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.

据报道，大麻素可挽救可卡因诱发的癫痫发作（CIS），这是可卡因使用者的一种严重并发症。但是，目前尚不清楚大麻素治疗CIS的分子靶点。在这里，我们报告大麻素的全身给药以CB ₁ / CB ₂受体独立的方式缓解了CIS 。在HEK293细胞和皮质神经元中，可卡因诱导的甘氨酸受体（GlyR）功能障碍通过大麻素得以恢复。这种恢复被^GlyRα1S296A突变阻断。一致的是，在CIS大麻素的治疗效果也消除了GlyRα1 ^S296A突变小鼠。基于分子动力学模拟，可卡因与GlyR之间的氢键相互作用因大麻素对接作用而减弱。在不改变可卡因在大脑中的分布的情况下，大麻素可通过恢复突触外GlyR功能来显着抑制可卡因夸大神经元在前额叶皮层（PFC）和海马中的兴奋性。将大麻素微注射到PFC和海马中可恢复可卡因迷惑的神经活动并缓解CIS。这些发现表明，使用GlyR过敏性大麻素可能代表了治疗CIS的潜在治疗策略。