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Rsu1 regulates ethanol consumption in Drosophila and humans

2015; National Academy of Sciences; Volume: 112; Issue: 30 Linguagem: Inglês

10.1073/pnas.1417222112

1091-6490

Shamsideen A. Ojelade, Tianye Jia, Aylin R. Rodan, Chenyang Tao, Julie L. Kadrmas, Anna Cattrell, Barbara Ruggeri, Pimphen Charoen, Hervé Lemaître, Tobias Banaschewski, Christian Büchel, Arun L.W. Bokde, Fabiana Carvalho, Patricia Conrod, Herta Flor, Vincent Frouin, Jürgen Gallinat, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Mark Lathrop, Steven Lubbe, Jean‐Luc Martinot, Tomáš Paus, Michael N. Smolka, Rainer Spanagel, Paul F. O’Reilly, Jaana Laitinen, Juha Veijola, Jianfeng Feng, Sylvane Desrivières, Marjo‐Riitta Järvelin, Günter Schumann, Adrian Rothenfluh, Lisa Albrecht, Mercedes Arroyo, Éric Artiges, Semiha Aydın, Christine Bach, Tobias Banaschewski, Alexis Barbot, Gareth J. Barker, Arun L.W. Bokde, Zuleima Bricaud, Uli Bromberg, Ruediger Bruehl, Christian Büchel, Anna Cattrell, Patricia Conrod, Katharina Czech, Jeffrey W. Dalley, Sylvane Desrivières, Tahmine Fadai, Herta Flor, Vincent Frouin, Jürgen Gallinat, Hugh Garavan, Fanny Gollier Briand, Penny Gowland, Bert Heinrichs, Andreas Heinz, Thomas Hübner, Albrecht Ihlenfeld, Alex Ing, Bernd Ittermann, Tianye Jia, Jennifer Jones, Eleanor Kennedy, Dirk Lanzerath, Mark Lathrop, Claire Lawrence, Hervé Lemaître, Katharina Lüdemann, Steven Lubbe, Christine Macare, Karl Mann, Adam C. Mar, Jean‐Luc Martinot, Eva Mennigen, Fabiana Mesquita de Carvahlo, Kathrin Müller, Frauke Nees, Charlotte Nymberg, Marie-Laure Paillère, Tomáš Paus, Zdenka Pausová, Jean‐Baptiste Poline, Luise Poustka, Erin Burke Quinlan, J.H. Reuter, Stephan Ripke, Trevor W. Robbins, Guillaume Robert, Sarah Rodehacke, Barbara Ruggeri, Dirk Schmidt, Sophia Schneider, Herta Flor, Michael N. Smolka, Wolfgang H. Sommer, Rainer Spanagel, Tade Matthias Spranger, Alicia Stedman, D.N. Stephens, Nicole Strache, Andreas Ströhle, Maren Struve, Naresh Subramaniam, Amir Tahmasebi, David Theobald, Nora C. Vetter, Hélène Vulser, Bernadeta Walaszek, Robert Whelan, Steven Williams, Bing Xu, Juliana Yacubian, Veronika Ziesch,

Zebrafish Biomedical Research Applications

Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high naïve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naïve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons to modulate naïve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating reward-related phenotypes, including ethanol consumption, across phyla.