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 (SA) escalates intake in male rats. Here we test the hypothesis that stress-induced escalation of cocaine SA requires CB1 cannabinoid receptor signaling. Male Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during 2-h sessions comprised of four 30-min SA components separated by 5-min shock sequences or 5-min shock-free periods for 14 days. Footshock produced an escalation of cocaine SA that persisted following shock removal. Systemic administration of the cannabinoid receptor type 1 (CB1R) antagonist, 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 SA, regardless of stress history, increases 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 SA. AM251 attenuated reinstatement only in rats with a stress history. Altogether, these data demonstrate that mesolimbic CB1R signaling is required to escalate intake and heighten relapse susceptibility and suggest that repeated stress at the time of cocaine use enhances mesolimbic CB1R signaling through a currently unknown mechanism.