Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 30, Pages E4085-E4093Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1417222112
Keywords
addiction; alcohol; genetics; actin
Categories
Funding
- Academy of Finland [104781, 120315, 129269, 1114194, 24300796]
- Biocentrum Helsinki
- NIH [DA007290, F31AA021340, K08DK091316, R01GM084103, R01AA019526]
- University of Texas Southwestern Medical Center
- European Union [IMAGEN LSHM-CT-2007-037286, IMAGEMEND 602450, 603016, 115300-2, 277849]
- Medical Research Council [93558]
- Swedish Funding Agency Forskningsradet
- National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London
- German Bundesministerium fur Bildung und Forschung [eMED SysAlc 01ZX1311A]
- NIH Big Data to Knowledge U54 Grant Enhancing Neuro-Imaging Genetics Through Meta-Analysis Center for Worldwide Medicine, Imaging and Genomics
- Center of Excellence in Complex Disease Genetics
- SALVE
- University Hospital Oulu, Biocenter, University of Oulu [75617]
- National Heart, Lung, and Blood Institute [5R01HL087679-02, 1RL1MH083268-01]
- NIH/National Institute of Mental Health [R01MH63706: 02]
- ENGAGE Project
- Medical Research Council, United Kingdom [G0500539, G0600705, G1002319]
- Prevention of the Metabolic Syndrome by New Lifestyle Intervention Methods/SALVE
- [HEALTH-F4-2007-201413]
- Medical Research Council [MC_UP_0801/1, G0901858, G1002319, G9817803B, G0600705] Funding Source: researchfish
- MRC [G1002319, G0600705, G0901858, MC_UP_0801/1] Funding Source: UKRI
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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 naive preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naive preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons tomodulate naive 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.
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