5-Hydroxytryptamine-Independent Antidepressant Actions of (R)-Ketamine in a Chronic Social Defeat Stress Model
Kai Zhang, Chao Dong, Yuko Fujita, Atsuhiro Fujita, Kenji Hashimoto
The International Journal of Neuropsychopharmacology November 15, 2017 DOI: 10.1093/ijnp/pyx100 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Control and chronic social defeat stress-susceptible mice |
| Interventions | (R)-ketamine para-chlorophenylalanine methyl ester hydrochloride |
| Dose | (R)-ketamine 10 mg/kg; para-chlorophenylalanine methyl ester hydrochloride 300 mg/kg twice daily for 3 consecutive days |
| Duration | Sucrose preference test at 2 and 5 days after a single dose of (R)-ketamine |
| Measures | tail suspension test, 1% sucrose preference test, high-performance liquid chromatography |
| Topics | Esketamine Ketamine |
| Citations | 48 |
| Key findings | Depleting 5-hydroxytryptamine with para-chlorophenylalanine methyl ester hydrochloride did not affect the antidepressant-like effects of (R)-ketamine (10 mg/kg) in a chronic social defeat stress mouse model. (R)-ketamine significantly attenuated increased immobility time and enhanced reduced sucrose consumption in stressed mice with or without serotonin depletion. The authors conclude that 5-hydroxytryptamine is unlikely to play a major role in (R)-ketamine's antidepressant actions. |
Abstract
Background: Previous reports suggest that 5-hydroxytryptamine might play a role in the antidepressant actions of (R,S)-ketamine. However, its role in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, is unknown. This study was conducted to examine whether 5-hydroxytryptamine depletion affects the antidepressant actions of (R)-ketamine in a chronic social defeat stress model.
Methods: An inhibitor of 5-hydroxytryptamine synthesis, para-chlorophenylalanine methyl ester hydrochloride (300 mg/kg, twice daily for 3 consecutive days), or vehicle was administered to control and chronic social defeat stress-susceptible mice. Levels of 5-hydroxytryptamine and its metabolite, 5-hydroxyindoleacetic acid, in mouse brain regions were measured using high-performance liquid chromatography. Furthermore, antidepressant effects of (R)-ketamine (10 mg/kg) in the vehicle- and para-chlorophenylalanine methyl ester hydrochloride-treated susceptible mice were assessed using tail suspension test and 1% sucrose preference test.
Results: para-Chlorophenylalanine methyl ester hydrochloride treatment caused marked reductions of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the brain regions of control and chronic social defeat stress susceptible mice. In the tail suspension test, (R)-ketamine significantly attenuated the increased immobility time in the chronic social defeat stress-susceptible mice with or without 5-hydroxytryptamine depletion. In the sucrose preference test (2 and 5 days after a single dose), (R)-ketamine significantly enhanced reduced sucrose consumption in the chronic social defeat stress-susceptible mice with or without 5-hydroxytryptamine depletion.
Conclusions: These findings show that 5-hydroxytryptamine depletion did not affect the antidepressant effects of (R)-ketamine in a chronic social defeat stress model. Therefore, it is unlikely that 5-hydroxytryptamine plays a major role in the antidepressant actions of (R)-ketamine.
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 28
- 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 and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites Translational Psychiatry November 7, 2019
- A historical review of antidepressant effects of ketamine and its enantiomers. Pharmacology, Biochemistry, and Behavior February 5, 2020
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Cites 13
- 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
- Mechanistic Target of Rapamycin-Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model. Biological Psychiatry 2018
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