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Novel role and regulation of HDAC4 in cocaine‐related behaviors
Author(s) -
Penrod Rachel D.,
Carreira Maria B.,
Taniguchi Makoto,
Kumar Jaswinder,
Maddox Stephanie A.,
Cowan Christopher W.
Publication year - 2018
Publication title -
addiction biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.445
H-Index - 78
eISSN - 1369-1600
pISSN - 1355-6215
DOI - 10.1111/adb.12522
Subject(s) - hdac4 , nucleus accumbens , histone deacetylase 5 , conditioned place preference , microbiology and biotechnology , biology , prenatal cocaine exposure , neuroscience , histone , histone deacetylase , addiction , genetics , dopamine , gene , prenatal exposure , pregnancy , offspring
Epigenetic mechanisms have been proposed to contribute to persistent aspects of addiction‐related behaviors. One family of epigenetic molecules that may regulate maladaptive behavioral changes produced by cocaine use are the histone deacetylases (HDACs)—key regulators of chromatin and gene expression. In particular, the class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) respond to changes in neuronal activity by modulating their distribution between the nucleus and cytoplasm—a process controlled in large part by changes in phosphorylation of conserved residues. Cocaine triggers a transient nuclear accumulation of HDAC5 that functions to limit the development of cocaine reward behavior. However, the role and regulation of the close family member, HDAC4, in cocaine behaviors remain largely unknown. In this study, we report that cocaine and cAMP signaling in striatum produced differential phosphorylation and subcellular localization of HDAC4 and HDAC5. Unlike HDAC5, cocaine exposure induced a modest hyperphosphorylation and nuclear export of HDAC4. Genetic deletion of HDAC4 in the nucleus accumbens reduced acute cocaine‐produced locomotion, maximum locomotor sensitization and cocaine reward‐related behavior. Interestingly, overexpression of an HDAC4 cytoplasm‐concentrated mutant (S266E) increased cocaine reward behavior in the cocaine conditioned place preference assay, suggesting that cocaine‐induced nuclear export of HDAC4 might function to facilitate the development of cocaine reward behaviors through a role in the cell cytoplasm. Together, our findings suggest that, despite high sequence homology, HDAC4 and HDAC5 are oppositely regulated by cocaine‐induced signaling in vivo and have distinct roles in regulating cocaine behaviors.