title: Small-molecule screen in adult Drosophila identifies VMAT as a regulator of sleep.
abstract: Sleep is an important physiological state, but its function and regulation remain elusive. In Drosophila melanogaster, a useful model organism for studying sleep, forward genetic screens have identified important sleep-modulating genes and pathways; however, the results of such screens may be limited by developmental abnormalities or lethality associated with mutation of certain genes. To circumvent these limitations, we used a small-molecule screen to identify sleep-modulating genes and pathways. We administered 1280 pharmacologically active small molecules to adult flies and monitored their sleep. We found that administration of reserpine, a small-molecule inhibitor of the vesicular monoamine transporter (VMAT) that repackages monoamines into presynaptic vesicles, resulted in an increase in sleep. Supporting the idea that VMAT is the sleep-relevant target of reserpine, we found that VMAT-null mutants have an increased sleep phenotype, as well as an increased arousal threshold and resistance to the effects of reserpine. However, although the VMAT mutants are consistently resistant to reserpine, other aspects of their sleep phenotype are dependent on genetic background. These findings indicate that small-molecule screens can be used effectively to identify sleep-modulating genes whose phenotypes may be suppressed in traditional genetic screens. Mutations affecting single monoamine pathways did not affect reserpine sensitivity, suggesting that effects of VMAT/reserpine on sleep are mediated by multiple monoamines. Overall, we identify VMAT as an important regulator of sleep in Drosophila and demonstrate that small-molecule screens provide an effective approach to identify genes and pathways that impact adult Drosophila behavior.
authors: Cell and Molecular Biology Program and Department of Neuroscience, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Aleksandra H
authors: AH
authors: Nall
authors: Amita
authors: A
authors: Sehgal
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D014150:Antipsychotic Agents / Q000494:pharmacology; D001143:Arousal / Q000187:drug effects / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015306:Biogenic Monoamines / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D009154:Mutation; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D012890:Sleep / Q000187:drug effects / Q000235:genetics*; D012892:Sleep Deprivation; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D015306:Biogenic Monoamines; D029721:Drosophila Proteins; D012333:RNA, Messenger; D050493:Vesicular Monoamine Transport Proteins
references: Nat Rev Neurosci. 2010 Aug;11(8):589-99
references: 20631712
references: Int Rev Neurobiol. 2011;99:213-44
references: 21906542
references: Neuron. 2011 Dec 22;72(6):964-76
references: 22196332
references: Science. 1983 Jul 8;221(4606):182-4
references: 6857280
references: Neuron. 2000 Jan;25(1):129-38
references: 10707978
references: Science. 2008 Jul 18;321(5887):372-6
references: 18635795
references: Genetics. 2009 Feb;181(2):525-41
references: 19033154
references: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):834-9
references: 21187381
references: J Neurosci. 2005 Aug 10;25(32):7377-84
references: 16093388
references: Nature. 2002 May 16;417(6886):287-91
references: 12015603
references: Sleep. 2012 Apr 01;35(4):545-57
references: 22467993
references: Curr Biol. 2005 Jul 12;15(13):1165-75
references: 16005288
references: Nat Neurosci. 2008 Mar;11(3):354-9
references: 18223647
references: Nature. 2012 Oct 11;490(7419):262-6
references: 23034651
references: Curr Biol. 2006 Jun 6;16(11):1051-62
references: 16753559
references: Ann N Y Acad Sci. 2008;1129:335-49
references: 18591493
references: Behav Genet. 2002 Mar;32(2):89-94
references: 12036114
references: Curr Biol. 2008 Aug 5;18(15):R670-R679
references: 18682212
references: Science. 1963 Jul 5;141(3575):53-5
references: 13983757
references: J Neurosci. 2011 Sep 7;31(36):12759-66
references: 21900555
references: Med Res Rev. 2011 Jul;31(4):483-519
references: 20135628
references: Genes Dev. 2010 Jun 15;24(12):1220-35
references: 20551171
references: Sleep. 2008 Apr;31(4):465-72
references: 18457233
references: Bioinformatics. 2009 Jun 1;25(11):1466-7
references: 19369499
references: Science. 2000 Mar 10;287(5459):1834-7
references: 10710313
references: Nature. 2005 Apr 28;434(7037):1087-92
references: 15858564
references: Sleep. 2004 Jun 15;27(4):628-39
references: 15282997
references: Neuron. 2009 Nov 25;64(4):522-36
references: 19945394
references: Science. 2012 Mar 30;335(6076):1617-21
references: 22461610
references: Psychopharmacologia. 1971;19(2):134-47
references: 4327707
references: Genetics. 2011 Jul;188(3):731-43
references: 21515576
references: Methods Enzymol. 2005;393:759-72
references: 15817323
references: Cell. 2011 Jul 22;146(2):194-207
references: 21784243
references: Ann N Y Acad Sci. 1955 Apr 15;61(1):56-71
references: 14377272
references: Genetics. 2004 Jun;167(2):797-813
references: 15238529
references: Nature. 2008 Jan 31;451(7178):569-72
references: 18185515
references: Science. 2010 Jan 15;327(5963):348-51
references: 20075256
references: J Neurosci. 2008 Sep 17;28(38):9377-85
references: 18799671
references: Genetics. 2013 Jan;193(1):159-76
references: 23086220