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PubMed1991

Gamma-aminobutyric acid (GABAB) receptor-mediated inhibition of tyrosine hydroxylase activity in the striatum of rat.

The effects of GABA and GABA agonists on calcium and depolarization-dependent stimulation of tyrosine hydroxylase activity in striatal slices were studied. gamma-Aminobutyric acid and (-)baclofen inhibited, while muscimol and (+)baclofen did not affect, the stimulation of tyrosine hydroxylase. The inhibitory effect of GABA and (-)baclofen was blocked by the GABAB antagonist, phaclofen but not by the GABAA antagonist, picrotoxin. The data suggest that the activity of tyrosine hydroxylase on dopaminergic nigrostriatal terminals may be modulated by GABA via GABAB receptors.

Animals↗
PubMed2004

Ethanol withdrawal-induced up-regulation of the alpha2 subunit of the GABAA receptor and its prevention by diazepam or gamma-hydroxybutyric acid.

The gamma-aminobutyric acid type A (GABA(A)) receptor is an important pharmacological target of ethanol. The effect of ethanol withdrawal on the expression of the alpha(2) subunit of this receptor was examined with rat cerebellar granule cells in primary culture. Long-term exposure of these cells to ethanol (100 mM, 5 days) did not affect the abundance of the mRNA for the alpha(2) subunit, as revealed by an RNase protection assay. In contrast, subsequent ethanol withdrawal for 3 h induced a marked increase in the amount of this mRNA (2.6-fold) as well as in that of the encoded polypeptide (2.2-fold), the latter revealed by immunoblot analysis. Exposure of the cells to gamma-hydroxybutyric acid (100 mM) during ethanol withdrawal prevented the increase in the amounts of both the alpha(2) mRNA and polypeptide, whereas similar treatment with diazepam (10 microM) blocked the increase in the abundance of the alpha(2) polypeptide but not that in the amount of the alpha(2) mRNA. The effect of gamma-hydroxybutyric acid was not blocked by the competitive GABA(B) receptor antagonist SCH 50911(10 microM). Given that the alpha(2) subunit of the GABA(A) receptor mediates the anxiolytic action of benzodiazepines, its up-regulation during discontinuation of long-term ethanol exposure might be relevant to the therapeutic efficacy of these drugs in the treatment of anxiety associated with ethanol withdrawal.

Animals↗
PubMed2000

Changes in [3H]zolpidem and [3H]Ro 15-1788 binding in rat globus pallidus and substantia nigra pars reticulata following a nigrostriatal tract lesion.

Changes in GABA(A) receptor alpha(1) subunit gene expression occur in the globus pallidus and substantia nigra pars reticulata following lesions of the nigrostriatal tract. To determine whether these changes are translated at the protein level, we performed quantitative autoradiography with the alpha(1) selective ligand, [3H]zolpidem, and the non-selective benzodiazepine site ligand, [3H]Ro 15-1788. Binding of both [3H]zolpidem and [3H]Ro 15-1788 was significantly increased in the substantia nigra pars reticulata (13. 5+/-4.1 and 26.3+/-2.9%, respectively) and significantly reduced in the globus pallidus (20.9+/-0.8 and 18.3+/-1.3%, respectively). These changes in alpha(1) subunit protein expression may help to compensate for the pathological changes in GABAergic activity that occur after striatal dopamine depletion.

Animals↗
PubMed2001

Behavioral effects of agents active at the gamma-aminobutyric acid receptor complex in the staircase paradigm.

This study examined the behavioral effects of agents active at the gamma-aminobutyric acid (GABA(A)) receptor complex in the mouse staircase paradigm. The neuroactivesteroids dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) were compared with the benzodiazepine agonist clonazepam, the non-benzodiazepine hypnotic compound zopiclone, and the antiepileptic agent gabapentin. Clonazepam, zopiclone and gabapentin reduced rearing activity at doses that did not affect climbing. The rearing-suppression effect of clonazepam and zopiclone, but not of gabapentin, was blocked by the benzodiazepine antagonist flumazenil, suggesting that the added effect of gabapentin is not mediated by the benzodiazepine receptor on the GABA complex. DHEA suppressed rearing behavior at doses that did not reduce climbing, but analysis with the Bonferroni post hoc test yielded no statistically significant difference. This inhibitory effect was attenuated by flumazenil. By contrast, DHEA-S suppressed, in a dose-dependent manner, both rearing and climbing behavior to the same extent. The findings support the potential value of the mouse staircase paradigm for demonstrating behaviorally relevant anxiolysis of test compounds shown to interact in vitro with the GABA(A) receptor complex.

Acetates↗
PubMed1999

Alterations of GABAA receptor subunit mRNA levels associated with increases in punished responding induced by acute alprazolam administration: an in situ hybridization study.

Changes in the mRNA encoding alpha1, alpha2, beta2 and gamma2 subunits of the GABAA receptor associated with the anxiolytic effects of alprazolam were measured in 20 brain regions using in situ hybridization techniques. Compared to non-punished controls, punishment decreased alpha1 mRNA levels in two nuclei of the amygdala, the cerebral cortex, and the mediodorsal thalamic nucleus and decreased alpha2 mRNA levels in the hippocampus. Punishment increased beta2 mRNA levels in ventroposterior thalamic nucleus and gamma2 mRNA levels in the CA2 area of the hippocampus. All of these effects were reversed when alprazolam increased punished responding, while alprazolam alone had no effect on either non-punished responding or GABAA receptor subunit regulation in these brain regions. Some brain regions that were unaffected by punishment were altered by alprazolam plus punishment. These results demonstrate that punishment and alprazolam can produce reciprocal changes in the mRNA levels for some subunits of the GABAA receptor. These changes may alter GABAergic synaptic inhibition by altering the density of GABAA receptors or their efficacy to bind drugs. They suggest that the underlying mechanisms by which drugs affect behavior can depend upon the conditions under which behavior is assessed.

Alprazolam↗
PubMed2000

Propofol increases agonist efficacy at the GABA(A) receptor.

Using the whole-cell patch-clamp technique, we have determined that propofol, but not midazolam, increases the efficacy of piperidine-4-sulphonic acid (P4S), a partial agonist at alpha1beta1gamma2s, GABA(A) receptors expressed in HEK 293 cells. These findings are consistent with the idea that propofol facilitates receptor gating, while midazolam increases receptor occupancy by the agonist.

Allosteric Regulation↗
PubMed1997

Involvement of supraspinal GABA receptors in majonoside-R2 suppression of clonidine-induced antinociception in mice.

Majonoside-R2 (MR2) is a major constituent of Vietnamese ginseng (Panax vietnamensis, Ha et Grushv. Araliaceae) that is known to exhibit antagonistic activity against opioid-induced antinociception. In this study, we investigated the effect of MR2 on the antinociception caused in mice by the alpha2-adrenoceptor agonist clonidine, and elucidated the role of supraspinal GABAergic systems in this effect of MR2. The systemic administration of clonidine (0.5-2.5 mg/kg, s.c.) dose-dependently suppressed the nociceptive response of mice in the tail-pinch and hot-plate tests. The intraperitoneal (i.p.), intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of idazoxan (a selective alpha2-adrenoceptor antagonist) significantly antagonized the antinociceptive effect of clonidine in both tests. MR2 administered systemically (1.5-6.2 mg/kg, i.p.) or centrally (5-10 microg/mouse, i.c.v. or i.t.) dose-dependently antagonized the clonidine (1 mg/kg, s.c.)-induced antinociception in the tail-pinch test but not in the hot-plate test. The antagonistic effect of i.c.v. MR2 on the systemic clonidine-induced antinociception in the tail-pinch test was significantly reversed by i.c.v. administrations of the selective benzodiazepine receptor antagonist flumazenil (5 microg/mouse) and the GABA(A) antagonist picrotoxin (0.25 microg/mouse). These results suggest that the supraspinal GABA(A)/benzodiazepine receptors are involved in the antagonistic effect of MR2 on the clonidine-induced antinociception in the tail-pinch test in mice.

Adrenergic alpha-Agonists↗
PubMed2001

The interaction of AR-A008055 and its enantiomers with the GABA(A) receptor complex and their sedative, muscle relaxant and anticonvulsant activity.

AR-A008055 [(+/-)-1-(4-methyl-5-thiazolyl)-1-phenylmethylamine] is structurally related to clomethiazole and has been used to probe the mechanism of the neuroprotective effect of clomethiazole. Clomethiazole, (+/-)-AR-A008055 and (S)-(-)-AR-A008055 all displaced [35S]-t-butyl-bicyclophosphorothionate ([35S]TBPS) from rat cerebral cortex tissue (IC50 values: GABA, 8.1+/-0.04 microM; clomethiazole, 130+/-30 microM; (+/-)-AR-A008055, 494+/-7 microM; (S)-(-)-AR-A008055, 221+/-14 microM. (R)-(+)-AR-A008055 was without significant effect (IC50>1000 microM). None of the compounds interacted with NMDA or AMPA receptors or with sodium or calcium (N, P/Q) channels. Brain penetration of both enantiomers following their i.p. administration was excellent, with brain and plasma concentrations being similar. Clomethiazole dose-dependently inhibited spontaneous locomotor activity in rats and was approximately 10 times more sedative than either enantiomer of AR-A008055. Clomethiazole was more potent than (S)-(-)-AR-A008055 in the "pull-up" test (muscle relaxation) and in producing loss of righting reflex, while (R)-(+)-AR-A008055 had little effect. The time animals remained on a Rota-rod was of the order: clomethiazole<(S)-(-)-AR-A008055<(R)-(+)-AR-A008055. (S)-(-)-AR-A008055 (210 micromol/kg) raised seizure threshold to pentylenetetrazole (i.v.) by 119+/-21%. The (R)-(+)- enantiomer was not anticonvulsant. Overall, (S)-(-)-AR-A008055 exhibited a similar pharmacology to clomethiazole. However, its sedative and muscle relaxant effects were substantially less than clomethiazole, emphasising that these properties are not directly related to neuroprotective efficacy. The current data suggest that the proposed GABA uptake inhibitory property of (R)-(+)-AR-A008055 fails to produce significant sedative, myorelaxant or anticonvulsant activity.

Animals↗
PubMed2002

Changes in GABA(A) receptor gene expression induced by withdrawal of, but not by long-term exposure to, zaleplon or zolpidem.

The effects of long-term treatment with and subsequent withdrawal of the two hypnotic drugs zaleplon and zolpidem on the abundance of gamma-aminobutyric acid type A (GABA(A)) receptor subunit mRNAs in cultured rat cerebellar granule cells were investigated. Incubation of neurons with either drug at a concentration of 10 microM for 5 days did not significantly affect the amounts of mRNAs encoding the alpha(1), alpha(4), beta(1), beta(2), beta(3), gamma(2)L, or gamma(2)S subunits. As expected, similar treatment with the nonselective benzodiazepine diazepam resulted in a decrease in the abundance of alpha(1), beta(2), gamma(2)L, and gamma(2)S subunit mRNAs as well as an increase in that of the beta(1) subunit mRNA. Withdrawal of zaleplon or zolpidem, like that of diazepam, induced a marked increase in the amount of the alpha(4) subunit mRNA. In addition, discontinuation of treatment with either hypnotic drug resulted in a decrease in the amounts of alpha(1), beta(2), gamma(2)L, and gamma(2)S subunit mRNAs as well as an increase in that of the beta(1) subunit mRNA. These effects of zaleplon and zolpidem on GABA(A) receptor gene expression are consistent with the reduced tolerance liability of these drugs, compared with that of diazepam, as well as with their ability to induce both physical dependence and withdrawal syndrome.

Acetamides↗
PubMed1996

Pharmacological properties of recombinant "diazepam-insensitive" GABAA receptors.

Both native and recombinant "diazepam-insensitive" GABAA receptors (DI) are characterized by the very low affinities of prototypic 1,4-benzodiazepines such as diazepam and the high affinity of an imidazobenzodiazepine, Ro 15-4513. The presence of either an alpha 4 or alpha 6 subunit imparts this unusual pharmacological profile to DI. Based on the affinities of these compounds at recombinant DI, the pharmacological properties of alpha 4- and alpha 6-bearing receptor isoforms appear to be very similar if not identical. Using a larger sample of structurally diverse compounds, we now demonstrate distinct but related ligand binding profiles of recombinant alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2 DI. Comparison of 18 ligands drawn from three principal structural groups (beta-carbolines, imidazobenzodiazepines and pyrazoloquinolinones) revealed that the affinity of at least one representative from each group differed by > 5-fold between alpha 4- and alpha 6 beta 2 gamma 2 receptors. While the high correlation (r2 = 0.926; p < 0.001) obtained between the affinities of these ligands at alpha 4- and alpha 6-containing receptors underscores the similarity between these receptor isoforms, a significant deviation of the slope of this correlation (0.792; 95% C.I. 0.673-0.911) from unity is substantive evidence that these DI possess distinct pharmacological profiles. These findings indicate that it is feasible to develop selective ligands for these DI isoforms.

Animals↗
PubMed1997

Benzodiazepine mediated antagonism of opioid analgesia.

Activation of supraspinal gamma-aminobutyric acid-A (GABAA) receptors is known to result in antagonism of opioid analgesia. Since benzodiazepines enhance the action of GABA at GABAA receptors, we hypothesized that administration of these agents for preoperative sedation might antagonize the analgesic effects of opioids administered postoperatively. If so, then administration of the benzodiazepine antagonist flumazenil should enhance postoperative morphine analgesia. In a double-blind, placebo-controlled study of patients who received a preoperatively administered benzodiazepine (diazepam) for sedation and a postoperatively administered opioid (morphine) for analgesia, we investigated opioid-benzodiazepine interactions affecting postoperative dental pain. We found that flumazenil significantly enhanced morphine analgesia consistent with the hypothesis that the preoperatively administered benzodiazepine exerts an ongoing antianalgesic effect. In addition, we followed these patients over the first and second postoperative days to determine if there were differences between the drug groups in post-discharge pain, analgesic consumption, or side-effects. Participants receiving flumazenil reported significantly less post-discharge nausea and used significantly less ibuprofen. Since post-discharge pain levels were not significantly different, these results suggest that the patients receiving flumazenil required less analgesic medication to achieve a comparable level of pain control. In summary, our results indicate that the benzodiazepine antagonist flumazenil enhances morphine analgesia and decreases post-discharge side-effects as well as post-discharge need for analgesic medication.

Adult↗
PubMed2002

GABA interacts with photic signaling in the suprachiasmatic nucleus to regulate circadian phase shifts.

Circadian rhythms of physiology and behavior in mammals are driven by a circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus. The majority of neurons in the suprachiasmatic nucleus are GABAergic, and activation of GABA receptors in the suprachiasmatic nucleus can induce phase shifts of the circadian pacemaker both in vivo and in vitro. GABA also modulates the phase shifts induced by light in vivo, and photic information is thought to be conveyed to the suprachiasmatic nucleus by glutamate. In the present study, we examined the interactions between GABA receptor agonists, glutamate agonists, and light in hamsters in vivo. The GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen were microinjected into the suprachiasmatic nucleus at circadian time 13.5 (early subjective night), followed immediately by a microinjection of N-methyl-D-aspartate (NMDA). Both muscimol and baclofen significantly reduced the phase shifting effects of NMDA. Further, coadministration of tetrodotoxin with baclofen did not alter the inhibition of NMDA by baclofen, suggesting a postsynaptic mechanism for the inhibition of NMDA-induced phase shifts by baclofen. Finally, the phase shifting effects of microinjection of muscimol into the suprachiasmatic nucleus during the subjective day were blocked by a subsequent light pulse. These data suggest that GABA regulates the phase of the circadian clock through both pre- and postsynaptic mechanisms.

Animals↗
PubMed1998

Functional GABA(A) receptors on human glioma cells.

Glioma cells in acute slices and in primary culture, and glioma-derived human cell lines were screened for the presence of functional GABA(A) receptors. Currents were measured in whole-cell voltage clamp in response to gamma-aminobutyric acid (GABA). While cells from the most malignant glioma, the glioblastoma multiforme, did not respond to GABA, an inward current (under our experimental conditions with high Cl- concentration in the pipette) was induced in gliomas of lower grades, namely in 71% of oligodendroglioma cells and in 62% of the astrocytoma cells. Glioma cell lines did not express functional GABA(A) receptors, irrespective of the malignancy of the tumour they originate from. The currents elicited by application of GABA were due to activation of GABA(A) receptors; the specific agonist muscimol mimicked the response, the antagonists bicuculline and picrotoxin blocked the GABA-activated current and the benzodiazepine receptor agonist flunitrazepam augmented the GABA-induced current and the benzodiazepine inverse agonist DMCM decreased the GABA current. Cells were heterogeneous with respect to the direction of the current flow as tested in gramicidin perforated patches: in some cells GABA hyperpolarized the membrane, while in the majority it triggered a depolarization. Moreover, GABA triggered an increase in [Ca2+]i in the majority of the tumour cells due to the activation of Ca2+ channels. Our results suggest a link between the expression of GABA receptors and the growth of glioma cells as the disappearance of functional GABA(A) receptors parallels unlimited growth typical for malignant tumours and immortal cell lines.

Anti-Bacterial Agents↗
PubMed2000

Differential sensitivity to Zolpidem of IPSPs activated by morphologically identified CA1 interneurons in slices of rat hippocampus.

Hippocampal pyramidal cells express several alpha-subunits, which determine the affinity of GABAA (gamma-aminobutyric acid) receptors for benzodiazepine site ligands. This study asked whether inhibitory postsynaptic potentials (IPSPs) elicited by specific interneuronal subclasses were differentially sensitive to the alpha1-preferring agonist Zolpidem, i.e. whether different receptors mediate different inhibitory connections. Paired intracellular recordings in which the presynaptic cell was an interneuron and the postsynaptic cell a CA1 pyramid were performed in slices of adult rat hippocampus. Resultant IPSPs were challenged with Zolpidem, cells filled with biocytin and identified morphologically. IPSPs elicited by fast spiking (FS) basket cells (n = 9) were enhanced more than IPSPs elicited by regular spiking (RS) basket cells (n = 10). At FS basket cell synapses the efficacy of Zolpidem was equivalent to that of Diazepam, while RS basket cell IPSPs are enhanced 50% less by Zolpidem than by Diazepam. Thus, while alpha1 subunits may dominate at synapses supplied by FS basket cells, RS basket cell synapses also involve alpha2/3 subunits. Two bistratified cell IPSPs tested with Zolpidem did not increase in amplitude, despite powerful enhancements of bistratified cell IPSPs by Diazepam, consistent with previous indications that these synapses utilize alpha5-containing receptors. Enhancements of basket cell IPSPs by Zolpidem and Diazepam were bi- or triphasic with steep amplitude increases separated by plateaux, occurring 10-15, 25-30 and 45-55 min after adding the drug to the bath. The entire enhancement was, however, blocked by the antagonist Flumazenil (n = 7). Flumazenil, either alone (n = 3), or after Zolpidem, reduced IPSP amplitude to approximately 90% of control, suggesting that alpha4-containing receptors were not involved.

Animals↗
PubMed2003

alpha2-gamma-Aminobutyric acid (GABA)A receptors are the molecular substrates mediating precipitation of narcosis but not of sedation by the combined use of diazepam and alcohol in vivo.

Classical benzodiazepines such as diazepam are widely used tranquillisers and hypnotics in various neuropsychiatric diseases including alcohol-related disorders. One of the major drawbacks of benzodiazepine therapy, however, is an exacerbation of the sedative and hypnotic effects associated with alcohol intake, even at low doses. Even though the gamma-aminobutyric acid (GABA)A receptor complex is a common target for the actions of both classes of drugs, the molecular mechanisms underlying the enhanced pharmacological properties of the combined use of benzodiazepines and alcohol remain to be identified. The present experiments aimed at clarifying which of the GABAA receptor subtypes mediate the augmented hypnotic-like and sedative effects of combined diazepam and alcohol using the righting reflex and motor activity assays, respectively, in histidine-to-arginine point mutated mice that possess diazepam-insensitive alpha1-, alpha2-, alpha3- or alpha5-GABAA receptors. The combination of diazepam (2 or 3 mg/kg) and ethanol (3 g/kg) induced loss of righting reflex with a significantly dose-dependent increase of the latency to its full recovery in wild-type, alpha1(H101R), alpha3(H126R) and alpha5(H105R) but not in alpha2(H101R) mice. A combined treatment with diazepam (1 mg/kg) and ethanol (2.5 g/kg) precipitated motor inhibition similarly in wild-type and alpha2(H101R) mice. Responsiveness of the alpha2(H101R) mice to ethanol alone was similar to that of wild-type mice. These results demonstrate that induction of loss of righting reflex by combined diazepam and alcohol is closely dependent on the activation of the alpha2-GABAA receptors by the benzodiazepine whereas precipitation of sedation involves GABAA receptors other than the alpha2-GABAA receptors.

Anesthesia↗
PubMed1999

Complementary regulation of anaesthetic activation of human (alpha6beta3gamma2L) and Drosophila (RDL) GABA receptors by a single amino acid residue.

1. The influence of a transmembrane (TM2) amino acid located at a homologous position in human beta1 (S290) and beta3 (N289) GABAA receptor subunits and the RDL GABA receptor of Drosophila (M314) upon allosteric regulation by general anaesthetics has been investigated. 2. GABA-evoked currents mediated by human wild-type (WT) alpha6beta3gamma2L or WT RDL GABA receptors expressed in Xenopus laevis oocytes were augmented by propofol or pentobarbitone. High concentrations of either anaesthetic directly activated alpha6beta3gamma2L, but not RDL, receptors. 3. GABA-evoked currents mediated by human mutant GABAA receptors expressing the RDL methionine residue (i.e. alpha6beta3N289Mgamma2L) were potentiated by propofol or pentobarbitone with approximately 2-fold reduced potency and, in the case of propofol, reduced maximal effect. Conspicuously, the mutant receptor was refractory to activation by either propofol or pentobarbitone. 4. Incorporation of the homologous GABAA beta1-subunit residue in the RDL receptor (i.e. RDLM314S) increased the potency, but not the maximal effect, of GABA potentiation by either propofol or pentobarbitone. Strikingly, either anaesthetic now activated the receptor, an effect confirmed for propofol utilizing expression of WT or mutant RDL subunits in Schnieder S2 cells. At RDL receptors expressing the homologous beta3-subunit residue (i.e. RDLM314N) the actions of propofol were similarly affected, whereas those of pentobarbitone were unaltered. 5. The results indicate that the identity of a homologous amino acid affects, in a complementary manner, the direct activation of human (alpha6beta3gamma2L) and RDL GABA receptors by structurally distinct general anaesthetics. Whether the crucial residue acts as a regulator of signal transduction or as a component of an anaesthetic binding site per se is discussed.

Amino Acids↗
PubMed2001

GABA(A) receptor epsilon-subunit may confer benzodiazepine insensitivity to the caudal aspect of the nucleus tractus solitarii of the rat.

1. Benzodiazepines (BZ) and barbiturates both potentiate chloride currents through GABA(A) receptors to enhance inhibition. However, unlike barbiturates BZ do not impair autonomic control of heart rate. We hypothesised that BZ might not significantly potentiate GABAergic transmission in the caudal nucleus of the solitary tract (cNTS), which is critically important for mediating the baroreceptor reflex. 2. In rat brain slices the BZ agonists chlordiazepoxide and midazolam (2 and 50 microM) did not significantly enhance currents evoked by GABA in voltage-clamped cNTS neurones. Chlordiazepoxide (50 microM) reversibly increased electrically evoked IPSPs in 5/10 rostral NTS (rNTS) neurones but only in 2/10 cNTS neurones. Pentobarbitone (50-100 microM) was effective in enhancing GABA(A)-mediated responses in all NTS neurones. An inverse BZ agonist, methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM; 1 or 10 microM), failed to depress GABA-induced currents in the cNTS. 3. Microinjections of midazolam (10 and 100 microM solutions) into the cNTS did not affect the baroreceptor reflex (P > 0.2) while pentobarbitone (100 microM) significantly and reversibly depressed it (gain decrease to 53 +/- 11 % of control, P < 0.01). 4. Reverse transcriptase polymerase chain reaction revealed the presence of alpha(1), alpha(2), beta(2), beta(3) and gamma(2) GABA(A) receptor subunit mRNA in the cNTS. No alternatively spliced variants of the alpha(1)- and gamma(2)-subunits were revealed. Moreover, GABA(A) epsilon-unit mRNA was found in both the cNTS and rNTS as two alternatively spliced transcripts. 5. Immunocytochemical analysis revealed numerous GABA(A) epsilon-subunit-positive neurones within the cNTS with significantly fewer epsilon-subunit-positive cells in the rNTS. 6. As incorporation of the epsilon-subunit in recombinant GABA(A) receptors may confer BZ insensitivity we propose that the paucity of BZ actions in the cNTS is due to a high level of epsilon-subunit expression. This is the first demonstration of a possible physiological impact of the epsilon-subunit on native GABA(A) receptors.

Animals↗
PubMed2003

Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs.

Enhancement of the activation of GABAA receptors is a common feature of many sedative and hypnotic drugs, and it is probable that the GABAA receptor complex is a molecular target for these drugs in the mammalian central nervous system. We set out to elucidate the role of the two predominant (alpha1 and beta2) subunits of GABAA receptor in sedative drug action by studying mice lacking these two subunits. Both alpha1 (-/-) and beta2 (-/-) null mutant mice showed markedly decreased sleep time induced by nonselective benzodiazepine, flurazepam, and GABAA agonist, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol. The sleep time induced by the beta-selective drug etomidate was decreased only in beta2 (-/-) knockout mice. In contrast, alpha1 (-/-) mice were more resistant to the alpha1-selective drug zolpidem than beta2 (-/-) or wild-type animals. Knockout mice of both strains were similar to wild-type mice in their responses to pentobarbital. The duration of loss of the righting reflex produced by ethanol was decreased in male mice for both null alleles compared with wild-type mice, but there were no differences in ethanol-induced sleep time in mutant females. Deletion of either the alpha1 or beta2 subunits reduced the muscimol-stimulated 36Cl36 influx in cortical microsacs suggesting that these mutant mice have reduced number of functional brain GABAA receptors. Our results show that removal of either alpha1 or beta2 subunits of GABAA receptors produce strong and selective decreases in hypnotic effects of different drugs. Overall, these data confirm the crucial role of the GABAA receptor in mechanisms mediating sedative/hypnotic effects.

Animals↗