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: 15.98). 01/2012; 73(1):108-20. DOI: 10.1016/j.neuron.2011.10.032
Source: PubMed

ABSTRACT 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, Jul 25, 2015
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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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    • "HDAC4 has been additionally shown to have an active pro-survival role in retinal neurons when resident in the cytoplasm (Chen and Cepko 2009). Furthermore, alterations to Class IIa activity mediate the actions of certain anti-depressants and control addiction pathways (Tsankova et al. 2006; Renthal et al. 2007; Taniguchi et al. 2012). Thus, signaling mechanisms that alter the subcellular localization of Class IIa HDACs have the capacity to influence important aspects of neuronal fate and function. "
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    • "RAC-alpha serine/ threonine-protein kinase (AKT1), another predicted target of miR-885-3p, is involved in cell survival where it is shown that activation of both VEGF and AKT1 is necessary to promote neuronal survival mediated by hypoxic preconditioning [39]. Histone deacetylase 5 (HDAC5) is also a target of miR-885-3p, and VPA [4], where its function in the CNS has been implicated in modulating angiogenesis [40] and cocaine addiction [41]. In terms of top neurological diseases predicted for miR-885-3p from our analysis , movement disorder, tauopathy, neurodegenerative disorder, Alzheimer's disease, and seizures were some of those represented (Table 4). "
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