title: Zebrafish behavioral profiling links drugs to biological targets and rest/wake regulation.
abstract: A major obstacle for the discovery of psychoactive drugs is the inability to predict how small molecules will alter complex behaviors. We report the development and application of a high-throughput, quantitative screen for drugs that alter the behavior of larval zebrafish. We found that the multidimensional nature of observed phenotypes enabled the hierarchical clustering of molecules according to shared behaviors. Behavioral profiling revealed conserved functions of psychotropic molecules and predicted the mechanisms of action of poorly characterized compounds. In addition, behavioral profiling implicated new factors such as ether-a-go-go-related gene (ERG) potassium channels and immunomodulators in the control of rest and locomotor activity. These results demonstrate the power of high-throughput behavioral profiling in zebrafish to discover and characterize psychotropic drugs and to dissect the pharmacology of complex behaviors.
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA. rihel@fas.harvard.edu
authors.forename: Jason
authors.initials: J
authors.lastname: Rihel
authors.forename: David A
authors.initials: DA
authors.lastname: Prober
authors.forename: Anthony
authors.initials: A
authors.lastname: Arvanites
authors.forename: Kelvin
authors.initials: K
authors.lastname: Lam
authors.forename: Steven
authors.initials: S
authors.lastname: Zimmerman
authors.forename: Sumin
authors.initials: S
authors.lastname: Jang
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: David
authors.initials: D
authors.lastname: Kokel
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Schier
mesh_terms: D000465:Algorithms; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D016000:Cluster Analysis; D016207:Cytokines / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D057166:High-Throughput Screening Assays; D007814:Larva / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000494:pharmacology*; D012146:Rest; D015398:Signal Transduction; D012890:Sleep / Q000187:drug effects; D054852:Small Molecule Libraries; D014851:Wakefulness / Q000187:drug effects*; D015027:Zebrafish / Q000254:growth & development / Q000502:physiology*; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D016207:Cytokines; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D011619:Psychotropic Drugs; D054852:Small Molecule Libraries; D029961:Zebrafish Proteins