Study on the treatment of depression in terms of the spontaneous activity, ACTH and THmRNA -Efficacy of CRF binding protein, α-helical CRF and imipramine-

目的：探讨丙咪嗪和促肾上腺皮质激素释放因子(CRF)拮抗剂对应激抑郁模型大鼠下丘脑-垂体-肾上腺(HPA)轴功能增强和蓝斑(LC)神经元去甲肾上腺素(NA)合成的影响。方法：成年大鼠暴露于强迫步行应激2周，造成自发跑轮活动减少、血浆ACTH和皮质酮浓度升高的动物模型。给抑郁模型大鼠腹腔注射丙咪嗪(8 mg/kg/d)和生理盐水20d后断头测定血浆促肾上腺皮质激素和皮质酮水平及LC酪氨酸羟化酶(TH)基因表达，另一模型组大鼠LC注射促肾上腺皮质激素释放激素(α-Helical，α)拮抗剂、促肾上腺皮质激素释放因子(5μg/d)和生理盐水3d后，可明显增强大鼠的自发活动，降低促肾上腺皮质激素和皮质酮的浓度，降低THRNA1的表达。结果：1.丙咪嗪可增强抑郁模型大鼠的自发活动，降低促肾上腺皮质激素和皮质酮的浓度，降低THRNA1的表达。结果：1.丙咪嗪可增强抑郁模型大鼠的自发活动，降低促肾上腺皮质激素和皮质酮的浓度，降低THRNA1的表达。α、促肾上腺皮质激素释放激素、促肾上腺皮质激素释放激素和芦荟素也能降低促肾上腺皮质激素和皮质酮的浓度。在这些病例中，自发活动和THmRNA在最后一次注射的第二天降低，但在两周后增加。3.CRF对大鼠行为学和生物学指标的影响与CRF拮抗剂的治疗结果完全相反。这些结果表明，CRF拮抗剂和抗抑郁药都能减弱静息一段时间的LC神经元的HPA功能和NA合成，然后反弹诱导自发活动的合成。

Purpose : This research was attempted to investigate whether both imipramine and corticotropine releasing factor (CRF) antagonists attenuate the increased function of hypothalamo-pituitary-adrenal (HPA) axis and noradrenaline (NA) synthesis in the locus coeruleus (LC) neurons of the stress-induced depressin-model rats. Methods : Adult rats were exposed to a forced walking stress for two weeks to produce animals with low spontaneous wheel-running activity, and high concentration of plasma ACTH and corticosterone. Imipramine (8mg/kg/day) and saline were intrapeitoneally injected to the depression-model rats for 20 days measuring spontaneous activity followed by decapitation to examine plasma ACTH and corticosterone as well as the expression of tyrosine hydroxylase (TH) mRNA in LC.α-helical (αh) CRF (10μg/day), astressin (10μg/day) : CRF antagonists, CRF (5μg/day) and saline were injected into LC of the other model rats for three days followed by the examination of activity, ACTH, corticosterone and THmRNA Results : 1. Imipramine enhanced the spontaneous activity, but lowered the concentration of ACTH and corticosterone, and the expression of THmRNA.2. αhCRF and astressin also lowered the concentration of ACTH and corticosterone. In these cases the spontaneous activity and THmRNA decreased on the next day of the last injection, but increased two weeks later. 3. The effects of CRF on the behavior and those biological markers were completely opposite to the results of treatment with CRF antagonists. These findings suggest that CRF antagonists as well as antidepressants attenuate the HPA function and NA synthesis in LC neurons which stay in a rest for a while, then rebound the synthesis that induces spontaneous activity.