The mechanisms by which miR-212 influences cocaine intake has also been explored. The miR-212/132 gene cluster is highly responsive to the cAMP signaling cascade, with both miRNAs upregulated by cAMP response element binding protein (CREB).116,117 We found that levels of phosphorylated (activated) CREB are increased in striatum of rats with extended but not restricted cocaine access115 — those that show upregulated miR-212 levels. An emerging theme in the miRNA field is the observation that miRNAs often feedback onto the signaling cascade that triggered alterations in their expression to amplify or curtail activity of these same signaling cascades.118 As CREB activity is known to regulate the motivational properties of cocaine,119-121 we investigated the possibility that miR-212 may regulate CREB activity. We found that miR-212 dramatically boosts CREB signaling in cultured cells and in the striatum of rats.115 We used a hypothesis-driven approach to identify the gene targets for miR-212 that may explain its actions on CREB. It is known that Rafl kinase can phosphorylate adenylyl cyclases to sensitize their activity, thereby increasing cAMP production and CREB activation, eg ref 123. Interestingly,
