Glucocorticoid & corticosteriod receptor-dependence of HPA activity and behavior

糖皮质激素

基本信息

批准号：
8124877
负责人：
LAUREN JACOBSON
金额：
$ 24.48万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8124877
关键词：
Acute Address Adrenal Glands Adrenalectomy Anhedonia Antidepressive Agents Behavior Behavioral Biological Markers Brain Chronic Corticosteroid Receptors Corticosterone Corticotropin Corticotropin-Releasing Hormone Dependence Depressed mood Dose Feedback Gene Expression Glucocorticoid Secretion Inhibition Glucocorticoids Goals Health Health Care Costs Hormones Hypothalamic structure Imipramine Knock-out Knockout Mice Measures Mental Depression Mineralocorticoid Receptor Mineralocorticoids Modeling Monitor Monoamine Oxidase Inhibitors Mood Disorders Moods Mus Pathology Patients Pharmacology Phenelzine Physiology Pituitary Gland Plasma Predictive Value Prosencephalon Public Health Recovery Reporting Role Signal Transduction Stress Sucrose Symptoms Testing Therapeutic Effect Time Tricyclic Antidepressive Agents Uncertainty Vasopressins Work behavior test clinically relevant depressive symptoms design drug development effective therapy interest novel preference prevent receptor research study response success theories therapy development

项目摘要

DESCRIPTION (provided by applicant): The use of elevated HPA activity as a biomarker for depression is limited by uncertainty as to the relationship between HPA activity, mood, and antidepressant (AD) effects. Increased HPA activity in depression has been attributed to impaired glucocorticoid feedback inhibition that can be corrected by antidepressant-induced increases in brain glucocorticoid (GR) and mineralocorticoid (MR) receptors. However, benefits to some depressed patients from antiglucocorticoid therapies suggest that increasing GR or MR may not be required or appropriate for antidepressant action, and further suggest that by increasing glucocorticoids, elevated HPA activity might be a cause, as well as a marker, of depression. To discriminate the role of decreased GR from that of increased glucocorticoid levels in HPA-related depression pathology, this proposal uses forebrain GR knockout (FBGRKO) mice, a model of HPA-hyperactive depression, to test the hypothesis that that basal and antidepressant-induced changes in depression behaviors depend on changes in glucocorticoid secretion. Aim I will define the relationship of basal and stress-induced HPA activity to acute and chronic antidepressant actions to identify conditions for testing glucocorticoid and antidepressant effects. Aim II will determine glucocorticoid effects on basal behavior by testing if adrenalectomy and fixed glucocorticoid replacement normalizes depression-like behavior in FBGRKO mice. Aim III will determine the role of glucocorticoids in antidepressant action by using adrenalectomized FBGRKO and floxed GR controls with and without fixed glucocorticoid replacement to test if chronic antidepressant treatment normalizes behavior and hypothalamic- pituitary activity independently of changes in glucocorticoids. These studies address long-standing theories and contradictions of the roles of corticosteroid receptors and glucocorticoids in depression. Forebrain GR- and glucocorticoid-independent effects identified by this work could explain how antidepressants normalize elevated HPA activity in depression without facilitating adverse glucocorticoid effects on mood. This information could be used to predict and monitor antidepressant response more accurately in HPA-hyperactive depression. PUBLIC HEALTH RELEVANCE This project will determine if adrenal glucocorticoid hormones, which often increase in depression, might contribute to depression symptoms and influence antidepressant effects. This information could help to identify more effective antidepressants for depressed patients with abnormal glucocorticoid levels and to design hormone tests that detect antidepressant response more accurately. Since depression recovery depends on early effective treatment, results from this work could ultimately reduce the public health costs of depression by maximizing initial treatment success.

描述（由申请人提供）：使用升高的 HPA 活性作为抑郁症的生物标志物受到 HPA 活性、情绪和抗抑郁 (AD) 效果之间关系的不确定性的限制。抑郁症患者 HPA 活性增加归因于糖皮质激素反馈抑制受损，这种抑制可以通过抗抑郁药诱导的大脑糖皮质激素 (GR) 和盐皮质激素 (MR) 受体增加来纠正。然而，抗糖皮质激素治疗对一些抑郁症患者的益处表明，增加 GR 或 MR 可能不需要或不适合抗抑郁作用，并进一步表明，通过增加糖皮质激素，HPA 活性升高可能是抑郁症的一个原因和标志。。为了区分 GR 降低和糖皮质激素水平升高在 HPA 相关抑郁病理学中的作用，本提案使用前脑 GR 敲除 (FBGRKO) 小鼠（一种 HPA 过度活跃抑郁症模型）来检验以下假设：基础药物和抗抑郁药物诱导抑郁行为的变化取决于糖皮质激素分泌的变化。目标我将定义基础和应激诱导的 HPA 活性与急性和慢性抗抑郁作用的关系，以确定测试糖皮质激素和抗抑郁作用的条件。目标 II 将通过测试肾上腺切除术和固定糖皮质激素替代疗法是否使 FBGRKO 小鼠的抑郁样行为正常化来确定糖皮质激素对基础行为的影响。目标 III 将通过使用肾上腺切除的 FBGRKO 和 floxed GR 对照（有或没有固定糖皮质激素替代）来确定糖皮质激素在抗抑郁作用中的作用，以测试长期抗抑郁治疗是否使行为和下丘脑-垂体活动正常化，而与糖皮质激素的变化无关。这些研究解决了皮质类固醇受体和糖皮质激素在抑郁症中作用的长期理论和矛盾。这项工作确定的前脑 GR 和糖皮质激素独立作用可以解释抗抑郁药如何使抑郁症患者升高的 HPA 活性正常化，而不促进糖皮质激素对情绪的不利影响。该信息可用于更准确地预测和监测 HPA 过度活跃抑郁症的抗抑郁反应。公共卫生相关性该项目将确定肾上腺糖皮质激素（通常在抑郁症中增加）是否可能导致抑郁症状并影响抗抑郁效果。这些信息有助于为糖皮质激素水平异常的抑郁症患者找到更有效的抗抑郁药物，并设计更准确地检测抗抑郁反应的激素测试。由于抑郁症的康复取决于早期有效的治疗，这项工作的结果最终可以通过最大限度地提高初始治疗的成功率来降低抑郁症的公共卫生成本。