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Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds

Nature Chemical Biology volume 12, pages 559–566 (2016)Cite this article

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Abstract

Many psychiatric drugs act on multiple targets and therefore require screening assays that encompass a wide target space. With sufficiently rich phenotyping and a large sampling of compounds, it should be possible to identify compounds with desired mechanisms of action on the basis of behavioral profiles alone. Although zebrafish (Danio rerio) behavior has been used to rapidly identify neuroactive compounds, it is not clear what types of behavioral assays would be necessary to identify multitarget compounds such as antipsychotics. Here we developed a battery of behavioral assays in larval zebrafish to determine whether behavioral profiles can provide sufficient phenotypic resolution to identify and classify psychiatric drugs. Using the antipsychotic drug haloperidol as a test case, we found that behavioral profiles of haloperidol-treated zebrafish could be used to identify previously uncharacterized compounds with desired antipsychotic-like activities and multitarget mechanisms of action.

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Figure 1: Antipsychotics and other psychiatric drugs affect zebrafish behavior.
Figure 2: Antipsychotic drugs cause specific behavioral profiles in the test battery.
Figure 3: Haloperidol causes complex behavioral phenotypes in the zebrafish.
Figure 4: Hit compounds show haloperidol-like target profiles.
Figure 5: Finazine phenocopies haloperidol in zebrafish and in mice.

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Acknowledgements

We thank members of our research groups for helpful advice. This work was supported by US National Institutes of Health (NIH) grants K01MH091449, U01MH105027 and R01AA022583 (D.K.); R44GM093456 (M.J.K.), T32EB009383 and T32GM008284 (L.G.) and R01MH086867 and R21MH085205 (R.T.P.); the Charles and Ann Sanders MGH Research Scholar Award (R.T.P.); and the Glenn Foundation Award for Research in Biological Mechanisms of Aging (D.K. and M.J.K.).

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Author notes

  1. Giancarlo Bruni, Andrew J Rennekamp and Andrea Velenich: These authors contributed equally to this work.

Authors and Affiliations

  1. Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Giancarlo Bruni, Andrew J Rennekamp & Randall T Peterson

  2. Teleos Therapeutics, Medford, Massachusetts, USA

    Giancarlo Bruni, Andrea Velenich, Dennis Lensen, Tama Evron & Galen Carey

  3. Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Andrew J Rennekamp & Randall T Peterson

  4. Department of Systems Biology, Harvard Medical School, Charlestown, Massachusetts, USA

    Andrew J Rennekamp & Randall T Peterson

  5. Broad Institute, Cambridge, Massachusetts, USA

    Andrew J Rennekamp & Randall T Peterson

  6. Department of Physiology, University of California, San Francisco, San Francisco, California, USA.,

    Matthew McCarroll, Ethan Fertsch, Jack Taylor, Parth Lakhani & David Kokel

  7. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, California, USA.,

    Matthew McCarroll, Leo Gendelev, Ethan Fertsch, Jack Taylor, Parth Lakhani, Michael J Keiser & David Kokel

  8. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.,

    Leo Gendelev & Michael J Keiser

  9. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.,

    Leo Gendelev & Michael J Keiser

  10. NeuroBehavior Laboratory, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Paul J Lorello & Barbara J Caldarone

  11. Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Paul J Lorello & Barbara J Caldarone

  12. Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina, USA

    Xi-Ping Huang & Bryan L Roth

  13. NIMH Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina, USA

    Xi-Ping Huang & Bryan L Roth

  14. Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland

    Sabine Kolczewski & Eric Prinssen

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Contributions

G.B. performed the behavior-based chemical screen and preliminary analysis of the data. A.J.R. assisted with the zebrafish assays, experimental design, analysis of the finazine data and with the manuscript preparation. A.V. designed statistical analyses to profile the reference set and analyze zebrafish data. L.G. performed target prediction and enrichment calculations and interpreted data with M.J.K. M.M., E.F., J.T., P.L., D.L., T.E. and G.C. performed the zebrafish behavioral profiling and interpreted the data. P.J.L. performed the rodent work and analyzed the data with B.J.C. X.-P.H. performed the target binding assays and analyzed the data with B.L.R. S.K. and E.P. designed the psychiatric drug reference set. R.T.P. and D.K. designed the experiments and wrote the paper. All authors analyzed the data and edited the manuscript.

Corresponding author

Correspondence to David Kokel.

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Competing interests

A.J.R., D.K. and R.T.P. are inventors on a pending patent application, PCT/US2015/037755, covering the finazine compounds described in this manuscript. A.V., T.E., G.C. and D.L. are full-time employees of Teleos Therapeutics. D.K. and R.T.P. consult for Teleos Therapeutics. S.K. and E.P. are full-time employees of F. Hoffmann–La Roche Ltd.

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Bruni, G., Rennekamp, A., Velenich, A. et al. Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds. Nat Chem Biol 12, 559–566 (2016). https://doi.org/10.1038/nchembio.2097

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