Histone Deacetylase 5 Limits Cocaine Reward through cAMP-Induced Nuclear Import
Author(s)
Taniguchi, Makoto; Carreira, Maria B.; Smith, Laura N.; Zirlin, Benjamin C.; Neve, Rachael L.; Cowan, Christopher W.; ... Show more Show less
DownloadTaniguchi-2012-Histone Deacetylase.pdf (1.160Mb)
PUBLISHER_POLICY
Publisher Policy
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Terms of use
Metadata
Show full item recordAbstract
Chromatin remodeling by histone deacetylases (HDACs) is a key mechanism regulating behavioral adaptations to cocaine use. We report here that cocaine and cyclic adenosine monophosphate (cAMP) signaling induce the transient nuclear accumulation of HDAC5 in rodent striatum. We show that cAMP-stimulated nuclear import of HDAC5 requires a signaling mechanism that involves transient, protein phosphatase 2A (PP2A)-dependent dephosphorylation of a Cdk5 site (S279) found within the HDAC5 nuclear localization sequence. Dephosphorylation of HDAC5 increases its nuclear accumulation, by accelerating its nuclear import rate and reducing its nuclear export rate. Importantly, we show that dephosphorylation of HDAC5 S279 in the nucleus accumbens suppresses the development, but not expression, of cocaine reward behavior in vivo. Together, our findings reveal a molecular mechanism by which cocaine regulates HDAC5 function to antagonize the rewarding impact of cocaine, likely by putting a brake on drug-stimulated gene expression that supports drug-induced behavioral changes.
Date issued
2012-01Department
Massachusetts Institute of Technology. Department of Brain and Cognitive SciencesJournal
Neuron
Publisher
Elsevier
Citation
Taniguchi, Makoto, Maria B. Carreira, Laura N. Smith, Benjamin C. Zirlin, Rachael L. Neve, and Christopher W. Cowan. “Histone Deacetylase 5 Limits Cocaine Reward through cAMP-Induced Nuclear Import.” Neuron 73, no. 1 (January 2012): 108–120. © 2012 Elsevier Inc.
Version: Final published version
ISSN
08966273
1097-4199