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

David Stacey, Ainhoa Bilbao, Matthieu Maroteaux, Tianye Jia, Alanna C. Easton, Sophie Longueville, Charlotte Nymberg, Tobias Banaschewski, Gareth J. Barker, Christian Buc̈hel, Fabiana Carvalho, Patricia J. Conrod, Sylvane Desrivier̀es, Mira Fauth-Buḧler, Alberto Fernandez-Medarde, Herta Flor, Jürgen Gallinat, Hugh Garavan, Arun L W Bokde, Andreas HeinzBernd Ittermann, Mark Lathrop, Claire Lawrence, Eva Loth, Anbarasu Lourdusamy, Karl F. Mann, Jean Luc Martinot, Frauke Nees, M. Palkóvits, 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

Research output: Contribution to journalArticle

52 Citations (Scopus)

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 meta-analysis 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 bothmice 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 IA 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 meta-analysis. 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.

Original languageEnglish
Pages (from-to)21128-21133
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number51
DOIs
Publication statusPublished - Dec 18 2012

Fingerprint

Guanine Nucleotide-Releasing Factor 2
ras-GRF1
Dopaminergic Neurons
Dopamine
Alcohols
Reward
Haplotypes
Alcoholism
Single Nucleotide Polymorphism
Meta-Analysis
Ethanol
Corpus Striatum
Functional Neuroimaging
Ventral Tegmental Area
MAP Kinase Signaling System
Genome-Wide Association Study
Genes
Drinking
Substance-Related Disorders
Motivation

Keywords

  • I current
  • Neuroimaging genetic reward-anticipation preference

ASJC Scopus subject areas

  • General

Cite this

RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release. / Stacey, David; Bilbao, Ainhoa; Maroteaux, Matthieu; Jia, Tianye; Easton, Alanna C.; Longueville, Sophie; Nymberg, Charlotte; Banaschewski, Tobias; Barker, Gareth J.; Buc̈hel, Christian; Carvalho, Fabiana; Conrod, Patricia J.; Desrivier̀es, Sylvane; Fauth-Buḧler, 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; Palkóvits, M.; 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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 51, 18.12.2012, p. 21128-21133.

Research output: Contribution to journalArticle

Stacey, D, Bilbao, A, Maroteaux, M, Jia, T, Easton, AC, Longueville, S, Nymberg, C, Banaschewski, T, Barker, GJ, Buc̈hel, C, Carvalho, F, Conrod, PJ, Desrivier̀es, S, Fauth-Buḧler, M, Fernandez-Medarde, A, Flor, H, Gallinat, J, Garavan, H, Bokde, ALW, Heinz, A, Ittermann, B, Lathrop, M, Lawrence, C, Loth, E, Lourdusamy, A, Mann, KF, Martinot, JL, Nees, F, Palkóvits, M, Paus, T, Pausova, Z, Rietschel, M, Ruggeri, B, Santos, E, Smolka, MN, Staehlin, O, Jarvelin, MR, Elliott, P, Sommer, WH, Mameli, M, Müller, CP, Spanagel, R, Girault, JA & Schumann, G 2012, 'RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 51, pp. 21128-21133. https://doi.org/10.1073/pnas.1211844110
Stacey, David ; Bilbao, Ainhoa ; Maroteaux, Matthieu ; Jia, Tianye ; Easton, Alanna C. ; Longueville, Sophie ; Nymberg, Charlotte ; Banaschewski, Tobias ; Barker, Gareth J. ; Buc̈hel, Christian ; Carvalho, Fabiana ; Conrod, Patricia J. ; Desrivier̀es, Sylvane ; Fauth-Buḧler, 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 ; Palkóvits, M. ; 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. / RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 51. pp. 21128-21133.
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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 meta-analysis 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 bothmice 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 IA 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 meta-analysis. 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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T1 - RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release

AU - Stacey, David

AU - Bilbao, Ainhoa

AU - Maroteaux, Matthieu

AU - Jia, Tianye

AU - Easton, Alanna C.

AU - Longueville, Sophie

AU - Nymberg, Charlotte

AU - Banaschewski, Tobias

AU - Barker, Gareth J.

AU - Buc̈hel, Christian

AU - Carvalho, Fabiana

AU - Conrod, Patricia J.

AU - Desrivier̀es, Sylvane

AU - Fauth-Buḧler, Mira

AU - Fernandez-Medarde, Alberto

AU - Flor, Herta

AU - Gallinat, Jürgen

AU - Garavan, Hugh

AU - Bokde, Arun L W

AU - Heinz, Andreas

AU - Ittermann, Bernd

AU - Lathrop, Mark

AU - Lawrence, Claire

AU - Loth, Eva

AU - Lourdusamy, Anbarasu

AU - Mann, Karl F.

AU - Martinot, Jean Luc

AU - Nees, Frauke

AU - Palkóvits, M.

AU - Paus, Tomas

AU - Pausova, Zdenka

AU - Rietschel, Marcella

AU - Ruggeri, Barbara

AU - Santos, Eugenio

AU - Smolka, Michael N.

AU - Staehlin, Oliver

AU - Jarvelin, Marjo Riitta

AU - Elliott, Paul

AU - Sommer, Wolfgang H.

AU - Mameli, Manuel

AU - Müller, Christian P.

AU - Spanagel, Rainer

AU - Girault, Jean Antoine

AU - Schumann, Gunter

PY - 2012/12/18

Y1 - 2012/12/18

N2 - 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 meta-analysis 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 bothmice 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 IA 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 meta-analysis. 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.

AB - 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 meta-analysis 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 bothmice 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 IA 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 meta-analysis. 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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