Lentiviral-mediated CD81 Modulation in the Nucleus Accumbens: Effects on Cocaine-Induced Conditioned Reward and Relapse in Male Rats.

Cocaine use disorder is a major public health issue with no approved pharmacological treatments. Drug-associated contextual memories can trigger intense craving and relapse. Although CD81 has been linked to cocaine-induced locomotion, its role in conditioned reward and relapse remains unclear. This study investigated the role of CD81 expression in the nucleus accumbens (NAc) during the acquisition and drug-primed reinstatement of cocaine-conditioned place preference (CPP) in rats. Adult male Wistar rats underwent viral manipulation of CD81 in the NAc via lentiviral vectors to induce either knockdown (shRNA) or overexpression. These manipulations were performed either before cocaine conditioning (10 mg/kg) to assess acquisition or after extinction and prior to a cocaine priming injection (5 mg/kg) to assess reinstatement. CD81 mRNA levels were measured postmortem, and Pearson correlation analyses were conducted between gene expression and behavioural outcomes. CD81 knockdown significantly reduced CPP acquisition and reinstatement, whereas CD81 overexpression increased conditioned preference in both phases. Doxycycline treatment suppressed transgene expression and abolished the behavioural effects of CD81 overexpression. Correlation analyses revealed a significant positive association between CD81 mRNA levels and CPP magnitude. These findings indicate that CD81 contributes to modulation of cocaine-conditioned reward and relapse-like behaviour within the NAc. Further investigation in additional preclinical models will be necessary to clarify the broader relevance of CD81 in addiction-related neuroplasticity.