title: 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.
abstract: 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.
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors: Alfred J
authors: AJ
authors: Robison
authors: Vincent
authors: V
authors: Vialou
authors: Michelle
authors: M
authors: Mazei-Robison
authors: Jian
authors: J
authors: Feng
authors: Saïd
authors: S
authors: Kourrich
authors: Miles
authors: M
authors: Collins
authors: Sunmee
authors: S
authors: Wee
authors: George
authors: G
authors: Koob
authors: Gustavo
authors: G
authors: Turecki
authors: Rachael
authors: R
authors: Neve
authors: Mark
authors: M
authors: Thomas
authors: Eric J
authors: EJ
authors: Nestler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000473:pathology*; D015331:Cohort Studies; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012457:Salicylamides / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D055815:Young Adult
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D016760:Proto-Oncogene Proteins c-fos; C534628:SCH 23390; D012457:Salicylamides; D049452:Green Fluorescent Proteins; D012694:Serine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003042:Cocaine; C045989:eticlopride; D002118:Calcium