This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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
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.
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