Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function
E. Lumsden, Timothy A. Troppoli, S. J. Myers, Panos Zanos, Y. Aracava, J. Kehr, Jacqueline Lovett, Sukhan Kim, Fu‐hua Wang, S. Schmidt, Carleigh E. Jenne, P. Yuan, Patrick J. Morris, Craig J. Thomas, Carlos A. Zarate, Ruin Moaddel, Stephen F Traynelis, E. Pereira, S. Thompson, E. Albuquerque, T. Gould
Proceedings of the National Academy of Sciences February 22, 2019 DOI: 10.1073/pnas.1816071116 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice and rats |
| Interventions | (2R 6R)-hydroxynorketamine ketamine (2S |
| Dose | 10 mg/kg |
| Topics | Esketamine Ketamine |
| Citations | 159 |
| Key points | Antidepressant-relevant concentrations of (2R,6R)-HNK do not inhibit NMDA receptors, indicating its rapid antidepressant effects are independent of NMDAR blockade. |
Abstract
Significance Standard antidepressant treatments require weeks to show effectiveness. A single subanesthetic dose of ketamine rapidly attenuates many clinical signs and symptoms of depression; however, ketamine treatment also has many adverse effects, including dissociation and potential for abuse, which are mediated by NMDA glutamate receptor (NMDAR) inhibition. Previous work has revealed that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) induces antidepressant-like responses in rodents while minimizing the adverse effects observed with ketamine. The results of this study, using a multitude of experimental approaches, confirm that antidepressant-relevant concentrations of (2R,6R)-HNK are not sufficient to block NMDARs. This provides a basis for work directed at alternative molecular targets and toward novel drugs that exert rapid antidepressant effects independent of NMDAR inhibition and NMDAR-mediated adverse effects. Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) is a putative fast-acting antidepressant candidate. Although inhibition of NMDA-type glutamate receptors (NMDARs) is one mechanism proposed to underlie ketamine’s antidepressant and adverse effects, the potency of (2R,6R)-HNK to inhibit NMDARs has not been established. We used a multidisciplinary approach to determine the effects of (2R,6R)-HNK on NMDAR function. Antidepressant-relevant behavioral responses and (2R,6R)-HNK levels in the extracellular compartment of the hippocampus were measured following systemic (2R,6R)-HNK administration in mice. The effects of ketamine, (2R,6R)-HNK, and, in some cases, the (2S,6S)-HNK stereoisomer were evaluated on the following: (i) NMDA-induced lethality in mice, (ii) NMDAR-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 field of mouse hippocampal slices, (iii) NMDAR-mediated miniature excitatory postsynaptic currents (mEPSCs) and NMDA-evoked currents in CA1 pyramidal neurons of rat hippocampal slices, and (iv) recombinant NMDARs expressed in Xenopus oocytes. While a single i.p. injection of 10 mg/kg (2R,6R)-HNK exerted antidepressant-related behavioral and cellular responses in mice, the ED50 of (2R,6R)-HNK to prevent NMDA-induced lethality was found to be 228 mg/kg, compared with 6.4 mg/kg for ketamine. The 10 mg/kg (2R,6R)-HNK dose generated maximal hippocampal extracellular concentrations of ∼8 µM, which were well below concentrations required to inhibit synaptic and extrasynaptic NMDARs in vitro. (2S,6S)-HNK was more potent than (2R,6R)-HNK, but less potent than ketamine at inhibiting NMDARs. These data demonstrate the stereoselectivity of NMDAR inhibition by (2R,6R;2S,6S)-HNK and support the conclusion that direct NMDAR inhibition does not contribute to antidepressant-relevant effects of (2R,6R)-HNK.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 60
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Role of BDNF in the pathophysiology and treatment of depression: Activity‐dependent effects distinguish rapid‐acting antidepressants European Journal of Neuroscience December 6, 2019
- Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites Translational Psychiatry November 7, 2019
- Mechanisms of Ketamine and its Metabolites as Antidepressants Biochemical Pharmacology December 1, 2021
- ( 2R,6R )-hydroxynorketamine exerts mGlu 2 receptor-dependent antidepressant actions Proceedings of the National Academy of Sciences March 13, 2019
and 55 more in the library
Cites 18
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
and 13 more in the library