Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2012-12, Vol.109 (51), p.21128-21133

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.