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: 8036093
• 负责人: janice C Froehlich
• 金额: $ 33.16万
• 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/8036093
• 关键词: Acute; Adrenergic Antagonists; Adrenergic Receptor; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Anxiety; Brain; Breeding; Clinical; Clinical Research; Clinical Treatment; Development; Disease; Dose; Ensure; FDA approved; 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; Sex Characteristics; Signal Transduction; Stress; United States; United States National Institutes of Health; Withdrawal; Work; absorption; 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、特性良好、耐受性好、口服活性好、价格低廉、FDA批准的11-肾上腺素能受体拮抗剂--可能在酒精滥用和酒精复发的药物治疗方面提供亟需的突破。然而，仍有许多工作要做，以确定使用哌唑嗪的最有效方法，并确定哌唑嗪如何减少饮酒。因此，拟议工作的一个目标是进行转化性研究，以确定在什么条件下哌唑嗪最有效。这些结果需要指导临床研究的最佳设计和临床环境中的治疗策略。另一个目标是确定哌唑嗪是如何减少饮酒的。总之，这些翻译和机制研究将为有效和高效地实施哌唑嗪作为一种治疗酒精中毒的新药物疗法提供必要的信息，并将提供指导其他相关药物治疗药物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信号的相关药物将减少持续饮酒和戒酒后的饮酒，并可能成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)抑制酒精依赖大鼠在急性戒断期间增加的酒精自我给药；b)通过选择性培育偏爱酒精的(P)大鼠减少自愿饮酒；c)阻止P大鼠因剥夺而导致的饮酒增加；以及d)减少酒精依赖男性再次饮酒。利用特征明确的高自愿饮酒啮齿动物模型(P鼠)，转化性研究(具体目标1)将确定影响哌唑嗪最有效使用的因素，包括最佳给药参数，单独或与纳曲酮联合使用哌唑嗪，对哌唑嗪治疗敏感的酒精成瘾/复发过程的各个阶段(获得、维持和戒酒后重新开始饮酒)，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人差异)。机制研究(特定目标2)将通过评估哌唑嗪是否改变酒精清除或酒精的正面或负面增强特性来确定哌唑嗪如何作用于减少饮酒，以及普奈洛尔是否也减少了大脑去甲肾上腺素能信号-但机制不同-是否也减少了饮酒。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的影响的临床工作还处于初级阶段。拟议的研究结果将是及时和有价值的，有助于确保在治疗这种在美国最普遍的成瘾性疾病方面取得更大的成功。这项拟议的工作还实现了美国国立卫生研究院路线图的一个关键目标，即增加翻译性的“从床到床”的研究。 公共卫生相关性：我们的目标是开发有效的药物疗法来治疗酗酒、依赖和复发。利用一个典型的饮酒增加的动物模型，我们将通过一种安全和耐受性良好的药物来确定治疗酒精滥用的最有效方法，这种药物已经被广泛用于其他疾病的临床，我们的初步研究表明，这种药物将有效地治疗饮酒和至少部分人的复发。这些研究还将为开发其他相关药物和成功治疗酗酒的范例提供基础。