Mechanistic Target of Rapamycin-Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model

Biol Psychiatry. 2018 Jan 1;83(1):18-28. doi: 10.1016/j.biopsych.2017.05.016. Epub 2017 May 31.

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.

Keywords: (R)-Ketamine; (S)-Ketamine; Antidepressant; ERK; Enantiomer; mTOR.

MeSH terms

  • Aminoacetonitrile / analogs & derivatives
  • Aminoacetonitrile / pharmacology
  • Animals
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / pharmacology*
  • Brain / drug effects*
  • Brain / metabolism
  • Chronic Disease
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / metabolism
  • Disease Models, Animal
  • Dominance-Subordination*
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Ketamine / chemistry
  • Ketamine / pharmacology*
  • Male
  • Mice, Inbred C57BL
  • Morpholines / pharmacology
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antidepressive Agents
  • Enzyme Inhibitors
  • Morpholines
  • SL 327
  • Aminoacetonitrile
  • Ketamine
  • (5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
  • mTOR protein, mouse
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Sirolimus