Glutamate NMDA Receptor Antagonists with Relevance to Schizophrenia: A Review of Zebrafish Behavioral Studies

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.

Keywords: MK-801; PCP; Schizophrenia; behavior; glutamate antagonists; ketamine; psychosis; zebrafish.

Fig (1)

A quantitative overview of the studies reporting the use of NMDAR antagonist drugs (MK-801, ketamine, PCP, memantine, tiletamine, and APV) in zebrafish behavioral research published in peer-reviewed scientific journals between 2000 and 2020. (A) The number of publications per year with each drug. (B) Percentage of publications with each drug. (C) The number of publications per behavioral domain with each drug. APV, DL-2-amino-5-phosphonopentanoic acid, MK-801, dizocilpine; PCP, phencyclidine.

Fig (2)

Description of relevant methodological details in the publications included in this review. For blinding and randomization, graphs depict the percentage of publications that reported implementation or not of these practices (unclear was computed when there was no mention). Sex of the animals used was computed as M:F when male and female were included but tested and analyzed as a mixed group, and M+F when male and female fish were discriminated in the experiments.

Fig (3)

Schematic illustration of the mechanism of action of NMDAR receptor antagonists in the zebrafish brain and behavioral phenotypes induced by the administration of these drugs. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; mGLU, metabotropic glutamate; NMDA, N-methyl-D-aspartate.