Rapid-Onset Antidepressant-Like Effect of Nelumbinis semen in Social Hierarchy Stress Model of Depression

Depression is a disease with increasing prevalence worldwide, and it is necessary to develop a therapeutic agent with better efficacy than existing antidepressant drugs. Antidepressants that act on the glutamatergic nervous system, such as ketamine, have a rapid-onset antidepressant effect and are effective against treatment-resistant depression. However, because of the addictive potential of ketamine, alternative substances without psychological side effects are recommended. In particular, many natural compounds have been tested for their antidepressant effects. The antidepressant effects of Nelumbinis semen (NS) have been tested in many studies, along with the various actions of NS on the glutamatergic system. Thus, it was expected that NS might have a rapid-onset antidepressant effect. To test the antidepressant potential, despair and anhedonic behaviors were measured after administering NS to mice exposed to social hierarchy stress (SHS), and biochemical changes in the prefrontal cortex and hippocampus were analyzed. NS reduced despair-like responses in the forced swim test and tail suspension test. Mice exposed to SHS showed depression-like responses such as increased despair, reduced hedonia, and an anxiety-like response in the novelty suppressed feeding test. NS, but not fluoxetine, improved those depression-like behaviors after acute treatment, and NBQX, an AMPA receptor blocker, inhibited the antidepressant-like effects of NS. The antidepressant-like effect of NS was related to enhanced phosphorylation of mTOR in the prefrontal cortex and dephosphorylation of GluR1 S845 in the hippocampus. Since NS has shown antidepressant-like potential in a preclinical model, it may be considered as a candidate for the development of antidepressants in the future.