The effects of acute administration of ethanol on t-[S-35]Butylbiclophosphorothionate (S-35-TBPS) binding measured ex vivo in unwashed membrane preparations of rat cerebral cortex were investigated. Ethanol, given i.g., decreased in a dose-related (0.5-4 g/kg) and time-dependent manner the binding of S-35-TBPS. This effect was similar to that induced by the administration of diazepam (0.5-4 mg/kg i.p.). Scatchard plot analysis of this radioligand binding revealed that ethanol, differently from diazepam, decreased the apparent affinity of S-35-TBPS recognition sites whereas it failed to change the density of these binding sites. The effect of ethanol on S-35-TBPS binding could not be reversed by the previous administration to rats of the benzodiazepine receptor antagonist, Ro 15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4]benzodiazepine-3-carboxylate). Vice versa, the benzodiazepine receptor partial inverse agonist, Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][4,4]benzodiazepine-3-carboxylate) (8 mg/kg i.p.), prevented completely ethanol-induced decrease of S-35-TBPS binding. The ability of Ro 15-4513 to prevent the action of ethanol was shared by the anxiogenic and proconvulsant beta-carboline derivatives, FG 7142 (N-methyl-beta-carboline-3-carboxamide) (12.5 mg/kg i.p.) and ethyl-beta-carboline-3-carboxylate (0.6 mg/kg i.v.), which, per se, enhanced this parameter. Moreover, ethanol (0.5-4 g/kg) was able to reverse the increase of S-35-TBPS binding elicited by the s.c. injection of isoniazid (350 mg/kg) and to clearly attenuate the severity of tonic-clonic seizures produced by this inhibitor of the GABAergic transmission. The capacity of ethanol to antagonize isoniazid-induced increase of S-35-TBPS binding was mimicked by diazepam. Moreover, the i.p. injection of a low dose of diazepam (0.25 mg/kg), which, per se, is uneffective on isoniazid-induced enhancement of S-35-TBPS binding, markedly potentiated the action of ethanol (0.5 g/kg) on this parameter. Finally, ethanol (1 g/kg), like diazepam (1 mg/kg), was effective in preventing the increase of S-35-TBPS binding induced by foot-shock stress. All together, these findings strongly suggest that ethanol, similarly to benzodiazepines and opposite to anxiogenic, proconvulsant and convulsant drugs, may exert some of its pharmacological and behavioral effects by enhancing the function of the gamma-aminobutyric acid-coupled chloride channel in the rat brain.
Ex vivo binding of tert-[S-35]butylbicyclophosphorothionate - A biochemical tool to study the pharmacology of ethanol at the gamma-aminobutyric acid-coupled chloride channel
Sanna E;CONCAS, ALESSANDRA;SERRA, MARIANGELA;
1991-01-01
Abstract
The effects of acute administration of ethanol on t-[S-35]Butylbiclophosphorothionate (S-35-TBPS) binding measured ex vivo in unwashed membrane preparations of rat cerebral cortex were investigated. Ethanol, given i.g., decreased in a dose-related (0.5-4 g/kg) and time-dependent manner the binding of S-35-TBPS. This effect was similar to that induced by the administration of diazepam (0.5-4 mg/kg i.p.). Scatchard plot analysis of this radioligand binding revealed that ethanol, differently from diazepam, decreased the apparent affinity of S-35-TBPS recognition sites whereas it failed to change the density of these binding sites. The effect of ethanol on S-35-TBPS binding could not be reversed by the previous administration to rats of the benzodiazepine receptor antagonist, Ro 15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4]benzodiazepine-3-carboxylate). Vice versa, the benzodiazepine receptor partial inverse agonist, Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][4,4]benzodiazepine-3-carboxylate) (8 mg/kg i.p.), prevented completely ethanol-induced decrease of S-35-TBPS binding. The ability of Ro 15-4513 to prevent the action of ethanol was shared by the anxiogenic and proconvulsant beta-carboline derivatives, FG 7142 (N-methyl-beta-carboline-3-carboxamide) (12.5 mg/kg i.p.) and ethyl-beta-carboline-3-carboxylate (0.6 mg/kg i.v.), which, per se, enhanced this parameter. Moreover, ethanol (0.5-4 g/kg) was able to reverse the increase of S-35-TBPS binding elicited by the s.c. injection of isoniazid (350 mg/kg) and to clearly attenuate the severity of tonic-clonic seizures produced by this inhibitor of the GABAergic transmission. The capacity of ethanol to antagonize isoniazid-induced increase of S-35-TBPS binding was mimicked by diazepam. Moreover, the i.p. injection of a low dose of diazepam (0.25 mg/kg), which, per se, is uneffective on isoniazid-induced enhancement of S-35-TBPS binding, markedly potentiated the action of ethanol (0.5 g/kg) on this parameter. Finally, ethanol (1 g/kg), like diazepam (1 mg/kg), was effective in preventing the increase of S-35-TBPS binding induced by foot-shock stress. All together, these findings strongly suggest that ethanol, similarly to benzodiazepines and opposite to anxiogenic, proconvulsant and convulsant drugs, may exert some of its pharmacological and behavioral effects by enhancing the function of the gamma-aminobutyric acid-coupled chloride channel in the rat brain.
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