Research on the addictive properties of cigarettes has, for many years, focused on nicotine (NIC);studies on human subjects and experimental animals have provided compelling evidence that NIC contributes to smoking. However, it is now clear that other chemicals among the more than 4000 compounds of cigarette smoke also contribute to the addictive properties of cigarettes, at least partly by interacting with the effects of NIC on the brain. Of the many compounds present in cigarette smoke, less than a dozen of these have been identified that interact in significant ways with NIC. These compounds can be viewed as fitting into four major classes: a group of so-called minor alkaloids (e.g., anabasine, nornicotine), the p-carbolines Harman and norharman, acetaldehyde, and additional compounds that inhibit monoamine oxidase (MAO). The goal of this project is to explore, in a well characterized rat model of NIC self-administration, the reinforcing effects of NIC within the context of other components of cigarette smoke that likely contribute to its abuse liability. There are four Specific Aims:  To determine the effects of a cocktail of tobacco constituents on the doseresponse relationship for NIC self-administration. Hypothesis: a cocktail of tobacco constituents including the minor alkaloids, p-carbolines, acetaldehyde, and MAO inhibitors will shift the dose-response curve for NIC self-administration, such that NIC is more potent and effective in supporting self-administration.  To determine whether changing the concentration of the components of the cocktail of tobacco constituents will alter the acquisition and maintenance of NIC self-administration. Hypothesis: increasing the concentrations of the compounds in a cocktail of tobacco constituents will increase self-administration of a specific dose of IC whereas decreasing the concentrations will decrease self-administration.  To determine whether changing the concentrations of compounds in the cocktail of tobacco constituents can offset or promote the reduction in NIC self-administration caused by reducing the dose of NIC over time. Hypothesis: the reduction in NIC self-administration caused by reducing the dose of NIC can be enhanced by also reducing the concentration of the cocktail constituents whereas the effects of reducing the dose of NIC can be lessened (or even prevented) by increasing the concentration of these compounds.  To determine the relative importance of the different classes of components in the cocktail in the interactions between NIC and the cocktail of tobacco constituents in supporting self-administration behavior.
A central premise of the Family Smoking Prevention and Tobacco Control Act is that the nicotine content of cigarettes can be reduced to a level that is non-addictive. However, since nicotine interacts with other components of cigarette smoke to reinforce behavior, understanding these interactions is essential in developing regulatory policies. The proposed preclinical studies provide a fundamental step in this process.
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