Clinical evidence suggests that cocaine abusers have an increased incidence of Human Immunodeficiency Virus (HIV) infection and HIV-related myocarditis. These data indicate a causal relationship between cocaine use and myocarditic viral pathogenicity, which we plan to investigate in this proposal by studying a readily reproducible murine model of viral myocarditis using Encephalomyocarditis (EMC) Virus as a surrogate for HIV. Our central, unifying hypothesis is that cocaine-induced exacerbation of viral myocarditis is an indirect effect mediated by drug-induced enhancement of catecholamine concentrations in the heart. When catecholamines from the systemic circulation and local release at cardiac sympathetic nerve endings reach toxic concentrations, they may compromise cellular integrity and specific cellular and humoral body defenses, making the myocardium more susceptible to infection. We will test this hypothesis by means of seven specific aims that employ techniques currently available in the laboratories of the collaborating Investigators. I. We will determine whether chronic cocaine treatment alone can induce myocarditis, necrosis or apoptosis. II. We will test the hypothesis that exposure to cocaine can enhance the susceptibility of mice to myocarditis after virus exposure. III. We will determine whether cocaine can enhance persistence of the viral genome. IV. We will determine whether cocaine can impair specific body defenses against viral infection by measuring T cell function and IgM levels. V. We will determine whether the adrenergic or local anesthetic properties of cocaine are responsible for increased viral myocarditic pathogenicity. VI. We will test the hypothesis that catecholamine-mediated stimulation of the adrenergic receptors on myocytes is responsible for increased viral myocarditic pathogenicity by use of sympatholytic agents. VII. We will demonstrate that the enhancement of viral myocarditic pathogenicity produced by cocaine is synergistic with other drugs, foods and activities that increase catecholamine levels. Taken together, these results will provide new mechanistic information about the etiology of viral myocarditis in cocaine abusers, should allow us to identify distinct risk factors for developing myocarditis in the general population, and may provide a rational basis for predicting who may place themselves at increased additional risk by the use of cocaine, particularly among the HIV-exposed population.
