2. Academic Validation
  3. Cannabinoids Rescue Cocaine-Induced Seizures by Restoring Brain Glycine Receptor Dysfunction

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

  • Cell Rep. 2020 Mar 24;30(12):4209-4219.e7. doi: 10.1016/j.celrep.2020.02.106.
Guichang Zou 1,  Xin Zuo 1,  Kai Chen 1,  Yushu Ge 1,  Xiaoqun Wang 2,  Guangwei Xu 1,  Huan Wang 1,  Chenjian Miao 1,  Zhenyu Xu 1,  Shuangshuang Tian 2,  Zhen Wang 3,  Yifeng Zhou 1,  Wei Wei 3,  Guangming Huang 2,  Dan Liu 1,  Wei Xiong 4
Affiliations

Affiliations

  • 1 Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China.
  • 2 Department of Chemistry, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei 230026, China.
  • 3 Institute of Clinical Pharmacology, Anhui Medical University, Key Lab of Anti-inflammatory and Immune Medicine, Ministry of Education of China, Hefei 230032, China.
  • 4 Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100070, China; Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: wxiong@ustc.edu.cn.
PMID: 32209479 DOI: 10.1016/j.celrep.2020.02.106
Abstract

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 GlyRα1S296A mutation. Consistently, the therapeutic effects of cannabinoids on CISs are also eliminated in GlyRα1S296A 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.

Keywords

cannabinoids; cocaine; extra-synaptic; glycine receptor; hippocampus; prefrontal cortex; seizure.

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