Nicotine addiction: all in the head?

“Chain smokers battling in vain to quit may be able to blame it on their miswired brains,” reported The Sun . It said that scientists have revealed that the problem lies in a gene within the brain that normally “squashes” the urge for more nicotine when intake reaches a critical level.

This news story is based on a study in rats and mice, so the relevance to humans is uncertain. It is yet to be established whether humans carry this gene, and this theory of addiction has not been tested outside the lab. However, early laboratory research such as this is important and valuable, and the results suggest a future direction for research into human addictions. It will be some time before these findings translate into addiction treatment or prevention.

Where did the story come from?

The study was carried out by researchers from the Scripps Research Institute in Florida and the University of Colorado in the USA. It was funded by the National Institute on Drug Abuse and the James and Esther King Biomedical Research Programme at the Florida Department of Health. The research paper was published in the peer-reviewed medical journal Nature .

This is a study in genetically modified mice and rats, and the findings may not be applicable to humans. Therefore The Sun’s interpretation that “chain smokers battling in vain to quit may be able to blame it on their miswired brains” is premature.

What kind of research was this?

This laboratory study in rats and mice investigated the role of a certain type of receptor found in the walls of nerve cells. Nicotine is able to bind to some of the receptors in the nerve cells leading to changes that are responsible for the key feelings a smoker may describe, including heightened activity, improved reaction time and a sense of reward and satisfaction. The receptors that nicotine can bind to are called nicotinic acetylcholine receptors (nAChRs) and they are each made up of five subunits.

Previous research has found an association between tobacco addiction and mutations in the genes that are responsible for how these molecular subunits are formed. In particular, mutations in the gene that is responsible for a subunit called "alpha 5" have been linked to lung cancer and COPD in smokers.

The researchers wanted to understand better the role that these receptors and genes have in the processing of nicotine in the body. They also wanted to see how important they are for the functioning of the receptor molecules.

What did the research involve?

The study included normal rats and mice and those that had been genetically modified not to have the gene responsible for the formation of the alpha 5 subunit. Normal mice and these mutant mice were exposed to a system where they could self-administer nicotine by pressing on a lever that would result in an hourly delivery of an intravenous dose, during a one-hour session, seven days a week.

The researchers assessed whether the presence or absence of the gene had any effect on how much nicotine the mice took in and their behaviour in seeking out nicotine. In separate experiments they also increased the dose of nicotine available to the mice so that they could determine whether the mice moderated their nicotine intake themselves accordingly.

The alpha 5 subunit occurs in many different cells in the brain, but seems concentrated in a group of areas collectively known as “the habenulo”. The researchers investigated where this region was responsible for regulating nicotine intake by injecting this region of rats’ brains with a virus that carried a working copy of the gene. They then tested whether this restored the expected regulation of nicotine intake in the rats, particularly with regards to limiting intake at high doses.

In a separate set of experiments, the researchers investigated whether normal and mutant rats differed in their reward-seeking and how nicotine fulfilled this. They implanted electrodes into the brain, which rats could self-stimulate. These induced a pleasurable stimulation and the researchers measured whether the rats modified their seeking of this type of pleasure depending on their nicotine exposure.

What were the basic results?

Normal mice appeared to moderate their intake of nicotine so that they were consuming about 1.5mg/kg per session, while those with the mutation took in greater quantities. The mutant mice also appeared to be more motivated to seek and obtain nicotine at high doses. Mutant and normal mice were not affected differently by nicotine itself and the researchers said that a deficiency in the functioning of the alpha 5 subunit actually seemed to prevent the negative feedback that may limit the intake of nicotine. The injection of functioning genes for the alpha 5 subunit into the habenulo regions restored the functioning of the subunit.

Rats and mice with mutations in the alpha 5 subunit did not demonstrate the same limits in reward from high doses of nicotine that normal mice did.

How did the researchers interpret the results?

The researchers said that genetically modified mice have a reduced ability to regulate their intake of nicotine, particularly at higher doses, and that “these findings are highly consistent with the increased vulnerability to tobacco addiction in human smokers” with mutations in these genes.

They found that mutations resulting in deficiencies in the functioning of the alpha 5 subunit leads to a relative insensitivity to the inhibitory effects of nicotine on reward pathways.

Conclusion

These findings are an important early step in investigating the biological causes of addiction in humans. Both newspapers and the researchers have applied these findings to human health. The researchers said that their findings have important implications for understanding the high incidence of lung cancer and COPD in individuals who have variations in the gene responsible for the functioning of the nicotinic receptors in nerve cells, particularly in shaping the alpha 5 subunit.

However, this is early research and it is too soon to say that the cause of addiction has been found and that it is due to a “faulty brain”. Given the complexities of human behaviour, it is highly unlikely that a mutation in a single gene is the reason why some people are addicted to nicotine. There may be many biological and environmental reasons why someone may start smoking and why they find it difficult to stop.

It will be some time before these findings can translate into approaches to treatment or prevention of addiction. Researchers treated mice in this study by injecting a virus into their brains. This virus carried a functioning gene that was able to restore the role played by the alpha 5 subunit and recover the nicotine self-regulation in mutant animals. Whether such a technology could work safely in humans is not yet known.