The glucocorticoid receptor: pivot of depression and of antidepressant treatment?
The glucocorticoid receptor: pivot of depression and of antidepressant treatment?
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DOI：
10.1016/j.psyneuen.2010.03.007
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发表时间：
2011-04
影响因子：
3.7
通讯作者：
Pariante, Carmine M.
中科院分区：
文献类型：
--
作者：
Anacker, Christoph;Zunszain, Patricia A.;Carvalho, Livia A.;Pariante, Carmine M.
抑郁症患者下丘脑 - 垂体 - 肾上腺（HPA）轴亢进以及糖皮质激素水平升高，大多归因于HPA轴的反馈调节受损，这可能是由糖皮质激素受体（GR）功能改变所致。反过来，抗抑郁药可改善抑郁症中的许多神经生物学紊乱，包括HPA轴亢进，从而缓解抑郁症状。有强有力的证据表明，抗抑郁药通过调节GR发挥这些作用。然而，这种调节可能是多方面的，从受体表达的调节到翻译后修饰，这可能导致GR核转位和GR依赖的基因转录的差异。抗抑郁药的治疗作用至少部分通过恢复GR功能来介导这一观点，与表明GR功能降低导致HPA轴亢进和抑郁症状发展的研究是一致的。相反，需要有活性GR的糖皮质激素信号过度与抑郁大脑中的功能损伤有关，特别是在海马体中，它导致神经发生减少和神经可塑性受损。
在这篇综述中，我们将重点关注GR作为抑郁症的诱发、发展和缓解过程中的关键因素。我们将讨论糖皮质激素抵抗与糖皮质激素信号过度的有害影响之间明显矛盾的可能解释。我们将回顾抗抑郁药调节GR的一些证据，并进一步深入了解抗抑郁药如何调节GR以克服抑郁症状。
Hyperactivity of the hypothalamus–pituitary–adrenal (HPA) axis and increased levels of glucocorticoid hormones in patients with depression have mostly been ascribed to impaired feedback regulation of the HPA axis, possibly caused by altered function of the receptor for glucocorticoid hormones, the glucocorticoid receptor (GR). Antidepressants, in turn, ameliorate many of the neurobiological disturbances in depression, including HPA axis hyperactivity, and thereby alleviate depressive symptoms. There is strong evidence for the notion that antidepressants exert these effects by modulating the GR. Such modulations, however, can be manifold and range from regulation of receptor expression to post-translational modifications, which may result in differences in GR nuclear translocation and GR-dependent gene transcription. The idea that the therapeutic action of antidepressants is mediated, at least in part, by restoring GR function, is consistent with studies showing that decreased GR function contributes to HPA axis hyperactivity and to the development of depressive symptoms. Conversely, excessive glucocorticoid signalling, which requires an active GR, is associated with functional impairments in the depressed brain, especially in the hippocampus, where it results in reduced neurogenesis and impaired neuroplasticity. In this review, we will focus on the GR as a key player in the precipitation, development and resolution of depression. We will discuss potential explanations for the apparent controversy between glucocorticoid resistance and the detrimental effects of excessive glucocorticoid signalling. We will review some of the evidence for modulation of the GR by antidepressants and we will provide further insight into how antidepressants may regulate the GR to overcome depressive symptoms.
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