Women and men differ in the ways stress affects the development and maintenance of alcoholism. However, no published studies in alcohol dependent patients have examined sex differences in stress responsiveness that most likely mediate these effects and influence the clinical course and treatment of the disorder. This revised application proposes to extend our preliminary work revealing sex-dependent alterations in basal and serotonin-induced stress responses in abstinent alcoholics. Serotonin regulates the brain's response to certain uncontrollable stressors, and there are sex differences in both serotonin and hypothalamic-pituitary-adrenal (HPA) function. Thus, our chief aim is to determine whether the hypersensitive and prolonged stress response we observed in female alcoholics is related to sex differences in serotonin signaling or HPA sensitivity. Our central hypothesis is that sex differences in serotonin function or HPA sensitivity conspire with genetically influenced alterations in serotonin signaling to produce maladaptive stress responses in some alcoholic women. To test this hypothesis, we will perform a randomized, double blind, crossover study where subjects receive provocative tests with citalopram, dexamethasone/corticotropin-releasing hormone and placebo on 3 separate, counterbalanced occasions at monthly intervals. Subjects will be verified abstinent, treatment seeking alcoholic women and men without comorbid psychiatric or other illicit substance use disorders residing in controlled sober living environments. Non-alcoholic women and men will serve as controls, and all groups will be balanced on the number of subjects with and without a family history of alcoholism. Subjects' DNA will be genotyped to determine allelic variants in the promoter region of the serotonin transporter gene that have been found to influence transporter function and stress responsiveness. Endocrine, behavioral, cardiovascular and catecholamine stress measures will be obtained along with measures of life stress and adverse life events that may influence the outcome measures. To our knowledge, this will be the first study conducted in alcohol dependent patients to simultaneously assess biological sex differences in stress responsivity, gender differences in environmental life stress, and the serotonin transporter polymorphism. The results should advance the field by identifying mechanisms underlying sex differences in stress responsiveness that influence vulnerability to develop alcoholism and responsiveness to serotonergic medications intended to prevent or treat the disorder.
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