Noradrenergic Agents As Potential New Pharmacotherapies for Alcohol Drinking

描述（由申请人提供）：我们最近的研究表明，prazosin是一种安全、特性明确、耐受性良好、口服有效、价格低廉、经fda批准的11-肾上腺素受体拮抗剂，可能为酒精滥用和酒精复发的药物治疗提供急需的突破。然而，仍有许多工作要做，以确定使用普拉唑嗪的最有效方法，并确定普拉唑嗪如何减少饮酒。因此，拟议工作的目的之一是进行转化研究，以确定吡唑嗪最有效的条件。这些结果需要指导临床研究的优化设计和临床设置的治疗策略。另一个目的是确定哌唑嗪是如何减少饮酒的。总之，这些转化和机制研究将为有效和高效地实施prazosin作为一种新的酒精中毒药物疗法提供必要的信息，并将为指导其他相关药物治疗药物的发现和开发提供见解。我们的总体假设是，prazosin和相关的降低大脑去甲肾上腺素能信号的药物将减少持续饮酒和戒酒后的饮酒，并可能作为治疗酒精中毒和酒精复发的新药物疗法。我们的初步研究表明，吡唑嗪：a)抑制酒精依赖大鼠急性戒断期间增加的酒精自我给药；b)通过选择性繁殖的酒精偏好(P)大鼠减少自愿饮酒；c)阻断剥夺诱导的P大鼠饮酒增加；d)减少酒精依赖男性的酒精复发。利用具有良好特征的高自愿饮酒啮齿动物模型（P大鼠），转化研究（具体目标1）将确定影响最有效使用普拉唑嗪的因素，包括最佳剂量参数、普拉唑嗪单独使用或与纳曲酮联合使用、酒精成瘾/复发过程中对普拉唑嗪治疗敏感的阶段（戒酒后获得、维持和重新获得饮酒）。以及预测对哌唑嗪治疗反应的人群特征（焦虑、惊吓反应和应激史方面的性别和个体差异）。机制研究（具体目标2）将通过评估prazosin是否改变酒精清除或积极或消极地增强酒精的特性，以及propranolol是否也能减少大脑去甲肾上腺素能信号-但通过不同的机制-也减少饮酒，来确定prazosin是如何减少饮酒的。目前，关于哌唑嗪和其他去甲肾上腺素能药物对酒精滥用和酒精中毒的影响的临床工作尚处于起步阶段。拟议研究的结果将是及时和有价值的，以确保在治疗美国最普遍的成瘾疾病之一方面取得更大的成功。这项提议的工作也实现了NIH路线图的一个关键目标，即增加转化性的“从实验室到床边”的研究。

DESCRIPTION (provided by applicant): Our recent studies suggest that prazosin - a safe, well-characterized, well-tolerated, orally active, inexpensive, FDA-approved 11-adrenergic receptor antagonist - may provide a much-needed breakthrough in the pharmacotherapeutic treatment of alcohol abuse and alcohol relapse. However, much work remains to be done to determine the most effective way to use prazosin and to determine how prazosin works to decrease alcohol drinking. Accordingly, one aim of the proposed work is to conduct translational studies to identify the conditions under which prazosin is most effective. These results are needed to guide the optimal design of clinical studies and treatment strategies in clinical settings. Another aim is to determine how prazosin works to decrease alcohol drinking. Together, these translational and mechanistic studies will provide needed information for the effective and efficient implementation of prazosin as a new pharmacotherapy for alcoholism and will provide insights that can guide the discovery and development of additional related pharmacotherapeutic agents. Our overall hypothesis has been that prazosin, and related agents that decrease brain noradrenergic signaling, will decrease ongoing alcohol drinking and drinking following alcohol abstinence, and may serve as new pharmacotherapies for the treatment of alcoholism and alcohol relapse. Our preliminary studies have demonstrated that prazosin: a) suppresses increased alcohol self- administration during acute withdrawal in alcohol-dependent rats; b) reduces voluntary alcohol drinking by selectively bred alcohol-preferring (P) rats; c) blocks deprivation-induced increases in alcohol drinking in P rats; and d) decreases relapse alcohol drinking in alcohol-dependent men. Using a well-characterized rodent model of high voluntary alcohol drinking (P rats), translational studies (Specific Aim 1) will identify factors influencing the most effective use of prazosin, including optimal dosing parameters, use of prazosin alone or in combination with naltrexone, phases of the alcohol addiction/relapse process that are sensitive to prazosin treatment (acquisition, maintenance, and re-access of drinking following alcohol abstinence), and population characteristics that predict responsiveness to prazosin treatment (gender and individual differences in anxiety, startle reactivity and stress history). Mechanistic studies (Specific Aim 2) will determine how prazosin works to decrease alcohol drinking by assessing whether prazosin alters alcohol clearance or the positively or negatively reinforcing properties of alcohol, and whether propranolol, which also decreases brain noradrenergic signaling - but by a different mechanism - also decreases alcohol drinking. Currently, clinical work on the effect of prazosin and other noradrenergic agents on alcohol abuse and alcoholism is in its infancy. The results of the proposed studies will be both timely and valuable in ensuring increased success in treating one of the most widespread of all addictive diseases in the United States. The proposed work also fulfills a key goal of the NIH roadmap, which is to increase translational, "bench-to-bedside" research.