expression in cultured cells (Im et al., 2010). Similarly, pharmacologically induced disruption of DNA methyltransferase activity, which would be expected to attenuate the inhibitory activity of MeCP2 on gene expression, also increased miR-212/132 levels. Furthermore, we found that knockdown of striatal MeCP2 expression, achieved by virus-mediated delivery of a short hairpin interfering RNA (shRNA) against MeCP2, resulted in profoundly decreased cocaine intake in rats with extended but not restricted access to cocaine (Figure 3). Knockdown of striatal MeCP2 dramatically increased the stimulatory effects of self-administered cocaine on striatal miR-212 expression in rats with extended but not restricted access to the drug. More importantly, disruption of striatal miR-212 signaling, achieved by striatal infusion of an antisense oligonucleotide, reversed the inhibitory effects of MeCP2 knockdown on cocaine intake in extended access rats (Im et al., 2010). These findings are consistent with an inhibitory effect of MeCP2 on miR-212 expression, suggesting that MeCP2 acts as a pro-addiction transcriptional repressor that, by attenuating miR-212 expression in response to cocaine, increases vulnerability to addiction.
