Efficacy of Novel Triple Uptake Inhibitors in Treating Alcoholism and Depression

描述（由申请人提供）：人类经常同时出现酒精中毒和抑郁症，但很难找到一种对这两种情况都有效的单一治疗方法。这种合并症经常在冲动性酗酒和人类强迫性饮酒后出现。本提案的主要目的是在临床前水平确定有效的化合物，这些化合物可以作为进一步评估治疗合并症的临床疗效的原型。为了实现这一目标，将对一系列已在抑郁症I期研究中成功测试并公布临床前抗抑郁药疗效的三单胺摄取抑制剂[TUIs][例如DOV 216,303, DOV 21,947和DOV 102,677]进行评估。第一个目的是通过使用嗜酒大鼠来验证口服TUIs可以有效地减少暴饮和长时间重复酒精剥夺（PRAD）模型中的过量饮酒。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6天内减少有限酒精反应。据推测，对狂饮的急性治疗和对PRAD饮酒的慢性治疗会选择性地减少两种模型的摄入量。第二个目标将检验这样一个假设，即在酒精诱导的暴饮和PRAD饮酒戒断后，TUIs将有效地减弱负面情感状态（例如，戒断症状），其特征是愉悦感减少（例如，快感缺乏症）和不动（例如，表明抑郁样行为）增加。负面情感状态将通过颅内自我刺激（ICSS）和强迫游泳测试（FST）模型来推断。我们假设急性和慢性DOV治疗都会减弱与两种重度饮酒模型中酒精引起的戒断相关的负面情感状态。目的3将检验类似的神经生物学底物介导与狂欢饮酒相关的酒精依赖和消极情感状态的假设[EA][即终纹床核（BST）]；杏仁核中央核（CeA）；伏隔核壳（nAcc）]；和内侧前额叶皮层（mPfc）。为了评估这一假设，我们将在EA位点和mPfc中进行特定位点的先导TUI微注射[DOV 102,677]。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），我们将首先在幼稚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。这些研究应该在临床前水平确定有效的化合物，这可能作为进一步评估治疗酒精中毒和抑郁症共病的临床疗效的原型，并阐明调节这两种疾病的神经生物学共性。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量饮酒和戒酒效果的能力。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.