When one plus one equals more than two.

当一加一大于二时。

• 批准号: 8851458
• 负责人: janice C Froehlich
• 金额: $ 30.26万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-10 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851458
• 关键词: Acute; Address; Adverse effects; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic beverage heavy drinker; Alcoholism; Alcohols; Animal Model; Brain; Breeding; Clinical Research; Clinical Treatment; Communities; Consumption; Data; Development; Disease; Disulfiram; Drug Delivery Systems; Drug usage; Effectiveness; FDA approved; Goals; Health; Heavy Drinking; Human; Individual; Laboratories; Lead; Mediating; Methods; Naltrexone; National Institute on Alcohol Abuse and Alcoholism; Opioid; Opioid Receptor; Oral; Pharmaceutical Preparations; Play; Property; Rattus; Records; Relapse; Research; Research Design; Rewards; Rodent; Role; Stress; System; Testing; Time; Translations; United States National Institutes of Health; Work; acamprosate; alcohol abuse therapy; alcohol relapse; base; bench to bedside; compliance behavior; dependence relapse; deprivation; drinking; drug efficacy; effective therapy; innovation; pre-clinical; preference; problem drinker; receptor; smoking cessation; varenicline

DESCRIPTION (provided by applicant): Alcoholism is the most prevalent and widespread of all addictive diseases and development of effective treatments is a world-wide priority. Only three drugs have been approved by the FDA for the treatment of alcohol dependence: disulfiram (antibuse), acamprosate, and naltrexone (Trexan or Revia) and, of these, naltrexone (NTX) is the most effective. Yet NTX is under- utilized in clinical treatment settings because the efficacy of NTX is modest, it is not effective for all alcoholics and, when it is effective, a significant number of alcoholics fail to maintain initial treatment gains and subsequently relapse to heavy drinking. There is a pressing need for additional medications to treat alcohol abuse, dependence and relapse. The long-term objective of this proposal is to increase the number of drugs available to treat alcohol abuse and alcoholism. Both the opioid and acetylcholinergic systems in the brain play important roles in mediating alcohol drinking. Our preliminary studies indicate that acute oral treatment with either naltrexone (NTX), a nonspecific opioid receptor antagonist, or varenicline (V), an ¿4¿2 nicotinic acetylcholinergic receptor partial agonist, decreases alcohol intake in alcohol-preferring (P) rats that have been selectively bred for high voluntary alcohol drinking. The question now is whether these two drugs are effective over the course of prolonged treatment, and whether combining these two drugs into a single oral medication enhances the effectiveness, or prolongs the duration of action, of the combination when compared with either drug alone. The research design uses a voluntary oral drug consumption method that we developed which allows us to assess the efficacy of drugs over long periods of time. Our hypothesis is that NTX and V will act either additively or synergisticall to more effectively reduce alcohol drinking than can either drug alone. The specific aims of this proposal are to determine whether a combination of NTX + V is more effective than is either drug alone: 1) in decreasing ongoing alcohol drinking in rats selectively bred for alcohol preference and high alcohol intake (P rats), 2) in blocking the initiation/acquisition of alcohol drinking in P rats and 3) in blocking the increase in alcohol drinking that occurs following reaccess to alcohol following alcohol deprivation (alcohol deprivation effect of ADE, an animal model of alcohol relapse) in P rats. Mechanistic studies will determine whether NTX + V alters the rewarding/reinforcing properties of alcohol and/or alcohol clearance [[or drinking-induced BACs]]. The significance of the proposed work is that the results may lead to a new pharmacotherapeutic approach to the treatment of alcohol abuse, alcohol dependence and relapse; an approach that may be particularly valuable for treating alcoholics who do not respond to treatment with the medications currently available.

描述（由适用提供）：酒精中毒是所有添加剂疾病中最普遍和宽度的，有效治疗的发展是全球优先事项。 FDA仅批准了三种药物来治疗酒精依赖性：二硫酸酯（抗胰岛素），丙型苯甲酸酯和纳曲酮（Trexan或revia），其中纳曲酮（NTX）是最有效的。然而，NTX在临床治疗环境中的利用不足，因为NTX的有效性是适度的，对所有酒精饮料都不是有效的，并且当有效时，大量酒精中毒无法保持初始治疗的增长，随后将其用于大量饮酒。迫切需要其他药物治疗酒精滥用，依赖和缓解。该提议的长期目标是增加可用于治疗酒精中毒和酒精中毒的药物数量。大脑中的阿片类药物和乙酰胆碱能系统在介导饮酒中起着重要作用。我们的初步研究表明，用纳曲酮（NTX）（一种非特异性的阿片受体拮抗剂）或varenicline（V），一种€4€4€4？2烟碱乙基胆碱能受体部分激动剂，可降低酒精（P）饮酒中酒精的酒精摄入量，以降低酒精的饮酒，以降低酒精的饮料，因此饮酒量是选择性地饮用的，因此，饮酒量是选择性地饮酒，因此饮酒量降低了高度的饮料。现在的问题是，这两种药物在延长治疗过程中是否有效，以及将这两种药物合并为单一的口服药物是否可以提高组合的有效性，或者与单独使用任何一种药物相比，延长了组合的作用持续时间。研究设计采用了一种自愿性的口服药物消费方法，我们可以评估长期内药物的有效性。我们的假设是，NTX和V将额外或协同作用以比单独药物更有效地减少饮酒。该提议的具体目的是确定NTX + V的组合是否比单独药物更有效：1）减少持续的饮酒，在大鼠中有选择地育种饮酒和高酒精摄入量（P RATS），在阻止饮酒的饮酒和3次酒精饮酒的饮酒中，饮酒的饮酒量会增加酒精的饮酒，以阻止酒精饮酒的起点/饮酒，以免饮酒，而不是饮酒。饮酒的动物模型）在P大鼠中。机械研究将确定NTX + V是否改变了酒精和/或酒精清除率的奖励/增强特性[[或饮酒诱导的BAC]]。拟议工作的意义在于，结果可能会导致一种新的药物治疗方法来治疗酒精滥用，酗酒和继电器；一种方法对于治疗对当前可用药物治疗的酗酒者来说可能特别有价值。