Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression
Open accessAbstract
Major depressive disorder (MDD) is the most common psychiatric illness worldwide, and it displays a striking sex-dependent difference in incidence, with two thirds of MDD patients being women. Ketamine treatment can produce rapid antidepressant effects in MDD patients, effects that are mediated-at least partially-through glutamatergic neurotransmission. Two active metabolites of ketamine, (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-HNK, also appear to play a key role in ketamine's rapid antidepressant effects through the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. In the present study, we demonstrated that estrogen plus ketamine or estrogen plus active ketamine metabolites displayed additive effects on the induction of the expression of AMPA receptor subunits. In parallel, the expression of estrogen receptor alpha (ERα) was also significantly upregulated. Even more striking, radioligand binding assays demonstrated that [3 H]-ketamine can directly bind to ERα (K D: 344.5 ± 13 nM). Furthermore, ketamine and its (2R,6R)-HNK and (2S,6S)-HNK metabolites displayed similar affinity for ERα (IC 50: 2.31 ± 0.1, 3.40 ± 0.2, and 3.53 ± 0.2 µM, respectively) as determined by [3 H]-ketamine displacement assays. Finally, induction of AMPA receptors by either estrogens or ketamine and its metabolites was lost when ERα was knocked down or silenced pharmacologically. These results suggest a positive feedback loop by which estrogens can augment the effects of ketamine and its (2R,6R)-HNK and (2S,6S)-HNK metabolites on the ERα-induced transcription of CYP2A6 and CYP2B6, estrogen inducible enzymes that catalyze ketamine's biotransformation to form the two active metabolites. These observations provide novel insight into ketamine's molecular mechanism(s) of action and have potential implications for the treatment of MDD.
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In mature astrocytes differentiated from human iPSC-derived astrocyte progenitors, ketamine exerts rapid antidepressant effects through activation of AMPA glutamate receptors.
“In mature astrocytes differentiated from human induced pluripotent stem cells (iPSC)-derived astrocyte progenitors, ketamine can exert rapid antidepressant effects through the activation of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptors”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [126]
The Methods (§2.1; page not provided) describe differentiating human iPSC-derived astrocyte progenitors into mature astrocytes, and the Results (§3.1) report increased AMPA receptor subunit mRNA expression after ketamine exposure in human astrocyte experiments. The Introduction (§1) discusses ketamine’s rapid antidepressant effects and says enhanced AMPA receptor activity might play a role. The paper does not show a rapid antidepressant effect in the cultured astrocytes or establish AMPA receptor activation as its mechanism there. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEstrogen enhances ketamine's effect by increasing gene expression of AMPA receptor subunits.
“and estrogen enhances this effect of ketamine by increasing the gene expression of AMPA receptor subunits. 126”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [126]
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- Authors
- Ho, M.-F., Correia, C., Ingle, J. N., Kaddurah-Daouk, R., Wang, L., Kaufmann, S. H., & Weinshilboum, R. M.
- Affiliations
- Mayo Clinic (US)
- Duke University (US)
- Corresponding author
- Weinshilboum, Richard M.
- ORCID
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 152
- Pages
- 279-292
- ISSN
- 0006-2952 (ISSN-L)
- PMC
- PMC5960634
- OpenAlex
- W2796261668
- Cited by
- 49
- References
- 38
- Citations by year
- 2025: 10 · 2024: 5 · 2023: 2 · 2022: 9 · 2021: 10 · 2020: 5 · 2019: 4 · 2018: 4
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (U19 GM61388, P50 CA11620, RO1 CA196648, RO1 GM28157, RO1 MH108348, U54 GM114838, RO1 CA138461)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- ketamine, ketamine metabolites, hydroxynorketamine, estrogen receptor alpha, AMPA receptors, major depressive disorder, rapid antidepressant effects, cytochrome P450 induction, CYP2A6, CYP2B6, estrogen receptor ligands, glutamatergic neurotransmission
- MeSH terms
- Animals, Astrocytes, Cell Line, Cloning, Molecular, Gene Expression Regulation, Humans, Ketamine, Receptors, Estrogen, RNA, Messenger, Receptors, AMPA, Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B6
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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