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, SPRED1 is a known inhibitor of Rafl activity and also a predicted target of miR-212 (www.targetscan.com). We found that miR-212 can repress SPRED1 expression in cultured cells and in striatum115), and thereby activates Rafl, which stimulates CREB activity. Moreover, we showed that enhancing CREB activity in striatum (accomplished by overexpressing the CREB coactivator CRTC1) decreased cocaine intake in rats with extended access to the drug. These findings show that mir-212 plays a key role in regulating cocaine intake and highlight an emerging signaling ”motif“ in which miRNAs play central roles in regulating signaling strength in neurons by controlling the activity of signaling cascades that modify their expression.
