Cocaine Administration and Its Withdrawal Enhance the Expression of Genes Encoding Histone-Modifying Enzymes and Histone Acetylation in the Rat Prefrontal Cortex.

Publisher: Springer Country of Publication: United States NLM ID: 100929017 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-3524 (Electronic) Linking ISSN: 10298428 NLM ISO Abbreviation: Neurotox Res Subsets: MEDLINE

Publication: <2009-> : New York : Springer
Original Publication: [Amsterdam?] : Harwood Academic Publishers,

Anesthetics, Local/*administration & dosage ; Cocaine/*administration & dosage ; Cocaine-Related Disorders/*metabolism ; Histone Acetyltransferases/*metabolism ; Histones/*metabolism ; Nerve Tissue Proteins/*metabolism ; Prefrontal Cortex/*drug effects; Acetylation/drug effects ; Anesthetics, Local/toxicity ; Animals ; Cocaine/toxicity ; Conditioning, Operant/drug effects ; Drug-Seeking Behavior ; Extinction, Psychological/drug effects ; Gene Expression Regulation/drug effects ; Histone Acetyltransferases/genetics ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/genetics ; Male ; Nerve Tissue Proteins/genetics ; Prefrontal Cortex/diagnostic imaging ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Self Administration ; Time Factors

Chronic exposure to cocaine, craving, and relapse are attributed to long-lasting changes in gene expression arising through epigenetic and transcriptional mechanisms. Although several brain regions are involved in these processes, the prefrontal cortex seems to play a crucial role not only in motivation and decision-making but also in extinction and seeking behavior. In this study, we applied cocaine self-administration and extinction training procedures in rats with a yoked triad to determine differentially expressed genes in prefrontal cortex. Microarray analysis showed significant upregulation of several genes encoding histone modification enzymes during early extinction training. Subsequent real-time PCR testing of these genes following cocaine self-administration or early (third day) and late (tenth day) extinction revealed elevated levels of their transcripts. Interestingly, we found the enrichment of Brd1 messenger RNA in rats self-administering cocaine that lasted until extinction training during cocaine withdrawal with concomitant increased acetylation of H3K9 and H4K8. However, despite elevated levels of methyl- and demethyltransferase-encoded transcripts, no changes in global di- and tri-methylation of histone H3 at lysine 4, 9, 27, and 79 were observed. Surprisingly, at the end of extinction training (10 days of cocaine withdrawal), most of the analyzed genes in the rats actively and passively administering cocaine returned to the control level. Together, the alterations identified in the rat prefrontal cortex may suggest enhanced chromatin remodeling and transcriptional activity induced by early cocaine abstinence; however, to know whether they are beneficial or not for the extinction of drug-seeking behavior, further in vivo evaluation is required.

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Keywords: Cocaine self-administration; Gene expression; Histone-modifying enzymes; Microarray; Posttranslational histone modifications

0 (Anesthetics, Local)
0 (BRD1 protein, rat)
0 (Histones)
0 (Nerve Tissue Proteins)
0 (RNA, Messenger)
0 (histone H2B type 1-A)
EC 2.1.1.43 (DOT1L protein, rat)
EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
EC 2.3.1.48 (Histone Acetyltransferases)
I5Y540LHVR (Cocaine)

Date Created: 20170411 Date Completed: 20180327 Latest Revision: 20231104

20240829

PMC5487868

10.1007/s12640-017-9728-7

28393332