DOPAMINERGIC AGENTS ON ACUTE RESPONSES TO SMOKING

目的：本研究的目的是探讨MAO-B抑制剂司来吉兰对戒烟尝试的影响。我们假设，与服用安慰剂的受试者相比，服用司来吉兰的受试者将表现出更高的戒烟率。最后，我们将确定实验室中对多巴胺能药物的急性反应是否可以预测临床环境中的吸烟状态。来自少数受试者的初步数据表明，与单独使用任何一种药物相比，联合使用氟哌啶醇和苯丙胺可以更大程度地降低吸烟满意度，是一种安全和可耐受的联合治疗方法。方法：在最初的研究设计中，18-55岁的经常吸烟者参与了一项两阶段的研究。在第一阶段，受试者参加了在GCRC上进行的四个实验室会议，在此期间，评估了四种预处理之一后对吸烟的急性反应：苯丙胺(15毫克)、氟哌啶醇(2毫克)、苯丙胺加氟哌啶醇或安慰剂。定期评估吸烟含尼古丁香烟和去尼古丁香烟的主观、行为和生理反应。在第二阶段，受试者参与了一项临床戒烟试验。所有受试者在戒烟前两周开始接受司来吉兰(5 Mg Po)或安慰剂6周的治疗。药品监管是双盲的。从戒烟之日开始，受试者开始在胶囊之外接受开放标签的活性尼古丁贴片(21毫克/24小时)。受试者参加每周一次的访问，在此期间评估吸烟戒断症状、生命体征和吸烟状况。结果：来自9名参加实验室会议的受试者的数据表明，苯丙胺和氟哌啶醇联合使用比单独治疗或单独服用安慰剂更能减弱对尼古丁的积极主观反应。这些发现表明，激动剂/拮抗剂联合治疗可能比单独使用其中任何一种更有益。结果还表明，这种联合的预处理可能比单独的激动剂或拮抗剂单独治疗更耐受。临床试验的数据还没有被分析，因为研究正在进行，密码还没有被破译。戒烟前参加实验室会议的要求大大减少了我们的招聘人数。因此，实验室(GCRC)部分已被删除。然而，临床试验仍在进行中。意义：近5000万美国人吸烟，尽管吸烟会导致大量的发病率和死亡率，包括冠心病、中风、慢性阻塞性肺疾病、周围血管疾病、消化性溃疡、肺癌和死亡。不幸的是，吸烟者试图减少吸烟经常是不成功的，即使在现有的药物治疗的帮助下。开发更成功的戒烟疗法在很大程度上取决于对尼古丁成瘾背后的神经化学机制的更好了解，以及对导致吸烟行为的非尼古丁因素的更多了解。本研究将有助于阐明多巴胺在吸烟引起的急性主观、行为和生理反应中的作用，并评估多巴胺能治疗戒烟的疗效。未来计划：该议定书的GCRC(实验室)部分已停止。司来吉兰的临床试验正在进行中。如果结果是有希望的，将进行更大规模的研究。

Purpose: The goal of this study is to to explore the effects of the MAO-B inhibitor, selegiline, on smoking cessation attempts. 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. Methods: In the original study design, regular smokers ages 18-55 participated in a two phase study. In the first phase, subjects attended four laboratory sessions, conducted on the GCRC, during which acute responses to smoking were assessed after one of four pretreatments: amphetamine (15 mg), haloperidol (2 mg), amphetamine plus haloperidol, or placebo. Subjective, behavioral and physiological responses to smoking nicotine-containing and denicotinized cigarettes were assessed at regular intervals. In a second phase, subjects participated in a clinical smoking cessation trial. All subjects received 6 weeks of treatment with selegiline (5 mg po) or placebo, beginning two weeks prior to their quit date. Drug administration is double-blind. Beginning on their quit smoking date, subjects begin receiving open-label active nicotine patch (21 mg/24 hr) in addition to the capsule. Subjects attended weekly visits during which smoking withdrawal symptoms, vital signs and smoking status were assessed. Results: Data from 9 subjects who participated in the laboratory sessions indicate that the combination of amphetamine and haloperidol attenuates positive subjective response to nicotine than either treatment alone or than placebo alone. These findings suggest that combined agonist/antagonist treatment may be more beneficial than either one alone. Results also suggest that this combined pretreatment may be more tolerable than either agonist alone or antagonist alone treatments. Data from the clinical trial have not been analyzed yet, since the study is ongoing and the code has not been broken. The requirement of participating in the laboratory session prior to quitting smoking significantly reduced our recruitment. Thus, the laboratory (GCRC) portion has been dropped. However, the clinical trial is ongoing. 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 dopamine in acute subjective, behavioral and physiological responses to cigarette smoking, and to assess the efficacy of a dopaminergic treatment for smoking cessation. Future Plans: The GCRC (laboratory) portion of this protocol was discontinued. The clinical trial with selegiline is ongoing. If the results are promising, a larger scale study will be conducted.