Zebrafish Larvae Behavior Models as a Tool for Drug Screenings and Pre-Clinical Trials: A Review

Abstract

To discover new molecules or review the biological activity and toxicity of therapeutic substances, drug development, and research relies on robust biological systems to obtain reliable results. Phenotype-based screenings can transpose the organism's compensatory pathways by adopting multi-target strategies for treating complex diseases, and zebrafish emerged as an important model for biomedical research and drug screenings. Zebrafish's clear correlation between neuro-anatomical and physiological features and behavior is very similar to that verified in mammals, enabling the construction of reliable and relevant experimental models for neurological disorders research. Zebrafish presents highly conserved physiological pathways that are found in higher vertebrates, including mammals, along with a robust behavioral repertoire. Moreover, it is very sensitive to pharmacological/environmental manipulations, and these behavioral phenotypes are detected in both larvae and adults. These advantages align with the 3Rs concept and qualify the zebrafish as a powerful tool for drug screenings and pre-clinical trials. This review highlights important behavioral domains studied in zebrafish larvae and their neurotransmitter systems and summarizes currently used techniques to evaluate and quantify zebrafish larvae behavior in laboratory studies.

Keywords: 3Rs; alternative model; anxiety-like behavior; behavioral repertoire; drug discovery; embryo-larval stage; neurological drugs; neurotransmitters.

Figure 1

Zebrafish development. Zebrafish embryo-larval stages permit the phenotypic observation of the whole organism in a large-scale chemical screening. If a molecule or drug is unable to induce death or teratogenicity during the period of embryonic development, the larvae can be used to assess changes in behavior.

Figure 2

Behavioral response in zebrafish larvae. Changes in movement and locomotion profile, driven by complex neural circuits that include perception, cognition and decision-make processes, and visuomotor functions, can be used for the screening and discovery of candidate neurological drugs in the pre-clinical stage of development.