Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation

Behavioral Profiling The complexity of the brain makes it difficult to predict how a drug will affect behavior without direct testing in live animals. Rihel et al. (p. 348) developed a high-throughput assay to assess the effects of thousands of drugs on sleep/wake behaviors of zebrafish larvae. The data set reveals a broad conservation of zebrafish and mammalian sleep/wake pharmacology and identifies pathways that regulate sleep. Moreover, the biological targets of poorly characterized small molecules can be predicted by matching their behavioral profiles to those of well-known drugs. Thus, behavioral profiling in zebrafish offers a cost-effective way to characterize neuroactive drugs and to predict biological targets of novel compounds. The effects of most neuroactive drugs are conserved and can be detected by behavioral screening. 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.

[1]  廣瀬雄一,et al.  Neuroscience , 2019, Workplace Attachments.

[2]  James M. Harris,et al.  Hematopoietic Stem Cell Development Is Dependent on Blood Flow , 2009, Cell.

[3]  M. Opp,et al.  How (and why) the immune system makes us sleep , 2009, Nature Reviews Neuroscience.

[4]  E. Poluzzi,et al.  The hERG K+ channel: target and antitarget strategies in drug development. , 2008, Pharmacological research.

[5]  Siamak Shahidi,et al.  BRAIN RES BULL , 2008 .

[6]  Giulio Tononi,et al.  Sleep in Kcna2 knockout mice , 2007, BMC Biology.

[7]  M. Pangalos,et al.  Drug development for CNS disorders: strategies for balancing risk and reducing attrition , 2007, Nature Reviews Drug Discovery.

[8]  C. Jang,et al.  Anxiolytic-like effects of sinapic acid in mice. , 2007, Life sciences.

[9]  L. Zon,et al.  Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis , 2007, Nature.

[10]  György Buzsáki,et al.  How can drug discovery for psychiatric disorders be improved? , 2007, Nature Reviews Drug Discovery.

[11]  E. Bar-Meir,et al.  Guidelines for Treating Cardiac Manifestations of Organophosphates Poisoning with Special Emphasis on Long QT and Torsades De Pointes , 2007, Critical reviews in toxicology.

[12]  Alexander F. Schier,et al.  Hypocretin/Orexin Overexpression Induces An Insomnia-Like Phenotype in Zebrafish , 2006, The Journal of Neuroscience.

[13]  L. Zon,et al.  A Chemical Genetic Screen for Cell Cycle Inhibitors in Zebrafish Embryos , 2006, Chemical biology & drug design.

[14]  M. Balduzzi,et al.  Curcumin treatment protects rat retinal neurons against excitotoxicity: effect on N-methyl-D-aspartate-induced intracellular Ca2+ increase , 2005, Experimental Brain Research.

[15]  刘金明,et al.  IL-13受体α2降低血吸虫病肉芽肿的炎症反应并延长宿主存活时间[英]/Mentink-Kane MM,Cheever AW，Thompson RW，et al//Proc Natl Acad Sci U S A , 2005 .

[16]  Giulio Tononi,et al.  Reduced sleep in Drosophila Shaker mutants , 2005, Nature.

[17]  M. Fishman,et al.  Discovery and use of small molecules for probing biological processes in zebrafish. , 2004, Methods in cell biology.

[18]  Gabriele Vacun,et al.  Zebrafish embryos express an orthologue of HERG and are sensitive toward a range of QT-prolonging drugs inducing severe arrhythmia. , 2003, Toxicology and applied pharmacology.

[19]  L. Bossaert,et al.  An unusual poisoning with the unusual pesticide amitraz , 1997, Human & experimental toxicology.

[20]  K. Jacobson,et al.  Pharmacological characterization of novel A3 adenosine receptor-selective antagonists , 1997, Neuropharmacology.

[21]  M. Won,et al.  Eugenol protects neuronal cells from excitotoxic and oxidative injury in primary cortical cultures , 1997, Neuroscience Letters.

[22]  K. Tipton,et al.  The nature of the inhibition of rat liver monoamine oxidase types A and B by the acetylenic inhibitors clorgyline, l-deprenyl and pargyline. , 1982, Biochemical pharmacology.

[23]  Burton S. Rosner,et al.  Neuropharmacology , 1958, Nature.

[24]  W. Bretz,et al.  Red Marine Algae Lithothamnion calcareum Supports Dental Enamel Mineralization , 2023, Marine drugs.