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Glutamate NMDA receptor antagonists with relevance to schizophrenia: a review of zebrafish behavioral studies

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journal contribution
posted on 23.06.2022, 11:15 by Radharani Benvenutti, Matheus Gallas-Lopes, Matheus Marcon, Cristina Ruedell ReschkeCristina Ruedell Reschke, Ana Paula Herrmann, Angelo Piato
Schizophrenia pathophysiology is associated with hypofunction of glutamate NMDA receptors (NMDAR) in GABAergic interneurons and dopaminergic hyperactivation in subcortical brain areas. The administration of NMDAR antagonists is used as an animal model that replicates behavioral phenotypes relevant to the positive, negative, and cognitive symptoms of schizophrenia. Such models overwhelmingly rely on rodents, which may lead to species-specific biases and poor translatability. Zebrafish, however, is increasingly used as a model organism to study evolutionarily conserved aspects of behavior. We thus aimed to review and integrate the major findings reported in the zebrafish literature regarding the behavioral effects of NMDAR antagonists with relevance to schizophrenia. We identified 44 research articles that met our inclusion criteria from 590 studies retrieved from MEDLINE (PubMed) and Web of Science databases. Dizocilpine (MK-801) and ketamine were employed in 29 and 10 studies, respectively. The use of other NMDAR antagonists, such as phencyclidine (PCP), APV, memantine, and tiletamine, was described in 6 studies. Fre-quently reported findings are the social interaction and memory deficits induced by MK-801 and circling behavior induced by ketamine. However, mixed results were described for several locomo-tor and exploratory parameters in the novel tank and open tank tests. The present review integrates the most relevant results while discussing variation in experimental design and methodological procedures. We conclude that zebrafish is a suitable model organism to study drug-induced behavioral phenotypes relevant to schizophrenia. However, more studies are necessary to further charac-terize the major differences in behavior as compared to mammals.


Brazilian Coordenação de Aperfeiçoamento de Pessoal de Nível 27 Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico 28 (CNPq)

Pró-Reitoria de Pesquisa (PROPESQ) at Universidade Federal do Rio Grande 29 do Sul (UFRGS)



The published manuscript is available at EurekaSelect via DOI:

Published Citation

Benvenutti R. et al. Glutamate NMDA receptor antagonists with relevance to schizophrenia: a review of zebrafish behavioral studies. Curr Neuropharmacol. 2022 Mar 4;20(3):494-509

Publication Date

15 February 2021

PubMed ID



  • FutureNeuro Centre
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Neurological and Psychiatric Disorders


Bentham Science Publishers Ltd.


  • Accepted Version (Postprint)