Efficacy of Novel Triple Uptake Inhibitors in Treating Alcoholism and Depression

项目摘要/摘要 酒精中毒和抑郁症经常在人类中共存，但很难找到一种单一的治疗方法 对这两种情况都有效。在冲动狂欢之后，经常会观察到这种并存的情况。 酒精消费，以及人类的强迫性饮酒。当前的首要目标 建议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研究的原型 合并症的临床疗效评价。为了做到这一点，一系列的三重 单胺摄取抑制剂[TUI][例如，DOV 216,303，DOV 21,947和DOV 102,677]，已被 在第一阶段研究中成功测试抑郁症，并公布了临床前抗抑郁药[AD]的疗效，Will 被评估。第一个目标将检验口服TUIs可以有效地减重的假设。 过度饮酒和长时间重复饮酒[PRAD]模型 嗜酒[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 减少一次服药后六天的限量饮酒反应。据推测，急性 对酗酒的治疗和对Prad饮酒的慢性治疗将选择性地减少这两种情况下的摄入量 模特们。第二个目标将检验TUIs将有效地减弱负面情绪的假设 状态[例如，戒断症状]，特征是快感减少[即快感缺乏]和 在酒精诱导的戒断后，运动不动增加[即，表明有抑郁样行为] 狂欢和原野饮酒。使用颅内自我刺激可以推断出消极的情感状态 [ICSS]和强迫游泳测试[FST]模型。我们假设急性和慢性DOV治疗都会 减轻两种大量饮酒引起的戒酒所致的负面情绪状态 模特们。目的3将测试假设，相似的神经生物底物介导酒精依赖和 与扩展杏仁核[EA][即床]内酗酒相关的负面情绪状态 终纹核、杏仁中央核、伏隔核壳核 (NACC)和内侧前额叶皮质(MPFC)。为了评估这一假说，我们的部位特异性微量注射 引线TUI[DOV 102,677]将在EA区域和mPFC中给出。然而，因为几乎没有数据 在调节TUI行为的精确大脑底物上可用，我们最初将使用c-fos 在NAVE P大鼠中描绘可能介导DOV 102,677作用的多个中枢神经系统基因座的技术。 这些研究应该确定临床前水平的有效化合物，这些化合物可以作为治疗 对酒精中毒与抑郁症共病的临床疗效的进一步评价及启示 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.