This document summarizes research on the molecular mechanisms and applications of a reserpine-induced rodent model of depression. Reserpine is an indole alkaloid that binds irreversibly to vesicular monoamine transporter 2, disrupting the storage of neurotransmitters like serotonin, dopamine, and norepinephrine. This depletion of neurotransmitters leads to depressive-like behaviors in rodents. The reserpine model has been used to study depression, pain-depression comorbidity, drug discovery, fibromyalgia, gene expression, and irritable bowel syndrome. Chronic low doses of reserpine more effectively induce depression-like behaviors than acute high doses by gradually depleting neurotransmitter levels.