The secretion of glucocorticoids (GCs) represents the final step in a neuroendocrine cascade beginning within the CNS. Somatic and psychogenic stressors, as well as circadian drive, initiate the cascade by releasing hypothalamic ACTH-secretagogues. A major advance in recent years in the recognition that CRF is only the principal of numerous secretagogues, icnluding vasopressin (AVP), oxytocin (OT) and catecholamines. Superimposed upon this complex regulatory system are the negative feedback actions of GCs, acting at both adenohypophysial and CNS sites. The demonstration of dexamethasone (DEX) resistance and hypercortisolism in depression and Alzheimer's disease (AD) was exciting for biological psychiatry, for these neuroendocrine abnormalities testifed to the biological underpinnings of such disorders. Furthermore, that only some patients had adrenocortical abnormalities gave credence to ideas of heterogeneity to affective disorders, and promised a diagnostic tool for sub-typing depressive individuals; however, some of this optimism has waned. While the endocrine abnormalities of DEX resistance and hypercortisolism still testify to the biological reality of affective disorders and of AD, it is not clear yet precisely what that biological reality is. Using various rat models of glucocorticoid hypersecretion and feedback resistance, this proposal addresses the broad issue: What are the mechanisms by which feedback regulation of the adrenocortical axis can fail at the CNS level? Knowledge concerning the anatomical locus of the defect underlying hypersecretion is slowly accumulating and implicate a CNS site of dysfunction. Two particularly interesting regions in this regard are the hippocampus and hypothalamus. We will focus our studies on the putative role of these structures of GC-mediated feedback inhibition of ACTH-secretagogue release, and attendant dysregulatory syndromes resulting from disruption of these structures. Specifically, we will investigate: (1) which ACTH-secretagogues are hypersecreted following destruction of the hippocampus or fornix, (2) the relationship between hippocampal or hypothalamic corticosteroid receptor occupancy and hypophysiotropic factor release, and (3) the nature of alterations in ACTH-secretagogue profile following up- or down-regulation of hippocampal or hypothalamic corticosteroid receptors.