When one plus one equals more than two.

描述(申请人提供)：酒精中毒是所有成瘾性疾病中最普遍和最普遍的，开发有效的治疗方法是世界范围内的优先事项。FDA只批准了三种药物用于治疗酒精依赖：双硫兰(抗酒依赖药)、氨基己酸酯和纳曲酮(特雷克生或瑞维亚)，其中纳曲酮(NTX)最有效。然而，NTX在临床治疗环境中没有得到充分利用，因为NTX的疗效不大，并不是对所有酗酒者都有效，而且当它有效时，相当数量的酗酒者未能保持最初的治疗成果，随后又重新酗酒。迫切需要更多的药物来治疗酗酒、依赖和复发。这项提议的长期目标是增加可用于治疗酗酒和酗酒的药物的数量。大脑中的阿片和乙酰胆碱能系统在调节饮酒方面都发挥着重要作用。我们的初步研究表明，无论是非特异性阿片受体拮抗剂纳曲酮(NTX)，还是烟碱型乙酰胆碱能受体部分激动剂varenicline(V)的急性口服治疗，都能减少选择性饲养用于高自愿饮酒的嗜酒(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，以及与单独使用其中一种药物相比，将这两种药物合并为一种口服药物是否会提高疗效或延长作用时间。这项研究设计使用了我们开发的一种自愿口服药物消耗方法，这种方法允许我们评估药物在较长时间内的疗效。我们的假设是，NTX和V将相加或协同作用，比单独使用任何一种药物都能更有效地减少饮酒。这项建议的具体目的是确定NTX V联合应用是否比单独使用任何一种药物更有效：1)减少为酒精偏好和高酒精摄入量而选择性培育的大鼠(P大鼠)的持续饮酒；2)阻止P大鼠开始/获得酒精饮酒；3)阻止P大鼠酒精剥夺后再次饮酒的增加(ADE的酒精剥夺效应，一种酒精复发的动物模型)。机制研究将确定NTX V是否改变了酒精的奖励/增强特性和/或酒精清除[[或饮酒诱导的BAC]]。这项拟议工作的意义在于，其结果可能导致一种治疗酗酒、酒精依赖和复发的新的药物治疗方法；这种方法可能对治疗用现有药物治疗无效的酗酒者特别有价值。

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.