title: Histone deacetylase 5 limits cocaine reward through cAMP-induced nuclear import.
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.
authors.affiliation: Departments of Psychiatry and Ophthalmology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Maria B
authors.initials: MB
authors.lastname: Carreira
authors.forename: Laura N
authors.initials: LN
authors.lastname: Smith
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Zirlin
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cowan
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects* / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology; D000242:Cyclic AMP / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004622:Embryo, Mammalian; D005518:Food Preferences / Q000187:drug effects / Q000502:physiology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051381:Rats; D012201:Reward; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D013997:Time Factors; D014162:Transfection
chemical_list: D018765:Dopamine Uptake Inhibitors; D013549:Sweetening Agents; D013395:Sucrose; D000242:Cyclic AMP; D051360:Cyclin-Dependent Kinase 5; D017868:Cyclic AMP-Dependent Protein Kinases; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2; C404500:HDAC5 protein, human; D006655:Histone Deacetylases; D003042:Cocaine