Epigenetics: A solution for alcoholism


Alcohol is the most popular psychoactive drug among young people and its excessive consumption represents a serious health problem with effects that may be irreversible in the long term. According to the World Health Organization (WHO), three million people die each year worldwide from the harmful use of alcohol (one every 10 seconds), which represents about 5% of all deaths. 13.5% of these deaths correspond to young people.

In Chile, one in 10 people have a risky alcohol consumption and, if you break down intake by age, adolescents and young adults (between 15 and 24 years old) drink more than the rest of the population. According to the National Service for the Prevention and Rehabilitation of Drug and Alcohol Use (SENDA) survey, 63% of eighth through fourth grade students report having had at least one episode in the past month, which means that nearly 2 out of every 3 schoolchildren reported excessive drinking in the past month.

Excessive alcohol consumption in adolescence can lead to the development of an alcohol use disorder in adulthood. Also known as ‘Alcoholism’, severe, it is a pattern of alcohol consumption that includes problems controlling intake, putting a person’s health and safety at risk. Furthermore, alcohol consumption in adolescence has long-term effects on neural connections in the brain. Especially in the amygdala, a brain region linked to the regulation of emotions and feelings, including fear and anxiety. This area is also associated with alcoholism.

The brain naturally undergoes orchestrated changes during adolescence that are disrupted by alcohol use. An example of this is what happens in the amygdala with the so-called Arc gene. Genes are short segments of DNA (deoxyribonucleic acid, a molecule that contains the genetic information of living things) that tell the body how to make specific proteins. The Arc gene codes for a protein of the same name, which plays a key role in synaptic plasticity, a biological process that allows the brain to change and adapt to new information.

This gene is epigenetically modified under the influence of adolescent alcohol consumption. Epigenetic modifications are reversible chemical changes to DNA. These changes mean that the Arc gene is not expressed and therefore the protein in question is not generated, resulting in an increased likelihood of developing alcohol use disorder and anxiety in adulthood.

genetic scissors

A group of researchers led by Subhash Pandey of the University of Illinois, USA, in 2019 showed that young rats, which consumed a lot of alcohol, had a lower amount of Arc protein in the amygdala. Researchers have found the same phenomenon in brain samples from deceased alcoholics.

In May 2022, the same team published new research seeking to find out whether changes in the Arc gene caused by alcohol use in adolescence can be reversed—that is, whether the “epigenetic switch” can be changed. To do this, they used the CRISPR-Cas technique, a 2020 Nobel Prize in Chemistry-winning technique known as “gene scissors” that allows changes to be made to DNA.

The first step of the research was the development of an animal model, for which the scientists repeatedly administered large quantities of alcohol (group 1) to young rats aged between 27 and 41 days (which equates to between 10 and 18 years old). The Humans). While the control rats (group 2) were given only a solution of sodium chloride (common salt).

Subsequently, when both experimental groups reached adulthood (92 days), an intracranial cannula was inserted directly into the tonsil and they were allowed to recover from the surgery. Subsequently, the researchers injected a solution with the CRISPR-Cas components through the cannula, which will allow the activation or deactivation of the Arc gene, and the behavior of the experimental groups was evaluated using for this purpose two experimental protocols: the open arm maze and the light-dark box.

Both are tests that measure anxiety in rodents: in the first case, the time the rodent spends with its arm open (without protection) is measured, and in the second, the time it remains in the box with the light on. The less time the rodent spends in either place, the more anxious he is. Finally they controlled how often the mice consumed alcohol instead of water.

In the first experiment, they wanted to see if activating the Arc gene could reverse the effect in rats that had been exposed to alcohol in their youth and exhibited anxiety and a preference for alcohol in adulthood. Following the methodology, CRISPR-Cas solution with a promoter whose purpose was to activate the Arc gene was delivered through the cannula and the behavior was evaluated.

The investigation showed that, in fact, when the Arc gene was activated and thus produced the Arc protein, the group 1 rats (exposed to alcohol) stayed longer both in the open arm of the maze and in the light box , which results in a decrease in anxiety, while the rats of the same group that did not have the Arc gene activated remained in these sectors for a very short time, showing higher levels of anxiety.

On the other hand, no effect was observed in group 2 (control) rats. The frequency with which the rats consumed alcohol also decreased in rats receiving the treatment, demonstrating that activation of the Arc gene in the amygdala can decrease both anxiety and alcohol consumption in alcohol-exposed rats in the adolescence. .

Next, the research focused on recreating the opposite effect, namely to demonstrate whether when the Arc gene was turned off in adult rats, which had not been exposed to alcohol consumption in their youth, they became anxious and started consuming alcohol instead of water. . For this, the cannula was inserted into adult rats not exposed to alcohol and after recovery, the CRISPR-Cas solution was delivered through the cannula, now with a repressor whose purpose was to switch off the Arc gene and the behavior was rated as indicated. previously.

As a result, they found that rats that received this treatment spent less time in the open arm of the maze and in the light box than adult rats that received no treatment. On the other hand, rats that had the Arc gene turned off increased the frequency with which they consumed alcohol instead of water compared to control rats. From these results, the researchers concluded that deactivating the Arc gene in the amygdala leads to increased anxiety and increased alcohol consumption in rats.

Taking into account that more than 100 million people worldwide are addicted to alcohol and that today’s existing drugs can only treat the consequences of alcoholism, not alcoholism itself, the research led by Dr. Pandey could be the key to develop future treatments that finally provide a solution to this global problem. However, there is still a long way to go before the method is ready for application in humans.

Sources:

*This article comes from the agreement with the Interdisciplinary Center of Neurosciences of the University of Valparaíso.

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