Why do not some people stop smoking? It's the fault of the CHRNA5 gene

French researchers show that the mutation of a gene could explain why some smokers fail to quit smoking, even after several smoking cessations.

Despite your multiple attempts to stop smoking permanently, you can not get rid of cigarettes? The answer behind this impossible stall is perhaps in your genes.

In an article published Thursday, October 4 in the scientific journal Current BiologyFrench researchers from the CNRS and INSERM link nicotine addiction to a mutation present in the CHRNA5 gene known in the medical world to "code for the? 5 subunit of nicotinic receptors". People affected by the mutation of this gene would indeed be more likely to resume smoking, even after weaning.

The mutation of the CHRNA5 gene involved

Smokers may know the toxicity of tobacco and the consequences of its consumption on their health, it is indeed sometimes very difficult to drop. Multifactorial, this dependence on cigarettes is explained by the presence of nicotine, a psychoactive substance that acts on the brain by binding to the nicotinic receptors of neurons and the modification of neurotransmitters. These then produce dopamine, a hormone that gives a feeling of well-being and satisfaction.

The more one smokes, the more the brain becomes accustomed to the presence of nicotine, and the more the receptors are sensitive: this explains the addiction to tobacco. When we stop smoking for too long, our body is in need of nicotine and a feeling of unease appears. This lack can be manifested in different ways. Enervation, feverishness, nervousness, anxiety, difficulty concentrating or falling asleep are all signs of lack, which disappear when the brain is again "supplied" with nicotine.

For Benoît Forget, a researcher in the Integrative Neurobiology of Cholinergic Systems Unit (Institut Pasteur / CNRS) and lead author of the study, this addiction to nicotine can, however, be reinforced by the mutation of the CHRNA5 gene. "Several human genetic studies have already shown that this genetic mutation increases the risk of tobacco addiction," he says, quoted by 20Minutes. "Based on this postulate, we sought to determine what phase of nicotine addiction was affected by the presence of this mutation and what could be its role in the relapse."

A greater risk of relapse after weaning

As part of his research, the team led by Benoît Forget has introduced into laboratory rats the genetic mutation responsible for tobacco addiction in humans. The researchers then observed the behavior of rodents. "We both found that this genetic mutation resulted in higher nicotine intake at higher doses, and found that it induced a higher proportion of relapses after nicotine withdrawal," the researcher explains.

It also appeared during the research that these frequent relapses after weaning are related to a "reduction of the activation of the neurons of the inter-peduncular nucleus", a specific area of ​​the brain that contains most of the Alpha5 subunits of the nicotinic receptors. and which is "composed essentially of inhibitory neurons". According to Benoît Forget, by reducing the activity of the inter-peduncular nucleus, "the genetic mutation could participate in the activation of other brain structures involved in the relapse and thus lead the weaned smoker to relapse into addiction when he is exposed again to a cigarette ".

This discovery could largely explain the nicotine addiction of many smokers. In fact, says the researcher, 35% of Europeans and 50% of the population of the Middle East carry this genetic mutation.

Towards a more effective targeted therapeutic treatment

For Benoît Forget, this discovery is also decisive for the future of tobacco smoking cessation because it will allow a very targeted action. "A drug capable of increasing the activity of nicotinic receptors containing the Alpha5 subunit could reduce tobacco consumption and the risk of relapse after weaning," says Uwe Maskos, head of the Integrative Neurobiology Systems Unit. cholinergic (Institut Pasteur / CNRS), co-author of the study.

But once this discovery has been made, what hope can it feed into the fight against tobacco addiction? "By putting your finger on a specific subunit of nicotinic receptors, we can consider therapeutic paths to imagine a very targeted action," projects Benoît Forget. These results "suggest that a drug capable of increasing the activity of nicotinic receptors containing the α5 subunit could help reduce tobacco consumption and the risk of relapse after withdrawal," adds Uwe Maskos, head of the unit. of Integrative neurobiology of cholinergic systems (Institut Pasteur / CNRS), co-author of the study.

A new therapeutic target

"If we can develop drugs that increase the activation of the neurons of the inter-stalk nucleus, it could help the brain better manage the craving to smoke after smoking cessation," adds Benoît Forget. "Such a drug would reduce nicotine consumption not only in people with the genetic mutation, or even in smokers who do not, but also prevent relapse after smoking cessation. all the more interesting because, by targeting receptors localized in certain particular structures of the brain, this therapeutic track makes it possible to hope in the long term to obtain a therapeutic effect of peak, very targeted and without too many side effects ".

A hope that prefers to qualify Jacques Le Houezec, a tobacco expert and independent consultant in public health and tobacco addiction. Asked by Slate, he acknowledges that the discovery made by the team of French researchers is important, but points out that "the metabolism of the rat is different from that of humans (like that of the mouse). the rat to observe these effects is very far from human behavior ". It also recalls that "we must take into account the large number of nicotinic receptor varieties present in the human brain, without neglecting the secondary reinforcements (affect, behavioral situation, social influences, etc.) that probably play a significant role in smoking relapses ".