MR: GR Balance in Depression

描述（由申请人提供）：压力与抑郁症密切相关，并且在大约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，即矿物皮质激素受体（MR）和糖皮质激素受体（GR）。大多数关于抑郁症的研究都集中在传统地塞米松抑制试验（DST）的GR上。但是，有很多理由可以预测MR可能与抑郁症有关。研究表明，MR与GR活性的平衡不仅对调节HPA轴很重要，而且与脑血清素系统特别相关。在尸检和神经影像学研究中发现，通过MR作用的皮质醇可以调节5HT1a受体，而5HT1a受体在重度抑郁症患者的大脑中被下调。应激和皮质醇升高，通过GR起作用，已被证明会增加5HT2a受体，抑郁症患者的5HT2a受体也会增加。我们建议根据MR和GR活性来表征重度抑郁症。具体来说，我们建议：1扩展我们之前的研究结果，即重度抑郁症患者的MR活动增加，通过对螺内酯刺激的ACTH和皮质醇反应来评估。根据我们的试点数据，我们假设在AM和PM螺内酯刺激下，与对照组相比，重度抑郁症患者的MR活性会增加。为了确定MR拮抗剂螺内酯评估的MR活性增加是否伴随着GR活性降低，在重度抑郁症受试者中，与GR激动剂地塞米松评估的相同个体。我们假设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.确定MR失调是否与抑郁症的高皮质醇血症有关。我们假设，与安慰剂相比，正常受试者在服用两剂量的螺内酯后，皮质醇会增加，而抑郁症患者在服用两剂量螺内酯后，皮质醇的增加幅度较小。4. 以确定核磁共振是否在人类的压力调节中起作用。我们将检查对特里尔社会压力测试的反应，并确定在螺内酯与安慰剂的存在下，ACTH和皮质醇对TSST的反应是否存在差异。我们将只在PM进行这些研究，这是TSST反应最强烈的时候，也是MR被认为发挥主要调节作用的时候。公共卫生相关性：压力在抑郁症中起着重要作用，抑郁症患者的典型压力激素皮质醇增加。皮质醇与两种不同的受体结合，MR和GR。但迄今为止的研究只真正研究了GR在抑郁症中的作用。我们建议描述MR和MR:GR平衡在抑郁症中的作用。

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.