Involvement of NMDA-AKT-mTOR Signaling in Rapid Antidepressant-Like Activity of Chaihu-jia-Longgu-Muli-tang on Olfactory Bulbectomized Mice

Abstract

Background: Fast-onset antidepressants are urgently needed. Chaihu-jia-Longgu-Muli-tang (CLM), a classic Chinese herbal medicine, has been used for antidepressant treatment with long history. Olfactory bulbectomization (OB) model is validated for identification of rapid antidepressant efficacy. Here we used OB model for investigating the rapid onset activity of CLM in mice, and also tested the involvement of prefrontal Akt-mTOR and associated AMPA/NMDA receptors as well as hippocampal BDNF in the rapid antidepressant-like effect of CLM.Methods: The OB model was first characterized with depression-like behaviors and the time course changes of the behaviors. The fast onset of antidepressant effect of CLM was evaluated using sucrose preference test, tail suspension test and forced swim test in OB mice after a single administration. The expression of synaptic proteins of AMPA and NMDA subunits as well as Akt/mTOR signaling in the prefrontal cortex, and hippocampal BDNF was evaluated with the immunoblotting method.Results: A single dose of CLM significantly improved the deficiency in the sucrose preference and decreased the immobility time in the tail suspension test in OB mice. In the prefrontal cortex (PFC) in OB mice, there was lower expression level of the AMPA receptor subunit GluR1, rescued by a single dose of CLM. Additionally, the expression of NMDA subunit NR1 was up-regulated in OB mice, whereas mTOR and its upstream Akt signalings were both down-regulated. These deficiencies were reversed by a single dose of CLM. The CLM treatment also attenuated the expressions of NMDA receptor subunits NR2A and NR2B, which did not change in OB mice. In the hippocampus, expressions of GluR1 and brain derived neurotrophic factor (BDNF) were both up-regulated in OB mice, although CLM increased GluR1, but not BDNF.Conclusion: CLM elicited rapid antidepressant-like effects in the OB model mice, and CLM reversal of the abnormality in PFC expression of AMPA and NMDA receptors and associated Akt-mTOR signaling may underlie the effects.

Chaihu Longgu Muli decoction, a Chinese herbal formula, for the treatment of insomnia

“…The individual herbs composing CLMD are Bupleuri radix, Fossilia ossis mastoid, Scutellariae radix, Zingiberis rhizoma, Ginseng radix, Cinnamomi cortex, Hoelen, Pinelliae tuber, Radix et Rhizoma Rhei, Osttreae testa, Zizyphi fructus, all of which are recorded in the Chinese Pharmacopoeia (Version 2010). [22] According to CHM theory, this prescription is reported to clear heat and eliminate dampness, and tranquilize with heavy prescription. The details of CLMD are summarized in Table 1 .…”

Traditional Chinese Medicine in Depression Treatment: From Molecules to Systems

“…A dose of ethanol extracts from Yueju pill (3 g/kg) rapidly attenuated depressive-like behaviors, increased hippocampal BDNF expression, activated prefrontal Akt-mTOR signaling, and downregulated NR1 expression within days (Xue et al, 2013;Tang et al, 2015;Xia et al, 2016). Chaihu-jia-Longgu-Muli-tang (a single dose of 2.1 g/kg) has also been shown to produce a rapid antidepressant-like activity in olfactory bulbectomization mice through activation of Akt-mTOR signaling and normalization of AMPA receptor/NMDA receptor ratio in PFC (Wang et al, 2019b). In addition, these formulas have previously been shown to produce antidepressant actions through monoaminergic systems as well as the HPA axis in chronic animal models (Mizoguchi et al, 2003;Wang et al, 2013).…”

mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse

“…Previous studies have reported the downregulation of the mTOR signaling pathway in postmortem human brain samples from subjects with MDD [39], as well as in PFC, hippocampus, and amygdala of several animal models of depression including the olfactory bulbectomy, chronic unpredictable stress (CUS), and chronic corticosterone exposure [40][41][42][43][44]. In order to examine the role of the mTOR pathway in the IL cortex as a neurobiological substrate in MDD, we evaluated in this study the effects of the mTOR knockdown in mouse IL cortex on the anxious-and depressive-like behavior, the expression of synaptic plasticity markers as the brain-derived neurotrophic factor (BDNF) using in situ hybridization, and used in vivo microdialysis to explore the evoked adaptive changes in cortico-subcortical circuits leading to the emergence of a depressive-like phenotype.…”