Document Detail

Extinction of aversive memories associated with morphine withdrawal requires ERK-mediated epigenetic regulation of brain-derived neurotrophic factor transcription in the rat ventromedial prefrontal cortex.
MedLine Citation:
PMID:  23035088     Owner:  NLM     Status:  MEDLINE    
Recent evidence suggests that histone deacetylase (HDAC) inhibitors facilitate extinction of rewarding memory of drug taking. However, little is known about the role of chromatin modification in the extinction of aversive memory of drug withdrawal. In this study, we used conditioned place aversion (CPA), a highly sensitive model for measuring aversive memory of drug withdrawal, to investigate the role of epigenetic regulation of brain-derived neurotrophic factor (BDNF) gene expression in extinction of aversive memory. We found that CPA extinction training induced an increase in recruiting cAMP response element-binding protein (CREB) to and acetylation of histone H3 at the promoters of BDNF exon I transcript and increased BDNF mRNA and protein expression in the ventromedial prefrontal cortex (vmPFC) of acute morphine-dependent rats and that such epigenetic regulation of BDNF gene transcription could be facilitated or diminished by intra-vmPFC infusion of HDAC inhibitor trichostatin A or extracellular signal-regulated kinase (ERK) inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene) before extinction training. Correspondingly, disruption of the epigenetic regulation of BDNF gene transcription with U0126 or suppression of BDNF signaling with Trk receptor antagonist K252a or BDNF scavenger tyrosine kinase receptor B (TrkB)-Fc blocked extinction of CPA behavior. We also found that extinction training-induced activation of ERK and CREB and extinction of CPA behavior could be potentiated or suppressed by intra-vmPFC infusion of d-cycloserine, a NMDA receptor partial agonist or aminophosphonopentanoic acid, a NMDA receptor antagonist. We conclude that extinction of aversive memory of morphine withdrawal requires epigenetic regulation of BDNF gene transcription in the vmPFC through activation of the ERK-CREB signaling pathway perhaps in a NMDA receptor-dependent manner.
Wei-Sheng Wang; Shuo Kang; Wen-Tao Liu; Mu Li; Yao Liu; Chuan Yu; Jie Chen; Zhi-Qiang Chi; Ling He; Jing-Gen Liu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  32     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-04     Completed Date:  2013-01-17     Revised Date:  2014-03-25    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13763-75     Citation Subset:  IM    
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MeSH Terms
Acetylation / drug effects
Association Learning / drug effects,  physiology*
Avoidance Learning / physiology*
Brain-Derived Neurotrophic Factor / biosynthesis,  genetics*
Butadienes / pharmacology
Chromatin Assembly and Disassembly / drug effects,  physiology
Conditioning, Classical / drug effects,  physiology
Cyclic AMP Response Element-Binding Protein / physiology
Epigenetic Repression / drug effects,  physiology*
Extinction, Psychological / physiology*
Histone Deacetylase Inhibitors / pharmacology
Histones / physiology
MAP Kinase Signaling System / drug effects,  physiology*
Morphine / toxicity*
Morphine Dependence / physiopathology*
Nitriles / pharmacology
Prefrontal Cortex / physiology*
Protein Kinase Inhibitors / pharmacology
Protein Processing, Post-Translational / drug effects
Rats, Sprague-Dawley
Receptor, trkB / antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate / physiology
Substance Withdrawal Syndrome / physiopathology*
Transcription, Genetic
Reg. No./Substance:
0/Brain-Derived Neurotrophic Factor; 0/Butadienes; 0/CREB1 protein, rat; 0/Cyclic AMP Response Element-Binding Protein; 0/Histone Deacetylase Inhibitors; 0/Histones; 0/Nitriles; 0/Protein Kinase Inhibitors; 0/Receptors, N-Methyl-D-Aspartate; 0/U 0126; 76I7G6D29C/Morphine; EC, trkB

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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