Nucleus accumbens CD81 regulates methamphetamine-induced locomotor activity, conditioned reward, and reinstatement in male and female rats.

BACKGROUND: Methamphetamine (METH) use disorder is characterized by high rates of relapse and persistent neurobehavioral alterations. CD81, a member of the tetraspanin family, has been implicated in synaptic plasticity and addiction-related behaviors, but its role in METH-induced behavioral adaptations remains unknown. AIMS: To determine whether METH-induced conditioned reward is associated with alterations in endogenous nucleus accumbens (NAcc) CD81 expression and to examine the effects of viral-mediated CD81 overexpression on METH-induced behavioral responses. METHODS: Male and female rats underwent METH-induced conditioned place preference (CPP), after which endogenous CD81 mRNA expression was quantified in the NAcc. Based on these findings, separate cohorts received bilateral intra-accumbal injections of either control or CD81-expressing lentiviral vectors. The effects of CD81 overexpression on acute METH-induced locomotor activity, CPP acquisition, and METH-primed reinstatement following extinction were subsequently evaluated. RESULTS: METH-conditioned animals exhibited significantly reduced accumbal CD81 mRNA expression, and endogenous CD81 levels were negatively correlated with CPP acquisition. Viral-mediated CD81 overexpression significantly attenuated METH-induced locomotor activation, reduced CPP acquisition, and suppressed METH-primed reinstatement following extinction. Accumbal CD81 mRNA expression was negatively correlated with locomotor activity, CPP magnitude, and reinstatement responses. Although females exhibited greater METH-induced locomotor activity than males, no significant sex differences were observed in CPP acquisition, reinstatement, or the behavioral effects of CD81 overexpression. CONCLUSIONS: Reduced endogenous CD81 expression in the NAcc is associated with METH reward learning, whereas restoration of CD81 expression attenuates METH-induced locomotor, rewarding, and relapse-like behaviors. These findings identify CD81 as a previously unrecognized regulator of METH-induced neurobehavioral adaptations and support a role for accumbal CD81 in addiction-related neuroplasticity.