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, Claes R Wahlestedt, M. Heilig

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.Molecular Psychiatry advance online publication, 30 August 2016; doi:10.1038/mp.2016.131.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Aug 30 2016

Fingerprint

Self Administration
Drinking
Alcohols
Alcoholism
Prefrontal Cortex
Genetic Epigenesis
High-Throughput Nucleotide Sequencing
Chromatin Immunoprecipitation
DNA Sequence Analysis
Epigenomics
Histones
Lysine
Psychiatry
Publications
Down-Regulation
Communication
Recurrence
Messenger RNA
histone methyltransferase
Genes

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Barbier, E., Johnstone, A. L., Khomtchouk, B. B., Tapocik, J. D., Pitcairn, C., Rehman, F., ... Heilig, M. (Accepted/In press). Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2. Molecular Psychiatry. https://doi.org/10.1038/mp.2016.131

Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2. / Barbier, E.; Johnstone, A. L.; Khomtchouk, B. B.; Tapocik, J. D.; Pitcairn, C.; Rehman, F.; Augier, E.; Borich, A.; Schank, J. R.; Rienas, C. A.; van Booven, D. J.; Sun, H.; Nätt, D.; Wahlestedt, Claes R; Heilig, M.

In: Molecular Psychiatry, 30.08.2016.

Research output: Contribution to journalArticle

Barbier, E, Johnstone, AL, Khomtchouk, BB, Tapocik, JD, Pitcairn, C, Rehman, F, Augier, E, Borich, A, Schank, JR, Rienas, CA, van Booven, DJ, Sun, H, Nätt, D, Wahlestedt, CR & Heilig, M 2016, 'Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2', Molecular Psychiatry. https://doi.org/10.1038/mp.2016.131
Barbier, E. ; Johnstone, A. L. ; Khomtchouk, B. B. ; Tapocik, J. D. ; Pitcairn, C. ; Rehman, F. ; Augier, E. ; Borich, A. ; Schank, J. R. ; Rienas, C. A. ; van Booven, D. J. ; Sun, H. ; Nätt, D. ; Wahlestedt, Claes R ; Heilig, M. / Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2. In: Molecular Psychiatry. 2016.
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