DIFFERENTIAL NEUROSTEROID RESPONSES IN PTSD AND ALCOHOL DEPENDENCE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 目的：对创伤后应激障碍患者、酒精依赖者和正常对照者的类固醇激素反应进行临床研究，以了解他们下丘脑-垂体-肾上腺轴和类固醇激素产生系统的共同点。 研究报告：第1-2组的受试者将入住位于大学医院的大学临床精神药理学实验室（UCPL），接受2天1夜的手术。 在入院当天上午确保生理和医学稳定后，这些受试者将在第1天下午接受两次线索暴露。 每名受试者将在两个单独的线索暴露阶段中暴露于控制线索和显著线索，计划间隔两小时，并以受试者之间平衡的顺序呈现。 对于第1组受试者，显著线索将是一个特殊脚本的三分钟音频阅读，该脚本描述了与受试者自我报告的危及生命的创伤事件经历相关的情况、景象、声音和感受。 这一组的控制提示将是一个类似的音频描述一个轻松的生活情况。 对于第2组受试者，显著线索将是酒精线索暴露，其中将向受试者呈现一罐他们最喜欢的冰镇啤酒。 在一个定时的3分钟程序中，受试者将打开啤酒罐，倒一些到杯子里，闻一闻香味，最后允许吃一口品尝和吞咽。 这组的控制提示将是一个类似的程序，一瓶水。 将从两组受试者开始前15分钟（即，在-15和-5分钟）和在每个提示暴露程序之后1小时（在+3、+10、+20、+30、+45、+60分钟）（#8 x 5 ml样品=总共40 ml）。 第1组和第2组的受试者随后将在出院前留院过夜，以便在第二天（第2天）进行孕酮激发程序。 对于第1组和第2组的受试者，孕酮激发程序将于第2天开始开始，但对于第3组的受试者，其将作为门诊患者进入UCPL进行为期一天的程序。 从上午10点半开始，将放置导管并从所有受试者中采集单个样本用于PBR分析。 受试者将在上午11：00接受300 mg黄体酮的口服剂量，并在口服给药前即刻和口服给药后3小时内每隔30分钟重复采集血样，然后在4、5和6小时再次采集血样。 因此，将抽取总计#12 x 5 ml样本=总计60 ml血液。 作为我们目前研究工作的一部分，我们有经验使用所有这些方法招募这些人群，进行行为和神经内分泌研究，并测定皮质醇，别孕烯醇酮和孕酮水平。 方法：这是一项由McMannis基金会小额资助的试点研究。 其目的是获得必要的初步数据，以证明我们有能力进行这些神经内分泌研究，并寻找神经内分泌假说的临床证据，该假说是由先前在动物和人类中的研究建立的。 基本上，我们假设健康对照受试者和两个诊断组之间的PBR结合和别孕烯醇酮反应存在统计学和临床上有意义的差异。 将通过单因素ANOVA比较三组之间的PBR结合结果以及激素峰值和对孕酮的AUC反应。 诊断组的反应显着的线索将对比内的主题对比与控制线索程序。 在那里，我们期望证明两种类型的线索之间的皮质醇反应差异，但是基线别孕烯醇酮水平和/或线索反应将与线索反应的幅度负相关。 临床相关性：神经类固醇似乎在对压力和压力相关疾病的适应性反应中发挥重要作用。 这些研究应该为更好地理解创伤后应激障碍与包括酒精依赖在内的其他精神障碍之间的共性提供基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: To conduct clinical studies of steroid hormone responses of Post-traumatic stress disorder, alcohol dependent, and normal healthy control subjects to understand the commonalities in their hypothalamic-pituitary-adrenal axis and steroid hormone production system. RESEARCH PLAN: Subjects from Groups 1-2 will be admitted to the University Clinical Psychopharmacology Laboratory (UCPL) located at University Hospital for a two day, one overnight procedure. After assuring physiologic and medical stability on the morning of admission, these subjects will undergo two cue exposures during the afternoon of Day 1. Each subject will be exposed to both Control Cues and Salient Cues in two separate cue exposure sessions, scheduled two hours apart, and presented in an order counter-balanced across subjects. For Group 1 subjects, the Salient Cues will be a three minute audio reading of an idiosyncratic script that describes the situation, sights, sounds, and feelings associated with the subject's self-reported experience with a life-threatening traumatic event. The Control Cues for this group will be a similar audio describing a relaxing life-situation. For Group 2 subjects, the Salient Cues will be an alcoholic cue exposure where subjects will be presented with a chilled can of their favorite beer. Over a timed 3 minute procedure, subjects will open the can of beer, pour some in into a cup, sniff and smell the aroma, and finally be allowed to take one mouthful to taste and swallow. The Control Cues for this group will be a similar procedure with a bottle of water. Brief subjective questionnaires and blood samples will be collected repeatedly from both groups of subjects beginning 15 minutes before (i.e., at -15 and -5 min) and for one hour after (at +3, +10, +20, +30, +45, +60 min) each cue exposure procedure (#8 x 5 ml samples = 40 ml total). Subjects from Group 1 and 2 subsequently will remain in the hospital overnight for the progesterone challenge procedure on the next day (Day 2), before discharge from the hospital. The progesterone challenge procedure will begin on Day 2 for subjects from Groups 1 and 2, but will be a single day procedure for Subjects from Group 3 who will be admitted to the UCPL as outpatients for the one day procedure. Beginning at 10:30 a.m., a catheter will be placed and a single sample will be collected from all subjects for PBR analysis. Subjects will receive an oral dose of 300 mg progesterone at 11:00 a.m. and blood samples will be collected repeatedly immediately before, and at 30 min intervals up to 3 hours and then again at 4, 5, and 6 hours after oral dosing. Thus, a total of #12 x 5 ml samples = 60 ml blood total will be drawn. As part of our current research efforts, we have experience using all of these methods to recruit these populations, to conduct behavioral and neuroendocrine studies, and to assay for cortisol, allopregnanolone, and progesterone levels. METHODS: This is a pilot study supported by a small grant from the McMannis Foundation. It is designed to obtain the preliminary data necessary to demonstrate our ability to conduct these neuroendocrine studies and to look for clinical evidence of a neuroendocrine hypothesis that is well founded by previous research in animals and in humans. Basically, we hypothesize that there will be statistically and clinically meaningful differences in PBR binding and allopregnanolone response between the healthy control subjects and the two diagnostic groups. PBR binding results as well as hormonal peak and AUC response to progesterone will be compared between the three groups by one-way ANOVA. The responses of the diagnostic groups to salient cues will be contrasted by within-subject contrasts with the control cue procedure. There we expect to demonstrate a cortisol response difference between the two types of cue, but that baseline allopregnanolone levels and/or cue response will negatively correlate with the magnitude of the cue response. CLINICAL RELEVANCE: Neurosteroids appear to play a fundamental role in adaptive responses to stress and stress-related disorders. These studies should provide the basis for an improved understanding of the commonalities between post-traumatic stress disorder and other psychiatric disturbances including alcohol dependence.