Perspectives on zebrafish models of hallucinogenic drugs and related psychotropic compounds

Abstract

Among different classes of psychotropic drugs, hallucinogenic agents exert one of the most prominent effects on human and animal behaviors, markedly altering sensory, motor, affective, and cognitive responses. The growing clinical and preclinical interest in psychedelic, dissociative, and deliriant hallucinogens necessitates novel translational, sensitive, and high-throughput in vivo models and screens. Primate and rodent models have been traditionally used to study cellular mechanisms and neural circuits of hallucinogenic drugs' action. The utility of zebrafish ( Danio rerio ) in neuroscience research is rapidly growing due to their high physiological and genetic homology to humans, ease of genetic manipulation, robust behaviors, and cost effectiveness. Possessing a fully characterized genome, both adult and larval zebrafish are currently widely used for in vivo screening of various psychotropic compounds, including hallucinogens and related drugs. Recognizing the growing importance of hallucinogens in biological psychiatry, here we discuss hallucinogenic-induced phenotypes in zebrafish and evaluate their potential as efficient preclinical models of drug-induced states in humans.

Figure 1

Three-dimensional (3D) spatiotemporal reconstructions (in X, Y, Time coordinates) of adult zebrafish swim paths reveal marked phenotypical differences between representative hallucinogenic drugs, including LSD (250 ug/L), ketamine (20 mg/L), ibogaine (20 mg/L), MDMA (120 mg/L) vs control (drug-free) fish. Following acute 20-min exposure, zebrafish novel tank behavior was video-tracked using EthoVision XT7-8.5 program, and raw tracks were processed, formatted, and visualized in a 3D scatter plot (X, Y, Time) using RapidMiner 5.0 software, according to ref (63). Representative 3D reconstructions were selected on a consensus basis by 2–3 independent highly trained observers, comparing swim paths of all subjects within a cohort, ranking them from 1 to n based on similarity to each other (no/low to high activity) and choosing the middle for the illustrations. For a more detailed analysis of 3D reconstructions, the average velocity (m/s) of each fish was reflected by the changes in color (from blue, green, yellow, to red) as the velocity increases. In particular, LSD and ketamine evoked a clear top dwelling, with ketamine exposed fish also exhibiting some decrease in velocity relative to controls. Similarly, MDMA also reduced anxiety-like behaviors in zebrafish, increasing time in top and reduced latency to top. Ibogaine-treated fish demonstrated a mild increase in motor activity, and a reversal of their natural diving response (geotaxis), inducing initial top swimming followed by bottom dwelling. Overall, these 3D traces reveal overt behavioral effects on zebrafish exposed to different hallucinogenic agents, thereby enabling a rapid visualization and interpretation of the observed drug-induced phenotypes (see ref (63) for details).