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RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release

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David Stacey, Ainhoa Bilbao, Matthieu Maroteaux, Tianye Jia, Alanna C Easton, Sophie Longueville, Charlotte Nymberg, Tobias Banaschewski, Gareth J Barker, Christian Büchel, Fabiana Carvalho, Patricia J Conrod, Sylvane Desrivières, Mira Fauth-Bühler, Alberto Fernandez-Medarde, Herta Flor, Jürgen Gallinat, Hugh Garavan, Arun L W Bokde, Andreas Heinz & 25 more Bernd Ittermann, Mark Lathrop, Claire Lawrence, Eva Loth, Anbarasu Lourdusamy, Karl F Mann, Jean-Luc Martinot, Frauke Nees, Miklós Palkovits, Tomas Paus, Zdenka Pausova, Marcella Rietschel, Barbara Ruggeri, Eugenio Santos, Michael N Smolka, Oliver Staehlin, Marjo-Riitta Jarvelin, Paul Elliott, Wolfgang H Sommer, Manuel Mameli, Christian P Müller, Rainer Spanagel, Jean-Antoine Girault, Gunter Schumann, The IMAGEN Consortium

Original languageEnglish
Pages (from-to)21128-21133
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number51
Publication statusPublished - Dec 2012

King's Authors


The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca(2+)-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2(-/-) mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2(-/-) mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I(A) potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive-delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.

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