INVOLVEMENT OF THE CANNABINOID SYSTEM IN STRESS-INDUCED REINSTATEMENT TO OPIOID USE: A STUDY IN CB1 KNOCKOUT MICE OF BOTH SEXES

Previous studies of our laboratory revealed sex differences in behavioural, molecular, and biochemical responses to morphine (MOR) withdrawal. Stress is a major factor contributing to relapse in drugs abuse. The aims of this study were: evaluate behavioural patterns (conditioning, extinction, and stress-induced reinstatement) of MOR rewarding effects and correlate these patterns with neurochemical changes in reward-related brain nuclei in wild-type (WT) CD1 and CB1 receptor knockout (KO CB1) mice of both sexes. MÒR rewarding effect was confirmed using the conditioned place preference paradigm, followed by extinction with saline sessions and stress-induced relapse caused by immobilization. Dopamine (DA) and its metabolite DOPAC were quantified in brain homogenates using high-performance liquid chromatography with electrochemical detection. Results showed MOR rewarding effects in both sexes of WT and KO CB1 mice (p<0.0001), with higher intensity in KO CB1 mice (p<0.0001). Extinction occurred only in WT mice of both sexes, while KO mice of both sexes did not extinguish the rewarding effect of MOR (p < 0.0001). Stress-induced relapse was only observed in WT females that had extinguished rewarding effects (p<0.01), while KO CB1 mice did not relapse. In addition, elevated DA and DOPAC levels were detected in the nucleus accumbens and caudate putamen during conditioning and reinstatement (p<0.05), in both sexes and genotypes (p<0.05), indicating dopaminergic activation of reward circuits. In conclusion, these findings suggest that CB1 receptors modulate MOR rewarding effects and stress-induced relapse in a sex-dependent manner, highlighting the CB1 receptor as a potential target for sex-specific opioid addiction therapies.