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Brain Pathway Found for Nicotine Vulnerability

Broken cigarette (


Scientists from the Scripps Research Institute in Jupiter, Florida have identified a pathway in the brain that regulates an individual’s vulnerability to the addictive properties of nicotine. The findings appear in the 30 January 2011 online issue of the journal Nature (paid subscription required).

In the study, the scientists examined the effects of a part of a receptor — a protein molecule where specific signaling molecules attach — that responds to nicotine in the brain. The scientists found that rodents with a genetic mutation inhibiting this part of the receptor consumed far more nicotine than normal. This effect could be reversed by boosting the power of that part of the receptor.

The receptor in question is known as “subunit a5,” 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 a part of the brain called the habenula, triggering a response that acts to dampen the urge to consume more of the drug.

Nicotine acts in the brain by stimulating proteins called nicotinic acetylcholine receptors (nAChRs). These nAChRs have a number of subunits, one of which is subunit a5, abbreviated “a5* nAChRs”, the focus of this study.

The Scripps Research team first assessed the addictive properties of nicotine in genetically altered mice lacking a5* nAChRs. The results showed that when these genetically altered mice were given access to high doses of nicotine, they consumed much larger quantities than normal mice.

The team next determined if the subunit was responsible for the sudden shift in appetite for nicotine. The scientists used a virus that restored the expression of a5* nAChRs only in the medial habenula and areas of the brain into which it projects. The results showed the nicotine consumption patterns of the altered mice returned to a normal range. The researchers repeated the experiments with rats and produced similar results.

The scientists then worked out the biochemical mechanisms through which a5* nAChRs operate in the medial habenula to control the addictive properties of nicotine. They found that a5* nAChRs regulate the responsiveness of the habenula to nicotine, and that the habenula is involved in some of the negative responses to nicotine consumption.

The researchers conclude that in cases when a5* nAChRs do not function properly, the habenula is less responsive to nicotine and much more of the drug can be consumed without negative feedback from the brain.

The team believes their findings can lead to help for smokers who want to kick the habit. Based on the new findings, the Scripps researchers plan to collaborate with scientists at the University of Pennsylvania to develop new drugs to boost a5* nAChR signaling and decrease the addictive properties of nicotine.

Read More: Panel: Make Cigarettes Non-Addictive

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