DESCRIPTION: Applicant's Abstract Epidemiological analysis of cocaine-related deaths in Metropolitan Dade County, Florida from 1978 - 1993 has revealed a number of important findings regarding the temporal trends and risk factors surrounding cocaine-related sudden death. The epidemiological findings indicate only 6 to 11 % of the cocaine overdose cases had significant underlying coronary artery disease or ventricular hypertrophy, suggesting that these risk factors may account for only a subgroup of the cocaine-related sudden deaths. High blood levels of cocaine are associated with seizures. However, the percentage of cocaine overdose deaths with seizures has declined during the epidemic. This pattern is consistent with toxicology findings which demonstrate that median plasma concentrations of cocaine associated with sudden death have declined annually. Polydrug abuse of cocaine and heroin and other opiates accounts for less than 11% per cent per year of the overdose deaths, analysis of the ethanol detections show that many subjects had combined cocaine with alcohol prior to death. One of the most serious psychiatric sequelae of cocaine abuse is excited delirium, which is associated with agitation, hyperthermia and sudden death. The annual incidence of cocaine delirium and sudden death cases in Miami has continued to closely follow the epidemic curve for cocaine overdose deaths in Dade County, Florida. Taken together, these observations suggest that different mechanisms may contribute to the potentially lethal neurologic, respiratory, and cardiovascular effects of cocaine in decedents with comparatively low concentration of cocaine in blood. Our hypothesis is that cocaine abuse results in abnormal activity in cortical, limbic and brainstem centers which control cardiac function. Abnormal neurochemical transmission in these pathways may, in addition to the direct cardiotoxic effects of cocaine, lead to the pathogenesis of cocaine-related sudden death. This proposal requests support to continue our ongoing studies aimed at characterizing neuroreceptor and neurotransporter regulation in the human brain postmortem from cocaine overdose deaths. The proposed studies in the human brain may pinpoint the neurotransmitter systems regulating cocaine's convulsant, respiratory and cardiovascular effects, suggest differences in neural recognition sites that mediate tolerance and sensitization, and provide a basis for pharmacotherapeutic interventions to treat cocaine toxicity.