Cannabinoids stopped cocaine-induced seizures by restoring glycine receptor function, not through CB1/CB2

Systemic cannabinoid administration alleviated cocaine-induced seizures independently of CB1 and CB2 receptors. Cannabinoids restored cocaine-disrupted glycine receptor (GlyR) function in cells and neurons. The therapeutic effect was eliminated in GlyRα1 S296A mutant mice. Molecular simulation showed cannabinoid docking weakened cocaine-GlyR hydrogen bonding. Cannabinoids suppressed cocaine-exaggerated neuronal excitability in the prefrontal cortex and hippocampus.

Combination of in vivo mouse seizure models, HEK293 cell electrophysiology, primary cortical neuron recordings, molecular dynamic simulation, and microinjection studies targeting specific brain regions. GlyRα1 S296A knock-in mice used to confirm mechanism.

Cocaine-induced seizures are a severe and potentially fatal complication. Identifying that cannabinoids work through glycine receptors (not classic cannabinoid receptors) opens a new avenue for targeted treatment.

This study reveals that cannabinoids have pharmacological actions beyond the endocannabinoid system. The glycine receptor interaction could be relevant to other conditions involving disrupted inhibitory neurotransmission.

Animal study using injected cannabinoids. The specific cannabinoid compounds tested and doses may not reflect typical cannabis use. GlyR-hypersensitive cannabinoid derivatives would need to be developed for clinical use. Cocaine-induced seizure model is specific and may not generalize.