Sasuga Y, Asakura M, Miyamoto S, Bodaiji N
Department of Neuropsychiatry, St. Marianna University School of Medicine, Kawasaki, Japan.
Nihon Shinkei Seishin Yakurigaku Zasshi. 1997 Oct;17(5):193-200.
Dysregulation in the negative feedback of the hypothalamus-pituitary-adrenal (HPA) system is observed in a subgroup of major depression. Recent studies have postulated that tricyclic antidepressant treatment increases the glucocorticoid receptor (GR) in the brain and that such GR up-regulation normalizes the hyperactivity of HPA systems. The GR is associated with heat-shock proteins (HSPs) as a functional complex with a high affinity for steroid binding. In this study, we have examined the effects of chronic fixed (restraint) stress (CFS) and chronic variable stress (CVS) on the subcellular localization of GR and HSP90 in rat hippocampus using an immunoblotting procedure. A single restraint stress for 1-2 h and a single treatment with dexamethasone (DEX) 0.5 mg/kg, s.c. induced a translocation of the cytosolic GR to nuclei. Long-term treatment with DEX 0.1 mg/kg, s.c. for 14 days caused a significant decrease in both cytosolic and nucleic GR. There was no significant change in either cytosolic or nucleic GR after CFS for 14 days. However, CVS for 14 days increased both cytosolic GRs and HSP90 while nucleic GR was not changed. CFS for 14 days had no influence on the DEX-induced translocation of GR to nuclei, whereas GR translocation by DEX was not observed after CVS for 14 days. Gel filtration chromatography of the hippocampal cytosol after CVS indicated an increase in monomeric GR (approximately 90 kDa) and a decrease in the GR-HSP complex (approximately 300 kDa). Since CVS has been reported to increase serum corticosterone in rats, our results suggest that CVS prevents formation of the GR-HSP complex. A new intracellular environment rather than excessive serum corticosterone caused by CVS may contribute to inhibition of the formation of GR-HSP complex. It is proposed that the CVS could be an appropriate model for disturbance in the negative feedback control of HPA systems.
在一部分重度抑郁症患者中观察到下丘脑-垂体-肾上腺（HPA）系统负反馈调节失调。最近的研究推测，三环类抗抑郁药治疗可增加大脑中的糖皮质激素受体（GR），且这种GR上调可使HPA系统的过度活跃恢复正常。GR与热休克蛋白（HSPs）结合形成一种对类固醇具有高亲和力的功能复合物。在本研究中，我们使用免疫印迹法检测了慢性固定（束缚）应激（CFS）和慢性可变应激（CVS）对大鼠海马体中GR和HSP90亚细胞定位的影响。单次1-2小时的束缚应激和单次皮下注射0.5mg/kg地塞米松（DEX）可诱导胞质GR向细胞核的转位。皮下注射0.1mg/kg DEX长期治疗14天导致胞质和核GR均显著降低。CFS 14天后，胞质或核GR均无显著变化。然而，CVS 14天可增加胞质GR和HSP90，而核GR未改变。CFS 14天对DEX诱导的GR向细胞核的转位没有影响，而CVS 14天后未观察到DEX诱导的GR转位。CVS后海马体胞质的凝胶过滤层析表明单体GR（约90 kDa）增加，GR-HSP复合物（约300 kDa）减少。由于据报道CVS可增加大鼠血清皮质酮，我们的结果表明CVS可阻止GR-HSP复合物的形成。CVS导致的新的细胞内环境而非过多的血清皮质酮可能有助于抑制GR-HSP复合物的形成。有人提出CVS可能是HPA系统负反馈控制紊乱的合适模型。
