Molecular and Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, CA 92037, USA.
Brain Res. 2010 Jun 21;1339:1-10. doi: 10.1016/j.brainres.2010.03.063. Epub 2010 Apr 10.
Adaptations in the anterior cingulate cortex (ACC) have been implicated in alcohol and drug addiction. To identify genes that may contribute to excessive drinking, here we performed microarray analyses in laser microdissected rat ACC after a single or repeated administration of an intoxicating dose of alcohol (3 g/kg). Expression of the small G protein K-ras was differentially regulated following both single and repeated alcohol administration. We also observed that voluntary alcohol intake in K-ras heterozygous null mice (K-ras(+/-)) did not increase after withdrawal from repeated cycles of intermittent ethanol vapor exposure, unlike in their wild-type littermates. To identify K-ras regulated pathways, we then profiled gene expression in the ACC of K-ras(+/-), heterozygous null mice for the K-ras negative regulator Nf1 (Nf1(+/-)) and wild-type mice following repeated administration of an intoxicating dose of alcohol. Pathway analysis showed that alcohol differentially affected various pathways in a K-ras dependent manner - some of which previously shown to be regulated by alcohol - including the insulin/PI3K pathway, the NF-kappaB, the phosphodiesterases (PDEs) pathway, the Jak/Stat and the adipokine signaling pathways. Altogether, the data implicate K-ras-regulated pathways in the regulation of excessive alcohol drinking after a history of dependence.
扣带皮层（ACC）的适应性变化与酒精和药物成瘾有关。为了确定可能导致过度饮酒的基因，我们在单次或重复给予致醉剂量酒精（3g/kg）后，对激光微切割的大鼠 ACC 进行了微阵列分析。小 G 蛋白 K-ras 的表达在单次和重复酒精给药后都有差异调节。我们还观察到，在从重复的间歇性乙醇蒸气暴露周期中戒酒后，K-ras 杂合缺失小鼠（K-ras(+/-)）的自愿饮酒量并没有增加，而其野生型同窝小鼠则增加了。为了确定 K-ras 调节的途径，我们随后对 K-ras(+/-)、K-ras 负调节剂 Nf1 杂合缺失小鼠（Nf1(+/-)）和野生型小鼠的 ACC 中的基因表达进行了分析，这些小鼠在重复给予致醉剂量的酒精后。通路分析表明，酒精以 K-ras 依赖的方式对各种通路产生不同的影响 - 其中一些通路以前被证明是受酒精调节的 - 包括胰岛素/PI3K 通路、NF-kappaB、磷酸二酯酶（PDEs）通路、Jak/Stat 和脂肪因子信号通路。总之，这些数据表明，K-ras 调节的途径参与了依赖史后过度饮酒的调节。
