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PubMed2003

Effects of isoflurane on gamma-aminobutyric acid type A receptors activated by full and partial agonists.

BACKGROUND: Volatile anesthetics prolong inhibitory postsynaptic potentials in central neurons an allosteric action on the gamma-aminobutyric acid type A (GABA(A)) receptor, an effect that may underlie the hypnotic actions of these agents. Inhaled anesthetics such as isoflurane act to enhance responses to submaximal concentrations of GABA, but it is not clear whether their effect is mediated by an increase in the binding of the agonist or by changes in receptor gating behavior. To address this question, the authors studied the effects of isoflurane on a mutant GABA(A) receptor with a gating defect that decreases receptor sensitivity by lowering agonist efficacy. They then compared the effects of clinically relevant concentrations of isoflurane on the actions of GABA and piperidine-4-sulfonic acid (P4S), a partial agonist at the GABA(A) receptor. METHODS: The authors created a mutant of the GABA receptor alpha subunit (L277A) by site-directed mutagenesis. The mutant subunit was coexpressed with beta(2) and gamma(2S) subunits in HEK293 cells, and responses to GABA and P4S were recorded using the whole-cell patch clamp technique. EC values were determined for the full agonist GABA and the partial agonist P4S. The authors also determined the relative efficacy (epsilon) of P4S. These measurements were then repeated in the presence of isoflurane. RESULTS: The concentration-response curve for GABA was shifted to the right (EC(50) = 278 microm) in the alpha(1)(L277A)beta(2)gamma(2S) mutant receptor, compared with the corresponding wild-type alpha(1)beta(2)gamma(2S) GABA(A) receptor (EC(50) = 16 microm). P4S is a partial agonist at both receptors, with a dramatically decreased relative efficacy at the mutant receptor (epsilon = 0.24). When the mutant receptor was studied in the presence of isoflurane, the concentration-response curves for both GABA and P4S were shifted to the left (EC(50) for GABA = 78 microm); the efficacy of P4S also increased significantly (epsilon = 0.40). CONCLUSION: By studying a mutant GABA receptor with impaired gating, the authors were able to demonstrate clearly that isoflurane can increase the efficacy of a partial agonist, as well as increase agonist potency. These data suggest that the volatile anesthetic isoflurane exerts at least some of its effects on the GABA(A) receptor via alterations in gating rather than simply changing binding or unbinding of the agonist.

Anesthetics, Inhalation↗
PubMed1981

Two types of gamma-aminobutyric acid receptor on embryonic sensory neurones.

1 Embryonic sensory neurones of the chick grown in dissociated cell culture respond to application of low concentrations of gamma-aminobutyric acid (GABA) with a change in resting membrane resistance (R(in)) and/or a change in action potential duration (APD) (Dunlap & Fischbach, 1978; Choi & Fischbach, 1981). Intracellular microelectrode recording techniques were employed to determine if these two effects are mediated by the same, or different, GABA receptors.2 Cells responded, for the most part, with a change in either R(in) or APD, but 10% of the cells exhibited both effects. In the latter cells the two responses were clearly distinguishable as discussed below.3 The proportion of neurones exhibiting a GABA-induced decrease in R(in) declined during the first week in vitro while the proportion exhibiting a decrease in APD increased during that time.4 The two effects were pharmacologically distinct. Muscimol, a GABA analogue, produced only the change in R(in) (ED(50) = 5.5 muM) while baclofen, another analogue of GABA, produced only the change in APD (ED(50) = 1 muM). The analogues were approximately equipotent with GABA. Bicuculline, a GABA antagonist, blocked the muscimol-induced change in R(in) (but not the baclofen-induced change in APD) in a dose-dependent fashion with an ID(50) = 0.7 muM.5 The time courses of the two effects were different. The change in APD resulting from a brief application of GABA (or baclofen) was prolonged relative to the rapid return to control associated with the GABA- (or muscimol-) induced change in R(in).6 Desensitization of the two responses exhibited separate time courses. In the continual presence of the agonists, GABA- and muscimol-induced decreases in R(in) completely desensitized in ca. 10 s while GABA- and baclofen-induced decreases in APD persisted undiminished throughout a prolonged (1 min) application of the drugs and returned to control only after cessation of application.7 It is concluded that embryonic chick sensory neurones in culture exhibit two types of GABA receptor that differ in their functional and pharmacological properties. Implications of these results are discussed.

Action Potentials↗
PubMed1987

gamma-Aminobutyric acid and 5-hydroxytryptamine interrelationship in the rat nucleus raphe dorsalis: combination of radioautographic and immunocytochemical techniques at light and electron microscopy levels.

Serotonin and gamma-aminobutyric acid (GABA) neurons in the nucleus raphe dorsalis were identified by immunocytochemistry using antibodies to 5-hydroxytryptamine or GABA. The pattern of the 5-hydroxytryptamine and GABA immunostaining presented similar features: 5-hydroxytryptamine or GABA immunoreactive somata were fusiform or ovoid (15-20 micron) and positive dendritic profiles were found either without any connection with other nerve elements or in contact with one or several terminals. In addition, some 5-hydroxytryptamine nerve endings were apposed to 5-hydroxytryptamine immunoreactive cell bodies or dendrites; also some GABA-immunopositive terminals were in contact with GABA-immunopositive nerve cell bodies. On the other hand, GABA and 5-hydroxytryptamine patterns may be differentiated in several respects: the 5-hydroxytryptamine-reactive nerve cell bodies were more numerous than the GABA ones. Some small, round (8-10 micron) nerve cell bodies were reactive with GABA antiserum, but no neurons of this type were reactive with a 5-hydroxytryptamine antiserum; finally, GABA nerve terminals were more numerous than 5-hydroxytryptamine ones. In order to understand the relationship between GABA and 5-hydroxytryptamine neurons, radioautographic and immunocytochemical procedures were combined: 5-hydroxytryptamine and GABA immunocytochemistry was combined with radioautography of [3H]GABA and [3H]5-hydroxytryptamine uptake, respectively. Some nerve cell bodies, dendrites or terminals, which were 5-hydroxytryptamine-immunopositive, were also capable of accumulating [3H]GABA and, conversely, some GABA-immunopositive elements were capable of accumulating [3H]5-hydroxytryptamine. Moreover, several nerve elements were reactive with both glutamate decarboxylase and 5-hydroxytryptamine antisera. These data confirm in electron microscopy previous studies suggesting the coexistence of both GABA and 5-hydroxytryptamine in the same neurons. The presence of uptake mechanisms for GABA and 5-hydroxytryptamine may indicate the action of both neurotransmitters in the same neuron. On the other hand, the [3H]GABA-labelled nerve endings in contact with 5-hydroxytryptamine-positive dendrites or nerve cell bodies indicate the possibility of a GABAergic control of the activity of some 5-hydroxytryptamine neurons; this corroborates biochemical and electrophysiological studies whereby a trans-synaptic control of the 5-hydroxytryptamine neurons by GABA may be envisaged.

Animals↗
PubMed1987

gamma-Aminobutyric acid receptor binding in fresh mouse brain membranes at 22 degrees C: ligand-induced changes in affinity.

Binding of [3H]muscimol to mouse brain gamma-aminobutyric acid receptors has been assayed under more physiological conditions (never-frozen membranes, 22 degrees) than in previous studies (0-4 degrees on frozen-thawed membranes). Binding affinities were lower and agreed more closely with physiological dose response curves. In addition, heterogeneity in affinity was still present, apparently due to a mixture of non-interconvertible subpopulations and ligand-induced changes in kinetics. Super-high affinity sites (Kd less than 10 nM) observed in frozen membranes were not observed in fresh membranes under equilibrium binding conditions, and high affinity sites (Kd congruent to 25 nM) seen at 0 degree had lower affinity (Kd congruent to 250 nM) at 22 degrees. Despite an apparent best fit single-component Scatchard plot for the latter data, cold ligand displacement and association and dissociation rates demonstrated heterogeneity of affinities. Pentobarbital greatly increased the amount of high affinity sites at the expense of low affinity sites in equilibrium binding at 0 degree and slightly increased affinity at 22 degrees. The kinetics of [3H]muscimol association at 22 degrees (kapp = 1-2/min) were virtually independent of the ligand concentration, suggesting either negative cooperativity or an agonist binding-dependent receptor isomerization. Dissociation triggered by addition of excess cold ligand to membranes equilibrated with [3H]muscimol at different concentrations revealed two off-rates with t1/2 values of under 10 sec and 1-3 min; unexpectedly, the ratio of these two populations did not vary with ligand concentration but was constant at 50:50. Dissociation triggered by infinite dilution gave two off-rates, but the slowest component had a t1/2 of about 20 min; including cold muscimol in the dilution buffer increased the off-rate toward that observed in the excess cold ligand method (t1/2 = 1-2 min). The very slow off-rate was only observed following removal of agonist from a previously occupied receptor and suggests receptor isomerization into a high affinity state; this state is similar to that observed at 0 degree. Pentobarbital also favored the production of the receptor state showing very slow [3H]muscimol dissociation upon infinite dilution, opposing the action of high receptor occupancy with cold muscimol. Thus, [3H]muscimol-binding sites observed at 22 degrees with fresh membranes do not show artificially high affinity and have a Kd of 0.2-0.3 microM, closer to the EC50 for chloride channel activation (approximately 2-3 microM and 0.4 microM with pentobarbital).(ABSTRACT TRUNCATED AT 400 WORDS)

Allosteric Regulation↗
PubMed2003

Decrease of morphine-induced reward effects and withdrawal symptoms in mice overexpressing gamma-aminobutyric acid transporter I.

Morphine addiction has been shown to result from neural adaptations produced by repeated drug exposure, but the mechanism is still unclear. In the present study, we found that gamma-aminobutyric acid (GABA) uptake was increased in mouse brain 120 min after, but not 20 min after, morphine (10 mg/kg, s.c.) injection. We generated GABA transporter I (GAT1)-overexpressing mice to investigate whether the GABAergic system and GABA transporter are involved in morphine-induced reward effects and withdrawal symptoms. Our results revealed that the rewarding effects induced by morphine were significantly decreased in GAT1-overexpressing mice as measured by the conditioned place preference (CPP) paradigm. Moreover, both somatic and vegetative signs of naloxone-induced morphine withdrawal symptoms were substantially reduced in GAT1-overexpressing mice. In addition, the decreased morphine rewarding in transgenic mice could be recovered when mice were coinjected with NO-711 (a GAT1 selective inhibitor) in the CPP paradigm. These findings suggest that the GABAergic system plays an important role in morphine addiction and point to the possibility of developing drugs that target GAT1 and extend the clinical application of opiates.

Adaptation, Physiological↗
PubMed1992

Estradiol plus progesterone promote glutamate-induced release of gamma-aminobutyric acid from preoptic area synaptosomes.

Treatment of ovariectomized rats with both estradiol and progesterone in vivo resulted in a marked enhancement of glutamate-induced release of newly synthesized [3H]gamma-aminobutyric acid (GABA) from synaptosomes of the preoptic area in vitro. With this treatment, as little as 0.01 nM glutamate, in vitro, enhanced release of GABA. In contrast, glutamate, in vitro, did not stimulate release of GABA from synaptosomes, obtained from rats treated with either estradiol or progesterone alone and only large concentrations of glutamate (1.0 and 10 mM) caused a modest release of GABA from synaptosomes from ovariectomized, vehicle-treated rats. Also, treatment with estradiol plus progesterone did not alter glutamate-induced release or exchange of [3H]glutamate. Glutamate-induced release of GABA was calcium-independent and attenuated by the putative chloride channel antagonist, 4,4'-diisothiocyanatostilbene-2,2'-DL-disulfonic acid. Thus, glutamate-induced, steroid-enhanced release of GABA may occur through a chloride-dependent carrier rather than by exocytosis. In addition to enhancement by glutamate, release of GABA was also enhanced by D-aspartate, an agent that is transported by the neuronal glutamate carrier. It is postulated that enhancement of glutamate-induced release of GABA, by estradiol plus progesterone in the preoptic area, represents one process by which these steroids modulate reproductive function in female rats.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2001

Engineered Zn(2+) switches in the gamma-aminobutyric acid (GABA) transporter-1. Differential effects on GABA uptake and currents.

Two high affinity Zn(2+) binding sites were engineered in the otherwise Zn(2+)-insensitive rat gamma-aminobutyric acid (GABA) transporter-1 (rGAT-1) based on structural information derived from Zn(2+) binding sites engineered previously in the homologous dopamine transporter. Introduction of a histidine (T349H) at the extracellular end of transmembrane segment (TM) 7 together with a histidine (E370H) or a cysteine (Q374C) at the extracellular end of TM 8 resulted in potent inhibition of [3H]GABA uptake by Zn(2+) (IC(50) = 35 and 44 microM, respectively). Upon expression in Xenopus laevis oocytes it was similarly observed that Zn(2+) was a potent inhibitor of the GABA-induced current (IC(50) = 21 microM for T349H/E370H and 51 microM for T349H/Q374C), albeit maximum inhibition was only approximately 40% in T349H/E370H versus approximately 90% in T349H/Q374C. In the wild type, Zn(2+) did not affect the Na(+)-dependent transient currents elicited by voltage jumps and thought to reflect capacitive charge movements associated with Na(+) binding. However, in both mutants Zn(2+) caused a reduction of the inward transient currents upon jumping to hyperpolarized potentials as reflected in rightward-shifted Q/V relationships. This suggests that Zn(2+) is inhibiting transporter function by stabilizing the outward-facing Na(+)-bound state. Translocation of lithium by the transporter does not require GABA binding and analysis of this uncoupled Li(+) conductance revealed a potent inhibition by Zn(2+) in T349H/E370H, whereas surprisingly the T349H/Q374C leak was unaffected. This differential effect supports that the leak conductance represents a unique operational mode of the transporter involving conformational changes different from those of the substrate translocation process. Altogether our results support both an evolutionary conserved structural organization of the TM 7/8 domain and a key role of this domain in GABA-dependent and -independent conformational changes of the transporter.

Amino Acid Sequence↗
PubMed1986

Spontaneous release of gamma-aminobutyric acid formed from putrescine and its enhanced Ca2+-dependent release by high K+ stimulation in the brains of freely moving rats.

The spontaneous release of [3H] gamma-aminobutyric acid ([3H]GABA) in various areas of rat brain injected with [3H]putrescine was examined using a push-pull perfusion technique. The release in a 25-min perfusate was highest in the caudate-putamen. The effect of high K+ stimulation on the release of [3H]GABA formed from [3H]putrescine was examined in the caudate-putamen. The release was enhanced by high K+ solution in a Ca2+-dependent manner.

Animals↗
PubMed1980

Primary afferent depolarization. Distribution of the gamma-aminobutyric acid system in frog spinal cord.

In the frog spinal cord primary afferent depolarization (PAD) constitutes a powerful inhibitory control mechanism. It has been suggested that gamma-aminobutyric acid (GABA) is the transmitter substance involved in the genesis of PAD. In these studies we show that maximal glutamic acid decarboxylase activity is localized roughly 400-600 micrometers from the dorsal surface, and that correlates well with the intraspinal distribution of field potentials associated with PAD. Measurements of GABA in serial spinal cord sections cut in a dorsal--ventral direction shows that high levels of GABA are seen at 400--600 micrometers, with a peak at 800 micrometers from the dorsal surface. Stimulation at frequencies shown to produce PAD augments the release of endogenous GABA from a superfused frog hemicord preparation.

Animals↗
PubMed1979

Responses of the guinea-pig isolated olfactory cortex slice to gamma-aminobutyric acid recorded with extracellular electrodes.

1. Potential changes between the pial and cut surfaces of slices of guinea-pig olfactory cortex in vitro produced by gamma-aminobutyric acid (GABA) were recorded with extracellular electrodes. 2. GABA, superfused over the pial surface (0.1 to 10 mM), produced a pial-negative potential deflection, accompanied by inhibition of the postsynaptic response to lateral olfactory tract (LOT) stimulation. 3. This effect was replicated by the following compounds (potency relative to GABA = 1, in brackets): 3-aminopropanesulphonic acid (5.3), epsilon-aminovaleric acid (0.07), beta-alanine (0.07), beta-amino-nibutyric acid 0.05), epsilon-aminocaproic acid, alpha-amino-isobutyric acid, L-leucine (less than 0.02). 4. L-Glutamate (1 to 10 mM) produced a very large surface negative shift, with relatively less synaptic inhibition. Glycine (1 to 10 mM) produced less surface negatively, accompanied by synaptic inhibition. 5. Responses to GABA were antagonized more effectively than those to glycine by bicuculline (3 to 30 micrometer) and picrotoxin (1 to 30 micrometer). Strychnine (1 to 10 micrometer) incompletely inhibited responses to glycine. 6. It is concluded that, while the locus within the slice of these effects is uncertain, the preparation may be useful for testing the interaction of drugs with cerebral GABA receptors.

Action Potentials↗
PubMed1986

Afferent fibers from the septum terminate on gamma-aminobutyric acid (GABA-) interneurons and granule cells in the area dentata of the rat.

Interneurons in the area dentata of the rat were immunostained with an antibody to gamma-aminobutyric acid. After septal lesions, degenerating terminals were found in asymmetric synaptic contact with granule cell somata and dendritic elements of immunoreactive and nonreactive cells in the supragranular part of the molecular layer.

Afferent Pathways↗
PubMed1983

Action of apomorphine, bromocriptine and lergotrile on gamma-aminobutyric acid and acetylcholine release in nucleus accumbens and corpus striatum.

The effect of three dopamine agonists, apomorphine, bromocriptine and lergotrile, was tested on the release of gamma-aminobutyric acid, (GABA) and acetylcholine (ACh) from tissue slices of rat nucleus accumbens and striatum. All three agents in vitro caused a dose dependent depression of the K+-evoked release of [14C]-GABA in corpus striatum. This effect was also obtained following in vivo drug application and when endogenous GABA release was determined. A similar depression of GABA release was obtained in the nucleus accumbens. Both dopamine and dibutyryl adenosine-3':5'-cyclic monophosphoric acid inhibited the K+-evoked release of [14C]-GABA in corpus striatum. This inhibitory effect was not reversed by sulpiride. Bromocriptine and lergotrile also depressed the K+-evoked release of [3H]-acetylcholine from tissue slices of corpus striatum but not nucleus accumbens, as has previously been demonstrated for dopamine and apomorphine. In contrast, sulpiride enhanced the release of [3H]-acetylcholine and molindone reversed the apomorphine inhibition of [3H]-acetylcholine release. These results indicate that dopaminergic agents may influence the release of both GABA and ACh in the corpus striatum but only GABA in the nucleus accumbens.

Acetylcholine↗
PubMed1993

Extracellular H+ iontophoresis modifies responses to gamma-aminobutyric acid and cyanide of reticulospinal vasomotor neurons in rats.

Responses of reticulospinal vasomotor neurons, recorded in the rostral ventrolateral reticular nucleus of the medulla oblongata, to gamma-aminobutyric acid (GABA) and cyanide microiontophoreses were examined during H+ iontophoresis in anesthetized rats. Extracellular H+ iontophoresis attenuated GABA-evoked decreases and enhanced cyanide-induced increases in the neuronal activity, but had no effect on the neuronal activity when applied alone. Opposite responses were produced during OH- iontophoresis. Similar effects were also observed on the glycine-evoked inhibition of these neurons during H+ and OH- iontophoreses, suggesting that H+ modulation of the GABA-evoked inhibition may not result from a specific action at the GABA receptor-channel complex. It is concluded that extracellular H+ ions exert a modulatory action on responses of the reticulospinal vasomotor neurons to other neuro-active substances and may significantly contribute to hypoxic-ischemic cardiovascular regulation.

Animals↗
PubMed1990

Pharmacological properties of the N-methyl-D-aspartate receptor system coupled to the evoked release of gamma-[3H] aminobutyric acid from striatal neurons in primary culture.

The actions of a series of endogenous excitatory amino acid (EAA) agonists and synthetic antagonists at the N-methyl-D-aspartate (NMDA) receptor system coupled to the evoked release of gamma-[3H]aminobutyric acid (GABA) from purified populations of striatal neurons in primary culture were examined. EAA agonists displayed the following rank order of potency in evoking [3H]GABA release: glutamate greater than homocysteate greater than aspartate, NMDA greater than cysteine sulfinate. Glutamate, homocysteate and cysteine sulfinate were equieffective, whereas at saturating concentrations, aspartate and NMDA reached 75 and 65%, respectively, of the maximum efficacy of the former three agonists. The release of [3H]GABA evoked by 100 microM NMDA was attenuated in a dose-dependent manner by the following antagonists (IC50, micromolar): MK-801 (0.067), phencyclidine (0.151), CGS-19755 (3.31), 2-aminophosphonovalerate (18.8), kynurenate (100) and gamma-D-glutamylglycine (100). The antagonist properties of MK-801 and phencyclidine were not competitive with NMDA, whereas NMDA dose-response curves performed in the absence and presence of increasing concentrations of CGS-19755 resulted in parallel rightward shifts (pA2 = 5.95). CGS-19755 produced similar rightward shifts of the homocysteate dose-response curve (pA2 = 5.89). At glutamate concentrations less than 100 microM, CGS-19755 and 2-aminophosphonovalerate were potent antagonists of glutamate-evoked release; however, at glutamate concentrations greater than 100 microM these agents were ineffective blockers. The blockade of NMDA-evoked release of [3H]GABA by kynurenate was not competitive in nature.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1984

Role of gamma-aminobutyric acid in anxiety.

The development of anxioselective agents has made it possible to examine the biochemical basis of anxiety. Electrophysiological analysis revealed that benzodiazepines selectively enhance gamma-aminobutyric acid (GABA) neurotransmission. Subsequent work demonstrated the presence of a specific population of benzodiazepine binding sites on neuronal membranes. These sites appear to be linked to certain GABA receptors such that occupation of the benzodiazepine component reveals a group of GABA recognition sites that may be more sensitive to the neurotransmitter. These data, coupled with the findings that barbiturates may act, at least in part, by interacting with the GABA receptor-coupled chloride channel, suggest that pharmacological manipulations of the GABA system can alleviate the symptoms of anxiety. The anxioselectivity of the benzodiazepines may be related to the fact that they activate only a certain population of GABA receptors, whereas barbiturates can potentiate the majority of these sites. These discoveries point to the possibility that alterations in the GABA system may partially explain the neurochemical basis of anxiety.

Anti-Anxiety Agents↗