title: Dynorphin/KOP and nociceptin/NOP gene expression and epigenetic changes by cocaine in rat striatum and nucleus accumbens.
abstract: Cocaine induces neurochemical changes of endogenous prodynorphin-kappa opioid receptor (pDYN-KOP) and pronociceptin/orphaninFQ-nociceptin receptor (pN/OFQ-NOP) systems. Both systems play an important role in rewarding mechanisms and addictive stimulus processing by modulating drug-induced dopaminergic activation in the mesocortico-limbic brain areas. They are also involved in regulating stress mechanisms related to addiction. The aim of this study was to investigate possible changes of gene expression of the dynorphinergic and nociceptinergic system components in the nucleus accumbens (NA) and in medial and lateral caudate putamen (mCPu and lCPu, respectively) of rats, following chronic subcutaneous infusion of cocaine. In addition, the epigenetic histone modifications H3K4me3 and H3K27me3 (an activating and a repressive marker, respectively) at the promoter level of the pDYN, KOP, pN/OFQ and NOP genes were investigated. Results showed that cocaine induced pDYN gene expression up-regulation in the NA and lCPu, and its down-regulation in the mCPu, whereas KOP mRNA levels were unchanged. Moreover, cocaine exposure decreased pN/OFQ gene expression in the NA and lCPu, while NOP mRNA levels appeared significantly increased in the NA and decreased in the lCPu. Specific changes of the H3K4me3 and H3K27me3 levels were found at pDYN, pN/OFQ, and NOP gene promoter, consistent with the observed gene expression alterations. The present findings contribute to better define the role of endogenous pDYN-KOP and pN/OFQ-NOP systems in neuroplasticity mechanisms following chronic cocaine treatment. The epigenetic histone modifications underlying the gene expression changes likely mediate the effects of cocaine on transcriptional regulation of specific gene promoters that result in long-lasting drug-induced plasticity.
authors.affiliation: Department of Pharmacy and Biotechnologies, Alma Mater Studiorum, University of Bologna, Irnerio 48, 40126 Bologna, Italy.
authors.forename: Francesca Felicia
authors.initials: FF
authors.lastname: Caputi
authors.affiliation: Department of Pharmacy and Biotechnologies, Alma Mater Studiorum, University of Bologna, Irnerio 48, 40126 Bologna, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Di Benedetto
authors.affiliation: Department of Pharmacy and Biotechnologies, Alma Mater Studiorum, University of Bologna, Irnerio 48, 40126 Bologna, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Carretta
authors.affiliation: Department of Pharmacy and Biotechnologies, Alma Mater Studiorum, University of Bologna, Irnerio 48, 40126 Bologna, Italy.
authors.forename: Sussy
authors.initials: S
authors.lastname: Bastias del Carmen Candia
authors.affiliation: Department of Pharmacy and Biotechnologies, Alma Mater Studiorum, University of Bologna, Irnerio 48, 40126 Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Addario
authors.affiliation: Department of Pharmacy and Biotechnologies, Alma Mater Studiorum, University of Bologna, Irnerio 48, 40126 Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cavina
authors.affiliation: Department of Pharmacy and Biotechnologies, Alma Mater Studiorum, University of Bologna, Irnerio 48, 40126 Bologna, Italy.
authors.forename: Sanzio
authors.initials: S
authors.lastname: Candeletti
authors.affiliation: Department of Pharmacy and Biotechnologies, Alma Mater Studiorum, University of Bologna, Irnerio 48, 40126 Bologna, Italy. Electronic address: patrizia.romualdi@unibo.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Romualdi
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004399:Dynorphins / Q000096:biosynthesis / Q000235:genetics*; D004745:Enkephalins / Q000096:biosynthesis / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D018847:Opioid Peptides / Q000096:biosynthesis / Q000235:genetics; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011957:Receptors, Opioid / Q000096:biosynthesis / Q000235:genetics*; D017473:Receptors, Opioid, kappa / Q000096:biosynthesis / Q000235:genetics*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D003042:Cocaine; D004399:Dynorphins; D004745:Enkephalins; D006657:Histones; D018847:Opioid Peptides; D011498:Protein Precursors; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C033660:preproenkephalin; C000722285:Oprl1 protein, rat
keywords: CPu; ChIP; Cocaine; DOP; DYN; Epigenetic; H3K27me3; H3K4me3; KOP; MOP; N/OFQ; NA; NOP; Prodynorphin; Pronociceptin; RT-qPCR; Rat; caudate-putamen; chromatin immunoprecipitation; delta-opioid receptor; dynorphin; kappa-opioid receptor; lCPu; lateral caudate-putamen; mCPu; medial caudate-putamen; mu-opioid receptor; nociceptin; nucleus accumbens; orphaninFQ-nociceptin receptor; real-time quantitative polymerase chain reaction; trimethylation of H3 at Lys27; trimethylation of H3 at Lys4 level