This research investigates three process-oriented hypotheses about the neurobiology of hypercortisolism during major depressions in humans using a model of hypercortisolism in monkeys. The first proposed process involves changes in adrenal responsiveness to the adrenocorticotropic hormone (ACTH). Recent accounts derived from clinical reports suggest that hypersecretion of cortisol in depressed human patients is initially driven by hypersecretion of ACTH. With prolonged depressions, however, cortisol levels remain elevated while ACTH levels are reduced. Apparently hypercortisolism is maintained, despite reductions in ACTH, because adrenal responsiveness to ACTH is enhanced. If this time-dependent process likewise occurs during social separation induced hypercortisolism in squirrel monkeys, then normal adrenal responses are expected in monkeys tested after acute separations, whereas adrenal hyper-responsiveness to ACTH is expected after chronic separations. To determine whether hyper-responsiveness is due to corticotropin releasing hormone (CRH) and/or ACTH potentiation effects on the adrenal cortex, ACTH stimulation tests will also be administered after chronic separations to dexamethasone pretreated monkeys. The second proposed process involves changes in pituitary responsiveness to the ACTH-releasing hormone CRH. Research suggests that pituitary corticotrophs in depressed human patients are initially stimulated by excessive hypothalamic CRH, but with prolonged depressions this stimulatory effect on the pituitary is suppressed by high circulating levels of cortisol. If a similar process occurs in the investigator's model of hypercortisolism in monkeys, then normal responses to CRH are expected after acute separations, whereas pituitary hypo-responsiveness to CRH is expected after chronic separations. To determine whether hypo-responsiveness to CRH is due to corticosteroid feedback on pituitary corticotrophs, CRH stimulation tests will also be administered after chronic separations to metyrapone pretreated monkeys. The third proposed process involves corticosteroid induced increases in central and peripheral measures of dopamine. Relative to nonpsychotic depressed patients or healthy human volunteers, major depressed patients that develop psychotic features typically show higher cortisol levels, higher plasma free dopamine levels, and higher plasma and cerebrospinal fluid (CSF) levels of the dopamine metabolite homovanillic acid (HVA). In squirrel monkeys, hypersecretion of cortisol is likewise associated with increases in plasma and CSF HVA, but not CSF levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenleneglycol (MHPG). Long-lasting increases in cortisol are apparent within hours of separation, whereas increases in HVA occur late (1-3 days post-separation) and persist for several days. This time course is consistent classic mechanisms of steroid hormone action on protein synthesis, and concurs with clinical reports that neuroendocrine stimulation tests that activate the hypothalamic-pituitary-adrenal (HPA) axis produce delayed increases in HVA, but not MHPG, in healthy human volunteers. In the proposed research, squirrel monkey cortisol, ACTH and HVA responses to direct stimulation of adrenocortical activity by synthetic ACTH, and indirect stimulation by synthetic oCRH, will be compared with neuroendocrine time course data collected from psychotic depressed patients, nonpsychotic depressed patients, and healthy human volunteers. These comparative longitudinal analyses provide unique opportunities to characterize the validity of the model with respect to clinical subtypes, and will therefore follow as closely as possible the doses of bioactive substances, their time of administration, and the sample collection schedules used in the investigator's ongoing studies of HPA dysregulation during major depressive disorders in humans.
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