The primary objective of the proposed research is to identify the central nervous system (CNS) cocaine binding sites influencing genetic vulnerability to toxic effects of cocaine, specifically the acute seizurgenic effects of cocaine. The proposed research will utilize genetically distinct strains of mice to assess the relationship between sensitivity to cocaine-induced seizurgenesis and the regional densities of specific CNS receptors as determined by receptor binding techniques. The focus will be on specific brain receptors which have been previously shown to be associated with the initiation of cocaine-induced seizures. These CNS receptors include serotonin transporters and serotonergic 5HT1, 5HT2, 5HT3, muscarinic M1, and sigma receptors. Another objective of this study is assessment of the effectiveness of specific pharmacological interventions in inhibiting or blocking the seizurgenic effects of cocaine in different strains of mice. Emphasis will be given to systematically and comprehensively studying the effectiveness of serotonergic, muscarinic and sigma receptor ligands over a range of doses. The proposed studies are important because 1) brain receptors associated with genetic vulnerability to toxic effects of cocaine will be elucidated; 2) the influence of interactions between receptor systems within specific brain regions on cocaine-induced seizures will be determined; 3) the effectiveness of specific pharmacological interventions in decreasing the incidence of cocaine-induced seizures observed in genetically distinct mouse strains will be determined; and 4) the results of these studies will substantially increase our understanding of high dose cocaine toxicity. These studies are a continuation of previous studies from our laboratory indicating the cocaine binding sites associated with the potency of cocaine and related compounds to produce seizures, and will contribute to a systematic analysis of brain receptors which mediate the many and varied effects of cocaine. In addition, these studies will determine whether any of these same cocaine binding sites may confer genetic vulnerability to cocaine- induced convulsions. Thus, these data will contribute to a body of knowledge that will aid in the study of the complex problems of cocaine abuse and toxicity.
