When one plus one equals more than two.

当一加一大于二时。

• 批准号: 8698683
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698683
• 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; 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; public health relevance; 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（由申请人提供）：酗酒是所有成瘾疾病中最普遍和最广泛的，开发有效的治疗方法是世界范围内的首要任务。 FDA 仅批准三种药物用于治疗酒精依赖：双硫仑（抗酒栓）、阿坎酸和纳曲酮（Trexan 或 Revia），其中纳曲酮 (NTX) 是最有效的。然而，NTX 在临床治疗中并未得到充分利用，因为 NTX 的疗效有限，并非对所有酗酒者都有效，而且即使有效，大量酗酒者也无法维持最初的治疗效果，随后又重新酗酒。迫切需要额外的药物来治疗酒精滥用、酒精依赖和复发。该提案的长期目标是增加可用于治疗酒精滥用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调节饮酒方面发挥着重要作用。我们的初步研究表明，用纳曲酮（NTX）（一种非特异性阿片受体拮抗剂）或伐尼克兰（V）（一种¿4¿2烟碱乙酰胆碱能受体部分激动剂）进行急性口服治疗，可以减少选择性饲养的高自愿饮酒的嗜酒（P）大鼠的酒精摄入量。现在的问题是，这两种药物在长期治疗过程中是否有效，以及与单独使用任何一种药物相比，将这两种药物组合成单一口服药物是否会增强疗效或延长作用持续时间。该研究设计使用我们开发的自愿口服药物消耗方法，使我们能够评估药物的长期疗效。我们的假设是，NTX 和 V 会相加或协同作用，比单独使用任何一种药物更有效地减少饮酒。该提案的具体目的是确定 NTX + V 的组合是否比单独使用任何一种药物更有效：1) 减少选择性饲养的酒精偏好和高酒精摄入大鼠 (P 大鼠) 的持续饮酒，2) 阻止 P 大鼠开始/获得饮酒，3) 阻止酒精剥夺后重新获得酒精后出现的饮酒增加（ADE 的酒精剥夺效应，动物 P大鼠酒精复吸模型）。机制研究将确定 NTX + V 是否会改变酒精的奖励/强化特性和/或酒精清除[[或饮酒引起的 BAC]]。这项工作的意义在于，研究结果可能会带来一种新的药物治疗方法来治疗酒精滥用、酒精依赖和复发；这种方法对于治疗对现有药物治疗没有反应的酗酒者可能特别有价值。