Cannabidiol decreases motivation for cocaine in a behavioral economics paradigm but does not prevent incubation of craving in mice

Cocaine is a highly consumed drug worldwide which directly targets brain areas involved in reinforcement processing and motivation. Cannabidiol is a phytocannabinoid that exerts protecting effects upon cocaine-induced addictive behavior, although many questions about the mechanisms of action and the specific affected processes remain unknown. Moreover, its effects on cue-induced cocaine-craving incubation have never been addressed. The present study aimed to assess the effects of cannabidiol (20 mg/kg, i.p.) administered during the acquisition of cocaine self-administration (0.75 mg/kg/infusion) and demand task or during cocaine abstinence and craving. Moreover, we measured the alterations in expression of AMPAR subunits and ERK_1/2 phosphorylation due to cannabidiol treatment or cocaine withdrawal. Our results showed that cannabidiol reduced cocaine intake when administered during the acquisition phase of the self-administration paradigm, increased behavioral elasticity and reduced motivation for cocaine in a demand task. Cannabidiol also reduced GluA1/2 ratio and increased ERK_1/2 phosphorylation in amygdala. No effects over cocaine-craving incubation were found when cannabidiol was administered during abstinence. Furthermore, cocaine withdrawal induced changes in GluA1 and GluA2 protein levels in the prelimbic cortex, ventral striatum and amygdala, as well as a decrease in ERK_1/2 phosphorylation in ventral striatum. Taken together, our results show that cannabidiol exerts beneficial effects attenuating the acquisition of cocaine self-administration, in which an operant learning process is required. However, cannabidiol does not affect cocaine abstinence and craving.