title: Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence.
abstract: Epigenetic consequences of exposure to psychostimulants are substantial but the relationship of these changes to compulsive drug taking and abstinence is not clear. Here, we used a paradigm that helped to segregate rats that reduce or stop their methamphetamine (METH) intake (nonaddicted) from those that continue to take the drug compulsively (addicted) in the presence of footshocks. We used that model to investigate potential alterations in global DNA hydroxymethylation in the nucleus accumbens (NAc) because neuroplastic changes in the NAc may participate in the development and maintenance of drug-taking behaviors. We found that METH-addicted rats did indeed show differential DNA hydroxymethylation in comparison with both control and nonaddicted rats. Nonaddicted rats also showed differences from control rats. Differential DNA hydroxymethylation observed in addicted rats occurred mostly at intergenic sites located on long and short interspersed elements. Interestingly, differentially hydroxymethylated regions in genes encoding voltage (Kv1.1, Kv1.2, Kvb1 and Kv2.2)- and calcium (Kcnma1, Kcnn1 and Kcnn2)-gated potassium channels observed in the NAc of nonaddicted rats were accompanied by increased mRNA levels of these potassium channels when compared with mRNA expression in METH-addicted rats. These observations indicate that changes in differentially hydroxymethylated regions and increased expression of specific potassium channels in the NAc may promote abstinence from drug-taking behaviors. Thus, activation of specific subclasses of voltage- and/or calcium-gated potassium channels may provide an important approach to the beneficial treatment for METH addiction.
authors.affiliation: Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Cadet
authors.affiliation: Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Brannock
authors.affiliation: Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD, USA.
authors.forename: I N
authors.initials: IN
authors.lastname: Krasnova
authors.affiliation: Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Jayanthi
authors.affiliation: Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD, USA.
authors.forename: B
authors.initials: B
authors.lastname: Ladenheim
authors.affiliation: Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: McCoy
authors.affiliation: Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Walther
authors.affiliation: Département de Biologie, École Normale Supérieure de Lyon, Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Godino
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: M
authors.identifier: 0000-0002-4210-6458
authors.initials: M
authors.lastname: Pirooznia
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Lee
mesh_terms: D000818:Animals; D016739:Behavior, Addictive; D000697:Central Nervous System Stimulants; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D008297:Male; D008694:Methamphetamine / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000697:Central Nervous System Stimulants; D015221:Potassium Channels; D008694:Methamphetamine; D004247:DNA; D011188:Potassium