García-Pérez Daniel, López-Bellido Roger, Hidalgo Juana M, Rodríguez Raquel E, Laorden Maria Luisa, Núñez Cristina, Milanés Maria Victoria
Group of Cellular and Molecular Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain; IMIB (Murcia Institute of Biomedical Investigation), Murcia, Spain.
Addict Biol. 2015 Jan;20(1):104-19. doi: 10.1111/adb.12083. Epub 2013 Aug 8.
Epigenetic changes such as microRNAs (miRs)/Ago2-induced gene silencing represent complex molecular signature that regulate cellular plasticity. Recent studies showed involvement of miRs and Ago2 in drug addiction. In this study, we show that changes in gene expression induced by morphine and morphine withdrawal occur with concomitant epigenetic modifications in the mesolimbic dopaminergic (DA) pathway [ventral tegmental area (VTA)/nucleus accumbens (NAc) shell], which is critically involved in drug-induced dependence. We found that acute or chronic morphine administration as well as morphine withdrawal did not modify miR-133b messenger RNA (mRNA) expression in the VTA, whereas Ago2 protein levels were decreased and increased in morphine-dependent rats and after morphine withdrawal, respectively. These changes were paralleled with enhanced and decreased NAc tyrosine hydroxylase (TH) protein (an early DA marker) in morphine-dependent rats and after withdrawal, respectively. We also observed changes in TH mRNA expression in the VTA that could be related to Ago2-induced translational repression of TH mRNA during morphine withdrawal. However, the VTA number of TH-positive neurons suffered no alterations after the different treatment. Acute morphine administration produced a marked increase in TH activity and DA turnover in the NAc (shell). In contrast, precipitated morphine withdrawal decreased TH activation and did not change DA turnover. These findings provide new information into the possible correlation between Ago2/miRs complex regulation and DA neurons plasticity during opiate addiction.
表观遗传变化，如微小RNA（miRs）/AGO2诱导的基因沉默，代表了调节细胞可塑性的复杂分子特征。最近的研究表明miRs和AGO2与药物成瘾有关。在本研究中，我们发现吗啡和吗啡戒断诱导的基因表达变化伴随着中脑边缘多巴胺能（DA）通路[腹侧被盖区（VTA）/伏隔核（NAc）壳]的表观遗传修饰，该通路在药物诱导的依赖性中起关键作用。我们发现，急性或慢性吗啡给药以及吗啡戒断均未改变VTA中miR-133b信使核糖核酸（mRNA）的表达，而AGO2蛋白水平在吗啡依赖大鼠中降低，在吗啡戒断后升高。这些变化分别与吗啡依赖大鼠和戒断后NAc酪氨酸羟化酶（TH）蛋白（一种早期DA标记物）的增加和减少平行。我们还观察到VTA中TH mRNA表达的变化，这可能与吗啡戒断期间AGO2诱导的TH mRNA翻译抑制有关。然而，不同处理后VTA中TH阳性神经元的数量没有改变。急性吗啡给药使NAc（壳）中的TH活性和DA周转率显著增加。相反，突然戒断吗啡会降低TH的活性，并且不会改变DA周转率。这些发现为阿片类药物成瘾期间AGO2/miRs复合物调节与DA神经元可塑性之间的可能相关性提供了新的信息。
