Cocaine abuse in the United States has become a major public health problem. Published reports demonstrate that cocaine can produce toxic effects in humans and experimental animals. Studies concerning the nature and mechanisms of these toxic effects have suggested that cocaine may modify cell function by either interacting directly with target cells and, thereby, affecting membrane function and ion flux, and/or by indirectly affecting target cell function through mechanisms involving drug induced modulation of endogenous catecholamine metabolism. A few reports in the literature and our preliminary data suggest that cocaine has a direct effect on lymphocyte function which is further modified by the addition of catecholamines. The experiments proposed in this application are designed to test the hypothesis that cocaine can directly influence T lymphocyte function and also that catecholamines can modify these cocaine effects. Studies are also contemplated which will explore some of the possible molecular mechanisms involved in the cocaine/catecholamine-induced changes of T lymphocyte function. We will examine the influence of cocaine on the lectin and anti-CD3 mediated proliferation response of cultured mouse and human T lymphocyte populations and cultured T lymphocyte clones. Next, related studies will be performed examining the influence of various adrenergic substances on cocaine-induced modification of T lymphocyte proliferation. Since T lymphocyte proliferation is driven mainly by IL 2 production and IL 2 receptor expression, we will analyze drug effects on IL 2 production and expression of high and low affinity IL 2 receptors. To further elucidate the mechanisms of drug effects on lymphocyte function, we will also examine the influence of cocaine/catecholamine on phorbol ester mediated activation of lymphocytes. We will extend these studies by examining the effect of drugs on certain key molecular events in lymphocyte activation such as alteration of cytosolic calcium levels, membrane phospholipid metabolism and cellular protein phosphorylation activity. These studies will answer questions concerning the direct effect of cocaine on lymphocyte proliferation and the involvement of adrenergic agents in modifying the cocaine effect. They will also enhance our understanding of the molecular basis for the modulation by cocaine of T lymphocyte function and will provide a greater understanding of the molecular events involved in the regulation of T lymphocyte activation and signal transduction.
