Characterization of Histone Deacetylase 4 and Histone Deacetylase 5 in Cocaine-Related Behaviors



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In recent years a focus on epigenetic mechanisms as mediators of cocaine-related behavioral, structural and functional plasticity has developed. One family of epigenetic molecules that may underlie cocaine behavioral and functional changes is the histone deacetylase family that acts to mediate transcriptional repression. The class IIa subgroup of histone deacetylases is poised as an intracellular signal detector and effector by virtue of their ability to shuttle subcellularly in a dynamic and activity-dependent manner primarily driven by phosphorylation status of the protein at multiple residues. The overlying goal of this thesis was to two-faceted: to characterize the regulation of two class IIa members, HDAC4 and HDAC5, by cocaine-mediated signaling and to characterize the role of HDAC4 and HDAC5 in cocaine-associated behavioral plasticity. We report the regulation of phosphorylation and localization of HDAC4 and HDAC5 is in opposition. HDAC5 is dephosphorylated and accumulated in the nuclear compartment in response to cocaine, dopamine dependent signaling and cAMP activity. Meanwhile, we observe that HDAC4 is weakly dephosphorylated by cAMP activity in culture but weakly phosphorylated in vivo. These findings encouraged the analysis of function of these highly homologous class members. We assessed the function of HDAC4 and HDAC5 in the nucleus accumbens, a critical region for reward, by over-expressing wildtype and nuclear variants by targeted viral-mediated gene transfer. We report an attenuation of cocaine reward learning by nuclear HDAC5 but not wildtype or HDAC4 over-expression. We further analyzed the role of HDAC5 in self-administration behavior and report an effect of nuclear HDAC5, but not wildtype, on models of reinstatement of seeking, a preclinical model of relapse. These effects were observed in the absence of an effect on intake, sensitivity or motivation to self-administer. Because HDAC4 and HDAC5 bind nuclear transcriptional regulators to exert transcriptional repression of target genes we analyzed the dependence of nuclear HDAC5 on interacting with MEF2, a primary binding partners, and report that this interaction is likely required for modulating reinstatement of seeking but dispensable for cocaine reward. Taken together, these findings highlight the role of nuclear HDAC5 but not HDAC4 to limit cocaine reward and aspects of cocaine addiction-like behavior.

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