Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell

The transcription factor Delta FosB and the brain-enriched calcium/calmodulin-dependent protein kinase II (CaMKII alpha) are induced in the nucleus accumbens (NAc) by chronic exposure to cocaine or other psychostimulant drugs of abuse, in which the two proteins mediate sensitized drug responses. Although Delta FosB and CaMKII alpha both regulate AMPA glutamate receptor expression and function in NAc, dendritic spine formation on NAc medium spiny neurons (MSNs), and locomotor sensitization to cocaine, no direct link between these molecules has to date been explored. Here, we demonstrate that Delta FosB is phosphorylated by CaMKII alpha at the protein-stabilizing Ser27 and that CaMKII is required for the cocaine-mediated accumulation of Delta FosB in rat NAc. Conversely, we show that Delta FosB is both necessary and sufficient for cocaine induction of CaMKII alpha gene expression in vivo, an effect selective for D-1-type MSNs in the NAc shell subregion. Furthermore, induction of dendritic spines on NAc MSNs and increased behavioral responsiveness to cocaine after NAc overexpression of Delta FosB are both CaMKII dependent. Importantly, we demonstrate for the first time induction of Delta FosB and CaMKII in the NAc of human cocaine addicts, suggesting possible targets for future therapeutic intervention. These data establish that Delta FosB and CaMKII engage in a cell-type-and brain-region-specific positive feedforward loop as a key mechanism for regulating the reward circuitry of the brain in response to chronic cocaine.