A pharmacogenetic evaluation of the role of local anesthetic actions in the cocaine kindling process

Abstract

Repeated administration of subconvulsant doses of lidocaine or cocaine results in the development of an increased susceptobility to seizures induced by the two drugs (pharmacological kindling). It has been hypothesized that the local anesthetic properties of cocaine are responsible for its convulsant and epileptogenic actions. As genetic factors appear to mediate acute sensitivity to the convulsant properties of cocaine and the development of cocaine-kindled seizures, the present studies used a pharmacogenetic approach to address this question further. The convulsant effects of lidocaine were evaluated in BALB, C57, DBA and SJL mice and compared with previous studies evaluating cocaine-induced seizures. We have evaluated the development of lidocaine- versus cocaine-kindled seizures and the effects of repeated treatment with cocaine or lidocaine on subsequent lidocaine seizure susceptibility in three of these inbred maouse strains. As observed for cocaine, genetic factors influence the convulsant properties of lidocaine; however, the differences between the strains of mice in susceptibility to lidocaine-induced seizures (SJL>DBA=BALB=C57) did not parallel those seen for cocaine-induced seizures (C57 >DBA=BALB>SJL). Similarly, the time course for the expression of kindled seizures and the differences between the various inbred strains were not the same for lidocaine kindling and cocaine kindling. However, depending on the genetic background of the subject, the repeated administration of lidocaine, or cocaine, resulted in the development of sensitization or tolerance to the convulsant effects of lidocaine in an identical manner. That is, within each of the inbred strains, the effect of a convulsant dose of lidocaine was the same 72 h after the end of 5 days of cocaine treatment as after 5 days of lidocaine treatment. These results suggest that the local anethetic properties of cocaine appear to be responsible, at least in part, for its convulsant and epileptogenic properties. However, additional actions of cocaine appear to obscure some of the genetic similarities in response to lidocaine and cocaine.