Loss of the sustained antidepressant-like effect of (2R,6R)-hydroxynorketamine in NMDA receptor GluN2D subunit knockout mice.
Aimi Yamagishi, Yuiko Ikekubo, Masayoshi Mishina, Kazutaka Ikeda, Soichiro Ide
Journal of Pharmacological Sciences March 1, 2024 DOI: 10.1016/j.jphs.2024.01.008 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Wildtype and GluN2D-knockout mice |
| Interventions | (2R 6R)-HNK (2S 6S)-HNK |
| Topics | Depression Ketamine |
| Keywords | Glun2d Hydroxynorketamine Tail-suspension test Depression treatment Antidepressant research Ketamine derivatives Mental health |
| Citations | 6 |
| Key findings | Sustained antidepressant-like effects of (2R,6R)-HNK require the GluN2D NMDA receptor subunit, while acute effects do not. |
Abstract
Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has attracted attention for its acute and sustained antidepressant effects in patients with depression. Hydroxynorketamine (HNK), a metabolite of ketamine, exerts antidepressant effects without exerting ketamine's side effects and has attracted much attention in recent years. However, the detailed pharmacological mechanism of action of HNK remains unclear. We previously showed that the GluN2D NMDA receptor subunit is important for sustained antidepressant-like effects of (R)-ketamine. Therefore, we investigated whether the GluN2D subunit is involved in antidepressant-like effects of (2R,6R)-HNK and (2S,6S)-HNK. Treatment with (2R,6R)-HNK but not (2S,6S)-HNK exerted acute and sustained antidepressant-like effects in the tail-suspension test in wildtype mice. Interestingly, sustained antidepressant-like effects of (2R,6R)-HNK were abolished in GluN2D-knockout mice, whereas acute antidepressant-like effects were maintained in GluN2D-knockout mice. When expression levels of GluN2A and GluN2B subunits were evaluated, a decrease in GluN2B protein expression in the nucleus accumbens was found in stressed wildtype mice but not in stressed GluN2D-knockout mice. These results suggest that the GluN2D subunit and possibly the GluN2B subunit are involved in the sustained antidepressant-like effect of (2R,6R)-HNK.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cited by 5
- The antidepressant potential of (2R,6R)-hydroxynorketamine: A detailed review of pre-clinical findings. European Journal of Pharmacology July 15, 2025
- Oral Prolonged-Release Ketamine for Treatment-Resistant Depression: Two Randomized Clinical Trials. JAMA Network Open June 1, 2026
- Integrating multi-receptor and neuron–glia mechanisms of ketamine's antidepressant action: a convergence framework for understanding efficacy Frontiers in Molecular Neuroscience October 21, 2026
- Generation of enantiospecific monoclonal antibodies against (2R,6R)-hydroxynorketamine. Bioorganic & Medicinal Chemistry January 17, 2026
- The NMDA receptor subunit GluN2D is a potential target for rapid antidepressant action Nature Communications November 26, 2025
Cites 13
- 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
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Ketamine: a paradigm shift for depression research and treatment Neuron March 1, 2019
and 8 more in the library