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

D. Stacey, A. Bilbao, M. Maroteaux, T. Jia, A. C. Easton, S. Longueville, C. Nymberg, T. Banaschewski, G. J. Barker, C. Buchel, F. Carvalho, P. J. Conrod, S. Desrivieres, M. Fauth-Buhler, A. Fernandez-Medarde, H. Flor, J. Gallinat, H. Garavan, A. L. W. Bokde, A. Heinz, B. Ittermann, M. Lathrop, C. Lawrence, E. Loth, A. Lourdusamy, K. F. Mann, J.-L. Martinot, F. Nees, M. Palkovits, T. Paus, Z. Pausova, M. Rietschel, B. Ruggeri, E. Santos, M. N. Smolka, O. Staehlin, M.-R. Jarvelin, P. Elliott, W. H. Sommer, M. Mameli, C. P. Muller, R. Spanagel, J.-A. Girault, G. Schumann,
Proceedings of the National Academy of Sciences. 2012-12-05; 109(51): 21128-21133
DOI: 10.1073/pnas.1211844110

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Stacey D(1), 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 AL,
Heinz A, Ittermann B, Lathrop M, Lawrence C, Loth E, Lourdusamy A, Mann KF,
Martinot JL, Nees F, Palkovits 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; IMAGEN Consortium.

Collaborators: 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 JF, Mar A,
Martinez-Medina L, Massicotte J, Mennigen E, Mignon X, Miranda R, Müller K,
Paillere ML, Pena-Oliver Y, Poline JB, 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 CP.

Author information:
(1)Institute of Psychiatry, King’s College, London SE5 8AF, United Kingdom.

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.

Auteurs Bordeaux Neurocampus