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NMDAR inhibition-independent antidepressant actions of ketamine metabolites
Open accessAbstract
Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.
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In the citing paper
“Ketamine can increase the level of BDNF in the prefrontal cortex, especially in the hippocampus, to exert antidepressant-like effects. 377”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [377]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“an increasing number of studies have shown that BDNF signaling is an important target of antidepressants. 377”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [377]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“(2R,6R)-HNK has a binding affinity (Ki) and IC50 greater than 100 μM with 24% inhibition at 100 μM, and fails to impact NMDA-evoked currents in CA1 interneurons (Moaddel et al., 2013; Morris et al., 2017; Zanos et al., 2016).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Zanos et al., 2016
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The rapidity and magnitude of ketamine's effects have been attributed to its ability to rapidly reverse neuroplasticity deficits in animal models 3,4,10,34 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [34]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Importantly, R,R-HNK binds to TRKB, but not to NMDARs, at concentrations that promote neural plasticity, suggesting that TRKB may be the hitherto unknown signaling receptor for R,R-HNK (Zanos et al., 2016).”
From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Zanos et al., 2016
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“and R,R-HNK does not bind to NMDARs at the doses that produce antidepressant-like responses in mice (Zanos et al., 2016).”
From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Zanos et al., 2016
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“produces antidepressant-like and plasticity-promoting effects without psychotomimetic effects in rodents (Zanos et al., 2016;Yao et al., 2018)”
From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Zanos et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“However, in-depth analysis of the antidepressant effects of ketamine found that its active metabolite (2R,6R)-hydroxynorketamine (HNK) does not block the NMDA receptor. Instead, HNK displays sustained activation of α-amino-3hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and lacks ketamine-related side effects81.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [81]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Additionally, hydroxynorketamine (HNK), a metabolite of ketamine, can exert its anti-depressive effects by an NMDAR-independent mechanism. 377”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [377]
The cited source says what the claim attributes to it.
In the citing paper
“its inability to displace MK-801 binding to NMDARs (10 μM).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Zanos et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“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 Zanos et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“The ketamine metabolite (2R,6R)-HNK has received significant attention due to its efficacy in rodent models of depression, while lacking psychotomimetic side effects and abuse potential (Zanos et al., 2016).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Zanos et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“Production of the 6-HNKs is important for the full antidepressant-like behavioral effects of ketamine (Zanos, Highland, Liu, et al., 2019; Zanos et al., 2016; Zheng et al., 2021).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Zanos et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“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 Zanos et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“there is evidence that (2R,6R)-HNK does not elicit the same desire to self-administer or hyperlocomotion effects as ketamine”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Zanos et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“Preclinical research first suggested that metabolism to (2S,6S;2R,6R)-HNK was essential for ketamine's antidepressantlike effects and that (2R,6R)-HNK could exert its own antidepressant effects in mice [45,46].”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [46]
The cited source says what the claim attributes to it.
In the citing paper
“a metabolite of R-ketamine lacking dissociative properties has also demonstrated robust antidepressant-like effects in rodents”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [234]
In the citing paper
“2R,6R-HNK was reported to have antidepressant-like effects and no side effects in rodents.44”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [44]
In the citing paper
“Furthermore, ketamine increased expression of AMPA receptor GluA1 and GluA2 subunits in the mouse hippocampus.44,101”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [44]
In the citing paper
“In mice, ketamine administration was not noted to affect mTOR phosphorylation in hippocampal or cortical tissue44,96 and rapamycin did not block ketamine-induced antidepressant effects.96”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [44]
In the citing paper
“Lastly, there is an exciting recent hypothesis that ketamine may exert its antidepressant actions not by blocking NMDARs, but rather by its neuroactive metabolites, particularly the hydroxynorketamines (HNKs).”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [153]
In the citing paper
“Zanos et al. [153] reported that the behavioral actions of ketamine in mice could be eliminated by deuterating the molecule to greatly reduce its rate of hydrolysis, suggesting that ketamine's inhibition of NMDARs is not sufficient for its antidepressant actions.”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [153]
In the citing paper
“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 [153]
In the citing paper
“Direct administration of HNKs mimicked the behavioral actions of ketamine in mice, promoted EEG gamma oscillations, promoted expression of AMPARs and BDNF, and decreased phosphorylation of eEF2 levels in the hippocampus, providing plenty of mechanisms that could be triggered independently from NMDAR inhibition.”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [153]
In the citing paper
“Indeed, ketamine and GABA A receptor negative allosteric modulators share an ability to promote gamma oscillations in the PFC at doses that reverse the behavioral consequences of chronic stress [152,153].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [153]
In the citing paper
“such as AZD6765 [149], mGluR 2/3 antagonists [150], alpha5 subunit-selective GABA A R-NAMs [151, 152], and the ketamine metabolite (2 R,6 R)-HNK [153], all of which enhance EEG power in the gamma frequency band.”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [153]
In the citing paper
“In the case of ketamine, recent evidence suggests that one of its metabolites, norketamime (HNK) is actually responsible for the antidepressant effects of this drug, through activation of glutamate AMPA receptor (GluA-R) (Zanos et al 2016).”
From Prefrontal cortex executive processes affected by stress in health and disease (2018) · cites this paper as Zanos et al 2016
In the citing paper
“The stereoselective engagement of protein targets is a feature of numerous chemical probes and drugs15–19”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [17]
In the citing paper
“Moreover, antidepressant effects of ketamine have been demonstrated in many antidepressant-relevant tests in experimental animals (e.g. 9, 10–14); also see 15.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Notably, ketamine 13, similar to negative allosteric modulators of alpha5-containing GABAA receptors 47, enhance gamma band electroencephalography power, which is hypothesized to be directly related to cortical disinhibition 49–52”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Following ketamine administration, (2S,6S;2R,6R)-HNK is the major HNK metabolite found in the plasma and brain of mice 13, as well as the plasma of humans 120.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Similar to these human data, animal studies show that the NMDAR channel-blocking antagonist MK-801 does not exert sustained antidepressant actions, though it does have acute actions in some studies 9, 10, 13, 103.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Nevertheless, we note that pre-clinical rodent studies have also indicated rapid-acting antidepressant behavioral actions of (S)-ketamine in mice 13, 116–118.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“The superiority of (R)-ketamine does not seem to be related to a U-shaped dose response of the drugs, as it has been shown superior to (S)-ketamine with up to a 30-fold range of doses in multiple mouse tests of antidepressant efficacy 13, 118.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Importantly, administration of equal, antidepressant-relevant, doses of (R)- and (S)-ketamine in mice did not yield different levels of these enantiomers in the brain of mice 13, indicating that the antidepressant superiority of (R)-ketamine in rodent models is not due to greater brain exposure.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“These data indicate that it is unlikely that ketamine exerts its full antidepressant actions solely via inhibition of the NMDAR, at least in rodents.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“(S)-ketamine has ~4-fold greater affinity/potency at inhibiting the NMDAR compared to its (R)-ketamine enantiomer 13, 111–115.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“These findings were subsequently replicated by Zanos et al. (2016), who showed that (S)-ketamine’s antidepressant behavioral actions require higher doses compared to those of (R)-ketamine 13.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“In mice, this behavioral effect was associated with higher brain levels of (2S,6S;2R,6R)-HNK, but not ketamine or norketamine levels 13”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“AMPAR containing GluA1 and/or GluA2 subunit upregulation was also observed in mPFC 75 and hippocampal 13 synaptoneurosome fractions at 24 hours post-injection, indicating a rapid-triggered and sustained recruitment of AMPAR in the synapse, consistent with synaptic strengthening.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“In addition, greater antidepressant behavioral responses of a single administration of ketamine have been observed in female compared to male rats and mice 13, 124, 125.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Indeed, a dose of 20 mg/kg was capable of reversing anhedonia following chronic social defeat stress in mice 13.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Important for the mechanism of action of (2R,6R)-HNK as an antidepressant (and thus ketamine’s action) is the fact that at relevant concentrations (i.e., 10 mg/kg or brain Cmax = ~10 μmol/kg in mice), (2R,6R)-HNK does not appear to inhibit the NMDAR.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“In accordance with the findings that (R)-ketamine is a more potent antidepressant compared to the (S)-ketamine 13, 116, 117, 127, the (2R,6R)-HNK metabolite, which is solely produced via the metabolism of (R)-ketamine, exerts more potent and longer-lasting antidepressant actions compared with the (2S,6S)-HNK enantiomer, which is produced via the metabolism of (S)-ketamine.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“In addition, at 10 μM concentration, (2R,6R)-HNK does not functionally inhibit the NMDARs localized at stratum radiatum interneurons in hippocampal slices, compared to ~50% inhibition by ketamine at this concentration 13.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Quantitative EEG measurements in humans 101, as well as rats e.g. 135 and mice e.g. 13 revealed ketamine-induced increases in gamma-band power, which, in addition to a putative measure of cortical disinhibition, also indicates activation of fast ionotropic excitatory receptors, including AMPARs 136–138.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“There is evidence that metabolism of ketamine to (2S,6S;2R,6R)-HNK is necessary for its antidepressant action in rodent tests 13.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“However, (2R,6R)-HNK did not induce any NMDAR inhibition-mediated side effects in mice in the open-field test (locomotor activity; doses up to 125 mg/kg), the rota-rod test (motor incoordination; doses up to 125 mg/kg) and the pre-pulse inhibition test (sensory dissociation; doses up to 375 mg/kg) 13, 130, in contrast to the antidepressant dose of 10 mg/kg.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Indeed, pre-treatment with the AMPAR antagonist NBQX prevents the antidepressant-like actions of ketamine in the forced-swim test 9, 13, 117, 139, 140, tail-suspension test 117, 141, novelty-suppressed feeding test 142, learned helplessness test 141 and stress-induced sucrose preference deficits 117, 143.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“This was shown by chemically altering ketamine via deuteration at the C6 position, which did not change its binding affinity for the NMDAR, but dramatically decreased its in vivo metabolism to (2S,6S;2R,6R)-HNK. This manipulation prevented ketamine’s antidepressant actions in mice 13”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Similar to ketamine, (2R,6R)-HNK treatment in mice induces an acute and transient increase in high frequency gamma power 13.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“This effect appears independent of any possible NMDAR inhibition by (2R,6R)-HNK, since the NMDAR antagonist AP-5 was present in the vehicle wash solution 13.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Importantly, administration of the AMPAR antagonist NBQX prior to (2R,6R)-HNK abolished the gamma power oscillation increases, as well as the acute and sustained antidepressant effects of this metabolite in mice, indicating that acute AMPAR activation is required for gamma power increase and its rapid and sustained antidepressant actions 13.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Importantly, administration of the AMPAR antagonist NBQX prior to (2R,6R)-HNK abolished the gamma power oscillation increases, as well as the acute and sustained antidepressant effects of this metabolite in mice, indicating that acute AMPAR activation is required for gamma power increase and its rapid and sustained antidepressant actions 13.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“In line with an AMPAR activation-dependent mechanism of ketamine’s antidepressant action, (2R,6R)-HNK induces an increase in AMPAR-mediated excitatory post-synaptic potentials recorded from the CA1 region of hippocampal slices following stimulation of Schaffer collateral axons, suggesting an enhancement of excitatory synaptic transmission 13 (see Figure 1).”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Consistent with a mechanistic model where the sustained activity of synaptic AMPARs is required for the long-lasting antidepressant actions of (2R,6R)-HNK, it was shown that similar to ketamine 140 blockade of the AMPAR (with NBQX) 23.5 hours after (2R,6R)-HNK administration abolished its antidepressant actions at 24 hours post-injection 13.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“In support of this, (2R,6R)-HNK, at the same concentration which did not alter NMDAR EPSCs (i.e., 10 μM), increases the frequency of AMPAR-mediated excitatory post-synaptic currents recorded from CA1 stratum radiatum interneurons, which receives glutamatergic inputs from the Schaffer collaterals 13.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“However, MK-801 failed to induce long-lasting antidepressant actions in several animal tests 9, 10, 13, 103.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“In addition, ketamine and (2R,6R)-HNK administration increases synaptoneurosomal BDNF protein levels 24 hours post-injection in the hippocampus of mice 13.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“(2R,6R)-HNK administration also induced a decrease in hippocampal eEF2 phosphorylation 1 and 24 hours post-treatment, concomitant with increased BDNF levels at 24 hours 13, suggesting that protein synthesis through the eEF2 kinase/BDNF translation pathway might be involved in the antidepressant actions of this metabolite.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“(2R,6R)-HNK administration also induced a decrease in hippocampal eEF2 phosphorylation 1 and 24 hours post-treatment, concomitant with increased BDNF levels at 24 hours 13, suggesting that protein synthesis through the eEF2 kinase/BDNF translation pathway might be involved in the antidepressant actions of this metabolite.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Indeed, it was shown that ketamine exerts NMDAR inhibition-independent antidepressant actions, and that these effects require the metabolism of ketamine to the (2S,6S;2R,6R)-HNK metabolite 13.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
In the citing paper
“Moreover, the (2R,6R)-HNK metabolite is sufficient to induce antidepressant actions, similar to those observed following ketamine administration, in animal tests.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [13]
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Metadata
- Authors
- Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. I., Alkondon, M., Yuan, P., Pribut, H. J., Singh, N. S., Dossou, K. S. S., Fang, Y., Huang, X.-P., Mayo, C. L., Wainer, I. W., Albuquerque, E. X., Thompson, S. M., Thomas, C. J., Zarate Jr, C. A., & Gould, T. D.
- Affiliations
- University of Maryland, Baltimore (US)
- National Institutes of Health (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Gould, Todd D.
- ORCID
- Venue
- Nature
- Published
- 2016-05-04
- Volume
- 533
- Issue
- 7604
- Pages
- 481-486
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4922311
- OpenAlex
- W2346390990
- Cited by
- 1,609
- References
- 40
- Citations by year
- 2026: 99 · 2025: 162 · 2024: 123 · 2023: 129 · 2022: 169 · 2021: 165 · 2020: 166 · 2019: 156 · 2018: 196 · 2017: 160 · 2016: 83
- FWCI
- 160.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (HHSN271201000008I, HHSN-271-2008-025C)
- National Institute of Mental Health (MH107615, R01MH086828, R21MH099345, MH099345, MH086828, R01MH107615)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- ketamine, hydroxynorketamine, antidepressant effects, major depressive disorder, NMDA receptor antagonism, enantiomers, rapid-acting antidepressants, ketamine side effects, glutamatergic neurotransmission, EEG, electrophysiology, mice
- MeSH terms
- Animals, Antidepressive Agents, Female, Ketamine, Male, Time Factors, Receptors, N-Methyl-D-Aspartate, Receptors, AMPA, Mice
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