(R,S)-Ketamine Metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine Increase the Mammalian Target of Rapamycin Function
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Background: Subanesthetic doses of ( R,S )-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of ( R,S )-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, ( R,S )-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown. Methods: Rats (n = 3 per time point) were given ( R,S )-ketamine, ( R,S )-norketamine, and ( 2S , 6S )-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 min. PC-12 pheochromocytoma cells (n = 3 per experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined. Results: The phosphorylation of mTOR and its downstream targets was significantly increased in rat prefrontal cortex tissue by more than ~2.5-, ~25-, and ~2-fold, respectively, in response to a 60-min postadministration of ( R,S )-ketamine, ( R,S )-norketamine, and ( 2S,6S )-hydroxynorketamine ( P < 0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with ~2-fold increases at 0.05 nM ( 2S , 6S )-hydroxynorketamine, 10 nM ( R,S )-norketamine, and 1,000 nM ( R,S )-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the α 7 -nicotinic acetylcholine receptor. Conclusions: The data demonstrate that ( R,S )-norketamine and ( 2S , 6S )-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of ( R,S )-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of ( R,S )-ketamine requires a full study of the parent compound and its metabolites.
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Ketamine and other NMDA receptor antagonists increase mTORC1 signaling via activation of Akt and ERK and increase synaptic number and function in the PFC.
“In contrast to the effects of stress, ketamine and other NMDA receptor antagonists increase mTORC1 signaling via activation of Akt and ERK and increase synaptic number and function in the PFC52,156–158(Figure 4).”
From Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants (2016) · cites this paper as [157]
A single antidepressant-dose ketamine administration induces a fast-onset (within 30 min of administration) induction of phospho-mTOR, phospho-p70S6 kinase and phospho-4EBP1 in the prefrontal cortex and hippocampus of mice and rats.
“A single antidepressant-dose ketamine administration induced a fast-onset (within 30 min of administration) induction of phospho-mTOR 71, 75, 124, 139, 177–179, phospho-p70S6 kinase and phospho-4EBP1 75, 177 in the prefrontal cortex and hippocampus of mice and rats, suggesting a mechanism whereby ketamine-induced protein translation occurs in an mTOR activation-dependent manner.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [177]
(2S,6S)-HNK metabolite administration rapidly induces mTOR phosphorylation in rats.
“Additionally, (2S,6S)-HNK metabolite administration was shown to rapidly induce mTOR phosphorylation in rats 177.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [177]
Ketamine-induced protein translation occurs in an mTOR activation-dependent manner.
“A single antidepressant-dose ketamine administration induced a fast-onset (within 30 min of administration) induction of phospho-mTOR 71, 75, 124, 139, 177–179, phospho-p70S6 kinase and phospho-4EBP1 75, 177 in the prefrontal cortex and hippocampus of mice and rats, suggesting a mechanism whereby ketamine-induced protein translation occurs in an mTOR activation-dependent manner.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [177]
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- Authors
- Paul, R. K., Singh, N. S., Khadeer, M., Moaddel, R., Sanghvi, M., Green, C. E., O’Loughlin, K., Torjman, M. C., Bernier, M., & Wainer, I. W.
- Affiliations
- SRI International (US)
- Corresponding author
- Wainer, Irving W.
- Venue
- Anesthesiology
- Published
- 2014-07
- Volume
- 121
- Issue
- 1
- Pages
- 149-159
- ISSN
- 0003-3022 (ISSN-L)
- PMC
- PMC4061505
- OpenAlex
- W2027590847
- Cited by
- 115
- References
- 24
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 5 · 2022: 6 · 2021: 2 · 2020: 12 · 2019: 7 · 2018: 17 · 2017: 13 · 2016: 13 · 2015: 13 · 2014: 7
- FWCI
- 11.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Anesthesiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 AG999999)
- U.S. Public Health Service (HHSN271201000008I)
- National Institute on Aging
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- ketamine metabolites, mTOR signaling, subanesthetic ketamine, serine racemase, prefrontal cortex, PC12 cells, neuropathic pain
- MeSH terms
- Aconitine, Animals, Brain, Ketamine, Male, Nicotine, Phosphorylation, Blotting, Western, Signal Transduction, PC12 Cells, Rats, Wistar, Prefrontal Cortex, Excitatory Amino Acid Antagonists, Nicotinic Agonists, Nicotinic Antagonists, Rats, TOR Serine-Threonine Kinases
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