Familial Alcoholism, Glutamaterger Genotypes and NMDA Receptor Antagonist

从历史上看，各种精神疾病的成功治疗方法的发展是基于 了解调节病情的机制。类似的原则也适用于 治疗物质使用障碍，包括饮酒;一个主要的例子是优雅的临床前临床 使用纳洛酮减少饮酒的发展概况。证据来自我们的 正在进行的CTNA 1项目显著增加了这一文献，并表明纳洛酮的疗效是 但有家族酗酒史的人影响不大 目前的建议是基于我们小组的初步证据，表明酒精的渴望是改变的 被一个叫美金刚的探员绑架了这遵循文献和临床中的临床前证据。 来自我们小组其他成员的证据表明，谷氨酸能拮抗剂具有酒精样作用 并且有酗酒家族史的人会改变这些药物的焦虑作用。 因此，我们现在建议评估美金刚在减少饮酒方面的疗效， 酒精自我管理的实验室模型。该模型已开发和验证使用 纳洛酮（O ′ Malley等，2002年），目前被我们和其他团体用于筛选药物。在 目前的建议，我们将评估美金刚对饮酒行为，酒精渴望， 和刺激/镇静在非寻求治疗，酒精依赖的重度饮酒者，无论是积极的或 有无酗酒家族史。我们将测试以下具体目标：具体目标1：评估 用三种剂量的美金刚（安慰剂，20 mg和40 mg）中的一种预处理7天的功效 mg/天），使用实验室模型，该模型包括暴露于酒精启动饮料和随后的自由选择 在三个小时的饮酒时间内。具体目标2：评估家庭的影响 对美金刚的疗效有影响探索性目标还将评估 嗜多杀菌素基因的多态性以及冲动和延迟折扣措施作为 酒精反应、饮酒行为和美金刚疗效。因此，本提案的结果将提供 关于美金刚胺在酒精中减少饮酒的潜在临床效用的初始信号 依赖的个体。

Historically, development of successful treatments for various psychiatric conditions has been based on an understanding of the mechanisms mediating the condition. Similar principles have been applied to the treatment of substance use disorders including alcohol drinking; a prime example is the elegant preclinicalclinical developmental profile of the use of naltrexone for reducing alcohol drinking. Evidence from our ongoing project in CTNA1 significantly adds to this literature and suggests that the efficacy of naltrexone is moderated by the presence of a family history of alcoholism. The current proposal is based on initial evidence from our group suggesting that alcohol craving is altered by the glutamatergic agent memantine. This follows preclinical evidence in the literature and clinical evidence from other members of our group indicating that glutamatergic antagonists have alcohol-like effects and that the presence of a family history of alcoholism alters the dysphoric effects of these agents. Therefore, we are now proposing to evaluate the efficacy of memantine in reducing alcohol drinking in a laboratory model of alcohol self-administration. This model has been developed and validated using naltrexone (O'Malley et al., 2002) and is currently used by our and other groups to screen medications. In the current proposal we will evaluate the effects of memantine on alcohol drinking behavior, alcohol craving and stimulation/sedation in non-treatment seeking, alcohol-dependent heavy drinkers with either a positive or negative family history of alcoholism. We will test the following specific aims: Specific Aim 1: To evaluate the efficacy of seven days of pretreatment with one of three doses of memantine (placebo, 20 mg and 40 mg/day) using a laboratory model consisting of exposure to a priming drink of alcohol and subsequent freechoice drinking during a three-hour drinking period. Specific Aim 2: To evaluate the influence of family history of alcoholism on the efficacy of memantine. Exploratory aims will also evaluate the presence of a polymorphism of the spinophillin gene as well impulsivity and delayed discounting measures as correlates of alcohol responses, drinking behavior and memantine efficacy. Thus, the results of this proposal will provide an initial signal regarding the potential clinical utility of memantine to reduce alcohol drinking in alcohol dependent individuals.