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January 4, 2011
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Addiction Gene


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Genetics researchers have confirmed that people with a different form of a certain gene are more susceptible to drug and alcohol addiction. They hope the finding will help predict who might get hooked and what treatments will help those who do. This ScienCentral News video has more.

Coded for Addiction

Researchers led by Wolfgang Sadee, a scientist at the Ohio State University, have figured out how differences in one gene can make the brain more sensitive to alcohol, narcotics, or nicotine. The gene Sadee's team looked at has long been known to code for a kind of brain protein called an opioid receptor, which acts like a switch, turning on pleasure and blocking pain when triggered by certain addictive drugs.

The surfaces of our brain cells are covered by different kinds of receptor proteins. These receptors act as chemical docking stations that allow individual brain cells to communicate with each other by sending and receiving small bursts of chemicals. Each type of receptor can only be activated by a certain class of chemicals, which makes the communication between brain cells specific and meaningful. However receptors can also respond to chemicals in the brain environment not sent by other cells, like things that we've ingested such as alcohol or particles from cigarette smoke. The mu-opioid receptor that Sadee's team looked at is the primary target for morphine, but it also plays a large part in responses to alcohol, nicotine, and narcotics such as cocaine.





As reported in the Journal of Biological Chemistry, Sadee and his colleagues looked at two variations, A118G and G118 of the mu-opioid receptor gene. "We've taken a variation in this gene that's already suspected to affect the response to therapy of addiction, as well as addiction itself. But we didn't know how and why," he explains.

The goal of looking at these two variations, then, was to figure out exactly how the A118G was causing increased sensitivity and therefore higher risk of addiction.

In order to do this, the researchers took 87 different human brain samples and extracted the DNA for the opioid receptor gene. This allowed them to see which of the two variations of the gene each brain sample contained. To take it a step further and see how this DNA would behave inside living tissue, they took both genetic variants and inserted them into living hamster cells in the lab. They let those cells translate the gene's code and compared the results.





DNA provides the instructions for making proteins. Each of our cells has a DNA master copy that stays protected in the nucleus. Whenever a certain protein needs to be made, the instructions from the DNA are transcribed into a temporary copy, a strand of messenger RNA, or mRNA. Each message copy gets made into a unit of the protein that it carries instructions for. So, it is the amount of this message getting made that determines how much of the target protein the cell will make, and that is what Sadee's team looked at. "We measure the message that's generated from the two variations and we determine whether one variant makes more than the other, more message," Sadee says.




It turns out that one of the variations did make a different amount of the message.

What the team found is that the variation linked to increased susceptibility to addiction made much less of the message, which explains how it could change the gene's function in brain cells. With less message, you will end up with less opioid receptors on the surface of your cells, which means you'll need more, constant stimulation to get the pleasure response they normally produce. That can lead to cravings for the feelings associated with alcohol or drugs — meaning addiction.

In spite of this finding, Sadee points out that regardless of what gene variant someone has, everyone has the potential to become addicted. "So it is not that some people will be completely protected against addiction," he says. This finding just points to one of the factors that control susceptibility.

Sadee says the method his team used here can also be used to find genetic variations important in other diseases. Just as this group did with genes associated with addiction, once you identify a target gene related to any condition, you can see how much message each of its variations produces in living cells. "We can make predictions as to who's susceptible to addiction, or to cancer for that matter, or heart disease," he says.

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Sadee's group plans to use this new method to examine almost 20 other genes that play a role in addiction. They hope that their results will help bring about personalized therapies, new treatments, and improved prevention for drug addiction. As Sadee says, "If we know which genes are involved, we can much better design new therapies that are based on those fundamental mechanisms that are revealed by these gene variations."

This research was published in the Journal of Biological Chemistry, in November, 2005 (280: 32618-32624), and was funded by the National Institutes of Health.


 
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