Aerobic exercise produces a host of psychological effects that are negatively correlated with substance abuse and dependence. For instance, long-term voluntary exercise increases measures of self-esteem and well-being, and decreases measures of depression and anxiety. Moreover, epidemiological studies report that participation in activities that promote physical fitness is associated with a lower incidence of tobacco and substance use among adolescent populations. Despite these promising findings, remarkably few clinical and laboratory stories have specifically examined a potential causal relationship between aerobic exercise and a decreased propensity to engage in drug-seeking behavior. In the proposed series of studies, we will evaluate the efficacy of aerobic exercise to (1) attenuate the escalation of cocaine intake under extended-access conditions, (2) prevent the dysregulated patterns of drug intake that emerge during a prolonged binge, and (3) decrease cocaine-primed and cue-induced reinstatement following a period of abstinence. This project will be the first systematic examination of the effects of exercise on a range of behavioral processes that are believed to be involved in the etiology of addictive behavior. Furthermore, these studies will examine the effects of exercise in both male and female subjects, and determine whether there are sex differences in these effects. As part of its translational appeal, the project will examine exercise as both a preventative intervention (i.e., before drug use has been initiated) and as a treatment intervention (i.e., after self-administration has been firmly established). Collectively, these studies should significantly advance our knowledge on how physical activity interacts with the endogenous reward system to alter sensitivity to cocaine and provide critical guidance for the design and execution of future studies examining the effects of exercise in clinical populations. PUBLIC HEALTH RELEVANCE: Aerobic exercise has been recommended as a potential treatment for substance abuse, but very little research has been conducted on its ability to reduce drug self-administration. The purpose of this project is to examine the effectiveness of aerobic exercise to (1) reduce the escalation of cocaine intake under free-access conditions, (2) prevent the high rates of cocaine intake during a prolonged binge, and (3) decrease the reinstatement of drug-seeking behavior following exposure to cocaine or cocaine-related cues. This project will be the first systematic examination of the effects of exercise on a range of behavioral processes that are believed to be involved in the development of substance use disorders.