Differential effects of antidepressant drugs on mTOR signalling in rat hippocampal neurons

Park, Sung Woo; Lee, Jung Goo; Seo, Mi Kyoung; Lee, Chan Hong; Cho, Hye Yeon; Lee, Bong Ju; Seol, Wongi; Kim, Young Hoon

doi:10.1017/s1461145714000534

Cited by 100 publications

(70 citation statements)

References 61 publications

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“…This is consistent with previous studies demonstrating that acute or chronic administration of fluoxetine or imipramine has no effect mTORC1 signaling in PFC (Li et al, 2010; Liu et al, 2015), although chronic fluoxetine administration reverses the down-regulation of mTORC1 signaling in mice exposed to chronic stress (Liu et al, 2015). Primary neuronal culture studies also report no effect of fluoxetine or imipramine on mTORC1 signaling, although incubation with high doses of escitalopram and paroxetine for 4 days reversed the down regulation of mTORC1 signaling caused by incubation with B27 depleted media (Park et al, 2014). …”

Section: Discussionmentioning

confidence: 99%

Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures

et al. 2016

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Recent preclinical and clinical studies demonstrate that three functionally different compounds, the NMDA receptor channel blocker ketamine, mGlu2/3 receptor antagonist LY341495, and NMDA receptor glycine site agent GLYX-13 produce rapid and long lasting antidepressant effects. Furthermore, these agents are reported to stimulate ERK and mTORC1 signaling in brain. Here we used rat primary cortical culture neurons to further examine the cellular actions of these agents. The results demonstrate that low concentrations of all three compounds rapidly increase levels of the phosphorylated and activated forms of ERK and a downstream target of mTORC1, p70S6 kinase, in a concentration and time dependent manner. In addition, each compound rapidly increases BDNF release into the culture media. Further studies demonstrate that induction of BDNF release, as well as stimulation of phospho-ERK is blocked by incubation with an AMPA receptor antagonist. The requirement for AMPA receptor stimulation suggests that the effects of these rapid agents are activity dependent. This possibility is supported by studies demonstrating that neuronal silencing, via incubation with the GABAA receptor agonist muscimol, completely blocks phospho-ERK and BDNF release by each agent. Finally, incubation with each drug for 24 hr increases the number and length of neuronal branches. Together, the results demonstrate that these three different rapid acting antidepressant agents increase ERK signaling and BDNF release in an activity dependent manner that leads to increased neuronal complexity. Further studies will be required to determine the exact mechanisms underlying these effects in cultured neurons and in rodent models.

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Section: Discussionmentioning

confidence: 99%

Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures

et al. 2016

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“…Neurotrophic factors regulate mTORC1 signaling; however, one’s nutritional, energy, endocrine, and metabolic status can also regulate mTORC1 signaling activity [40, 42]. For example, the expression of mTORC1 in primary rat hippocampal neurons decreases under B27-deprivation conditions [17], while treadmill exercise increases the level of mTORC1 and synaptic proteins in the rat hippocampus following 7 days of immobilization stress [41]. Additionally, ketamine increases mTORC1 activity and the production of synaptic proteins in the mouse prefrontal cortex and rat primary hippocampal neurons [5, 13, 17, 32].…”

Section: Discussionmentioning

confidence: 99%

“…For example, the expression of mTORC1 in primary rat hippocampal neurons decreases under B27-deprivation conditions [17], while treadmill exercise increases the level of mTORC1 and synaptic proteins in the rat hippocampus following 7 days of immobilization stress [41]. Additionally, ketamine increases mTORC1 activity and the production of synaptic proteins in the mouse prefrontal cortex and rat primary hippocampal neurons [5, 13, 17, 32]. Therefore, it is possible that mTORC1 is a convergence pathway for synaptic plasticity and the production of synaptic proteins [5, 32, 43].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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BackgroundRecent studies have suggested that the activation of mammalian target of rapamycin (mTOR) signaling may be related to antidepressant action. Therefore, the present study evaluated whether antidepressant drugs would exert differential effects on mTOR signaling in the rat hippocampus under conditions of chronic restraint stress. Male Sprague–Dawley rats were subjected to restraint stress for 6 h/days for 21 days with either escitalopram (10 mg/kg) or paroxetine (10 mg/kg) administered after the chronic stress procedure. Western blot analyses were used to assess changes in the levels of phospho-Ser2448-mTOR, phospho-Thr37/46-4E-BP-1, phospho-Thr389-p70S6 K, phospho-Ser422-eIF4B, phospho-Ser240/244-S6, phospho-Ser473-Akt, and phospho-Thr202/Tyr204-ERK in the hippocampus.ResultsChronic restraint stress significantly decreased the levels of phospho-mTOR complex 1 (mTORC1), phospho-4E-BP-1, phospho-p70S6 K, phospho-eIF4B, phospho-S6, phospho-Akt, and phospho-ERK (p < 0.05); the administration of escitalopram and paroxetine increased the levels of all these proteins (p < 0.05 or 0.01). Additionally, chronic restraint stress reduced phospho-mTORC1 signaling activities in general, while escitalopram and paroxetine prevented these changes in phospho-mTORC1 signaling activities.ConclusionThese findings provide further data that contribute to understanding the possible relationships among mTOR activity, stress, and antidepressant drugs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-017-0357-0) contains supplementary material, which is available to authorized users.

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“…Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates neurogenesis, dendritic spine growth, protein translation initiation, and protein synthesis via a phosphorylation of p70S6 kinase and repression of 4E binding proteins (4EBP 173–175 ). mTOR signaling has been implicated in the antidepressant responses of several classical antidepressant drugs 176 .…”

Section: Downstream Mechanisms Involved In Ketamine’s Antidepressant mentioning

confidence: 99%

Mechanisms of ketamine action as an antidepressant

2018

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Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions in treatment-resistant patients. Although this finding has been met with enthusiasm, ketamine’s widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the unique antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine’s antidepressant actions but lack its undesirable effects. Here, we review hypotheses for the mechanism of action of ketamine as an antidepressant, including direct synaptic or extra-synaptic (GluN2B-selective) NMDAR inhibition, selective inhibition of NMDARs localized on GABAergic interneurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) activation. We also discuss links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR), and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine’s (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine’s action are not mutually exclusive and may act in a complementary fashion to exert the acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine’s antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression.

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Differential effects of antidepressant drugs on mTOR signalling in rat hippocampal neurons

Cited by 100 publications

References 61 publications

Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures

Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures

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

Mechanisms of ketamine action as an antidepressant

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