Alcohol dependent patients respond to stress differently than non- dependent healthy controls. Difficulties coping with stress result in heightened risk for the development of problem drinking and the precipitation of relapse. Alcohol-related changes in the hypothalamic- pituitary-adrenal (HPA) axis, a critical stress response system, may therefore be an important factor in the addictive process. Previous studies in alcohol dependent men have demonstrated altered HPA axis functioning in response to pharmacologic and behavioral challenges. However, the distinct functional integrity of the hypothalamus, the pituitary, and the adrenal glands in alcohol dependent patients has been obscured by the complex feedback system between these integrated units. We propose to identify the specific levels of HPA axis disruption in four to six week abstinent alcohol dependent women and men using standardized biological and statistical techniques. Neuroendocrine challenges will be coupled with a pharmacologic """"""""clamp"""""""" to isolate the pituitary and adrenal gland from their major source of endogenous regulation. Pituitary sensitivity to human CRH will be assessed both prior to and following the suppression of endogenous glucocorticoid feedback by metyrapone. Adrenal gland sensitivity to ACTH/alpha1-24 will be assessed both prior to and following the suppression of adrenals as isolated components will be determined. Twenty-four hour basal measures of ACTH and cortisol levels, hypothalamic responsiveness to naloxone, pituitary corticotroph sensitivity to dexamethasone and glucocorticoid withdrawal, and at-risk personality characteristics will also be assessed. Deconvolutional statistical techniques will be used to identify pulsatile secretion and clearance rates of ACTH and cortisol. We hypothesize that the following separate and distinct abnormalities will be observed at each level of the axis: (1) hypothalamic sensitivity will be decreased, (2) pituitary sensitivity will be decreased, (2) pituitary sensitivity will be decrease, (3) adrenal gland sensitivity will be decreased, and (4) pituitary ACTH response to glucocorticoid inhibitory feedback and glucocorticoid withdrawal will be decreased. The work proposed will provide the framework for developing focused treatments to regulate the HPA axis in alcohol dependent patients in order to help this patients maintain physiologic and emotional homeostasis, thereby reducing their risk of relapse.
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