Cannabinoids Rescue Cocaine-Induced Seizures by Restoring Brain Glycine Receptor Dysfunction

Cannabinoids are reported to rescue cocaine-induced seizures (CISs), a severe complication in cocaine users. However, the molecular targets for cannabinoid therapy of CISs remain unclear. Here, we report that the systemic administration of cannabinoids alleviates CISs in a CB₁/CB₂-receptor-independent manner. In HEK293 cells and cortical neurons, cocaine-induced dysfunction of the glycine receptor (GlyR) is restored by cannabinoids. Such restoration is blocked by GlyRα1^S296A mutation. Consistently, the therapeutic effects of cannabinoids on CISs are also eliminated in GlyRα1^S296A mutant mice. Based on molecular dynamic simulation, the hydrogen-bonding interaction between cocaine and the GlyR is weakened by cannabinoid docking. Without altering cocaine distribution across the brain, cannabinoids significantly suppress cocaine-exaggerated neuronal excitability in the prefrontal cortex (PFC) and hippocampus by rehabilitating extra-synaptic GlyR function. Microinjection of cannabinoids into the PFC and hippocampus restores cocaine-puzzled neural activity and alleviates CISs. These findings suggest that using GlyR-hypersensitive cannabinoids may represent a potential therapeutic strategy for treating CISs.