Written by - Zou Guichang, Xiong Wei, eds.

In the latest Nature Metabolism paper, researchers first used the animal baton behavior paradigm to demonstrate in mouse models that the combination of THC and alcohol can lead to more severe dyskinesia behavior than alcohol or THC alone (Figure 1a, b
).

Subsequently, the researchers found through c-Fos nucleus screening that Pukenye's cells in the 4/5Cb cerebral region are critical for dyskinesia behavior caused by the synergy of THC and alcohol (Figure 1c-f
).

To further elucidate the function of cerebellar 4/5Cb, the researchers used the microinjection technique of brain region to inject THC directly into the cerebellum 4/5Cb and found that injection of THC in the brain region combined with intraperitoneal injection of alcohol can also lead to severe dysregulated behavior (Figure 1g, h).


Ultimately, the researchers used chemical genetic manipulation techniques to inhibit or activate the cerebellum 4/5Cb and confirmed that cerebellar 4/5Cb is the key nucleus that synergistically causes dyskinesic behavior (Figure 1i-m).

Figure 1 Cerebellar region 4/5Cb is a key nucleus for the synergy of alcohol and cannabis (Source: Zou, GC et al.
, Nat Metab, 2022)

Next, the researchers explored the role
of CB1R and GlyR of 4/5Cb in the cerebellar in synergistically enhancing dyskinesic behavior by THC and alcohol.

The researchers used intraperitoneal injections of a wide variety of blockers and found that intraperitoneal injection of CB1R's blocker AM251 and GlyR's blocker Strychnine significantly blocked the movement disorder behavior caused by THC and alcohol (Figure 2a-c), while intraperitoneal injection of other receptor blockers such as AM630 and tranilast had no effect (Figure 2d, e).


To further elucidate the function of CB1R in the cerebellar 4/5Cb region, the researchers used the brain-region microinjection technique to inject AM251 directly into the cerebellum 4/5Cb and found that injecting AM251 into the brain region combined with intraperitoneal injection of THC and alcohol can also block the disordered behavior caused by THC and alcohol (Figure 2f, g
).

In order to elucidate the function of GlyR in the 4/5Cb region of the cerebellum, the researchers constructed a transgenic mouse GlyRα1^S296A based on the early research results of the research group, which can specifically block the enhanced effect
of THC on GlyR.

The researchers found that the dyskinesia behavior caused by the synergy of intraperitoneal injection of THC and alcohol in this transgenic mouse was also significantly blocked (Figure 2h, i
).

Combining various electrophysiological experiments, the researchers finally confirmed that cerebellar 4/5Cb Pukenye cells presynaptic CB1R and extrasynaptic GlyR are key targets for the synergistic action of alcohol and marijuana
.

Figure 2 Cerebellar 4/5Cb Pukenye cells presynaptic CB1R and extrasynaptic GlyR are key targets for the synergistic effect of alcohol and cannabis (Source: Zou, GC et al.
, Nat Metab, 2022)
The above results show that antagonists blocking CB1R or GlyR can effectively inhibit the dyskinesia behavior caused by THC and alcohol synergy, and therefore have the potential
to treat THC and alcohol synergy leading to psychotoxicity.

However, the antagonists of CB1R or GlyR inevitably cause a series of mental side effects such as anxiety, depression, and epilepsy, which greatly limits the development
of related drugs.

Dideoxytetrahydrocannabinol (Di-desoxy-THC, DDT) is a chemically modified tetrahydrocannabinol that removes hydroxyl and oxygen groups (Figure 3a) and has been shown to selectively disrupt THC-GlyR interactions without affecting the basic functions
of CB1R and GlyR.

Therefore, the researchers explored whether DDT can treat dyskinesic behavior
caused by the synergy of THC and alcohol.

The researchers found through electrophysiological biopsy recording that DDT significantly inhibited the extrasynaptic GlyR-mediated current enhancement of 4/5Cb Pukenyene cells caused by the combination of THC and alcohol, and restored the decrease in neuronal excitability caused by the combination of the two (Figure 3b-f).


What's more, the researchers found that DDT can dose-dependently block dyskinesias caused by the combination of THC and alcohol (Figure 3g-i) without producing any toxic and psychiatric side effects (Figure 3j-s
).

These studies have shown that DDT can treat neurotoxicity caused by the synergy of alcohol and marijuana, and has strong medicinal value
.
Figure 3 DDT can significantly restore the dyskinesia behavior caused by the combination of THC and alcohol (Source: Zou, GC et al.
, Nat Metab, 2022).

Figure 4 Work Summary Figure: Neural Mechanisms of Alcohol and Cannabis Synergy Causing Movement Disorders (Source: Xiong Wei Laboratory, University of Science and Technology of China) Article Conclusion and discussion, inspiration and prospect In summary, in this article, researchers used animal behavior analysis techniques, chemical genetic manipulation, brain microinjection, chemical synthesis, small animal imaging and mass spectrometry analysis to analyze the neural mechanisms of tetrahydrocannabinol (THC) and alcohol synergy leading to motor disorders at different levels (Figure 4): First, It was found that THC and alcohol can synergistically enhance the function of synaptic receptors such as cerebellar presynaptic cannabinoid CB1 receptor (CB1R) and extrasynaptic glycine receptor (GlyR), thereby synergistically inactivating cerebellar Purkinye cells and ultimately leading to dyskinesia
.

Second, alcohol can enhance THC's ability to pass through cell membranes and the blood-brain barrier, leading to a dramatic increase
in THC levels in the brain.

Thus, the dyskinesia behavior caused by the synergy of THC and alcohol is a combined result of alcohol-THC interactions at multiple levels, from the molecular level to the cellular level to the brain circuit level
.

In addition to the cerebellum, THC has been reported to cause motor disorders
by destroying autophagy of the striatum.

This effect in the striatum is likely to also indirectly contribute to the dyskinesia caused by the synergy of THC and alcohol
.

Although this study found that the combination of THC and alcohol does not affect the expression of striatal c-Fos, the combination of the two may synergistically affect the autophagy of the striatum, leading to the occurrence
of dyskinesia.

However, whether autophagy in the striatum is involved in dyskinesia caused by the combination of THC and alcohol remains to be further studied
.

Original link:_mstmutation="1" _istranslated="1"> first author Zou Guichang (first row right 6th), first author Xia Jing (second row left second), corresponding author Xiong Wei (first row right 7th place) (photo provided from: University of Science and Technology of China Xiong Wei laboratory) Author profile (up and down slide reading)

Xiong Wei (Corresponding Author)

Vice Dean, Professor, Doctoral Supervisor
, School of Life Sciences, University of Science and Technology of China.

He is the winner of the National Outstanding Youth Science Fund, the leading talent of scientific and technological innovation of the "10,000 people plan", and the chief scientist
of the "13th Five-Year Plan" key research and development plan of the Ministry of Science and Technology.

Professor Xiong Wei's research group has long been engaged in relevant scientific research in the field of neurobiology and neurochemistry, including brain aging and neurodegenerative diseases, neural circuits and neurometabolic regulation, research and development of new metabolomics technology, ion channel regulation, etc.
, and has achieved a series of important research results
.

Research was published in Cell, Nature Methods, Nature Metabolism, Nature Neuroscience, Nature Chemical Biology, Nature Communications, Journal of Experimental Medicine, PNAS, Cell Reports and other international academic journals
.

The work was selected as one of the "Top Ten Advances in China's Life Sciences"
in 2018.

He has received a number of state-level fund funding such as the key research and development plan of the Ministry of Science and Technology and the key project of
the Fund Committee.

Zou Guichang (first author)

Zou Guichang, an associate researcher at the University of Science and Technology of China, has long been involved in the study of the pathogenesis of various neurological diseases such as inhibitory ion channels such as GlyR, in Nature Metabolism, Nature Communications, PNAS, Cell Reports, iScience, Journal of Biological Chemistry, Molecular Magazines such as Brain have published a range of high-level articles
.

Received postdoctoral funding and National Natural Science Foundation funding
.

Selected
articles from previous issues【1】Neuron-New molecular mechanism of intrasynaptic initiation protein regulation of ultrafast endocytosis [2] JNNP-Qiu Wei/Yu Qingfen's team discovered the susceptibility gene of familial optic neuromyelitis spectrum disease [3] Nat Neurosci - breakthrough! Brain electrical stimulation can sustainably improve work and long-term memory in the elderly[4] Nat Methods—Zhang Yang's team released a common structural comparison algorithm for proteins/nucleic acids and their complexes: US-align[5] J Neuroinflammation Review - COVID-19 and cognitive disorders: neural invasion and blood-brain barrier dysfunction [6] CRPS review - Shen Guozhen's team reviews the research progress of optoelectronic artificial synaptic devices [7] Science | Evolutionary Atlas of Primates' Lateral Prefrontal Cortex Molecules and Cell Levels [8] BMC Medicine-Song Huan/Suo Chen's team found that genetic susceptibility to mental illness was associated with the risk of COVID-19 infection[9] Mol Neurobiology-Yang Li/Longcheng research group revealed a molecular pathway in which microglia mediate anxiety behaviors caused by chronic stress [10] Nat Commun-Ye Keqiang's team found that TrkB agonist prodrug - R13 can inhibit bone loss quality scientific research training course recommendation [1] R language clinical prediction biomedical statistics special training (October 15-16, Beijing Chinese Academy of Sciences Institute of Genetics and Developmental Biology) conference/forum preview [1] Preview | Neuromodulation and Brain-Computer Interface Conference (October 13-14, Beijing Time) Welcome to "Logical Neuroscience" [1] Talent Recruitment - "Logical Neuroscience" Active Article Interpretation/Writing Position (Network Part-time, Online Office)

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