Stress is a major determinant of vulnerability to debilitating psychiatric disorders including, depression, anxiety and substance abuse. The guiding goal of this research is to determine how neuromediators of the stress response interact with neural systems involved in emotion and behavior to produce mental and/or behavioral pathology. Towards this goal, we identified a critical link between stress and affective disorders by demonstrating that corticotropin-releasing factor (CRF), the neuropeptide that orchestrates the stress response, regulates activity of the dorsal raphe (DR)-serotonin (5-HT) system, a neurotransmitter system implicated in psychiatric disorders. Moreover, it was demonstrated that a history of stress changes the nature of CRF regulation of the DR-5-HT system from inhibition to excitation and that this is associated with a shift from active to passive coping behavior. Because passive behavior and inability to make decisions are characteristic and debilitating features of depression, understanding the mechanism of this stress-induced adaptation, the specific conditions that produce it and its sensitivity to pharmacological manipulation will advance our understanding of the pathophysiology of depression and our ability to design appropriate therapeutic strategies. This proposal for a competing renewal integrates diverse technical approaches (PCR, functional neuroanatomy, neurophysiology, microdialysis and behavior) and levels of analyses to achieve the following Specific Aims: 1) Identify molecular and cellular mechanisms underlying stress-induced changes in CRF regulation of the DR-5-HT system that promote a shift from active to passive behavior; 2) Determine whether certain social stressors (e.g., neonatal maternal separation or adult social stress) produce a shift in CRF regulation of the DR and whether this is responsible for depressive-like behavior in these models; and 3) Determine whether the stress-induced adaptations can be reversed by classical or novel antidepressant agents and the mechanisms by which these agents do this. The manner in which individuals respond to stress is a major factor in determining physical and mental health. The proposed studies will advance our knowledge of 1) the biological determinants of different coping styles, 2) mechanisms by which stress results in the debilitating course of depression and 3) how this can be manipulated by pharmacological agents and thereby guide development of novel antidepressants. ? ? ?
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