Rattus norvegicus breed:Sprague–Dawley Epigenomics

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 helps to segregate rats that reduce or stop their methamphetamine (METH) intake (non-addicted) from those that continue to take the drug compulsively (addicted) in the presence of footshocks. We use 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 to both control and non-addicted rats. Non-addicted 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 (LINEs and SINEs, respectively). Interestingly, differentially hydroxymethylated regions (DHMRs) 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 non-addicted rats were accompanied by increased mRNA levels of these potassium channels when compared to mRNA expression in METH-addicted rats. These observations indicate that changes in DHMRs 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.