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Chronic nicotine treatment in primates; role of a6b2 nAChRs

Institution: SRI International
Investigator(s): Maryka Quik, Ph.D.
Award Cycle: 2008 (Cycle 17) Grant #: 17RT-0119A Award: $382,500
Subject Area: Nicotine Dependence
Award Type: Research Project Awards

Initial Award Abstract
Smoking is associated with major health problems worldwide, including respiratory disease, cardiovascular disease and cancer. Since tobacco use has such deleterious health consequences, strategies to reduce or stop smoking are urgently needed. However, the addictive nature of tobacco is very strong with success quit rates after 1 year only about 10%. An important question is; what is the addictive component in tobacco? as such information will provide leads as to how to prevent addiction. Although tobacco products contain over 4000 chemicals, nicotine appears to be the most likely candidate. The idea that nicotine is responsible for the addictive properties of tobacco is supported by work showing that smokers have a preference for cigarettes that contain nicotine compared to those that do not.

The finding that nicotine is the addictive component suggests it is important to understand the changes it causes in the brain even though nicotine is not the primary cause of smoking-related diseases, including cancer, cardiovascular and respiratory disease. Knowledge of these changes may allow for the development of smoking cessation therapies directly targeted to the molecular steps that are modified with smoking. Currently available smoking cessation regimens have only limited success. One reason is that the molecular changes in the brain responsible for nicotine addiction are only beginning to be understood. Nicotine causes its effect in the brain by acting on molecules called nicotinic receptors, of which there are several types. One type that is known to be involved in addiction is called the alpha4 nicotinic receptor. Indeed, drugs that act specifically at these receptors are currently under development as an approach to assist in smoking cessation, with some success. Very recent work shows that there is also another nicotinic receptor in brain regions important for addiction, called the alpha6 nicotinic receptor. Experiments in our laboratory show that this alpha6 receptor is, in fact, responsible for a large part (75%) of the nerve cell activity (dopamine release) that may be important for the addictive properties of smoking. These results suggest that development of new drugs directed to these alpha6 receptors may be important for smoking cessation therapies. However, very little is known about the alpha6 receptors and how they interact with the alpha4 receptors, which are known to be important for addiction.

The goal of our work, therefore, is to determine the role of alpha6 nicotinic receptors in brain activity linked to smoking. These studies represent a new direction for understanding the changes in the brain that may be responsible for addiction. Such knowledge may lead to more effective treatment strategies for smoking cessation using drugs that specifically act at alpha6 nicotinic receptors. The importance of achieving success in this area cannot be over-estimated in view of the detrimental health related affects associated with tobacco use.