Antidepressant effects of repeated s-ketamine administration as NMDAR Antagonist: Involvement of CaMKIIα and mTOR signaling in the hippocampus of CUMS mice.

With the approval of s-ketamine nasal spray as a novel antidepressant, its robust antidepressant effects have been intensively examined in clinical trials. However, the therapeutic efficacy and mechanisms of repeated intermittent drug administration remain unclear. In the present study, we applied a classic chronic unpredictable mild stress (CUMS) model to induce depressive-like behaviors of mice and evaluated the role of repeated s-ketamine administration (10 mg/kg, 7 consecutive days) in ameliorating depressive-like behaviors and modulating related molecular pathways. A battery of behavioral tests were performed to assess CUMS-induced depression. The protein expressions of GluN1, GluN2A, GluN2B, GluR1, CaMKIIα, phosphorylated CaMKIIα (p-CaMKIIα), BDNF, TrkB, phosphorylated TrkB (p-TrkB), mTOR, and phosphorylated mTOR (p-mTOR) as well as modification of synaptic ultrastructure was identified in hippocampal tissues. It turned out that s-ketamine manifested evident antidepressant effects with improved synaptic plasticity. Meanwhile, the results suggested that s-ketamine could differentially modulate glutamate receptors with upregulated GluN1 and GluR1 levels and downregulated GluN2B levels. CUMS-induced elevation of CaMKIIα phosphorylation and decline of BDNF, TrkB phosphorylation and mTOR could also be reversed through s-ketamine treatment. Together, our study provided evidence that selectively modulated glutamate receptors as well as CaMKIIα and mTOR signaling were involved in repeated s-ketamine administration. Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

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Bingjie Liu, Yuxin Du, Chang Xu, Qingzhen Liu, Lidong Zhang. Antidepressant effects of repeated s-ketamine administration as NMDAR Antagonist: Involvement of CaMKIIα and mTOR signaling in the hippocampus of CUMS mice. Brain research. 2023 Jul 15;1811:148375

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PMID: 37146745

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