Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 50411, Estonia.
Institute of Chemistry, University of Tartu, Ravila 14a, Tartu 50411, Estonia.
Neuropharmacology. 2018 Sep 1;139:13-25. doi: 10.1016/j.neuropharm.2018.06.036. Epub 2018 Jun 28.
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 Therefore, in this study, we evaluated cocaine treatment and withdrawal (animals were withdrawn from seven days of repeated injections of cocaine that caused behavioral sensitization) effects on epigenetic DNA modifiers (i.e., DNA methyltransferases,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.
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，尚无研究关注 DNA 甲基化和去甲基化在大脑和外周组织中应激诱导成瘾的机制中的复杂作用。因此，在这项研究中，我们评估了可卡因治疗和戒断（动物从连续 7 天注射可卡因引起的行为敏化中戒断）对成瘾特异性脑区（NAc）、中脑边缘多巴胺系统以外的结构（小脑，Cer）和外周血细胞（PBC）中的表观遗传 DNA 修饰物（即 DNA 甲基转移酶[DNMTs]和十 - 十一易位酶[TETs]）的影响。使用小鼠行为敏化模型，我们证明了急性可卡因（AC；0.5 h）治疗可显著降低 NAc 和 PBC 中的 Dnmt1、Dnmt3a、Tet1 和 Tet2 mRNA 水平，而在 AC 治疗 24 h 后，Dnmt mRNA 表达和酶活性水平显著增加。急性普鲁卡因处理对 PBC 中 Dnmt3a mRNA 水平产生相反的影响；这一结果表明，电压门控钠离子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 的表达增加以及 NAc 中 Tet1 和 Tet3 的表达减少有关。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 中全基因组和选定候选基因启动子区域的 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脑结构和中脑边缘多巴胺系统以外的结构以及 PBC 中表观遗传 DNA 修饰物的表达。
