Search for the Source

When scientists first observed that offspring of women who abused drugs during pregnancy were more likely to become abusers themselves, they wondered whether the cause was environmental or genetic. Extensive research showed that both the environment and genetics had a strong effect, but no one was able to identify the origin of addiction or explain how it worked.

Now, a team of scientists at Florida Atlantic University’s Stiles-Nicholson Brain Institute suggest that adults born of women who abused drugs during pregnancy do not have a higher risk of addiction because of their genes; it’s because amphetamines revise the expression of proteins their genes produce. The scientists’ findings may indicate a new pathway to treatment for addiction.

"For a long time, scientists focused on finding the genes responsible for addiction. Our study shows that it’s not the genes but the epigenetics — what the drug does to the expression of the gene," said Lucia Carvelli, Ph.D., the study’s senior author and associate professor of neuroscience, Harriet L. Wilkes Honors College, Brain Institute investigator and associate professor of biomedical science, Charles E. Schmidt College of Science, which was published in the International Journal of Molecular Sciences.

Genes are bits of DNA strung together into a long strand wrapped around a "spool." The "spool" is made of proteins called histones, which keep the strand wrapped by forming reversible interactions with the DNA. The tightness of the wrap affects which genes are turned into proteins — molecules that carry out specific functions within the cell — and which are not. Carvelli and her team discovered that amphetamine changes how tightly the DNA is wound around the spool and, therefore, which proteins are produced.

In this paper, Carvelli and her team focused on the production of two proteins involved in addiction — one that synthesizes dopamine and one that packages dopamine into special containers called vesicles inside the cell. In a previous paper, the team identified a third protein that retrieves the dopamine and brings it back inside the cell. Dopamine sends chemical messages that, among other things, create goal-directed and reward-seeking behaviors.

Working with C. elegans — a tiny worm that responds to dopamine the same way humans do — the team found that the change in gene expression caused by amphetamines led to a buildup of dopamine in adult animals exposed to amphetamine during embryogenesis.

A higher level of dopamine didn’t change the worms’ behavior in normal conditions, said Carvelli, comparing worms that had been exposed to amphetamines during embryogenesis and worms that had not. She explained that while amphetamine exposure during embryogenesis creates adult animals with a higher basal level of dopamine, they’re able to adapt to the higher level they’ve had since they were embryos.

The problem arose, they found, when the animals that had been exposed to amphetamine as embryos were presented with amphetamines as adults. These animals exhibited extreme hypersensitivity to the drug.

"Besides reward, amphetamines increase risk-taking behaviors," said Carvelli. "For addiction, that’s not good, because it makes a person more likely to risk taking the drug — which is highly addictive — and thus more likely to develop addiction."

Their findings may have clinical implications. Using a technique that investigates the interaction between histones and DNA, Carvelli and her colleagues discovered that amphetamines changed gene expression by adding a molecule called a methyl group at various points on the histones. This job is done by a protein called methyl transferase. If its activity is blocked, amphetamines can’t change gene expression.

Several medications approved by the United States Food and Drug Administration, used primarily to treat leukemia, block the activity of methyl transferase. That’s the good news. The bad news: When it’s blocked, it’s blocked everywhere in the body, including places where it may perform a beneficial function.

Carvelli and her team are broadening the scope of their research, investigating whether the effect of amphetamine is maintained transgenerationally. "We saw that the behavioral impacts of amphetamine exposure during embryogenesis extends to the second and third generation, but we haven’t yet done any studies to see if this is also true for the changes in histone modifications and gene expression," Carvelli said. Co-authors Katie E. Poquette and Sophia L. Amro Gazze, Florida Atlantic undergraduate students at the Wilkes Honors College, are testing other enzymes that may remove the methyl groups and whether they’re affected by amphetamines.

"For many years scientists have studied how amphetamine produces addiction, but we still don’t know each step of this process. That means that what is being identified so far is not the full picture," Carvelli said. "We’re using C. elegans to see if we can find the missing pieces, but there’s still a lot to do."