Lack of Antidepressant Effects of (2R,6R)-Hydroxynorketamine in a Rat Learned Helplessness Model: Comparison with (R)-Ketamine
Yukihiko Shirayama, Kenji Hashimoto
The International Journal of Neuropsychopharmacology November 14, 2017 DOI: 10.1093/ijnp/pyx108 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal model study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | (R)-ketamine (R)-norketamine (2R 6R)-hydroxynorketamine |
| Dose | 20 mg/kg for (R)-ketamine and (R)-norketamine; 20 and 40 mg/kg for (2R,6R)-hydroxynorketamine |
| Duration | Single injection |
| Topics | Ketamine Esketamine |
| Keywords | Learned helplessness Antidepressant Pharmacology Metabolite Animal model Developmental psychology Hippocampus |
| Citations | 113 |
| Key points | Neither (R)-norketamine nor (2R,6R)-hydroxynorketamine showed antidepressant effects in the rat learned helplessness model, unlike (R)-ketamine. |
Abstract
Background: (R)-Ketamine exhibits rapid and sustained antidepressant effects in animal models of depression. It is stereoselectively metabolized to (R)-norketamine and subsequently to (2R,6R)-hydroxynorketamine in the liver. The metabolism of ketamine to hydroxynorketamine was recently demonstrated to be essential for ketamine's antidepressant actions. However, no study has compared the antidepressant effects of these 3 compounds in animal models of depression.
Methods: The effects of a single i.p. injection of (R)-ketamine, (R)-norketamine, and (2R,6R)-hydroxynorketamine in a rat learned helplessness model were examined.
Results: A single dose of (R)-ketamine (20 mg/kg) showed an antidepressant effect in the rat learned helplessness model. In contrast, neither (R)-norketamine (20 mg/kg) nor (2R,6R)-hydroxynorketamine (20 and 40 mg/kg) did so.
Conclusions: Unlike (R)-ketamine, its metabolite (2R,6R)-hydroxynorketamine did not show antidepressant actions in the rat learned helplessness model. Therefore, it is unlikely that the metabolism of ketamine to hydroxynorketamine is essential for ketamine's antidepressant actions.
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 55
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 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
- Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine. Biochemical Pharmacology July 1, 2020
and 50 more in the library
Cites 12
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression American Journal of Psychiatry October 1, 2015
- Taming the Ketamine Tiger Anesthesiology August 6, 2010
- Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories Psychological Medicine February 12, 2016
and 7 more in the library