Metoclopramide as a Potential Antipsychotic Against Long-Term Methionine Exposure in Zebrafish

Methionine (MET) contributes to brain function and is required for proper functioning of the central nervous system. However, exceptionally high levels of MET and its metabolites in plasma have been found to be toxic and can lead to cell alterations. Long-term exposure to MET has been shown to mimic psychotic symptoms in schizophrenic patients and rodents. The present study evaluated behavioral and neurochemical effects of long-term exposure to MET in zebrafish. Five groups of zebrafish were exposed to MET at a concentration of 4.5 mM for 7 days, along with acute exposure to 25 μM of clozapine and 750, 1000, and 1250 μM of metoclopramide. In contrast, the normal group was exposed to only water and dimethyl sulfoxide. After the treatment, social interaction, anxiety, memory, and locomotion of zebrafish and serotonin levels in zebrafish brains were evaluated. Our results showed that metoclopramide was not only beneficial in improving MET-induced cognitive impairment but it also prevented social withdrawal in zebrafish exposed to MET. In addition, metoclopramide reversed anxiety-like behavior, as indicated by significant changes in locomotion activity. Despite slight changes in serotonin levels in the zebrafish brain, an in vitro serotonin assay failed to demonstrate significant differences between the disease control, normal, and two treatment groups. Finally, results from the study showed that repeated administration of MET induced schizophrenia-like symptoms, although metoclopramide ameliorated the MET-mediated negative symptoms and cognitive deficits in zebrafish. Overall, our findings suggest a new perspective to further explore the antipsychotic properties of metoclopramide.