Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2

E. Barbier, A. L. Johnstone, B. B. Khomtchouk, J. D. Tapocik, C. Pitcairn, F. Rehman, E. Augier, A. Borich, J. R. Schank, C. A. Rienas, D. J. Van Booven, H. Sun, D. Nätt, C. Wahlestedt, M. Heilig

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence.

Original languageEnglish (US)
Pages (from-to)1746-1758
Number of pages13
JournalMolecular psychiatry
Volume22
Issue number12
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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