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
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    • "Together, these results had suggested that cocaine SA might have produced HDAC5 export from the nucleus or cytoplasmic retention of HDAC5, with differential alterations in the expression of HDAC5 target genes. The idea is in contrast to the observations of Taniguchi et al. (2012) [56] who found that chronic cocaine injections caused HDAC5 dephosphorylation and increased HDAC5 nuclear accumulation in the mouse striatum. They also reported that HDAC5 dephosphorylation resulted in decreased cocaine CPP. "

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