Researchers seek to unravel the mystery of addiction susceptibility


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

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

Geneticists Trudy Mackay and Robert Anholt are leading a team of researchers from the Clemson University Center for Human Genetics working to unravel these mysteries using Drosophila melanogasteror the common fruit fly.

The work, funded by a nearly $2.5 million five-year grant renewal from the National Institute on Drug Abuse (NIDA) of the National Institutes of Health, builds on previous work by Mackay and Anholt to identify the genetic basis of cocaine and methamphetamine use. 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.

Costly problem

Drug addiction is one of the costliest public health problems in the country. The US Department of Health and Human Services estimates that illicit drug use accounts for $193 billion in health care costs, lost productivity, crime, incarceration and drug enforcement.

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

Robert Anholt holds a test tube with fruit flies inside.

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

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

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

Make a choice

This study allowed both male and female flies to ingest a fixed amount of sucrose or sucrose supplemented with cocaine in less than two hours. The researchers then dissected the brains and dissociated them into individual cells. Using next-generation sequencing technology, they built an atlas of gene expression changes after cocaine exposure.

fruit flies under a microscope
Fruit flies make good model organisms because their environment can be precisely controlled. Image credit: College of Science/Robert P. Bradley.

“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 inbred fly lines with fully sequenced genomes derived from a natural population. DGRP allows researchers to use natural variation to examine genetic variants that contribute to susceptibility to various stressors.

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

Actual measure of dependency

“We can look at those rows that have an innate preference and ask if we can develop the addiction model further. In other words, if they are repeatedly exposed, will they start to prefer it more and develop unwanted behavioral or physiological responses? 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 study from the Mackay lab involving 46 genetically diverse lines of flies showed genetic variation in preference that changed over time.

“It shows that the larger experiment we’re running 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 therapies that may treat or prevent addiction.

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