DIFFERENTIAL NEUROSTEROID RESPONSES IN PTSD AND ALCOHOL DEPENDENCE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：通过对创伤后应激障碍、酒依赖患者和正常对照组的类固醇激素反应进行临床研究，了解其下丘脑-垂体-肾上腺轴和类固醇激素分泌系统的共性。 研究计划：1-2组的受试者将被纳入位于大学医院的大学临床精神药理学实验室(UCPL)，为期两天，一夜之间的程序。在保证入院当天上午的生理和医疗稳定性后，这些受试者将在第一天下午接受两次线索暴露。每个受试者将在两次单独的线索暴露会话中同时接触到控制线索和突出线索，时间间隔为两个小时，并按不同受试者之间平衡的顺序呈现。对于第一组受试者，突出提示将是对一个特殊脚本的三分钟音频朗读，该脚本描述与受试者自我报告的危及生命的创伤事件相关的情况、景象、声音和感觉。这组人的控制线索将是一段类似的音频，描述一种放松的生活状况。对于第二组受试者，醒目的线索将是酒精线索暴露，受试者将被呈现一罐他们最喜欢的冰镇啤酒。在一个3分钟的过程中，受试者将打开啤酒罐头，将一些倒入杯子中，闻一闻气味，最后允许一口品尝和吞咽。这组人的控制提示将与一瓶水类似的过程。每次线索暴露前15分钟(即-15分钟和-5分钟)和之后1小时(3分钟、10分钟、20分钟、30分钟、45分钟、60分钟)，从两组受试者身上重复采集简短的主观问卷和血液样本(#8 x 5毫升样本=40毫升)。第一组和第二组的受试者随后将在出院前的第二天(第二天)在医院过夜接受黄体酮挑战程序。 黄体酮挑战程序将于第2天开始，适用于第1组和第2组的受试者，但第3组受试者将作为门诊患者进入UCPL进行为期一天的程序。从上午10：30开始，将放置导尿管，并从所有受试者身上采集单个样本进行PBR分析。受试者将在上午11点口服300毫克孕酮。在口服前立即重复采集血样，间隔30分钟至3小时，然后在口服后4、5和6小时再次采集血样。因此，总共将抽取#12 x 5毫升样本=60毫升血液总数。 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来招募这些人群，进行行为和神经内分泌研究，并测定皮质醇、别孕酮和黄体酮水平。 方法：这是一项由麦克曼尼斯基金会提供的小额资助的先导性研究。它的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，该假说建立在以前的动物和人类研究的基础上。基本上，我们假设在健康对照组和两个诊断组之间，在PBR结合和别孕酮反应方面会有统计学和临床上有意义的差异。用单因素方差分析比较三组间的PBR结合结果以及激素峰值和AUC对孕酮的反应。诊断组对显著线索的反应将通过受试者内部对比和对照线索程序进行对比。在那里，我们希望展示两种类型的线索之间的皮质醇反应差异，但基线别孕酮水平和/或线索反应将与线索反应的大小负相关。 临床意义：神经类固醇似乎在对应激和应激相关疾病的适应性反应中起着基础性作用。这些研究应该为更好地理解创伤后应激障碍和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.