When one plus one equals more than two.

描述（由申请人提供）：酗酒是所有成瘾性疾病中最普遍和最广泛的，开发有效的治疗方法是全世界的优先事项。只有三种药物被FDA批准用于治疗酒精依赖：双硫仑（抗药）、阿坎普罗酸和纳曲酮（曲尚或瑞维亚），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，因为它的疗效有限，并不是对所有的酗酒者都有效，而且，当它有效时，有相当数量的酗酒者未能保持最初的治疗效果，随后又重新酗酒。迫切需要额外的药物来治疗酒精滥用、依赖和复发。这项建议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。大脑中的阿片系统和乙酰胆碱能系统在调节饮酒中都起着重要作用。我们的初步研究表明，急性口服纳曲酮（NTX），一种非特异性阿片受体拮抗剂，或伐尼克兰(V)，一种烟碱乙酰胆碱能受体部分激动剂，减少酒精偏好(P)大鼠的酒精摄入量，这些大鼠已经被选择性地培养为高自愿饮酒。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，将这两种药物合并为一种口服药物是否会提高疗效或延长作用时间。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在长时间内的功效。我们的假设是，NTX和V可以加或协同作用，比单独使用任何一种药物更有效地减少饮酒。本提案的具体目的是确定NTX + V联合使用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量大鼠（P大鼠）持续饮酒，2)阻断P大鼠饮酒的开始/获得，3)阻断P大鼠在酒精剥夺后重新获得酒精后饮酒的增加（ADE的酒精剥夺效应，酒精复发的动物模型）。机制研究将确定NTX + V是否会改变酒精和/或酒精清除的奖励/强化特性[[或饮酒引起的bac]]。提出的工作的意义在于，结果可能导致一种新的药物治疗方法来治疗酒精滥用，酒精依赖和复发；这一方法可能对治疗目前可用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.