Cannabidiol attenuates heroin seeking in male rats associated with normalization of discrete neurobiological signatures within the nucleus accumbens with subregional specificity.

Abstract

Background: Opioid use disorder is a chronic relapsing condition characterized by cycles of compulsive drug use, abstinence, and relapse. Cannabidiol (CBD), a non-intoxicating cannabinoid, is under investigation as an anti-relapse 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 anti-relapse 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 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 the NAc subregions in response to heroin, with a more robust impact of heroin in the NAcS. Though CBD had minimal impact on the 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 to heroin-seeking behavior. Those genes were specifically linked to the extracellular matrix, astrocyte function, and their upstream regulators related to immune function.

Conclusion: These findings underscore the NAc subregional signatures of heroin-induced neurobiological perturbations and provide novel biological targets relevant for CBD's apparent anti-relapse effects.