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.

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.