Scholz Henrike, Franz Mirjam, Heberlein Ulrike
Department of Anatomy, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany.
Nature. 2005 Aug 11;436(7052):845-7. doi: 10.1038/nature03864.
Repeated alcohol consumption leads to the development of tolerance, simply defined as an acquired resistance to the physiological and behavioural effects of the drug. This tolerance allows increased alcohol consumption, which over time leads to physical dependence and possibly addiction. Previous studies have shown that Drosophila develop ethanol tolerance, with kinetics of acquisition and dissipation that mimic those seen in mammals. This tolerance requires the catecholamine octopamine, the functional analogue of mammalian noradrenaline. Here we describe a new gene, hangover, which is required for normal development of ethanol tolerance. hangover flies are also defective in responses to environmental stressors, such as heat and the free-radical-generating agent paraquat. Using genetic epistasis tests, we show that ethanol tolerance in Drosophila relies on two distinct molecular pathways: a cellular stress pathway defined by hangover, and a parallel pathway requiring octopamine. hangover encodes a large nuclear zinc-finger protein, suggesting a role in nucleic acid binding. There is growing recognition that stress, at both the cellular and systemic levels, contributes to drug- and addiction-related behaviours in mammals. Our studies suggest that this role may be conserved across evolution.
反复饮酒会导致耐受性的形成，简单来说，耐受性就是对药物的生理和行为效应产生的一种后天获得的抗性。这种耐受性会使饮酒量增加，随着时间的推移会导致身体依赖，甚至可能成瘾。先前的研究表明，果蝇会产生乙醇耐受性，其获得和消退的动力学过程与哺乳动物相似。这种耐受性需要儿茶酚胺章鱼胺，它是哺乳动物去甲肾上腺素的功能类似物。在此，我们描述了一个新基因——宿醉基因，它是乙醇耐受性正常发育所必需的。宿醉基因缺陷的果蝇对环境应激源，如热和产生活性氧的百草枯，也有反应缺陷。通过遗传上位性试验，我们表明果蝇的乙醇耐受性依赖于两条不同的分子途径：一条由宿醉基因定义的细胞应激途径，以及一条需要章鱼胺的平行途径。宿醉基因编码一种大型核锌指蛋白，表明其在核酸结合中发挥作用。人们越来越认识到，细胞和全身水平的应激都会导致哺乳动物的药物和成瘾相关行为。我们的研究表明，这种作用在进化过程中可能是保守的。
