(2R,6R)-hydroxynorketamine rapidly potentiates hippocampal glutamatergic transmission through a synapse-specific presynaptic mechanism
Open accessAbstract
Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) retains the rapid and sustained antidepressant-like actions of ketamine, but is spared its dissociative-like properties and abuse potential. While (2R,6R)-HNK is thought to exert its antidepressant-like effects by potentiating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission, it is unknown how it exerts this effect. The acute synaptic effects of (2R,6R)-HNK were examined by recording field excitatory postsynaptic potentials (fEPSPs) and miniature excitatory postsynaptic currents (mEPSCs) in rat hippocampal slices. (2R,6R)-HNK bath application caused a rapid and persistent potentiation of AMPAR-mediated Schaffer collateral (SC)-CA1 fEPSPs in slices derived from male and female rats. The (2R,6R)-HNK-induced potentiation occurred independent of N-methyl-D-aspartate receptor (NMDAR) activity, was accompanied by a concentration-dependent decrease in paired pulse ratios, and was occluded by raising glutamate release probability. In additon, in the presence of tetrodotoxin, (2R,6R)-HNK increased the frequency, but not amplitude, of mEPSC events, confirming a presynaptic site of action that is independent of glutamatergic network disinhibition. A dual extracellular recording configuration revealed that the presynaptic effects of (2R,6R)-HNK were synapse-selective, occurring in CA1-projecting SC terminals, but not in CA1-projecting temporoammonic terminals. Overall, we found that (2R,6R)-HNK enhances excitatory synaptic transmission in the hippocampus through a concentration-dependent, NMDAR-independent, and synapse-selective increase in glutamate release probability with no direct actions on AMPAR function. These findings provide novel insight regarding (2R,6R)-HNK's acute mechanism of action, and may inform novel antidepressant drug mechanisms that could yield superior efficacy, safety, and tolerability.
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HNKs, which have antidepressant-like effects in preclinical models, may not require NMDARs for their long-lasting effects on behavior or synaptic plasticity in hippocampus.
“HNKs, which also have antidepressant-like effects in preclinical models, may not require NMDARs for their long-lasting effects on behavior or synaptic plasticity in the hippocampus (Gould et al., 2017; Riggs et al., 2020; Zanos et al., 2016).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Riggs et al., 2020
The Introduction and Results report antidepressant-like effects of (2R,6R)-HNK in preclinical models and show that its acute potentiation of hippocampal synaptic transmission occurs despite NMDAR blockade. The Discussion explicitly distinguishes those acute effects from the sustained adaptations associated with persistent behavioral effects. This paper therefore does not establish that NMDARs are unnecessary for the long-lasting behavioral or hippocampal plasticity effects, and it studies (2R,6R)-HNK rather than HNKs generally. (LLM, conf=0.87)
Experimental — accuracy not yet measured(2R,6R)-HNK 10 μM for 60 minutes increased AMPAR-mediated synaptic strength in rat CA1, likely presynaptically by raising glutamate release probability.
“Likewise, (2R,6R)-HNK (10 μM, 60-minute bath application) was observed to increase AMPAR-mediated synaptic strength in the CA1 of rats, however it appears that this effect is likely presynaptic due to an increase in glutamate release probability”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Riggs et al., 2020
(2R,6R)-HNK produces antidepressant-like effects and enhancement in AMPAR signaling independent of NMDAR antagonism, suggesting NMDARs do not fully explain ketamine's mechanism of action.
“It appears that (2R,6R)-HNK produces antidepressant-like effects and an enhancement in AMPAR signaling independent of NMDAR antagonism which suggests that NMDARs do not fully explain the mechanism of action of ketamine (Riggs et al., 2020; Zanos et al., 2016).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Riggs et al., 2020
Acute hydroxynorketamine application to hippocampal slices potentiates SC-CA1 synaptic transmission via increased presynaptic glutamate release probability.
“Acute application of HNKs to hippocampal brain slices also produces a direct potentiation of SC-CA1 synaptic transmission [153], mediated by an increase in the probability of presynaptic glutamate release [161].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [161]
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Research works printed but not linked: 2
- Lumsden EW, Troppoli TA, Myers SJ, Zanos P, Aracava Y, Kehr J. et al. Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)- hydroxynorketamine do not block NMDA receptor function. Proc Natl Acad Sci USA. 2019;116:5160-69.
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- Authors
- Riggs, L. M., Aracava, Y., Zanos, P., Fischell, J., Albuquerque, E. X., Pereira, E. F. R., Thompson, S. M., & Gould, T. D.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Gould, Todd D.
- Venue
- Neuropsychopharmacology
- Published
- 2019-06-19
- Volume
- 45
- Issue
- 2
- Pages
- 426-436
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC6901515
- OpenAlex
- W2953365016
- Cited by
- 66
- References
- 62
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 4 · 2023: 10 · 2022: 15 · 2021: 9 · 2020: 7 · 2019: 2
- FWCI
- 5.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (T32-GM008181, R25-GM055036)
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (T32-NS063391)
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01-MH086828, R01-MH107615)
- U.S. Department of Veterans Affairs (1I01BX004062)
- Harrington Project for Discovery and Development Scholar Innovator Award
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- (2R,6R)-hydroxynorketamine, antidepressant mechanism, AMPA receptor potentiation, hippocampus, Schaffer collateral-CA1 synapses, paired-pulse ratio, field excitatory postsynaptic potentials, miniature excitatory postsynaptic currents
- MeSH terms
- Animals, Female, Hippocampus, Ketamine, Male, Synaptic Transmission, Organ Culture Techniques, Synapses, Rats, Sprague-Dawley, Presynaptic Terminals, Glutamic Acid, Excitatory Postsynaptic Potentials, Rats
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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