2. Academic Validation
  3. Combined alcohol and cannabinoid exposure leads to synergistic toxicity by affecting cerebellar Purkinje cells

Combined alcohol and cannabinoid exposure leads to synergistic toxicity by affecting cerebellar Purkinje cells

  • Nat Metab. 2022 Sep;4(9):1138-1149. doi: 10.1038/s42255-022-00633-6.
Guichang Zou # 1 2,  Jing Xia # 1,  Heyi Luo 1,  Dan Xiao 1,  Jin Jin 1,  Chenjian Miao 1,  Xin Zuo 1,  Qianqian Gao 3,  Zhi Zhang 1,  Tian Xue 1,  Yezi You 3,  Ye Zhang 4,  Li Zhang 5,  Wei Xiong 6 7 8
Affiliations

Affiliations

  • 1 Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 2 Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China.
  • 3 CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, China.
  • 4 Department of Anesthesiology and Perioperative Medicine, The Second Hospital of Anhui Medical University, Hefei, China.
  • 5 Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
  • 6 Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. wxiong@ustc.edu.cn.
  • 7 Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China. wxiong@ustc.edu.cn.
  • 8 Anhui Province Key Laboratory of Biomedical Aging Research, Hefei, China. wxiong@ustc.edu.cn.
  • # Contributed equally.
PMID: 36109623 DOI: 10.1038/s42255-022-00633-6
Abstract

Combined use of cannabis and alcohol results in greater psychoactive toxicity than either substance alone, but the underlying central mechanisms behind this worsened outcome remain unclear. Here we show that the synergistic effect of Δ9-tetrahydrocannabinol (THC) and ethanol on motor incoordination in mice is achieved by activating presynaptic type 1 cannabinoid receptors (CB1R) and potentiating extrasynaptic glycine receptors (GlyR) within cerebellar Purkinje cells (PCs). The combination of ethanol and THC significantly reduces miniature excitatory postsynaptic current frequency in a CB1R-dependent manner, while increasing the extrasynaptic GlyR-mediated chronic chloride current, both leading to decreased PC activity. Ethanol enhances THC actions by boosting the blood-brain-barrier permeability of THC and enriching THC in the cell membrane. Di-desoxy-THC, a designed compound that specifically disrupts THC-GlyR interaction without affecting the basic functions of CB1R and GlyR, is able to restore PC function and motor coordination in mice. Our findings provide potential therapeutic strategies for overcoming the synergistic toxicity caused by combining cannabis and alcohol use.

Figures
Products