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.