PMID- 28651788
OWN - NLM
STAT- MEDLINE
DCOM- 20180709
LR  - 20220408
IS  - 1873-2402 (Electronic)
IS  - 0006-3223 (Linking)
VI  - 83
IP  - 1
DP  - 2018 Jan 1
TI  - Mechanistic Target of Rapamycin-Independent Antidepressant Effects of 
      (R)-Ketamine in a Social Defeat Stress Model.
PG  - 18-28
LID - S0006-3223(17)31618-9 [pii]
LID - 10.1016/j.biopsych.2017.05.016 [doi]
AB  - 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.
CI  - Copyright (c) 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All 
      rights reserved.
FAU - Yang, Chun
AU  - Yang C
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, Japan.
FAU - Ren, Qian
AU  - Ren Q
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, Japan.
FAU - Qu, Youge
AU  - Qu Y
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, Japan.
FAU - Zhang, Ji-Chun
AU  - Zhang JC
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, Japan.
FAU - Ma, Min
AU  - Ma M
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, Japan.
FAU - Dong, Chao
AU  - Dong C
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, Japan.
FAU - Hashimoto, Kenji
AU  - Hashimoto K
AD  - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental 
      Health, Chiba, Japan. Electronic address: hashimoto@faculty.chiba-u.jp.
LA  - eng
PT  - Journal Article
DEP - 20170531
PL  - United States
TA  - Biol Psychiatry
JT  - Biological psychiatry
JID - 0213264
RN  - 0 (Antidepressive Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Morpholines)
RN  - 0 (SL 327)
RN  - 3739OQ10IJ (Aminoacetonitrile)
RN  - 690G0D6V8H (Ketamine)
RN  - 970JJ37FPW 
      ((5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Biol Psychiatry. 2018 Jan 1;83(1):2-4. PMID: 29173705
EIN - Biol Psychiatry. 2020 Apr 1;87(7):686-687. PMID: 32164916
MH  - Aminoacetonitrile/analogs & derivatives/pharmacology
MH  - Animals
MH  - Antidepressive Agents/chemistry/*pharmacology
MH  - Brain/*drug effects/metabolism
MH  - Chronic Disease
MH  - Depressive Disorder/*drug therapy/metabolism
MH  - Disease Models, Animal
MH  - *Dominance-Subordination
MH  - Enzyme Inhibitors/pharmacology
MH  - Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism
MH  - Ketamine/chemistry/*pharmacology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Morpholines/pharmacology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/pharmacology
MH  - Stress, Psychological/*drug therapy/metabolism
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
OTO - NOTNLM
OT  - (R)-Ketamine
OT  - (S)-Ketamine
OT  - Antidepressant
OT  - ERK
OT  - Enantiomer
OT  - mTOR
EDAT- 2017/06/28 06:00
MHDA- 2018/07/10 06:00
CRDT- 2017/06/28 06:00
PHST- 2017/03/23 00:00 [received]
PHST- 2017/05/16 00:00 [revised]
PHST- 2017/05/16 00:00 [accepted]
PHST- 2017/06/28 06:00 [pubmed]
PHST- 2018/07/10 06:00 [medline]
PHST- 2017/06/28 06:00 [entrez]
AID - S0006-3223(17)31618-9 [pii]
AID - 10.1016/j.biopsych.2017.05.016 [doi]
PST - ppublish
SO  - Biol Psychiatry. 2018 Jan 1;83(1):18-28. doi: 10.1016/j.biopsych.2017.05.016. 
      Epub 2017 May 31.