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.

• Authors: Sami Ben Hamida, Jeremie Neasta, Amy W Lasek, Viktor Kharazia, Mimi Zou, Sebastien Carnicella, Patricia H Janak, Dorit Ron
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 32 Issue 45 Pg. 15849-58 (Nov 07 2012) ISSN: 1529-2401 [Electronic] United States
• PMID: 23136424 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• FTI 276
• ras-GRF1
• Ethanol
• Sucrose
• Methionine
• Farnesyltranstransferase
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Alcohol Drinking (genetics, metabolism)
• Animals
• Binge Drinking (genetics, metabolism)
• Choice Behavior (drug effects, physiology)
• Ethanol (pharmacology)
• Farnesyltranstransferase (antagonists & inhibitors)
• Male
• Methionine (analogs & derivatives, pharmacology)
• Mice
• Mice, Transgenic
• Nucleus Accumbens (drug effects, metabolism)
• Phosphorylation
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Rats
• Rats, Long-Evans
• Sucrose (pharmacology)
• ras-GRF1 (genetics, metabolism)