Role of mesolimbic cannabinoid receptor 1 in stress-driven increases in cocaine self-administration in male rats

Stress is prevalent in the lives of those with substance use disorders (SUDs) and influences SUD outcomes. Understanding the neurobiological mechanisms through which stress promotes drug use is important for the development of effective SUD interventions. We have developed a model wherein exposure to a stressor, uncontrollable electric footshock, daily at the time of cocaine self-administration escalates intake in male rats. Here we test the hypothesis that stress-induced escalation of cocaine self-administration requires the CB1 cannabinoid receptor. Male Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during 2-h sessions comprised of four 30-min self-administration components separated by 5-min shock sequences or 5-min shock-free periods for 14 days. Footshock produced an escalation of cocaine self-administration that persisted following shock removal. Systemic administration of the cannabinoid receptor type 1 (CB1R) antagonist/inverse agonist, AM251, attenuated cocaine intake only in rats with a history of stress. This effect was localized to the mesolimbic system, as intra-nucleus accumbens (NAc) shell and intra-ventral tegmental area (VTA) micro-infusions of AM251 attenuated cocaine intake only in stress-escalated rats. Cocaine self-administration, regardless of stress history, increased CB1R binding site density in the VTA, but not NAc shell. Following extinction, cocaine-primed reinstatement (10 mg/kg, ip) was increased in rats with prior footshock during self-administration. AM251 attenuated reinstatement only in rats with a stress history. Altogether, these data demonstrate that mesolimbic CB1Rs are required to escalate intake and heighten relapse susceptibility and suggest that repeated stress at the time of cocaine use regulates mesolimbic CB1R activity through a currently unknown mechanism.