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Behavioral and structural responses to chronic cocaine require a feedforward loop involving delta fosb and calcium/calmodulin-dependent protein kinase ii in the nucleus accumbens shell

Academic Article
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Overview

authors

  • Robison, A. J.
  • Vialou, V.
  • Mazei-Robison, M.
  • Feng, J.
  • Kourrich, S.
  • Collins, M.
  • Wee, Sunmee
  • Koob, George
  • Turecki, G.
  • Neve, R.
  • Thomas, M.
  • Nestler, E. J.

publication date

  • 2013

journal

  • Journal of Neuroscience  Journal

abstract

  • The transcription factor ?FosB and the brain-enriched calcium/calmodulin-dependent protein kinase II (CaMKII?) 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 ?FosB and CaMKII? 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 ?FosB is phosphorylated by CaMKII? at the protein-stabilizing Ser27 and that CaMKII is required for the cocaine-mediated accumulation of ?FosB in rat NAc. Conversely, we show that ?FosB is both necessary and sufficient for cocaine induction of CaMKII? 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 ?FosB are both CaMKII dependent. Importantly, we demonstrate for the first time induction of ?FosB and CaMKII in the NAc of human cocaine addicts, suggesting possible targets for future therapeutic intervention. These data establish that ?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.
  • 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.

subject areas

  • Adolescent
  • Adult
  • Aged
  • Analysis of Variance
  • Animals
  • Benzazepines
  • Calcium
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Chromatin Immunoprecipitation
  • Cocaine
  • Cocaine-Related Disorders
  • Cohort Studies
  • Dopamine Antagonists
  • Dopamine Uptake Inhibitors
  • Female
  • Gene Expression Regulation
  • Genetic Vectors
  • Green Fluorescent Proteins
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Neural Pathways
  • Nucleus Accumbens
  • Phosphorylation
  • Proto-Oncogene Proteins c-fos
  • Rats
  • Salicylamides
  • Serine
  • Young Adult
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Identity

PubMed Central ID

  • PMC3658178

International Standard Serial Number (ISSN)

  • 0270-6474

Digital Object Identifier (DOI)

  • 10.1523/jneurosci.5192-12.2013

PubMed ID

  • 23467346
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Additional Document Info

start page

  • 4295

end page

  • 4307

volume

  • 33

issue

  • 10

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