title: Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2.
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.
authors: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Center for Social and Affective Neuroscience, Linköping University Hospital, Linköping, Sweden.
authors: E
authors: E
authors: Barbier
authors: The Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: A L
authors: AL
authors: Johnstone
authors: The Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: B B
authors: BB
authors: Khomtchouk
authors: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors: J D
authors: JD
authors: Tapocik
authors: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors: C
authors: C
authors: Pitcairn
authors: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors: F
authors: F
authors: Rehman
authors: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Center for Social and Affective Neuroscience, Linköping University Hospital, Linköping, Sweden.
authors: E
authors: E
authors: Augier
authors: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors: A
authors: A
authors: Borich
authors: Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA, USA.
authors: J R
authors: JR
authors: Schank
authors: The Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: C A
authors: CA
authors: Rienas
authors: John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: D J
authors: DJ
authors: Van Booven
authors: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors: H
authors: H
authors: Sun
authors: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Center for Social and Affective Neuroscience, Linköping University Hospital, Linköping, Sweden.
authors: D
authors: D
authors: Nätt
authors: The Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: C
authors: C
authors: Wahlestedt
authors: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Center for Social and Affective Neuroscience, Linköping University Hospital, Linköping, Sweden.|Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors: M
authors: M
authors: Heilig
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000437:Alcoholism / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003192:Compulsive Behavior / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000378:metabolism; D058999:Drug-Seeking Behavior / Q000502:physiology; D044127:Epigenesis, Genetic; D000431:Ethanol / Q000008:administration & dosage; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D012646:Self Administration; D013315:Stress, Psychological; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002492:Central Nervous System Depressants; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000431:Ethanol; D011495:Histone-Lysine N-Methyltransferase; C489242:Prdm2 protein, mouse; C000627651:Prdm2 protein, rat