Effects of a ketamine metabolite on synaptic NMDAR function

Suzuki, Kanzo; Nosyreva, E. D.; Hunt, Kevin W.; Kavalali, Ege T.; Monteggia, Lisa M.

doi:10.1038/nature22084

Cited by 151 publications

(147 citation statements)

References 12 publications

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“…This is predicted to decrease inhibition and increase pyramidal neuron discharge via disinhibition, thus enhancing excitatory glutamatergic neurotransmission [147]. This is also consistent with recent findings indicating that peripheral or intra-mPFC administration of ( 2R,6R )-HNK increases extracellular glutamate levels 24-h post-administration, an effect that was associated with its antidepressant behavioral actions in the 24-h forced-swim test [104]; however, this effect is not due to NMDAR inhibition [45, 107, 108]. …”

Section: Mechanisms Underlying Fast/rapid Onset Antidepressants Acsupporting

confidence: 87%

“…Although NMDAR inhibition was long assumed to underlie ketamine’s antidepressant actions, recent evidence indicates that additional downstream mechanisms are likely to be involved. Indeed, it was recently shown that the ( 2S,6S;2R,6R )-HNK metabolite of ketamine is essential for its antidepressant actions and that ( 2R,6R )-HNK possesses robust antidepressant efficacy with low potency at the NMDAR [45, 107, 108, 353, 354]. …”

Section: Discussionmentioning

confidence: 99%

“…Importantly, ( 2R,6R )-HNK does not inhibit the NMDAR at antidepressant-relevant concentrations, as was demonstrated by a lack of MK-801 displacement binding studies (Inhibitory constant: Ki > 100 μM; half maximal inhibitory concentration: IC 50 > 100 μM), lack of functional activity on NMDARs localized in stratum radiatum interneurons in rat hippocampal slices or dissociated primary cell culture [45, 107–109]. However, it does result in modest inhibition of mEPSC-NMDAR responses in mouse hippocampal cell cultures at higher concentrations [i.e., 50 μM; 108]. …”

Section: Mechanisms Underlying Fast/rapid Onset Antidepressants Acmentioning

confidence: 99%

“…Application of ketamine to hippocampal slices induces AMPAR-mediated synaptic potentiation in the CA1 region [264], even in the absence of ongoing synaptic stimulation [43, 259]. Similar to ketamine, application of ( 2R,6R )-HNK increases AMPAR-mediated excitatory post-synaptic potentials recorded from the CA1 region of hippocampus [45] at a concentration that does not alter the NMDA-evoked responses in brain slices [45] or hippocampal cell cultures [107, 108]. However, there is no evidence indicating that these actions are a direct effect of ketamine or its metabolite on the AMPARs.…”

Section: Downstream Pathways Involved In Rapid Antidepressant Actionsmentioning

confidence: 99%

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Convergent Mechanisms Underlying Rapid Antidepressant Action

et al. 2018

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Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal and anti-anhedonic actions following a single administration to depressed patients. Proposed mechanisms of ketamine’s antidepressant action include N-methyl-D-aspartate receptor (NMDAR) modulation, GABAergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergoing pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine - pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists (i.e. GLYX-13 (rapastinel)), metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.

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Section: Mechanisms Underlying Fast/rapid Onset Antidepressants Acsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Mechanisms Underlying Fast/rapid Onset Antidepressants Acmentioning

confidence: 99%

Section: Downstream Pathways Involved In Rapid Antidepressant Actionsmentioning

confidence: 99%

See 2 more Smart Citations

Convergent Mechanisms Underlying Rapid Antidepressant Action

et al. 2018

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“…Zanos et al gave behavioural and pharmacological evidence that (2R,6R)-HNK, unlike ketamine, was not acting at the NMDA glutamate receptor, but most likely at the AMPA glutamate receptor 4. However, another study in cultured hippocampal neurons showed that (2R,6R)-HNK inhibited synaptic NMDA receptors 24. Since our naloxone study demonstrated in the plantar hindpaw incision model that (2R,6R)-HNK does not act at the mu-opioid receptor, the combination of prolonged analgesia with low side effects makes (2R,6R)-HNK an attractive candidate for pain control.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain

Kroin

Das

Moric

et al. 2019

Regional Anesthesia &Amp; Pain Medicine

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Background and objectivesKetamine has been shown to reduce chronic pain; however, the adverse events associated with ketamine makes it challenging for use outside of the perioperative setting. The ketamine metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) has a therapeutic effect in mice models of depression, with minimal side effects. The objective of this study is to determine if (2R,6R)-HNK has efficacy in both acute and chronic mouse pain models.MethodsMice were tested in three pain models: nerve-injury neuropathic pain, tibia fracture complex regional pain syndrome type-1 (CRPS1) pain, and plantar incision postoperative pain. Once mechanical allodynia had developed, systemic (2R,6R)-HNK or ketamine was administered as a bolus injection and compared with saline control in relieving allodynia.ResultsIn all three models, 10 mg/kg ketamine failed to produce sustained analgesia. In the neuropathic pain model, a single intraperitoneal injection of 10 mg/kg (2R,6R)-HNK elevated von Frey thresholds over a time period of 1–24hours compared with saline (F=121.6, p<0.0001), and three daily (2R,6R)-HNK injections elevated von Frey thresholds for 3 days compared with saline (F=33.4, p=0.0002). In the CRPS1 model, three (2R,6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 4 days compared with saline (F=116.1, p<0.0001). In the postoperative pain model, three (2R,6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 5 days compared with saline (F=60.6, p<0.0001).ConclusionsThis study demonstrates that (2R,6R)-HNK is superior to ketamine in reducing mechanical allodynia in acute and chronic pain models and suggests it may be a new non-opioid drug for future therapeutic studies.

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Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression

et al. 2020

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IMPORTANCE A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain. OBJECTIVE To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and γ-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects. DESIGN, SETTING, AND PARTICIPANTS This randomized, parallel-group, triple-masked clinical trial included 38 physically healthy, psychotropic medication-free adult outpatients who were in a major depressive episode of MDD but not actively suicidal.

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Effects of a ketamine metabolite on synaptic NMDAR function

Cited by 151 publications

References 12 publications

Convergent Mechanisms Underlying Rapid Antidepressant Action

Convergent Mechanisms Underlying Rapid Antidepressant Action

Efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain

Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression

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