title: Cocaine Administration and Its Withdrawal Enhance the Expression of Genes Encoding Histone-Modifying Enzymes and Histone Acetylation in the Rat Prefrontal Cortex.
abstract: 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.
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Laboratory of Drug Addiction Pharmacology, Polish Academy of Sciences, ul. Smetna 12, 31-343, Krakow, Poland. annasc@if-pan.krakow.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Sadakierska-Chudy
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Laboratory of Drug Addiction Pharmacology, Polish Academy of Sciences, ul. Smetna 12, 31-343, Krakow, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Frankowska
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Laboratory of Drug Addiction Pharmacology, Polish Academy of Sciences, ul. Smetna 12, 31-343, Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jastrzębska
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Laboratory of Drug Addiction Pharmacology, Polish Academy of Sciences, ul. Smetna 12, 31-343, Krakow, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Wydra
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Laboratory of Drug Addiction Pharmacology, Polish Academy of Sciences, ul. Smetna 12, 31-343, Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Miszkiel
authors.affiliation: Laboratory of Molecular Biology and Clinical Genetics, Medical College, Jagiellonian University, ul. Skawinska 8, 31-066, Krakow, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Sanak
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Laboratory of Drug Addiction Pharmacology, Polish Academy of Sciences, ul. Smetna 12, 31-343, Krakow, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Filip
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage* / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D003216:Conditioning, Operant / Q000187:drug effects; D058999:Drug-Seeking Behavior; D005108:Extinction, Psychological / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D013997:Time Factors; D000092468:Bromodomain Containing Proteins
chemical_list: D000779:Anesthetics, Local; D003042:Cocaine; D051548:Histone Acetyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C548159:BRD1 protein, rat; D000092468:Bromodomain Containing Proteins; C081018:histone H2B type 1-A; C583894:DOT1L protein, rat
keywords: Cocaine self-administration; Gene expression; Histone-modifying enzymes; Microarray; Posttranslational histone modifications