( R )-Ketamine Shows Greater Potency and Longer Lasting Antidepressant Effects Than Its Metabolite (2 R ,6 R )-Hydroxynorketamine

Yang, Chun; Qu, Youge; Abe, Masahito; Nozawa, Dai; Chaki, Shigeyuki; Hashimoto, Kenji

doi:10.1016/j.biopsych.2016.12.020

Cited by 143 publications

(135 citation statements)

References 9 publications

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“…We did find that a slightly higher dose of (2R,6R)-HNK (30 mg/kg) was required to produce effects equivalent to ketamine (10 mg/kg) and that the effects of (2R,6R)-HNK in the FUST were not as long lasting as ketamine. There have been some discrepancies in reports of the antidepressant actions of (2R,6R)-HNK, particularly in models of stress (learned helplessness) and social defeat (24,25). The exact reasons for these discrepancies are unclear but could be due to variations in strain, species, or testing conditions (26).…”

Section: Discussionmentioning

confidence: 99%

Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine

Fukumoto

Fogaça

Liu

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

146

151

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Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, produces rapid and long-lasting antidepressant effects in major depressive disorder (MDD) patients. (2R,6R)-Hydroxynorketamine [(2R,6R)-HNK], a metabolite of ketamine, is reported to produce rapid antidepressant effects in rodent models without the side effects of ketamine. Importantly, (2R,6R)-HNK does not block NMDA receptors like ketamine, and the molecular signaling mechanisms for (2R,6R)-HNK remain unknown. Here, we examined the involvement of BDNF/TrkB/mechanistic target of rapamycin complex 1 (mTORC1) signaling in the antidepressant actions of (2R,6R)-HNK. Intramedial prefrontal cortex (intra-mPFC) infusion or systemic (2R,6R)-HNK administration induces rapid and long-lasting antidepressant effects in behavioral tests, identifying the mPFC as a key region for the actions of (2R,6R)-HNK. The antidepressant actions of (2R,6R)-HNK are blocked in mice with a knockin of the BDNF Val66Met allele (which blocks the processing and activity-dependent release of BDNF) or by intra-mPFC microinjection of an anti-BDNF neutralizing antibody. Blockade of L-type voltage-dependent Ca2+ channels (VDCCs), required for activity-dependent BDNF release, also blocks the actions of (2R,6R)-HNK. Intra-mPFC infusion of pharmacological inhibitors of TrkB or mTORC1 signaling, which are downstream of BDNF, also block the actions of (2R,6R)-HNK. Moreover, (2R,6R)-HNK increases synaptic function in the mPFC. These findings indicate that activity-dependent BDNF release and downstream TrkB and mTORC1 signaling, which increase synaptic function in the mPFC, are required for the rapid and long-lasting antidepressant effects of (2R,6R)-HNK, supporting the potential use of this metabolite for the treatment of MDD.

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Section: Discussionmentioning

confidence: 99%

Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine

Fukumoto

Fogaça

Liu

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

146

151

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“…Nevertheless, Yang et al . (2017) 128 failed to identify antidepressant-relevant actions of a single dose of ( 2R,6R )-HNK (10 mg/kg) following chronic social defeat stress in mice, indicating that further studies are required to establish the effective doses of this metabolite in different animal tests predictive of antidepressant efficacy. Indeed, a dose of 20 mg/kg was capable of reversing anhedonia following chronic social defeat stress in mice 13 .…”

Section: Nmdar Inhibition-independent Mechanismsmentioning

confidence: 99%

Mechanisms of ketamine action as an antidepressant

2018

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Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions in treatment-resistant patients. Although this finding has been met with enthusiasm, ketamine’s widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the unique antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine’s antidepressant actions but lack its undesirable effects. Here, we review hypotheses for the mechanism of action of ketamine as an antidepressant, including direct synaptic or extra-synaptic (GluN2B-selective) NMDAR inhibition, selective inhibition of NMDARs localized on GABAergic interneurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) activation. We also discuss links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR), and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine’s (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine’s action are not mutually exclusive and may act in a complementary fashion to exert the acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine’s antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression.

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“…However, Yang et al . (2017) [105] did not observe significant antidepressant behavioral actions using a single dose of ( 2R,6R )-HNK (i.e., 10 mg/kg) following chronic social defeat stress in mice and the same group reported no effects of ( 2R,6R )-HNK in the learned helplessness paradigm in rats [106], highlighting that further studies are required to establish the effective doses of this metabolite in different animal tests predictive of antidepressant efficacy. 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].…”

Section: Mechanisms Underlying Fast/rapid Onset Antidepressants Acmentioning

confidence: 99%

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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( R )-Ketamine Shows Greater Potency and Longer Lasting Antidepressant Effects Than Its Metabolite (2 R ,6 R )-Hydroxynorketamine

Cited by 143 publications

References 9 publications

Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine

Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine

Mechanisms of ketamine action as an antidepressant

Convergent Mechanisms Underlying Rapid Antidepressant Action

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