title: 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.affiliation: Ernest Gallo Research Center and Department of Neurology, University of California, San Francisco, Emeryville, California 94608, USA.
authors.forename: Sami
authors.initials: S
authors.lastname: Ben Hamida
authors.forename: Jeremie
authors.initials: J
authors.lastname: Neasta
authors.forename: Amy W
authors.initials: AW
authors.lastname: Lasek
authors.forename: Viktor
authors.initials: V
authors.lastname: Kharazia
authors.forename: Mimi
authors.initials: M
authors.lastname: Zou
authors.forename: Sebastien
authors.initials: S
authors.lastname: Carnicella
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Janak
authors.forename: Dorit
authors.initials: D
authors.lastname: Ron
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D063425:Binge Drinking / Q000235:genetics / Q000378:metabolism*; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D013395:Sucrose / Q000494:pharmacology; D020666:ras-GRF1 / Q000235:genetics / Q000378:metabolism
chemical_list: C404062:FTI 276; D020666:ras-GRF1; D000431:Ethanol; D013395:Sucrose; D008715:Methionine; D051231:Farnesyltranstransferase; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)