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 cannabi- noids alleviates CISs in a CB1/CB2-receptor-indepen- dent manner. In HEK293 cells and cortical neurons, cocaine-induced dysfunction of the glycine receptor (GlyR) is restored by cannabinoids. Such restoration is blocked by GlyRa1S296A mutation. Consistently, the therapeutic effects of cannabinoids on CISs are also eliminated in GlyRa1S296A 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, canna- binoids 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.