This competitive renewal application seeks support to continue our preclinical and clinical studies concerning the neurobiology of corticotropin-releasing factor (CRF) and its role in the pathophysiology of major depression. Considerable evidence from a number of investigators using different experimental approaches has accrued in the last decade consistent with the hypothesis that CRF mediates the endocrine, behavioral and autonomic responses of mammals to stress. Preclinical investigations focus on stress-associated alterations in CRF neurons, CRF receptors and CRF signal transduction, interactions of CRF with neurons in the locus coeruleus and nearby parabrachial nucleus, and the modification of these observed effects by treatment with anxolytic and antidepressant drugs. In addition, the effects of stress in neonatal rats on subsequent stress responsiveness of CRF neurons and CRF signal transduction in adult rats is proposed. The preclinical studies utilize behavioral, neurochemical and electrophysiological measures. One focus of the clinical studies is an analysis of CRF neuronal systems in postmortem brain tissue of depressed suicide victims. In both the preclinical studies and the postmortem studies, the following measures are obtained: CRF concentrations, CRF mRNA levels, CRF receptor binding and CRF signal transduction. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most well-- documented findings in major depression. Therefore another focus of the clinical studies proposed is to determine the relationship between pituitary and adrenal gland enlargement, as assessed by magnetic resonance imaging (MRI) and computed tomography (CT), respectively, the attenuated ACTH response to CRF and elevations in CSF CRF concentrations. These studies will provide further information on the role of CRF in the CNS, and in particular the role of hypersecretion of CRF in the pathophysiology of major depression. Such studies have important implications for the development of novel treatments for major depression and perhaps anxiety disorders.
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