Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Estonia.
Institute of Chemistry, University of Tartu, Estonia.
Addict Biol. 2020 Jan;25(1):e12720. doi: 10.1111/adb.12720. Epub 2019 Feb 7.
An increasing number of reports have provided crucial evidence that epigenetic modifications, such as DNA methylation, may be involved in initiating and establishing psychostimulant-induced stable changes at the cellular level by coordinating the expression of gene networks, which then manifests as long-term behavioral changes. In this study, we evaluated the enzyme activity of DNA methyltransferases (DNMTs) after cocaine treatment and during withdrawal. Furthermore, we studied how genetic or pharmacological inhibition of DNMTs in mouse nucleus accumbens (NAc) affects the induction and expression of cocaine-induced behavioral sensitization. Our results showed that after silencing Dnmt3a in the NAc during the induction phase of cocaine-induced sensitization, overall DNMT activity decreases, correlating negatively with behavioral sensitization. Reduced Dnmt3a mRNA during this phase was the largest contributing factor for decreased DNMT activity. Cocaine withdrawal and a challenge dose increased DNMT activity in the NAc, which was associated with the expression of behavioral sensitization. Long-term selective Dnmt3a transcription silencing in the NAc did not alter DNMT activity or the expression of cocaine-induced behavioral sensitization. However, bilateral intra-NAc injection of a non-specific inhibitor of DNMT (RG108) during withdrawal from cocaine decreased DNMT activity in the NAc and had a small effect on the expression of cocaine-induced behavioral sensitization. Thus, cocaine treatment and withdrawal is associated with biphasic changes in DNMT activity in the NAc, and the expression of behavioral sensitization decreases with non-selective inhibition of DNMT but not with selective silencing of Dnmt3a.
越来越多的报告提供了重要证据，表明表观遗传修饰（如 DNA 甲基化）可能通过协调基因网络的表达，从而在细胞水平上参与启动和建立精神兴奋剂诱导的稳定变化，并表现为长期的行为变化。在这项研究中，我们评估了可卡因处理后和戒断期间 DNA 甲基转移酶（DNMTs）的酶活性。此外，我们研究了在小鼠伏隔核（NAc）中遗传或药理学抑制 DNMTs 如何影响可卡因诱导的行为敏感化的诱导和表达。我们的结果表明，在可卡因诱导的敏感化诱导阶段沉默 NAc 中的 Dnmt3a 后，整体 DNMT 活性降低，与行为敏感化呈负相关。在此阶段减少的 Dnmt3a mRNA 是导致 DNMT 活性降低的最大因素。可卡因戒断和挑战剂量增加了 NAc 中的 DNMT 活性，与行为敏感化的表达相关。在 NAc 中长期选择性沉默 Dnmt3a 转录不会改变 DNMT 活性或可卡因诱导的行为敏感化的表达。然而，在可卡因戒断期间双侧 NAc 内注射非特异性 DNMT 抑制剂（RG108）会降低 NAc 中的 DNMT 活性，并对可卡因诱导的行为敏感化的表达产生微小影响。因此，可卡因处理和戒断与 NAc 中 DNMT 活性的双相变化有关，并且行为敏感化的表达随着非选择性 DNMT 抑制而降低，但不随 Dnmt3a 的选择性沉默而降低。
