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首页> 外文期刊>Molecular Psychiatry >Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence
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Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

机译：全基因组DNA羟甲基化识别伏隔核中的钾通道是甲基苯丙胺成瘾和戒酒的鉴别剂

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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.
机译：暴露于精神兴奋剂的表观遗传学后果是巨大的，但这些变化与强迫性吸毒和禁欲之间的关系尚不清楚。在这里，我们使用了一种范例，该范例有助于将减少或停止摄入甲基苯丙胺（METH）的大鼠与那些在有足部震颤的情况下继续强迫性服用该药物的大鼠隔离开来。我们使用该模型调查伏隔核（NAc）中全局DNA羟甲基化的潜在变化，因为NAc中的神经塑性变化可能参与了吸毒行为的发展和维持。我们发现，与对照和非成瘾大鼠相比，METH成瘾的大鼠确实显示出差异的DNA羟甲基化。不上瘾的大鼠也显示出与对照大鼠的差异。在成瘾的大鼠中观察到的差异DNA羟甲基化主要发生在长短穿插元件上的基因间位点。有趣的是，在未成年大鼠的NAc中观察到的编码电压（Kv1.1，Kv1.2，Kvb1和Kv2.2）和钙（Kcnma1，Kcnn1和Kcnn2）门控钾离子通道的基因中的羟甲基化区域存在差异与METH成瘾的大鼠的mRNA表达相比，这些钾离子通道的水平这些观察结果表明，NAc中不同的羟甲基化区域的变化和特定钾通道的表达增加，可能会促进戒毒行为。因此，激活电压和/或钙门控钾离子通道的特定亚类可能为METH成瘾的有益治疗提供重要途径。

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