title: Rsu1 regulates ethanol consumption in Drosophila and humans.
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.
authors.affiliation: 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;
authors.forename: Shamsideen A
authors.initials: SA
authors.lastname: Ojelade
authors.affiliation: 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;
authors.forename: Tianye
authors.initials: T
authors.lastname: Jia
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390;
authors.forename: Aylin R
authors.initials: AR
authors.lastname: Rodan
authors.affiliation: Center for Computational Systems Biology, Faculty of Mathematics, Fudan University, Shanghai 200433, China; Department of Computer Science, Warwick University, Coventry CV4 7AL, United Kingdom;
authors.forename: Tao
authors.initials: T
authors.lastname: Chenyang
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112;
authors.forename: Julie L
authors.initials: JL
authors.lastname: Kadrmas
authors.affiliation: 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;
authors.forename: Anna
authors.initials: A
authors.lastname: Cattrell
authors.affiliation: 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;
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruggeri
authors.affiliation: 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;
authors.forename: Pimphen
authors.initials: P
authors.lastname: Charoen
authors.affiliation: 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;
authors.forename: Hervé
authors.initials: H
authors.lastname: Lemaitre
authors.affiliation: Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Heidelberg, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Banaschewski
authors.affiliation: Department for Systems Neuroscience, Universitätsklinikum Hamburg Eppendorf, D-20246 Hamburg, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Büchel
authors.affiliation: Institute of Neuroscience, Trinity College, Dublin 2, Ireland;
authors.forename: Arun L W
authors.initials: AL
authors.lastname: Bokde
authors.affiliation: 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;
authors.forename: Fabiana
authors.initials: F
authors.lastname: Carvalho
authors.affiliation: 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;
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Conrod
authors.affiliation: Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Heidelberg, Germany;
authors.forename: Herta
authors.initials: H
authors.lastname: Flor
authors.affiliation: Neurospin, Commissariat à l'Energie Atomique, 91191 Gif-sur-Yvette, France;
authors.forename: Vincent
authors.initials: V
authors.lastname: Frouin
authors.affiliation: Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin, 10117 Berlin, Germany;
authors.forename: Jürgen
authors.initials: J
authors.lastname: Gallinat
authors.affiliation: Institute of Neuroscience, Trinity College, Dublin 2, Ireland; Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT 05405;
authors.forename: Hugh
authors.initials: H
authors.lastname: Garavan
authors.affiliation: Sir Peter Mansfield Magnetic Resonance Centre, University of Nottingham, Nottingham NG7 2RD, United Kingdom;
authors.forename: Penny A
authors.initials: PA
authors.lastname: Gowland
authors.affiliation: Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin, 10117 Berlin, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Sir Peter Mansfield Magnetic Resonance Centre, University of Nottingham, Nottingham NG7 2RD, United Kingdom;
authors.forename: Bernd
authors.initials: B
authors.lastname: Ittermann
authors.affiliation: CEA, Centre National de Génotypage, 91057 Evry, France;
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: 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;
authors.forename: Steven
authors.initials: S
authors.lastname: Lubbe
authors.affiliation: 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;
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Martinot
authors.affiliation: 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;
authors.forename: Tomás
authors.initials: T
authors.lastname: Paus
authors.affiliation: Department of Psychiatry and Psychotherapy, Technische Universität Dresden, 01187 Dresden, Germany; Neuroimaging Center, Department of Psychology, Technische Universität Dresden, 01062 Dresden, Germany;
authors.forename: Michael N
authors.identifier: http://orcid.org/0000-0001-5398-5569
authors.initials: MN
authors.lastname: Smolka
authors.affiliation: Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Heidelberg, Germany;
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
authors.affiliation: 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;
authors.forename: Paul F
authors.initials: PF
authors.lastname: O'Reilly
authors.affiliation: Centre of Expertise for Health and Work Ability, Finnish Institute of Occupational Health, FI-00250, Helsinki, Finland;
authors.forename: Jaana
authors.initials: J
authors.lastname: Laitinen
authors.affiliation: Department of Psychiatry, University of Oulu and Oulu University Hospital, 90210, Oulu, Finland;
authors.forename: Juha M
authors.initials: JM
authors.lastname: Veijola
authors.affiliation: 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;
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Feng
authors.affiliation: 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;
authors.forename: Sylvane
authors.initials: S
authors.lastname: Desrivières
authors.affiliation: 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.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.affiliation: 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.
authors.forename: Gunter
authors.initials: G
authors.lastname: Schumann
authors.affiliation: 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.
authors.forename: Adrian
authors.initials: A
authors.lastname: Rothenfluh
mesh_terms: D000199:Actins / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002648:Child; D015331:Cohort Studies; D003599:Cytoskeleton / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D000431:Ethanol / Q000737:chemistry; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008297:Male; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D011110:Polymorphism, Genetic; D011795:Surveys and Questionnaires; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D000199:Actins; D015815:Cell Adhesion Molecules; D029721:Drosophila Proteins; D016023:Integrins; D014157:Transcription Factors; C495946:ics protein, Drosophila; C076224:RSU1 protein, human; D000431:Ethanol; D020558:GTP Phosphohydrolases
keywords: actin; addiction; alcohol; genetics