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Behavioral Effects of Alcohol May Be Caused by Breakdown Products Produced in the Brain

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Researchers have demonstrated that alcohol metabolism can occur in the mouse brain, due to the presence of the enzyme aldehyde dehydrogenase 2 (ALDH2). They also demonstrated that expression of ALDH2 in the mouse cerebellum mediates behavioral effects related to alcohol intoxication. The paper was published in Nature Metabolism.

The behavioral effects of alcohol

There are several known
short-term adverse effects associated with alcohol, including but not limited to, impaired motor coordination, loss of judgment and decreased concentration.

The behavioral effects observed in both humans and mice are thought to be caused by the presence of breakdown products or “metabolites” that are produced during the metabolism of alcohol. Acetate, which results from the detoxification of
acetaldehyde can travel to the brain, cross the blood–brain barrier and impair motor function by influencing the signaling of GABA, an inhibitory neurotransmitter located in the central nervous system. 

“Our previous study showed hepatocytic ALDH2 contributed to heavy alcohol drinking behavior. We have shown that liver-targeted ALDH2 inhibition can decrease heavy drinking but not moderate drinking,” said the study’s corresponding author, Dr Li Zhang,
Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health.

While it has been established that the liver is the primary site for alcohol metabolism, the central mechanisms fundamental to the process and to what extent metabolism occurs in other locations (e.g., the brain) remains ambiguous.

What is aldehyde dehydrogenase?

Aldehyde dehydrogenases are a family of enzymes responsible for catalyzing the oxidation of aldehydes. They can be broadly divided into two isoforms in the liver – cytosolic (ALDH1) and mitochondrial (ALDH2). ALDH2 plays a key role in the metabolism of alcohol as it converts acetaldehyde to acetate. Acetaldehyde is a toxic metabolite and can cause cellular and DNA damage. Individuals with a deficiency in ALDH2 are more vulnerable to acetaldehyde’s effects due to elevated levels of the metabolite in the body. Almost 50% of East Asians lack an active mitochondrial isoform, which could explain the higher frequency of alcohol intoxication observed and “alcohol flushing syndrome” that is related to the presence of the “inactive” ALDH2*2 variant.

New insights into the role and distribution of ALDH2 in the brain could help to shed further light on the metabolism of alcohol and whether the site of metabolism impacts the drug’s behavioral effects.

Zhang commented on the challenges of studying ALDH2 in the brain: “The key enzymes for alcohol metabolism are present only at comparatively low levels in the brain. Compared to liver ALDH2, for example, the level of brain ALDH2 is very low. This made it difficult to study brain ALDH2 function until more sensitive techniques were developed for distinguishing between central (brain) and peripheral (such as liver) metabolic pools for alcohol breakdown.”

ALDH2’s localization

Li Zhang
and colleagues used in vitro and in vivo approaches to investigate the cell-specific-distribution of ALDH2 in the cerebellum and to explore the mechanisms within the brain that are responsible for the behavioral effects related to intoxication.

They discovered that ALDH2 was expressed in star-shaped glial cells called astrocytes within the cerebellum. The 
cerebellum is involved in balance, posture and motor coordination. 

Zhang elaborated on the methods used in the study: “We used a highly sensitive RNA in situ hybridization (RNAscope) technique to identify astrocyte-specific ALDH2 expression in human and mouse brain slices. Combining in vivo magnetic resonance spectroscope (MRS) with several high-resolution in vitro analytical methods, we quantitatively measured the levels of alcohol metabolites and neurotransmitters in the cerebellum in cell-type (astrocyte, neuron or hepatocyte) specific ALDH2 deficient mice that were developed with sophisticated genetic approaches.”

“It is important for us to learn more about the dynamics of astrocytic ALDH2 regulation of alcohol pharmacokinetics in the brain to develop therapeutics targeting these astrocytic functions,” – Dr Li Zhang.

The team showed that an absence of astrocytic ALDH2 in the cerebellum rendered mice “resistant” to alcohol-induced motor impairment and balance, and coordination skills appeared unaffected. In addition, they observed that the removal of
astrocytic ALDH2 prevented elevation of acetate and GABA in the brain. To confirm that these findings were directly associated with astrocytic ALDH2, the team conducted experiments whereby they removed hepatocytic ALDH2 only. This did not affect the levels of acetate or GABA in the brain.

“This ethanol-promoted acetate–GABA signaling pathway observed in our in vivo experiments was also replicated in brain slices and single astrocytes by electrophysiological recording and single-cell protein measurements (proteomics),” explained Zhang.

“We propose that ethanol metabolism in the brain astrocytes promotes acetate–GABA synthesis, which should drive some behaviors during ethanol intoxication such as ethanol-induced impairment of coordination and balance skills. Our experiments indicate such an ALDH2 role in cerebellum, but this enzyme may also contribute to alcohol effects in other brain regions.”

The authors conclude that their data supports the assumption that “astrocytic ALDH2 controls the production, cellular and behavioral effects of alcohol metabolites in a brain-region-specific manner,” and that ALDH2’s ability to impact motor function is related to its location in the brain.

Therapeutically targeting astrocytic functions

Armed with a more comprehensive understanding of astrocytic ALDH2 and its role in ethanol metabolism could help to develop therapeutics against it. Zhang discussed the potential of ALDH2 in this context and elaborated on existing therapeutic strategies: “Alcohol-seeking behavior is controlled by ALDH2 genotypes. And there are several ALDH2 inhibition-based drugs available for the treatment of alcohol use disorders (AUD).”

Although these drugs are effective in reducing alcohol drinking behavior, Zhang cautioned that they are also associated with unwanted adverse effects. “Chronic use of ALDH2 inhibitors may increase the risk of cancer development in alcoholics because these agents could elevate systemic and local acetaldehyde levels,” said Zhang.

In efforts to limit the occurrence of adverse effects, Zhang explained that tissue-specific and cell-type-specific ALDH2 inhibition for the treatment of AUD has been proposed.

“A very recent study has suggested that brain acetate derived from alcohol consumption contributes to alcohol preference and dependence. We observed that astrocytic ALDH2-deficient mice selectively reduced the production of acetate in the brain without altering blood and brain acetaldehyde content, following alcohol consumption. It is feasible to specifically inhibit astrocytic ALDH2 in the brain, and we hope our study may serve as a basis for the development of a new therapy targeting astrocytic ALDH2 in the treatment of AUD,” said Zhang.

“Once we understand the mechanisms through which acetate contributes to alcohol actions in brain, we may be able to develop drugs or other therapeutic approaches to prevent these actions.”

Jin S, Cao Q, Yang F, et al. Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication. Nat. Metab. 2021. doi: 10.1038/s42255-021-00357-z

Li Zhang was speaking with Laura Elizabeth Lansdowne, Managing Editor for Technology Networks.