PT  - JOURNAL ARTICLE
AU  - Sami Ben Hamida
AU  - Jeremie Neasta
AU  - Amy W. Lasek
AU  - Viktor Kharazia
AU  - Mimi Zou
AU  - Sebastien Carnicella
AU  - Patricia H. Janak
AU  - Dorit Ron
TI  - The Small G Protein H-Ras in the Mesolimbic System Is a Molecular Gateway to Alcohol-Seeking and Excessive Drinking Behaviors
AID  - 10.1523/JNEUROSCI.2846-12.2012
DP  - 2012 Nov 07
TA  - The Journal of Neuroscience
PG  - 15849--15858
VI  - 32
IP  - 45
4099  - http://www.jneurosci.org/content/32/45/15849.short
4100  - http://www.jneurosci.org/content/32/45/15849.full
SO  - J. Neurosci.2012 Nov 07; 32
AB  - 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.