Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2 R ,6 R )-hydroxynorketamine
Kenichi Fukumoto, Manoela V. Fogaça, Rong-Jian Liu, Catharine H. Duman, T. Kato, Xiaoyuan Li, Ronald S. Duman
Proceedings of the National Academy of Sciences December 17, 2018 DOI: 10.1073/pnas.1814709116 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Animal models |
| Topics | Ketamine |
| Keywords | Antidepressant Brain-derived neurotrophic factor Neurotrophic factors Pharmacology Hippocampus Receptor |
| Citations | 191 |
| Key points | The antidepressant effects of (2R,6R)-HNK require activity-dependent release of BDNF mediated by stimulation of voltage-dependent Ca2+ channels, leading to TrkB and mTORC1 signaling that increases synaptic function in the medial prefrontal cortex. |
Abstract
Significance A metabolite of ketamine, (2 R ,6 R )-hydroxynorketamine [(2 R ,6 R )-HNK], produces rapid and sustained antidepressant effects in animal models but without the side effects of ketamine. Notably, (2 R ,6 R )-HNK does not block the NMDA receptor, the primary target of ketamine. Here, we demonstrate that the antidepressant effects of (2 R ,6 R )-HNK require activity dependent release of BDNF that is mediated by stimulation of voltage-dependent Ca 2+ channels. Importantly, increased BDNF release leads to activation of downstream TrkB and mechanistic target of rapamycin complex 1 signaling that increases synaptic function of pyramidal neurons in the medial prefrontal cortex. Stimulation of BDNF release and increased synaptic function block or reverse the detrimental effects of stress and depression and thereby underlie the antidepressant actions of (2 R ,6 R )-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 67
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- Role of BDNF in the pathophysiology and treatment of depression: Activity‐dependent effects distinguish rapid‐acting antidepressants European Journal of Neuroscience December 6, 2019
- Ketamine: A tale of two enantiomers Journal of Psychopharmacology November 6, 2020
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
- Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers Therapeutic Advances in Psychopharmacology 2020
and 62 more in the library
Cites 14
- 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
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
and 9 more in the library