The purpose of this project is to use a pharmacogenetic approach to evaluate individual differences in response to chronic administration of drugs of abuse or drugs proposed for the treatment of drug abuse. Genetic differences in response to the convulsant and epileptogenic effects of cocaine have been demonstrated by examining the development of increased susceptibility to the seizure inducing properties of cocaine following repeated administration of the drug (pharmacological kindling). Genetically distinct strains of mice that differ quantitatively and qualitatively in their response to chronic cocaine have been identified and are being employed to study the mechanisms underlying the effects of long-term cocaine use and to assess possible treatments for cocaine toxicity. We have demonstrated that individual differences in response to the epileptogenic effects of cocaine are associated with its local anesthetic properties. Evaluation of the ability of carbamazepine to modulate the convulsant and epileptogenic effects of cocaine have shown that chronic carbamazepine attenuates the development of increased sensitivity to cocaine-induced seizures in a genotype-specific manner. In addition to genetic difference, the regimen of carbamazepine administration appears to be important in determining its ability to attenuate cocaine's effects. These studies also revealed that chronic carbamazepine administration, in conjunction with chronic cocaine treatment, has lethal consequences in certain genotypes. Assessment of the biochemical mechanisms underlying the changes observed following chronic cocaine treatment are presently being conducted. Preliminary results suggest that cocaine kindling is associated with a downregulation of GABAergic function. Genetic differences in response to pharmacological kindling with a benzodiazepine inverse agonist have also been demonstrated and are being compared with the differences observed for cocaine kindling. Assessments of biochemical changes associated with chronic opiate treatment are also being conducted.
