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Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins.

Changes in gene expression contribute to the long-lasting regulation of the brain's reward circuitry seen in drug addiction; however, the specific genes regulated and the transcriptional mechanisms underlying such regulation remain poorly understood. Here, we used chromatin immunoprecipitation coupled with promoter microarray analysis to characterize genome-wide chromatin changes in the mouse nucleus accumbens, a crucial brain reward region, after repeated cocaine administration. Our findings reveal several interesting principles of gene regulation by cocaine and of the role of DeltaFosB and CREB, two prominent cocaine-induced transcription factors, in this brain region. The findings also provide comprehensive insight into the molecular pathways regulated by cocaine-including a new role for sirtuins (Sirt1 and Sirt2)-which are induced in the nucleus accumbens by cocaine and, in turn, dramatically enhance the behavioral effects of the drug.

Pubmed ID: 19447090

Authors

  • Renthal W
  • Kumar A
  • Xiao G
  • Wilkinson M
  • Covington HE
  • Maze I
  • Sikder D
  • Robison AJ
  • LaPlant Q
  • Dietz DM
  • Russo SJ
  • Vialou V
  • Chakravarty S
  • Kodadek TJ
  • Stack A
  • Kabbaj M
  • Nestler EJ

Journal

Neuron

Publication Data

May 14, 2009

Associated Grants

  • Agency: NIDA NIH HHS, Id: P01 DA008227
  • Agency: NIDA NIH HHS, Id: P01 DA008227-14
  • Agency: NIDA NIH HHS, Id: P01 DA008227-15
  • Agency: NIDA NIH HHS, Id: P01 DA008227-16
  • Agency: NIDA NIH HHS, Id: P01 DA008227-170003
  • Agency: NIDA NIH HHS, Id: R01 DA007359
  • Agency: NIDA NIH HHS, Id: R01 DA007359-19
  • Agency: NIDA NIH HHS, Id: R01 DA007359-20
  • Agency: NIDA NIH HHS, Id: R01 DA007359-21
  • Agency: NIDA NIH HHS, Id: R01 DA014133
  • Agency: NIDA NIH HHS, Id: R01 DA014133-08
  • Agency: NIDA NIH HHS, Id: R01 DA014133-09

Mesh Terms

  • Animals
  • Chromatin
  • Cocaine
  • Cyclic AMP Response Element-Binding Protein
  • Dopamine Uptake Inhibitors
  • Feedback, Physiological
  • Gene Expression Regulation
  • Genome-Wide Association Study
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nucleus Accumbens
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-fos
  • Reinforcement (Psychology)
  • Signal Transduction
  • Sirtuins