Differential effect of opioid and cannabinoid receptor blockade on heroin-seeking reinstatement and cannabinoid substitution in heroin-abstinent rats.

BACKGROUND AND PURPOSE Opioids and cannabinoids interact in drug addiction and relapse. We investigated the effect of the opioid receptor antagonist naloxone and/or the cannabinoid CB(1) receptor antagonist rimonabant on cannabinoid-induced reinstatement of heroin seeking and on cannabinoid substitution in heroin-abstinent rats. EXPERIMENTAL APPROACH Rats were trained to self-administer heroin (30 µg·kg(-1) per infusion) under a fixed-ratio 1 reinforcement schedule. After extinction of self-administration (SA) behaviour, we confirmed the effect of naloxone (0.1-1 mg·kg(-1)) and rimonabant (0.3-3 mg·kg(-1)) on the reinstatement of heroin seeking induced by priming with the CB(1) receptor agonist WIN55,212-2 (WIN, 0.15-0.3 mg·kg(-1)). Then, in a parallel set of heroin-trained rats, we evaluated whether WIN (12.5 µg·kg(-1) per infusion) SA substituted for heroin SA after different periods of extinction. In groups of rats in which substitution occurred, we studied the effect of both antagonists on cannabinoid intake. KEY RESULTS Cannabinoid-induced reinstatement of heroin seeking was significantly attenuated by naloxone (1 mg·kg(-1)) and rimonabant (3 mg·kg(-1)) and fully blocked by co-administration of sub-threshold doses of the two antagonists. Moreover, contrary to immediate (1 day) or delayed (90 days) drug substitution, rats readily self-administered WIN when access was given after 7, 14 or 21 days of extinction from heroin, and showed a response rate that was positively correlated with the extinction period. In these animals, cannabinoid intake was increased by naloxone (1 mg·kg(-1)) and decreased by rimonabant (3 mg·kg(-1)). CONCLUSIONS AND IMPLICATIONS Our findings extend previous research on the crosstalk between cannabinoid and opioid receptors in relapse mechanisms, which suggests a differential role in heroin-seeking reinstatement and cannabinoid substitution in heroin-abstinent rats.