A Georgetown University Medical Center research team has been awarded a grant from the National Institute on Drug Abuse to discover and develop new smoking cessation drugs based on an unconventional theory about nicotine addiction. Kenneth Kellar, PhD, a professor of pharmacology at GUMC is principal investigator of the five year grant totaling $4.6 million.
The theory, developed in Kellar's lab over the last 20 years, stems from observations that continual administration of nicotine in laboratory animals leads to an increase in the number of nicotinic acetylcholine receptors in the brain. A similar increase in these receptors is seen in the brains of human smokers.
A second important effect of nicotine that has been known for more than 100 years is that it rapidly desensitizes these nicotinic receptors after exposure. Kellar's theory combines both theories: nicotine addiction results from smokers trying to maintain the increased number of brain nicotinic acetylcholine receptors in a desensitized state to avoid over-activity of the increased receptors and the brain circuits they serve.
According to this theory, if a person doesn't smoke for one, two, or three hours, the receptors become active (again), and because smokers have more of these receptors in their brains, this excess activity results in feelings of anxiety. "An addicted smoker has learned that the easiest way to relieve this anxiety is to smoke another cigarette, which then turns off these receptors by desensitizing them. And that starts the cycle again," says Kellar.
"All drug addictions take a toll on life, but nicotine makes the largest impact on health and life expectancy", says Kellar. In fact, according to the Centers for Disease Control, lifelong smokers on average lose more than a decade of life.
The goal of the work supported by this research grant is to discover selective nicotinic receptor desensitizers that can be developed into new treatments for nicotine addiction with higher efficacy than currently available treatments.
Kellar's lab has a long history of research into nicotine addiction. In the 1990's, Kellar and his colleagues produced autoradiographic images showing the increased nicotinic receptors in the brains of long-time smokers. The images helped the FDA to seek regulation of the nicotine in cigarettes.
Yingxian Xiao, PhD, an associate professor of pharmacology at GUMC, is a project leader on this grant. His studies with the novel compound sazetidine-A, developed in the Kellar lab in 2005, led to the proposal to develop selective receptor desensitizers for smoking cessation. Other project leaders include Milton Brown, MD, PhD, director of the GUMC Drug Discovery Program, and Edward Levin, PhD of Duke University.
Kellar, Xiao and Brown are three of the inventors on patent applications held by Georgetown University that are related to the technology involved in the research supported by this grant.
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