Behavioral effects of subchronic ketamine administration in adult zebrafish

Abstract

Ketamine, a glutamate N-methyl-D-aspartic (NMDA) receptor antagonist, is used to recapitulate schizophrenia-related behavioral phenotypes in model animals. The zebrafish (Danio rerio) is a model animal used in neurobehavioral translational research that presents high genetic and physiological conservation compared to humans. However, relevant behavioral assays related to the symptoms and neurobiology of schizophrenia are not well established and validated in this species. We evaluated the effects of subchronic exposure to ketamine on behavioral phenotypes of adult zebrafish using the social preference and open tank tests. 128 adult zebrafish were randomly allocated to one of four treatment groups: control, ketamine 10 mg/L, ketamine 20 mg/L, and ketamine 40 mg/L (n = 32). Drug exposure occurred by immersion in water for 20 minutes once a day for 5 consecutive days; after a washout on day 6, the animals were re-exposed on day 7 to the same treatments. Tests were conducted sequentially on experimental days 1, 5, and 7 immediately after the treatments. The animals were recorded and their behavior was analyzed using the ANY-Maze tracking software. The data were analyzed by two-way ANOVA with treatment group and experimental day as factors. In the social preference test, subchronic exposure to ketamine reduced the time spent in the interaction zone, while in the open tank test it increased rotations. In general, ketamine induced behavioral changes with relevance to schizophrenia symptoms throughout all testing days. However, unlike what is observed in mammals, there was no sensitization or tolerance to ketamine over time. Further studies are still needed to better understand the long-lasting effects of ketamine in zebrafish.