Cocaine-induced epigenetic DNA modification in mouse addiction-specific and non-specific tissues
Cocaine-induced epigenetic DNA modification in mouse addiction-specific and non-specific tissues
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DOI：
10.1016/j.neuropharm.2018.06.036
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发表时间：
2018-09-01
影响因子：
4.7
通讯作者：
Kalda, Anti
中科院分区：
文献类型：
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作者：
Anier, Kaili;Urb, Mari;Kalda, Anti
可卡因相关的 DNA 甲基化研究主要集中在与药物成瘾相关的特定大脑区域（例如伏隔核，NAc）。迄今为止，还没有研究关注 DNA 甲基化和去甲基化在精神兴奋剂诱导的大脑和周围组织成瘾机制中的复杂作用。因此，在这项研究中，我们评估了可卡因治疗和戒断（动物从重复注射导致行为敏化的可卡因 7 天中戒断）对成瘾特异性大脑区域（NAc）中表观遗传 DNA 修饰剂（即 DNA 甲基转移酶，[DNMT] 和 10-11 易位酶 [TET]）的影响，NAc 是中脑边缘多巴胺能系统（小脑，Cer）外部的结构，以及外周血细胞 (PBC) 中。使用小鼠行为致敏模型，我们证明急性可卡因（AC；0.5小时）治疗显着降低NAc和PBC中的Dnmt1、Dnmt3a、Tet1和Tet2 mRNA水平，而AC治疗24小时后，Dnmt mRNA表达和酶活性水平显着增加。急性普鲁卡因治疗对 PBC 中 Dnmt3a mRNA 水平产生相反的影响；这一结果表明电压门控钠通道的抑制可能是改变 PBC 中 Dnmt 表达的机制。可卡因戒断与 NAc、Cer 和 PBC 中 Dnmts 表达增加以及 NAc 中 Tet1 和 Tet3 表达减少有关。此外，可卡因戒断增加了 DNMT，但降低了 TET 活性水平，这些变化与 NAc 和 PBC 中整体和选定候选基因启动子区 DNA 甲基化和羟甲基化水平的增强有关。总之，这些数据表明，可卡因治疗和戒断会影响成瘾特异性大脑结构以及中脑边缘多巴胺能系统和 PBC 之外的结构中表观遗传 DNA 修饰剂的表达。 (C) 2018 Elsevier Ltd. 保留所有权利。
Cocaine-related DNA methylation studies have primarily focused on the specific brain regions associated with drug addiction (e.g., the nucleus accumbens, NAc). To date, no studies have focused on the complex role of both DNA methylation and demethylation in the mechanisms of psychostimulant-induced addiction in the brain and peripheral tissues. Therefore, in this study, we evaluated cocaine treatment and withdrawal (animals were withdrawn from seven days of repeated injections of cocaine that caused behavioral sensitization) effects on epigenetic DNA modifiers (i.e., DNA methyltransferases, [DNMTs] and ten-eleven translocation enzymes [TETs]) in an addiction-specific brain region (NAc), a structure outside the mesolimbic dopaminergic system (cerebellum, Cer), and in peripheral blood cells (PBCs). Using a mouse behavioral sensitization model, we demonstrated that acute cocaine (AC; 0.5 h) treatment significantly decreased Dnmt1, Dnmt3a, Tet1, and Tet2 mRNA levels in the NAc and PBC, whereas at 24 h after AC treatment, Dnmt mRNA expression and enzyme activity levels were significantly increased. Acute procaine treatment caused the opposite effect on the Dnmt3a mRNA level in PBCs; this outcome suggests that the inhibition of voltage-gated sodium channels may be the mechanism that alters Dnmt expression in PBCs. Cocaine withdrawal is associated with increased expression of Dnmts in the NAc, Cer and PBCs and the decreased expression of Tet1 and Tet3 in the NAc. Additionally, cocaine withdrawal increased DNMT but decreased TET activity levels, and these changes were associated with enhanced global and selected candidate gene promoter-region DNA methylation and hydroxymethylation levels in the NAc and PBCs. Together, these data indicate that cocaine treatment and withdrawal affect the expression of epigenetic DNA modifiers in both addiction-specific brain structures and structures outside of the mesolimbic dopaminergic system and PBCs. (C) 2018 Elsevier Ltd. All rights reserved.