In vivo discovery of psychotropic drugs by high-throughput behavioral phenotyping the challenge despite their ubiquity and impact, diseases of the central nervous system (CNS) remain among the most poorly treated medical conditions. New CNS drugs are needed, but the complexity of the nervous system has largely made CNS drug discovery refractory to reductionist and in vitro approaches. For this reason, most existing CNS drugs were discovered by serendipitous observation of behavioral effects in living animals, not by rational design or in vitro screening. Discovering new CNS drugs is limited by the difficulty of modeling complex brain function in vitro and the impracticality of screening for new drugs in vivo with existing mammalian behavioral assays. Our approach we propose to use high-throughput behavioral assays as a means of screening for novel neuroactive drugs. We are developing fully-automated systems capable of tracking and quantifying zebrafish behaviors in high- throughput, 96-well format. Using one of these assays, we have tested 700 psychotropic drugs from several functional classes and identified strong correlations between specific functional classes and the zebrafish behavioral profiles they induce. We now propose to expand the panel of automated behavioral assays and conduct screens of vast small molecule libraries to identify novel compounds with in vivo neurological activity. The potential impact the automated panel of zebrafish assays we are developing is the first high-throughput screen capable of assessing behavioral effects of small molecules in a vertebrate. Because the zebrafish behaviors integrate inputs from several major neurotransmitter systems, the assays can be used to identify compounds that act on the CNS through diverse mechanisms. Successful completion of this project will create a robust and flexible system for discovering neuroactive compounds. It will also lead directly to discovery of novel compounds that alter CNS function through diverse mechanisms of action. These compounds will be powerful tools for studying the nervous system and in some cases may be developed further for treating nervous system disorders. Nervous system disorders like schizophrenia and Alzheimer's disease are widespread and frequently devastating, but they remain poorly treated because conventional drug discovery methods are poorly equipped to deal with the complexity of the brain. This project proposes a bold new approach to nervous system drug discovery based on robotic testing of thousands of potential new drugs for their ability to alter brain function in microscopic zebrafish.

Public Health Relevance

Nervous system disorders like schizophrenia and Alzheimer's disease are widespread and frequently devastating, but they remain poorly treated because conventional drug discovery methods are poorly equipped to deal with the complexity of the brain. This project proposes a bold new approach to nervous system drug discovery based on robotic testing of thousands of potential new drugs for their ability to alter brain function in microscopic zebrafish.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH086867-04
Application #
8259222
Study Section
Special Emphasis Panel (ZMH1-ERB-L (05))
Program Officer
Driscoll, Jamie
Project Start
2009-07-02
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$350,460
Indirect Cost
$152,460
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Kokel, David; Dunn, Timothy W; Ahrens, Misha B et al. (2013) Identification of nonvisual photomotor response cells in the vertebrate hindbrain. J Neurosci 33:3834-43
van Ham, Tjakko J; Kokel, David; Peterson, Randall T (2012) Apoptotic cells are cleared by directional migration and elmo1- dependent macrophage engulfment. Curr Biol 22:830-6
Laggner, Christian; Kokel, David; Setola, Vincent et al. (2012) Chemical informatics and target identification in a zebrafish phenotypic screen. Nat Chem Biol 8:144-6
Groeneweg, Jolijn W; White, Yvonne A R; Kokel, David et al. (2011) cables1 is required for embryonic neural development: molecular, cellular, and behavioral evidence from the zebrafish. Mol Reprod Dev 78:22-32
Kokel, David; Peterson, Randall T (2011) Using the zebrafish photomotor response for psychotropic drug screening. Methods Cell Biol 105:517-24
Kokel, David; Bryan, Jennifer; Laggner, Christian et al. (2010) Rapid behavior-based identification of neuroactive small molecules in the zebrafish. Nat Chem Biol :
Rihel, Jason; Prober, David A; Arvanites, Anthony et al. (2010) Zebrafish behavioral profiling links drugs to biological targets and rest/wake regulation. Science 327:348-51
van Ham, Tjakko J; Mapes, James; Kokel, David et al. (2010) Live imaging of apoptotic cells in zebrafish. FASEB J 24:4336-42