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Key Mechanism Governing Nicotine Addiction Discovered

ScienceDaily (Jan. 30, 2011)—

Scientists from the Florida campus of The Scripps Research Institutehave identified a pathway in the brain that regulates an individual’s vulnerability to the addictiveproperties 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 whichspecific signaling molecules attach) that responds to nicotine in the brain. The scientists found thatanimal models with a genetic mutation inhibiting this receptor subunit consumed far more nicotinethan 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 drivesin 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 pointto a promising target for the development of potential anti-smoking therapies.”Specifically, the new study focused on the nicotinic receptor subunit ?5, in a discrete pathway of thebrain called the habenulo-interpeduncular tract. The new findings suggest that nicotine activatesnicotinic receptors containing this subunit in the habenula, triggering a response that acts to dampenthe urge to consume more of the drug.”It was unexpected that the habenula, and brain structures into which it projects, play such a profoundrole in controlling the desire to consume nicotine,” said Christie Fowler, the first author of the studyand research associate in the Kenny laboratory. “The habenula appears to be activated by nicotinewhen consumption of the drug has reached an adverse level. But if the pathway isn’t functioningproperly, you simply take more. Our data may explain recent human data showing that individualswith genetic variation in the ?5 nicotinic receptor subunit are far more vulnerable to the addictiveproperties of nicotine, and far more likely to develop smoking-associated diseases such as lung cancerand chronic obstructive pulmonary disease.”A Previously Unknown Pathway Inhibits MotivationTobacco smoking is one of the leading causes of death worldwide, with more than five million peopledying each year as a result of it, according to statistics cited in the study. Smoking is considered thecause of more than 90 percent of lung cancer deaths. Scientists have established that a tendencytowards smoking can be inherited — more than 60 percent of the risk of becoming addicted to nicotinecan be laid at the door of genetic factors.

Nicotine is the major addictive component of tobacco smoke, and nicotine acts in the brain bystimulating proteins called nicotinic acetylcholine receptors (nAChRs). These nAChRs are made upof different types of subunits, one of which is the ?5 subunit — the focus of the new study.In their experiments, the Scripps Research scientists set out to determine the role of nAChRscontaining?5 subunits (?5* nAChRs) in regulating nicotine consumption.First, the team assessed the addictive properties of nicotine in genetically altered mice lacking ?5*nAChRs. The results showed that when these “knockout” mice were given access to high doses ofnicotine, they consumed much larger quantities than normal mice. Next, to determine if the subunitwas responsible for the sudden shift in appetite for nicotine, the scientists used a virus that “rescued”the expression of ?5* nAChRs only in the medial habenula and areas of the brain into which itprojects. The results showed the nicotine consumption patterns of the knockout mice returned to anormal range.The scientists repeated the experiments with rats and produced similar results. In this case, thescientists used a virus to “knock out” ?5 nAChR subunits in the medial habenula. When the ?5*nAChRs were decreased, the animals were more aggressive in seeking higher doses of nicotine. Whenthe subunit remained unaltered, the animals showed more restraint.The scientists then worked out the biochemical mechanisms through which ?5* nAChRs operate inthe medial habenula to control the addictive properties of nicotine. They found that ?5* nAChRsregulate just how responsive the habenula is to nicotine, and that the habenula is involved in some ofthe negative responses to nicotine consumption. So when ?5* nAChRs do not function properly, thehabenula is less responsive to nicotine and much more of the drug can be consumed without negativefeedback from the brain.The scientists are optimistic that their findings may one day lead to help for smokers who want to kickthe habit. Based on the new findings, the Scripps Florida scientists have started a new program ofresearch in collaboration with scientists at the University of Pennsylvania to develop new drugs toboost ?5* nAChR signaling and decrease the addictive properties of nicotine.In addition to Kenny and Fowler, authors of the paper, “Habenular ?5* Nicotinic Receptor SignalingRegulates Nicotine Intake,” include Qun Lu and Paul M. Johnson of Scripps Research and Michael J.Marks of the University of Colorado, Boulder.The study was funded by the National Institutes of