Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum.
Given that cocaine induces neuroadaptations through regulation of gene expression, we investigated whether chromatin remodeling at specific gene promoters may be a key mechanism. We show that cocaine induces specific histone modifications at different gene promoters in striatum, a major neural substrate for cocaine's behavioral effects. At the cFos promoter, H4 hyperacetylation is seen within 30 min of a single cocaine injection, whereas no histone modifications were seen with chronic cocaine, consistent with cocaine's ability to induce cFos acutely, but not chronically. In contrast, at the BDNF and Cdk5 promoters, genes that are induced by chronic, but not acute, cocaine, H3 hyperacetylation was observed with chronic cocaine only. DeltaFosB, a cocaine-induced transcription factor, appears to mediate this regulation of the Cdk5 gene. Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity.
Kumar
Arvind
A
Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Choi
Kwang-Ho
KH
Renthal
William
W
Tsankova
Nadia M
NM
Theobald
David E H
DE
Truong
Hoang-Trang
HT
Russo
Scott J
SJ
Laplant
Quincey
Q
Sasaki
Teresa S
TS
Whistler
Kimberly N
KN
Neve
Rachael L
RL
Self
David W
DW
Nestler
Eric J
EJ
D000107:Acetylation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000502:physiology*; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques / Q000523:psychology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000145:classification / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D016716:PC12 Cells / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D002087:Butyrates; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D006657:Histones; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D051360:Cyclin-Dependent Kinase 5; D006655:Histone Deacetylases; D003042:Cocaine