Research could find a way for future medications for alcohol use dysfunction.
The poor coordination, garbled speech, and sedative effects of taking too much alcohol are probably caused by the breakdown of alcohol products produced in the brain, not in the liver as researchers currently think.
That is the conclusion of new research led by scientists from the National Institute on Alcohol Abuse and Alcoholism and the University of Maryland School of Medicine (UMSOM). It was issued freshly in the journal Nature Metabolism and presents unique insights into how alcohol may affect the brain and the potential for innovative approaches to treat alcohol misuse.
The liver is the main organ that metabolizes alcohol, with the help of the enzyme alcohol dehydrogenase to transform alcohol into a compound called acetaldehyde. Acetaldehyde, which has virulent effects, is immediately broken down into a substance called acetate. This occurs by a distinct enzyme called acetaldehyde dehydrogenase 2 (ALDH2).
Till now, two important players alcohol and acetaldehyde, produced by the liver, have been responsible for triggering the cognitive impairment associated with drinking. On the other side, Acetate was considered comparatively less important in producing effects like confusion, slurred speech, and motor impairment. Scientists also did not identify particular brain cells or brain region which were most essential for alcohol metabolism.
To know more about the part played by the brain in alcohol metabolism, the scientists measured the concentration of the ALDH2 enzyme in the cerebellum, using magnetic resonance (MR) scanners in both human tissue and mice. They noticed that ALDH2 was shown in the cerebellum, which is a kind of nerve cell known as an astrocyte, in both living mice and human brain tissue.
Scientists discovered that this enzyme restrained the conversion of acetaldehyde into acetate in the brain. They also noticed alcohol-induced behavioral and cellular effects in particular areas of the brain where this enzyme was expressed. Acetate was found to associate with GABA, the chemical brain messenger, which is known to restrict activity in the nervous system. This restricted activity can lead to impaired coordination, lower normal feelings of inhibition, and drowsiness.
“We discovered ALDH2 was shown in cells known as astrocytes in the cerebellum, a brain region that regulates balance and motor coordination,” said Qi Cao, Ph.D., Assistant Professor of Diagnostic Radiology and Nuclear Medicine at the University of Maryland School of Medicine. “We also discovered that when ALDH2 was extracted from these cells, the mice were repellent to motor impairment caused by alcohol consumption.”
Su Xu, PhDHe and his team also discovered the enzyme ALDH2 in other brain regions liable for decision-making and emotional regulation (both impaired by excess alcohol consumption), including in the prefrontal cortex, amydala, and hippocampus.
These conclusions suggest that specific brain regions are essential for alcohol metabolism and that irregularities in the enzyme production in these brain regions can lead to harmful effects linked with alcohol misuse. They also propose that acetate produced in the liver and the brain vary in their ability to affect cognitive and motor function.
“Our subsequent step is to resolve whether these mechanisms are seen in mice also exist in people,” said Dr. Cao. “We would like to learn whether alcohol metabolism is directly controlled in the human brain. If further study confirms this to be the case, it could lead to possible new targets for treating alcohol use disorder.
Shiyun Jin, Qi Cao, Qi Chen, Ziyi Wang, Fanghan Yang, Hongying Zhu, Su Xu, Yuhong Lin, Resat Cinar, Wei Xiong, Bin Gao, George F. Koob, Robert J. Pawlosky, Ye Zhang, David M. Lovinger, Li Zhang. Brain ethanol metabolism by astrocytic ALDH2 drives the behavioral effects of ethanol intoxication. Nature Metabolism, 2021; 3 (3): 337 DOI: 10.1038/s42255-021-00357-z