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

描述（由申请人提供）：压力是吸烟维持和复发的主要因素，将压力相关的复发作为药物开发策略是一个关键但相对未开发的研究领域。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，其操作可能具有治疗益处。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，通过刺激α -2肾上腺素能受体来降低去甲肾上腺素能张力的胍法辛，与安慰剂相比，增加了抵抗吸烟的能力，减少了烟草渴望和压力后的临时吸烟。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。在随后的短暂治疗期间，胍法辛也减少了吸烟。基于去甲肾上腺素对其受体的回路水平作用，我们假设α -1肾上腺素能受体拮抗剂应该具有与α -2受体激动剂相似的作用。为了阐明肾上腺素能受体介导去甲肾上腺素作用的类型，我们在实验室中收集了选择性α -1肾上腺素受体拮抗剂普拉唑嗪的应激反应性的初步数据，支持α -1肾上腺素受体在应激诱导的烟草复吸中的作用。然而，吡唑嗪是短效的，必须每天给药三次，降低了服药依从性的可能性，限制了其潜在的有效性。Doxazosin （Cardura(R)，辉瑞公司，用于高血压和良性前列腺增生）是一种类似于prazosin的α -1药物，但具有较长的半衰期（22小时），提高了该药的可能依从性和有效性。因此，本探索性/发展性R21申请的主要目的是开展一项初始的II期双盲、受试者之间、安慰剂对照的试点研究，以评估α -1肾上腺素能拮抗剂多沙唑嗪（0mg/天、4mg/天、8mg/天）是否能在实验室中抵消应激诱导的吸烟行为影响（即增加抵抗吸烟的能力，减少吸烟），并在随后的短暂治疗阶段改善临床结果(即：减少吸烟行为)。我们还将研究压力导致的戒烟的潜在机制（例如，渴望、情绪、心血管反应性、HPA轴反应性、儿茶酚胺），并探索假设的去肾上腺素能对吸烟行为的影响的其他机制（例如，戒断症状的减少和吸烟相关强化）。据我们所知，这将是第一次研究选择性α -1肾上腺素能拮抗剂doxazosin治疗烟草依赖的治疗潜力和相关机制。阳性结果将验证我们关于去甲肾上腺素受体亚型在应激反应中的作用的假设，并将为将该研究扩展到临床试验提供必要的关键信息。

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.