The Efficacy of Exercise to Attenuate Cocaine Relapse is Associated with Changes in Bdnf and Altered by Sex and Estrous Cycle Phase.

Exercise is a potential intervention for cocaine addiction that has shown promise in both human and animal studies. However, the conditions that produce the most efficacious response have yet to be determined. Thus, the goal of this dissertation is to determine the exercise conditions that produce the most efficacious response in a preclinical model of cocaine addiction. The overall hypothesis is that exercise will be an effective intervention that reduces cocaine relapse vulnerability and blocks subsequent neuroadaptations that develop over an abstinence period. Although exercise is known to induce widespread effects in the brain and act on many different signaling pathways (e.g., norepinephrine, opioid, serotonin, endocannabinoid, cortisol); this dissertation will focus on its effects on brain derived neurotrophic factor (Bdnf) exon IV expression in the prefrontal cortex (PFC) as potential mechanism given that it is a marker of epigenetic regulation implicated in cocaine relapse and known to be regulated by exercise.
Chapter I of this dissertation provides background on the behavior and underlying neurobiology (i.e. epigenetic regulation of Bdnf) of cocaine addiction. This chapter also provides evidence to support the hypothesis that the efficacy of exercise for preventing relapse vulnerability is associated with alterations in Bdnf expression. Chapter II demonstrates that the efficacy of wheel running, an animal model of exercise, is dose-dependent, with greatest effects following longer access, and is associated with epigenetic regulation of Bdnf exon IV expression in the PFC. Chapter III demonstrates that early, but not late, access to a running wheel during abstinence attenuates subsequent cocaine-seeking. Chapter IV demonstrates that the efficacy of wheel running is influenced by sex, estrous cycle phase, and dose conditions. In this chapter I demonstrate that males are more sensitive to the beneficial effects of wheel running, while in females longer access conditions is required to override estrus-induced vulnerability. Overall, the data presented in this dissertation establishes exercise as a promising intervention that has the ability to reduce cocaine relapse vulnerability likely by blocking cocaine-induced neuroadaptations (e.g. Bdnf) that develop over an abstinence period.