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

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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; 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; Consortium, IMAGEN.

In: P NATL ACAD SCI USA, Vol. 109, No. 51, 51, 2012, p. 21128-21133.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Stacey, D, Bilbao, A, Maroteaux, M, Jia, T, Easton, AC, Longueville, S, Nymberg, C, Banaschewski, T, Barker, GJ, Büchel, C, Carvalho, F, Conrod, PJ, Desrivières, S, Fauth-Bühler, 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, J-L, Nees, F, Palkovits, M, Paus, T, Pausova, Z, Rietschel, M, Ruggeri, B, Santos, E, Smolka, MN, Staehlin, O, Jarvelin, M-R, Elliott, P, Sommer, WH, Mameli, M, Müller, CP, Spanagel, R, Girault, J-A, Schumann, G & Consortium, IMAGEN 2012, 'RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release.', P NATL ACAD SCI USA, vol. 109, no. 51, 51, pp. 21128-21133. <http://www.ncbi.nlm.nih.gov/pubmed/23223532?dopt=Citation>

APA

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. W., ... Consortium, IMAGEN. (2012). RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release. P NATL ACAD SCI USA, 109(51), 21128-21133. [51]. http://www.ncbi.nlm.nih.gov/pubmed/23223532?dopt=Citation

Vancouver

Stacey D, Bilbao A, Maroteaux M, Jia T, Easton AC, Longueville S et al. RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release. P NATL ACAD SCI USA. 2012;109(51):21128-21133. 51.

Bibtex

@article{6f0d25fd485c4fe5943d4e055c79530e,
title = "RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release.",
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 = "Animals, Humans, Male, Adolescent, Child, Time Factors, Genotype, Mice, Mice, Transgenic, Haplotypes, Neurons/*metabolism, Calcium/metabolism, Extracellular Signal-Regulated MAP Kinases/metabolism, RNA, Messenger/metabolism, Dopamine/*metabolism, Brain/metabolism, Reinforcement (Psychology), Dopaminergic Neurons/metabolism, Electrophysiology/methods, Ethanol/pharmacology, Ventral Tegmental Area/metabolism, ras Guanine Nucleotide Exchange Factors/*genetics/*physiology, Animals, Humans, Male, Adolescent, Child, Time Factors, Genotype, Mice, Mice, Transgenic, Haplotypes, Neurons/*metabolism, Calcium/metabolism, Extracellular Signal-Regulated MAP Kinases/metabolism, RNA, Messenger/metabolism, Dopamine/*metabolism, Brain/metabolism, Reinforcement (Psychology), Dopaminergic Neurons/metabolism, Electrophysiology/methods, Ethanol/pharmacology, Ventral Tegmental Area/metabolism, ras Guanine Nucleotide Exchange Factors/*genetics/*physiology",
author = "David Stacey and Ainhoa Bilbao and Matthieu Maroteaux and Tianye Jia and Easton, {Alanna C} and Sophie Longueville and Charlotte Nymberg and Tobias Banaschewski and Barker, {Gareth J} and Christian B{\"u}chel and Fabiana Carvalho and Conrod, {Patricia J} and Sylvane Desrivi{\`e}res and Mira Fauth-B{\"u}hler and Alberto Fernandez-Medarde and Herta Flor and J{\"u}rgen Gallinat and Hugh Garavan and Bokde, {Arun L W} and Andreas Heinz and Bernd Ittermann and Mark Lathrop and Claire Lawrence and Eva Loth and Anbarasu Lourdusamy and Mann, {Karl F} and Jean-Luc Martinot and Frauke Nees and Mikl{\'o}s Palkovits and Tomas Paus and Zdenka Pausova and Marcella Rietschel and Barbara Ruggeri and Eugenio Santos and Smolka, {Michael N} and Oliver Staehlin and Marjo-Riitta Jarvelin and Paul Elliott and Sommer, {Wolfgang H} and Manuel Mameli and M{\"u}ller, {Christian P} and Rainer Spanagel and Jean-Antoine Girault and Gunter Schumann and IMAGEN Consortium",
year = "2012",
language = "English",
volume = "109",
pages = "21128--21133",
journal = "P NATL ACAD SCI USA",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "51",

}

RIS

TY - JOUR

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 - Büchel, Christian

AU - Carvalho, Fabiana

AU - Conrod, Patricia J

AU - Desrivières, Sylvane

AU - Fauth-Bühler, 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 - Palkovits, Miklós

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

AU - Consortium, IMAGEN

PY - 2012

Y1 - 2012

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 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.

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 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.

KW - Animals

KW - Humans

KW - Male

KW - Adolescent

KW - Child

KW - Time Factors

KW - Genotype

KW - Mice

KW - Mice, Transgenic

KW - Haplotypes

KW - Neurons/metabolism

KW - Calcium/metabolism

KW - Extracellular Signal-Regulated MAP Kinases/metabolism

KW - RNA, Messenger/metabolism

KW - Dopamine/metabolism

KW - Brain/metabolism

KW - Reinforcement (Psychology)

KW - Dopaminergic Neurons/metabolism

KW - Electrophysiology/methods

KW - Ethanol/pharmacology

KW - Ventral Tegmental Area/metabolism

KW - ras Guanine Nucleotide Exchange Factors/genetics/physiology

KW - Animals

KW - Humans

KW - Male

KW - Adolescent

KW - Child

KW - Time Factors

KW - Genotype

KW - Mice

KW - Mice, Transgenic

KW - Haplotypes

KW - Neurons/metabolism

KW - Calcium/metabolism

KW - Extracellular Signal-Regulated MAP Kinases/metabolism

KW - RNA, Messenger/metabolism

KW - Dopamine/metabolism

KW - Brain/metabolism

KW - Reinforcement (Psychology)

KW - Dopaminergic Neurons/metabolism

KW - Electrophysiology/methods

KW - Ethanol/pharmacology

KW - Ventral Tegmental Area/metabolism

KW - ras Guanine Nucleotide Exchange Factors/genetics/physiology

M3 - SCORING: Journal article

VL - 109

SP - 21128

EP - 21133

JO - P NATL ACAD SCI USA

JF - P NATL ACAD SCI USA

SN - 0027-8424

IS - 51

M1 - 51

ER -