Although the liver remains the primary organ for alcohol metabolism, the brain’s cerebellum plays a bigger role in this process than once believed, according to a study in mice published on March 22 in Nature Metabolism. The researchers found that when an alcohol-processing enzyme is missing from the cerebellum in mice, the animals metabolized alcohol differently.
“My hypothesis is that the brain has a metabolic pathway in alcohol metabolism, and this pathway mediates some behavioral change,” says lead author Li Zhang, a staff scientist at the Laboratory for Integrative Neuroscience at the National Institute on Alcohol Abuse and Alcoholism. “This hypothesis is actually against dogma in the research of alcohol,” adds Zhang, who argues that the prevailing view is that metabolic work in the liver drives the effects of alcohol in the brain.
Zhang and colleagues sought to build on neuroimaging findings that cerebellar uptake of acetate, a common metabolite of alcohol, is produced by the enzyme aldehyde dehydrogenase 2 (ALDH2) in brain astrocytes. These are glial cells that provide nutrients to nervous tissues and regulate local blood flow, among other duties. In addition, researchers have previously found a relationship between acetate levels in the cerebellum, the brain region that regulates balance and coordination, and worse motor skills in mice.
In this study, they focused on the role that ALDH2 plays in alcohol metabolism in the cerebellum. In mice not given alcohol, they found that expression levels of ALDH2 mRNA and proteins were higher in the cerebellum compared to other brain regions such as the prefrontal cortex. ALDH2 mRNA was mainly expressed within astrocytes.
They were able to really show how pharmacokinetics can be exploited as a new target for treating alcohol use disorder. This is a huge advancement.—Carolina Haass-Koffler, Brown University
The researchers then compared the effects of alcohol on the neurobiology of two different mouse strains bred to have ALDH2 deficiencies. In one strain, these deficiencies were in the brain’s astrocytes, in the other, the liver. After giving the mice direct injections of a low dose of alcohol, the mice with the liver ALDH2 deficiency exhibited higher levels of acetate and the neurotransmitter GABA in the brain than they started with. GABA is believed to be part of the impaired motor response linked to alcohol use and is generally elevated with alcohol consumption.
In contrast, GABA levels in the cerebellum dropped when mice with astrocytic ALDH2 deficiency received alcohol, and their acetate levels did not rise. This indicates that astrocytic ALDH2 within the cerebellum is part of normal alcohol processing, Zhang says.
Another test was behavioral: mice tried for as long as possible to prevent themselves from falling off a rotating bar. Here the researchers found that alcohol-treated mice with an astrocytic ALDH2 deficiency had better motor skills than did mice with their enzyme levels intact, possibly because less ALDH2 meant they could not metabolize alcohol into acetate as efficiently.
Zhang notes that all of the experiments used low alcohol doses, not high doses such as people might imbibe during a night of heavy drinking. “We tested low doses of alcohol. It’s very possible that when you consume a very high amount of alcohol, the liver remains the major organ for alcohol metabolites and breakdown,” Zhang says.
“They were able to really show how pharmacokinetics can be exploited as a new target for treating alcohol use disorder,” says Carolina Haass-Koffler, who studies the mechanisms of addiction at Brown University. “This is a huge advancement.” Haass-Koffler, who is involved in developing drug treatments for alcohol use disorder, says these results suggest that directly targeting ALDH2 may be appropriate.
Excessive alcohol use contributes to 2.8 million premature deaths each year worldwide, according to the Institute for Health Metrics and Evaluation. GABA-targeting drugs currently focus on conditions such as anxiety or insomnia, and Haass-Koffler suggests they could play a role in helping people with alcohol use disorder too.
“It’s very nice, because they go from the enzyme through the metabolic pathway all the way to the neurochemistry, the signaling in those cells, and then the behavior,” says Susan Smith, a professor at the University of North Carolina who studies fetal alcohol exposure. (Smith has served on the council of the National Institute on Alcohol Abuse and Alcoholism but was not involved in this research.) “My collaborators and I are already talking about these mice and how they could inform our own work,” says Smith.
Zhang readily acknowledges that mice are far different from humans, and is quick to issue the proviso that there are always many steps and much more research needed to test a link between basic science results and clinical applications. That said, he is hopeful that links between this work and treatment in humans will emerge with time.
“In terms of ALDH2 deficiency, I think humans and mice so far share a very similar mechanism,” Zhang says. This similarity suggests that these results could be translated to humans, but Zhang cautions that understanding the effects of ALDH2 on human behavior will require much more work.
S. Jin et al., “Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication,” Nat Metab, 3:337–51, 2021.