Cannabidiol Mitigates Ketamine-Induced Hyperlocomotion via Allosteric Potentiation of Ventral Tegmental GlyRα1 Signaling.

Ketamine produces rapid antidepressant and antidepressant-like effects in both humans and animal models. However, its therapeutic benefits are tempered by psychoactive side effects, such as hyperlocomotion associated with enhanced dopaminergic activity in the ventral tegmental area (VTA). We tested CBD's therapeutic action in locomotor activity after systemic (30 mg/kg) or bilateral intra-VTA CBD administration (10 g per mouse) in ketamine-treated mice. Whole-brain imaging of c-Fos expression in mice after ketamine treatment was used to identify brain areas that mediated ketamine/GlyR interactions. Region-specific pharmacological and genetic interference with CBD-GlyR signaling was used to test predictions of whole-brain imaging results. Electrophysiological profiling revealed that cannabinoid-ketamine interplay modulated on GlyR. Whole-brain imaging revealed neuronal hyperactivity induced by ketamine in the VTA, PFC and NAc, which was mitigated by CBD adminstration into the VTA and PFC. Behaviorally, CBD blocked ketamine-induced hyperlocomotion. Further investigation indicated that this behavioral suppression is mediated by VTA glycine receptors (GlyRs). Specifically, ketamine was found to suppress GlyR function, whereas CBD reversed ketamine-mediated GlyR dysfunction through selective antagonism of ketamine-driven delays in GlyR activation. Moreover, CBD pharmacologically blocked ketamine-induced dysfunction of postsynaptic GlyRs in the VTA. The attenuating effect of CBD on ketamine-induced hyperlocomotion was abolished in GlyRα1S296A mice, confirming the essential role of VTA GlyRα1 signaling in this process. These data suggest that CBD acts at GlyRα1 expressed in VTA neurons to dissociate ketamine's therapeutic and adverse effects, with the S296 residue being a key site for precision GlyR modulators.