( 2R,6R )-hydroxynorketamine exerts mGlu 2 receptor-dependent antidepressant actions
Panos Zanos, Jaclyn N. Highland, Brent W. Stewart, Polymnia Georgiou, Carleigh E. Jenne, Jacqueline Lovett, Patrick J. Morris, Craig J. Thomas, Ruin Moaddel, Carlos A. Zarate, Todd D Gould
Proceedings of the National Academy of Sciences March 13, 2019 DOI: 10.1073/pnas.1819540116 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Intervention | ketamine |
| Topics | Ketamine |
| Keywords | Antidepressant Metabotropic receptor Pharmacology Metabotropic glutamate receptor Depression economics Bioinformatics Hippocampus Anesthesia |
| Citations | 153 |
| Key points | The antidepressant-relevant actions of (2R,6R)-HNK converge with mGlu2 receptor signaling, and high-frequency EEG oscillations are a marker associated with rapid antidepressant responses. |
Abstract
Significance Despite available medications for depression, currently approved antidepressants take months to exert therapeutic effects, and ∼30% of patients remain treatment resistant. In contrast, a single subanesthetic dose of ketamine exerts rapid (within hours) and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite ( 2R , 6R )-hydroxynorketamine [( 2R , 6R )-HNK] is a rapid-acting antidepressant candidate with limited adverse effects compared with ketamine. Using behavioral, genetic, and pharmacological approaches and EEG measurements, we determined that the mechanism underlying antidepressant-relevant actions of ( 2R , 6R )-HNK converges with metabotropic glutamate receptor subtype 2 (mGlu 2 ) receptor signaling and identified high-frequency EEG oscillations as a marker associated with rapid antidepressant responses. Our data support the use of individually subtherapeutic doses of mGlu 2 receptor inhibitors with ketamine or ( 2R , 6R )-HNK in clinical trials for the treatment of depression.
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 57
- Role of BDNF in the pathophysiology and treatment of depression: Activity‐dependent effects distinguish rapid‐acting antidepressants European Journal of Neuroscience December 6, 2019
- Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics TIPS - Trends in Pharmacological Sciences September 24, 2021
- Ketamine: A tale of two enantiomers Journal of Psychopharmacology November 6, 2020
- 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
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Cites 37
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- 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 Journal of Neuroscience April 15, 1997
- 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 32 more in the library