Effects of escitalopram and paroxetine on mTORC1 signaling in the rat hippocampus under chronic restraint stress

Seo, Mi Kyoung; Choi, Cheol Min; McIntyre, Roger S.; Cho, Hye Yeon; Lee, Chan Hong; Mansur, Rodrigo B.; Lee, Yena; Lee, Jae-Hon; Kim, Young Hoon; Park, Sung Woo; Lee, Jung Goo

doi:10.1186/s12868-017-0357-0

Cited by 29 publications

(18 citation statements)

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“…In the present study, DEX treatment decreased the BDNF level, total dendritic outgrowth, and spine density of primary hippocampal cells of rats, and both LY341495 and ketamine treatment dose-dependently reversed these effects, confirming that LY341495 affects BDNF level, dendritic outgrowth, and spine density. Our results are similar to those of previous studies 38,49,50 . Zanos et al reported that the ketamine metabolite (2R,6R)-hydroxynorketamine-(2R,6R)-HNK acts on mGlu2 receptor and that combined sub-effective doses of the mGlu 2/3 receptor antagonist LY341495 and (2R,6R)-HNK have synergistic effects on gamma oscillations and antidepressant-relevant behavioral actions 51 .…”

Section: Discussionsupporting

confidence: 93%

AMPA receptor-mTORC1 signaling activation is required for neuroplastic effects of LY341495 in rat hippocampal neurons

Seo

Hiền

Park

et al. 2020

Sci Rep

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The group II metabotropic glutamate 2/3 (mGlu 2/3) receptor antagonist LY341495 produces antidepressant-like effects by acting on mammalian target of rapamycin complex 1 (mTORC1) signaling and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors in rodent. We investigated whether LY341495 affects neuroplasticity via these mechanisms in rat primary hippocampal cultures under conditions of dexamethasone (DEX)-induced neurotoxicity. Ketamine was used for comparison. Hippocampal cultures were treated with LY341495 under conditions of DEX-induced toxicity. Changes in mTORC1-mediated proteins were determined by Western blotting analyses. Changes in dendritic outgrowth and spine density were evaluated via immunostaining. LY341495 significantly prevented DEX-induced decreases in the levels of mTORC1, 4E-BP1, and p70S6K phosphorylation as well as the levels of the synaptic proteins. These effects were blocked by pretreatment with the AMPA receptor inhibitor 2,3-dihydroxy-6-nitro-7sulfamoyl-benzo(f)quinoxaline (NBQX) and the mTORC1 inhibitor rapamycin. LY341495 significantly attenuated DEX-induced decreases in dendritic outgrowth and spine density. Pretreatment with rapamycin and NBQX blocked these effects of LY341495. Further analyses indicted that induction of BDNF expression produced by LY341495 was blocked by pretreatment with NBQX and rapamycin. LY341495 has neuroplastic effects by acting on AMPA receptor-mTORC1 signaling under neurotoxic conditions. Therefore, activation of AMPA receptor and mTORC1 signaling, which enhance neuroplasticity, may be novel targets for new antidepressants. Depression is a very common mental disorder characterized by depressed mood, decreased interest, decreased cognitive function, and a chronic course with multiple physical symptoms 1. Antidepressant drugs are the most commonly used method of treating depression 2. Most antidepressant drugs currently used in clinical practice modulate the function of monoamines, such as serotonin, dopamine, and noradrenaline, in the central nervous system 3,4. However, the current research shifts the focus to molecular mechanisms that underlie long-lasting downstream changes in the brain after chronic antidepressant use. Among newly discovered findings regarding the molecular mechanisms of antidepressant drugs, there has been a great deal of research interest in the antidepressant effects of mammalian target of rapamycin (mTOR) signaling activation 5. A randomized trial reported that ketamine infusion improved the symptoms of depression in patients with treatment-resistant depression 6. In a systemic review and meta-analysis of patients with depression, a single ketamine infusion was shown to have a rapid antidepressant effect, but the effect lasted from 4 to 7 days 7. Thus, it has been clinically confirmed that ketamine has an antidepressant effect, but its mechanism of action has not been clearly elucidated. Li et al.

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Section: Discussionsupporting

confidence: 93%

AMPA receptor-mTORC1 signaling activation is required for neuroplastic effects of LY341495 in rat hippocampal neurons

Seo

Hiền

Park

et al. 2020

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“…12 rats in each group were used for behavioral experiments, and the remaining 18 were used for subsequent experiments. The chronic restraint stress procedure was performed between 9:00 and 15:00, as previously described (Zhao et al, 2013; Seo et al, 2017). Briefly, except rats in C group, all rats were daily restrained into a transparent plexiglass tube (26 cm long and 8 cm in diameter) for 6 h over 21 consecutive days (Figures 1A,B).…”

Section: Methodsmentioning

confidence: 99%

Glucocorticoid-Driven NLRP3 Inflammasome Activation in Hippocampal Microglia Mediates Chronic Stress-Induced Depressive-Like Behaviors

Feng

Zhao

Yang

et al. 2019

Front. Mol. Neurosci.

123

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Chronic stress is a key risk factor for depression, and microglia have been implicated in the pathogenesis of the disease. Recent studies show that the Nod-like receptor protein 3 (NLRP3) inflammasome is expressed in microglia and may play a crucial role in depression. However, the mechanism of NLRP3 inflammasome activation in hippocampal microglia and its role in depressive-like behaviors remain poorly understood. In this study, rats were subjected to 6 h of restraint stress per day for 21 days to produce a model of stress-induced depression. Behavioral tests and serum corticosterone were used to assess the success of the model. Furthermore, HAPI cells were pretreated with dexamethasone (5 × 10 –7 M) to assess stress-induced changes in microglial cells in culture. The microglial marker Iba-1, reactive oxygen species (ROS), nuclear factor kappa B (NF-κB) and key components of the NLRP3 inflammasome and its downstream inflammatory effectors (IL-1β and IL-18) were measured. Chronic stress induced depressive-like behavior, increased serum corticosterone levels and produced hippocampal structural changes. Chronic stress and dexamethasone both increased Iba-1 expression and ROS formation and also elevated levels of NF-κB, NLRP3, cleaved caspase-1, IL-1β and IL-18. After use of the NF-κB inhibitor BAY 117082 and knocked out NLRP3 in vitro decreased ROS formation and the expression of Iba-1, NF-κB and NLRP3 as well as levels of cleaved caspase-1, IL-1β and IL-18. These findings suggest that activation of the glucocorticoid receptor-NF-κB-NLRP3 pathway in hippocampal microglia mediates chronic stress-induced hippocampal neuroinflammation and depression-like behavior.

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“…Concerning the signaling pathways involved in the effects of cannabinoid drugs in stress-related neuroplasticity, the mechanistic (or mammalian) target of rapamycin (mTOR) protein has been implicated in synaptogenesis, proliferative processes, and synaptic strength modulation (Li et al, 2010 ; Ma et al, 2010 ; Romine et al, 2015 ; Liang et al, 2016 ). Some studies showed that different paradigms of stress exposure reduce mTOR activity (Iiu et al, 2016 ; Xia et al, 2016 ; Zhuang et al, 2016 ; Seo et al, 2017 ), and cannabinoid drugs can interfere with this signaling pathway (Puighermanal et al, 2009 ; Palazuelos et al, 2012 ; Gobira et al, 2015 ; Giacoppo et al, 2017 ). For example, Zhong et al ( 2014 ) demonstrated that the antidepressant-like responses trigged by JZL184, an inhibitor of 2-AG hydrolysis, in chronically stressed mice were dependent on mTOR signaling.…”

Section: Stress Induces Changes In Cannabinoid-mediated Hippocampal Nmentioning

confidence: 99%

Cannabinoid Modulation of the Stressed Hippocampus

Scarante

Vila-Verde

Detoni

et al. 2017

Front. Mol. Neurosci.

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Exposure to stressful situations is one of the risk factors for the precipitation of several psychiatric disorders, including Major Depressive Disorder, Posttraumatic Stress Disorder and Schizophrenia. The hippocampal formation is a forebrain structure highly associated with emotional, learning and memory processes; being particularly vulnerable to stress. Exposure to stressful stimuli leads to neuroplastic changes and imbalance between inhibitory/excitatory networks. These changes have been associated with an impaired hippocampal function. Endocannabinoids (eCB) are one of the main systems controlling both excitatory and inhibitory neurotransmission, as well as neuroplasticity within the hippocampus. Cannabinoids receptors are highly expressed in the hippocampus, and several lines of evidence suggest that facilitation of cannabinoid signaling within this brain region prevents stress-induced behavioral changes. Also, chronic stress modulates hippocampal CB1 receptors expression and endocannabinoid levels. Moreover, cannabinoids participate in mechanisms related to synaptic plasticity and adult neurogenesis. Here, we discussed the main findings supporting the involvement of hippocampal cannabinoid neurotransmission in stress-induced behavioral and neuroplastic changes.

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Effects of escitalopram and paroxetine on mTORC1 signaling in the rat hippocampus under chronic restraint stress

Cited by 29 publications

References 62 publications

AMPA receptor-mTORC1 signaling activation is required for neuroplastic effects of LY341495 in rat hippocampal neurons

AMPA receptor-mTORC1 signaling activation is required for neuroplastic effects of LY341495 in rat hippocampal neurons

Glucocorticoid-Driven NLRP3 Inflammasome Activation in Hippocampal Microglia Mediates Chronic Stress-Induced Depressive-Like Behaviors

Cannabinoid Modulation of the Stressed Hippocampus

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