microM, respectively. However, beta-alanine was unable to inhibit the induced GABA uptake significantly (IC50 approximately 2,500 microM). In situ hybridization studies showed that mouse retinal GAT-1 mRNA was present in a subpopulation of amacrine, interplexiform, and displaced amacrine cells. Hybridization signal in the Müller cells was significantly lower, and GAT-1 transcripts were not detected in the bipolar, horizontal, or photoreceptor cells of mouse retina. CONCLUSIONS: The mouse retinal GAT-1 cDNA encodes a Na(+)-dependent, high-affinity GABA transporter that is mainly expressed in a subset of mouse retinal inter neurons.

Animals↗

PubMed1992

m-Sulfonate benzene diazonium chloride: a powerful affinity label for the gamma-aminobutyric acid binding site from rat brain.

m-Sulfonate benzene diazonium chloride (MSBD) was used to affinity-label the gamma-aminobutyric acid (GABA) binding site from rat brain membranes. To assess the irreversibility of the labeling reaction, we used an efficient ligand dissociation procedure combined to a rapid [3H]muscimol binding assay, both steps being performed on filter-adsorbed membranes. Inactivation of specific [3H]-muscimol binding sites by MSBD and its prevention by GABA were both time- and concentration-dependent. The time course of MSBD labeling was shortened as the pH of the incubation medium was increased from 6.2 to 8. These data suggest that MSBD can efficiently label the GABA binding site through alkylation of a residue having an apparent dissociation constant around neutrality.

Affinity Labels↗

PubMed2000

A single glycine residue at the entrance to the first membrane-spanning domain of the gamma-aminobutyric acid type A receptor beta(2) subunit affects allosteric sensitivity to GABA and anesthetics.

Site-directed mutagenesis of the gamma-aminobutyric acid type A (GABA(A)) receptor beta(2) subunit has demonstrated that conversion of a conserved glycine residue located at the entrance to the first transmembrane domain into the homologous rho(1) residue phenylalanine alters the modulating effects of four different i.v. anesthetics: pentobarbital, alphaxalone, etomidate, and propofol. Using the baculovirus expression system in Spodoptera frugiperda 9 cells, anesthetic-induced enhancement of [(3)H]muscimol and [(3)H]flunitrazepam binding in receptors containing the beta(2)(G219F) point mutation displayed a significantly reduced efficacy in modulation by all four i.v. anesthetics tested. Furthermore, GABA(A) receptors containing the alpha(1)(G223F) point mutation also significantly decreased the maximal effect of etomidate- and propofol-induced enhancement of ligand binding. Conversely, the homologous point mutation in rho(1) receptors (F261G) changed the i.v. anesthetic-insensitive receptor to confer anesthetic modulation of [(3)H]muscimol binding. Consistent with the binding, functional analysis of pentobarbital-enhanced GABA currents recorded with whole-cell patch clamp demonstrated the beta(2)(G219F) subunit mutation eliminated the potentiating effect of the anesthetic. Similarly, propofol-enhanced GABA currents were potentiated less in alpha(1)beta(2)(G219F)gamma(2) receptors than in alpha(1)beta(2)gamma(2) receptors. Although ligand binding displayed comparable K(D) values for muscimol among wild-type, alpha(1)beta(2)gamma(2), and mutant receptors, patch-clamp recordings showed that alpha(1)beta(2)(G219F)gamma(2) receptors had a significantly more potent response to GABA than did alpha(1)beta(2)gamma(2) or alpha(1)(G223F)beta(2)gamma(2). The alpha(1)beta(2)(G219F)gamma(2) receptors also were more sensitive to direct channel activation by pentobarbital and propofol in the absence of GABA. These results suggest that the first transmembrane glycine residue on the beta(2) subunit may be important for conformational or allosteric interactions of channel gating by both GABA and anesthetics.

Allosteric Regulation↗

PubMed1979

The gamma-aminobutyric acid system in rabbit retina: localization by immunocytochemistry and autoradiography.

The localization of gamma-aminobutyric acid (GABA) neurons in the rabbit retina has been studied by immunocytochemical localization of the GABA-synthesizing enzyme L-glutamate decarboxylase (L-glutamate I-carboxy-lyase, EC 4.1.1.15) and by [3H]GABA uptake autoradiography. When Triton X-100 was included in immunocytochemical incubations with a modified protein A-peroxidase-antiperoxidase method, reaction product was found in four broad, evenly spaced laminae within the inner plexiform layer. In the absence of the detergent, these laminae were seen to be composed of small, punctate deposits. When colchicine was injected intravitreally before glutamate decarboxylase staining, cell bodies with the characteristic shape and location of amacrine cells were found to be immunochemically labeled. Intravitreally administered [3H]GABA produced a diffuse labeling of the inner plexiform layer and a dense labeling of certain amacrine cell bodies in the inner nuclear layer. Both immunocytochemical and autoradiographic results support the notion that certain, if not all, amacrine cells use GABA as their neurotransmitter.

Animals↗

PubMed1987

The effect of antibodies to gangliosides on Ca2+ channel-linked release of gamma-aminobutyric acid in rat brain slices.

Antibodies to GM1 ganglioside enhance the release of gamma-aminobutyric acid (GABA) from rat brain slices induced by depolarization with either 40 mM K+ or 200 microM veratrine. Three new observations are now reported. (a) GABA release induced by the Ca2+ ionophore A23187 was not affected by these antibodies. Because this Ca2+ ionophore causes transmitter release by bypassing depolarization-induced opening of Ca2+ channels, this result suggests that gangliosides participate either in the functioning of such Ca2+ channels or in the Na+ channels involved in depolarization. (b) The enhancement (by antibodies to GM1 ganglioside) of GABA release induced by high K+ levels occurred in the presence of tetrodotoxin (0.01 microM). (c) GABA release induced by veratrine in the absence of Ca2+ was not affected by the antibodies. These latter two observations indicate that Na+ channels are not involved in the action of the antibodies. We conclude that this evidence points to the participation of gangliosides in Ca2+ channel functions involved in GABA release in rat brain slices.

Animals↗

PubMed1978

A comparison of similar ionic responses to gamma-aminobutyric acid and acetylcholine.

1. Fast Na+-, Cl-, and K+-Conductance increase responses to gamma-aminobutyric acid (GABA) show times to peak similar to the comparable ionic responses to acetylcholine (ACh). 2. On some identified neurons, both putative transmitters elicit responses due to the same conductance change. For example, in cell R2 both substances cause an increase in Cl- conductance. Receptors for GABA and ACh on R2 do not cross desensitize and therefore are distinct. The ACh but not the GABA response is blocked by alpha-bungarotoxin and strychnine. 3. In R2 both responses reverse at -58 mV, and the Cl- ionophore (for both responses) appears to be partially permeant to propionate and isethionate, but impermeant to acetate, sulfate, and methylsulfate. 4. The Cl- responses but not the Na+ responses to both ACh and GABA are blocked by both picrotoxin and bicuculline, the classical GABA antagonists. 5. These results are compatible with the hypothesis that the ionophores associated with receptors to different neurotransmitters but mediating the same ionic conductance change have many common properties and may, in fact, be identical. Bicuculline and picrotoxin may be specific blockers of the Cl- ionophore, not the GABA receptor.

Acetylcholine↗

PubMed2001

Synaptic connections between trigemino-parabrachial projection neurons and gamma-aminobutyric acid- and glycine-immunoreactive terminals in the rat.

The synaptic connections between gamma-aminobutyric acid (GABA)- and glycine-immunoreactive terminals and neurons projecting to the lateral parabrachial region were examined by a combination of retrograde tracing and immunohistochemical staining in the rat medullary dorsal horn. After injection of horseradish peroxidase (HRP) into the right lateral parabrachial region, HRP retrogradely labeled neurons were observed bilaterally in laminae I, II and III of the medullary dorsal horn with an ipsilateral predominance. GABA- and glycine-like immunoreactive terminals were found in laminae I, II and III. Some of these GABA- and glycine-like immunoreactive terminals were observed chiefly to make symmetric synapses with HRP-labeled neuronal cell bodies and dendritic processes. The present results indicate that neurons in the medullary dorsal horn projecting to the lateral parabrachial region might be modulated by GABAergic and glycinergic inhibitory intrinsic neurons, which might be significantly involved in the regulation of the noxious information transmission.

Animals↗

PubMed1988

Immunohistochemical localization of gamma-aminobutyric acid in the rat pituitary gland and related hypothalamic regions.

The distribution of gamma-aminobutyric acid (GABA) containing neurons in the rat pituitary gland and related hypothalamic areas was immunohistochemically investigated using antibodies raised against GABA conjugated to bovine serum albumin by glutaraldehyde. A dense network of GABA-like immunoreactive fine varicose nerve fibers was observed within the posterior and intermediate lobes of the pituitary gland, surrounding endocrine cells and capillaries, but not in the anterior lobe. In the pituitary stalk, the dense varicose fibers ran along the anterior wall of the posterior lobe into the posterior and intermediate lobes. A small number of GABA-like immunoreactive cell bodies were evident in the intermediate lobe. GABA-like immunoreactive fibers occurred at low to high density in most parts of the hypothalamus. GABA-like immunoreactive neurons were observed in some regions related to the pituitary gland (such as periventricular nucleus, paraventricular nucleus, arcuate nucleus and accessory magnocellular nucleus). These results provide morphological evidence for the presence of GABAergic neurons in the rat hypothalamo-pituitary system.

Animals↗

PubMed1987

Characterization of gamma-aminobutyric acid receptors in the neurointermediate lobe of the amphibian Xenopus laevis.

The neurotransmitter gamma-aminobutyric acid (GABA) is involved in the regulation of secretion of MSH from the intermediate lobe of Xenopus laevis. The purpose of this study was to identify the GABA receptor(s) involved by determination of the effect of specific receptor agonists and antagonists on the release of immunoreactive MSH from superfused neurointermediate lobes of Xenopus. Exogenous GABA induces a rapid inhibition of MSH secretion. There was no evidence for a transitory stimulatory effect of GABA as reported for the rat melanotropes. Both the GABA agonists (GABAa) homotaurine and isoguvacine and the GABA agonist (GABAb) baclofen inhibited MSH release in a dose-dependent manner. In vivo, homotaurine and baclofen caused aggregation of pigment in dermal melanophores. The MSH release-inhibiting effect of homotaurine and isoguvacine could be antagonized by the specific GABAa receptor antagonist bicuculline. However, bicuculline and picrotoxin failed to block the effect of exogenous GABA. We conclude that in the neurointermediate lobe of Xenopus laevis both GABAa and GABAb receptors are present, suggesting a dual inhibitory regulation.

Animals↗

PubMed1983

Serum levels of gamma-aminobutyric-acid-like activity in acute and chronic hepatocellular disease.

Serum levels of GABA (gamma-aminobutyric acid)-like activity were measured by a radioreceptor assay in 22 healthy subjects and 170 patients with liver diseases. Levels were within normal limits (mean +/- SEM in healthy controls 0.52 +/- 0.04 mumol/l; range 0.2-0.8 mumol/l GABA equivalents) in most patients with uncomplicated acute viral hepatitis, compensated chronic hepatitis, and primary biliary cirrhosis (PBC). In 96% of patients with compensated (non-PBC) cirrhosis levels were slightly high (1.5 +/- 0.06 mumol/l). In 4 patients with decompensated cirrhosis but without hepatic encephalopathy (range 3.0-6.4 mumol/l) and in most of 26 patients with overt hepatic encephalopathy due to acute or chronic hepatocellular failure (range 2.3-18.0 mumol/l) levels were very high. Levels did not correlate closely with the clinical stage of hepatic encephalopathy or with arterial plasma ammonia concentrations. particularly high levels were detected in patients with cirrhosis 12-16 h after gastrointestinal haemorrhages. These findings are compatible with the hypothesis that the GABA neurotransmitter system is involved in the pathogenesis of hepatic encephalopathy in man.

Adult↗

PubMed1980

The effect of antivitamin B6 administration on gamma-aminobutyric acid metabolism in retina and electroretinogram.

The effect of several antivitamin B6 on gamma-aminobutyric acid (GABA) metabolism was studied in the rat retina. The rat electroretinogram (ERG) was also recorded after administration of these drugs. Aminooxyacetic acid (AOAA) and hydrazine administration increased the GABA content and inhibited the GABA degrading enzyme, GABA transaminase in retina. In addition, there drugs elongated the peak latency of the oscillatory potential in the rat ERG. In contrast, 4-deoxypyridoxine (DOP) or isonicotinic acid hydrazide (INAH) administration decreased the GABA content and inhibited the GABA synthesizing enzyme, glutamic acid decarboxylase in retina, and administration of these drugs together with AOAA lessened the degrees of elevation of GABA content and of the elongation of the peak latency produced as compared with AOAA alone, though neither of the former drugs had a significant effect on ERG. The retinal GABA seems to play an important role in relation to the oscillatory potential of ERG.

4-Aminobutyrate Transaminase↗

PubMed2005

In vivo characterization of the angiotensin-(1-7)-induced dopamine and gamma-aminobutyric acid release in the striatum of the rat.

The effect of angiotensin (Ang)-1-7 on dopamine, gamma-aminobutyric acid (GABA) and glutamate release in the striatum of the rat was examined using in vivo microdialysis. Ang-(1-7) was administered locally in the striatum through the microdialysis probe. At a concentration of 100 microm, Ang-(1-7) caused a significant increase in extracellular dopamine and GABA but had no effect on glutamate release. The Ang-(1-7)-induced dopamine release was blocked by EC33, an inhibitor of aminopeptidase A, an enzyme which converts Ang-(1-7) into Ang-(3-7), suggesting that this effect occurs after metabolism into Ang-(3-7). Indeed, administration of Ang-(3-7) (10-100 microm) into the striatum caused a more potent increase in the striatal dopamine release than Ang-(1-7). Because Ang-(3-7) is an inhibitor of insulin-regulated aminopeptidase (IRAP) and because Ang IV, another IRAP inhibitor, also causes a concentration-dependent increase in dopamine in the rat striatum, IRAP may be involved in this effect. In contrast, EC33 had no effect on the Ang-(1-7)-induced GABA increase but the GABA release was blocked by the putative AT(1-7) receptor antagonist A779 (0.1 microm) and by the nitric oxide synthase inhibitor L-NAME (1 mm). These drugs could not block the effect of Ang-(1-7) on the striatal dopamine release suggesting that only the observed effects on GABA release are mediated by the AT(1-7) receptor and/or are associated with a release of nitric oxide.

Angiotensin I↗

PubMed2004

[Determination of gamma-aminobutyric acid and glutamate in human gastric mucosa by high performance liquid chromatography].

A method for analysis of gamma-aminobutyric acid (GABA) and glutamate (Glu) in human gastric mucosa by high performance liquid chromatography (HPLC) was developed. A gradient elution was used for the separation and quantification of GABA and Glu after pre-column derivatization with phenylisothiocyanate (PITC). The column was Pico x Tag for free amino acids. GABA and Glu were determined with UV detector at 254 nm. Good linearities were observed within the ranges from 0.125 to 6.25 micromol/L for GABA and from 0.025 to 2.5 mmol/L for Glu. The average recoveries were 95.4% for GABA and 93.5% for Glu. The intra- and inter-precision values were within 3.56% and 7.47% for GABA, and 1.12% and 5.98% for Glu, respectively. The method is sensitive, specific and accurate. It can be used in the determination of GABA and Glu in human gastric mucosa tissue. The concentrations of GABA and Glu in cancer tissues are significantly higher than those in normal tissue.

Chromatography, High Pressure Liquid↗

PubMed1991

Inhibition of calcium influx and calcium current by gamma-aminobutyric acid in single synaptic terminals.

Inhibition of Ca influx and Ca current by gamma-aminobutyric acid (GABA) was studied in single synaptic terminals of isolated retinal bipolar neurons. Measurements of intracellular Ca concentration [( Ca]i) using the fluorescent Ca indicator fura-2 showed that GABA potently inhibited Ca influx into the terminal elicited by high extracellular K concentration ([K]o). This inhibition was attributed to GABA type A (GABAA) receptor-activated chloride ion conductance that prevented bipolar neurons from depolarizing sufficiently to activate the Ca current, even in response to increased [K]o. Patch-clamp recordings of the Ca current revealed a second effect of GABA: GTP-dependent inhibition of the Ca current. This inhibition was not mediated by GABAA receptors, but baclofen, which binds to the GABA type B (GABAB) receptor and is known to inhibit the Ca current in other systems, was not able to mimic the action of GABA. This suggests the involvement of a different type of GABAB-like receptor in the inhibition of Ca current by GABA. GABA did not cause an overall suppression of the Ca current; rather, the voltage-dependence of Ca-channel activation was shifted to more depolarized potentials. Thus, maximal inhibition of the Ca current by GABA occurred in the physiological range of potential.

Animals↗

PubMed2002

Tracazolate reveals a novel type of allosteric interaction with recombinant gamma-aminobutyric acid(A) receptors.

Tracazolate, a pyrazolopyridine, is an anxiolytic known to interact with gamma-aminobutyric acid (GABA)(A) receptors, adenosine receptors, and phosphodiesterases. Its anxiolytic effect is thought to be via its interaction with GABA(A) receptors. We now report the first detailed pharmacological study examining the effects of tracazolate on a range of recombinant GABA(A) receptors expressed in Xenopus laevis oocytes. Replacement of the gamma2s subunit within the alpha1beta3gamma2s receptor with the epsilon subunit caused a dramatic change in the functional response to tracazolate from potentiation to inhibition. The gamma2s subunit was not critical for potentiation because alpha1beta3 receptors were also potentiated by tracazolate. gamma2/epsilon chimeras revealed a critical N-terminal domain between amino acids 206 and 230 of gamma2, governing the nature of this response. Replacement of the beta3 subunit with the beta1 subunit within alpha1beta3gamma2s and alpha1beta3epsilon receptors also revealed selectivity of tracazolate for beta3-containing receptors, determined by asparagine at position 265 within transmembrane 2. Replacement of gamma2s with gamma1 or gamma3 revealed a profile intermediate to that of alpha1beta1epsilon and alpha1beta1gamma2s. alpha1beta1delta receptors were also potentiated by tracazolate; however, the maximum potentiation of the EC(20) was much greater than on alpha1beta1gamma2. Concentration-response curves to GABA in the presence of tracazolate for alpha1beta1epsilon and alpha1beta1gamma2s revealed a concentration-related decrease in maximum current amplitude, but a leftward shift in the EC(50) only on alpha1beta1gamma2. Like alpha1beta1gamma2s, GABA concentration-response curves on alpha1beta1delta receptors were shifted to the left with increased maximum responses. Tracazolate has a unique pharmacological profile on recombinant GABA(A) receptors: its potency (EC(50)) is influenced by the nature of the beta subunit; but more importantly, its intrinsic efficacy, potentiation, or inhibition is determined by the nature of the third subunit (gamma1-3, delta, or epsilon) within the receptor complex.

Allosteric Regulation↗