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Zebrafish Behavior Helps Identify New Candidate Antipsychotic Drugs

6 Jul 2016

News Story: 

July 7, 2016. Treatment options for people with schizophrenia have not progressed much since the initial discovery of antipsychotic drugs decades ago, so researchers are on the hunt for new drugs that work better and have fewer side effects.

Traditionally, new drugs have been identified by whether they bind to specific receptor molecules in test tubes or in petri dishes in a laboratory (called "in vitro" assays). But the complexity of schizophrenia, which among other complications involves many receptors, makes this approach difficult. Instead, screening compounds in an animal, referred to as "in vivo" screening, allows researchers to use a complex biological system and target multiple receptors at once.

Two studies, published online May 30 in Nature Chemical Biology, used a new systematic way to screen compounds based on their behavioral effects in zebrafish, a technique called phenotype profiling.

The first study, led by David Kokel of the University of California, San Diego, found that known antipsychotic drugs produce a signature behavior profile in zebrafish. The researchers quantified the behavior profiles of nearly 25,000 different compounds and compared them to the signature profile of the antipsychotic haloperidol. Some of the compounds whose profiles matched that of haloperidol had unknown binding profiles, which indicates either false positives or new antipsychotic-like compounds with different mechanisms of action than haloperidol. "Those are simultaneously both probably the most exciting hit compounds, but also the most challenging ones to follow up on, because we have no idea how they might be working," said Kokel.

The second study, led by Randall Peterson of Massachusetts General Hospital, Harvard Medical School, and The Broad Institute, found that a compound identified by Kokel and colleagues altered zebrafish behavioral response to threat. The researchers then worked backward to identify the mechanism of its action, and found that its effects stemmed from binding to the sigma-1 receptor. This receptor is a known target of haloperidol and was identified in the first study as a likely target of the uncharacterized compounds with antipsychotic-like phenotypes.

Eric Nestler of the Mount Sinai Medical Center in New York City, who was not involved in the study, believes that these screens can help find molecules that will make it into the brain and have effects there, but is skeptical that zebrafish are a suitable model. "I would just be skeptical of whether a behavioral phenotype in the fish would be rich enough to capture a mechanism that would have the subtlety needed to treat schizophrenia," he said.

For his part, Kokel sees zebrafish phenotype profiling merely as a first step to drug discovery and hopes that the community will get interested in some of the uncharacterized compounds to identify new drugs with better side effect profiles or that work through novel mechanisms. (For more details, see the related news story.)—Lesley McCollum.