L-type voltage-dependent calcium channels in the ventromedial orbitofrontal and prefrontal cortices mediate the inhibitory effects of (S)-ketamine but not (R)-ketamine on marble burying in male mice
Satoshi Deyama, Kenji Mishiro, Munetaka Kunishima, Katsuyuki Kaneda
European Journal of Pharmacology October 25, 2025 DOI: 10.1016/j.ejphar.2025.178301 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experiment Peer reviewed |
|---|---|
| Population | Male ICR mice |
| Interventions | (R)-ketamine (S)-ketamine verapamil |
| Dose | 10 mg/kg (S)-ketamine, 30 mg/kg (R)-ketamine, 10 mg/kg verapamil, 2 μg/side verapamil |
| Duration | 2 h, 24 h, and 7 days after treatment |
| Topics | Esketamine Ketamine |
| Key findings | (R)-ketamine at 30 mg/kg produces anticompulsive-like effects comparable to those of a 3-fold lower dose of (S)-ketamine, and the activation of L-VDCCs in the vmOFC and vmPFC mediates the anticompulsive-like effects of (S)-ketamine but not those of (R)-ketamine. |
Abstract
Glutamatergic abnormalities in several brain regions, including the ventromedial orbitofrontal cortex (vmOFC) and prefrontal cortex (vmPFC), have been implicated in the pathophysiology of obsessive-compulsive disorder (OCD). (R, S)-ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, and enantiopure (S)-ketamine may have therapeutic effects in patients and animal models of OCD. However, whether (R)-ketamine produces similar effects, and the neural basis underlying the anticompulsive effects of these enantiomers are unclear. In this study, we compared the effects of (R)- and (S)-ketamine on marble burying in male ICR mice. We also investigated the role of the L-type voltage-dependent Ca2+ channel (L-VDCC) in the effects of ketamine chirality on marble burying since L-VDCC is a key mediator of the antidepressant actions of (R, S)-ketamine. Similar to (S)-ketamine (10 mg/kg), a single dose of (R)-ketamine at 30 mg/kg, but not 10 mg/kg, reduced marble burying 2 h, 24 h, and 7 days after treatment without affecting locomotor activity. Systemic pretreatment with verapamil (10 mg/kg), an L-VDCC inhibitor, blocked the effects of (S)-ketamine, but not of (R)-ketamine, on marble burying, with no change in locomotor activity. Moreover, intra-vmOFC or vmPFC infusion of verapamil (2 μg/side) attenuated the effects of (S)-ketamine on marble burying. These findings suggest that (R)-ketamine produces anticompulsive-like effects comparable to those of a 3-fold lower dose of (S)-ketamine, and the activation of L-VDCCs in the vmOFC and vmPFC mediates the anticompulsive-like effects of (S)-ketamine, but not those 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
Cites 16
- 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
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Mechanistic Target of Rapamycin-Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model. Biological Psychiatry 2018
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
and 11 more in the library