Repurposing alpha1 noradrenergic antagonists for alcoholism treatment

描述(由申请人提供)：当前提案的第一个目标是通过使用复杂的实验室应激任务与α1受体阻滞剂哌唑嗪结合使用，来暗示去甲肾上腺素α1受体参与人类对应激事件的反应。第二个目标是确定FDA批准的降压药哌唑嗪是否有效地减少试图戒酒的戒酒者的应激反应。目前还没有针对酒精中毒的药物治疗选择是专门为防止压力引起的复发而设计的，而压力是实现长期康复的常见障碍。随着制药行业近年来大幅减少对开发治疗酒精中毒的新药的投资，确定现有具有已知神经生物学机制的药物，如哌唑嗪，可能是治疗成瘾的有效替代药物变得越来越重要。目前的研究旨在评估哌唑嗪对戒酒早期酗酒者应激反应的影响，并与健康志愿者进行比较。参与者将在两个实验室疗程中服用哌唑嗪或安慰剂药片，之后他们将完成一项压力任务。这项任务将包括三种情况，使参与者面临不可预测的电击、可预测的电击或不电击。眨眼惊吓反应将被测量为参与者对压力任务(即可预测和不可预测的电击)的反应的生理指标。以前的研究一直表明，减少压力反应的药物，如酒精和苯二氮卓类药物，特别是对不可预测的压力源，会减少惊吓反应。此外，药物依赖者的药物缺乏(如尼古丁、大麻或酒精)选择性地增加了在不可预测的应激源中的惊吓反应。这是一项有吸引力的实验室任务，因为非常类似的方法(如不可预测的休克)和措施(如惊吓)已在啮齿动物和非人类灵长类动物中广泛使用，因此该领域对这种应激系统涉及的神经生物学有丰富的理解。特别是，神经递质去甲肾上腺素与应激反应密切相关，而一种阻断去甲肾上腺素α1受体的药物哌唑嗪已被证明可以减少酒精中毒啮齿动物模型中因应激而导致的复发。这项研究将检验与健康志愿者相比，在戒酒早期的戒酒患者中，哌唑嗪是否能减少在不可预测的应激因素下的惊吓反应。这些发现表明，去甲肾上腺素α1受体参与了人类的应激反应，而哌唑嗪可能是寻求戒酒的酗酒者治疗应激诱导复发的有效方法。考虑到进行大规模临床试验以审查成瘾治疗方法所涉及的巨大成本，目前的提议代表了一种基于实验室的有效筛选程序，以评估新药物疗法的潜在疗效。这种类型的转化研究旨在扩大美国1800万酒精使用障碍患者的治疗选择。

DESCRIPTION (provided by applicant): The first objective of the current proposal is to implicate norepinephrine alpha1 receptor involvement in reactivity to stressful events in humans by using a sophisticated laboratory stress task in conjunction with an alpha1-blocker, Prazosin. The second objective is to determine whether Prazosin, an FDA-approved blood pressure medication, is effective at reducing stress-reactivity among abstinent alcoholics who are trying to quit drinking. No currently available pharmacotherapy treatment options for alcoholism are specifically designed to prevent relapse caused by stress, which is a common hurdle in the way of attaining long-term recovery. As the pharmaceutical industry has drastically reduced its investment in developing novel medications to treat alcoholism in recent years, it is becoming increasingly essential to identify currently available drugs with known neurobiological mechanisms, such as Prazosin, that may be effective treatment alternatives for addiction. The current study aims to evaluate the effects of Prazosin on stress-reactivity in alcoholics in early abstinence versus healthy volunteers. Participants will take either Prazosin or a placebo pill at two laboratory sessions, after which they will complete a stress task. The task will consist of three conditions exposing participants to unpredictable shock, predictable shock, or no shock. The eye blink startle response will be measured as a physiological index of the participants' reactivity to the stressful task (i.e., predictable and unpredictable shocks). Previous research has consistently demonstrated that drugs that reduce the stress response, such as alcohol and benzodiazepines, reduce the startle response specifically to unpredictable stressors. Furthermore, drug deprivation among drug dependent individuals (e.g., nicotine, marijuana or alcohol) selectively increases the startle response during unpredictable stressors. This is an attractive lab task as very similar methods (e.g. unpredictable shock) and measures (e.g., startle) have been used extensively in rodents and non-human primates, so the field has a rich understanding of the neurobiology involved in this stress system. In particular, the neurotransmitter norepinephrine has been critically implicated in the stress response, and Prazosin, a drug that blocks norepinephrine alpha1 receptors, has been shown to reduce stress-induced relapse in rodent models of alcoholism. This study will examine whether Prazosin reduces the startle response during unpredictable stressors in abstinent alcoholics in early recovery vs. healthy volunteers. These findings would suggest that norepinephrine alpha1 receptors are involved in stress-reactivity in humans and that Prazosin may be an effective treatment of stress-induced relapse for alcoholics pursuing abstinence. Given the tremendous cost associated with conducting large scale clinical trials to vet treatments for addiction, the current proposal represents an efficient laboratory-based screening procedure to evaluate the potential efficacy of novel pharmacotherapies. This type of translational research aims to expand treatment options for the eighteen million people in the United States who suffer from an alcohol use disorder.