Rapid behavior-based identification of neuroactive small molecules in the zebrafish

Abstract

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 (HT) behavior—based approach to neuroactive small molecule discovery in the zebrafish. We use automated screening assays to evaluate thousands of chemical compounds and find that diverse classes of neuroactive molecules cause distinct patterns of behavior. These `behavioral barcodes' can be used to rapidly identify novel psychotropic chemicals and to predict their molecular targets. For example, we identify novel acetylcholinesterase and monoamine oxidase inhibitors using phenotypic comparisons and computational techniques. By combining HT screening technologies with behavioral phenotyping in vivo, behavior—based chemical screens may accelerate the pace of neuroactive drug discovery and provide small—molecule tools for understanding vertebrate behavior.

A mutation in the enzyme monoamine oxidase explains part of the Astyanax cavefish behavioural syndrome

“…In fish, monoaminergic systems have recently attracted interest, partly because the zebrafish (Danio rerio) appears as a suitable laboratory animal to model some aspects of complex behaviours 28 and to study and screen neuroactive molecules 29,30 . Indeed, monoaminergic systems are globally well conserved and seem to serve the same types of functions in fish and mammals, with some anatomical and genetic exceptions 31,32 .…”

Chemical Screening in Zebrafish for Novel Biological and Therapeutic Discovery

“…Changes in such movements can be scored for alteration by chemical perturbation. Zebrafish have been screened for psychotropic and neuroactive drugs by characterizing changes in their photomotor response (PMR) (Kokel et al, 2010, rest/ wake behavior (Rihel et al, 2010), habituation to acoustic startle (Wolman, Jain, Liss, & Granato, 2011), and convulsive behaviors and electrographic seizures (Baraban, Dinday, & Hortopan, 2013). This type of screen showcases the robustness of the zebrafish in identifying drugs that target complex pathways in vivo.…”

“…Cardiotoxicity screening has shown a high degree of correlation between humans and zebrafish (Milan, Peterson, Ruskin, Peterson, & MacRae, 2003). In addition, screens to discover novel neuroactive and psychotropic drugs detected known human drugs with similar effects on zebrafish (Baraban et al, 2013;Kokel et al, 2010Kokel et al, , 2013Rihel et al, 2010;Wolman et al, 2011). Furthermore, 50-70% of chemicals in a zebrafish cell cycle screen show similar effects when tested in a mammalian cell culture assay (Zon & Peterson, 2005).…”

(Zebra)fishing for drugs

“…1 The technology could streamline drug discovery by providing initial in vivo data about neuroactive drug candidates earlier and more cheaply than the rodent models used in preclinical development.…”

“…1 The technology could streamline drug discovery by providing initial in vivo data about neuroactive drug candidates earlier and more cheaply than the rodent models used in preclinical development.Most compound screens use in vitro assays that reproduce only a few of the interactions that occur in whole organisms. This lack of complexity is especially challenging to drug discovery in neurology because in vitro assays cannot model a compound's effect on behavior and brain activity.…”