Glucocorticoid & corticosteriod receptor-dependence of HPA activity and behavior

描述(由申请人提供)：HPA活性升高作为抑郁症的生物标记物的使用受到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活性的升高归因于糖皮质激素反馈抑制的受损，这种抑制可以通过抗抑郁药诱导的脑糖皮质激素(GR)和盐皮质激素(MR)受体的增加来纠正。然而，抗糖皮质激素治疗给一些抑郁症患者带来的好处表明，增加GR或MR可能不是抗抑郁药物所必需或合适的，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的原因和标志。为了区分GR降低和糖皮质激素水平升高在HPA相关性抑郁症病理中的作用，本研究利用HPA过敏性抑郁症的模型--前脑GR基因敲除(FBGRKO)小鼠，验证了基础和抗抑郁剂诱导的抑郁行为的改变依赖于糖皮质激素分泌变化的假设。目的我将定义基础和应激诱导的HPA活性与急、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。目的II将通过测试肾上腺切除和固定糖皮质激素替代是否使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。目的III将通过使用肾上腺切除的FBGRKO和有无固定的糖皮质激素替代的GR对照来确定糖皮质激素在抗抑郁作用中的作用，以测试慢性抗抑郁治疗是否独立于糖皮质激素的变化而恢复正常的行为和下丘脑-垂体活动。这些研究解决了长期以来关于皮质类固醇受体和糖皮质激素在抑郁症中的作用的理论和矛盾。这项工作确定的前脑GR和糖皮质激素非依赖性效应可以解释抗抑郁药如何在不促进糖皮质激素对情绪的不利影响的情况下，使抑郁症患者升高的HPA活性正常化。这一信息可以用来更准确地预测和监测HPA多动症患者的抗抑郁反应。公共卫生相关性该项目将确定肾上腺糖皮质激素是否可能导致抑郁症状并影响抗抑郁效果。这些信息可能有助于为糖皮质激素水平异常的抑郁症患者识别更有效的抗抑郁药物，并设计更准确地检测抗抑郁药物反应的激素测试。由于抑郁症的康复依赖于早期有效的治疗，这项工作的结果可能最终通过最大限度地提高最初的治疗成功率来降低抑郁症的公共卫生成本。

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.