Department of Psychological Medicine, Section of Perinatal Psychiatry and Stress, Psychiatry and Immunology Laboratory (SPI-Lab), Institute of Psychiatry, King's College London, London, UK.
Psychoneuroendocrinology. 2012 May;37(5):618-28. doi: 10.1016/j.psyneuen.2011.08.011. Epub 2011 Sep 29.
Our previous work in cellular and animal models has shown that antidepressants activate glucocorticoid receptor (GR) translocation, induce GR down-regulation, and decrease GR-mediated effects in the presence of GR agonists. However, whether these effects can be extrapolated to the human brain is still unclear. In this study, the effects of four days of treatment with the antidepressant, citalopram (20 mg/day), or placebo, were assessed in a double-blind, placebo-controlled, cross-over study. Central GR-mediated effects were examined by the effects of a single dose of cortisol (30 mg, orally) on two measures known to be sensitive to glucocorticoid administration: EEG alpha power and working memory function. Twenty healthy male subjects aged between 18 and 33 years participated to the study. The results suggest that GR activation by antidepressants, and the subsequent decrease in GR-mediated effects in the presence of GR agonists, indeed occurs in the human brain. Specifically, pre-treatment with citalopram decreased the well-known ability of cortisol to increase EEG alpha power and to impair working memory: cortisol-induced increase in EEG alpha power was (anteriorly) +15 to +20% (p=0.01) after placebo and +5 to +8% (p>0.5) after citalopram; and cortisol-induced increase in working memory errors was (at level 12, on average) 2.50 vs. 4.55 (p<0.05) after placebo and 4.10 vs. 3.35 (p>0.05) after citalopram. No effects were detected on alerting. These results are consistent with the notion that citalopram treatment activates GR translocation and inhibits the functional consequences of the subsequent cortisol administration. Our study further emphasizes the importance of the GR as a target for antidepressant action in humans.
我们之前的细胞和动物模型研究表明，抗抑郁药激活糖皮质激素受体 (GR) 易位，诱导 GR 下调，并在 GR 激动剂存在的情况下降低 GR 介导的作用。然而，这些作用是否可以推断到人类大脑中尚不清楚。在这项研究中，我们在一项双盲、安慰剂对照、交叉研究中评估了抗抑郁药西酞普兰（20mg/天）或安慰剂治疗 4 天的效果。通过单次给予皮质醇（30mg，口服）对两种已知对糖皮质激素给药敏感的测量值的影响来检查中枢 GR 介导的作用：脑电图α功率和工作记忆功能。20 名年龄在 18 至 33 岁之间的健康男性受试者参加了这项研究。结果表明，抗抑郁药确实会激活 GR，并在 GR 激动剂存在的情况下降低 GR 介导的作用。具体而言，西酞普兰预处理降低了皮质醇增加脑电图α功率和损害工作记忆的已知能力：皮质醇诱导的脑电图α功率增加在前额分别为+15 至+20%（p=0.01），安慰剂后为+5 至+8%（p>0.5），西酞普兰后为+5 至+8%（p>0.5）；皮质醇诱导的工作记忆错误增加（平均在 12 级），安慰剂后为 2.50 比 4.55（p<0.05），西酞普兰后为 4.10 比 3.35（p>0.05）。警觉性没有检测到影响。这些结果与西酞普兰治疗激活 GR 易位并抑制随后皮质醇给药的功能后果的观点一致。我们的研究进一步强调了 GR 作为人类抗抑郁药作用靶点的重要性。
