Ketamine-induced NMDA receptor hypofunction alters social and locomotor behavior in adult zebrafish
Matheus Gallas‐lopes, Dagobert Müller, Thailana Stahlhofer-buss, Leonardo M. Bastos, Sofia Z. Becker, Samara Machado Bruck, Ângelo Piato, Ana Paula Herrmann
bioRxiv (Cold Spring Harbor Laboratory) September 17, 2025 preprint DOI: 10.1101/2025.09.16.676572 via OpenAlex
Summary
Ketamine exposure in adult zebrafish led to significant changes in behavior, including reduced social interaction and increased locomotor activity. However, these effects did not become more pronounced with repeated exposure and were not sustained after a 48-hour washout. This suggests that while zebrafish can model acute responses to NMDA receptor antagonism relevant to schizophrenia, they do not exhibit behavioral sensitization or lasting disruptions as seen in rodent studies.
Study at a glance
| Design | experimental study |
|---|---|
| Population | adult zebrafish |
| Key finding | Ketamine caused immediate behavioral changes in zebrafish but did not lead to sustained effects or behavioral sensitization. |
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.