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

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.

Wuling powder prevents the depression-like behavior in learned helplessness mice model through improving the TSPO mediated-mitophagy

“…Shuttle box test is used to evaluate the helpless behavior, the increased number of escape failures and the extended escape latency are defined as coping deficits. FST is a widely used paradigm for evaluating behavioral despair and antidepressant response in rodents (Tang et al, 2015). The mice were considered immobile when floating in the water without struggling and making only those movements necessary to keep their heads above the water.…”

“…The latency to chew the pellet was recorded by an observer blind to this test. Immediately afterwards animals were returned in their home cage (Gai et al, 2014;Tang et al, 2015).…”

“…The mice were considered immobile when floating in the water without struggling and making only those movements necessary to keep their heads above the water. Total immobility times during the last 4 min of the 6-minute test period were recorded (Bambico et al, 2010;Tang et al, 2015;Zanos et al, 2015).…”

The molecular mechanism underlying GABAergic dysfunction in nucleus accumbens of depression‐like behaviours in mice

“…The behavioural test was performed to evaluate whether the mice following exposure to different stressors presented depression‐like behaviour (anhedonia and behavioural despair). The paradigm of the sucrose preference test (SPT) and novelty suppressed feeding test (NSF) was used to assess the anhedonia behaviour . The behavioural despair was assessed by the forced swimming test (FST) and tail suspension test (TST) .…”

“…The paradigm of the sucrose preference test (SPT) and novelty suppressed feeding test (NSF) was used to assess the anhedonia behaviour. 21,22 The behavioural despair was assessed by the forced swimming test (FST) and tail suspension test (TST). 19,23 All the behavioural experiments were conducted in the sound-proof behavioural facility with the light cycle.…”