Amitriptyline increases food intake via prdx-2 without altering other physiological parameters in C. elegans under a modified bacterial diet

Amitriptyline, a tricyclic antidepressant, is associated with various metabolic side effects, including increased appetite and weight gain. In this study, we used the nematode C. elegans to investigate the drug's effects on food intake, fat content, lifespan, and several genetic pathways. Amitriptyline increased food intake in a dose-responsive manner. It increased the food intake primarily through elevated on-food pharyngeal pumping. Supplementation with glucose exacerbated these effects and significantly shortened lifespan, mimicking metabolic risks seen in humans. Despite increased feeding, no changes in fat content were observed, reflecting distinct mechanisms regulating feeding and fat storage. The critical function of prdx-2 in the drug's effect on food intake was revealed through genetic analyses. In contrast, several receptors and signaling components in the serotonergic, dopaminergic, and insulin-like pathways were not implicated. These results underscore the potential of C. elegans as a model for investigating antidepressant-induced metabolic alterations and establish the foundation for strategies to mitigate these effects.