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.

Enhanced CRFR1-Dependent Regulation of a Ventral Tegmental Area to Prelimbic Cortex Projection Establishes Susceptibility to Stress-Induced Cocaine Seeking.

The ability of stress to trigger cocaine seeking in humans and rodents is variable and is determined by the amount and pattern of prior drug use. This study examined the role of a corticotropin releasing factor (CRF)-regulated dopaminergic projection from the ventral tegmental area (VTA) to the prelimbic cortex in shock-induced cocaine seeking and its recruitment under self-administration conditions that establish relapse vulnerability. Male rats with a history of daily long-access (LgA; 14 × 6 h/d) but not short-access (ShA; 14 × 2 h/d) self-administration showed robust shock-induced cocaine seeking. This was associated with a heightened shock-induced prelimbic cortex Fos response and activation of cholera toxin b retro-labeled VTA neurons that project to the prelimbic cortex. Chemogenetic inhibition of this pathway using a dual virus intersectional hM4Di DREADD (designer receptor exclusively activated by designer drug) based approach prevented shock-induced cocaine seeking. Both shock-induced reinstatement and the prelimbic cortex Fos response were prevented by bilateral intra-VTA injections of the CRF receptor 1 (CRFR1) antagonist, antalarmin. Moreover, pharmacological disconnection of the CRF-regulated dopaminergic projection to the prelimbic cortex by injection of antalarmin into the VTA in one hemisphere and the D1 receptor antagonist, SCH23390, into the prelimbic cortex of the contralateral hemisphere prevented shock-induced cocaine seeking. Finally, LgA, but not ShA, cocaine self-administration resulted in increased VTA CRFR1 mRNA levels as measured using in situ hybridization. Altogether, these findings suggest that excessive cocaine use may establish susceptibility to stress-induced relapse by recruiting CRF regulation of a stressor-responsive mesocortical dopaminergic pathway.SIGNIFICANCE STATEMENT Understanding the neural pathways and mechanisms through which stress triggers relapse to cocaine use is critical for the development of more effective treatment approaches. Prior work has demonstrated a critical role for the neuropeptide corticotropin releasing factor (CRF) in stress-induced cocaine seeking. Here we provide evidence that stress-induced reinstatement in a rat model of relapse is mediated by a CRF-regulated dopaminergic projection from the ventral tegmental area (VTA) that activates dopamine D1 receptors in the prelimbic cortex. Moreover, we report that this pathway may be recruited as a result of daily cocaine self-administration under conditions of extended drug access/heightened drug intake, likely as a result of increased CRFR1 expression in the VTA, thereby promoting susceptibility to stress-induced cocaine seeking.