DOPAMINERGIC AGENTS ON ACUTE RESPONSES TO SMOKING

目的：本研究的目的是探讨单胺氧化酶-B抑制剂司来吉兰对戒烟尝试的影响。我们假设接受司来吉兰治疗的受试者戒烟率高于接受安慰剂治疗的受试者。最后，我们将确定在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况。来自少数受试者的初步数据表明，氟哌啶醇和安非他明联合预处理比单独使用任何一种药物更大程度地降低吸烟满意度，是一种安全且可耐受的治疗组合。方法：在最初的研究设计中，年龄在18-55岁之间的经常吸烟者参加了一项两阶段研究。在第一阶段，受试者参加了四个实验室会议，进行GCRC，在此期间，急性吸烟反应进行评估后，四个预处理之一：安非他明（15毫克），氟哌啶醇（2毫克），安非他明加氟哌啶醇，或安慰剂。定期评估对吸食含尼古丁和脱尼古丁香烟的主观、行为和生理反应。在第二阶段，受试者参加了临床戒烟试验。所有受试者在戒烟日期前两周开始接受6周司来吉兰（5 mg po）或安慰剂治疗。给药为双盲。从戒烟日期开始，受试者开始接受开放标签活性尼古丁贴片（21 mg/24 hr）和胶囊。受试者参加每周一次的访视，在此期间评估吸烟戒断症状、生命体征和吸烟状态。结果如下：参加实验室检查的9例受试者的数据表明，与单独治疗或安慰剂单独治疗相比，安非他明和氟哌啶醇联合治疗可减弱对尼古丁的阳性主观反应。这些发现表明，联合激动剂/拮抗剂治疗可能比单独使用任何一种更有益。结果还表明，这种联合预处理可能比单独的激动剂或单独的拮抗剂治疗更耐受。尚未分析临床试验数据，因为研究正在进行中，代码尚未破盲。戒烟前参加实验室会议的要求大大减少了我们的招募。因此，实验室（GCRC）部分已被删除。然而，临床试验正在进行中。重要性：近5000万美国人吸烟，尽管吸烟与大量的发病率和死亡率有关，包括冠心病、中风、慢性阻塞性肺病、外周血管疾病、消化性溃疡、肺癌和死亡。不幸的是，吸烟者试图减少吸烟的尝试经常是不成功的，即使在目前可用的药物治疗的帮助下。开发更成功的戒烟治疗方法在很大程度上依赖于更好地了解尼古丁成瘾的神经化学机制，以及增加对导致吸烟行为的非尼古丁因素的了解。这项研究将有助于阐明多巴胺在吸烟的急性主观、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：本方案的GCRC（实验室）部分已停止。司来吉兰的临床试验正在进行中。如果结果有希望，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.