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，哌唑嗪——一种安全、特性良好、耐受性良好、口服有效、廉价、FDA 批准的 11-肾上腺素能受体拮抗剂——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，以确定使用哌唑嗪的最有效方法以及确定哌唑嗪如何减少饮酒。因此，拟议工作的目的之一是进行转化研究，以确定哌唑嗪最有效的条件。这些结果需要指导临床研究和临床环境中治疗策略的优化设计。另一个目的是确定哌唑嗪如何减少饮酒。总之，这些转化和机制研究将为有效和高效地实施哌唑嗪作为酒精中毒的新药物疗法提供所需的信息，并将提供可指导其他相关药物治疗剂的发现和开发的见解。我们的总体假设是哌唑嗪和减少大脑去甲肾上腺素能信号传导的相关药物将减少持续饮酒和戒酒后饮酒，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，哌唑嗪： a) 抑制酒精依赖大鼠急性戒断期间酒精自我给药的增加； b) 通过选择性饲养嗜酒 (P) 大鼠来减少自愿饮酒； c) 阻止 P 大鼠因剥夺而导致的饮酒量增加； d) 减少酒精依赖男性的饮酒复发。使用特征明确的高自愿饮酒啮齿动物模型（P 大鼠），转化研究（具体目标 1）将确定影响哌唑嗪最有效使用的因素，包括最佳剂量参数、哌唑嗪单独使用或与纳曲酮联合使用、对哌唑嗪治疗敏感的酒精成瘾/复发过程的阶段（戒酒后饮酒的获得、维持和重新获得），以及预测反应性的群体特征哌唑嗪治疗（焦虑、惊吓反应和应激史方面的性别和个体差异）。机理研究（具体目标 2）将通过评估哌唑嗪是否改变酒精清除率或酒精的正增强或负增强特性，以及普萘洛尔（也可降低大脑去甲肾上腺素信号传导，但通过不同的机制）是否也能减少饮酒，来确定哌唑嗪如何减少饮酒。目前，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还处于起步阶段。拟议研究的结果对于确保美国最普遍的成瘾疾病之一的治疗取得更大成功来说既及时又有价值。拟议的工作还实现了 NIH 路线图的一个关键目标，即增加转化性的“实验室到临床”研究。 公共卫生相关性：我们的目标是开发针对酒精滥用、依赖和复发的有效药物疗法。通过使用良好表征的饮酒增加的动物模型，我们将确定使用安全且耐受性良好的药物治疗酒精滥用的最有效方法，该药物已在临床上广泛用于其他疾病，并且我们的初步研究表明，该药物将有效治疗至少某些个体的饮酒和复发。这些研究还将为开发其他相关药物和成功治疗酒精滥用的范例提供基础。

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. PUBLIC HEALTH RELEVANCE: Our goal is to develop effective pharmacotherapy for alcohol abuse, dependence and relapse. Using a well-characterized animal model of increased alcohol drinking, we will determine the most effective approaches to treating alcohol abuse with a safe and well-tolerated medication which is already in widespread clinical use for other conditions and which our preliminary studies demonstrate will be effective for treating alcohol drinking and relapse in at least some individuals. These studies will also provide the basis for development of additional related medications and paradigms for successfully treating alcohol abuse.