DEXAMETHASONE RESISTANCE; NEUROENDOCRINE MECHANISMS

地塞米松耐药性；

• 批准号: 3384893
• 负责人: PAUL M PLOTSKY
• 金额: $ 28.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3384893
• 关键词: Alzheimer's disease; centrally acting drug; circadian rhythms; clinical depression; corticosteroid receptors; corticotropin releasing factor; dexamethasone; drug adverse effect; drug resistance; glucocorticoids; hippocampus; hypothalamus; laboratory rat; neural information processing; neuroendocrine system; oxytocin; psychological stressor; secretion; vasopressins

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.

糖皮质激素（GCS）的分泌代表了A中的最后一步 神经内分泌级联反应从中枢神经系统内开始。 躯体和 心理压力源以及昼夜节律启动级联 通过释放下丘脑ACTH-sectagogues。 最近的重大进步 认识到CRF只是众多的主要内容的年份 促分子，Icnluding加压素（AVP），催产素（OT）和 儿茶酚胺。 叠加在这个复杂的调节系统上 GCS的负面反馈动作，作用于两种腺型物理 和CNS站点。 地塞米松（DEX）耐药性和高皮质醇的演示 在抑郁症和阿尔茨海默氏病（AD）中，生物学令人兴奋 精神病学，因为这些神经内分泌异常证明了 这种疾病的生物基础。 此外，只有一些 患者的肾上腺皮质异常使人相信 情感障碍的异质性，并答应了一种诊断工具 亚型抑郁症患者；但是，这种乐观有些乐观 衰弱。 而DEX耐药性的内分泌异常和 超皮质醇仍然证明了情感的生物学现实 疾病和AD，尚不清楚该生物学 现实是。 使用各种大鼠模型的糖皮质激素过度分泌 和反馈抵抗，该提案解决了一个广泛的问题： 反馈调节的机制是什么 肾上腺皮质轴可能在中枢神经系统水平上失败？ 有关基础缺陷的解剖基因座的知识 超级分泌正在缓慢积累，并暗示 功能障碍。 在这方面的两个特别有趣的地区是 海马和下丘脑。 我们将把研究重点放在 GC介导的反馈抑制的这些结构的推定作用 ACTH转换式发行，以及随之而来的失调综合症 这些结构的破坏导致。 具体来说，我们会的 调查：（1）遵循哪些ACTH销售的转向纪录。 海马或福尼克斯的破坏，（2） 海马或下丘脑皮质类固醇受体占用和 下生理因子释放，（3）改变的性质 ACTH转换概况介绍了上调或下调的 海马或下丘脑皮质类固醇受体。