Research Could Pave Way for Future Treatments for Alcohol Use Disorder
The slurred speech, poor coordination, and sedative effects of drinking too much alcohol may actually be caused by the breakdown of alcohol products produced in the brain, not in the liver as scientists currently think. That is the finding of a new study led by researchers from the University of Maryland School of Medicine (UMSOM) and the National Institute on Alcohol Abuse and Alcoholism. It was published recently in the journal Nature Metabolism and provides new insights into how alcohol may affect the brain and the potential for new treatments to treat alcohol misuse.
It is well known that the liver is the major organ that metabolizes alcohol, using the enzyme alcohol dehydrogenase to convert alcohol into a compound called acetaldehyde. Acetaldehyde, which has toxic effects, is quickly broken down into a more benign substance called acetate. This occurs through a different enzyme called acetaldehyde dehydrogenase 2 (ALDH2). Until now, alcohol and acetaldehyde, produced by the liver, have been considered important players in triggering the cognitive impairment associated with imbibing. Acetate, on the other hand, was considered relatively unimportant in producing effects like motor impairment, confusion, and slurred speech. Researchers also did not know which brain region or particular brain cells were most important for alcohol metabolism.
To learn more about the role played by the brain in alcohol metabolism, the researchers measured the distribution of ALDH2 enzyme in the cerebellum, using magnetic resonance (MR) scanners in both mice and in human tissue. They observed that ALDH2 was expressed in the cerebellum, in a type of nerve cell called an astrocyte, in both human brain tissue and in living mice.
The researchers found that this enzyme controlled the conversion of acetaldehyde into acetate in the brain. They also found alcohol-induced cellular and behavioral effects in specific regions of the brain where this enzyme was expressed. Acetate was found to interact with the brain messenger chemical called GABA, which is known to decrease activity in the nervous system. This decreased activity can lead to drowsiness, impair coordination, and lower normal feelings of inhibition.
“We found ALDH2 was expressed in cells known as astrocytes in the cerebellum, a brain region that controls balance and motor coordination,” said Qi Cao, PhD, Assistant Professor of Diagnostic Radiology and Nuclear Medicine at the University of Maryland School of Medicine. “We also found that when ALDH2 was removed from these cells, the mice were resistant to motor impairment inducted by alcohol consumption.”
He and his team also found the enzyme ALDH2 in other brain regions responsible for emotional regulation and decision-making (both impaired by excess alcohol consumption), including in the hippocampus, amydala, and prefrontal cortex.
These findings suggest that certain brain regions are important for alcohol metabolism and that abnormalities in the enzyme production in these brain regions can lead to detrimental effects associated with alcohol misuse. They also suggest that acetate produced in the brain and in the liver differ in their ability to affect motor and cognitive function.
“Our next step is to determine whether these mechanisms observed in mice also exist in people,” said Dr. Cao. “We would like to know whether alcohol metabolism is directly regulated in the human brain. If further research confirms this to be the case, it could lead to potential new targets for treating alcohol use disorder.
Su Xu, PhD, Professor of Diagnostic Radiology and Nuclear Medicine, was a co-author on this study.
“This is an exciting basic research finding that elucidates important pathways involved in the body’s metabolism of alcohol. It suggests that acetate serves as the important missing link connecting the body’s metabolism of alcohol with cognitive changes in the brain,” said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. "Replication of this research could eventually lead to new avenues for treatment of alcohol use disorder.”
About the University of Maryland School of Medicine
Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world -- with 46 academic departments, centers, institutes, and programs, and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research. With an operating budget of more than $1.2 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic and clinically based care for nearly 2 million patients each year. The School of Medicine has nearly $600 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, trainees, residents, and fellows. The combined School of Medicine and Medical System (“University of Maryland Medicine”) has an annual budget of over $6 billion and an economic impact of nearly $20 billion on the state and local community. The School of Medicine, which ranks as the 8th highest among public medical schools in research productivity (according to the Association of American Medical Colleges profile) is an innovator in translational medicine, with 606 active patents and 52 start-up companies. In the latest U.S. News & World Report ranking of the Best Medical Schools, published in 2021, the UM School of Medicine is ranked #9 among the 92 public medical schools in the U.S., and in the top 15 percent (#27) of all 192 public and private U.S. medical schools. The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu