Efficacy of Novel Triple Uptake Inhibitors in Treating Alcoholism and Depression

描述（由申请人提供）：酗酒和抑郁症经常在人类中同时发生，但很难找到一种对这两种情况都有效的治疗方法。这种共病经常在人类冲动性酗酒以及强迫性饮酒后观察到。本提案的主要目标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评估治疗共病的临床疗效的原型。为了实现这一目标，将对一系列三元单胺摄取抑制剂 [TUI] [例如 DOV 216,303、DOV 21,947 和 DOV 102,677] 进行评估，这些抑制剂已在抑郁症 I 期研究中成功进行测试，并已发表临床前抗抑郁药 [AD] 功效。第一个目标将测试以下假设：使用偏好酒精的 [P] 大鼠，口服 TUI 可以有效减轻暴饮暴食和长期重复酒精剥夺 [PRAD] 模型中的过量饮酒。初步研究将采用 DOV 102,677 [我们的先导化合物]，最近显示，单次给药后六天内可减少有限的酒精反应。据推测，对酗酒的急性治疗和对 PRAD 饮酒的慢性治疗将选择性地减少这两种模型的摄入量。第二个目标将检验这一假设，即 TUI 将有效减轻负面情感状态（例如戒断症状），其特征是在酒精引起的酗酒和 PRAD 戒酒后，愉悦感减少（即快感缺失）和不动感增加（即抑郁样行为）。将使用颅内自我刺激 [ICSS] 和强迫游泳测试 [FST] 模型来推断负面情感状态。我们假设急性和慢性 DOV 治疗都会减轻与两种酗酒模型中酒精诱导的戒酒相关的负面情感状态。目标 3 将检验这样的假设：相似的神经生物学底物介导酒精依赖以及与扩展杏仁核 [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）；伏隔核壳 (nAcc)]；和内侧前额皮质（mPfc）。为了评估这一假设，我们的先导 TUI [DOV 102, 677] 将在 EA 基因座和 mPfc 中进行位点特异性显微注射。然而，由于关于调节 TUI 作用的精确脑底物的数据很少（如果有的话），我们将首先在 naove P 大鼠中采用 c-fos 技术来描绘可能介导 DOV 102、677 作用的多个 CNS 位点。这些研究应在临床前水平鉴定有效化合物，这些化合物可作为进一步评估治疗共病酒精中毒和抑郁症的临床疗效的原型，并为神经生物学提供线索。调节这两种条件的共同点。 公共卫生相关性 本提案将评估一系列新型抗抑郁药物在酗酒啮齿动物模型中减少过量饮酒和戒酒效果的能力。该提案的主要目标是成功识别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.