DOPAMINERGIC MECHANISMS IN NICOTINE ADDICTION

有相当多的证据表明尼古丁在吸烟中起主要作用。 吸烟行为的维持，但精确的神经化学 尼古丁发挥其有益作用的机制仍然存在 不清楚。更好地了解尼古丁如何作用于 加强吸烟行为可能最终导致 新的戒烟策略。尼古丁会产生多种不同的 中枢神经系统的药理作用，包括 中边缘脑区多巴胺(DA)水平升高。 对实验动物的研究以及来自 人类吸烟者认为尼古丁的这些影响可能有助于 它的强化作用。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的效果，单独和在 结合吸烟的急性主观和行为反应， 以及临时吸烟率。测量两个吸烟率 主观反应将使我们能够确定行为 调节吸烟满意度的后果并确定 吸烟和吸烟率的严重回报效应是否 受DA系统的不同影响。受试者会同时吸烟 含尼古丁和不含尼古丁的香烟。去尼古丁的人 香烟将作为感官方面的控制条件 抽烟。使用受试者内的安慰剂对照设计，研究1 将研究DA激动剂溴隐亭对急性 对吸烟和吸烟的主观和行为反应 一夜戒烟的吸烟者的消费情况。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 比率和敏感度。最后，在研究3中，联合使用 将探索溴隐亭和氟哌啶醇的给药方法。 先前的研究表明，联合应用 尼古丁和尼古丁拮抗剂甲乙胺减少吸烟 并在更大程度上减弱对香烟的反应 比任何一种单独治疗都要好，而且副作用更少。我们 将探索在多大程度上综合 激动剂/拮抗剂给药延伸到DA系统。如果这个 治疗方法确实适用于神经化学系统，我们 期望在这项研究中获得与 尼古丁和甲基乙胺。我们假设两者结合在一起 溴隐亭和氟哌啶醇的应用将减弱 吸烟对主观和强化的影响明显更大 幅度比任何一种药物都要大，而且会产生更好的副作用 侧写。

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.