Chronic dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis, manifest as elevated or suppressed plasma glucocorticoid levels, is often associated with neuropsychiatric disorders in humans. However, few satisfactory animal models, especially of chronic HPA suppression, are available. One potential model is the common marmoset (Callithrix jacchus), a small, New World monkey in which socially subordinate females undergo chronic hypogonadotropic anovulation and suppression of circulating cortisol levels. This research will begin to elucidate the physiological mechanisms underlying this socially induced suppression of cortisol by investigating HPA function in anovulatory subordinate females as compared to ovary-intact dominant females and bilaterally ovariectomized females. In Experiment 1, plasma concentrations of cortisol and adrenocorticotrophic hormone (ACTH) will be characterized both under baseline conditions and in response to a mild stressor (confinement in a novel cage) and a moderate stressor (restraint). This experiment will determine whether suppression of baseline cortisol levels in subordinate females is associated with suppression of ACTH levels and with altered responsiveness to stressors. Experiment 2 will determine whether differences in plasma cortisol and, possibly, ACTH concentrations are caused by increased metabolic clearance of these hormones, by characterizing the plasma clearance rate of exogenous cortisol and ACTH. Experiment 3 will characterize ACTH and cortisol responses to dexamethasone, a synthetic glucocorticoid, to determine whether enhanced sensitivity to glucocorticoid negative feedback contributes to cortisol suppression in female marmosets. In Experiment 4, cortisol responses to exogenous ACTH will be determined, following administration of dexamethasone to suppress baseline cortisol secretion; this experiment will determine whether subordinate females exhibit reduced adrenocortical sensitivity to ACTH stimulation. Finally, in Experiment 5, the ACTH response to exogenous corticotropin-releasing hormone (CRH) will be characterized, following suppression of endogenous glucocorticoid synthesis by administration of the adrenal steroidogenesis inhibitor metyrapone; this experiment will determine whether suppression of cortisol in subordinate females is associated with altered pituitary responsiveness to CRH in the absence of glucocorticoid negative feedback. Together, these five experiments are expected to indicate that socially induced HPA suppression in subordinate female marmosets is caused by altered hypothalamic release of CRH or other ACTH secretagogs.
