J Neurosci：科学家发现治疗酗酒的新靶点

2012年11月27日 讯 /生物谷BIOON/ --据加州大学旧金山分校的研究人员完成的一项研究证实一个关键脑蛋白水平的降低，能抑制大鼠和小鼠少饮酒和酗酒行为。

科学家们发现H-ras基因的蛋白质是一个很有前途的新的药物靶点来治疗酒精滥用。这项研究发表在11月7日的Journal of Neuroscience上。

Dorit Ron博士领导的研究首次发现酒精的摄入量显著增加动物伏隔核的H-ras基因水平，伏隔核是大脑活动区域，调控啮齿类动物和人类奖励制度，影响对酒精以及其它能使人成瘾物质的渴望。

然后，他们发现针对性的病毒作用于小鼠H-ras基因，抑制伏隔核H-ras基因水平后小鼠酒精消费量减少。

然后，研究人员给予动物FTI-276，已被证明能够抑​​制H-ras基因的产生，结果他们观察到酒精消费显著减少。

更重要的是H-ras基因被抑制时，老鼠对酒水，糖液，糖精和奎宁的消费不减少。研究已经表明，H-ras基因是一个治疗酒精滥用的可能的靶标。

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The small G protein H-Ras in the mesolimbic system is a molecular gateway to alcohol-seeking and excessive drinking behaviors.
Abstract
Uncontrolled consumption of alcohol is a hallmark of alcohol abuse disorders; however, the central molecular mechanisms underlying excessive alcohol consumption are still unclear. Here, we report that the GTP binding protein, H-Ras in the nucleus accumbens (NAc) plays a key role in neuroadaptations that underlie excessive alcohol-drinking behaviors. Specifically, acute (15 min) systemic administration of alcohol (2.5 g/kg) leads to the activation of H-Ras in the NAc of mice, which is observed even 24 h later. Similarly, rat operant self-administration of alcohol (20%) also results in the activation of H-Ras in the NAc. Using the same procedures, we provide evidence suggesting that the exchange factor GRF1 is upstream of H-Ras activation by alcohol. Importantly, we show that infection of mice NAc with lentivirus expressing a short hairpin RNA that targets the H-Ras gene produces a significant reduction of voluntary consumption of 20% alcohol. In contrast, knockdown of H-Ras in the NAc of mice did not alter water, quinine, and saccharin intake. Furthermore, using two-bottle choice and operant self-administration procedures, we show that inhibiting H-Ras activity by intra-NAc infusion of the farnesyltransferase inhibitor, FTI-276, produced a robust decrease of rats' alcohol drinking; however, sucrose consumption was unaltered. Finally, intra-NAc infusion of FTI-276 also resulted in an attenuation of seeking for alcohol. Together, these results position H-Ras as a central molecular mediator of alcohol's actions within the mesolimbic system and put forward the potential value of the enzyme as a novel target to treat alcohol use disorders