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Rapid behavior-based identification of neuroactive small molecules in the zebrafish

Nature Chemical Biology volume 6, pages 231237 (2010) | Download Citation


Neuroactive small molecules are indispensable tools for treating mental illnesses and dissecting nervous system function. However, it has been difficult to discover novel neuroactive drugs. Here, we describe a high-throughput, behavior-based approach to neuroactive small molecule discovery in the zebrafish. We used automated screening assays to evaluate thousands of chemical compounds and found that diverse classes of neuroactive molecules caused distinct patterns of behavior. These 'behavioral barcodes' can be used to rapidly identify new psychotropic chemicals and to predict their molecular targets. For example, we identified new acetylcholinesterase and monoamine oxidase inhibitors using phenotypic comparisons and computational techniques. By combining high-throughput screening technologies with behavioral phenotyping in vivo, behavior-based chemical screens can accelerate the pace of neuroactive drug discovery and provide small-molecule tools for understanding vertebrate behavior.

  • Compound C11H17NO3


  • Compound C16H13ClN2O


  • Compound C17H17NO2


  • Compound C23H34O4


  • Compound C13H14N4O2


  • Compound C12H18Cl2N2O


  • Compound C9H13NO3


  • Compound C35H41N5O5


  • Compound C17H17NO2


  • Compound C14H19NO3


  • Compound C34H47NO11


  • Compound C36H51NO11


  • Compound C25H32O7

    Strophanthidinic acid

  • Compound C14H19N3O2


  • Compound C18H22N2O3


  • Compound C18H9ClN4O


  • Compound C20H16O4

    6-Oxo-7,8,9,10-tetrahydrobenzo[c]chromen-3-yl benzoate

  • Compound C11H13N


  • Compound C19H16O4


  • Compound C10H12N3O3PS2

    Azinphos methyl

  • Compound C17H23NO3


  • Compound C7H9N2O+


  • Compound C23H28N2O3


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We thank E. Scolnick, M. Granato, J. Dowling, D. Milan, C. Felts, J. Rihel, A. Schier and members of our research groups for encouragement and advice. This work was supported by US National Institutes of Health training grant HL07208 (D.K.) and grants NS063733 (R.T.P.), MH085205 (R.T.P.), MH086867 (R.T.P.) and GM71896 (B.K.S. and J. Irwin), the National Sciences and Engineering Council of Canada (J.B.), the Canadian Institutes of Health Research (J.B.), the Max Kade Foundation (C.L.) and the Stanley Medical Research Institute (S.J.H.).

Author information


  1. Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.

    • David Kokel
    • , Chung Yan J Cheung
    • , Rita Mateus
    • , David Healey
    • , Sonia Kim
    • , Andreas A Werdich
    • , Calum A MacRae
    •  & Randall T Peterson
  2. Broad Institute, Cambridge, Massachusetts, USA.

    • David Kokel
    • , Chung Yan J Cheung
    • , Rita Mateus
    • , David Healey
    • , Sonia Kim
    • , Stephen J Haggarty
    •  & Randall T Peterson
  3. Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada.

    • Jennifer Bryan
    •  & Rick White
  4. Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.

    • Jennifer Bryan
  5. Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.

    • Christian Laggner
    •  & Brian Shoichet
  6. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Stephen J Haggarty
  7. Stanley Center for Psychiatric Research, Cambridge, Massachusetts, USA.

    • Stephen J Haggarty


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D.K. designed and performed the research, analyzed the data and wrote the manuscript. J.B., C.L., R.W. and B.S. analyzed and interpreted the data and contributed to the manuscript. C.Y.J.C., R.M., D.H. and S.K. performed experiments. A.A.W. contributed to hardware design. S.J.H. and C.A.M. contributed reagents. R.T.P designed the research, analyzed the data and wrote the manuscript. All authors contributed to data interpretation and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to David Kokel or Randall T Peterson.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–5, Supplementary Tables 1–2 and Supplementary Methods


  1. 1.

    Supplementary Movie 1

    Movie of the PMR in zebrafish embryos in a petri dish at low magnification.

  2. 2.

    Supplementary Movie 2

    Movie of the PMR at higher magnification.

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    Supplementary Movie 3

    Movie of the PMR behavior at 30 hpf, showing that animals do not normally respond to a second pulse of light.

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    Supplementary Movie 4

    Movie of the robotic screening hardware delivering light pulses to the individual wells of a 96-well plate.

  5. 5.

    Supplementary Movie 5

    Movie of an untreated control well in the ETR assay.

  6. 6.

    Supplementary Movie 6

    Movie of the slow to relax (STR) phenotype in a well treated with STR-1 during the ETR assay.

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