Scripps Research scientists reveal key mechanism governing nicotine addiction

Embargoed by the journal Nature until January 30, 1 PM Eastern time – Scientists from the Florida campus of The Scripps Research Institute have identified a pathway in the brain that regulates an individual's vulnerability to the addictive properties of nicotine. The findings suggest a new target for anti-smoking therapies.

The study appeared January 30, 2011, in an advance, online issue of the journal Nature.

In the study, the scientists examined the effects of a part of a receptor (a protein molecule to which specific signaling molecules attach) that responds to nicotine in the brain. The scientists found that animal models with a genetic mutation inhibiting this receptor subunit consumed far more nicotine than normal. This effect could be reversed by boosting the subunit's expression.

"We believe that these new data establish a new framework for understanding the motivational drives in nicotine consumption and also the brain pathways that regulate vulnerability to tobacco addiction," said Scripps Research Associate Professor Paul Kenny, who led the study. "These findings also point to a promising target for the development of potential anti-smoking therapies."

Specifically, the new study focused on the nicotinic receptor subunit α5, in a discrete pathway of the brain called the habenulo-interpeduncular tract. The new findings suggest that nicotine activates nicotinic receptors containing this subunit in the habenula, triggering a response that acts to dampen the urge to consume more of the drug.

"It was unexpected that the habenula, and brain structures into which it projects, play such a profound role in controlling the desire to consume nicotine," said Christie Fowler, the first author of the study and research associate in the Kenny laboratory. "The habenula appears to be activated by nicotine when consumption of the drug has reached an adverse level. But if the pathway isn't functioning properly, you simply take more. Our data may explain recent human data showing that individuals with genetic variation in the α5 nicotinic receptor subunit are far more vulnerable to the addictive properties of nicotine, and far more likely to develop smoking-associated diseases such as lung cancer and chronic obstructive pulmonary disease."

A Previously Unknown Pathway Inhibits Motivation

Tobacco smoking is one of the leading causes of death worldwide, with more than five million people dying each year as a result of it, according to statistics cited in the study. Smoking is considered the cause of more than 90 percent of lung cancer deaths. Scientists have established that a tendency towards smoking can be inherited – more than 60 percent of the risk of becoming addicted to nicotine can be laid at the door of genetic factors.

Nicotine is the major addictive component of tobacco smoke, and nicotine acts in the brain by stimulating proteins called nicotinic acetylcholine receptors (nAChRs). These nAChRs are made up of different types of subunits, one of which is the α5 subunit—the focus of the new study.