How do zebrafish (Danio rerio) respond to MK‐801 and amphetamine? Relevance for assessing schizophrenia‐related endophenotypes in alternative model organisms

Abstract

Schizophrenia pathophysiology has been associated with dopaminergic hyperactivity, NMDA receptor hypofunction, and redox dysregulation. Most behavioral assays and animal models to study this condition were developed in rodents, leaving room for species‐specific biases that could be avoided by cross‐species approaches. As MK‐801 and amphetamine are largely used in mice and rats to mimic schizophrenia features, this study aimed to compare the effects of these drugs in several zebrafish (Danio rerio) behavioral assays. Male and female adult zebrafish were exposed to MK‐801 (1, 5, and 10 μM) or amphetamine (0.625, 2.5, and 10 mg/L) and observed in paradigms of locomotor activity and social behavior. Oxidative parameters were quantified in brain tissue. Our results demonstrate that MK‐801 disrupted social interaction, an effect that resembles the negative symptoms of schizophrenia. It also altered locomotion in a context‐dependent manner, with hyperactivity when fish were tested in the presence of social cues and hypoactivity when tested alone. On the other hand, exposure to amphetamine was devoid of effects on locomotion and social behavior, while it increased lipid peroxidation in the brain. Key outcomes induced by MK‐801 in rodents, such as social interaction deficit and locomotor alterations, were replicated in zebrafish, corroborating previous studies and reinforcing the use of zebrafish to study schizophrenia‐related endophenotypes. More studies are necessary to assess the predictive validity of preclinical paradigms with this species and ultimately optimize the screening of potential novel treatments.

Advantages and Limitations of Animal Schizophrenia Models

“…On a molecular level, DAergic enhancers, such as amphetamine, may lead to increased tumor necrosis factor α (TNFα) and malondialdehyde (MDA) levels, suggesting ongoing increased inflammatory and oxidative processes [ 16 ]. Similar effects were observed in zebrafish, in which amphetamine was able to alter the oxidative status [ 23 ]. Proteomic analyses conducted by Wearne et al [ 24 ] identified 96 proteins that are differentially expressed in the prefrontal cortex in a rat methamphetamine-based model of sensitization; of these differentially expressed proteins, 20% are connected to schizophrenia pathogenesis and linked to synaptic regulation, protein phosphatase signaling, mitochondrial function, and impairments in the inhibitory gamma-aminobutyric acid (GABA) system.…”

Effects of taurine in mice and zebrafish behavioral assays with translational relevance to schizophrenia

“…Zebrafish is increasingly considered as a model organism suitable to study drug-induced behavioral phenotypes relevant to schizophrenia (Gawel et al, 2019; Benvenutti et al, 2021). Figure 3A shows that zebrafish exposed to MK-801 spent less time in the side of the tank where conspecifics were presented, denoting decreased social preference in comparison to control groups (MK-801 main effect: F 1,86 = 29.28, p<0.0001).…”

“…In regards to zebrafish, it has been demonstrated that MK-801 induces hyperlocomotion, although it is not clear which neuronal mechanisms might be involved (Menezes et al, 2015; Tran et al, 2016; Benvenutti et al, 2021; Franscescon et al, 2021). Zebrafish increasing use is a great solution to avoid species biases and focus on a robust cross-species approach, aside from being an accessible way to screen for potential novels treatments (Bruni et al, 2016; Burrows and Hannan, 2016; Gawel et al, 2019).…”

“…The protocol for the social interaction test in zebrafish followed the method described by Benvenutti et al (2021). Animals were individually exposed to water or taurine solutions at 42, 150 or 400 mg/L in 500-mL beakers containing 200-mL solution for 20 min.…”

Micronized Curcumin Causes Hyperlocomotion in Zebrafish Larvae

“…Zebrafish have been used as a model organism for biomedical research in drug discovery, developmental biology, and genetics as it presents high mammalian homology [1]. Zebrafish present rapid development and a relatively long lifespan, being used to investigate the neurobehavioral foundations of various neurological and psychiatric conditions such as epilepsy, Alzheimer's and Parkinson's disease, schizophrenia, and stress-and drug-related disorders [1][2][3][4][5][6][7][8][9].…”