title: Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving.
abstract: One of the major challenges of cocaine addiction is the high rate of relapse to drug use after periods of withdrawal. During the first few weeks of withdrawal, cue-induced cocaine craving intensifies, or "incubates," and persists over extended periods of time. Although several brain regions and molecular mechanisms were found to be involved in this process, the underlying epigenetic mechanisms are still unknown. Herein, we used a rat model of incubation of cocaine craving, in which rats were trained to self-administer cocaine (0.75 mg/kg, 6 h/d, 10 d), and cue-induced cocaine-seeking was examined in an extinction test after 1 or 30 d of withdrawal. We show that the withdrawal periods, as well as cue-induced cocaine seeking, are associated with broad, time-dependent enhancement of DNA methylation alterations in the nucleus accumbens (NAc). These gene methylation alterations were partly negatively correlated with gene expression changes. Furthermore, intra-NAc injections of a DNA methyltransferase inhibitor (RG108, 100 μm) abolished cue-induced cocaine seeking on day 30, an effect that persisted 1 month, whereas the methyl donor S-adenosylmethionine (500 μm) had an opposite effect on cocaine seeking. We then targeted two proteins whose genes were demethylated by RG108-estrogen receptor 1 (ESR1) and cyclin-dependent kinase 5 (CDK5). Treatment with an intra-NAc injection of the ESR1 agonist propyl pyrazole triol (10 nm) or the CDK5 inhibitor roscovitine (28 μm) on day 30 of withdrawal significantly decreased cue-induced cocaine seeking. These results demonstrate a role for NAc DNA methylation, and downstream targets of DNA demethylation, in incubation of cocaine craving.
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Renaud
authors.initials: R
authors.lastname: Massart
authors.affiliation: Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan 52900, Israel, Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Royi
authors.initials: R
authors.lastname: Barnea
authors.affiliation: Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan 52900, Israel, Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Yahav
authors.initials: Y
authors.lastname: Dikshtein
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada, McGill Centre for Bioinformatics, McGill University, Montreal, Quebec H3G 0B1, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Suderman
authors.affiliation: Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan 52900, Israel, Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Meir
authors.affiliation: McGill Centre for Bioinformatics, McGill University, Montreal, Quebec H3G 0B1, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Hallett
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, and.
authors.forename: Pamela
authors.initials: P
authors.lastname: Kennedy
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, and.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada, Sackler Program for Epigenetics and Psychobiology, McGill University, Montreal, Quebec H3G 0B1, Canada moshe.szyf@mcgill.ca yadidg@gmail.comgmail.com.
authors.forename: Moshe
authors.initials: M
authors.lastname: Szyf
authors.affiliation: Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan 52900, Israel, Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel, moshe.szyf@mcgill.ca yadidg@gmail.comgmail.com.
authors.forename: Gal
authors.initials: G
authors.lastname: Yadid
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D066249:Craving / Q000187:drug effects / Q000502:physiology*; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration
chemical_list: D003042:Cocaine
keywords: DNA methylation; cocaine addiction; incubation of cocaine craving; nucleus accumbens