This ongoing study will evaluate the role of dopamine (DA) in cigarette smoking. We will assess the effects of a DA agonist (d-amphetamine), an antagonist (haloperidol), and an agonist/antagonist combination (d- amphetamine + haloperidol) on acute subjective responses to cigarette smoking (e.g., ratings of smoking satisfaction, craving reduction). We hypothesize that by blocking post-synaptic DA receptors, haloperidol will attenuate the satisfaction gained from smoking and thereby may increase craving for cigarettes. We also expect that d-amphetamine will reduce smoking satisfaction and reduce craving for cigarettes, by substituting for the DA-releasing effects of nicotine. Since both haloperidol and d- amphetamine are expected to reduce smoking satisfaction when administered alone, we predict that the combined administration of haloperidol and d- amphetamine will reduce satisfaction to an even greater extent. We will also explore the efficacy and tolerability of the MAO-B inhibitor, selegiline, as a pharmacotherapy for smoking cessation. We hypothesize that subjects receiving selegiline will show higher rates of smoking abstinence as compared to subjects receiving placebo. Finally, we will determine whether acute responses to dopaminergic agents in the laboratory are predictive of smoking status in the clinical setting. Preliminary data from a small number of subjects suggests that combined pretreatment with haloperidol and amphetamine attenuates smoking satisfaction to a greater extent than either drug alone, and is a safe and tolerable treatment combination. Significance: Nearly fifty million Americans smoke cigarettes, despite the association of smoking with substantial morbidity and mortality, including coronary heart disease, stroke, chronic obstructive pulmonary disease, peripheral vascular disease, peptic ulcers, lung cancer, and death. Unfortunately, smokers attempts to reduce their smoking are frequently unsuccessful, even with the aid of currently available pharmacological treatments. The development of more successful treatments for smoking cessation relies heavily on gaining a better understanding of the neurochemical mechanisms underlying nicotine addiction, as well as increased knowledge of non-nicotine factors that contribute to smoking behavior. This study will help to elucidate the role of DA in acute subjective, behavioral and physiological responses to cigarette smoking, and to assess the efficacy of a dopaminergic treatment for smoking cessation.
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