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

Details

Serval ID
serval:BIB_A73C4FE904B1
Type
Article: article from journal or magazin.
Collection
Publications
Title
RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Stacey D., Bilbao A., Maroteaux M., Jia T., Easton A.C., Longueville S., Nymberg C., Banaschewski T., Barker G.J., Büchel C., Carvalho F., Conrod P.J., Desrivières S., Fauth-Bühler M., Fernandez-Medarde A., Flor H., Gallinat J., Garavan H., Bokde A.L., Heinz A., Ittermann B., Lathrop M., Lawrence C., Loth E., Lourdusamy A., Mann K.F., Martinot J.L., Nees F., Palkovits M., Paus T., Pausova Z., Rietschel M., Ruggeri B., Santos E., Smolka M.N., Staehlin O., Jarvelin M.R., Elliott P., Sommer W.H., Mameli M., Müller C.P., Spanagel R., Girault J.A., Schumann G.
Working group(s)
IMAGEN Consortium
Contributor(s)
Albrecht L., Andrew C., Arroyo M., Artiges E., Aydin S., Bach C., Barbot A., Boddaert N., Bokde A., Bricaud Z., Bromberg U., Bruehl R., Cachia A., Cattrell A., Constant P., Crombag H., Czech K., Dalley J., Decideur B., Fadai T., Fernandes A., Frouin V., Fuchs B., Gollier Briand F., Gowland P., Head K., Heinrichs B., Heym N., Hübner T., Ihlenfeld A., Ireland J., Ivanov N., Jones J., Kepa A., Klaassen A., Lalanne C., Lanzerath D., Lemaitre H., Lubbe S., Lüdemann K., Mallik C., Mangin J.F., Mar A., Martinez-Medina L., Massicotte J., Mennigen E., Mignon X., Miranda R., Müller K., Paillere M.L., Pena-Oliver Y., Poline J.B., Poustka L., Rapp M., Reed L., Reuter J., Ripke S., Ripley T., Robbins T., Rodehacke S., Rogers J., Romanowski A., Schilling C., Schmäl C., Schmidt D., Schneider S., Schroeder M., Schubert F., Schwartz Y., Speiser C., Spranger T., Steiner S., Stephens D., Strache N., Ströhle A., Struve M., Subramaniam N., Tahmasebi A., Theobald D., Topper L., Vollstaedt-Klein S., Walaszek B., Werts H., Whelan R., Williams S., Yacubian J., Ziesch V., Zibovicius M., Wong C.P.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
18/12/2012
Peer-reviewed
Oui
Volume
109
Number
51
Pages
21128-21133
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.

Keywords
Adolescent, Animals, Brain/metabolism, Calcium/metabolism, Child, Dopamine/metabolism, Dopaminergic Neurons/metabolism, Electrophysiology/methods, Ethanol/pharmacology, Extracellular Signal-Regulated MAP Kinases/metabolism, Genotype, Haplotypes, Humans, Male, Mice, Mice, Transgenic, Neurons/metabolism, RNA, Messenger/metabolism, Reinforcement (Psychology), Time Factors, Ventral Tegmental Area/metabolism, ras Guanine Nucleotide Exchange Factors/genetics, ras Guanine Nucleotide Exchange Factors/physiology
Pubmed
Web of science
Open Access
Yes
Create date
31/01/2017 15:06
Last modification date
20/08/2019 15:12
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