MeCP2 in the nucleus accumbens regulates operant cocaine self-administration and effort-based responding

Abstract

Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator implicated in diverse brain functions, including addiction. However, its specific role in drug-seeking motivation remains unclear. To investigate this, we targeted MeCP2 knockdown within the nucleus accumbens (NAc), a key region involved in reward processing, and assessed its impact on cocaine intake. Mice with NAc-specific MeCP2 knockdown (shMeCP2) underwent a cocaine self-administration paradigm. During the initial 7-day food training period, both control and shMeCP2 groups showed comparable improvements in lever-reward learning, with no significant differences in food intake or body weight. These results indicate that MeCP2 knockdown in the NAc does not produce gross impairments in food-reinforced operant performance under the conditions tested. In contrast, during cocaine self-administration sessions, shMeCP2 mice exhibited significantly increased cocaine intake and a higher number of active lever presses compared to controls. In a progressive ratio task, shMeCP2 mice also demonstrated elevated effort-based responding to obtain cocaine. To complement the operant findings and assess cocaine-conditioned reward under matched passive exposure, we conducted a conditioned place preference (CPP) test. No significant group differences were observed in CPP scores, indicating that CPP-assessed cocaine-conditioned reward did not differ between groups under matched passive exposure at the tested dose. Together, these findings indicate that reducing MeCP2 in the NAc increases operant cocaine self-administration and effort-based responding at the unit dose tested, while CPP-assessed cocaine-conditioned reward did not show a detectable group difference under matched passive exposure at the tested dose.