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.