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 subst...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2005-10, Vol.48 (2), p.303-314
Main Authors: Kumar, Arvind, Choi, Kwang-Ho, Renthal, William, Tsankova, Nadia M., Theobald, David E.H., Truong, Hoang-Trang, Russo, Scott J., LaPlant, Quincey, Sasaki, Teresa S., Whistler, Kimberly N., Neve, Rachael L., Self, David W., Nestler, Eric J.
Format: Article
Language:English
Subjects:
Acetylation
Animals
Behavior
Behavior, Animal - drug effects
Brain-Derived Neurotrophic Factor - genetics
Brain-Derived Neurotrophic Factor - metabolism
Butyrates - pharmacology
Chromatin
Chromatin Assembly and Disassembly - drug effects
Chromatin Assembly and Disassembly - physiology
Cocaine
Cocaine - administration & dosage
Conditioning, Operant - drug effects
Corpus Striatum - drug effects
Corpus Striatum - physiology
Cyclin-Dependent Kinase 5 - genetics
Cyclin-Dependent Kinase 5 - metabolism
Dopamine Uptake Inhibitors - administration & dosage
Drug Administration Schedule
Drug Interactions
Enzyme Inhibitors - pharmacology
Enzymes
Gene expression
Gene Expression Regulation - drug effects
Gene Transfer Techniques - psychology
Histone Deacetylases - metabolism
Histones - classification
Histones - metabolism
Immunohistochemistry - methods
Immunoprecipitation - methods
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Motor Activity - drug effects
Neuronal Plasticity - drug effects
Neurons
PC12 Cells - metabolism
Promoter Regions, Genetic - physiology
Protein Subunits
Proto-Oncogene Proteins c-fos - genetics
Rats
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction - methods
RNA, Messenger - biosynthesis
Rodents
Time Factors
Transcription factors
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Summary: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. ΔFosB, 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.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2005.09.023