CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China.
Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
Addict Biol. 2021 Jan;26(1):e12875. doi: 10.1111/adb.12875. Epub 2020 Feb 7.
The development of opioid addiction involves DNA methylation. Accordingly, the DNA demethylation, induced by ten-eleven translocation (Tet) enzymes, may represent a novel approach to prevent opioid addiction. The present study examined the role of TET1 and TET3 in the development of morphine-seeking behavior in rats. We showed that 1 day of morphine self-administration (SA) training upregulated TET3 but not TET1 expression in the hippocampal CA1. With 7 days of morphine SA training, the expression of TET3 in the CA1 returned to the baseline level, while the TET1 expression was downregulated. No change of TET1 and TET3 in the nucleus accumbens shell was observed in morphine SA trained rats, or in the yoked morphine rats, or in rats trained for saccharin SA. Furthermore, we found that knocking down TET3 expression in the CA1 accelerated the acquisition of morphine SA, while overexpression of the catalytic domain of TET1 in the CA1 attenuated the acquisition. Together, these findings suggest that TET1 and TET3 in the CA1 are important epigenetic modulators involved in the morphine-seeking behavior and provide a new strategy in the treatment of opioid addiction.
阿片类药物成瘾的发展涉及 DNA 甲基化。因此，十号十一号转位（Tet）酶诱导的 DNA 去甲基化可能代表一种预防阿片类药物成瘾的新方法。本研究探讨了 TET1 和 TET3 在大鼠吗啡觅药行为发展中的作用。我们发现，1 天的吗啡自我给药（SA）训练上调了海马 CA1 中的 TET3，但没有上调 TET1 的表达。经过 7 天的吗啡 SA 训练，CA1 中的 TET3 表达回到基线水平，而 TET1 的表达下调。在吗啡 SA 训练的大鼠、配对吗啡的大鼠或蔗糖 SA 训练的大鼠中，没有观察到伏隔核壳中的 TET1 和 TET3 发生变化。此外，我们发现 CA1 中的 TET3 表达下调加速了吗啡 SA 的获得，而 CA1 中 TET1 的催化结构域的过表达则减弱了吗啡 SA 的获得。综上所述，这些发现表明 CA1 中的 TET1 和 TET3 是参与吗啡觅药行为的重要表观遗传调节剂，并为治疗阿片类药物成瘾提供了一种新策略。
