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International Journal of Neuropsychopharmacology

International Journal of Neuropsychopharmacology

IF: 4.5
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Activation of mTORC1 Signaling Cascade in Hippocampus and Medial Prefrontal Cortex Is Required for Antidepressant Actions of Vortioxetine in Mice

Published:19 October 2023 DOI: 10.1093/ijnp/pyad017 PMID: 37025079
Wei-Yu Li, Tian-Shun Shi, Jie Huang, Yan-Mei Chen, Wei Guan, Bo Jiang, Cheng-Niu Wang

Abstract

Background: Although thought of as a multimodal-acting antidepressant targeting the serotonin system, more molecules are being shown to participate in the antidepressant mechanism of vortioxetine. A previous report has shown that vortioxetine administration enhanced the expression of rapamycin complex 1 (mTORC1) in neurons. It has been well demonstrated that mTORC1 participates in not only the pathogenesis of depression but also the pharmacological mechanisms of many antidepressants. Therefore, we speculate that the antidepressant mechanism of vortioxetine may require mTORC1.

Methods: Two mouse models of depression (chronic social defeat stress and chronic unpredictable mild stress) and western blotting were first used together to examine whether vortioxetine administration produced reversal effects against the chronic stress-induced downregulation in the whole mTORC1 signaling cascade in both the hippocampus and medial prefrontal cortex (mPFC). Then, LY294002, U0126, and rapamycin were used together to explore whether the antidepressant effects of vortioxetine in mouse models of depression were attenuated by pharmacological blockade of the mTORC1 system. Furthermore, lentiviral-mTORC1-short hairpin RNA-enhanced green fluorescence protein (LV-mTORC1-shRNA-EGFP) was adopted to examine if genetic blockade of mTORC1 also abolished the antidepressant actions of vortioxetine in mice.

Results: Vortioxetine administration produced significant reversal effects against the chronic stress-induced downregulation in the whole mTORC1 signaling cascade in both the hippocampus and mPFC. Both pharmacological and genetic blockade of the mTORC1 system notably attenuated the antidepressant effects of vortioxetine in mice.

Conclusions: Activation of the mTORC1 system in the hippocampus and mPFC is required for the antidepressant actions of vortioxetine in mice.

Substances (20)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Rapamycin 53123-88-9 C51H79NO13 1033 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1033 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1033 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1033 suppliers $9.00-$6160.00
LY 294002 Hydrochloride 154447-36-6 C19H17NO3 405 suppliers $12.00-$3350.00
LY 294002 Hydrochloride 154447-36-6 C19H17NO3 405 suppliers $12.00-$3350.00
LY 294002 Hydrochloride 154447-36-6 C19H17NO3 405 suppliers $12.00-$3350.00
LY 294002 Hydrochloride 154447-36-6 C19H17NO3 405 suppliers $12.00-$3350.00
Vortioxetine 508233-74-7 C18H22N2S 305 suppliers $8.00-$2880.00
Vortioxetine 508233-74-7 C18H22N2S 305 suppliers $8.00-$2880.00

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