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）：将HPA活性升高作为抑郁症的生物标志物的使用受到HPA活性，情绪和抗抑郁（AD）效应之间关系的不确定性的限制。抑郁症中HPA活性的增加已归因于糖皮质激素反馈抑制受损，可以通过抗抑郁药诱导的脑糖皮质激素（GR）和矿物皮质激素（MR）受体的增加来纠正。但是，对来自抗核皮质类药物疗法的一些抑郁症患者的益处表明，增加或MR可能不需要或适合于抗抑郁作用，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原因，也可能是抑郁症的原因。。为了区分GR的作用与HPA相关抑郁病理学中糖皮质激素水平的降低的作用，该提案使用前脑GR基因敲除（FBGRKO）小鼠，这是HPA - 肌抑郁症的模型抑郁行为的变化取决于糖皮质激素分泌的变化。目的我将定义基础和应力诱导的HPA活性与急性和慢性抗抑郁作用的关系，以识别测试糖皮质激素和抗抑郁作用的条件。 AIM II将通过测试肾上腺切除术和固定糖皮质激素的替代方法来确定糖皮质激素对基础行为的影响，这使FBGRKO小鼠的抑郁样行为正常化。 AIM III将通过使用肾上腺切除术FBGRKO和FLOXED GR对照组来确定糖皮质激素在抗抑郁作用中的作用，并进行有或没有固定的糖皮质激素替代剂，以测试慢性抗抑郁治疗是否可以使行为和下丘脑 - 下垂体 - 垂体 - 垂体的活性在葡萄糖皮质激素的变化中独立于。这些研究涉及皮质类固醇受体和糖皮质激素在抑郁症中的作用的长期理论和矛盾。这项工作确定的前脑gr-和糖皮质激素非依赖性作用可以解释抗抑郁药如何使抑郁症的HPA活性升高而不促进不良糖皮质激素对情绪的影响。这些信息可用于在HPA肌抑郁症中更准确地预测和监测抗抑郁反应。公共卫生相关性该项目将确定肾上腺糖皮质激素通常会增加抑郁症，可能导致抑郁症状并影响抗抑郁作用。这些信息可以帮助鉴定出异常糖皮质激素水平的抑郁症患者的更有效的抗抑郁药，并设计激素测试，以更准确地检测抗抑郁药反应。由于抑郁症的恢复取决于早期有效治疗，因此这项工作的结果最终可以通过最大程度地提高初始治疗成功来降低抑郁症的公共卫生成本。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dorsal raphé nucleus glucocorticoid receptors inhibit tph2 gene expression in male C57BL/6J mice.

DOI：
10.1016/j.neulet.2017.11.041
发表时间：
2018-02-05
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Vincent MY;Donner NC;Smith DG;Lowry CA;Jacobson L
通讯作者：
Jacobson L

Glucocorticoid receptor deletion from the dorsal raphé nucleus of mice reduces dysphoria-like behavior and impairs hypothalamic-pituitary-adrenocortical axis feedback inhibition.

DOI：
10.1111/ejn.12538
发表时间：
2014-05
期刊：
The European journal of neuroscience
影响因子：
0
作者：
Vincent MY;Jacobson L
通讯作者：
Jacobson L

Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors.

DOI：
10.1016/j.brainres.2013.05.031
发表时间：
2013-08-07
期刊：
Brain research
影响因子：
2.9
作者：
Vincent MY;Hussain RJ;Zampi ME;Sheeran K;Solomon MB;Herman JP;Khan A;Jacobson L
通讯作者：
Jacobson L

Glucocorticoid status affects antidepressant regulation of locus coeruleus tyrosine hydroxylase and dorsal raphé tryptophan hydroxylase gene expression.