PT  - JOURNAL ARTICLE
AU  - Alfred J. Robison
AU  - Vincent Vialou
AU  - Michelle Mazei-Robison
AU  - Jian Feng
AU  - Saïd Kourrich
AU  - Miles Collins
AU  - Sunmee Wee
AU  - George Koob
AU  - Gustavo Turecki
AU  - Rachael Neve
AU  - Mark Thomas
AU  - Eric J. Nestler
TI  - 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
AID  - 10.1523/JNEUROSCI.5192-12.2013
DP  - 2013 Mar 06
TA  - The Journal of Neuroscience
PG  - 4295--4307
VI  - 33
IP  - 10
4099  - http://www.jneurosci.org/content/33/10/4295.short
4100  - http://www.jneurosci.org/content/33/10/4295.full
SO  - J. Neurosci.2013 Mar 06; 33
AB  - The transcription factor ΔFosB and the brain-enriched calcium/calmodulin-dependent protein kinase II (CaMKIIα) 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 ΔFosB and CaMKIIα 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 ΔFosB is phosphorylated by CaMKIIα at the protein-stabilizing Ser27 and that CaMKII is required for the cocaine-mediated accumulation of ΔFosB in rat NAc. Conversely, we show that ΔFosB is both necessary and sufficient for cocaine induction of CaMKIIα gene expression in vivo, an effect selective for D1-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 ΔFosB are both CaMKII dependent. Importantly, we demonstrate for the first time induction of ΔFosB and CaMKII in the NAc of human cocaine addicts, suggesting possible targets for future therapeutic intervention. These data establish that ΔFosB 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.