Repeated footshock stress enhances cocaine self-administration in male and female rats: Role of the cannabinoid receptor 1

Stress is a significant contributor to the development and progression of substance use disorders (SUDs) and is problematic as it is unavoidable in daily life. Therefore, it is important to understand the neurobiological mechanisms that underlie the influence of stress on drug use. We have previously developed a model of rat self- administration that employs an electric footshock stressor at the time of cocaine self-administration, resulting in an enhancement of cocaine self-administration. This stress enhancement of cocaine intake involves neurobiological mediators of stress and reward such as cannabinoid signaling. However, all of this work has been conducted in male rats. Here we test the hypothesis that repeated daily stress enhances cocaine self-administration in male and female rats. We further hypothesize that cannabinoid receptor 1 (CB1R) signaling is recruited by repeated stress to influence cocaine self-administration in both male and female rats. Male and female SpragueDawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during a modified short-access paradigm wherein the 2 hr access was separated into four 30 min self-administration blocks separated by four 5 min drug free periods. Footshock stress significantly increased cocaine self-administration similarly in both male and female rats. Females displayed greater stress-enhanced time-out, non-reinforced responding, and stress-specific "front-loading" behavior. In males, systemic administration of a CB1R inverse agonist/antagonist Rimonabant only attenuated cocaine intake in rats with a history of combined repeated stress and cocaine self-administration. However, in females, Rimonabant attenuated cocaine self-administration in the no stress control group but only at the highest dose of Rimonabant (3 mg/kg, i.p.) suggesting that females show a greater sensitivity to CB1R antagonism. However, female rats with a history of stress showed even greater sensitivity to CB1R antagonism as both doses of Rimonabant (1, 3 mg/kg) attenuated cocaine self-administration in stress-enhanced rats, similar to males. Altogether these data demonstrate that stress can produce significant changes in cocaine self-administration and suggests that repeated stress at the time of cocaine self-administration recruits CB1Rs to regulate cocaine-taking behavior across sexes.