Efficacy of Novel Triple Uptake Inhibitors in Treating Alcoholism and Depression

描述（由申请人提供）：酒精中毒和抑郁症通常共同发生在人类身上，但很难找到一种对这两种疾病都有效的单一治疗方法。这种共病的情况下经常观察到以下冲动狂欢饮酒，以及在强迫性饮酒的人。本提案的主要目的是在临床前水平鉴定有效化合物，其可作为进一步评价治疗共病病症的临床疗效的原型。为了实现这一点，一系列三重单胺摄取抑制剂[TUI] [例如，DOV 216，303、DOV 21，947和DOV 102，677]，这些药物已在抑郁症I期研究中成功测试，并已发表临床前抗抑郁[AD]疗效。第一个目的是检验以下假设：口服TUI可以有效地减少酗酒和长期重复酒精剥夺[PRAD]模型中的过度饮酒，使用酒精偏好[P]大鼠。最初的研究将使用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。据推测，急性治疗暴饮暴食，慢性治疗PRAD饮酒，将选择性地减少摄入量在这两个模型。第二个目标将检验TUI将有效减弱消极情感状态的假设[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，指示抑郁样行为]后，酒精诱导的戒酒狂欢和PRAD饮酒。将使用颅内自我刺激[ICSS]和强迫游泳试验[FST]模型推断负面情感状态。我们假设，急性和慢性DOV治疗将减弱与酒精诱导的戒酒从两个酗酒模型的负面情感状态。目的3将检验以下假设：类似的神经生物学底物介导酒精依赖和与扩展杏仁核[EA]内的酗酒相关的负面情感状态[即，终纹床核（BST）;杏仁核中央核（CeA）;杏仁核壳（nAcc）];和内侧前额叶皮质（mPfc）。为了评估这一假设，将在EA位点和mPfc中进行我们的导联TUI [DOV 102，677]的位点特异性显微注射。然而，由于几乎没有任何关于调节TUI作用的精确脑基质的数据，我们将首先在naove P大鼠中使用c-fos技术来描绘可能介导DOV作用的多个CNS位点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，进一步评估临床疗效，在治疗共病酒精中毒和抑郁症，以及阐明调节这两种条件的神经生物学共性。 公共卫生相关性本提案将评估一系列新型抗抑郁药物在酒精滥用啮齿动物模型中减少过度饮酒和戒酒作用的能力。该提案的主要目标将是成功地确定可用于治疗人类抑郁症和酒精成瘾的药物。

DESCRIPTION (provided by applicant): 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 naove 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. PUBLIC HEALTH RELEVANCE The present proposal will evaluate a series of novel antidepressant medications for their capacity to reduce excessive alcohol drinking and alcohol abstinence effects in a rodent model of alcohol abuse. The primary objective of the proposal will be to successfully identify agents that may be used to treat both depression and alcohol addiction in humans.