Pariante Carmine M, Thomas Sarah A, Lovestone Simon, Makoff Andrew, Kerwin Robert W
Institute of Psychiatry, King's College London, 1 Windsor Walk, Denmark Hill, London SE5 8AF, UK.
Psychoneuroendocrinology. 2004 May;29(4):423-47. doi: 10.1016/j.psyneuen.2003.10.009.
Although the effects of antidepressants on glucocorticoid hormones and their receptors are relevant for the therapeutic action of these drugs, the molecular mechanisms underlying these effects are unclear. Studies in depressed patients, animals and cellular models have demonstrated that antidepressants increase glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression and function; this, in turn, is associated with enhanced negative feedback by endogenous glucocorticoids, and thus with reduced resting and stimulated hypothalamic-pituitary-adrenal (HPA) axis activity. In a series of studies conducted over the last few years, we have shown that antidepressants modulate GR function in vitro by inhibiting membrane steroid transporters that regulate the intracellular concentration of glucocorticoids. In this paper, we will review the effects of membrane steroid transporters and antidepressants on corticosteroid receptors. We will then present our unpublished data on GR live microscopy in vitro, showing that ligand-induced translocation of the GR starts within 30 seconds and is completed within minutes. Furthermore, we will present our new data using an in situ brain perfusion model in anaesthetised guinea-pigs, showing that entry of cortisol to the brain of these animals is limited at the blood-brain barrier (BBB). Finally, we will present a comprehensive discussion of our published findings on the effects of chemically unrelated antidepressants on membrane steroid transporters, in mouse fibroblasts and rat cortical neurones. We propose that antidepressants in humans could inhibit steroid transporters localised on the BBB and in neurones, like the multidrug resistance p-glycoprotein, and thus increase the access of cortisol to the brain and the glucocorticoid-mediated negative feedback on the HPA axis. Enhanced cortisol action in the brain might prove to be a successful approach to maximise therapeutic antidepressant effects.
尽管抗抑郁药对糖皮质激素及其受体的作用与这些药物的治疗作用相关，但其潜在的分子机制尚不清楚。对抑郁症患者、动物和细胞模型的研究表明，抗抑郁药可增加糖皮质激素受体（GR）和盐皮质激素受体（MR）的表达及功能；这反过来又与内源性糖皮质激素增强的负反馈相关，从而与静息和刺激状态下下丘脑 - 垂体 - 肾上腺（HPA）轴活性降低有关。在过去几年进行的一系列研究中，我们已经表明，抗抑郁药通过抑制调节糖皮质激素细胞内浓度的膜类固醇转运体在体外调节GR功能。在本文中，我们将综述膜类固醇转运体和抗抑郁药对皮质类固醇受体的影响。然后，我们将展示我们未发表的体外GR实时显微镜数据，表明配体诱导的GR易位在30秒内开始并在数分钟内完成。此外，我们将展示我们使用麻醉豚鼠原位脑灌注模型的新数据，表明皮质醇进入这些动物脑内的过程在血脑屏障（BBB）处受到限制。最后，我们将全面讨论我们已发表的关于化学结构不相关的抗抑郁药对小鼠成纤维细胞和大鼠皮质神经元膜类固醇转运体影响的研究结果。我们提出，人类中的抗抑郁药可能会抑制位于血脑屏障和神经元上的类固醇转运体，如多药耐药p - 糖蛋白，从而增加皮质醇进入脑内的机会以及糖皮质激素对HPA轴的负反馈。增强脑内皮质醇的作用可能被证明是最大化抗抑郁治疗效果的一种成功方法。
