Researchers seek to unravel the mystery of susceptibility to drug addiction

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

What role does genetics play? Which genes or networks of genes are key?

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

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

Costly problem

Substance abuse is one of the costliest public health problems in the nation. The U.S. Department of Health and Human Services estimates Illicit drug use accounts for $193 billion in health care, productivity loss, crime, incarceration and drug enforcement.

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

“Not everybody becomes addicted. Some people become very easily addicted while others can be social drinkers or users and never become addicted, so we know there’s a genetic component,” said Anholt, Provost’s Distinguished Professor of Genetics and Biochemistry.

The researchers use fruit flies in their research because approximately 70 percent of fruit fly genes have human counterparts. Plus, unlike humans, the flies’ genetic background and environment can be precisely controlled. 

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

Making a choice

That study allowed male and female flies to ingest a fixed amount of sucrose or sucrose supplemented with cocaine over no more than two hours. 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 cocaine exposure.

“Through the previous grant, we learned a lot about the genetic basis of flies consuming cocaine or sucrose when they weren’t given a choice. But as the field is evolving, it is thought that preference is a better model of what could be considered addictive behaviors in humans,” said Mackay, the director of the CHG and the Self Family Endowed Chair in Human Genetics.

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

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

Real measure of addiction

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

A small-scale Mackay lab study involving 46 genetically diverse lines of flies showed a genetic variation for preference that changed over time.

“That shows that the larger experiment we’re doing now is likely to succeed,” 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 therapeutics that could treat or prevent addiction.

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