# Involvement of normalized NMDA receptor and mTOR-related signaling in rapid antidepressant effects of Yueju and ketamine on chronically stressed mice

## TL;DR

Yueju, a traditional Chinese medicine, shows rapid and long-lasting antidepressant effects in stressed mice, similar to ketamine, by affecting brain signaling pathways.

## Contribution

Yueju's long-term antidepressant effects and its impact on NR1 and Akt/mTOR signaling are newly demonstrated in this study.

## Key findings

- Yueju improved behavioral deficits in stressed mice as quickly as ketamine but with longer-lasting effects.
- Yueju reversed CMS-induced changes in mTOR-related signaling and NMDA receptor subunit NR1 expression for up to 6 days.
- Yueju's effects on phosphor-Akt and NR1 lasted longer than ketamine's, suggesting a more sustained therapeutic mechanism.

## Abstract

Yueju, a Traditional Chinese Medicine formula, exhibited fast-onset antidepressant responses similar to ketamine. This study focused on assessing the rapid and persistent antidepressant efficacy of Yueju and ketamine in chronically stressed mice and its association with alternations in prefrontal N-methyl-D-aspartate (NMDA) receptor and mammalian target of rapamycin (mTOR)-related activity. Chronic mild stress (CMS) led to deficits in sucrose preference test (SPT), forced swim test, tail suspension test, and novelty-suppressed feeding test, which were improved differently by acute Yueju or ketamine administration. The improvement in SPT started as soon as 2 hours post Yueju and ketamine but lasted for 6 days only by Yueju. Body weight was regained by Yueju more than ketamine at post-drug administration day (PAD) 6. CMS decreased phosphorylation of the mTOR effectors 4E-BP1 and p70S6K, their upstream regulators ERK and Akt, and downstream targets including synaptic protein GluR1. Yueju or ketamine reversed these changes at PAD 2, but only Yueju reversed phosphor-Akt at PAD 6. CMS selectively and lastingly increased NMDA receptor subunit NR1 expression, which was reversed by ketamine or Yueju at PAD 2 but only by Yueju at PAD 6. These findings suggest that NR1 and Akt/mTOR signaling are important therapeutic targets for depression.