DOPAMINERGIC MECHANISMS IN NICOTINE ADDICTION

有相当多的证据表明，尼古丁在 维持吸烟行为，但精确的神经化学物质 尼古丁发挥其奖励作用的机制仍然存在， 不清楚 更好地了解尼古丁的功能， 加强吸烟行为可能最终导致的发展 新的戒烟策略。 尼古丁产生多种 对中枢神经系统的药理作用，包括 中脑边缘脑区多巴胺（DA）水平的增强。 对实验室动物的研究以及来自 人类吸烟者认为，尼古丁的这些作用可能有助于 其强化效果。 拟议研究的目的是 进一步评估DA在人类吸烟中的作用。 我们 将评估两种多巴胺能药物单独和联合给药的效果。 结合，对急性主观和行为反应吸烟， 以及随意吸烟的比率。 测量吸烟率 和主观反应将使我们能够确定 吸烟满意度调节的后果，并确定 吸烟和吸烟率的急性奖励效应是否 受到DA系统的不同影响。 受试者将同时吸烟 含尼古丁和脱尼古丁香烟。 脱尼古丁 香烟将作为感官方面的控制条件， smoking. 采用受试者内安慰剂对照设计，研究1 将检查DA激动剂溴隐亭对急性 对吸烟和对香烟的主观和行为反应 在夜间戒烟的吸烟者中的消耗量。 在研究2中，我们 将评估多巴胺拮抗剂氟哌啶醇对吸烟的影响， 率和急性反应。 最后，在研究3中， 将探索溴隐亭和氟哌啶醇的给药。 以前的研究表明，联合施用 尼古丁和尼古丁拮抗剂美加明减少吸烟 对香烟的反应也大大减弱 比单独使用任何一种治疗都要少，副作用也更少。 我们 将探讨在多大程度上， 激动剂/拮抗剂给药扩展到DA系统。 如果这 治疗方法确实可以推广到神经化学系统，我们 期望在本研究中获得与使用 尼古丁和美加明。 我们假设 溴隐亭和氟哌啶的给药将减弱 吸烟的主观和强化作用，以显着更大 比任何一种药物沿着的程度，并会产生更好的副作用 profile.

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.