title: Discovering novel neuroactive drugs through high-throughput behavior-based chemical screening in the zebrafish.
abstract: Most neuroactive drugs were discovered through unexpected behavioral observations. Systematic behavioral screening is inefficient in most model organisms. But, automated technologies are enabling a new phase of discovery-based research in central nervous system (CNS) pharmacology. Researchers are using large-scale behavior-based chemical screens in zebrafish to discover compounds with new structures, targets, and functions. These compounds are powerful tools for understanding CNS signaling pathways. Substantial differences between human and zebrafish biology will make it difficult to translate these discoveries to clinical medicine. However, given the molecular genetic similarities between humans and zebrafish, it is likely that some of these compounds will have translational utility. We predict that the greatest new successes in CNS drug discovery will leverage many model systems, including in vitro assays, cells, rodents, and zebrafish.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School Charlestown, MA, USA.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Bruni
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School Charlestown, MA, USA.
authors.forename: Parth
authors.initials: P
authors.lastname: Lakhani
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School Charlestown, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kokel
keywords: antipsychotics; behavior-based drug discovery; phenomics; screening; zebrafish
references.citation: NCHS Data Brief. 2010 Sep;(42):1-8
references.pmid: 20854747
references.citation: Psychopharmacologia. 1968 Sep 20;13(3):222-57
references.pmid: 5679627
references.citation: Nat Commun. 2013;4:2410
references.pmid: 24002024
references.citation: Nat Biotechnol. 2009 Dec;27(12):1077-8
references.pmid: 20010575
references.citation: JAMA. 2011 Sep 28;306(12):1359-69
references.pmid: 21954480
references.citation: Nat Neurosci. 2010 Aug;13(8):1027-32
references.pmid: 20581843
references.citation: Nat Commun. 2013;4:1467
references.pmid: 23403568
references.citation: Neuron. 2007 May 24;54(4):535-45
references.pmid: 17521567
references.citation: Brain Res Bull. 2008 Mar 28;75(5):619-28
references.pmid: 18355638
references.citation: Curr Biol. 2010 Feb 23;20(4):381-6
references.pmid: 20153194
references.citation: Genesis. 2010 Jun;48(6):354-61
references.pmid: 20533403
references.citation: Nat Biotechnol. 2013 Mar;31(3):227-9
references.pmid: 23360964
references.citation: J Neurosci. 2006 Dec 20;26(51):13400-10
references.pmid: 17182791
references.citation: Bioinformatics. 2008 Aug 1;24(15):1733-4
references.pmid: 18596077
references.citation: Brain Res Bull. 2011 Apr 25;85(1-2):58-63
references.pmid: 21371538
references.citation: J Neurosci Methods. 2012 Sep 30;210(2):266-71
references.pmid: 22884772
references.citation: Zebrafish. 2013 Mar;10(1):70-86
references.pmid: 23590400
references.citation: Acta Psychiatr Scand Suppl. 2004;(420):55-64
references.pmid: 15128388
references.citation: Behav Brain Res. 2013 Jun 15;247:1-8
references.pmid: 23518435
references.citation: Curr Biol. 2010 Dec 21;20(24):2211-6
references.pmid: 21145744
references.citation: Curr Biol. 2013 Feb 18;23(4):307-11
references.pmid: 23375894
references.citation: Pharmacol Biochem Behav. 2013 Jul;108:54-60
references.pmid: 23583441
references.citation: Nat Rev Cancer. 2007 Jan;7(1):54-60
references.pmid: 17186018
references.citation: J Neurosci. 2005 Oct 5;25(40):9294-303
references.pmid: 16207889
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21347-52
references.pmid: 19934034
references.citation: Nat Methods. 2010 Aug;7(8):634-6
references.pmid: 20639868
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D887-94
references.pmid: 22102583
references.citation: Nucleic Acids Res. 2011 Jul;39(Web Server issue):W486-91
references.pmid: 21576229
references.citation: J Psychiatry Neurosci. 2006 May;31(3):168-76
references.pmid: 16699602
references.citation: Nat Rev Drug Discov. 2009 Apr;8(4):286-95
references.pmid: 19337271
references.citation: Zebrafish. 2004;1(1):40-5
references.pmid: 18248204
references.citation: Nature. 2012 Oct 11;490(7419):187-91
references.pmid: 23060188
references.citation: Brief Funct Genomic Proteomic. 2008 Nov;7(6):483-90
references.pmid: 18784194
references.citation: Front Neural Circuits. 2013 Jan 25;6:125
references.pmid: 23355810
references.citation: Curr Biol. 2012 Mar 20;22(6):538-44
references.pmid: 22365850
references.citation: J Pharmacol Exp Ther. 2009 May;329(2):404-11
references.pmid: 19182069
references.citation: Zebrafish. 2014 Jun;11(3):185-97
references.pmid: 24575942
references.citation: J Neurosci. 2008 Oct 1;28(40):10102-10
references.pmid: 18829968
references.citation: PLoS One. 2011;6(10):e26510
references.pmid: 22039502
references.citation: Nat Rev Drug Discov. 2010 Mar;9(3):203-14
references.pmid: 20168317
references.citation: Nat Chem Biol. 2013 Apr;9(4):257-63
references.pmid: 23396078
references.citation: Development. 2013 Sep;140(18):3927-31
references.pmid: 23946442
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15468-73
references.pmid: 21876167
references.citation: Neuropharmacology. 2012 Jan;62(1):135-43
references.pmid: 21843537
references.citation: J Clin Psychiatry. 2014 Feb;75(2):169-77
references.pmid: 24345349
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19126-31
references.pmid: 18025459
references.citation: PLoS Comput Biol. 2011 Nov;7(11):e1002282
references.pmid: 22125487
references.citation: J Neurophysiol. 2012 Jul;108(1):148-59
references.pmid: 22490555
references.citation: Nat Rev Drug Discov. 2008 Jan;7(1):68-83
references.pmid: 18064038
references.citation: Nat Methods. 2013 May;10(5):413-20
references.pmid: 23524393
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2012 Jan;155(1):33-8
references.pmid: 21382508
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2012 Apr 27;37(1):194-202
references.pmid: 22251567
references.citation: Neuron. 2014 Mar 19;81(6):1328-1343
references.pmid: 24656252
references.citation: PLoS One. 2013 Jul 09;8(7):e68708
references.pmid: 23874735
references.citation: Learn Mem. 2012 Mar 20;19(4):170-7
references.pmid: 22434824
references.citation: Pharmacoepidemiol Drug Saf. 2011 Feb;20(2):177-84
references.pmid: 21254289
references.citation: Nature. 2012 May 09;485(7399):471-7
references.pmid: 22622571
references.citation: Zebrafish. 2006;3(2):215-26
references.pmid: 18248262
references.citation: Nucleic Acids Res. 2007;35(19):6501-16
references.pmid: 17897967
references.citation: J Neurosci. 2007 May 2;27(18):4984-94
references.pmid: 17475807
references.citation: J Exp Biol. 2007 Jul;210(Pt 14):2526-39
references.pmid: 17601957
references.citation: Neuroscience. 2005;131(3):759-68
references.pmid: 15730879
references.citation: Lab Chip. 2012 Feb 21;12(4):711-6
references.pmid: 22159032
references.citation: J Neurosci. 2010 Jul 14;30(28):9359-67
references.pmid: 20631165
references.citation: Genes Brain Behav. 2009 Jul;8(5):500-11
references.pmid: 19496826
references.citation: Front Syst Neurosci. 2011 Dec 16;5:101
references.pmid: 22203793
references.citation: PLoS One. 2012;7(3):e30837
references.pmid: 22470415
references.citation: Science. 2010 Oct 29;330(6004):669-73
references.pmid: 21030657
references.citation: J Neurosci. 2011 Aug 10;31(32):11633-44
references.pmid: 21832193
references.citation: Science. 2010 Jan 15;327(5963):348-51
references.pmid: 20075256
references.citation: Nature. 2009 Sep 17;461(7262):407-10
references.pmid: 19759620
references.citation: J Neurosci. 2013 Feb 27;33(9):3834-43
references.pmid: 23447595
references.citation: Nat Chem Biol. 2010 Mar;6(3):231-237
references.pmid: 20081854
references.citation: Brain Res. 2013 Aug 21;1527:108-16
references.pmid: 23827499
references.citation: PLoS One. 2011;6(6):e21715
references.pmid: 21738776
references.citation: J Vis Exp. 2012 Jul 16;(65):e4203
references.pmid: 22825322
references.citation: Genome Res. 2014 Jan;24(1):142-53
references.pmid: 24179142
references.citation: Nat Neurosci. 2010 Nov;13(11):1354-6
references.pmid: 20935642
references.citation: J Clin Psychiatry. 2014 Mar;75(3):247-53
references.pmid: 24717378
references.citation: J Cardiovasc Transl Res. 2010 Oct;3(5):438-47
references.pmid: 20677029
references.citation: Curr Biol. 2012 Nov 6;22(21):2042-7
references.pmid: 23000151
references.citation: PLoS One. 2011 Mar 07;6(3):e17597
references.pmid: 21408171
references.citation: Nature. 2013 Apr 25;496(7446):498-503
references.pmid: 23594743
references.citation: PLoS Biol. 2007 Oct 16;5(10):e277
references.pmid: 17941721
references.citation: Zebrafish. 2012 Mar;9(1):8-14
references.pmid: 22171801
references.citation: Behav Pharmacol. 2011 Jun;22(3):275-80
references.pmid: 21522057
references.citation: Nat Neurosci. 2013 Apr;16(4):507-16
references.pmid: 23455609
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20508-13
references.pmid: 23197836
references.citation: Science. 2006 Sep 29;313(5795):1929-35
references.pmid: 17008526
references.citation: Brain Res. 2014 Jan 16;1543:109-19
references.pmid: 24216135
references.citation: Nat Neurosci. 2004 May;7(5):462-6
references.pmid: 15114359
references.citation: Behav Brain Res. 2008 Mar 17;188(1):168-77
references.pmid: 18054804