| Summary: | 碩士 === 長庚大學 === 生物醫學研究所 === 98 === Stress is one of the major triggering factors related to major depression with characteristic HPA axis (hypothalamus-pituitary-adrenal) over-reactivity. Previous studies indicated the deficiency of HPA axis negative feedback during chronic stress is mainly caused by glucocorticoid receptor (GR) resistance which resulted in high concentration of corticosterone (CORT) in blood circulation though the mechanism of GR resistance remains unclear. On the other hand, the mineralocorticoid receptor (MR) also plays a role in regulating the basal HPA activity though mechanism of GR on stress and/or depression remained unclear. To investigate the role of CORT and GR/MR on stress-induced depression as well as the relationship with hippocampal serotonin system, we established an animal model by injecting ICR mice with chronic low dose CORT (40 mg/kg) for 21 days. In an attempt to correlate with depressive symptoms, a series of behavioral tests were evaluated. In the CORT-treated group, we found the immobility time of forced swim test (FST) significantly increased while the amount of sucrose intake significantly decreased as compared to vehicle control. The stereotypic counts at latter testing session of CORT-treated animals were higher than control group whiles the discrimination index of the novel object recognition test of CORT-treated animals was lower than the control, suggesting that CORT-treated animals display a cognitive deficiency and anxiety. On the other hand, results from Nissl stain indicated hippocampal CA1, CA3 and dentate gyrus displayed similar size between CORT-treated and control groups. Biochemical analysis revealed that amount of hippocampal serotonin increased significantly in the CORT-treated group, along with an increase in amount of TPH, but not the SERT in hippocampus. These preliminary results suggest chronic treatment with low-dose CORT triggers certain depressive behaviors and increases serotonin synthesis in hippocampus, possibly due to a feedback regulation against excess corticosterone. To investigate the relationship between GR resistance and depression, we further examined total amount and function of GR via immunoprecipitation of GR for its associated chaperone, heat-shock protein (HSP) 90 but found no difference in between these two groups. On the contrary, we found amount of MR in both hippocampus and hypothalamus decreased in the CORT group. When animals were co-administered with both CORT and MR antagonist spironolactone, we found MR antagonist could reverse the effect of CORT on novel object recognition test. In addition, MR antagonist treatment showed a tendency to decrease the immobility time in FST of CORT-treaed group, suggests MR antagonist might be practically used to treat major depression. The detailed biochemical and morphological analyses in regard of spironolactone and CORT co-treatment will be assessed in the near future.
|
|---|
