Hippocampal mTOR signaling is required for the antidepressant effects of paroxetine

De-sheng, XU; Sun, Yuyu; Wang, Chengniu; Wang, Hao; Wang, Yingjie; Zhao, Wei; Bao, Guofeng; Wang, Fei; Cui, Zhiming; Jiang, Bo

doi:10.1016/j.neuropharm.2017.10.008

Cited by 54 publications

(31 citation statements)

References 46 publications

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“…By analyzing, we hypothesize that antidepressants initiate the 5-HT-mediated brain-derived neurotrophic factor (BDNF) biosynthesis through inhibiting the 5-HT reuptake transporter, then promoting the BDNF downstream signaling cascades (MAPK/ERK and/or PI3K/AKT pathways), and finally inducing the mTOR phosphorylation causing antidepresssive effects. Current studies show that ketamine activates mTOR through AMPA receptors, which seems to have a relatively shorter (a few minutes) pathway compared to other antidepressants (Xu et al, 2018 ). Pharmacological agents that target serotonergic receptors have been reported to induce fast-onset antidepressant effects in rodents, including the 5-HT 2C receptor antagonist (Opal et al, 2014 ), 5-HT 4 agonists (Lucas et al, 2007 ) and 5-HT 7 antagonists (Mnie-Filali et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Hypidone Hydrochloride (YL-0919) Produces a Fast-Onset Reversal of the Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure

Ran

Jin

Chen

et al. 2018

Front. Cell. Neurosci.

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Our previous study showed that hypidone hydrochloride (YL-0919), a partial serotonin 1A (5-HT1A) receptor agonist and 5-HT reuptake inhibitor, exerts a significant antidepressant effect in various animal models. The aim of the present study was to further investigate the underlying mechanisms and whether it could act as a fast-onset antidepressant. In the current study, depressive-like behavior was induced in rats by a chronic unpredictable stress (CUS) model and assessed with the Sucrose Preference Test (SPT). Treatment with YL-0919 (2.5 mg/kg, i.g.), but not with fluoxetine (Flx; 10 mg/kg, i.g.), caused a fast improvement in the SPT scores. In CUS-exposed rats, YL-0919 treatment for 5 days decreased the immobility time in a forced swimming test (FST), and a 10-day treatment decreased the latency to feed in a Novelty-Suppressed Feeding Test (NSFT). In addition to the behavioral tests, the effects of YL-0919 on synaptic protein expression were also evaluated. Western blotting showed that YL-0919 significantly enhanced the expression levels of synaptic proteins such as synapsin I, postsynaptic density protein 95 (PSD95), phosphorylated mammalian targeting of rapamycin (pmTOR) and brain-derived neurotrophic factor (BDNF) in the hippocampus. To determine how the mTOR signaling is involved in the fast-onset antidepressant-like effects of YL-0919, the mTOR-specific inhibitor rapamycin was administered intracerebroventricularly (i.c.v.) together with the YL-0919 treatment. The observed changes in behavioral tests and protein expression could be reversed by rapamycin treatment. This suggests that the fast-onset antidepressant effects of YL-0919 were partially caused by changes in synaptogenesis mediated by activation of mTOR pathways. Our data suggest that YL-0919 may be a powerful/effective antidepressant with fast-onset.

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Section: Introductionmentioning

confidence: 99%

Hypidone Hydrochloride (YL-0919) Produces a Fast-Onset Reversal of the Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure

Ran

Jin

Chen

et al. 2018

Front. Cell. Neurosci.

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“… 69 , 70 Preclinical studies in rats and mice have demonstrated that both mTOR signaling and BDNF are required for ketamine's antidepressant effect; one preclinical study 71 found that the antidepressant response to ketamine was attenuated when study animals were pretreated with a single dose of rapamycin, an mTOR kinase inhibitor, infused directly into the medial prefrontal cortex (mPFC), one of the regions of the brain implicated in depression pathophysiology and the mechanism of action of ketamine. Interestingly, a number of traditional antidepressants, including fluoxetine, 72 paroxetine, 73 and fluvoxamine, 74 led to mTOR activation in a region-specific manner after chronic administration to mice in preclinical studies. In each of these studies, administration of rapamycin prevented antidepressant effects.…”

Section: Resultsmentioning

confidence: 99%

Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action

Irwin

VandenBerg

2021

Mental Health Clinician

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Introduction MDD represents a significant burden worldwide, and while a number of approved treatments exist, there are high rates of treatment resistance and refractoriness. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, is a novel, rapid-acting antidepressant, however the mechanisms underlying the efficacy of ketamine are not well understood and many other mechanisms outside of NMDAR antagonism have been postulated based on preclinical data. This focused review aims to present a summary of the proposed mechanisms of action by which ketamine functions in depressive disorders supported by preclinical data and clinical studies in humans. Methods A literature search was completed using the PubMed and Google Scholar databases. Results were limited to clinical trials and case studies in humans that were published in English. The findings were used to compile this article. Results The antidepressant effects associated with ketamine are mediated via a complex interplay of mechanisms; key steps include NMDAR blockade on γ-aminobutyric acid interneurons, glutamate surge, and subsequent activation and upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Discussion Coadministration of ketamine for MDD with other psychotropic agents, for example benzodiazepines, may attenuate antidepressant effects. Limited evidence exists for these effects and should be evaluated on a case-by-case basis.

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“…It regulates various cellular processes, including protein synthesis, growth, metabolism, senescence, regeneration, and autophagy. At present, the mTOR gene has been found to play a role in a variety of diseases [65], such as neurological diseases [66][67][68][69][70], tumors [39,[71][72][73][74], and diabetes [75,76]. mTOR contains two complexes, mTORC1 and mTORC2.…”

Section: Discussionmentioning

confidence: 99%

Genomic and Transcriptome Analysis to Identify the Role of the mTOR Pathway in Kidney Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance

Che

et al. 2021

Oxidative Medicine and Cellular Longevity

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The mTOR pathway, a major signaling pathway, regulates cell growth and protein synthesis by activating itself in response to upstream signals. Overactivation of the mTOR pathway may affect the occurrence and development of cancer, but no specific treatment has been proposed for targeting the mTOR pathway. In this study, we explored the expression of mTOR pathway genes in a variety of cancers and the potential compounds that target the mTOR pathway and focused on an abnormal type of cancer, kidney renal clear cell carcinoma (KIRC). Based on the mRNA expression of the mTOR pathway gene, we divided KIRC patient samples into three clusters. We explored possible therapeutic targets of the mTOR pathway in KIRC. We predicted the IC50 of some classical targeted drugs to analyze their correlation with the mTOR pathway. Subsequently, we investigated the correlation of the mTOR pathway with histone modification and immune infiltration, as well as the response to anti-PD-1 and anti-CTLA-4 therapy. Finally, we used a LASSO regression analysis to construct a model to predict the survival of patients with KIRC. This study shows that mTOR scores can be used as tools to study various treatments targeting the mTOR pathway and that we can predict the recovery of KIRC patients through the expression of mTOR pathway genes. These research results can provide a reference for future research on KIRC patient treatment strategies.

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Hippocampal mTOR signaling is required for the antidepressant effects of paroxetine

Cited by 54 publications

References 46 publications

Hypidone Hydrochloride (YL-0919) Produces a Fast-Onset Reversal of the Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure

Hypidone Hydrochloride (YL-0919) Produces a Fast-Onset Reversal of the Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure

Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action

Genomic and Transcriptome Analysis to Identify the Role of the mTOR Pathway in Kidney Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance

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