Chemobehavioural phenomics and behaviour-based psychiatric drug discovery in the zebrafish

Abstract

Despite their ubiquity and impact, psychiatric illnesses and other disorders of the central nervous system remain among the most poorly treated diseases. Most psychiatric medicines were discovered due to serendipitous observations of behavioural phenotypes in humans, rodents and other mammals. Extensive behaviour-based chemical screens would likely identify novel psychiatric drugs. However, large-scale chemical screens in mammals are inefficient and impractical. In contrast, zebrafish are very well suited for high-throughput behaviour-based drug discovery. Furthermore, the vast amounts of data generated from large-scale behavioural screens in zebrafish will facilitate a systems-level analysis of how chemicals affect behaviour. Unlike serendipitous discoveries in mammals, a comprehensive and integrative analysis of zebrafish chemobehavioural phenomics may identify functional relationships that would be missed by more reductionist approaches. Thus, behaviour-based chemical screens in the zebrafish may improve our understanding of neurobiology and accelerate the pace of psychiatric drug discovery.

Figure 1:

Zebrafish combine high-throughput screening and physiologically complex phenotyping. Behavioural assays in mammals are a physiologically complex but low-throughput approach to drug discovery. Conversely, in vitro target-based assays are a high-throughput but low-content approach. Behaviour-based chemical screens in the zebrafish combine the advantages of behavioural assays with high-throughput screening methodologies and are a promising way to identify novel neuroactive drugs.

Figure 2:

Psychiatric drugs act though conserved mechanisms to alter behavioural phenotypes. Evolutionarily conserved drug targets mediate different behavioural phenotypes in a variety of organisms.

Figure 3:

Chemobehavioural phenomics—a vision for the future. In this hypothetical analysis, chemicals are clustered by their phenotypic signatures, which are generated from a battery of standardized behavioural tests. Chemicals annotated as anxiolytics, stimulants or sedatives cluster into three families. A group of chemicals with unknown mechanisms of action appears to partially phenocopy anxiolytics and stimulants, suggesting that they may represent a novel class of psychoactive molecules with some anxiolytic and stimulant properties. Grey boxes indicate drug activity in a given behavioural assay, black boxes indicates no activity.