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Nat Neurosci. 2015 Mar;18(3):415-22. doi: 10.1038/nn.3932. Epub 2015 Feb 2.

Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area.

Author information

1
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Physiology, Michigan State University, East Lansing, Michigan, USA.
3
1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
4
Department of Pharmacology and Toxicology, The State University of New York at Buffalo, Buffalo, New York, USA.
5
1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Institut National de la Santé et de la Recherche Médicale, U952, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7224, UPMC, Paris, France.
6
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
7
Institut National de la Santé et de la Recherche Médicale, U952, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7224, UPMC, Paris, France.
8
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

Abstract

Brain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VTA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters. Furthermore, we found that morphine suppressed binding of phospho-CREB (cAMP response element binding protein) to Bdnf promoters in VTA, which resulted from enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributed to Bdnf repression and associated behavioral plasticity to morphine. Our findings suggest previously unknown epigenetic mechanisms of morphine-induced molecular and behavioral neuroadaptations.

Comment in

PMID:
25643298
PMCID:
PMC4340719
DOI:
10.1038/nn.3932
[Indexed for MEDLINE]
Free PMC Article

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