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开发都是基于 对调节这种情况的机制的理解。类似的原则也被应用于 治疗物质使用障碍，包括饮酒；一个最好的例子是优雅的临床前临床 纳曲酮用于减少饮酒的发展概况。来自我们的证据 正在进行的CTNA1项目显著增加了这方面的文献，并表明纳曲酮的疗效是 因有酗酒家族史而有所缓和。 目前的建议是基于我们小组的初步证据，即酒精渴望被改变 谷氨酸能药美金刚。这遵循了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类似酒精的作用 而且，有酗酒家族史的存在会改变这些药物的焦虑症效果。 因此，我们现在建议评估美金刚在减少饮酒方面的疗效。 酒精自我给药的实验室模型。该模型已使用以下工具进行开发和验证 纳曲酮(O‘Malley等人，2002年)，目前被我们和其他小组用于筛选药物。在……里面 目前的建议我们将评估美金刚对饮酒行为、酒精渴求的影响 以及刺激/镇静作用于不寻求治疗、酗酒且阳性或阳性的酗酒者 有酗酒家族史。我们将测试以下具体目标：具体目标1：评估 美金刚三种剂量之一(安慰剂、20毫克和40毫克)预治疗7天的疗效 毫克/天)，使用实验室模型，包括接触启动酒精饮料和随后的自由选择 在三小时的饮酒期内饮酒。具体目标2：评估家庭的影响 酒精中毒史对美金刚疗效的影响。探索性目标还将评估是否存在 刺青素基因的多态以及冲动和延迟折扣措施与 酒精反应、饮酒行为和美金刚疗效。因此，这项提案的结果将提供 美金刚减少酒精饮酒的潜在临床效用的初步信号 独立的个体。

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.