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Proc Natl Acad Sci U S A. 2015 Jul 28;112(30):E4085-93. doi: 10.1073/pnas.1417222112. Epub 2015 Jul 13.

Rsu1 regulates ethanol consumption in Drosophila and humans.

Author information

1
Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390; Program in Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390;
2
Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom; Medical Research Council (MRC) Social, Genetic and Developmental Psychiatry Centre, London SE5 8AF, United Kingdom;
3
Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390;
4
Center for Computational Systems Biology, Faculty of Mathematics, Fudan University, Shanghai 200433, China; Department of Computer Science, Warwick University, Coventry CV4 7AL, United Kingdom;
5
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112;
6
Department of Epidemiology and Biostatistics, MRC Health Protection Agency Centre for Environment and Health, School of Public Health, Imperial College London W2 1PG, London, United Kingdom; Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
7
INSERM, INSERM Commissariat à l'Energie Atomique (CEA) Unit 1000 Imaging and Psychiatry, University Paris Sud, 91401 Orsay, France; Assistance Publique Hôpitaux de Paris Department of Adolescent Psychopathology and Medicine, Maison de Solenn, University Paris Descartes, 75013 Paris, France;
8
Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Heidelberg, Germany;
9
Department for Systems Neuroscience, Universitätsklinikum Hamburg Eppendorf, D-20246 Hamburg, Germany;
10
Institute of Neuroscience, Trinity College, Dublin 2, Ireland;
11
Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom; Department of Psychiatry, Université de Montreal, Centre Hospitalier Universitaire Ste Justine Hospital, Montreal, QC, Canada H3T 1C5;
12
Neurospin, Commissariat à l'Energie Atomique, 91191 Gif-sur-Yvette, France;
13
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin, 10117 Berlin, Germany;
14
Institute of Neuroscience, Trinity College, Dublin 2, Ireland; Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT 05405;
15
Sir Peter Mansfield Magnetic Resonance Centre, University of Nottingham, Nottingham NG7 2RD, United Kingdom;
16
CEA, Centre National de Génotypage, 91057 Evry, France;
17
School of Psychology, University of Nottingham, Nottingham NG7 2RD, United Kingdom; Rotman Research Institute, University of Toronto, Toronto, Ontario, Canada M6A 2E1; Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4;
18
Department of Psychiatry and Psychotherapy, Technische Universität Dresden, 01187 Dresden, Germany; Neuroimaging Center, Department of Psychology, Technische Universität Dresden, 01062 Dresden, Germany;
19
Centre of Expertise for Health and Work Ability, Finnish Institute of Occupational Health, FI-00250, Helsinki, Finland;
20
Department of Psychiatry, University of Oulu and Oulu University Hospital, 90210, Oulu, Finland;
21
Center for Computational Systems Biology, Faculty of Mathematics, Fudan University, Shanghai 200433, China; Department of Computer Science, Warwick University, Coventry CV4 7AL, United Kingdom; School of Life Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200433, China;
22
Department of Epidemiology and Biostatistics, MRC Health Protection Agency Centre for Environment and Health, School of Public Health, Imperial College London W2 1PG, London, United Kingdom; Institute of Health Sciences, University of Oulu, FI-90014, Oulu, Finland; Biocenter Oulu, University of Oulu, FI-90014, Oulu, Finland; Unit of Primary Care, Oulu University Hospital, FI-90220, Oulu, Finland; Department of Children and Young People and Families, National Institute for Health and Welfare, FI-90101, Oulu, Finland.
23
Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom; Medical Research Council (MRC) Social, Genetic and Developmental Psychiatry Centre, London SE5 8AF, United Kingdom; Gunter.Schumann@kcl.ac.uk Adrian.Rothenfluh@utsouthwestern.edu.
24
Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390; Program in Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390; Gunter.Schumann@kcl.ac.uk Adrian.Rothenfluh@utsouthwestern.edu.

Abstract

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.

KEYWORDS:

actin; addiction; alcohol; genetics

Comment in

PMID:
26170296
PMCID:
PMC4522778
DOI:
10.1073/pnas.1417222112
[Indexed for MEDLINE]
Free PMC Article

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