Glutamate NMDA Receptor Antagonists with Relevance to Schizophrenia: A Review of Zebrafish Behavioral Studies.
Radharani Benvenutti, Matheus Gallas‐lopes, Matheus Marcon, Cristina R Reschke, Ana Paula Herrmann, Ângelo Piato
Current Neuropharmacology March 4, 2022 DOI: 10.2174/1570159x19666210215121428 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Interventions | Dizocilpine (MK-801) Ketamine Phencyclidine (PCP) APV Memantine Tiletamine |
| Topics | Ketamine |
| Keywords | Mk-801 Pcp Schizophrenia Behavior Glutamate antagonists Psychosis Zebrafish |
| Key findings | Zebrafish is a suitable model organism to study drug-induced behavioral phenotypes relevant to schizophrenia, but more studies are needed to characterize behavioral differences from mammals. |
Abstract
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. Frequently 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 locomotor 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 characterize the major differences in behavior as compared to mammals.
Comparable studies
Other systematic reviews and meta-analyses on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis Depressed patients with suicidal ideation at baseline | 2017 | Systematic review and individual participant data meta-analysis | n = 167 |
| Ketamine use: a review Ketamine users | 2011 | Systematic review | |
| Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression Participants with major depression in placebo-controlled, double-blind, randomized... | 2015 | Systematic review and meta-analysis | |
| Ketamine and postoperative pain – a quantitative systematic review of randomised trials Surgical patients from 25 countries | 2004 | Systematic review | n = 2,839 |
| Side-effects associated with ketamine use in depression: a systematic review. Patients with depression | 2018 | Systematic review |
Citations in the library
Cited by 2
- Ketamine modulates the exploratory dynamics and homebase-related behaviors of adult zebrafish. Pharmacology, Biochemistry, and Behavior December 1, 2024
- Ketamine-induced NMDA receptor hypofunction alters social and locomotor behavior in adult zebrafish bioRxiv (Cold Spring Harbor Laboratory) September 17, 2025
Cites 19
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- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
- Taming the Ketamine Tiger Anesthesiology August 6, 2010
- Ketamine activates psychosis and alters limbic blood flow in schizophrenia Neuroreport April 1, 1995
and 14 more in the library