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.