Pharmacological and behavioral characterization of cocaine-kindled seizures in mice

Rationale: Convulsions associated with cocaine toxicity are a serious aspec t of cocaine-related emergency room incidents. Seizures can result from a s ingle high dose of cocaine, and evidence is accumulating that correlates re petitive administration of sub-convulsive doses of cocaine with a decreased seizure threshold, a phenomenon known as pharmcological kindling. A murine model of cocaine kindling has not been characterized. Objectives: To deter mine the necessary and sufficient conditions for generating increased sensi tivity to the convulsive and lethal effects of cocaine and to characterize some of the basic pharmacological and behavioral consequences of this pheno menon in mice. Methods: Male, Swiss-Webster mice were given repeated inject ions of cocaine. Results: Daily administration of 60 mg/kg cocaine produced robust kindling: significant leftward shifts in the dose-effect curves for seizures were observed in cocaine-kindled mice. Cocaine kindling was endur ing as these left shifts persisted for at least 20 days, indicating possibl e permanent synaptic changes. Induction of convulsions per se, utilizing 75 mg/kg cocaine. was not sufficient to engender kindling with a non-optimal dose (40 mg/kg). However, administration of a non-kindling dose of cocaine (40 mg/kg) for as few as four occasions produced increased seizure sensitiv ity to a 60-mg/kg cocaine challenge. The lethal potencies of cocaine and me thamphetamine were significantly increased in cocaine-kindled mice. The bas eline locomotor activity of kindled mice was not different from that of non -kindled mice. However, challenge doses of cocaine revealed significant dif ferences in the vertically directed activity of kindled versus non-kindled mice. Conclusions: Overall, this study provides a description of important parameters for a model of cocaine kindling in mice that may be useful for t he elucidation of mechanisms responsible for the long-term changes in sensi tivity to cocaine and the discovery of novel pharmacological treatments.