Pharmacogenetic assessment of the effects of carbamazepine on cocaine-kindled and cocaine-induced seizures

Abstract

The effects of chronic carbamazepine (CBZ) on the development and expression of cocaine-kindled seizures and seizures produced by an acute injection of cocaine were evaluated in BALB/cByJ, C57B1/6J and SJL/J mice. The repeated administration of a subconvulsant dose of cocaine initially resulted in the development of an increased sensitivity to the convulsant effects of cocaine in the three strains. Chronic, dietary carbamazepine attenuated this initial sensitization to cocaine-induced seizures. While the continued administration of cocaine resulted in a relatively permanent sensitization to cocaine-induced seizures among SJL mice, tolerance to cocaine-induced seizures ultimately developed among C57 mice and to a lesser degree among BALB mice. Genetic factors were found to mediate the effects of chronic CBZ on the development of sensitization and/or tolerance to the convulsant effects of cocaine. Among BALB mice, chronic CBZ appears to have eliminated the development of tolerance to cocaine-induced seizures and allowed an underlying sensitization to be manifest. Among SJL mice, however, the sensitization observed following repeated cocaine injections was reduced, but not eliminated. Genetic factors were also found to be associated with the effects of CBZ on seizures induced by the acute administration of cocaine. BALB and C57 mice, but not SJL mice, chronically treated with dietary CBZ were less susceptible to a consulvant dose of cocaine than their corresponding dietary controls for at least 72 h after stopping CBZ administration. In addition, there were genotype-specific lethal effects associated with the concurrent administration of CBZ and cocaine.