This new R01 proposal will examine neuroendocrine factors mediating sleep disturbances in men and women with chronic Posttraumatic Stress Disorder (PTSD). We previously demonstrated that; 1) metyrapone administration, which blocks adrenal cortisol synthesis and stimulates the release of hypothalamic Corticotropin Releasing Factor (CRF), resulted in a decrease in sleep time, an increase in awakenings, and a robust decrease in quantitative delta sleep in both PTSD and control subjects; 2) The sleep and endocrine (increase in ACTH) responses to metyrapone were significantly decreased in PTSD suggesting diminished sensitivity to CRF challenge; and 3) The metyrapone-related disruption to sleep was predicted by the increase in ACTH measured the following morning. These findings strongly suggest that the CRF response to metyrapone accounts for the observed disruption to sleep. This data is consistent with an extensive literature in animal studies documenting the role of CRF in mediating arousal responses and sleep fragmentation. The proposed study will test the hypothesis that the immediate endocrine response to metyrapone challenge accounts for the observed disruption in total sleep time and quantitative delta sleep. This will be accomplished by repeated sampling of nocturnal hormone activity during the sleep recordings both before and after metyrapone administration. Further, given the known relationship between delta sleep and growth hormone (GH) release, and the fact that CRF release suppresses GH, we will measure GH responses to metyrapone to add a convergent test of the role of CRF in disrupting sleep. Finally, given that there are important gender differences in sleep, HPA, and somatotropic axis function, we will examine if gender affects the response of sleep to a CRF manipulation. We will compare immediate nocturnal cortisol, 11 deoxycortisol, ACTH, and GH responses to metyrapone in a 2x2 design crossing group status (PTSD vs controls) and gender (half men/half women). We will study medication-free, medically healthy, non-obese, non-substance abusing men and women ages 20 to 50 with chronic PTSD versus normal controls. Three nights of polysomnography with nocturnal blood sampling (night 1= adaptation, nights 2-3= pre and post metyrapone administration) will be conducted on the General Clinical Research Center at the University of California, San Francisco. The focus on the role of CRF in mediating disturbed sleep in PTSD has broader implications for understanding the mechanism of disturbed sleep found in normal subjects responding to acute and chronic stressors. This proposal will also be the first study to examine gender effects on sleep and HPA ever conducted in the PTSD field. Finally, the results from the study have implications for the clinical applicability of CRF receptor antagonists, which continue to be developed.
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