CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China.
Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
Addict Biol. 2020 Mar;25(2):e12730. doi: 10.1111/adb.12730. Epub 2019 Apr 5.
Drug-reinforced excessive operant responding is one fundamental feature of long-lasting addiction-like behaviors and relapse in animals. However, the transcriptional regulatory mechanisms responsible for the persistent drug-specific (not natural rewards) operant behavior are not entirely clear. In this study, we demonstrate a key role for one of the de novo DNA methyltransferase, DNMT3a, in the acquisition of morphine self-administration (SA) in rats. The expression of DNMT3a in the hippocampal CA1 region but not in the nucleus accumbens shell was significantly up-regulated after 1- and 7-day morphine SA (0.3 mg/kg/infusion) but not after the yoked morphine injection. On the other hand, saccharin SA did not affect the expression of DNMT3a or DNMT3b. DNMT inhibitor 5-aza-2-deoxycytidine (5-aza) microinjected into the hippocampal CA1 significantly attenuated the acquisition of morphine SA. Knockdown of DNMT3a also impaired the ability to acquire the morphine SA. Overall, these findings suggest that DNMT3a in the hippocampus plays an important role in the acquisition of morphine SA and may be a valid target to prevent the development of morphine addiction.
药物强化的过度操作性反应是动物长期成瘾样行为和复吸的一个基本特征。然而，负责持久的药物特异性（非自然奖励）操作性行为的转录调控机制尚不完全清楚。在这项研究中，我们证明了一种新的 DNA 甲基转移酶 DNMT3a 在大鼠吗啡自我给药（SA）获得中的关键作用。DNMT3a 的表达在海马 CA1 区而非伏隔核壳区在 1 天和 7 天的吗啡 SA（0.3mg/kg/次）后显著上调，但在配对的吗啡注射后没有上调。另一方面，蔗糖 SA 不影响 DNMT3a 或 DNMT3b 的表达。DNMT 抑制剂 5-氮杂-2-脱氧胞苷（5-aza）注入海马 CA1 区可显著减弱吗啡 SA 的获得。DNMT3a 的敲低也损害了获得吗啡 SA 的能力。总的来说，这些发现表明，海马中的 DNMT3a 在吗啡 SA 的获得中起着重要作用，可能是预防吗啡成瘾的有效靶点。
