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

A single injection of (R)-ketamine at 30 mg/kg, but not 10 mg/kg, reduced marble burying—a measure of compulsive-like behavior—in male mice at 2 hours, 24 hours, and 7 days after treatment, without affecting general movement. (S)-ketamine at 10 mg/kg also reduced burying. Blocking L-type voltage-dependent calcium channels (L-VDCCs) with verapamil prevented the effect of (S)-ketamine but not of (R)-ketamine. Infusing verapamil directly into the ventromedial orbitofrontal cortex or ventromedial prefrontal cortex also blocked (S)-ketamine's effect. These findings suggest (R)-ketamine produces anticompulsive-like effects comparable to a 3-fold lower dose of (S)-ketamine, and that L-VDCC activation in those brain regions mediates the effects of (S)-ketamine but not (R)-ketamine.

Study at a glance

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.