期刊
CELL REPORTS
卷 30, 期 12, 页码 4209-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.02.106
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资金
- National Natural Science Foundation of China [91849206, 91649121, 81901157]
- National Key R&D Program of China [2016YFC1300500-2]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDPB1005]
- Key Research Program of Frontier Science (CAS) [ZDBS-LY-SM002]
- CAS Interdisciplinary Innovation Team [JCTD-2018-20]
- Fundamental Research Funds for the Central Universities
- Major Program of Development Foundation of Hefei Center for Physical Science and Technology [2017FXZY006]
- Users with Excellence Program/Project of Hefei Science Center CAS [2019HSC-UE006]
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 GlyR alpha 1(S296A) mutation. Consistently, the therapeutic effects of cannabinoids on CISs are also eliminated in GlyR alpha 1(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.
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