Corticotropin-releasing Factor/Serotonergic Interactions

描述(由申请人提供)：压力是易患衰弱精神疾病的主要决定因素，包括抑郁、焦虑和药物滥用。这项研究的指导目标是确定应激反应的神经介质如何与涉及情绪和行为的神经系统相互作用，以产生心理和/或行为病理。为了达到这一目标，我们通过证明促肾上腺皮质激素释放因子(CRF)是协调应激反应的神经肽，调节中缝背核(DR)-5-羟色胺(5-HT)系统的活动，确定了应激与情感障碍之间的关键联系，该系统是与精神障碍有关的神经递质系统。此外，研究还表明，应激史将CRF对DR-5-HT系统的调节性质从抑制性改变为兴奋性，这与主动应对行为向被动应对行为的转变有关。由于被动行为和不能做出决定是抑郁症的特征和衰弱特征，了解这种应激诱导适应的机制、产生这种适应的特定条件以及它对药物操纵的敏感性将促进我们对抑郁症的病理生理学的理解和我们设计适当治疗策略的能力。这种竞争性更新的建议结合了不同的技术方法(聚合酶链式反应、功能神经解剖学、神经生理学、微透析和行为)和分析水平，以实现以下具体目标：1)确定压力诱导的DR-5-HT系统CRF调节的潜在分子和细胞机制，促进从主动行为向被动行为的转变；2)确定某些社会应激源(例如，新生儿母体分离或成人社交应激)是否导致CRF对DR的调节发生变化，以及这是否对这些模型中的抑郁样行为负责；3)确定应激诱导的适应能否被经典或新型抗抑郁药物逆转，以及这些药物逆转的机制。个体对压力的反应方式是决定身心健康的一个主要因素。这些研究将促进我们对1)不同应对方式的生物学决定因素，2)应激导致抑郁衰弱过程的机制，以及3)如何通过药理作用从而指导新型抗抑郁药物的开发的了解。

DESCRIPTION (provided by applicant): 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.