Clinical evidence suggests that Nelumbinis Semen extracts have antidepressive properties and may offer an interesting alternative for the treatment of mood disorders. It was the aim of the present study to compare the effects of Nelumbinis Semen extracts with those of fluoxetine and hypericum perforatum extract in the rat forced swimming test (FST) and chronic mild stress (CMS), a model of depression. In the FST, p.o. administration of Nelumbinis Semen extracts (1 mg) induced a statistically significant reduction of immobility. The active behaviors in that test did not reflect decreased general activity because Nelumbinis Semen extracts failed to alter the locomotor activity of rats, measured in the open field test. Moreover Nelumbinis Semen extracts was superior to fluoxetine and hypericum perforatum extract in the incidence of sexual side-effects. These effects of Nelumbinis Semen extracts on the rat behavior is to be ascribed to increased Cytochrome c oxidase polypeptide Vla-liver, Mitogen-activated protein kinase 1 , Adenylosuccinate synthetase, and Aldehyde dehydrogenase in rat hippocampus.