Scientists from the Florida campus of The Scripps Research Institute say that they have identified a pathway in the brain that regulates an individual’s vulnerability to the addictive properties of nicotine. The team is now collaborating with the University of Pennsylvania to develop new drugs to boost signaling in this pathway and decrease the addictive properties of nicotine.
The study appeared January 30 in an advance, online issue of the journal Nature. The paper is titled “Habenular α5* Nicotinic Receptor Signaling Regulates Nicotine Intake.”
Specifically, the research focused on the nicotinic receptor subunit α5, in a discrete pathway of the brain called the habenulo-interpeduncular tract. They 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.
The results 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. “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,” says Christie Fowler, the first author of the study and research associate in the Kenny laboratory.
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.
In their experiments, the Scripps Research team set out to determine the role of nAChRs-containing α5 subunits (α5* nAChRs) in regulating nicotine consumption. First, they assessed the addictive properties of nicotine in genetically altered mice lacking α5* nAChRs. The results showed that when these knockout mice were given access to high doses of nicotine, they consumed much larger quantities than normal mice.
Next, to determine if the subunit was responsible for the sudden shift in appetite for nicotine, the scientists used a virus that rescued the expression of α5* nAChRs only in the medial habenula and areas of the brain into which it projects. The results showed the nicotine consumption patterns of the knockout mice returned to a normal range.
The scientists repeated the experiments with rats and produced similar results. In this case, the scientists used a virus to knock out α5 nAChR subunits in the medial habenula. When the α5* nAChRs were decreased, the animals were more aggressive in seeking higher doses of nicotine. When the subunit remained unaltered, the animals showed more restraint.
The scientists then worked out the biochemical mechanisms through which α5* nAChRs operate in the medial habenula to control the addictive properties of nicotine. They found that α5* nAChRs regulate just how responsive the habenula is to nicotine, and that the habenula is involved in some of the negative responses to nicotine consumption. So when α5* 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.