Study on the possibility of the Fischer 344 rats with stress-vulnerability for an animal model for depression

本研究的目的是探讨Fischer 344大鼠作为抑郁症动物模型的可能性。我们研究了长期服用抗抑郁药丙咪嗪对Fischer 344大鼠慢性应激适应不良的影响。本研究以下丘脑-垂体-肾上腺（HPA）轴的应激反应（糖皮质激素（GC）血药浓度）和c-fos mRNA表达作为应激适应的指标，在不给予抗抑郁药的情况下，重复束缚应激13 d后，GC血药浓度的变化规律没有改变。在c-fos mRNA表达的应激反应方面，Fischer 344大鼠在重复束缚应激7 d后出现延迟适应性变化，如应激诱导的c-fos mRNA表达增加减少。长期应用丙咪嗪可防止Fischer 344大鼠HPA轴对重复应激的适应不良，而Fischer 344大鼠c-fos mRNA表达的适应不良主要表现在下丘脑室旁核、隔外侧核和梨状皮质。长期服用丙咪嗪不能纠正。长期服用丙咪嗪后，应激开始60 min时GC血药浓度显著下降，而应激开始30 min时GC血药浓度峰值无明显变化，提示抗抑郁药对Fischer 344大鼠应激易感性有预防作用。因此，这是合理的，Fischer 344大鼠可能是一个合适的动物模型，抑郁症与先天性应激脆弱性。

The aim of this study is to investigate the possibility of the Fischer344 rats, who have been confirmed to be vulnerable to chronic stress, for a suitable animal model for depression. We investigated the effects of long-term administration of an antidepressant, imipramine, on maladaptation of Fischer344 rats to chronic stress. In this study, we used stress-responses of Hypothalamo-pituitary-adrenal (HPA) axis (blood concentration of glucocorticoids (GC)) and expression of c-fos mRNA as indices of stress adaptation.Without antidepressant administration, the pattern of blood concentration alteration of GC during stress was not changed with repeated restraint stress for 13 days. As for stress response of c-fos mRNA expression, Fischer344 rats showed delayed adapted change, such as a reduction of stress-induced increase in expression of c-fos mRNA, after repeated restraint stress for seven days. Usually, this adapted change of c-fos mRNA is revealed after three days stress in normal adaptation.Long-term administration of imipramine prevented the HPA axis of Fischer344 rats from maladaptaion to repeated stress, while maladaptation of c-fos mRNA expression of Fischer344 rats, which was revealed in paraventricular nucleus of hypothalamus, lateral nucleus of septum, and piriform cortex, was not corrected by long-term administration of imipramine. With long-term administration of imipramine, blood concentration of GC was decreased dramatically 60 min after the beginning of stress after seven days repeated stress, without an alteration of peak concentration at 30 min after the beginning of stress.These results suggest the preventive effect of antidepressants on stress vulnerability of Fischer344 rats. Consequently, it is plausible that Fischer344 rats could be a suitable animal model for depression with congenital stress vulnerability.