Efficacy of Novel Triple Uptake Inhibitors in Treating Alcoholism and Depression

项目总结/摘要 酒精中毒和抑郁症经常同时发生在人类身上，但很难找到一种单一的治疗方法， 对这两种情况都有效。这种共病的情况下，经常观察到以下冲动狂欢 酒精消费，以及人类的强迫性饮酒。目前的主要目标 一项建议是在临床前水平鉴定有效的化合物，这些化合物可以作为进一步研究的原型。 评价治疗共病的临床疗效。为了实现这一点，一系列的三重 单胺摄取抑制剂[TUI] [例如，216，303，21，947和102，677]， 在抑郁症的I期研究中成功测试，具有已发表的临床前抗抑郁[AD]疗效， 被评价。第一个目的是检验口服TUI可以有效地减弱 在狂欢和长期重复酒精剥夺[PRAD]模型中过量饮酒， 嗜酒精[P]大鼠初步研究将使用DOV 102，677 [我们的先导化合物]，最近显示， 在单次给药后六天内减少有限的酒精反应。假设急性 治疗酗酒和慢性治疗PRAD饮酒，将选择性地减少这两种疾病的摄入量。 模型第二个目的是检验TUI将有效地减弱消极情感的假设， 状态[例如，戒断症状]，其特征是快乐减少[即，快感缺乏]和 增加的不动性[即，在酒精诱导的戒断后， 狂欢和PRAD饮酒。使用颅内自我刺激将推断负性情感状态 [ICSS]和强迫游泳试验[FST]模型。我们假设急性和慢性DOV治疗都将 减弱与酒精引起的戒酒相关的负面情感状态 模型目的3将检验类似的神经生物学底物介导酒精依赖的假设， 在扩展杏仁核[EA]内与狂饮相关的负面情感状态[即，床 终纹核;杏仁核中央核;杏仁核壳 （nAcc）];和内侧前额叶皮层（mPfc）。为了评估这一假设，位点特异性显微注射我们的 将在EA位点和mPfc中给出导联TUI [DOV 102，677]。然而，由于几乎没有任何数据， 为了在调节TUI作用的精确大脑基质上获得，我们将首先使用c-fos 技术在幼稚P大鼠中描绘多个CNS位点，这些位点可能介导DOV的作用102，677。 这些研究应确定有效的化合物在临床前水平，可作为原型， 进一步评估治疗酒精中毒和抑郁症共病的临床疗效， 调节这两种情况的神经生物学共性。

Project Summary/Abstract Alcoholism and depression often co-occur in humans, but it has been difficult to find a single treatment which is effective against both conditions. This comorbid condition is frequently observed following impulsive binge alcohol consumption, as well as in compulsive drinking in humans. The primary objective of the present proposal is to identify effective compounds at the preclinical level that may serve as prototypes for further evaluation of clinical efficacy in treating the comorbid condition. To accomplish this, a series of triple monoamine uptake inhibitors [TUIs] [e.g., DOV 216,303, DOV 21,947, and DOV 102,677], which have been successfully tested in Phase I studies for depression with published preclinical-antidepressant [AD] efficacy, will be evaluated. The first aim will test the hypothesis that orally-administered TUIs can effectively attenuate excessive alcohol drinking in the binge and prolonged repeated alcohol deprivation [PRAD] models using the alcohol-preferring [P] rat. Initial studies will employ DOV 102,677 [our lead compound], recently shown to reduce limited alcohol responding for six days after a single administration. It is hypothesized that acute treatment for binge drinking, and chronic treatment for PRAD drinking, will selectively reduce intake in both models. The second aim will test the hypothesis that TUIs will effectively attenuate the negative affective states [e.g., withdrawal symptomatology], characterized by reductions in pleasure [i.e., anhedonia] and increased immobility [i.e., indicative of depressive-like behaviors] following alcohol-induced abstinence from binge and PRAD drinking. Negative affective states will be inferred using the intracranial self-stimulation [ICSS] and forced swim test [FST] models. We hypothesize that both acute and chronic DOV treatments will attenuate the negative affective states associated with alcohol-induced abstinence from the two heavy drinking models. Aim 3 will test the hypothesis that similar neurobiological substrates mediate alcohol dependence and the negative affective states associated with binge drinking within the extended amygdala [EA] [i.e., bed nucleus of the stria terminalis (BST); central nucleus of the amygdala (CeA); shell of the nucleus accumbens (nAcc)]; and medial prefrontal cortex (mPfc). To evaluate this hypothesis, site-specific microinjection of our lead TUI [DOV 102, 677] will be given in the EA loci and mPfc. However, because little if any data are available on the precise brain substrates which regulate the actions of TUIs, we will initially employ the c-fos technology in na¿ve P rats to delineate multiple CNS loci which may mediate the actions of DOV 102, 677. These studies should identify effective compounds at the preclinical level which may serve as prototypes for further evaluation of clinical efficacy in treating comorbid alcoholism and depression, as well as shed light on the neurobiological commonalities which regulate the two conditions.