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 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; 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

doi:10.1073/pnas.1211844110

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 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 HeinzBernd 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

Research output: Contribution to journal › Article › peer-review

79 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 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.

Original language	English
Pages (from-to)	21128-21133
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	109
Issue number	51
DOIs	https://doi.org/10.1073/pnas.1211844110
Publication status	Published - Dec 2012

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10.1073/pnas.1211844110

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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., ... The IMAGEN Consortium (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, 109(51), 21128-21133. https://doi.org/10.1073/pnas.1211844110

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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.",

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 {The IMAGEN Consortium}",

year = "2012",

month = dec,

doi = "10.1073/pnas.1211844110",

language = "English",

volume = "109",

pages = "21128--21133",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Acad Sciences",

number = "51",

}

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 & The IMAGEN Consortium 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

RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release. / Stacey, David; Bilbao, Ainhoa; Maroteaux, Matthieu et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 51, 12.2012, p. 21128-21133.

Research output: Contribution to journal › Article › peer-review

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 - The IMAGEN Consortium

PY - 2012/12

Y1 - 2012/12

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.

U2 - 10.1073/pnas.1211844110

DO - 10.1073/pnas.1211844110

M3 - Article

C2 - 23223532

SN - 0027-8424

VL - 109

SP - 21128

EP - 21133

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 51

ER -

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

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