Latest developments in causes and treatments



Advances in Epigenetic Editing for Addiction Treatment

What causes people who suffer from substance use disorder to prioritize drug taking to the extent that it becomes self-harming? That’s the question behind a deep dive into the chemical components of addiction in Chemistry World magazine.

Leading the investigation is the senior science correspondent for Chemistry World,  Jamie Durrani. His main focus appears to be how addiction affects gene expression in cells:

In recent years, scientists have shown that these epigenetic processes are an important feature of many diseases, and our growing understanding of this is promising to transform the treatment of various illnesses. In the case of addiction, it is believed that long-lasting epigenetic changes to the activity of certain genes, and thus the expression of many proteins, helps to drive drug-seeking behaviour — offering an explanation for why users might still feel strong cravings for a drug many weeks, months or even years after the last time they took it.

Durrani interviews a number of neuroscientists for his article, including Jeremy Day from the University of Alabama at Birmingham, and Eric Nestler at the Friedman Brain Institute at Mount Sinai in New York. Nestler’s team has shown that there is a buildup of a certain protein in the nucleus accumbens — a key part of the brain’s reward mechanism — which triggers “a whole cascade of downstream molecular signals that seem to play crucial roles in addiction.”

Regarding the uniform results despite the substance of abuse, Dr. Nestler says, “There is something common to all of these drugs, despite their very different chemical structures and the proteins with which the drugs interact initially.” Dr. Nestler points to another “transcription factor” called Creb found throughout the brains of addicted mice that “would cause an animal to take more drug because it wants to treat this negative emotional state — so-called negative reinforcement.” Both the positive reinforcement of euphoria and the negative reinforcement of avoiding anxiety are involved in substance use disorders, researchers say.

Dr. Day’s group found they could turn on addiction in mice by flipping a sequence of 16 genes using Crispr. While they have not reported being able to turn off the addiction, “after using Crispr tools to knock out the Rheb gene in mice, the researchers found that drug exposure no longer reduced the rodents’ desire to seek out natural rewards like food and water.”

An interesting wrinkle in the research turns out to be sex differences in the results. Until the past decade, writes Durrani, lab research was conducted almost exclusively with male rodents. And the sex differences in addiction are pronounced:

In 2021, a team led by Vanderbilt University’s Erin Calipari showed that self-administration of cocaine over ten days significantly changes the expression of 82 proteins in the nucleus accumbens of male mice, whereas only 50 proteins were impacted to a similar extent in female mice. Across all of these proteins, only five were altered in both sexes and only three of those were regulated in the same direction.

Dr. Calipari is the director of Vanderbilt University’s Center for Addiction Research. She explained to Durrani that the behavior in male and female rats regarding the use of cocaine is similar, but the molecular mechanisms that get them there are different, requiring different targeting.

In an interesting twist that might explain the “dead to pleasure” feelings induced by Ozempic and other GLP-1 agonist drugs, Dr. Calipari says that dopamine is “really not a reward molecule at all — it just helps us learn really important information… If you block that, people can’t learn, they can’t move — because dopamine is involved in motor — they don’t have motivation.” That, combined with the fact that altering one gene can result in alterations to dozens or thousands of other genes, means that research in this area is still slow and deliberate at this time.

Written by Steve O’Keefe. First published July 1, 2024.


“The proteins that drive drug addiction,” Chemistry World, June 2024.

“Epigenetic editing: the next generation of genetic medicine,” Drug Target Review, July 2023.

Image courtesy National Institutes of Health, used under Public Domain.


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