DOPAMINERGIC MECHANISMS IN NICOTINE ADDICTION

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There is considerable evidence that nicotine plays a primary role in the maintenance of smoking behavior, but the precise neurochemical mechanisms by which nicotine exerts its rewarding effects remain unclear. Gaining a better understanding of how nicotine functions to reinforce smoking behavior may ultimately lead to the development of new smoking cessation strategies. Nicotine produces a variety of pharmacological effects in the central nervous system, including enhancement of dopamine (DA) levels in mesolimbic brain areas. Studies with laboratory animals as well as preliminary data from human smokers suggest that these effects of nicotine may contribute to its reinforcing effects. The purpose of the proposed studies is to further evaluate the role of DA in cigarette smoking in humans. We will evaluate the effects of two dopaminergic agents, alone and in combination, on acute subjective and behavioral responses to smoking, as well as on rates of ad lib smoking. Measuring both rate of smoking and subjective responses will enable us to determine the behavioral consequences of modulations in smoking satisfaction and to determine whether the acute rewarding effects of smoking and rates are differentially influenced by DA systems. Subjects will smoke both nicotine-containing and de-nicotinized cigarettes. The de-nicotinized cigarettes will serve as a control condition for the sensory aspects of smoking. Using a within-subjects, placebo-controlled design, Study 1 will examine the effects of the DA agonist, bromocriptine, on acute subjective and behavioral responses to smoking and on cigarette consumption in smokers who are overnight abstinent. In Study 2, we will assess the effects of the DA antagonist, haloperiodol, on smoking rates and acute responses. Finally, in Study 3, the effects of combined administration of bromocriptine and haloperidol will be explored. Previous studies have shown that the combined administration of nicotine and the nicotine antagonist, mecamylamine, reduced smoking and attenuated responses to cigarettes to a significantly greater extent than either treatment alone, and resulted in fewer side effects. We will explore the extent to which the effects of combined agonist/antagonist administration extend to the DA system. If this treatment approach does generalize across neurochemical systems, we expect to obtain similar results in this study to those obtained with nicotine and mecamylamine. We hypothesize that combined administration of bromocriptine and haloperiodol will attenuate the subjective and reinforcing effects of smoking to a significantly greater extent than either drug along, and will yield a better side effects profile.