S30. SCHIZOPHRENIA IN A FISH: EFFECTS OF NMDA ANTAGONISM ON LOCOMOTOR BEHAVIOR AND SOCIAL INTERACTION IN ZEBRAFISH
Authors: Gallas-Lopes Matheus , Benvenutti Radharani , Sachett Adrieli , Chitolina Rafael , Guilherme Reis Carlos , Herrmann Ana Paula , Piato Angelo 
Published: May 2020

Abstract

Background
Applying cross-species approaches in animal preclinical studies of psychiatric disorders can minimize the overinterpretations often generated using specific strains or species in animal models of human conditions. Zebrafish is a model organism widely used in neuroscience research as an alternative to rodents, but protocols relevant to the symptoms and neurobiology of schizophrenia have not been fully established and validated in this species. MK-801, an NMDA receptor antagonist, is frequently used to recapitulate schizophrenia symptoms in rodent models. We thus aimed to evaluate the effects of a concentration curve of MK-801 on locomotor activity, social interaction, and neurochemical parameters related to oxidative stress in adult zebrafish.

Methods
Wild-type male and female zebrafish (50:50 ratio) were randomly allocated to 4 groups: control; 1 µM MK-801; 5 µM MK-801 or 10 µM MK-801 (n = 12). In the locomotor activity test animals were individually and sequentially placed in (1) a beaker with 200 mL of water for 20 min, (2) test aquarium for 30 min to assess basal locomotor activity, (3) beaker with water or MK-801 at the different concentrations for 20 min, and (4) test aquarium for 60 min. Locomotor and exploratory parameters (total distance traveled and upper zone time) were automatically analyzed using ANY-Maze software. In the social interaction test animals were individually exposed to water or MK-801 for 20 min and then placed for 7 min in a tank flanked by two identical tanks either empty or containing 10 zebrafish serving as social stimuli. Distance traveled was automatically tracked while social interaction time was manually and blindly scored using Boris software; only the last 5 minutes were analyzed. Oxidative damage in the brain was assessed by the levels of thiobarbituric acid reactive substances (TBARS). Data were analyzed by ANOVA followed by Tukey post hoc test.

Results
Exposure to 5 µM MK-801 decreased the total distance traveled in the locomotor activity test. In the social interaction test, exposure to 5 and 10 µM MK-801 significantly increased the total distance traveled while reduced the time of social interaction with the stimulus animals. No differences in TBARS levels were found between the groups.

Discussion
Unlike what is observed in rodents after MK-801 administration, zebrafish did not show hyperlocomotion at the concentrations tested. Other studies point to the context-dependent effect of this drug, as an increase in locomotor activity is only observed when animals are tested in a novel environment. In the social interaction test, on the other hand, animals were tested in a novel context with social stimulus and zebrafish exhibited hyperlocomotion and decreased social interaction, similar to what is observed in rodents. In contrast to chronic animal models and patients with schizophrenia, there were no differences in TBARS levels after acute exposure to MK-801. These preliminary results reinforce that zebrafish is an alternative model organism useful to the study of psychotic disorders. More behavioral and biochemical tests are needed to achieve reproducible tests and models to study multiple schizophrenia domains in zebrafish.