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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.: H-Ras in the NAc and alcohol consumption

Sami Ben Hamida 1 Jeremie Neasta 1 Amy Lasek 1 Viktor Kharazia 1 Mimi Zou 1 Sebastien Carnicella 2 Patricia Janak 1, 3 Dorit Ron 1, 3, *
* Corresponding author
2 INSERM U836, équipe 10, Dynamique des réseaux neuronaux du mouvement
GIN - Grenoble Institut des Neurosciences, Department of neurology, Cell Biology of Addiction in Neurology
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.
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https://www.hal.inserm.fr/inserm-00802982
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Sami Ben Hamida, Jeremie Neasta, Amy Lasek, Viktor Kharazia, Mimi Zou, et al.. The small G protein H-Ras in the mesolimbic system is a molecular gateway to alcohol-seeking and excessive drinking behaviors.: H-Ras in the NAc and alcohol consumption. Journal of Neuroscience, Society for Neuroscience, 2012, 32 (45), pp.15849-58. ⟨10.1523/JNEUROSCI.2846-12.2012⟩. ⟨inserm-00802982⟩

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