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Nicotine/norharmane as a model of tobacco dependence

Institution: University of California, Irvine
Investigator(s): Frances Leslie, Ph.D.
Award Cycle: 2009 (Cycle 18) Grant #: 18XT-0085H Award: $263,962
Subject Area: Nicotine Dependence
Award Type: Exploratory/Developmental Award

Initial Award Abstract
Although the harmful health effects of smoking are well known, quitting is very difficult. Pharmacological treatments to enhance success in quitting have been only partially effective, with smoking cessation rates ranging from 5-35%. Such findings emphasize the need to establish better experimental models for analysis of the mechanisms underlying tobacco addiction and for identifying new drug treatments. The self-administration model is commonly used as an animal test for screening new addiction therapies. Although nicotine self-administration has been used extensively as a medication screen for therapeutic compounds to treat tobacco dependence, there have been no studies to date of nicotine co-administered with other tobacco constituents. Tobacco smoke consists of approximately four thousand chemical constituents, some of which have been shown to influence the behavioral effects of nicotine.

In the present application, we propose the first ever use of the self-administration model to assess the effect of a natural tobacco constituent, norharmane, on the neural mechanisms underlying nicotine-seeking behavior. We propose to examine the effectiveness of several drugs in reducing self-administration of nicotine as compared to a combination of nicotine and norharmane. Not only will we evaluate the effects of these drugs in reducing stable self-administration, we will also assess their efficacy in blocking cue-induced reinstatement of responding following extinction. The reinstatement test is widely used to model relapse to addiction, which is particularly important in identifying drugs that may reduce craving in abstinent smokers.

Using this pharmacological approach, we will test the hypothesis that norharmane alters the mechanisms underlying nicotine-seeking, with a resulting change in sensitivity to therapeutic drugs. Such a finding would provide strong evidence for a need to establish better animal models to evaluate the mechanisms underlying tobacco addiction and for screening new medications. We will also evaluate the effectiveness of two drugs that are currently in clinical use for treatment of hypertension, as inhibitors of nicotine-seeking behavior. A positive finding in our preclinical tests would identify these drugs as possible candidate therapies for treatment of tobacco dependence.