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PubMed1976

A comparative study of the action of gamma-aminobutyric acid and piperazine on the lobster muscle fibre and the frog spinal cord.

1 The effects of gamma-aminobutyric acid (GABA) and piperazine were compared on two in vitro preparations, the lobster muscle fibre and the frog spinal cord. 2 Both GABA and piperazine increased the membrane conductance of single lobster muscle fibres without changing the membrane potential; sigmoidal log dose-conductance curves for these agents were obtained and a similar model expressed the receptor interaction of both substances. 3 The actions of GABA and piperazine on lobster muscle were antagonized by picrotoxin and were Cl-dependent. 4 In the frog spinal cord GABA depolarized the dorsal roots presumably by mimicking the activity of the transmitter depolarizing the primary afferents; sigmoidal log dose-response curves for GABA were obtained. 5 On the dorsal roots piperazine produced either depolarizations or biphasic responses; these were mainly indirect effects as was shown by experiments in the presence of tetrodotoxin (TTX). 6 The effects of GABA on the dorsal root (in TTX-treated cords) were antagonized by picrotoxin whereas those of piperazine were more resistant to this alkaloid. The GABA-induced responses appeared to be largely Na+-dependent while both Na+ and Cl- seemed to mediate the effects of piperazine. 7 It is proposed that piperazine has GABA-agonist activity on lobster muscle but little GABA-like activity on the frog spinal cord.

Aminobutyrates↗
PubMed1998

Propofol and other intravenous anesthetics have sites of action on the gamma-aminobutyric acid type A receptor distinct from that for isoflurane.

Both volatile and intravenous general anesthetics allosterically enhance gamma-aminobutyric acid (GABA)-evoked chloride currents at the GABA type A (GABAA) receptor. Recent work has revealed that two specific amino acid residues within transmembrane domain (TM)2 and TM3 are necessary for positive modulation of GABAA and glycine receptors by the volatile anesthetic enflurane. We now report that mutation of these residues within either GABAA alpha2 (S270 or A291) or beta1 (S265 or M286) subunits resulted in receptors that retain normal or near-normal gating by GABA but are insensitive to clinically relevant concentrations of another inhaled anesthetic, isoflurane. To determine whether receptor modulation by intravenous general anesthetics also was affected by these point mutations, we examined the effects of propofol, etomidate, the barbiturate methohexital, and the steroid alphaxalone on wild-type and mutant GABAA receptors expressed in human embryonic kidney 293 cells. In most cases, these mutations had little or no effect on the actions of these intravenous anesthetics. However, a point mutation in the beta1 subunit (M286W) abolished potentiation of GABA by propofol but did not alter direct activation of the receptor by high concentrations of propofol. These data indicate that the receptor structural requirements for positive modulation by volatile and intravenous general anesthetics may be quite distinct.

Anesthetics, Inhalation↗
PubMed1994

Effect of gamma-aminobutyric acid on synaptic transmission and long-term potentiation in rat superior cervical ganglion.

The effect of gamma-aminobutyric acid (GABA) on synaptic transmission in rat superior cervical ganglion (SCG) was assessed in vitro by extracellular recording. Postganglionic compound action potentials (CAPs) triggered by preganglionic stimulation were blocked in a reversible and concentration-dependent fashion by short, 60 s long, superfusion with GABA (IC50 = 39.3 microM), with the GABAA agonist muscimol (IC50 = 8.7 microM) or with the GABAB agonist baclofen (IC50 = 145 microM). Responses to GABA and muscimol, but not to baclofen, exhibited desensitization after 5 min long superfusions with the drugs. In a long-term potentiation (LTP) paradigm, the degree of potentiation found 30 min after a tetanic train of stimuli (20 Hz for 20 s) was strongly inhibited by GABA (100-250 microM), when superfused at the time of tetanic stimulus or shortly thereafter. The effect of GABA on SCG LTP was mimicked by muscimol but not by baclofen. The results are compatible with the view that GABA exerts overall inhibitory effects in rat SCG, including transmission blockade of single impulses (through activation of GABAA and GABAB receptors) and impairment of activity-dependent potentiation of nicotinic transmission (through activation of GABAA receptors).

Action Potentials↗
PubMed1999

Intracellular chloride and calcium transients evoked by gamma-aminobutyric acid and glycine in neurons of the rat inferior colliculus.

Microfluorometric recordings showed that the inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and glycine activated transient increases in the intracellular Cl- concentration in neurons of the inferior colliculus (IC) from acutely isolated slices of the rat auditory midbrain. Current recordings in gramicidin-perforated patch mode disclosed that GABA and glycine mainly evoked inward or biphasic currents. These currents were dependent on HCO3- and characterized by a continuous shift of their reversal potential (E(GABA/gly)) in the positive direction. In HCO3- -buffered saline, GABA and glycine could also evoke an increase in the intracellular Ca2+ concentration. Ca2+ transients occurred only with large depolarizations and were blocked by Cd2+, suggesting an activation of voltage-gated Ca2+ channels. However, in the absence of HCO3-, only a small rise, if any, in the intracellular Ca2+ concentration could be evoked by GABA or glycine. We suggest that the activation of GABAA or glycine receptors results in an acute accumulation of Cl- that is enhanced by the depolarization owing to HCO3- efflux, thus shifting E(GABA/gly) to more positive values. A subsequent activation of these receptors would result in a strenghtened depolarization and an enlarged Ca2+ influx that might play a role in the stabilization of inhibitory synapses in the auditory pathway.

Animals↗
PubMed1982

Reversible effects of tetanus toxin on striatal-evoked responses and [3H]-gamma-aminobutyric acid release in the rat substantia nigra.

1 The effects of sublethal doses of tetanus toxin on gamma-aminobutyric acid (GABA)-mediated synaptic transmission and [3H]-GABA release were studied in the rat substantia nigra. 2 Intranigral injections of tetanus toxin at 1-5 times the mouse LD50 dose produced ipsiversive circling behaviour which was maximal after 1 week and lasted 2-3 weeks. Rats then displayed normal behavior suggesting that the effects of the toxin were fully reversible. 3 In the treated nigra of circling rats there was a reduction in the striatal-evoked inhibition of compacta and reticulata neurones, but no change in their spontaneous firing rates. Some forms of striatal-evoked excitation were also reduced. Once rats had recovered from circling no alterations in the synaptic responses were detected. 4 In circling rats there were no differences in the sensitivities of neurones in the treated and untreated nigra to GABA or to other inhibitory neurotransmitters. 5 The Ca2+-dependent, K+-evoked release of [3H]-GABA from slices prepared from the treated nigra of circling rats was less than that from the untreated nigra of circling rats. No differences in nigral [3H]-GABA release were observed once rats had recovered from the circling behaviour. 6 The results demonstrate that doses of tetanus toxin which produce reversible behavioural effects can interfere reversibly with GABA-mediated synaptic transmission by a presynaptic mechanism which probably involves a reduction in transmitter release.

Animals↗
PubMed2004

Effect of thiopental sodium on the release of glutamate and gamma-aminobutyric acid from rats prefrontal cortical synaptosomes.

To investigate the effect of thiopental sodium on the release of glutamate and gamma-aminobutyric acid (GABA) from synaptosomes in the prefrontal cortex, synaptosomes were made, the spontaneous release and the evoked release by 30 mmol/L KCl or 20 micromol/L veratridine of glutamate and GABA were performed under various concentrations of thiopental sodium (10-300 micromol/L), glutamate and GABA concentrations were determined by reversed-phase high-performance liquid chromatography. Our results showed that spontaneous release and evoked release of glutamate were significantly inhibited by 30 micromol/L, 100 micromol/L and 300 micromol/L thiopental sodium, IC50 of thiopental sodium was 25.8 +/- 2.3 micromol/L for the spontaneous release, 23.4 +/- 2.4 micromol/L for KCl-evoked release, and 24.3 +/- 1.8 micromol/L for veratridine-evoked release. But GABA spontaneous release and evoked release were unaffected. The study showed that thiopental sodium with clinically related concentrations could inhibit the release of glutamate, but had no effect on the release of GABA from rats prefrontal cortical synaptosomes.

Animals↗
PubMed1986

'Concentration-clamp' study of gamma-aminobutyric-acid-induced chloride current kinetics in frog sensory neurones.

Kinetics of the activation and desensitization phases of gamma-aminobutyric acid (GABA)-induced Cl- current (ICl) were studied in single frog sensory neurones using the 'concentration-clamp' technique which enables perfusion of drugs with the time constant of about 3 ms. Both activation and desensitization phases of GABA response consisted of a single exponential at low concentrations and a double exponential at high concentrations. The time constant of the fast kinetic component in each phase was relatively stable, about 5 ms for activation and 3 s for desensitization over concentrations from 3 X 10(-5) to 3 X 10(-4) M, whereas those of the slow kinetic component decreased with increasing concentrations. The two kinetic components in both phases showed the same reversal potential. The slow and fast activation components recovered sensitivity from desensitization with different time courses: the recovery rate of the fast activation component was slow and that of the slow one, rapid. The peak ICl elicited at GABA concentrations below 10(-5) M increased disproportionally at more negative membrane potentials, thereby suggesting that the activation kinetics is voltage dependent. The steady-state ICl-voltage relationship obtained with less than 10(-5) M-GABA showed a non-linearity, probably due to voltage dependence of activation rather than that of desensitization kinetics. These results suggest the presence of at least two different GABA receptor-Cl- ionophore complexes with a different affinity and kinetics.

Action Potentials↗
PubMed1986

Effects of gamma-aminobutyric acid (GABA) receptor agonists on the neurotoxicity and anticonvulsant activity of barbiturates in mice.

The effects of gamma-aminobutyric acid (GABA) receptor agonists [4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol THIP]; [progabide and baclofen] on the minimal neurotoxicity and anticonvulsant activity of pentobarbital and phenobarbital in mice were investigated. When either progabide, THIP or baclofen were administered with pentobarbital, the components of this combination interacted additively by the rotorod test. Combinations of pentobarbital and progabide or phenobarbital and progabide interacted additively when subjected to the pentylenetetrazol (PTZ) minimal threshold seizure (clonic) test. THIP, even at toxic doses, did not alter the anti-PTZ activity of either pentobarbital or phenobarbital. In contrast, baclofen at toxic doses potentiated the anti-PTZ activity of pentobarbital and phenobarbital. Combinations of progabide and pentobarbital or progabide and phenobarbital interacted additively by the maximal electroshock seizure (MES) test. THIP, even when given in toxic doses, had no effect on the anti-MES activity of pentobarbital and phenobarbital. However, baclofen at nontoxic doses potentiated the anti-MES activity of phenobarbital but not that of pentobarbital. These results suggest that 1) in vitro interactions between barbiturates and GABAa receptor agonists may not be the same in vivo, 2) GABAa receptors may play a minor role in the minimal neurotoxicity and anticonvulsant activity of barbiturates and 3) inhibition of glutamate-induced excitation by baclofen may be an important action in potentiating the anti-MES activity of phenobarbital.

Animals↗
PubMed1987

Contrasting properties of K+ conductances induced by baclofen and gamma-aminobutyric acid in slices of the guinea pig hippocampus.

Properties of membrane K+ conductances induced by baclofen and gamma-aminobutyric acid (GABA) in the hippocampus were investigated by using guinea-pig brain slices. Baclofen hyperpolarized the membrane and decreased the input resistance of pyramidal cells through the activation of a membrane K+ conductance. GABA caused a biphasic response in pyramidal cells, consisting of hyperpolarizing and depolarizing components. Combined application of picrotoxin and bicuculline eliminated the major part of the depolarizing component of the biphasic response and produced a relatively pure hyperpolarizing response which was also mediated by an increase in K+ conductance. The K+ conductance change induced by baclofen showed prominent inward rectification. However, the K+ conductance induced by GABA did not show an obvious rectifying property. The K+ conductance activated by baclofen was strongly antagonized by a low concentration (5 x 10(-6) M) of 4-aminopyridine (4-AP). In contrast, the K+ conductance activated by GABA was insensitive to 4-AP even at a high concentration of 10(-3) M. The slow inhibitory postsynaptic potential (slow i.p.s.p.) evoked by stimulation of the mossy fibres was totally suppressed by a low concentration of baclofen (5 x 10(-6) M). Whereas GABA (10(-3) M) decreased the amplitude of the slow i.p.s.p., the reduction of the amplitude was proportional to the decrease in the amplitude of the electrotonic potentials produced by constant inward current injections. These results suggest that the hyperpolarizations induced by GABA and baclofen may be generated by K+ conductances of different kinetic and pharmacologic properties.

Animals↗
PubMed2002

Profiles of in vivo gamma-aminobutyric acid release in the medial preoptic area of intact and castrated male rats.

We have suggested that gamma-aminobutyric acid (GABA) in the hypothalamus plays a tonic inhibitory role in the control of the luteinizing hormone (LH) release in intact male rats. To assess whether feedback from the testis alters the inhibitory GABAergic tone in the medial preoptic area (MPO) of male rats, an in vivo microdialysis study was performed in gonadally intact (n = 10), castrated (n = 12) and castrated testosterone-primed (n = 10) male rats. The microdialysis samples were collected and sequential blood samples were also obtained at 1-hour intervals. GABA in the dialysate was determined by high-performance liquid chromatography system and serum LH concentration was determined by radioimmunoassay. Episodic GABA release in the MPO was observed in all three groups of male rats, although castrated male rats showed lower GABA release (2.3 +/- 0.3 ng/h) than intact and castrated testosterone-primed male rats (4.0 +/- 0.5 and 4.6 +/- 1.0 ng/h, respectively). Conversely, castrated male rats showed higher serum LH concentration (7.31 +/- 0.46 ng/ml) than intact and castrated testosterone-primed male rats (0.71 +/- 0.04 and 0.53 +/- 0.07 ng/ml, respectively). In addition, intravenous infusion of bicuculline significantly increased serum LH in intact male rats, whereas bicuculline did not alter serum LH concentrations in castrated male rats. These results are consistent with the hypothesis that the feedback of testosterone stimulates GABA release in the region of the GnRH cell bodies and dendrites in male rats.

Animals↗
PubMed1987

gamma-Aminobutyric acid stimulates pituitary growth hormone secretion in the neonatal rat. A superfusion study.

The putative inhibitory neurotransmitter gamma-aminobutyric acid (GABA) elicited a dose-dependent increase in GH secretion from the pituitary of newborn rats. GH secretion increased within 3 min after GABA administration with a peak response at 5-6 min. The lowest effective dose of the GABA agonist muscimol was about 10 times smaller than that of GABA. The GABA effect was antagonized by picrotoxin and bicuculline, suggesting that GABA acts at GABA-A type receptors. The pituitary responsiveness to GABA gradually decreased during the second and third postnatal weeks. If the neonatal pituitaries were continuously exposed to GABA for 3 h GH secretion rapidly increased to a maximum within the first 10 min and then gradually decreased to a less elevated level by 1 h and remained at this level for the next 2 h. After 3 h of GABA exposure muscimol had no effect on GH secretion but human pancreatic GH-releasing factor stimulated it, indicating receptor desensitization during prolonged GABA administration. The significance of GABAergic regulation of GH secretion in the neonate is emphasized by the finding that simultaneous administration of picrotoxin diminished the GH releasing activity of the hypothalamic extract of 2-day-old rats by more than 60%. These results indicate that in the postnatal period the regulation of GH secretion differs from that of the adult animal and GABA might play an important role in the maintenance of the high GH secretion during the first days of life.

Animals↗
PubMed1997

A study of gamma-aminobutyric acid (GABA) in amniotic fluid.

OBJECTIVE: The purpose of the study was to evaluate the role of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, in amniotic fluid (AF) during fetal distress, because it has been reported that several neurotransmitters, e.g. norepinephrine, are affected by GABA. METHODS: AF was obtained during elective cesarean section (CS, n = 11) and cesarean section due to fetal distress without labor pain (FD, n = 7). Maternal and umbilical-cord blood, as well as the first urine of the neonates, also were collected. GABA, norepinephrine (NE), and epinephrine (EP) concentrations were measured using HPLC. RESULTS: The GABA concentration was higher in the AF than in either maternal or fetal circulation, or in the first urine of neonates. The GABA concentrations in the AF and in the first urine of neonates were significantly higher in the FD group than in the CS group (p < 0.05). Furthermore, significant positive correlations were observed between the NE and GABA concentrations and between the EP and GABA concentrations in the AF. GABA was produced in a time-dependent manner in cultured amnion cells. CONCLUSION: The highest concentration of GABA was found in the AF. The GABA in the AF appeared to be derived from both the amniotic membrane and the fetal urine. The increase in the GABA concentration in cases of fetal distress might be partially derived from the fetus via fetal urine. The positive correlations between the concentrations of GABA and those of NE and EP in the AF, suggest that GABA, NE, and EP might play important roles during fetal distress.

Adrenergic alpha-Agonists↗
PubMed1987

Desensitization of gamma-aminobutyric acid receptor from rat brain: two distinguishable receptors on the same membrane.

Transmembrane chloride flux mediated by gamma-aminobutyric acid (GABA) receptor can be measured with a mammalian brain homogenate preparation containing sealed membrane vesicles. The preparation can be mixed rapidly with solutions of defined composition. Influx of 36Cl- tracer initiated by mixing with GABA was rapidly terminated by mixing with bicuculline methiodide. The decrease in the isotope influx measurement due to prior incubation of the vesicle preparation with GABA, which increased with preincubation time and GABA concentration, was attributed to desensitization of the GABA receptor. By varying the time of preincubation with GABA between 10 ms and 50 s with quench-flow technique, the desensitization rates could be measured over their whole time course independently of the chloride ion flux rate. Most of the receptor activity decreased in a fast phase of desensitization complete in 200 ms (t 1/2 = 32 ms) at saturation with GABA. Remaining activity was desensitized in a few seconds (t 1/2 = 533 ms). These two phases of desensitization were each kinetically first order and were shown to correspond with two distinguishable GABA receptors on the same membrane. The receptor activities could be estimated, and the faster desensitizing receptor was the predominant one, giving on average ca. 80% of the total activity. The half-response concentrations were similar, 150 and 114 microM for the major and minor receptors, respectively. The dependence on GABA concentration indicated that desensitization is mediated by two GABA binding sites. The fast desensitization rate was approximately 20-fold faster than previously reported rates while the slower desensitization rate was slightly faster than previously reported rates.

Animals↗
PubMed1994

Effect of anions on the uptake and release of gamma-aminobutyric acid by isolated synaptic plasma membranes.

The influence of various anions on the uptake and release of gamma-aminobutyric acid (GABA) was investigated in synaptic plasma membrane (SPM) vesicles isolated from sheep brain cortex. We observed that substitution of Cl- by various anions greatly reduces [3H]GABA accumulation by SPM vesicles. The magnitude of the effect is about 30, 85, 95 and 100% when Cl- is replaced by Br-, NO3-, CH3COO- and SO4(2-), respectively. However, no effect was observed when these anions were added together with Cl-, which indicates that they do not inhibit the [3H]GABA uptake mechanism by SPM vesicles. On the other hand, we observed that [3H]GABA release, either by homoexchange or induced by K+ depolarization, is maximal in the presence of Cl- or Br-, whereas the other anions (NO3-, CH3COO- and SO4(2-)) caused a 50% reduction in the two processes of [3H]GABA release. We also observed that the basal release of [3H]GABA is not greatly altered by Br- and NO3-, but it is greatly enhanced by CH3COO- and SO4(2-) in substitution of Cl-. In contrast to these alterations in [3H]GABA movements, the membrane potential is not significantly affected by any of the anions tested. The results confirm the idea that GABA uptake implies Cl- co-transport and they demonstrate that the maximal release of [3H]GABA through its carrier (homoexchange or K+ depolarization-induced release) requires the presence of small anions (Cl- or Br-) at the opposite side of the membrane from where the neurotransmitter is translocated. Furthermore, it appears that CH3COO- and SO4(2-) uncouple the system by inducing basal release, whereas it remains coupled in the presence of Cl-, Br- and NO3-.

Animals↗
PubMed1984

The actions of gamma-aminobutyric acid, glycine and their antagonists upon horizontal cells of the Xenopus retina.

We examined the effects of gamma-aminobutyric acid (GABA) and glycine and their respective antagonists, picrotoxin and strychnine, upon the membrane potential and light-evoked responses of the type H1 horizontal cell of the Xenopus retina. This horizontal cell receives mixed input from rod and cone receptors. Under control conditions the mean membrane potential was -37.8 +/- 9.7 mV. Addition of 5 mM-GABA to the superfusate hyperpolarized the cell by 4.0 +/- 2.6 mV within 3-5 min; addition of 0.5 mM-picrotoxin depolarized the cell by 4.3 +/- 2.1 mV. Prolonged (greater than 15 min) exposures to the drugs elicited more pronounced changes in membrane potential. GABA and picrotoxin affected primarily the cone-dependent input to the H1 horizontal cell. Under dark-adapted conditions, response wave forms were essentially unaltered by the drugs, but when the horizontal cell was moderately or fully light adapted, GABA reduced and picrotoxin enhanced the cone-dependent component of its response to light. Long-term (greater than 15 min) exposures to GABA and picrotoxin elicited changes in response kinetics usually associated with dark and light adaptation, respectively. Glycine, at bath concentrations of 0.6 mM or greater, depolarized horizontal cells by 21 mV on average and reduced or abolished their light response. This action did not occur in the presence of 0.1 mM-strychnine. When all light-evoked activity was blocked by 20-40 mM-magnesium, the depolarizing action of glycine still occurred. Thus, glycine appears to act directly upon the horizontal cell membrane. Neither GABA nor glycine, nor their respective antagonists, affected the spatial extent of the horizontal cell receptive field.

Action Potentials↗