Does doxazosin attenuate stress-induced smoking and improve clinical outcomes?

描述（由申请人提供）：压力是维持吸烟和复吸的主要因素，将压力相关复吸作为药物开发策略是一个关键但相对未探索的研究领域。临床前研究结果表明，去甲肾上腺素能通路参与应激诱导的复发，它们的操纵可能具有治疗益处。使用我们验证的人类实验室模型来检查压力诱发的吸烟行为，我们已经证明了胍法辛，其通过刺激α-2肾上腺素能受体降低去甲肾上腺素能紧张，与安慰剂相比增加了抵抗吸烟的能力，并且减少了压力后的烟草渴望和即兴吸烟。这表明去甲肾上腺素能系统在应激诱导的烟草复吸中的作用。胍法辛也减少了吸烟在随后的短暂治疗期间。基于去甲肾上腺素对其受体的回路水平效应，我们假设α-1肾上腺素能受体拮抗剂应具有与α-2受体激动剂相似的效应。为了阐明肾上腺素能受体介导的去甲肾上腺素的作用的类型，我们收集了初步的数据，在实验室的压力反应与选择性α-1肾上腺素能受体拮抗剂，哌唑嗪，支持α-1肾上腺素能受体在压力诱导的烟草复吸的作用。然而，哌唑嗪是短效的，必须每天给药三次，降低了药物依从性的可能性，并限制了其潜在的有效性。多沙唑嗪（Cardura（R），辉瑞公司，销售用于高血压和良性前列腺增生）是一种α-1药物类似于哌唑嗪，但具有更长的半衰期（22小时），提高了这种药物的可能依从性和有效性。 因此，该探索性/开发性R21应用的主要目的是进行初始的II期双盲、受试者间、安慰剂对照的初步研究，以评估α-1肾上腺素能拮抗剂多沙嗪（0 mg/天、4 mg/天、8 mg/天）是否在实验室中抵消压力诱导的对吸烟行为的影响（即，增加抵抗吸烟的能力，减少随意吸烟）并在随后的短暂治疗阶段改善临床结果（即，减少吸烟行为）。我们还将研究潜在的机制，压力促使吸烟的失败（例如，渴望、情绪、心血管反应性、HPA轴反应性、儿茶酚胺）并探索假设为吸烟行为的去甲肾上腺素能效应的基础的另外的机制（例如，减少戒断症状和吸烟相关的强化）。据我们所知，这将是第一次调查研究的治疗潜力和相关机制的选择性α-1肾上腺素能拮抗剂，多沙唑嗪治疗烟草依赖。积极的发现将验证我们的假设的作用，去甲肾上腺素受体亚型的应激反应，并将提供必要的关键信息，扩大这项调查的临床试验。

DESCRIPTION (provided by applicant): Stress is a primary contributor to the maintenance of, and relapse to smoking, and targeting stress-related relapse as a medication development strategy is a critical yet relatively unexplored area of research. Preclinical findings suggest tha noradrenergic pathways are involved in stress-induced relapse and that their manipulation may be of therapeutic benefit. Using our validated human laboratory model to examine stress- precipitated smoking lapse behavior, we have demonstrated that guanfacine, which reduces the noradrenergic tone by stimulating the alpha-2 adrenergic receptors, increased the ability to resist smoking compared to placebo, and decreased tobacco craving and ad-lib smoking following stress. This suggests a role for the noradrenergic system in stress-induced tobacco relapse. Guanfacine also reduced smoking during a subsequent brief treatment period. Based on the circuit level effects of norepinephrine on its receptors, we hypothesize that an alpha-1 adrenergic receptor antagonist should have similar effects to the alpha-2 receptor agonist. To elucidate the type of adrenergic receptors mediating the effects of norepinephrine, we collected preliminary data on stress reactivity in the laboratory with a selective alpha-1 adrenergic receptor antagonist, prazosin, supporting a role for alpha-1 adrenergic receptors in stress-induced tobacco relapse. However, prazosin is short-acting and must be administered three times daily, reducing the likelihood of medication compliance and limiting its potential effectiveness. Doxazosin (Cardura(R), Pfizer, marketed for hypertension and benign prostatic hyperplasia) is an alpha-1 agent similar to prazosin, but has a longer half-life (22hrs) improving the likely compliance with and effectiveness of this medication. Thus, the primary aim of this Explorarory/Developmental R21 application is to conduct an initial Phase II double-blind, between-subject, placebo-controlled pilot study to evaluate whether an alpha-1 adrenergic antagonist, doxasozin (0mg/day, 4mg/day, 8mg/day) counteracts stress-induced effects on smoking behavior in the laboratory (i.e., increases the ability to resist smoking, reduces ad-lib smoking) and improves clinical outcomes during a subsequent brief treatment phase (i.e., reductions in smoking behavior). We will also examine potential mechanisms underlying stress-precipitated smoking lapse (e.g., craving, mood, cardiovascular reactivity, HPA axis reactivity, catecholamines) and explore additional mechanisms hypothesized to underlie noradrenergic effects on smoking behavior (e.g., reductions in withdrawal symptoms and smoking-related reinforcement). To our knowledge, this will be the first investigation examining the therapeutic potential and associated mechanisms of a selective alpha-1 adrenergic antagonist, doxazosin for the treatment of tobacco dependence. Positive findings will validate our hypothesis on the role of norephinephrine receptor subtypes in stress reactivity, and will provide key information necessary to expand this investigation to a clinical trial.