Recent clinical reports describing cocaine associated rhabdomyblysis and acute renal failure and the deaths of athletes following cocaine use has raised questions on the mechanism(s) responsible for cocaine's toxicity on cardiac and skeletal muscle. The cardiotoxic effects of cocaine have been extensively studied, however very little is known about the underlying mechanism(s) of cocaine's toxicity on skeletal muscle. It can be postulated that cocaine-induced muscle damage could be mediated via vasoconstriction in muscle vasculature leading to ischemia. The subsequent reperfusion of this tissue could result in the formation of free radicals which cause lipid peroxidation. With chronic cocaine use, repeated ischemia-reperfusion bouts would occur in skeletal muscle, which if not counterbalanced by protective mechanisms, could lead to muscle damage or rhabdomyolysis. Cocaine's toxicity, particularly in trained individuals, could be the result of the further generation of free radicals in muscle that occurs during exercise. In addition, exercise could alter the pharmacokinetics and disposition of cocaine and/or its metabolites. Cocaine and its metabolites, norcocaine and benzoylecgonine, have been shown to cause vasoconstriction and toxicity in other tissues. The specific hypotheses to be tested are: 1) whether muscle damage results from free radical formation and lipid peroxidation following cocaine administration, 2) whether this toxicity is exacerbated upon exercise training which would increase free radical formation and modify cocaine's pharmacokinetic profile, and 3) whether this toxicity is exacerbated by multiple cocaine administration through increased drug and/or metabolite tissue accumulation.
The specific aims of this project are: l) to determine the causal association between cocaine SINgLE dose pharmacokinetics and metabolite profile with skeletal muscle free radical formation and lipid peroxidation in exercised and sedentary male Fisher 344 rats and 2) to determine the causal association between cocaine MULTIPLE dose pharmacokinetics and metabolite profile with skeletal muscle free radical formation and lipid peroxidation in exercised and sedentary male Fisher 344 rats.
