Carvalho Livia A, Pariante Carmine M
Section and Laboratory of Stress, Psychiatry and Immunology, Division of Psychological Medicine, Institute of Psychiatry, King's College London, London, UK.
Stress. 2008 Nov;11(6):411-24. doi: 10.1080/10253890701850759.
Clinical studies have demonstrated an impairment of glucocorticoid receptor (GR)-mediated negative feedback on the hypothalamus-pituitary-adrenal (HPA) axis in patients with major depression (GR resistance), and its resolution by antidepressant treatment. Accordingly, reduced GR function has also been demonstrated in vitro, in peripheral tissues of depressed patients, as shown by reduced sensitivity to the effects of glucocorticoids on immune and metabolic functions. We and others have shown that antidepressants in vitro are able to modulate GR mRNA expression, GR protein level and GR function. This paper reviews the in vitro studies that have examined the effect of antidepressants on GR expression, number and function in human and animal cell lines, and the possible molecular mechanisms underlying these effects. Antidepressants are shown to both increase and decrease GR function in vitro, based on different experimental conditions. Specifically, increased GR function is likely to be mediated by an increased intracellular concentration of glucocorticoids, while decreased GR function seems to be the consequence of GR downregulation. We suggest that the study of the effects of antidepressants on glucocorticoid function might help clarify the therapeutic action of these drugs.
临床研究表明，重度抑郁症患者的糖皮质激素受体（GR）介导的下丘脑 - 垂体 - 肾上腺（HPA）轴负反馈存在损害（GR抵抗），而抗抑郁治疗可使其恢复。相应地，在体外研究中，抑郁症患者外周组织中也显示出GR功能降低，表现为对糖皮质激素对免疫和代谢功能影响的敏感性降低。我们和其他人已经表明，体外抗抑郁药能够调节GR mRNA表达、GR蛋白水平和GR功能。本文综述了体外研究，这些研究考察了抗抑郁药对人和动物细胞系中GR表达、数量和功能的影响，以及这些影响背后可能的分子机制。基于不同的实验条件，抗抑郁药在体外既显示出增加GR功能，也显示出降低GR功能。具体而言，GR功能增加可能是由细胞内糖皮质激素浓度升高介导的，而GR功能降低似乎是GR下调的结果。我们认为，研究抗抑郁药对糖皮质激素功能的影响可能有助于阐明这些药物的治疗作用。
