Researchers try to unravel the mystery of drug addiction susceptibility

Newswise: Why do some people become addicted to drugs and alcohol while others don’t?

What role does genetics play? Which genes or gene networks are critical?

Geneticists Trudy Mackay and Robert Anholt lead a team of researchers from Clemson University Center for Human Genetics who work to unravel those mysteries using Drosophila melanogasteror the common fruit fly.

The work, funded by a nearly $ 2.5 million five-year renewal from the National Institutes of Health’s National Institute on Drug Abuse (NIDA), builds on previous work by Mackay and Anholt to identify the genetic basis of cocaine use and methamphetamine. The research could lay the groundwork for the development of new drugs or the reuse of drugs already approved to treat or prevent addiction in humans.

Expensive problem

Substance abuse is one of the nation’s most costly public health problems. The United States Department of Health and Human Services estimates that illicit drug use accounts for $ 193 billion in health care, lost productivity, crime, incarceration, and drug enforcement.

Scientists know that genetics play a role in human susceptibility to drug addiction.

“Not everyone becomes addicted. Some people become addicted very easily, while others may be social drinkers or consumers and never become addicted, so we know there is a genetic component, ”said Anholt, Provost’s distinguished professor of genetics and biochemistry.

Researchers use fruit flies in their research because about 70 percent of fruit fly genes have human counterparts. Furthermore, unlike humans, the genetic background and environment of flies can be precisely controlled.

In a previous study, Mackay and Anholt found that cocaine use causes rapid and widespread changes in gene expression throughout the brain of fruit flies, and that the differences are more pronounced in males than females.

Make a choice

That study allowed male and female flies to ingest a fixed amount of sucrose or sucrose supplemented with cocaine for no more than two hours. The researchers then dissected the brains and dissociated them into single cells. Using next-generation sequencing technology, they constructed an atlas of gene expression changes after exposure to cocaine.

“Through the previous grant, we learned a lot about the genetic basis of flies consuming cocaine or sucrose when they had no choice. But as the field evolves, preference is thought to be a better model of what might be considered addictive behaviors in humans, ”said Mackay, director of CHG and the Self Family Endowed Chair in Human Genetics.

Mackay’s lab developed the Drosophila melanogaster Genetic Reference Panel (DGRP), which consists of consanguineous mouse lines with fully sequenced genomes derived from a natural population. The DGRP allows researchers to use natural variations to examine genetic variants that contribute to susceptibility to various stressors.

Using those flight lines and a high-throughput method CHG Ph.D. student Spencer Hatfield and former postdoctoral fellow Joshua Walters have developed to measure preference (choosing sucrose containing cocaine over plain sucrose when given the chance to choose), researchers will map the variants associated with preference and the genes associated with those variants.

True measure of addiction

“We can look at those lines that have an innate preference and ask ourselves if we can further develop the model for addiction. In other words, if they are repeatedly exposed, will they start to prefer it more and develop adverse behavioral or physiological reactions? And despite this adversity, will they continue to show a preference for cocaine? It will be a real measure of addiction, ”Anholt said.

A small-scale Mackay laboratory study involving 46 genetically diverse fly lines showed genetic variation by preference that changed over time.

“This shows that the larger experiment we’re doing now is likely to be successful,” Mackay said. “It showed that, even on a small scale, there is genetic variation.”

Genes identified as important in cocaine preference that have human counterparts could be potential targets for therapies that could cure or prevent addiction.

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