Yau Joyce L W, Noble June, Thomas Sarah, Kerwin Robert, Morgan Phillip E, Lightman Stafford, Seckl Jonathan R, Pariante Carmine M
Endocrinology Unit, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Neuropsychopharmacology. 2007 Dec;32(12):2520-9. doi: 10.1038/sj.npp.1301389. Epub 2007 Mar 14.
The mechanisms by which antidepressants regulate the hypothalamic-pituitary-adrenal (HPA) axis are still unknown. The ABCB1-type multiple drug resistance (MDR) p-glycoprotein (PGP) regulates the HPA axis by limiting the access of glucocorticoids to the brain in mice and humans. Previous work in cell cultures has found that antidepressants enhance glucocorticoid receptor (GR) function in vitro by inhibiting MDR PGP, and therefore by increasing the intracellular concentration of glucocorticoids-but this model has never been tested directly in animals. Here, the tricyclic antidepressant, desipramine (20 mg/kg/day, i.p., for seven days), was administered to abcb1ab MDR PGP knockout mice (congenic on the FVB/N background strain) and to FVB/N controls. The hippocampal mRNA expression of GR, mineralocorticoid receptor (MR), MDR (Mdr1a) PGP, and 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) were measured, together with plasma corticosterone levels. In FVB/N controls, desipramine induced a significant upregulation of GR mRNA in the CA1 region (+31%; p=0.045); in contrast, in abcb1ab (-/-) mice, desipramine induced a significant downregulation of GR mRNA in the CA1 region (-45%; p=0.004). MR mRNA expression was unaltered. Desipramine decreased corticosterone levels in both FVB/N controls and in abcb1ab (-/-) mice, but in abcb1ab (-/-) mice the effects were smaller. Specifically, in FVB/N controls (but not in abcb1ab (-/-) mice), desipramine reduced corticosterone levels not only compared with saline-treated mice but also compared with the 'physiological' levels of untreated mice (-39%; p=0.05). Finally, desipramine reduced Mdr1a mRNA expression across all hippocampus areas (-9 to -23%), but had no effect on 11beta-HSD1 mRNA expression. These data support the notion that the MDR PGP is one of the molecular targets through which antidepressants regulate the HPA axis.
抗抑郁药调节下丘脑 - 垂体 - 肾上腺（HPA）轴的机制尚不清楚。ABCB1型多药耐药（MDR）P - 糖蛋白（PGP）通过限制糖皮质激素进入小鼠和人类大脑来调节HPA轴。先前的细胞培养研究发现，抗抑郁药在体外通过抑制MDR PGP来增强糖皮质激素受体（GR）功能，从而增加细胞内糖皮质激素浓度——但该模型从未在动物身上直接进行过测试。在此，将三环类抗抑郁药地昔帕明（20毫克/千克/天，腹腔注射，共七天）给予abcb1ab MDR PGP基因敲除小鼠（FVB/N背景品系的同源基因小鼠）和FVB/N对照小鼠。检测了GR、盐皮质激素受体（MR）、MDR（Mdr1a）PGP和11β - 羟基类固醇脱氢酶1型（11β - HSD1）的海马mRNA表达，以及血浆皮质酮水平。在FVB/N对照小鼠中，地昔帕明诱导CA1区GR mRNA显著上调（+31%；p = （0.045）；相反，在abcb1ab（-/-）小鼠中，地昔帕明诱导CA1区GR mRNA显著下调（-45%；p = 0.004）。MR mRNA表达未改变。地昔帕明降低了FVB/N对照小鼠和abcb1ab（-/-）小鼠的皮质酮水平，但在abcb1ab（-/-）小鼠中的作用较小。具体而言，在FVB/N对照小鼠中（而非abcb1ab（-/-）小鼠中），地昔帕明不仅与生理盐水处理的小鼠相比降低了皮质酮水平，而且与未处理小鼠的“生理”水平相比也降低了皮质酮水平（-39%；p = 0.05）。最后，地昔帕明降低了整个海马区域的Mdr1a mRNA表达（-9%至 - 23%），但对11β - HSD1 mRNA表达没有影响。这些数据支持了MDR PGP是抗抑郁药调节HPA轴的分子靶点之一这一观点。
