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.
Highlights
Major depressive disorder (MDD), a serious mental disorder, is the leading cause of disability and a major contributor to disease burden in the world’s population[1]
The present study focused on examining changes in glutamatergic receptors and mammalian target of rapamycin (mTOR) signaling affected by chronic stress and therapeutic mechanisms for two distinct rapid-acting antidepressants, ketamine and Yueju
Chronic mild stress (CMS) compromised ERK/Akt signaling and downstream mTOR effectors in the prefrontal cortex (PFC) of CMS mice, which were resumed by Yueju or ketamine treatment
Summary
Major depressive disorder (MDD), a serious mental disorder, is the leading cause of disability and a major contributor to disease burden in the world’s population[1]. Several studies suggest that ketamine and other fast-acting antidepressants, mediated by glutamate and/or neurotrophic receptors, stimulate the mammalian target of rapamycin (mTOR) pathway in the prefrontal cortex (PFC)[6,15], leading to transient activation of the downstream effectors, 4E-BP1 and p70S6K, which regulate gene expression and protein synthesis. Recent studies have suggested that mTOR signaling is compromised in depressed patients and animal models of depression[16,17] These findings raise the possibility that mTOR signal pathways are potential therapeutic targets for antidepressant actions in depressed subjects. An increasing number of studies indicate that dysregulation of NMDA and AMPA receptor expression and activity by stress may contribute to mental disorders including depression[20,21,22]. An evaluation of NMDA receptor subunits would provide a better understanding of the glutamate neurotransmission mechanism of rapid antidepressant responses, in depressed subjects who may have abnormal NMDA and/or AMPA functions
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