Rapid behavior-based identification of neuroactive small molecules in the zebrafish.
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.
Kokel
David
D
[1] Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA. [2] Broad Institute, Cambridge, Massachusetts, USA.
Bryan
Jennifer
J
Laggner
Christian
C
White
Rick
R
Cheung
Chung Yan J
CY
Mateus
Rita
R
Healey
David
D
Kim
Sonia
S
Werdich
Andreas A
AA
Haggarty
Stephen J
SJ
Macrae
Calum A
CA
Shoichet
Brian
B
Peterson
Randall T
RT