Considering that miR-212 expression levels may play a key role in regulating vulnerability to cocaine addiction, we next investigated the mechanisms by which baseline and cocaine-induced increases in striatal miR-212 levels are regulated. Interestingly, sequence analysis of the miR-212/132 gene cluster reveals that it is located in a CpG enriched region, which can serve as substrate for DNA methylation and gene regulation. Methyl CpG binding protein 2 (MeCP2) is known to bind to methylated DNA and can act as a gene repressor by recruiting other chromatin remodeling proteins that combine to form the so-called repressor complex (Guy et al., 2011). Based on these observations, we hypothesized that MeCP2 may regulate baseline and cocaine-induced changes in miR-212 expression in striatum and thereby influence cocaine-taking behavior. Consistent with this hypothesis, in vitro studies showed that knockdown of MeCP2 increased miR-212 (and miR-132) 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
