Effects of wheel running on cocaine seeking in rats: behavior and neurobiology

Abstract

Cocaine addiction is a pervasive public health problem, but currently there are no highly effective treatments to reduce its extent or duration. Emerging research in humans and animals suggests that aerobic exercise may decrease drug use and prevent relapse. This set of experiments focused on the use of exercise as a behavioral treatment for cocaine addiction using rodent (rat) models of relapse. Concurrent access to a voluntary running wheel decreased reinstatement of cocaine-seeking behavior in response to a cocaine injection (Experiments 1-3), cocaine-paired cues (Experiment 2-3), and the pharmacological stressor yohimbine (Experiment 2). Wheel running during the withdrawal period also prevented incubation of cocaine seeking or time-dependent increases in reactivity to cocaine-paired cues, a situation that often precipitates relapse (Experiment 5). Further, using pharmacological treatments such as progesterone (Experiment 2) or atomoxetine (Experiment 3) in combination with wheel running led to an additive treatment effect, suggesting a larger role for exercise as a singular or adjunct treatment in the prevention of cocaine relapse. While these behavioral models have revealed exercise to be an efficacious method to attenuate cocaine-motivated behaviors, long-term wheel running also changed cocaine-induced activation of brain reward circuitry (Experiment 4). Using c-Fos immunohistochemistry to evaluate neuronal activation, results demonstrated that exercising and control rats showed differential activation of the nucleus accumbens, caudate putamen, and prefrontal cortex in response to an acute cocaine injection. These results suggest that exercise may alter reactivity to cocaine by inducing plasticity in the mesolimbic dopamine system. Overall, results across these experiments have demonstrated that aerobic exercise has the ability to attenuate activation of the neurobiological substrates of addiction in addition to robustly reducing relapse to cocaine-seeking behavior.