Neuroactive compounds are among the most powerful tools available for neuroscience research. Identifying novel compounds with new activities would likely aid neuroscience research. However, these neuroactive drugs are difficult to identify. Here, we propose a new approach to identify neuroactive compounds that affect startle and anxiety-related behaviors behaviors in living zebrafish. These studies aim to accelerate the pace of neuroactive drug discovery and provide small-molecule tools for understanding vertebrate behavior. Anxiety disorders such as generalized anxiety disorder, panic disorder and post-traumatic stress disorder are widespread and devastating illnesses. Despite the need for improved psychiatric medicines, drug discovery success rates for psychiatric illnesses and other disorders of the nervous system are lower than for other therapeutic areas. To meet the vast unmet need for novel neuroactive drugs, it will be essential to develop new approaches to neuroactive drug discovery. But, lacking a detailed understanding of the biochemical mechanisms that cause psychiatric disease, how can novel neuroactive drugs be discovered? Genetics and pharmacology are the two dominant approaches for understanding molecular signaling pathways in the nervous system. However, traditional pharmacogenetic approaches are heavily biased towards the genome side of systems biology. Genome-wide applications for investigating the effects of single drugs are becoming more common. By contrast, large-scale analyses of how chemicals affect specific genotypes and phenotypes have been much slower to develop. One reason is that phenotype based chemical screens have not been practical or cost-effective using most model organisms. Given the impact of small molecules that were discovered via low throughput and non-systematic approaches, it is likely that systematic behavior-based chemical screening has much to offer. Phenotype based chemical screens in the zebrafish are a non-conventional approach for identifying novel bioactive compounds. It is likely that uncharacterized compounds with valuable neuroactive activity already exist in the wells of modern chemical libraries. However, in vitro assays are too simplistic and phenotypic assays in mammals too low throughput, to efficiently identify these valuable molecules. Unlike larger vertebrates, zebrafish are small enough to be easily arrayed in the individual wells of a 96-well plate along with chemicals from a chemical library. As a result, behavior-based chemical screens in the zebrafish provide the opportunity to systematically assess how chemicals affect the intact vertebrate nervous system.

Public Health Relevance

Neuroactive drugs are among our most powerful tools for understanding the nervous system and treating psychiatric disease. Behavior-modifying compounds have revolutionized neuroscience research and the treatment of anxiety disorders. Most neuroactive drugs were discovered via unexpected behavioral phenotypes. However, technologies for systematic behavior based screening for chemical modifiers of startle and anxiety- related behaviors have not been possible. Here, we combine high-throughput chemical screening strategies with complex behavioral phenotyping to identify novel startle modifying compounds. These efforts may improve our understanding of the brain and accelerate the pace of neuroactive drug discovery.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CB-Z (56))
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Bechtholt-Gompf, Anita
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Massachusetts General Hospital
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Bruni, Giancarlo; Rennekamp, Andrew J; Velenich, Andrea et al. (2016) Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds. Nat Chem Biol 12:559-66
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