The Small G Protein H-Ras in the Mesolimbic System Is a Molecular Gateway to Alcohol-Seeking and Excessive Drinking Behaviors

被引:32
作者
Ben Hamida, Sami [1 ]
Neasta, Jeremie [1 ]
Lasek, Amy W. [1 ]
Kharazia, Viktor [1 ]
Zou, Mimi [1 ]
Carnicella, Sebastien [1 ,2 ]
Janak, Patricia H. [1 ,2 ]
Ron, Dorit [1 ,2 ]
机构
[1] Univ Calif, Ernest Gallo Res Ctr, Emeryville, CA 94608 USA
[2] Univ Calif, Dept Neurol, Emeryville, CA 94608 USA
基金
美国国家卫生研究院;
关键词
LONG-TERM-MEMORY; SIGNALING PATHWAY; EXCHANGE FACTOR; ETHANOL-CONSUMPTION; NEUROTROPHIC FACTOR; PYRAMIDAL NEURONS; RNA INTERFERENCE; PLASTICITY; PHOSPHORYLATION; ADDICTION;
D O I
10.1523/JNEUROSCI.2846-12.2012
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:15849 / 15858
页数:10
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