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Cited by 105Treatment of Major DepressionTryptophan and brain disordersNeuroscience and Neuropharmacology Research

(2R,6R)-Hydroxynorketamine is not essential for the antidepressant actions of (R)-ketamine in mice

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Yamaguchi, Jun-ichi, Toki, Hidetoh, Qu, Youge, Yang, Chun, Koike, Hiroyuki, Hashimoto, Kenji, Mizuno-Yasuhira, Akiko, Chaki, Shigeyuki·2018·Neuropsychopharmacology
DOI 10.1038/s41386-018-0084-yPMC PMC6046044
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Abstract

(R,S)-Ketamine has rapid and sustained antidepressant effects in depressed patients. Although the metabolism of (R,S)-ketamine to (2 R,6 R)-hydroxynorketamine (HNK), a metabolite of (R)-ketamine, has been reported to be essential for its antidepressant effects, recent evidence suggests otherwise. The present study investigated the role of the metabolism of (R)-ketamine to (2 R,6 R)-HNK in the antidepressant actions of (R)-ketamine. Antidepressant effects were evaluated using the forced swimming test in the lipopolysaccharide (LPS)-induced inflammation model of mice and the tail suspension test in naive mice. To prevent the metabolism of (R)-ketamine to (2 R,6 R)-HNK, mice were pretreated with cytochrome P450 (CYP) inhibitors. The concentrations of (R)-ketamine, (R)-norketamine, and (2 R,6 R)-HNK in plasma, brain, and cerebrospinal fluid (CSF) samples were determined using enantioselective liquid chromatography-tandem mass spectrometry. The concentrations of (R)-norketamine and (2 R,6 R)-HNK in plasma, brain, and CSF samples after administration of (R)-norketamine (10 mg/kg) and (2 R,6 R)-HNK (10 mg/kg), respectively, were higher than those generated after administration of (R)-ketamine (10 mg/kg). Nonetheless, while (R)-ketamine attenuated, neither (R)-norketamine nor (2 R,6 R)-HNK significantly altered immobility times of LPS-treated mice. Treatment with CYP inhibitors prior to administration of (R)-ketamine increased the plasma levels of (R)-ketamine, while generation of (2 R,6 R)-HNK was almost completely blocked. (R)-Ketamine exerted the antidepressant effects at a lower dose in the presence of CYP inhibitors than in their absence, which is consistent with exposure levels of (R)-ketamine but not (2 R,6 R)-HNK. These results indicate that metabolism to (2 R,6 R)-HNK is not necessary for the antidepressant effects of (R)-ketamine and that unmetabolized (R)-ketamine itself may be responsible for its antidepressant actions.

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Authors
Yamaguchi, J.-I., Toki, H., Qu, Y., Yang, C., Koike, H., Hashimoto, K., Mizuno-Yasuhira, A., & Chaki, S.
Affiliations
  • Taisho Pharmaceutical (Japan) (JP)
  • Chiba University (JP)
Corresponding author
Chaki, Shigeyuki
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2018-05-03
Volume
43
Issue
9
Pages
1900-1907
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-018-0084-y
PMC
PMC6046044
OpenAlex
W2800551343
Cited by
105
References
7
Citations by year
2026: 7 · 2025: 7 · 2024: 9 · 2023: 10 · 2022: 16 · 2021: 17 · 2020: 18 · 2019: 14 · 2018: 7
FWCI
8.76
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
(2R,6R)-hydroxynorketamine, antidepressant effects, cytochrome P450 inhibitors, lipopolysaccharide-induced inflammation, forced swim test, tail suspension test, enantiomers
MeSH terms
Animals, Antidepressive Agents, Cytochrome P-450 Enzyme System, Depressive Disorder, Inflammation, Ketamine, Lipopolysaccharides, Male, Mice, Inbred C57BL, Mice, Inbred ICR, Cytochrome P-450 Enzyme Inhibitors

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