Medial prefrontal cannabinoid CB₁ receptors modulate consolidation and extinction of cocaine-associated memory in mice

Rationale: Cannabinoid CB₁ receptors are implicated in various forms of learning and memory, including acquisition and reinstatement of cocaine-associated memory. However, roles of CB₁ receptors in consolidation and extinction processes of cocaine-associated memory and the brain areas potentially involved remain unknown. Objective: This study examined the effect of rimonabant, a CB₁ receptor antagonist, administered systemically or directly into the medial prefrontal cortex (mPFC) on memory consolidation and extinction of cocaine-induced conditioned place preference (CPP). Materials and methods: Male C57BL/6J mice were trained to acquire cocaine-induced CPP. Rimonabant (0.1-3 mg/kg, i.p. or 1.5 μg bilaterally in the mPFC) or vehicle was administered either immediately after each CPP training (consolidation) or forced extinction (extinction) trial. Cocaine-induced CPP was tested after training, extinction, or cocaine priming. Results: Systemic or intra-mPFC administration of rimonabant impaired consolidation of CPP induced by a high dose (20 or 40 mg/kg) of cocaine but facilitated that induced by a low dose (2.5, 5, or 10 mg/kg). Moreover, systemic or intra-mPFC administration of rimonabant enhanced extinction of CPP memory induced by a high-dose (20 mg/kg) cocaine. Conclusion: Our results suggest that antagonism of CB₁ receptors in the mPFC bidirectionally modulates consolidation but facilitates extinction of cocaine-induced CPP memory. Therefore, CB₁ receptor blockade with the concomitant extinction behavioral procedure may hint important therapeutic intervention strategies for the heavy cocaine addicts in a clinical setting.