Antagonizing the anticonvulsant effect of ethanol using drugs acting at the benzodiazepine/GABA receptor complex

Abstract

The ability of various benzodiazepine receptor ligands to antagonize the anticonvulsant action of ethanol was investigated using intravenous infusion of the GABA antagonist bicuculline. The partial inverse agonists FG 7142, RO 15-4513 and RO 15-3505 produced dose-related reductions in seizure threshold. These compounds also partially reversed the anticonvulsant action of ethanol. However, the magnitude of the effects in each case was only equivalent to the reduction in seizure threshold caused by each compound when administered alone. This is the proconvulsant effect of each compound merely subtracted from the anticonvulsant effect of ethanol. ZK 93426, a benzodiazepine receptor antagonist which alone failed to alter seizure threshold, did not affect the anticonvulsant action of ethanol. Both RO 15-4513 and RO 15-3505 also lowered the seizure threshold of barbiturate-treated mice, again in a subtractive fashion. The ability of RO 15-4513 and other inverse agonists to antagonize the anticonvulsant effect of ethanol appears to result from their intrinsic proconvulsant properties.