Cannabidiol Mitigates Ketamine-Induced Hyperlocomotion Via Allosteric Potentiation of Ventral Tegmental Glycine Receptor α1 Signaling.

Ketamine produces rapid antidepressant effects but also causes hyperlocomotion, a side effect linked to increased dopamine activity in the ventral tegmental area (VTA). Cannabidiol (CBD) blocked ketamine-induced hyperlocomotion in mice when given systemically (30 mg/kg) or directly into the VTA (10 μg per mouse). Whole-brain imaging showed that ketamine increased neuronal activity in the VTA, prefrontal cortex, and nucleus accumbens, which CBD reduced. Electrophysiology revealed that ketamine suppressed glycine receptor (GlyR) function, while CBD reversed this dysfunction by antagonizing ketamine-driven delays in GlyR activation. In GlyRα1S296A mice, CBD's effect on hyperlocomotion was abolished, indicating that VTA GlyRα1 signaling, particularly the S296 residue, is essential for CBD's dissociation of ketamine's therapeutic and adverse effects.

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Abstract

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 the therapeutic effect of cannabidiol (CBD) on locomotor activity after systemic (30 mg/kg) or bilateral intra-VTA CBD administration (10 μg 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/glycine receptor (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 GlyRs. Whole-brain imaging revealed neuronal hyperactivity induced by ketamine in the VTA, prefrontal cortex (PFC), and nucleus accumbens, which was mitigated by CBD administration into the VTA and PFC. Behaviorally, CBD blocked ketamine-induced hyperlocomotion. Further investigation indicated that this behavioral suppression was mediated by VTA 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.