Genetic factors influence changes in sensitivity to the convulsant properties of cocaine following chronic treatment.

Repeated administration of doses of cocaine below the threshold for seizure induction results in the development of an increased susceptibility to cocaine-induced seizures (cocaine-kindling). Genetic differences in susceptibility to cocaine-kindled seizures were evaluated in 4 inbred mouse strains and compared with susceptibility to seizures induced by acute administration of cocaine. The acute administration of cocaine produced convulsant activity in mice from all 4 genotypes, however, there were significant differences in the dose of cocaine required to induce seizures. C57 mice were highly susceptible and SJL mice highly resistant to convulsions induced by acute administration of cocaine, while BALB and DBA mice showed an intermediate degree of seizure susceptibility. The repeated administration of subconvulsant doses of cocaine resulted in rapid sensitization to cocaine-induced seizures. The 4 strains differed in the rate at which sensitization to cocaine-induced seizures developed, with the SJL strain being most sensitive and the C57 strain the least sensitive to the cocaine-kindling process. The susceptibility of the 4 strains to cocaine kindling was virtually opposite to their susceptibility to seizures induced by the acute administration of cocaine, suggesting that different mechanisms may be involved in the control of acute and kindled seizures did not persist upon further exposure to cocaine. Following a period of increased sensitivity to cocaine-induced seizures, tolerance to the convulsant properties of cocaine developed among C57, BALB and DBA mice. Only among the SJL mice did the development of a kindled state persist upon repeated exposure to cocaine. These differences emphasize the potential importance of inheritance in determining the effects of cocaine and suggest novel approaches to understanding the the mechanisms underlying the effects of cocaine.