Tesone-Coelho Carolina, Morel Lydie J, Bhatt Jeena, Estevez Lucie, Naudon Laurent, Giros Bruno, Zwiller Jean, Daugé Valérie
Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg, France.
Addict Biol. 2015 Jan;20(1):120-31. doi: 10.1111/adb.12084. Epub 2013 Aug 26.
We previously showed that maternal deprivation predisposes male rats to anxiety, accompanied with an increase in their opiate consumption. In the present report, we searched for brain epigenetic mechanisms that possibly underlie this increase. For that, we examined the expression of the methyl-CpG-binding protein MeCP2 and of the histone deacetylases HDAC2 and HDAC3, as well as the acetylation status of histone H3 and H4 in mesolimbic structures of adult maternally deprived rats, using immunohistochemistry and Western blot analysis. A long-lasting increase in MeCP2 expression was found throughout the striatum of deprived rats. Enhanced HDAC2 expression and increased nuclear HDAC activity in the nucleus accumbens of deprived rats were associated with lower acetylation levels of histone H3 and H4. Treatment for 3 weeks with the HDAC inhibitor sodium valproate abolished HDAC activation together with the decrease in the acetylation levels of histone H4, and was accompanied with normalized oral morphine consumption. The data indicate that epigenetic mechanisms induced by early adverse environment memorize life experience to trigger greater opiate vulnerability during adult life. They suggest that sodium valproate may lessen vulnerability to opiate intake, particularly in subgroups of individuals subjected to adverse postnatal environments.
我们之前的研究表明，母体剥夺会使雄性大鼠易患焦虑症，并伴有阿片类药物摄入量的增加。在本报告中，我们探寻了可能是导致这种增加的大脑表观遗传机制。为此，我们使用免疫组织化学和蛋白质印迹分析，检测了成年期经历母体剥夺的大鼠中脑边缘结构中甲基化CpG结合蛋白MeCP2、组蛋白去乙酰化酶HDAC2和HDAC3的表达，以及组蛋白H3和H4的乙酰化状态。在被剥夺大鼠的整个纹状体中发现MeCP2表达持续增加。被剥夺大鼠伏隔核中HDAC2表达增强和核HDAC活性增加与组蛋白H3和H4的乙酰化水平降低有关。用组蛋白去乙酰化酶抑制剂丙戊酸钠治疗3周可消除HDAC激活以及组蛋白H4乙酰化水平的降低，并伴有口服吗啡摄入量恢复正常。数据表明，早期不良环境诱导的表观遗传机制会记忆生活经历，从而在成年期引发更大的阿片类药物易感性。它们表明丙戊酸钠可能会降低阿片类药物摄入的易感性，尤其是在经历过不良产后环境的个体亚组中。
