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PubMed2003

Distribution of gamma-aminobutyric acid receptors in cultured adrenergic and noradrenergic bovine chromaffin cells.

Fluorescence imaging techniques for recording cytosolic [Ca(2+)](i) from single chromaffin cells were used to characterize and discriminate between cell subpopulations containing gamma-aminobutyric acid (GABA)(A) and GABA(B) receptor subtypes. By combining this methodology with the immunoidentification of individual chromaffin cells using specific antibodies against tyrosine hydroxylase (TH), phenyl-etanolamine-N-methyl transferase (PNMT), and glutamic acid decarboxylase (GAD) linked to different fluorescent probes, we have been able to ascribe single-cell calcium responses to identified adrenergic and noradrenergic chromaffin cells. GAD enzyme is present in 30% of the chromaffin cell population, located primarily in adrenergic cells; 86% of GAD(+) cells were also PNMT(+). GAD expression was not correlated with the presence of GABA receptors. GABA-responsive cells were found with equal frequency in the GAD(+) and GAD(-) groups. However, the expression of GABA receptors was correlated with the adrenergic phenotype. [Ca(2+)](i) responses to GABA were found more frequently in adrenergic than in noradrenergic cells. GABA(A) receptors are more evenly distributed; about 90% of GABA-responsive cells have them. GABA(B) receptors have a more restricted distribution (present in 45% of responding cells). The coexpression of both GABA(A) and GABA(B) subtypes is the rule; only a minor subpopulation (about 12%) displays exclusively GABA(B) receptors. GABA receptor subtypes are distributed in a similar way when chromaffin cells are separated according to GAD(+)/GAD(-) or PNMT(+)/PNMT(-) classifications, with only minor differences. These data indicate that the intrinsic GABAergic system in the adrenal medulla is not designed as a paracrine model in which a group of cells specializes in transmitter synthesis and a different group serves as a specific target.

Animals↗
PubMed1986

Ion channels activated by acetylcholine and gamma-aminobutyric acid in freshly dissociated sympathetic neurones of the rat.

Transmitter-activated channels in freshly isolated neurones from sympathetic ganglia of young rats have been examined using the patch-clamp technique. Acetylcholine (ACh), gamma-aminobutyric acid (GABA) and (in about one third of cells) glycine produced an inward current and an increase in current noise when perfused onto voltage-clamped neurones. The ACh noise was fitted with a single Lorentzian spectrum with a time constant of 13.1 ms at -70 mV. Outside-out membrane patches allowed high-resolution measurements of single ACh- and GABA-activated channels. The ACh-channels had a conductance of 30 pS.

Acetylcholine↗
PubMed1980

Localization of sensitive sites to taurine, gamma-aminobutyric acid, glycine and beta-alanine in the molecular layer of guinea-pig cerebellar slices.

1 The localization, in the molecular layer of guinea-pig cerebellar slices, of the sites most sensitive to iontophoretically applied taurine, gamma-aminobutyric acid (GABA), glycine and beta-alanine was investigated. 2 The most sensitive sites were located (expressed as the distance from the Purkinje cell body to the pial surface): 0 micrometers, 60 micrometers and 220 micrometers for taurine; 0 micrometers and 180 micrometers for GABA; 80 micrometers and 200 micrometers for glycine, and 80 micrometers, 180 micrometers and 300 micrometers for beta-alanine. 3 The sensitive site (at 0 micrometers) to GABA was considered to represent the basket synapses on the Purkinje cell soma, while the sites (60 to 80 micrometers and 200 to 300 micrometers) for taurine, glycine and beta-alanine were tentatively assigned to the synapses of the stellate neurones on the Purkinje cell dendrites. 4 Inhibitory actions of all four amino acids tested at the most sensitive sites were antagonized by both picrotoxin and strychnine. 5 The possibility that taurine might be the neurotransmitter of the stellate neurones in guinea-pig cerebellum is discussed.

Amino Acids↗
PubMed2006

Felbamate is a subunit selective modulator of recombinant gamma-aminobutyric acid type A receptors expressed in Xenopus oocytes.

Felbamate (2-phenyl-1,3-propanediol dicarbamate) is clinically available for the treatment of refractory epileptic seizures, and is known to modulate several ion channels including gamma-aminobutyric acid type A (GABA(A)) receptors. To determine felbamate subunit selectivity for GABA(A) receptors we expressed 15 different GABA(A) receptor combinations in Xenopus laevis oocytes. Felbamate positively modulated GABA-currents of alpha(1)beta(2)gamma(2S), alpha(1)beta(3)gamma(2S), alpha(2)beta(2)gamma(2S) and alpha(2)beta(3)gamma(2S), whereas felbamate was either ineffective or negatively modulated the other 11 receptor combinations. Regional distributions of GABA(A) receptor subunits suggest that felbamate may differentially modulate distinct inhibitory circuits, a possibility that may have relevance to felbamate efficacy in refractory epilepsies.

Animals↗
PubMed1995

Subtype specificity of gamma-aminobutyric acid type A receptor antagonism by clozapine.

Clozapine, an atypical neuroleptic, functionally antagonizes the gamma-aminobutyric acid-induced chloride uptake via the main central inhibitory receptor, gamma-aminobutyric acid type A (GABAA) receptor, in brain vesicles. GABAA antagonism by micromolar concentrations of clozapine is more efficient in rat cerebrocortical and hippocampal membranes than in cerebellar membranes, as evidenced by clozapine reversal GABA-inhibition of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding. A typical neuroleptic, haloperidol, failed to antagonize GABA in any of these brain regions, while the specific GABAA antagonist 2'-(3'-carboxy-2',3'-propyl)-3-amino-6-p -methoxyphenylpyrazinium bromide (SR 95531) was efficient in all three brain regions. Clozapine action on [35S]TBPS binding was unaffected by the benzodiazepine receptor antagonist flumazenil. Clozapine inhibited the binding of [3H]muscimol and [3H]SR 95531 to the GABA recognition site, but this effect only partially correlated with the regional differences in and the potency of clozapine antagonism of GABA-inhibition of [35S]TBPS binding, suggesting that also other than GABA sites may mediate clozapine actions. Autoradiography of [35S]TBPS binding revealed GABA antagonism by clozapine in most brain regions. Main exceptions were cerebellar granule cell and molecular layers, olfactory bulb external plexiform and glomerular layers and primary olfactory cortex, where clozapine antagonized GABA inhibition less than average, and lateral hypothalamic and preoptic areas where its antagonism was greater than average. Recombinant alpha 6 beta 2 gamma 2 receptors, the predominant alpha 6 subunit-containing receptor subtype in cerebellar granule cells, failed to show GABA antagonism by clozapine up to 100 microM. In contrast, recombinant alpha 1 beta 2 gamma 2 receptors, forming the predominant receptor subtype in the brain, were clozapine sensitive. Recombinant alpha 6 beta 2 gamma 2 and alpha 6 beta 3 gamma 2 receptors resulted in clozapine-insensitive receptors, whereas alpha 6 beta 1 gamma 2 receptors were clozapine sensitive. The efficacy of clozapine to antagonize GABA in alpha 1 beta x gamma 2 receptors decreased in the order of alpha 1 beta 1 gamma 2 > alpha 1 beta 2 gamma 2> alpha 1 beta 3 gamma 2. The results indicate that clozapine antagonizes the function of most GABAA receptor subtypes, and that the interaction is determined by the interaction of the alpha and beta subunit variants. GABA antagonism is a unique property of clozapine, not shared by haloperidol, which might be involved in the pharmacological mechanism for the increased seizure susceptibility associated with clozapine treatment.

Animals↗
PubMed1989

Methylmercury-induced movement and postural disorders in developing rat: high-affinity uptake of choline, glutamate, and gamma-aminobutyric acid in the cerebral cortex and caudate-putamen.

Subcutaneous administration of methylmercuric chloride to neonatal rats resulted in movement and postural disorders during the fourth postnatal week. Sodium-dependent high-affinity uptake of radiolabeled choline, glutamate, and gamma-aminobutyric acid (GABA) was measured in homogenates of cerebral cortex and caudate-putamen. There was a significant decrease in the uptake of [3H]choline in the cerebral cortex, but not in the caudate-putamen, at the onset of neurological impairment (73-75%) and at one subclinical stage of toxicity (58-64%). No significant differences in [3H]glutamate uptake were detected in either region. The uptake of [3H]GABA in the presence of 1 mM beta-alanine, which was employed to inhibit the glial uptake process, was reduced significantly in both the cerebral cortex and caudate-putamen at the onset of neurological impairment (50-62%) and at one subclinical stage (40-51%). This decrease in [3H]GABA uptake is consistent with the results of previous studies using this animal model, which demonstrated a preferential degeneration of GABAergic neurons in the cerebral cortex and caudate-putamen of methylmercury-treated animals. Because the high-affinity uptake of choline is the rate-limiting step for acetylcholine synthesis by cholinergic neurons, the decrease in [3H]choline uptake may reflect an abnormal development of cholinergic innervation of the cerebral cortex.

Animals↗
PubMed1993

A study on gamma-aminobutyric acid (GABA) and its analogues by using molecular orbital methods: on epileptogenicity of new quinolones.

Using the molecular orbital methods, we examined molecular structure, electron density distribution, electrostatic potential field and receptor structure of gamma-aminobutyric acid (GABA), and its analogues. The following findings were obtained: a comparison of the biological activity and the morphology electrostatic potentials of GABA analogues disclosed that the active site is the amino group, and the biological activity correlates closely with the electrostatic potential structure around the amino group. The active sites were compared between the receptor-binding molecules and the GABA uptake inhibitory molecules, and the results suggested that the receptor structure differed between the two groups of molecules and that the GABA A receptors had two subtypes. On these results, the epileptogenicity of new quinolones was studied using this method. These results suggested that the new quinolones blockaded the GABA receptor-binding system and that the important active site of the new quinolones for GABA receptor-binding was the the piperazyl amino group. These results suggested that the concentration of zwitterion type of the new quinolones was very important clinically.

Animals↗
PubMed1991

Endogenous gamma-aminobutyric acid tonically inhibits release of alpha-melanocyte-stimulating hormone from rat hypothalamic slices.

Release of immunoreactive alpha-melanocyte-stimulating hormone (alpha-MSH) from superfused slices of rat hypothalamus was stimulated by the gamma-aminobutyric acid (GABA) receptor antagonist, bicuculline, and inhibited by the benzodiasepine, chlordiazepoxide, an allosteric GABA receptor modulator, demonstrating the presence of tonic inhibition of alpha-MSH release by endogenous GABA in hypothalamic tissue. Chlordiazepoxide increased the effect of exogenous GABA which by inhibiting basal release of alpha-MSH demonstrated that the tonic inhibition was not maximal in the resting state.

Animals↗
PubMed1985

Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock.

The action of different classes of clinically effective antidepressants and electroshock on gamma-aminobutyric acid (GABA) B recognition sites in the frontal cortex was compared to that of other psychotropic agents. After either prolonged (6-18 days) s.c. infusion via osmotic minipumps or repeated i.p. injections of different antidepressants, or a series of electroshocks, treatment was halted and 72 hr later the animals were sacrificed, the brain was dissected and frozen. All major antidepressants (desipramine, amitryptyline or maprotiline), several newer compounds with reported antidepressant activity (viloxazine, zimelidine, fluoxetine, citalopram, progabide, fengabine, sodium valproate, mianserin, trazodone or nomifensine) as well as pargyline and repeated electroshocks, up-regulated GABA B binding in the rat frontal cortex but not hippocampus. This appeared to be a maximum binding effect, but in some instance the kinetics were more complex. Reserpine, diphenylhydantoin and phenobarbital down-regulated GABA B binding in the frontal cortex, whereas this was unaltered by haloperidol, chlorpromazine or diazepam administration. Desipramine up-regulated GABA B binding in a dose- and time-dependent manner (minimum effective dose, 1.25 mg/kg/day s.c. for 18 days; onset of action, 6 days at 5 mg/kg/day s.c.). Together with the rather sparse data in the literature on GABA in depression and antidepressant drug action, these findings support a common GABAergic mechanism of action of antidepressant drugs and electroshock, mediated via GABA B synapses.

Animals↗
PubMed1990

gamma-Aminobutyric acid inhibits the potassium-stimulated release of somatostatin from rat spinal cord slices.

Evidence supports the idea that somatostatin (SO) is a neurotransmitter or neuromodulator of primary afferent neurons involved in nociception. Since gamma-aminobutyric acid (GABA), norepinephrine, and morphine alter nociception at the level of the spinal cord, we examined whether these agents could alter the potassium-stimulated release of somatostatin from rat spinal cord slices. Male Sprague-Dawley rats were decapitated and a 2 cm segment of the lumbar spinal cord removed and chopped into 0.5 x 0.5 mm pieces and perfused at 37 degrees C in individual perfusion chambers with a modified Krebs-bicarbonate buffer at a flow rate of 0.5 ml/min. Perfusates were collected at 2 min intervals and assayed for SO using radioimmunoassay. Exposure of spinal cord tissue to 50 mM KCl resulted in a 3-fold increase in release of SO from a basal level of approximately 0.2 to 0.6 pg/mg tissue/min. This evoked release was calcium dependent. Pre-exposure of tissue to GABA at 10(-4) and 10(-5) M significantly inhibited the potassium-stimulated release of SO, but did not alter basal release. The GABA receptor antagonist, bicuculline methiodide, at 10(-5) but not 10(-6) M attenuated the GABA-induced inhibition of somatostatin release. Bicuculline methiodide alone did not significantly alter either basal or stimulated release. Neither baclofen (10(-5) M, 5 x 10(-5) M), norepinephrine (10(-5) M), nor morphine (10(-5) M) had any significant effect on basal or stimulated release of SO from spinal cord tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Mechanism-based inactivation of gamma-aminobutyric acid aminotransferase by 3-amino-4-fluorobutanoic acid.

The mechanism of inactivation of the pyridoxal 5'-phosphate (PLP)-dependent enzyme gamma-aminobutyric acid (GABA) aminotransferase by 3-amino-4-fluorobutanoic acid (2) has been investigated. As in the case of the homologue, 4-amino-5-fluoropentanoic acid (1), 2 equiv of radiolabeled inactivator become covalently attached to the enzyme, and no transamination, as determined by the lack of conversion of [1-14C] alpha-ketoglutarate into [1-14C] glutamate during inactivation, was observed. In the case of 1, the conclusion was that inactivation was completely the result of modification of the coenzyme and that there was no metabolic turnover; every enzyme molecule catalysed the conversion of one molecule of inactivator to the activated species, which inactivated the enzyme by an enamine mechanism. With 2, however, 6.7 +/- 0.7 equiv of fluoride ions were released during inactivation, and it took 7.6 +/- 0.7 inactivator molecules to inactivate each enzyme dimer. Since no transamination was occurring, another metabolic event besides inactivation must result from the PLP form of the enzyme. Inactivation of GABA amino-transferase with [1,2-14C]-2 produced [14C] acetoacetic acid (about 5.5 equiv) as the metabolite. The 1.93 +/- 0.25 equiv of radioactivity covalently bound to the enzyme after inactivation with [1,2-14C]-2 and gel filtration were completely released by base treatment. HPLC analysis showed that three radioactive compounds, identified as 2, the product of reaction of PLP with acetone (3), and the product of reaction of PLP with acetoacetate (4), were detected. The release of 3 and 4 and the prevention of release of radioactivity by treatment with sodium borohydride are consistent with the formation of covalent intermediates that have beta-carbonyl-like character, such as 6 and/or 7 (Scheme 2). Inactivation of [3H] PLP-reconstituted GABA aminotransferase with 2 followed by gel filtration then base denaturation released all of the radioactivity as a mixture of PLP, 3, and 4. Inactivation with [1,2-14C]-2 resulted in the release of 1.37 equiv of 14CO2, which was shown to be the result of decarboxylation of the acetoacetate/4 after release from the enzyme. These results are not consistent with a Michael addition mechanism (Scheme 3), but are consistent with inactivation by an enamine mechanism; release of the enamine five out of seven turnovers accounts for the formation of acetoacetate as the metabolite. To account for the detection of PLP and 2 after denaturation, it is suggested that a nonproductive formation of the Schiff base of PLP with 2 occurs in the second subunit of the enzyme; this complex is released and hydrolysed to PLP and 2 upon base denaturation.

4-Aminobutyrate Transaminase↗
PubMed1994

Excitatory action of gamma-aminobutyric acid (GABA) on crustacean neurosecretory cells.

1. Intracellular and voltage-clamp recordings were obtained from a selected population of neurosecretory (ns) cells in the X organ of the crayfish isolated eyestalk. Pulses of gamma-aminobutyric acid (GABA) elicited depolarizing responses and bursts of action potentials in a dose-dependent manner. These effects were blocked by picrotoxin (50 microM) but not by bicuculline. Picrotoxin also suppressed spontaneous synaptic activity. 2. The responses to GABA were abolished by severing the neurite of X organ cells, at about 150 microns from the cell body. Responses were larger when the application was made at the neuropil level. 3. Topical application of Cd2+ (2 mM), while suppressing synaptic activity, was incapable of affecting the responses to GABA. 4. Under whole-cell voltage-clamp, GABA elicited an inward current with a reversal potential dependent on the chloride equilibrium potential. The GABA effect was accompanied by an input resistance reduction up to 33% at a -50 mV holding potential. No effect of GABA was detected on potassium, calcium, and sodium currents present in X organ cells. 5. The effect of GABA on steady-state currents was dependent on the intracellular calcium concentration. At 10(-6) M [Ca2+]i, GABA (50 microM) increased the membrane conductance more than threefold and shifted the zero-current potential from -25 to -10 mV. At 10(-9) M [Ca2+]i, GABA induced only a 1.3-fold increase in membrane conductance, without shifting the zero-current potential. 6. These results support the notion that in the population of X organ cells sampled in this study, GABA acts as an excitatory neurotransmitter, opening chloride channels.

Action Potentials↗
PubMed1995

Effects of systemic and local ethanol on responses of rat cerebellar Purkinje neurons to iontophoretically applied gamma-aminobutyric acid.

The goals of this study were: (1) to determine the effects of acute systemic or local application of ethanol (ETOH) on the response of cerebellar Purkinje cells (P-cells) to iontophoretically applied gamma-aminobutyric acid (GABA) and (2) to characterize the effects of Ro15-4513, a putative antagonist of ETOH-GABA interactions, on ETOH-induced changes in GABA responsiveness. Male Sprague-Dawley rats (230-370 g) were anesthetized with halothane and implanted with intraperitoneal catheters for administration of ETOH (1.0-2.0 g/kg), before the recording session. Extracellular activity of single P-cells was recorded with the central barrel of a five-barrel micropipette, the other barrels of which were used for microiontophoresis of GABA and electro-osmosis of ETOH at the recording site. Spontaneous discharge and response of P-cells to GABA were monitored during a pre-ETOH control and for 1-1.5 h after systemic or electro-osmotic administration of ETOH. Transient suppression of spontaneous P-cell discharge was usually observed within 4-8 min of systemic ETOH injection. This effect lasted 2-4 min in 10 out of 19 rats tested. GABA-mediated inhibitory responses of cerebellar P-cells were increased by 45-50% relative to pre-ETOH values at 10 and 90 min post-ETOH injection. Prior administration of the imidazobenzodiazepine Ro15-4513 (4-6 mg/kg) failed to antagonize either the ETOH-induced enhancement of GABA-mediated inhibition or the transient inhibition of spontaneous P-cell activity rat cerebellar P-cell produced by ETOH. In these studies, electro-osmotically applied ETOH produced a potent suppression of spontaneous P-cell activity which precluded further augmentation of unit responses to GABA. These results show that doses of systemically administered ETOH which are mildly intoxicating in the awake, behaving animal, enhance the inhibitory action of GABA on cerebellar P-cell discharge.

Action Potentials↗
PubMed1986

In vivo release of [3H]gamma-aminobutyric acid in the rat neostriatum--II. Opposing effects of D1 and D2 dopamine receptor stimulation in the dorsal caudate putamen.

The effects of several dopaminergic agonists and antagonists on the spontaneous release of [3H]gamma-aminobutyric acid were investigated in the dorsal striatum of halothane-anaesthetized rats. A push-pull cannula was implanted and the tissue was superfused continuously with a physiological medium containing [3H]glutamine, the precursor of [3H]GABA. Drugs were added to the superfusion medium. 2-Amino,6,7-dihydroxy,1,2,3,4-tetrahydro-naphtalene (ADTN, a mixed D1 and D2 receptor agonist) and D-amphetamine (a drug that enhances the release of endogenous dopamine) increased the release of 3H-GABA. The effect of ADTN was blocked by a D1 antagonist [R-(+),8-chloro, 7-hydroxy,2,3,4,5-tetrahydro,3-methyl,5-phenyl,1-H,3-benzazepine (SCH 23390)] but not by a D2 antagonist (S-sulpiride). Furthermore the stimulation of D1 receptors either by 2,3,4,5-tetrahydro,7,8-dihydroxy,1-phenyl,1-H,3-benzazepine or by D-amphetamine in the presence of S-sulpiride also enhanced the release of [3H]GABA. On the other hand, a selective D2 receptor agonist (3-(2-(N-3-hydroxy-phenylethyl)N-propylamino)ethyl-phenol) decreased the release of [3H]GABA. This effect was blocked in the presence of S-sulpiride. By itself the D1 receptor antagonist (SCH 23390) decreased the release of [3H]GABA whereas the D2 receptor antagonist (S-sulpiride) had no effect. It was concluded that stimulation of D1 and D2 receptors produces opposing effects on the spontaneous release of [3H]GABA in the dorsal striatum. Stimulation of D1 receptors facilitates the release of [3H]GABA whilst stimulation of D2 receptors inhibits it. The effect of D1 receptor stimulation appears to be predominant, and endogenous dopamine may activate tonically the release of GABA through these receptors in our experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Protein kinase C regulation of glycine and gamma-aminobutyric acid release in brain stem auditory nuclei.

Protein kinase C (PKC) can regulate transmitter release in several brain areas. We determined if PKC could regulate the electrically evoked release of radiolabeled glycine (Gly) and gamma-aminobutyric acid (GABA) in dissected samples of several brain stem auditory nuclei, such as the major subdivisions of the cochlear nucleus (CN) and the main nuclei of the superior olivary complex (SOC). The PKC activators, phorbol 12,13-diacetate (PDA) or phorbol 12,13-dibutyrate (PDBu) (3 microM), elevated the release by 1.4- to 2.0-fold. The PKC inhibitor, Ro31-8220 (50 nM), did not alter the release in most of the tissues but blocked the stimulatory effects of PDA and PDBu. This suggested that PKC positively regulates glycinergic and GABAergic release in the sampled nuclei. In the dorsal CN (DCN), Ro31-8220 elevated the release of [(14)C]Gly by 23%, suggesting that PKC negatively regulates glycinergic release in a proportion of DCN synapses. We also determined if PKC could regulate release after unilateral cochlear ablation (UCA). In the anteroventral (AVCN) and posteroventral (PVCN) CN and in the lateral (LSO) and medial (MSO) superior olive, the stimulatory effects of PDBu declined after this lesion and Ro31-8220 failed to alter release. Since UCA failed to alter release in these tissues, the stability of the release correlated with the lack of regulatory capacity of PKC. In the DCN and the medial nucleus of the trapezoid body (MNTB), the stimulatory effects of PDBu persisted after UCA. We previously demonstrated a postablation decline of Gly release in the DCN and elevated GABA release in the MNTB. Treatment of these tissues with Ro31-8220 reversed these changes in release. These findings suggested that PKC regulation persisted in the DCN and MNTB after UCA. Moreover, endogenous regulatory mechanisms activated after UCA probably act through PKC to alter release in these tissues. Thus, limiting PKC activation or activity might ameliorate pathological symptoms that accompany hearing loss and that stem from these plasticities in the DCN and MNTB.

Animals↗
PubMed1986

Prolongation of calcium action potentials by gamma-aminobutyric acid in primary sensory neurones of lamprey.

Intracellular recordings from primary mechanosensory neurones (dorsal cells) in the lamprey spinal cord were used to test the membrane effects of a variety of putative neuromodulatory agents. gamma-Aminobutyric acid (GABA) produced a dose-dependent increase in the duration of mixed Na-Ca or pure Ca action potentials in these cells. L-Glutamate and glycine produced minimal broadening of Ca action potentials. Acetylcholine, noradrenaline, serotonin, met-enkephalin, D-glutamate and dopamine had no effect. The pharmacology of GABA's action appeared to be complex. While the GABAA receptor antagonists, bicuculline, picrotoxin and curare, did not block GABA's effect, both the GABAA receptor agonist, muscimol, and the GABAB-receptor agonist, baclofen, occasionally broadened Ca action potentials in these cells. GABA had no effect on the resting potential, passive current-voltage (I-V) characteristics and pure Na action potential of dorsal cells, ruling out an action on passive membrane channels, transmitter-activated channels, or on those voltage-dependent channels activated during the Na action potential. Thus, GABA affected dorsal cells only when a significant Ca current was evident. GABA appeared not to increase the conductance of the Ca channels since its action was accompanied by an increase in input resistance, suggesting an inhibition of Ca-dependent conductance that normally acts to repolarize the membrane during a Ca action potential. An inhibitory effect of GABA on a Ca-dependent Cl conductance was ruled out in experiments where the Cl gradient was altered by removal of extracellular Cl without affecting GABA-induced Ca action potential prolongation. Dorsal cells have a prominent Ca-dependent K conductance (gK(Ca], and it is this conductance that GABA may inhibit. Consistent with this was the observation that the hyperpolarizing after-potential that follows Ca action potentials in dorsal cells, which reflects gK(Ca) in these cells and whose duration is normally increased when the Ca action potential duration increases, was not prolonged when the Ca action potential was broadened by GABA. Further, the failure of GABA to prolong Ba action potentials was consistent with this proposed mechanism of action, since Ba apparently does not activate gK(Ca) in these cells. Forskolin, a specific adenylate cyclase activator, caused broadening of Ca action potentials in lamprey dorsal cells comparable in magnitude to that of GABA. Thus, an increase in intracellular cyclic AMP is a candidate for the intracellular mediator of GABA's effect on these cells.

Action Potentials↗
PubMed1974

[Effect of gamma-aminobutyric acid on the concentration of noradrenaline in the synaptosoma fraction of the meso-diencephalic region of rat brain].

We had previously shown [1, 2, 3, 4] that intraperitoneal administrations of 5 mg/kg amounts of gamma-aminobutyric acid (GABA) lower norepinephrine (NE) level of rat brain, this effect being most pronounced in the hypothalamic region. Subsequent studies showed that GABA increased normetanephrine level in iproniazid pretreated rats (II) and decreased NE content of crude mitochondrial fractions (12). These data implied changes in NE content of nerve endings. The results of the present study indicate that the NE content of the synaptosomal fraction of the mesodiencephalic region of GABA treated rats is significantly lower than that of untreated animals. This is a further confirmation of our previous results favouring a release of NE from nerve endings following the administration of GABA.

Aminobutyrates↗

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