Chronic cocaine-induced H3 acetylation and transcriptional activation of CaMKIIalpha in the nucleus accumbens is critical for motivation for drug reinforcement

Neuropsychopharmacology. 2010 Mar;35(4):913-28. doi: 10.1038/npp.2009.193. Epub 2009 Dec 9.


The regulation of gene expression in the brain reward regions is known to contribute to the pathogenesis and persistence of drug addiction. Increasing evidence suggests that the regulation of gene transcription is mediated by epigenetic mechanisms that alter the chromatin structure at specific gene promoters. To better understand the involvement of epigenetic regulation in drug reinforcement properties, rats were subjected to cocaine self-administration paradigm. Daily histone deacetylase (HDAC) inhibitor infusions in the shell of the nucleus accumbens (NAc) caused an upward shift in the dose-response curve under fixed-ratio schedule and increased the break point under progressive-ratio schedule, indicating enhanced motivation for self-administered drug. The effect of the HDAC inhibitor is attributed to the increased elevation of histone acetylation induced by chronic, but not acute, cocaine experience. In contrast, neutralizing the chronic cocaine-induced increase in histone modification by the bilateral overexpression of HDAC4 in the NAc shell reduced drug motivation. The association between the motivation for cocaine and the transcriptional activation of addiction-related genes by H3 acetylation in the NAc shell was analyzed. Among the genes activated by chronic cocaine experiences, the expression of CaMKIIalpha, but not CaMKIIbeta, correlated positively with motivation for the drug. Lentivirus-mediated shRNA knockdown experiments showed that CaMKIIalpha, but not CaMKIIbeta, in the NAc shell is essential for the maintenance of motivation to self-administered cocaine. These findings suggest that chronic drug-use-induced transcriptional activation of genes, such as CaMKIIalpha, modulated by H3 acetylation in the NAc is a critical regulatory mechanism underlying motivation for drug reinforcement.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Chromatin Immunoprecipitation / methods
  • Cocaine / administration & dosage*
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Food Preferences / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Green Fluorescent Proteins / genetics
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Hydroxamic Acids / pharmacology
  • Male
  • Microinjections / methods
  • Motivation / drug effects*
  • Mutation / genetics
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / enzymology
  • Rats
  • Rats, Sprague-Dawley
  • Reinforcement Schedule
  • Reinforcement, Psychology*
  • Repressor Proteins / genetics
  • Self Administration / methods
  • Statistics, Nonparametric
  • Time Factors
  • Transduction, Genetic / methods
  • Vorinostat


  • Dopamine Uptake Inhibitors
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Repressor Proteins
  • Green Fluorescent Proteins
  • trichostatin A
  • Vorinostat
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • HDAC4 protein, human
  • Histone Deacetylases
  • histone deacetylase 3
  • Cocaine