Noradrenergic Agents As Potential New Pharmacotherapies for Alcohol Drinking

去甲肾上腺素能药物作为潜在的饮酒新药物疗法

• 批准号: 7917969
• 负责人: janice C Froehlich
• 金额: $ 35.25万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917969
• 关键词: Acute; Adrenergic Antagonists; Adrenergic Receptor; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Anxiety; Brain; Breeding; Clinical; Clinical Research; Development; Disease; Dose; Ensure; FDA approved; Gender; Goals; Individual; Individual Differences; Ligands; Maintenance; Naltrexone; Pharmaceutical Preparations; Pharmacotherapy; Phase; Population Characteristics; Prazosin; Process; Property; Propranolol; Rattus; Recording of previous events; Relapse; Research; Rodent Model; Self Administration; Signal Transduction; Stress; United States; United States National Institutes of Health; Withdrawal; Work; absorption; addiction; alcohol abstinence; alcohol abuse pharmacotherapy; alcohol abuse therapy; alcohol relapse; alcoholism pharmacotherapy; alcoholism therapy; base; bench to bedside; dependence relapse; deprivation; design; drinking; infancy; insight; men; noradrenergic; public health relevance; success; translational study; treatment strategy

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.

描述（由申请人提供）：我们最近的研究表明，哌唑嗪-一种安全、特征良好、耐受性良好、口服活性、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，以确定最有效的方式使用哌唑嗪，并确定如何哌唑嗪工程，以减少饮酒。因此，拟议工作的一个目的是进行转化研究，以确定哌唑嗪最有效的条件。需要这些结果来指导临床研究的最佳设计和临床环境中的治疗策略。另一个目的是确定哌唑嗪如何减少饮酒。总之，这些翻译和机制的研究将提供必要的信息，有效和高效的实施哌唑嗪作为一种新的药物治疗酒精中毒，并将提供见解，可以指导发现和开发其他相关的药物。我们的总体假设是，哌唑嗪和相关药物，减少大脑去甲肾上腺素能信号，将减少持续饮酒和饮酒后戒酒，并可能作为新的药物治疗酒精中毒和酒精复发。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）减少选择性饲养的酒精偏好（P）大鼠的自愿饮酒; c）阻断P大鼠中剥夺诱导的饮酒增加; d）减少酒精依赖男性的复发性饮酒。使用高度自愿饮酒（P大鼠）的良好表征的啮齿动物模型，（具体目标1）将确定影响哌唑嗪最有效使用的因素，包括最佳给药参数、哌唑嗪单独使用或与纳洛酮联合使用、对哌唑嗪治疗敏感的酒精成瘾/复发过程阶段（戒酒后获得、维持和重新获得饮酒）和预测哌唑嗪治疗反应性的人群特征（焦虑、惊吓反应和应激史的性别和个体差异）。机制研究（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或负增强特性，以及普萘洛尔（也降低大脑去甲肾上腺素能信号传导，但通过不同的机制）是否也降低饮酒，来确定哌唑嗪如何减少饮酒。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影响的临床研究尚处于起步阶段。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广泛的所有成瘾性疾病之一方面取得更大的成功。拟议的工作也实现了NIH路线图的一个关键目标，即增加转化，“从实验室到床边”的研究。 公共卫生相关性：我们的目标是开发有效的药物治疗酒精滥用，依赖和复发。使用一个良好表征的饮酒增加的动物模型，我们将确定用一种安全且耐受性良好的药物治疗酒精滥用的最有效方法，这种药物已经广泛用于其他疾病的临床应用，我们的初步研究表明，至少在一些人中，这种药物对治疗饮酒和复发有效。这些研究还将为成功治疗酒精滥用的其他相关药物和范例的开发提供基础。