Department of Physiology and Institute of Physiology and Biophysics, School of Medicine, University of Buenos Aires, Paraguay 2155 7thfloor (C1121ABG), Ciudad Autónoma de Buenos Aires, Argentina.
Laboratoire de Neurosciences Cognitives et Adaptatives, Université de Strasbourg, Strasbourg, France.
Mol Neurobiol. 2021 Jun;58(6):2590-2607. doi: 10.1007/s12035-020-02260-2. Epub 2021 Jan 21.
In zebrafish, nicotine is known to regulate sensitivity to psychostimulants via epigenetic mechanisms. Little however is known about the regulation of addictive-like behavior by DNA methylation processes. To evaluate the influence of DNA methylation on nicotine-induced conditioned place preference (CPP), zebrafish were exposed to methyl supplementation through oral L-methionine (Met) administration. Met was found to reduce dramatically nicotine-induced CPP as well as behaviors associated with drug reward. The reduction was associated with the upregulation of DNA methyltransferases (DNMT1 and 3) as well as with the downregulation of methyl-cytosine dioxygenase-1 (TET1) and of nicotinic receptor subunits. Met also increased the expression of histone methyltransferases in nicotine-induced CPP groups. It reversed the nicotine-induced reduction in the methylation at α7 and NMDAR1 gene promoters. Treatment with the DNMT inhibitor 5-aza-2'-deoxycytidine (AZA) was found to reverse the effects of Met in structures of the reward pathway. Interestingly, Met did not modify the amount of the phospho-form of CREB (pCREB), a key factor establishing nicotine conditioning, whereas AZA increased pCREB levels. Our data suggest that nicotine-seeking behavior is partially dependent on DNA methylation occurring probably at specific gene loci, such as α7 and NMDAR1 receptor gene promoters. Overall, they suggest that Met should be considered as a potential therapeutic drug to treat nicotine addiction.
在斑马鱼中，已知尼古丁通过表观遗传机制调节对精神兴奋剂的敏感性。然而，关于 DNA 甲基化过程对成瘾样行为的调节知之甚少。为了评估 DNA 甲基化对尼古丁诱导的条件性位置偏好 (CPP) 的影响，斑马鱼通过口服 L-蛋氨酸 (Met) 给药进行甲基补充。发现 Met 可显著减少尼古丁诱导的 CPP 以及与药物奖励相关的行为。这种减少与 DNA 甲基转移酶 (DNMT1 和 3) 的上调以及甲基胞嘧啶双加氧酶-1 (TET1) 和烟碱受体亚基的下调有关。Met 还增加了在尼古丁诱导的 CPP 组中组蛋白甲基转移酶的表达。它逆转了尼古丁诱导的 α7 和 NMDAR1 基因启动子甲基化减少。用 DNA 甲基转移酶抑制剂 5-氮杂-2'-脱氧胞苷 (AZA) 处理被发现可逆转 Met 在奖励途径结构中的作用。有趣的是，Met 没有改变磷酸化形式的 CREB(pCREB)的量，pCREB 是建立尼古丁条件的关键因素，而 AZA 增加了 pCREB 水平。我们的数据表明，尼古丁寻求行为部分依赖于可能发生在特定基因座（如 α7 和 NMDAR1 受体基因启动子）的 DNA 甲基化。总的来说，它们表明 Met 应该被认为是治疗尼古丁成瘾的潜在治疗药物。
