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

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.

• Authors: Guichang Zou, Xin Zuo, Kai Chen, Yushu Ge, Xiaoqun Wang, Guangwei Xu, Huan Wang, Chenjian Miao, Zhenyu Xu, Shuangshuang Tian, Zhen Wang, Yifeng Zhou, Wei Wei, Guangming Huang, Dan Liu, Wei Xiong
• Journal: Cell reports (Cell Rep) Vol. 30 Issue 12 Pg. 4209-4219.e7 (03 24 2020) ISSN: 2211-1247 [Electronic] United States
• PMID: 32209479 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Cannabinoids
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2
• Receptors, Glycine
• Cannabidiol
• Dronabinol
• Cocaine

Topics

• Animals
• Brain (metabolism, physiopathology)
• Cannabidiol (pharmacology)
• Cannabinoids (pharmacology)
• Cocaine (adverse effects, chemistry)
• Dronabinol (pharmacology)
• HEK293 Cells
• Hippocampus (metabolism, physiopathology)
• Humans
• Hydrogen Bonding
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Molecular Dynamics Simulation
• Neurons (metabolism)
• Prefrontal Cortex (metabolism, physiopathology)
• Rats, Sprague-Dawley
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2
• Receptors, Glycine (chemistry, metabolism)
• Seizures (chemically induced, physiopathology)
• Synapses (metabolism)