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

基本信息

批准号：
8610862
负责人：
janice C Froehlich
金额：
$ 32.07万
依托单位：
SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610862
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

项目摘要

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.

描述（由申请人提供）：我们最近的研究表明，一种安全，良好的，耐受性良好，口服，廉价，经FDA批准的11-肾上腺素受体拮抗剂 - 可能在药物滥用和酒精复发的药物治疗中急需的突破。但是，要确定使用帕索辛的最有效方法并确定prazosin如何工作以减少酒精饮用的最有效方法还有许多工作要做。因此，拟议的工作的一个目的是进行翻译研究，以确定prazosin最有效的条件。需要这些结果来指导临床环境中临床研究和治疗策略的最佳设计。另一个目的是确定prazosin如何工作以减少饮酒。这些翻译和机械研究将共同提供必要的信息，以有效，有效地实施帕索辛作为酒精中毒的新药物疗法，并将提供可以指导和开发其他相关药物治疗剂的见解。我们的总体假设是，帕索辛和降低大脑去甲肾上腺素能信号传导的相关药物将减少戒酒后正在进行的饮酒和饮酒，并且可以作为治疗酒精中毒和酒精复发的新药物治疗。我们的初步研究表明，prazosin：a）抑制酒精依赖大鼠急性戒断期间的酒精自我给药； b）通过有选择的育种饮酒（P）大鼠减少自愿饮酒； c）阻止剥夺引起的P大鼠饮酒的增加； D）减少依赖酒精依赖男性的复发饮酒。 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禁欲）和人口特征，这些特征可以预测对帕索辛治疗的反应能力（性别和焦虑，惊吓反应性和压力病史的个体差异）。机械研究（特定目标2）将通过评估丙唑嗪如何改变酒精清除率，积极或负面增强酒精的特性，以及降低脑脱甲肾上腺素能信号的普罗诺酚是如何减少酒精的清除，但通过不同的机制来减少饮酒。目前，临床工作尚处于起步阶段的肾上腺素和其他去甲肾上腺素对酒精滥用和酒精中毒的影响。拟议的研究的结果将既及时又有价值，可确保在美国最广泛的上瘾疾病中的最广泛疾病之一的成功中获得成功。拟议的工作还实现了NIH路线图的关键目标，即增加翻译为“基准对床”的研究。