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Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2
Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
University of Miami, FL 33136 USA.
University of Miami, FL 33136 USA.
NIAAA, MD USA.
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2017 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 22, no 12, p. 1746-1758Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 22, no 12, p. 1746-1758
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Neurosciences
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URN: urn:nbn:se:liu:diva-143625DOI: 10.1038/mp.2016.131ISI: 000416224100011PubMedID: 27573876OAI: oai:DiVA.org:liu-143625DiVA, id: diva2:1165582
Note

Funding Agencies|NIAAA division of Intramural Research; Swedish Research Council; NIAAA R01 [1R01AA023781-01A1]; United States Department of Defense (DoD), through the National Defense Science and Engineering Graduate Fellowship (NDSEG) Program; US National Institute of Health [DA035592, MH084880, NS071674]; DoD; Army Research Office (ARO); National Defense Science and Engineering Graduate (NDSEG) Fellowship [32 CFR 168a]

Available from: 2017-12-13 Created: 2017-12-13 Last updated: 2018-01-13

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Barbier, EstelleAugier, EricNätt, DanielHeilig, Markus
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