October 3, 2022 October 4, 2022
Why do some people become addicted to drugs and alcohol while others do not?
What role does genetics play? Which genes or gene networks are key?
Geneticists Trudy Mackay and Robert Anholt lead a team of researchers at Clemson University’s Center for Human Genetics working to unravel these mysteries using Drosophila melanogaster, or the common fruit fly.
The work, funded by a five-year renewal of a nearly $2.5 million grant 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 foundations of cocaine and methamphetamine use. The research could lay the groundwork for developing new drugs or repurposing drugs already approved to treat or prevent addiction in humans.
Substance abuse is one of the nation’s costliest public health problems. The US 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.
Robert Anholt holds a test tube with fruit flies inside.
“Not everyone becomes addicted. Some people become addicted very easily, while others may be heavy drinkers or social users and never become addicted, so we know there is a genetic component,” said Anholt, distinguished professor of Provost genetics and biochemistry.
The researchers use fruit flies in their research because about 70 percent of fruit fly genes have human counterparts. Also, 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 fruit fly brain, and that the differences are more pronounced in males than in females. women.
Making a choice
This 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 individual cells. Using next-generation sequencing technology, they built an atlas of changes in gene expression following cocaine exposure.
Fruit flies are 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 given no choice. But as the field evolves, preference is believed to be a better model of what might be considered addictive behaviors in humans,” said Mackay, 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 completely sequenced genomes derived from a natural population. The DGRP allows researchers to use natural variation to examine genetic variants that contribute to susceptibility to various stressors.
Using these flight 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 plain sucrose when given the choice), the researchers will map variants associated with the preference and the genes associated with these variants.
Actual measure of addiction
“We can look at those lines that have an innate preference and ask if we can further develop the addiction model. That is, 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? That will be a true measure of addiction,” Anholt said.
A small-scale Mackay lab study involving 46 genetically diverse lines of flies showed genetic variation in 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 therapeutics that could treat or prevent addiction.
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Source: Researchers seek to unravel the mystery of susceptibility to drug addiction