ROLE OF METABOLITES IN NICOTINE DEPENDENCE

Nicotine has been considered to be the primary drug that produces dependence on tobacco products. However, several studies that have been recently conducted show that metabolites of nicotine, particularly cotinine, may play a role in the complex dependence process. These studies have shown that cotinine administered to smokers during cigarette abstinence produces specific symptoms and may reduce tobacco withdrawal symptoms in a dose-related manner. The proposed studies attempt to elucidate the role of cotinine in tobacco dependence and its possible role for tobacco cessation. The studies will examine the effects of cotinine on tobacco withdrawal symptoms, physical dependence on cotinine, the self-administration of cotinine, and the effects of cotinine on the amount of tobacco use. More specifically, the first study will examine the effects of cotinine in comparison with the effects of the transdermal nicotine system (TNS), and a combination of both products during smoking withdrawal. The purpose of the second study will be similar to the first except the study will be undertaken on an outpatient basis. An outpatient study is essential since cues for smoking are different in the natural environment as opposed to an inpatient environment. For both the first two studies, the hypothesized result is that the administration of cotinine will show a different profile of effects than the nicotine transdermal system; cotinine will affect withdrawal symptoms differently than placebo; and the combination of cotinine and nicotine may either show an augmented or antagonistic effect. The third outpatient study will determine whether cotinine produces physical dependence. The potential symptoms of withdrawal from cotinine will be compared with those from cigarettes. The hypothesized result is that cotinine will lead to fewer withdrawal symptoms than from cigarette smoking and that cotinine withdrawal symptoms will be minimal. The fourth study will determine the self-administration of cotinine compared to placebo, and various doses of cotinine compared to each other during cigarette withdrawal. The hypothesized result is that cotinine will be chosen over placebo, and higher doses over lower doses. The purpose of the fifth study is to determine the effects of cotinine vs. placebo on the self- administration of cigarettes. The hypothesized result is that cotinine will reduce the self-administration of cigarettes, and higher doses will reduce cigarette smoking to a greater degree. These studies should provide a better understanding of how a metabolite may contribute to the dependence on a drug.