Mechanistic Target of Rapamycin-Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model
Authors: Chun Yang
Ji-Chun Zhang
Kenji Hashimoto
Min Ma
Chao Dong
Qian Ren
Youge Qu
Journal: Biological psychiatry (2018)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: (R)-Ketamine; (S)-Ketamine; Antidepressant; ERK; Enantiomer
Affiliations: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan., Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Electronic address: .

Abstract:  Background: The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. (R)-Ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers. Methods: The effects of mTOR inhibitors (rapamycin and AZD8055) and an ERK inhibitor (SL327) on the antidepressant effects of ketamine enantiomers in the chronic social defeat stress (CSDS) model (n = 7 or 8) and on those of ketamine enantiomers in these signaling pathways in mouse brain regions were examined. Results: The intracerebroventricular infusion of rapamycin or AZD8055 blocked the antidepressant effects of (S)-ketamine, but not (R)-ketamine, in the CSDS model. Furthermore, (S)-ketamine, but not (R)-ketamine, significantly attenuated the decreased phosphorylation of mTOR and its downstream effector, ribosomal protein S6 kinase, in the prefrontal cortex of susceptible mice after CSDS. Pretreatment with SL327 blocked the antidepressant effects of (R)-ketamine but not (S)-ketamine. Moreover, (R)-ketamine, but not (S)-ketamine, significantly attenuated the decreased phosphorylation of ERK and its upstream effector, mitogen-activated protein kinase/ERK kinase, in the prefrontal cortex and hippocampal dentate gyrus of susceptible mice after CSDS. Conclusions: This study suggests that mTOR plays a role in the antidepressant effects of (S)-ketamine, but not (R)-ketamine, and that ERK plays a role in (R)-ketamine's antidepressant effects. Thus, it is unlikely that the activation of mTOR signaling is necessary for antidepressant actions of (R)-ketamine. 

Retracted: No

PubPeer comments:
 2020 retraction. http: www.scielo.br scielo.php?script=sci_arttext pid=S1415-47572020000400950 tlng=en [RETRACTION]: Expression of serum microRNA-378 and its clinical significance in renal cell carcinoma On request received from the corresponding author, the following article is retracted because the authors noted problems in the statistical analysis of the data, so the conclusions drawn in this study cannot be sustained: Shi, Lixin, Zhang, Lei, Wang, Chunyang, Sun, Shengkun, Cao, Xiyuan, Zhang, Xu. (2017). Expression of serum microRNA-378 and its clinical significance in renal cell carcinoma. Genetics and Molecular Biology, 40(2), 525-529. 10.1590 1678-4685-gmb-2016-0121 Prof. Dr. Carlos Frederico Martins Menck Editor in chief , 
 I cannot speak to the statistical analysis, but it seems this paper was virtually a carbon copy of the paper Expression of serum microRNA-378 and its clinical significance in laryngeal squamous cell carcinoma (2016), Xu et al. (PMID: 28051256) The text is almost identical, with small tweaks to accomodate the fact that the papers ostensibly discuss different types of carcinomas. ![file] This could be the case of the authors following a template, but the numbers in the tables ... ![file] ... and the figures ... ![file] ... have too much in common for this to be a coincidence or the use of a template for reporting. I think it is fair to presume that there were additional reasons for the retraction than simply shoddy statistical analysis. ,