Anticonvulsant modification of cocaine-induced toxicity in the rat.

A number of anticonvulsant drugs were studied for their efficacy in preventing seizures and death from intoxication with cocaine. Rats were first pretreated with the test drug then subjected to large doses of intraperitoneally administered cocaine. In this model, control animals developed seizures in approximately 6 min, followed by death in approximately 10 min. Statistically significant protection against seizures and death was afforded by pretreatment with diazepam, phenobarbitol and the blocker of the uptake of gamma-aminobutyric acid (GABA), SKF 100330A. Only partial protection was afforded by the N-methyl-d-aspartate (NMDA) antagonist MK 801, the benzodiazepine antagonist, flumazenil and the novel aminobenzamide, LY 201116. Valproic acid and phenytoin demonstrated limited efficacy against cocaine-induced seizures, without consistently reducing death. Carbamazepine and ethosuximide did not significantly reduce seizures or death. In this model of acute cocaine toxicity, the anticonvulsants diazepam, phenobarbital and the blocker of the uptake of GABA, SKF 100330A were the most effective in protecting rats from cocaine-induced seizures and death. These data offer insight into future approaches for the treatment of patients with the acute toxic effects of cocaine.