Study: A Mysterious Gene Variant That Makes Quitting Smoking Easier

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Smokers with a variant gene linked to higher risk for heroin addiction and more relapse in alcoholism actually have an easier time quitting cigarettes — and a new study finds that their pleasure from nicotine varies with the availability of certain receptors made by the gene.

The receptor in question is called the mu-opioid receptor, which is normally home to naturally occurring opioids in the brain; these receptors are also activated by opioid drugs like heroin and Oxycontin. Whether activated by natural opioids or drugs, mu-opioid receptors trigger a reduction in stress, relieve pain and increase euphoria.

Nicotine doesn’t act directly on opioid receptors, but by affecting levels of other neurotransmitters in the brain, it indirectly prompts the brain’s own opioids to attach to mu-opioid receptors and generate comfort and joy.

In the new study, led by Caryn Lerman, director of the Tobacco Use Research Center at the University of Pennsylvania, researchers focused on the A118 G variant of the OPRM1 gene, which affects the number of mu-receptors in the brain. The variant occurs in about 15% to 20% of the population. Human studies have connected the presence of the variant to increased sensitivity to pain and social rejection. It’s also linked to greater liking for sweet, fatty foods and, at least in monkeys, to increased separation distress in babies and increased maternal protectiveness in mothers. The gene also affects the brain’s response to stress in ways that are not yet clear.

For the Penn study, researchers imaged the brains of 22 smokers — 10 of whom had the gene variant — while they smoked either ordinary or “placebo” cigarettes, which looked the same as regular cigarettes but without the nicotine in them. The scans showed that the amount of pleasure that smokers with the variant derived from nicotine depended on the availability of these receptors. The greater the number of available receptors, the more pleasure those with the gene variant reported getting from real cigarettes, compared with the placebos.

“The key finding is that the number of mu-opioid receptors in the brains of smokers can be predicted based on [the A118 G] variation in a gene called OPRM1,” says Lerman. She says that the study is the first to connect this particular genotype with the activity of receptors in the brain and the level of pleasure that smokers with the gene get from their habit.

“It’s a fascinating study,” says Dr. Nora Volkow, director of the National Institute on Drug Abuse.

It’s easy to imagine how a gene variant that affects the activity of opioid receptors in the brain and makes people more sensitive to pain and rejection might also make people more vulnerable to heroin addiction. The fact that gene is linked to increased liking for sweets and fat could also affect a person’s risk of food addiction (incidentally, both heroin addicts and alcoholics are known to have cravings for junk food, not just drugs and booze). It also makes sense that abuse or neglect in a child already made more sensitive by the variant could help trigger such addictions.

But why the variant makes nicotine easier to kick and exactly how opioid receptors are involved remains mysterious. “Smokers with the [variant gene] have an easier time quitting with nicotine replacement therapy and they experience fewer withdrawal symptoms,” says Lerman.

The gene may also affect placebo response, which is highly associated with opioid receptors. Volkow and Lerman note that study participants with the variant who got placebo cigarettes also showed heightened activity in the pleasure centers of the brain — as if they were smoking real cigarettes. The researchers say that some important effects of the variant might be hidden by that fact.

And, of course, as with all genetics research, study results looking at the same gene tend to vary, with some studies replicating earlier effects, a few finding opposite effects and others finding no effect. “It’s extremely complicated,” says Lerman. “There are so many different pathways in the brain and this plays a role in just one. It’s just one SNP [change in one letter of the genetic code] in one gene in one pathway and they’re all interacting.”

She adds, “In some contexts, the gene may be protective, in others, it may increase risk. With different environmental or pharmacological stimuli, the direction of the association varies. To complicate things even further, there seem to be some sex differences as well.”

For smokers, genetic information could ultimately help determine which medications are most likely to help them quit. For example, smokers with this variant may do well with simple nicotine replacement, while others who are prone to worse withdrawal symptoms might do better with drugs like Xyban or Chantix.

Further research could help determine how genetic testing can play a role in addiction treatment and, perhaps, allow people to estimate their own genetic risk for various addictions.

The study was published in the Proceedings of the National Academy of Sciences.

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