Comparison of rapid and long-lasting antidepressant effects of negative modulators of α5-containing GABAA receptors and (R)‑ketamine in a chronic social defeat stress model.
Zhongwei Xiong, Kai Zhang, Tamaki Ishima, Qian Ren, Lijia Chang, Jincao Chen, Kenji Hashimoto
Pharmacology, Biochemistry, and Behavior December 2018 DOI: 10.1016/j.pbb.2018.10.005 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study with postmortem human brain comparison Peer reviewed |
|---|---|
| Population | CSDS-susceptible mice and postmortem brain samples from depressed patients and control subjects |
| Interventions | MRK-016 L-655 708 |
| Measures | tail suspension test, forced swimming test, sucrose preference test |
| Topics | Esketamine Ketamine |
| Keywords | R‑ketamine Antidepressant Negative allosteric modulators Postmortem brain Α5 gabaa |
| Key points | Α5 GABAA receptor expression was higher in prefrontal cortex and hippocampus of CSDS-susceptible mice and in parietal cortex of depressed patients than controls. A single injection of (R)-ketamine or MRK-016 reduced immobility and improved sucrose preference at two days, but only (R)-ketamine maintained the sucrose preference effect at seven days; L-655,708 showed no antidepressant effects. The authors argue elevated α5 GABAA receptors may contribute to depression-like phenotypes after CSDS and that MRK-016 is unlikely to have long-lasting antidepressant effects. |
Abstract
The negative allosteric modulators (NAMs: L-655,708 and MRK-016) of α5 subunit-containing GABAA receptors are reported to show rapid-acting antidepressant effects in rodents. However, there are no reports comparing these NAMs and (R)‑ketamine, (R)-enantiomer of the rapid-acting antidepressant ketamine, in a chronic social defeat stress (CSDS) model. Here we measured expression of α5 GABAA receptor in the brain regions from CSDS susceptible mice and postmortem brain samples from depressed patients. Expression of α5 GABAA receptor in the prefrontal cortex and hippocampus from CSDS susceptible mice was significantly higher than that of control mice. Furthermore, expression of α5 GABAA receptor in the parietal cortex from depressed patients was also higher than that of control subjects. In the tail suspension and forced swimming tests, (R)‑ketamine and MRK-016 significantly attenuated the increased immobility time in the susceptible mice, compared with the vehicle-treated group. In the sucrose preference test, (R)‑ketamine and MRK-016 significantly enhanced the reduced preference in CSDS susceptible mice two days after a single injection. Unlike (R)‑ketamine, MRK-016 did not attenuate the reduced sucrose preference in susceptible mice 7 days after a single injection. In contrast, L-655,708 did not show antidepressant effects in the same model. In conclusion, this study shows that increased levels of α5 GABAA receptors in the PFC and hippocampus may play a role in depression-like phenotype after CSDS. It is unlikely that MRK-016 has long-lasting antidepressant effects although it elicits rapid-acting antidepressant effects.
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 7
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine. Pharmacology, Biochemistry, and Behavior June 1, 2019
- NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine Journal of Neuroscience January 3, 2023
- Rapid-acting antidepressants. Advances in pharmacology (San Diego, Calif.) 2019
- Rapid-Acting Antidepressants Current Pharmaceutical Design October 19, 2018
and 2 more in the library
Cites 16
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression Archives of General Psychiatry August 1, 2010
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Taming the Ketamine Tiger Anesthesiology August 6, 2010
and 11 more in the library