Trajkovska Viktorija, Kirkegaard Lisbeth, Krey Gesa, Marcussen Anders B, Thomsen Morten S, Chourbaji Sabine, Brandwein Christiane, Ridder Stephanie, Halldin Christer, Gass Peter, Knudsen Gitte M, Aznar Susana
Neurobiology Research Unit and Centre for Integrated Molecular Brain Imaging (CIMBI), Copenhagen University Hospital, Unit 9201, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark.
Exp Neurol. 2009 Jul;218(1):83-91. doi: 10.1016/j.expneurol.2009.04.008. Epub 2009 Apr 18.
Major depression is associated with both dysregulation of the hypothalamic pituitary adrenal axis and serotonergic deficiency, not the least of the 5-HT2A receptor. However, how these phenomena are linked to each other, and whether a low 5-HT2A receptor level is a state or a trait marker of depression is unknown. In mice with altered glucocorticoid receptor (GR) expression we investigated 5-HT2A receptor levels by Western blot and 3H-MDL100907 receptor binding. Serotonin fibre density was analyzed by stereological quantification of serotonin transporter immunopositive fibers. To establish an effect of GR activation on 5-HT2A levels, mature organotypic hippocampal cultures were exposed to corticosterone with or without GR antagonist mifepristone and mineralocorticoid receptor (MR) antagonist spironolactone. In GR under-expressing mice, hippocampal 5-HT2A receptor protein levels were decreased (26.3 +/- 1.6%, p < 0.05) and frontal 5-HT2A receptor binding was decreased (20 +/- 15%, p < 0.01) as compared to wild-type mice. Conversely, in over-expressing GR mice hippocampal 5-HT2A receptor protein levels were increased (60.8 +/- 4.0%, p = 0.0001) and 5-HT2A receptor binding was increased in dorsal hippocampus (77 +/- 35%, p < 0.05) as compared to wild-type mice. No difference in serotonin fibre density was observed in the GR over-expressing mice, while the GR under-expressing mice showed lower serotonergic innervation in the frontal cortex area. An effect of GR activation on 5-HT2A receptor levels was further corroborated by the culture studies as long-term exposure of 3 microM corticosterone to organotypic hippocampal cultures increased 5-HT2A receptor levels (p < 0.05). The corticosterone-induced 5-HT2A receptor up-regulation was blocked by addition of either spironolactone or mifepristone.
重度抑郁症与下丘脑-垂体-肾上腺轴功能失调及血清素缺乏均有关联，5-HT2A受体的情况尤为突出。然而，这些现象如何相互关联，以及5-HT2A受体水平较低是抑郁症的一种状态标记还是特质标记尚不清楚。在糖皮质激素受体（GR）表达改变的小鼠中，我们通过蛋白质免疫印迹法和3H-MDL100907受体结合来研究5-HT2A受体水平。通过对5-羟色胺转运体免疫阳性纤维进行体视学定量分析血清素纤维密度。为确定GR激活对5-HT2A水平的影响，将成熟的海马脑片培养物分别暴露于有或无GR拮抗剂米非司酮及盐皮质激素受体（MR）拮抗剂螺内酯的皮质酮中。与野生型小鼠相比，GR表达不足的小鼠海马5-HT2A受体蛋白水平降低（26.3±1.6%，p<0.05），额叶5-HT2A受体结合减少（20±15%，p<0.01）。相反，与野生型小鼠相比，GR过表达的小鼠海马5-HT2A受体蛋白水平升高（60.8±4.0%，p = 0.0001），背侧海马的5-HT2A受体结合增加（77±35%，p<0.05）。在GR过表达的小鼠中未观察到血清素纤维密度有差异，而GR表达不足的小鼠在额叶皮质区域显示出较低的血清素能神经支配。培养研究进一步证实了GR激活对5-HT2A受体水平的影响，因为将3 microM皮质酮长期暴露于海马脑片培养物中会增加5-HT2A受体水平（p<0.05）。添加螺内酯或米非司酮可阻断皮质酮诱导的5-HT2A受体上调。
