Repunte-Canonigo Vez, Chen Jihuan, Lefebvre Celine, Kawamura Tomoya, Kreifeldt Max, Basson Oan, Roberts Amanda J, Sanna Pietro Paolo
Molecular and Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA.
Addict Biol. 2014 Sep;19(5):791-9. doi: 10.1111/adb.12047. Epub 2013 Feb 28.
We have investigated the expression of chromatin-regulating genes in the prefrontal cortex and in the shell subdivision of the nucleus accumbens during protracted withdrawal in mice with increased ethanol drinking after chronic intermittent ethanol (CIE) vapor exposure and in mice with a history of non-dependent drinking. We observed that the methyl-CpG binding protein 2 (MeCP2) was one of the few chromatin-regulating genes to be differentially regulated by a history of dependence. As MeCP2 has the potential of acting as a broad gene regulator, we investigated sensitivity to ethanol and ethanol drinking in MeCP2(308/) (Y) mice, which harbor a truncated MeCP2 allele but have a milder phenotype than MeCP2 null mice. We observed that MeCP2(308/) (Y) mice were more sensitive to ethanol's stimulatory and sedative effects than wild-type (WT) mice, drank less ethanol in a limited access 2 bottle choice paradigm and did not show increased drinking after induction of dependence with exposure to CIE vapors. Alcohol metabolism did not differ in MeCP2(308/) (Y) and WT mice. Additionally, MeCP2(308/) (Y) mice did not differ from WT mice in ethanol preference in a 24-hour paradigm nor in their intake of graded solutions of saccharin or quinine, suggesting that the MeCP2(308/) (Y) mutation did not alter taste function. Lastly, using the Gene Set Enrichment Analysis algorithm, we found a significant overlap in the genes regulated by alcohol and by MeCP2. Together, these results suggest that MeCP2 contributes to the regulation of ethanol sensitivity and drinking.
我们研究了慢性间歇性乙醇（CIE）蒸汽暴露后饮酒量增加的小鼠以及有非依赖性饮酒史的小鼠在长期戒断期间前额叶皮质和伏隔核壳部中染色质调节基因的表达。我们观察到，甲基化CpG结合蛋白2（MeCP2）是少数受依赖史差异调节的染色质调节基因之一。由于MeCP2有作为广泛基因调节因子的潜力，我们研究了携带截短MeCP2等位基因但表型比MeCP2基因敲除小鼠轻的MeCP2(308/)（Y）小鼠对乙醇和饮酒的敏感性。我们观察到，MeCP2(308/)（Y）小鼠比野生型（WT）小鼠对乙醇的刺激和镇静作用更敏感，在有限接触的两瓶选择范式中饮用的乙醇较少，并且在暴露于CIE蒸汽诱导依赖后饮酒量没有增加。MeCP2(308/)（Y）小鼠和WT小鼠的酒精代谢没有差异。此外，在24小时范式中，MeCP2(308/)（Y）小鼠与WT小鼠在乙醇偏好方面以及在糖精或奎宁分级溶液的摄入量方面没有差异，这表明MeCP2(308/)（Y）突变没有改变味觉功能。最后，使用基因集富集分析算法，我们发现受酒精和MeCP2调节的基因有显著重叠。总之，这些结果表明MeCP2有助于调节乙醇敏感性和饮酒行为。
