Abstract
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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Acetylation
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Animals
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Behavior, Animal / drug effects
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Brain-Derived Neurotrophic Factor / genetics
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Brain-Derived Neurotrophic Factor / metabolism
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Butyrates / pharmacology
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Chromatin Assembly and Disassembly / drug effects
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Chromatin Assembly and Disassembly / physiology*
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Cocaine / administration & dosage*
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Conditioning, Operant / drug effects
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Corpus Striatum / drug effects*
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Corpus Striatum / physiology
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Cyclin-Dependent Kinase 5 / genetics
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Cyclin-Dependent Kinase 5 / metabolism
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Dopamine Uptake Inhibitors / administration & dosage*
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Drug Administration Schedule
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Drug Interactions
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation / drug effects
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Gene Transfer Techniques / psychology
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Histone Deacetylases / metabolism
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Histones / classification
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Histones / metabolism
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Immunohistochemistry / methods
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Immunoprecipitation / methods
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Motor Activity / drug effects
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Neuronal Plasticity / drug effects*
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PC12 Cells / metabolism
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Promoter Regions, Genetic / physiology
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Protein Subunits
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Proto-Oncogene Proteins c-fos / genetics
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RNA, Messenger / biosynthesis
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Rats
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Rats, Sprague-Dawley
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Time Factors
Substances
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Brain-Derived Neurotrophic Factor
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Butyrates
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Dopamine Uptake Inhibitors
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Enzyme Inhibitors
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Histones
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Protein Subunits
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Proto-Oncogene Proteins c-fos
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RNA, Messenger
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Cyclin-Dependent Kinase 5
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Histone Deacetylases
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Cocaine