Ketamine-induced NMDA receptor hypofunction alters social and locomotor behavior in adult zebrafish

Ketamine, an NMDA receptor antagonist, produced concentration-dependent behavioral changes in adult zebrafish. Acute exposure reduced social interaction and increased swimming activity and rotational behavior. These effects did not intensify with repeated daily dosing over five days and were not present 48 hours after the final treatment, indicating no behavioral sensitization or lasting disruption. The findings support zebrafish as a model for acute schizophrenia-like behavioral phenotypes induced by NMDA receptor blockade, but the lack of sustained effects differs from rodent studies.

Study at a glance

Abstract

ABSTRACT Background NMDA receptor antagonists, such as ketamine, are widely used to model schizophrenia-related phenotypes in preclinical studies. While zebrafish have emerged as a promising model organism for neuropsychiatric research, few studies have characterized their behavioral responses to repeated ketamine exposure. Methods Three independent experiments were conducted to evaluate the acute, repeated and sustained behavioral effects of ketamine in adult zebrafish. In Experiment I, fish were exposed to 10, 20, or 40 mg/L ketamine once daily for five days, and submitted to the social preference (SPT) and open tank (OTT) tests on days 1 and 5, and re-exposed and re-tested on day 7 after a 48-hour washout. Experiments II and III assessed whether behavioral changes persisted following 5- or 14-day exposure protocols, with testing conducted 48 hours after the final treatment. Results Ketamine induced robust, concentration-dependent alterations in Experiment I: it reduced social interaction and increased locomotor activity in the SPT on all experimental days, while increased rotational behavior in the OTT on days 1 and 5. These effects did not intensify over repeated exposure and were not sustained after a 48-hour washout in either protocol (Experiments II and III). Conclusions The results support the utility of zebrafish for modeling acute behavioral responses to NMDA receptor antagonism, capturing features of schizophrenia-like phenotypes. However, no evidence of behavioral sensitization or lasting disruption was observed, diverging from rodent studies. Future studies should incorporate antipsychotic validation, neurochemical analyses, and alternative exposure strategies to further develop zebrafish as a translational model for psychiatric research.