The Two Sides Of Tobacco: Penn Researchers Discover Molecular Complexities Of Nicotine's Action

November 14, 1997

Although it has been known for some time that nicotine is responsible for addiction to tobacco and interacts with acetylcholine receptors, scientists are now starting to realize that the many types of receptors for the neurotransmitter rule out a simple explanation for how nicotine behaves in the brain. Nicotine simultaneously effects many subtypes of acetylcholine receptors to create a variety of physiological reactions. Some are agreeable, like focusing attention and suppressing anxiety, appetite, and pain; while others are less desirable, like elevating blood pressure and heart rate and causing addiction. The resulting mix involves both activating some receptors and inactivating others. Understanding this complicated interplay between nicotine and acetylcholine receptors is also important in developing nicotine-like drugs to treat such neurological disorders as Alzheimer's disease, Parkinson's disease, and chronic pain.

Recent studies of acetylcholine receptors by investigators at the University of Pennsylvania Medical Center are shedding light on the molecular biology of dependence on, tolerance to, and withdrawal from nicotine. The researchers--led by Jon Lindstrom, PhD, professor of neuroscience--found that chronic exposure to concentrations of nicotine typical of that found in a smoker's blood first stimulates, then permanently inactivates the two most- prominent subtypes of human acetylcholine receptors--alpha-4 and alpha-7, but affects a third type--alpha-3--much less.

"This finding provides an appealing explanation for why chronic tobacco users become tolerant to levels of tobacco that would sicken the naive user," says Lindstrom. Essentially, when alpha-4 and alpha-7 receptors are inactivated, a person could become tolerant to nicotine. It acts like a neurotransmitter to activate acetylcholine receptors, but unlike acetylcholine, nicotine persists in the body for hours.

Habitual users become dependent on nicotine through the same neural reward pathways observed with cocaine and other addictive drugs. "The continuing activation of alpha-3 receptors--and perhaps other subtypes--suggests that this activation, possibly in concert with the inactivation of alpha-4 and -7, may play a role in addiction to nicotine," notes Lindstrom. He suggests that alpha-3 receptors remain active to respond to nicotine, thus stimulating the reward pathway. The researchers published their results in the November issue of the Journal of Pharmacology and Experimental Therapeutics.

Penn neuroscientists Felix Olale, Volodymyr Gerzanich, Alexander Kuryatov, and Fan Wang also collaborated on this study, which was funded by the National Institutes of Health, the Smokeless Tobacco Research Council, Inc., and the Muscular Dystrophy Association.

Editor's Note: Dr. Lindstrom can be reached at 215-662-4392.

The University of Pennsylvania Medical Center's sponsored research ranks fifth in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation. In federal fiscal year 1996, the medical center received $149 million. In addition, for the second consecutive year, the institution posted the highest growth rate in research activity--9.1 percent--of the top-ten U.S. academic medical centers during the same period. News releases from the medical center are available to reporters by direct E-mail, fax, or U.S. mail, upon request. They are also posted to the center's webpage ( and EurekAlert! (, a resource sponsored by the American Association for the Advancement of Science.

University of Pennsylvania School of Medicine

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