Non-psychoactive cannabis extract promotes extinction and reduces reinstatement by priming dose in smoked...

The therapeutic potential of Cannabis sativa L. and cannabidiol (CBD) for substance use disorders is being actively investigated using murine addiction models. However, the efficacy of cannabis or its constituents in attenuating dependence indicators associated with smoked cocaine consumption remains unclear. This study employed a Conditioned Place Preference (CPP) paradigm using anhydroecgonine methyl ester and cocaine (AEME-COC) as the reinforcing agent to model smoked cocaine consumption in mice. The model was utilized to evaluate the preclinical efficacy of a non-psychoactive cannabis extract (NPCE) and CBD on extinction parameters and reinstatement induced by stress and priming doses. Experiment 1 compared conditioning phase (Cond) and extinction times between subjects administered cocaine and those receiving AEME-COC. Experiment 2 investigated the effects of CBD and NPCE on extinction latency in AEME-COC-induced CPP. Experiment 3 examined the competitive 5-HT1A receptor antagonist WAY-100,135 and CB2 receptor inverse agonist AM630 on NPCE-mediated inhibition of stress-induced and priming-induced reinstatement of AEME-COC-induced CPP. The results showed that subjects administered cocaine exhibited greater exploration of the conditioned compartment during Cond compared to those administered AEME-COC, with the latter group displaying prolonged extinction latency (Experiment 1). NPCE, but not CBD, significantly reduced the extinction latency of AEME-COC-induced CPP (Experiment 2). In Experiment 3, NPCE selectively inhibited priming-induced reinstatement but did not affect stress-induced reinstatement. The 5-HT1A receptor attenuated NPCE's inhibitory effects on priming-induced reinstatement, whereas the CB2 receptor had no significant modulatory impact on this indicator. These findings suggest that NPCE influences smoked cocaine dependence indicators primarily through serotonergic receptor modulation.