Histone Deacetylase 5 Limits Cocaine Reward through cAMP-Induced Nuclear Import

Departments of Psychiatry and Ophthalmology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
Neuron (Impact Factor: 15.05). 01/2012; 73(1):108-20. DOI: 10.1016/j.neuron.2011.10.032
Source: PubMed


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.

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Available from: Makoto Taniguchi, Sep 30, 2015
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    • "al - induced neurotoxicity ( Sulzer et al . , 2005 ) . Schmidt et al . ( 2013 ) highlighted that the epigenetic mechanisms including histone modification and DNA methylation contribute to drug - induced gene expression profile . Cocaine also increased the expression of methyl - CpG binding protein 2 ( MeCP2 ) and produced de novo DNA methylation ( Taniguchi et al . , 2012 ; Kennedy et al . , 2013 ) ."
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    • "Hyperexcitability of DRD1 neurons is thought to underlie the dyskinetic response to L-DOPA treatment in animal models of Parkinson’s Disease [5,6]. Neurotransmission to and from DRD1-expressing cells, as well as chromatin remodeling within these cells, have been shown to control the reward and locomotor effects of cocaine and psychostimulants [7–10]. Research on these cells has been facilitated by the making of bacterial artificial chromosome (BAC) transgenic mice using modified Drd1a-BACs to express fluorescent reporters for identification of DRD1-expressing cells [11,12] and to express Cre recombinase for Cre/LoxP genetic manipulations specifically within DRD1 cells [13–15]. "
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    • "Thus, we decided to investigate the role of HDAC5, a class II HDAC, that can shuttle between the nucleus and the cytosol and deacetylates MEF2 [16], which is essential for synaptic plasticity. Moreover, HDAC5 has been associated previously with behavioral adaptations to emotional stimuli such as cocaine addiction [17] [18] [19]. Thus, our aim was to test the hypothesis that targeting HDAC5 could be a suitable strategy to treat cognitive decline linked to AD pathogenesis. "
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