Discovery of a key mechanism in the brain that regulates vulnerability to nicotine addiction could pave the way for new anti-smoking treatments that boost a signalling pathway that is normally weaker in susceptible individuals because of a gene mutation, said US researchers in a Nature study published online this week.

Scientists from the Florida campus of The Scripps Research Institute said their findings could lead to new treatments that boost people’s natural resistance to smoking addiction.

Study leader Associate Professor Paul Kenny, told the press that:

“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.”

“These findings also point to a promising target for the development of potential anti-smoking therapies,” he added.

For their study, Kenny and colleagues examined a signalling pathway that involves a receptor in the brain that responds to nicotine, the major addictive component in tobacco smoke. A receptor is a protein molecule that acts as a “docking station” on the surface of cells and to which particular signalling molecules that control cell activity attach themselves.

The receptor they focused on is the nicotinic acetylcholine receptor (nAChR), which is made up of subunits, one of which is called the alpha5 subunit, located in a part of the brain known as the habenulo-interpeduncular tract.

Kenny and colleagues tested lab mice and found that carrying a genetic mutation that inhibits the activity of this alpha5 subunit made the animals consume far more nicotine than normal and the effect could be reversed by boosting its expression.

First author Dr Christie Fowler, a research associate in Kenny’s lab, said they were surprised to find that the habenula, and the brain structures it projects into, played such an important part in controlling the urge to consume nicotine. She explained how it seems to work:

“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 alpha5 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,” she added.

The researchers did two sets of tests, one in mice, and the other in rats, and found similar results: when the alpha5 subunits were depleted, either in the genetically engineered mice or in rats where they knocked out the subunits using a virus, the animals went berzerk trying to find higher doses of nicotine.

Kenny and colleagues also tried to find out what the underlying biochemical mechanisms might be.

They found that the relevant alpha5 subunits control the habenula’s sensitivity to nicotine, and that the habenula appears to be involved in some of the negative (ie unpleasant) responses to nicotine consumption, such that when the pathway is not working properly, the habenula is less sensitive to nicotine, so much more of the chemical is consumed before the negative effects kick in.

Funds from the National Institutes of Health and The James and Esther King Biomedical Research Program, Florida Department of Health, paid for the study.

“Habenular [alpha]5 nicotinic receptor subunit signalling controls nicotine intake.”
Christie D. Fowler, Qun Lu, Paul M. Johnson, Michael J. Marks, Paul J. Kenny.
Nature Published online 30 January 2011
DOI:10.1038/nature09797

Additional source: Scripps Research Institute (News release 30 Jan 2011).

Written by: Catharine Paddock, PhD