Efficacy of Novel Triple Uptake Inhibitors in Treating Alcoholism and Depression

新型三重摄取抑制剂治疗酒精中毒和抑郁症的功效

• 批准号: 7746463
• 负责人: Harry L June
• 金额: $ 35.27万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746463
• 关键词: Abstinence; Acute; Affective; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amygdaloid structure; Anhedonia; Antidepressive Agents; Attenuated; Behavior; Brain; Cell Nucleus; Chronic; DOV 216303; Data; Dependence; Evaluation; FOS gene; Heavy Drinking; Human; Human Volunteers; Individual; Intake; Lead; Light; Medial; Mediating; Mental Depression; Microinjections; Modeling; Neurobiology; Nucleus Accumbens; Pharmaceutical Preparations; Pre-Clinical Model; Prefrontal Cortex; Property; Publishing; Rattus; Rodent Model; Schedule; Selective Serotonin Reuptake Inhibitor; Self Stimulation; Series; Site; Structure of terminal stria nuclei of preoptic region; Swimming; Technology; Testing; Tricyclic Antidepressive Agents; Withdrawal; alcohol abstinence; binge drinking; clinical efficacy; depressive symptoms; deprivation; drinking; inhibitor/antagonist; monoamine; neurobiological mechanism; novel; phase 1 study; pleasure; pre-clinical; prototype; public health relevance; uptake

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.

描述（由申请人提供）：酒精中毒和抑郁症经常在人类中同时发生，但是很难找到一种在两种情况下有效的治疗方法。在冲动性暴饮暴食以及人类强迫性饮酒之后，经常观察到这种合并症。本提案的主要目的是在临床前识别有效化合物，该化合物可以作为原型，以进一步评估治疗合并症的临床功效。为此，一系列三重单胺摄取抑制剂[TUIS] [例如DOV 216,303，DOV 21,947和DOV 102,677]，这些抑郁症已在I期中成功测试，并评估已发表的Prinlinical-antical-Antide-Antidepressant [AD]效率，将评估。第一个目的将检验以下假设：口服的TUIS可以有效地减弱暴饮暴食中的过量饮酒，并使用酒精优先[P]大鼠延长饮酒[PRAD]模型。最初的研究将采用DOV 102,677 [我们的铅化合物]，最近证明可以减少一次给药后六天的酒精反应。假设急性饮酒的急性治疗以及用于PRAD饮用的慢性治疗将有选择地减少两种模型的摄入量。第二个目的将检验以下假设：TUIS将有效地衰减负面情感状态[例如戒断症状]，其特征是愉悦感（即Anhedonia]的降低[即Anhedonia]和增加的不动行为[即表明抑郁样行为]在酒精引起的酒精引起的饮酒中引起了暴饮暴食和饮酒后的饮酒后。使用颅内自我刺激[ICS]和强迫游泳测试[FST]模型，将推断出负面情感状态。我们假设急性和慢性DOV治疗都会减轻与酒精引起的两种繁重饮酒模型相关的负面情感状态。 AIM 3将检验以下假设：相似的神经生物学底物介导了酒精依赖性和与扩展的杏仁核内的暴饮暴食相关的负面情感状态[ea] [ea] [即，斯特里亚斯末端的床核（BST）；杏仁核的中央核（CEA）；伏隔核的外壳（NACC）]；和内侧前额叶皮层（MPFC）。为了评估这一假设，将在EA基因座和MPFC中给出我们铅TUI的位点特异性显微注射[DOV 102，677]。但是，因为几乎没有任何数据可用于调节TUIS动作的精确脑底物，我们最初将采用Naove P Rats中的C-Fos技术来描述多个CNS基因座，这些CNS基因座可以介导DOV 102，677的作用。这些研究应在临床上进行抑郁症，并在临床上识别有效的化合物，并在临床上进行促进型，并在临床上进行促进，以实现良好的效果，并在临床上进行良好的效果，并可以进行良好的效果。对调节这两种情况的神经生物学共同点的光。 公共卫生相关性本提案将评估一系列新型的抗抑郁药，以减少酗酒模型中过量饮酒和戒酒的能力。该提案的主要目的是成功识别可用于治疗人类抑郁症和酒精成瘾的药物。