Cannabidiol Attenuates Heroin Seeking in Male Rats Associated With Normalization of Discrete Neurobiological Signatures Within the Nucleus Accumbens With Subregional Specificity

Background Opioid use disorder is a chronic relapsing condition characterized by cycles of compulsive drug use, abstinence, and relapse. Cannabidiol (CBD), a nonintoxicating cannabinoid, is under investigation as an antirelapse treatment. CBD attenuates cue-induced heroin seeking in a rodent model of relapse and reduces craving and anxiety induced by drug-associated cues in abstinent individuals with heroin use disorder. The neurobiological mechanisms by which CBD may exert its antirelapse effects are unknown. Methods The objective of the current study was to evaluate the effects of CBD administration on heroin-seeking behavior in conjunction with transcriptomic profiling in the nucleus accumbens core (NAcC) and NAc shell (NAcS). Results Heroin-trained animals exhibited high levels of cue-induced heroin-seeking behavior. Importantly, CBD attenuated cue-induced heroin-seeking behaviors. Postmortem RNA sequencing of the NAcC and NAcS revealed shared transcriptomic alterations in the NAc subregions in response to heroin, with a more robust impact of heroin in the NAcS. Although CBD had minimal impact on heroin-induced perturbations in the NAcC, it normalized components of the transcriptomic signature altered by heroin in both NAc subregions including transcripts that correlated with heroin-seeking behavior. In contrast, CBD normalized a particular subset of NAcS genes that correlated with heroin-seeking behavior. Those genes were specifically linked to the extracellular matrix and astrocyte function, and their upstream regulators were related to immune function. Conclusions These findings underscore the NAc subregional signatures of heroin-induced neurobiological perturbations and provide novel biological targets relevant for CBD’s apparent antirelapse effects.