MR: GR Balance in Depression

描述（由申请人提供）：压力与抑郁症密切相关，在约30%的重度抑郁症患者中发现主要压力激素系统（下丘脑垂体肾上腺（HPA）轴）的基础激活增加。糖皮质激素通过两种不同的受体系统起作用，盐皮质激素受体（MR）和糖皮质激素受体（GR）。抑郁症的大多数工作都集中在GR与传统的地塞米松抑制试验（DST）。但是，有很多理由可以预期MR可能与抑郁症有关。研究表明，MR与GR活性的平衡不仅在调节HPA轴中很重要，而且与脑5-羟色胺系统特别相关。皮质醇通过MR起作用，已被证明可以调节5 HT 1a受体，在尸检和神经影像学研究中，这些受体在重度抑郁症患者的大脑中被下调。压力和皮质醇增加，通过GR起作用，已被证明增加5 HT 2a受体，这也增加了抑郁症患者。我们建议以MR和GR活性来表征抑郁症。具体而言，我们建议：1扩展我们先前的研究结果，即重度抑郁症受试者的MR活动增加，通过ACTH和皮质醇对螺内酯挑战的反应进行评估。根据我们的试点数据，我们假设与对照受试者相比，重度抑郁症患者在AM和PM螺内酯激发后的MR活动将增加。为了确定在重度抑郁症受试者中，MR拮抗剂螺内酯评估的MR活性增加是否伴随GR活性降低，与GR激动剂地塞米松评估的相同个体。我们推测抑郁症患者在地塞米松刺激后会表现出GR下调，从而增加血浆ACTH和皮质醇水平。结合增强的MR激活，这将导致MR：GR平衡的改变。3.探讨抑郁症患者高皮质醇血症是否与MR失调有关。我们假设，正常受试者将显示增加皮质醇，与安慰剂日相比，响应于2剂量的螺内酯，而抑郁症患者将显示响应于2剂量的螺内酯挑战的较小增加。4.确定MR是否在人类的压力调节中发挥作用。我们将检查对特里尔社会应激试验的反应，并确定在螺内酯与安慰剂存在下，ACTH和皮质醇对TSST的反应是否存在差异。我们将仅在PM中进行这些研究，此时TSST响应最稳健，并且认为MR发挥主要调节作用。公共卫生相关性：压力在抑郁症中起着重要的作用，抑郁症患者的原型压力激素皮质醇增加。皮质醇与两种不同的受体MR和GR结合，但迄今为止的研究只真正研究了GR在抑郁症中的功能。我们建议的特点的作用，MR和MR：GR平衡在抑郁症。

DESCRIPTION (provided by applicant): Stress is strongly linked to depression and increased basal activation of the main stress hormone system, the hypothalamic pituitary adrenal (HPA) axis, has been found in approximately 30% of patients with major depression. Glucocorticoids act through two different receptor systems, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Most work in depression has focused on GR with the traditional dexamethasone suppression test (DST). But, there are a number of reasons to expect that MR may be relevant for depression. Studies have suggested that the balance of MR to GR activity is important not only in regulating the HPA axis, but also particularly relevant to brain serotonin systems. Cortisol, acting through MR has been shown to regulate 5HT1a receptors, which have been shown to be down-regulated in brain in patients with major depression in both post-mortem and neuroimaging studies. Stress and increased cortisol, acting through GR, have been shown to increase 5HT2a receptors, which are also increased in patients with depression. We propose to characterize major depression in terms of MR and GR activity. Specifically, we propose: 1 To extend our previous findings of increased MR activity in subjects with major depression, as assessed by the ACTH and cortisol response to a spironolactone challenge. Based on our pilot data, we hypothesize that MR activity will be increased in patients with major depression compared to control subjects in response to both AM and PM spironolactone challenge. To determine if increased MR activity as assessed by the MR antagonist spironolactone is accompanied by decreases in GR activity is the same individuals, as assessed by the GR agonist dexamethasone, in subjects with major depression. We hypothesize that depressed patients will show GR downregulation and thus increased plasma ACTH and cortisol levels following dexamethasone challenge. Combined with enhanced MR activation, this will lead to an alteration in MR:GR balance. 3.To determine if MR dysregulation is involved in the hypercortisolemia of depression. We hypothesize that normal subjects will show increased cortisol, compared to placebo day, in response to 2 doses of spironolactone while depressed patients will show a smaller increase in response to the 2 dose spironolactone challenge. 4. To determine if MR plays a role in stress regulation in humans. We will examine response to the Trier Social stress test and determine if the there are differences in the ACTH and cortisol response to the TSST in the presence of spironolactone vs placebo. We will conduct these studies in the PM only, the time when the TSST response is most robust, and when MR is believed to play the predominant regulatory role. PUBLIC HEALTH RELEVANCE: Stress plays an important role in depression and the prototypical stress hormone, cortisol, is increased in patients with depression. Cortisol binds to 2 different receptors, MR and GR. But studies to date have only really examined GR function in depression. We propose to characterize the role of MR and the MR:GR balance in depression.