PDF《Induced Plasticity》

Neurobiology of Disease Epigenetic Readers of Lysine Acetylation Regulate Cocaine- Induced Plasticity Gregory C.

Sartor, XSamuel K. Powell, Shaun P. Brothers, and Claes Wahlestedt Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida

33136 Epigenetic processes that regulate histone acetylation play an essential role in behavioral and molecular responses to cocaine. To date, however,onlyasmallfractionofthemechanismsinvolvedintheaddiction-associatedacetylomehavebeeninvestigated.Membersofthe bromodomain and extraterminal (BET) family of epigenetic reader proteins (BRD2, BRD3, BRD4, and BRDT) bind acetylated histones and serve as a scaffold for the recruitment of macromolecular complexes to modify chromatin accessibility and transcriptional activity. The role of BET proteins in cocaine-induced plasticity, however, remains elusive. Here, we used behavioral, pharmacological, and molecular techniques to examine the involvement of BET bromodomains in cocaine reward. Of the BET proteins, BRD4, but not BRD2 or BRD3, was significantly elevated in the nucleus accumbens (NAc) of mice and rats following repeated cocaine injections and self- administration.Systemicandintra-accumbalinhibitionofBRD4withtheBETinhibitor,JQ1,attenuatedtherewardingeffectsofcocaine inaconditionedplacepreferenceprocedurebutdidnotaffectconditionedplaceaversion,nordidJQ1aloneinduceconditionedaversion or preference. Investigating the underlying mechanisms, we found that repeated cocaine injections enhanced the binding of BRD4, but notBRD3,tothepromoterregionofBdnfintheNAc,whereassystemicinjectionofJQ1attenuatedcocaine-inducedexpressionofBdnfin the NAc. JQ1 and siRNA-mediated knockdown of BRD4 in vitro also reduced expression of Bdnf. These findings indicate that disrupting the interaction between BET proteins and their acetylated lysine substrates may provide a new therapeutic avenue for the treatment of drug addiction. Key words: BDNF;

BET;

BRD4;

bromodomain;

cocaine;

epigenetic Introduction Dysfunction in histone acetylation has been linked with the patho- physiology of a wide range of psychiatric disorders (Tremolizzo et al.,2002;

Kumaretal.,2005;

Renthaletal.,2007;

Malvaezetal.,2010;

Kurita et al., 2012;

Stafford et al., 2012;

Moonat et al., 2013). In drug addiction, for example, repeated cocaine administration elevates global histone acetylation levels in reward-related brain regions, suchasthenucleusaccumbens(NAc)(Renthaletal.,2009).Further- more, manipulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs) by pharmacological inhibition, viral- mediated gene transfer, and/or knock-out models has confirmed that histone acetylation is critically involved in behavioral and mo- lecular responses to cocaine (Kumar et al., 2005;

Renthal et al., 2007, 2009;

Sunetal.,2008;

Imetal.,2010;

Malvaezetal.,2010,2011,2013;

Wang et al., 2010;

Kennedy et al., 2013;

Rogge et al., 2013). As a consequence,HATandHDACinhibitorshaveemergedasattractive targets for the treatment of drug addiction;

however, additional reg- Received Feb. 27, 2015;

revised Sept. 28, 2015;

accepted Oct. 4, 2015. Authorcontributions:G.C.S.andC.W.designedresearch;

G.C.S.andS.K.P.performedresearch;

G.C.S.,S.K.P.,and S.P.B. analyzed data;

G.C.S., S.K.P., S.P.B., and C.W. wrote the paper. ThisworkwassupportedbyNationalInstituteonDrugAbuseGrantsR01DA035055andR21DA035592.Wethank AndreaMalvezzi,SandyVogt,AndreaJohnstone,ChiaraPastori,MarcoMagistri,andSariIzenwasserforassistance. The cocaine used in these studies was obtained from the National Institute on Drug Abuse Drug Supply Program. The authors declare no competing financial interests. CorrespondenceshouldbeaddressedtoDr.ClaesWahlestedt,DepartmentofPsychiatryandBehavioralSciences, University of Miami Miller School of Medicine,