电针和“宁心健脾”中药对慢性应激模型鼠HPA轴-GR-NMDAR通路的影响
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摘要
抑郁症(depression)由复杂原因引起的以情绪低落为主要症状的一组临床症状群或状态,是一类心境障碍(mood disorders)或情感障碍(affective disorders)疾病。抑郁症给人类带来的危害极大,数百年来现代医学一直致力于研究和揭示该病的发生机制,但是目前仍然不能完全而确切的解释该病的来龙去脉,西药治疗抑郁症目前还存在一些盲点和附带反应。祖国医学源远流长,中医药方法治疗情致类疾病由来已久,中医理论从独特的视角认识并治疗情致疾病,且具有现代医学不可替代的许多优势,不仅对抑郁症情绪改变的核心症状有明确的疗效,对该病的周边症状的改善也有明显的作用。因此,为了更好的推广中医药方法治疗抑郁症这一手段,并在世界范围内得到认可,作为中医药科研工作者必然要致力于用现代科技手段来揭示传统医学方法原理的科研工作中。
我们的课题小组已经完成了大量的前期工作,我的论文是在这一基础上的延伸与拓展,是一系列有关抑郁症的基础动物实验研究部分,为进一步的临床研究提供前期的工作依据和理论基础。
目的:通过建立慢性应激大鼠模型,一方面围绕若干抑郁症的核心精神症状设立一系列行为学指标的检测,观察中医药方法对这些行为学的影响,并进行系统的动态行为学观察,观察中药和电针的不同起效时段,并进一步探讨建立慢性应激的证侯模型的可能性;另一方面试图进一步发掘抑郁症发病机制的某些新途径,并观察中医药方法是否通过这些新途径来干预抑郁症的发生,以及电针、中药和氟西丁在抗抑郁的过程中各自的作用特点。
方法:采用慢性应激结合孤养的方法建立抑郁大鼠模型;将大鼠随机分为5组,分别为正常组、模型组、氟西丁组、中药组、电针组,每组10只;采用开野实验、强迫游泳实验、“Y”型电迷宫实验,糖水消耗实验等判断模型的可靠程度并观察中药和电针对模型大鼠活动性、绝望程度、学习记忆能力以及快感缺失等行为表现的影响;放免法检测大鼠下丘脑CRF,垂体ACTH、肾上腺CORT;免疫组化方法检测海马内GR、NMDA、NR2B;PKA、CREB;Nestin。
结果:
1.慢性应激结合孤养方法建立抑郁模型大鼠行为学检测:
1.1 Open-Field试验:
1.1.1水平运动结果:与空白组比较,模型大鼠活动总路程显著下降(P<0.01),中药组和电针组总路程与空白组比较也有明显下降(P<0.01),但是与模型组比较差异性仍有显著意义(P<0.01);中药和电针组与氟西丁组比较有显著差异(P<0.05,P<0.01)。实验第10天各组大鼠水平运动的总路程即表现出一定的差异,电针和中药NY-3号都有一定的作用,但电针组起效快,中药组的起效过程较为平稳。
1.1.1垂直运动结果:与空白组比较,造模各组站立次数均显著减少(P<0.01);与模型组比较,中药组和电针组有统计学意义(分别P<0.01,P<0.05);电针组与氟西丁组比较无统计学意义(P>0.05),而中药组与氟西丁组比较有统计学意义(P<0.05);中药组与电针组之间比较有统计学意义(P<0.05)。实验第10天各组大鼠站立次数也开始表现出一定的差异,氟西丁和电针起效较早,中药组作用较为平稳。
1.2强迫游泳试验:
各组大鼠强迫游泳实验成绩显示:与空白组比较,应激使模型大鼠的游泳不动时间显著延长(P<0.01);三个治疗组与模型组比较游泳不动时间也有统计学意义(分别P<0.01,P<0.05)。实验开始后第一周,各造模组游泳不动时间即迅速延长,但治疗各组均表现出一定的拮抗作用。与空白组和模型组比较,三组的游泳不动时间较空白组差距较大,虽然与模型组比较有统计学意义,但仍然距模型组水平比较接近。
1.3“Y”型电迷宫实验:
1.3.1各组大鼠学习成绩显示:与空白组比较,应激使各组造模大鼠的学习能力大幅度下降(P<0.01);与模型组比较,中药组和电针组学习成绩有所提高(P<0.01,P<0.05);与氟西丁组比较,中药组学习成绩有显著差异(P<0.05),电针组无显著差异(P>0.05)。电针组与中药组比较其学习成绩有统计学意义(P<0.05)。
1.3.2各组大鼠记忆成绩结果显示:与空白组比较,应激使各组造模大鼠的记忆能力大幅度下降(P<0.01,P<0.05);与模型组比较,中药组和电针组记忆成绩有所提高(P<0.01);与氟西丁组比较,中药组和电针组的记忆成绩无显著差异(P>0.05)。电针组与中药组比较其学习成绩无统计学意义(P<0.05)。
1.4各组大鼠糖水消耗实验结果:
与空白组比较,应激使各组造模大鼠一小时内糖水摄入量明显减少(P<0.01),但治疗各组与模型组比较能明显增加糖水的摄取量(P<0.05或P<0.01);其中电针组的糖水摄取量多于中药组,结果有显著性意义(P<0.01)。
2.各组大鼠下丘脑CRF,垂体ACTH、肾上腺CORT放免法检测结果:与空白组比较,模型组大鼠下丘脑CRF,垂体ACTH,肾上腺CORT显著升高(P<0.01或P<0.05)。与模型组比较,除中药、电针对垂体ACTH的含量影响没有显著性意义(P>0.05)外,各组治疗组对大鼠HPA轴各激素含量升高都有明显拮抗作用(P<0.01或P<0.05)。在垂体ACTH含量上,电针和中药治疗后仅显示出降低垂体ACTH含量的趋势。
3.各组大鼠海马GR、NMDAR、NR2B免疫组化检测结果:
3.1海马GR:与空白组比较,模型组大鼠海马内GR表达强度有显著差异(P<0.01),而中药组、电针组和氟西丁组均无统计学差异(P>0.05);与模型组比较,氟西丁组差异无显著性(P>0.05),中药组和电针组GR表达强度有显著性意义(P<0.05,P<0.01),三个治疗组之间比较都没有统计学意义(P>0.05),但从秩和和平均秩和的数据来看,电针组比氟西丁组和中药组的作用更接近于正常组。
3.2海马NMDAR:与空白组比较,模型组大鼠海马内GR表达强度有显著差异(P<0.05),而中药组、电针组和氟西丁组均无统计学差异(P>0.05);与模型组比较,氟西丁组未表现出显著差异(P>0.05),而中药和电针组与之比较有显著性差异(P<0.01);三个治疗组之间海马GR表达强度无统计学差异(P>0.05)。
3.3海马NR2B:与空白组比较,模型组和中药组大鼠海马内NR2B表达强度有显著差异(P<0.01),而电针组和氟西丁组均无统计学差异(P>0.05);与模型组比较,氟西丁组和电针组有显著性差异(P<0.01,P<0.05),中药组与之比较无统计学差异(P>0.05);与氟西丁组比较,中药组有显著性差异(P<0.01),电针组差异无显著性(P>0.05);电针组与中药组之间比较也有显著性差异(P<0.01)。
4.各组大鼠海马PKA、CREB免疫组化检测结果:
4.1海马PKA:与空白组比较,模型大鼠海马内PKA阳性表达强度有显著差异(P<0.05),三个治疗组与之比较差异无显著性(P>0.05);与模型组比较,氟西丁组无显著性差异(P>0.05)而中药和电针组差异有显著性(P<0.01);与氟西丁组比较,中药组无显著差异(P>0.05)而电针组有差异有显著性(P<0.01);中药和电针组之间无显著性差异(P<0.05)。
4.2海马CREB:与空白组比较,模型大鼠海马内CREB阳性表达强度有显著差异(P<0.01),三个治疗组与之比较差异无显著性(P>0.05);与模型组比较,三个治疗组都表现出显著性差异(分别P<0.05,P<0.01,P<0.01);三组治疗组之间两两比较也没有显著性差异(P>0.05)。
5.各组大鼠海马Nestin免疫组化检测结果:
与空白组比较,模型大鼠海马内Nestin阳性表达强度差异未表现出显著性(P>0.05),中药和电针组与之比较也没有显著性差异(P>0.05)而氟西丁组与之有显著性差异(P<0.01);与模型组比较,电针组有显著性差异外(P<0.01),其余两个治疗组与之比较差异无显著性(P>0.05);与氟西丁组比较,中药和电针组均有显著性差异(P<0.01),而中药和电针组之间差异无显著性(P<0.01)。
结论:
1.本实验所采用的慢性应激结合孤养的动物模型能够表现出一定的活动性和兴趣降低,快感缺失以及学习记忆能力减退等现象,证明实验在行为学上能够模仿抑郁的某些精神症状的表现。在参考抑郁症的“病”“证”结合研究成果后,我们初步假设本次实验所建立的慢性应激结合孤养的动物模型可能与“肝郁”和“脾气虚”两种证型关系较为密切。实验结果提示中药和电针具有很好的抵抗大鼠活动度和兴趣减低、改善慢性应激大鼠的行为绝望程度、提高学习记忆能力,增加大鼠对奖赏刺激的敏感性、改善大鼠的快感缺失等一系列拟抑郁症精神症状的行为学改变。电针对大鼠的活动性和探究行为的影响起效较快,而氟西丁和中药则表现出较为平稳的疗效。2.慢性应激结合孤养能持续激活脑内HPA轴,提示实验造模能够模仿抑郁发病中的HPA轴持续亢进的状态。中药和电针具有拮抗模型鼠体内异常的HPA轴亢进。3.慢性应激结合孤养大鼠模型的海马GR、NMDAR、NR2B的阳性表达降低,其原因可能是由于Glu的在突触内长期堆积,导致三种受体的敏感性降低。这样可以使HPA轴的负反馈作用降低,导致其过度激活而引发一系列症状。中药和电针具有拮抗模型鼠海马GR、NMDAR、NR2B敏感性降低的作用。
4.慢性应激结合孤养大鼠模型的海马各亚区PKA、CREB降低,这种改变可能进一步通过其下游机制影响学习记忆功能和造成海马神经元的损伤,其下游通路有待进一步探讨。中药和电针具有拮抗模型鼠海马各亚区PKA、CREB降低的作用。
5.慢性应激结合孤养大鼠模型的海马内Nestin的阳性表达有降低趋势,我们认为这种改变可能是HPA轴-GR-NMDA通路的作用结果。中药和电针具有增强海马内Nestin的作用,且其作用机制可能与氟西丁不同。
Depression is a series clinical symptom or states in which was caused by many complex reason and the patients experience a sustained low mood, it is a kind of mood disorders or affective disorders. Depression has bring many serious harm to us and modern chemical medicine have put many efforts on the study of depression, but several hundred years have passed, we still can’t make it fully clarified in the field of modern medicines. Also, in treating depression, there are some bland spots and secondary action in modern medicines.
But, as a matter of fact, Chinese medicine has already been used as a therapy to treat depression for thousands of years. We have our special theory to deal with this disease and it has been confirmed effectiveness in treating both the core and the side symptoms. So how to develop its advantages, clarify its mechanism, and improve its positive effectiveness, has become an urgent and valuable researching topic to the scientific researchers.
This thesis is a foundation research which is a part of a series projects of depression belong to my tutor professor Tu, and this research will supply the basis theory foundation for the clinical research next to it.
Objective: We built some behaviors tests to observe the depression-like symptoms of the chronic stress depression rats model and the influences of Traditional Chinese Medicine on them. At the same time, we try to find some new ways of how depression occurs and whether the anti-depression mechanisms of T.C.M. methods are through this ways.
Methods: The depression rats model was built by chronic stress on them, then they were assigned into 5 groups: the control group, the model group, the Prozac group, the NY-3 group, the EA group, each has 10 rats. To observe the influence of T.C.M. on the behaviors about movements, appetite and learning of them; The expression of GR、NMDA、NR2B、PKA、CREB、Nestin、ChAT and 5-HT in hippocampal tissue was detected by immunohistochemical technology. Results:
1. Behavior results of the chronic stress depression rats models:
1.1 Open-Field test:
1.1.1 Results of plane-moving:The total distance traveled by the model rats was declined compare with the contral group(P<0.01), and which of the EA group and NY-3 group was also declined(P<0.01) but still more than the model rats(P<0.01).While the distance has no significant change in the Prozac group(P>0.05). There is no difference between the NY-3 group and the EA group(P>0.05)。The total distance of each group was changed at the 10th day, the EA group does work faster than the other two treating groups and it’s total distance was the nearest to the control group. But the later effect of EA was not so good.
1.1.1 Results of vertical-moving:Compare with the contral group, the numbers of standup of the model rats was declined significantly(P<0.01) but which of the EA group and NY-3 group were more than the model group(P<0.01,P<0.05). The numbers of standup of the EA group is more than the NY-3 group(P<0.05)。The total distance of each group was changed at the 10th day, the Prozac group does work faster than the other two treating groups and it’s total distance was the nearest to the control group. There is no difference between the NY-3 group and the EA group. In this test, the EA group work well in the first 10 days, but it’s effection dropped in the last 10 days.
1.2 Force swimming test:It showes that the still-swimming time of the model group declined than the contral group(P<0.01), and which of the three treating groups was increased than the model group(P<0.01,P<0.01,P<0.05). The results of stilling-time of this three treating group is not as much as the contral group.
1.3“Y”-mazing test:
1.3.1 Learning results:Compare with the contral group, chronic stress could week the rats‘ability of learning(P<0.01), and the NY-3 group and the EA group can anty this change(P<0.01) while the Prozac group showes no changes(P>0.05).
1.3.2 Memory results:Compare with the contral group, chronic stress could reduce the rats‘ability of memory ability(P<0.01,P<0.05) and the NY-3 group and the EA group could enhance this ability(P<0.01).
1.4 Results of Sugar intake test: Compare with the contral group, the sugar intake a- mount of model group dropped (P<0.01). While the sugar intake amount of all the tresting groups was much more than the model rats(P<0.05或P<0.01); EA group shows significantly differences when compared with the other treating groups(P<0.01).
2.Results of the CRF in hypothalamus, ACTH in pituitary gland, CORT in adrenal gland by RIA method: CRF, ACTH and CORT were increased greatly in the model group (P<0.01, P<0.05)and even the EA and the NY-3 group did not show great effect of decreased the CRF and CORT level significantly but we can see the kind of trend in them.
3.The expression of GR、NMDA、NR2B in hippocampal tissue detected by immunohistochemical technology:
3.1 GR in hippocampal:Compared with the contral group, GR in hippocampal of the model rats was reduced than the contral group(P<0.01) while GR in hippocampal of the three treating groups showes no difference(P>0.05). GR in hippocampal of the EA groups was the nearest to the contral group than the other two.
3.2 NMDAR in hippocampal : Compared with the contral group, NMDAR in hippocampal of the model rats was reduced than the contral group(P<0.05) while the three treating groups showes no difference(P>0.05). There was no difference among the EA ,NY-3 and the Prozac group(P>0.05).
3.3 NR2B in hippocampal:Compared with the contral group, NR2B in hippocampal of the model and NY-3 groups was reduced than the contral group(P<0.01) while the EA and the Prozac groups showes no difference(P>0.05). The NY-3 group shows the weakest effection among the three treating groups. (P<0.01)
4.The expression of PKA、CREB in hippocampal tissue detected by immunohisto- chemical technology:
4.1 PKA in hippocampal:Compared with the contral group, PKA in hippocampal of the model rats was reduced than the contral group(P<0.05) while PKA in hippocampal of the three treating groups showes no difference(P>0.05). In this test, it showes that the Prozac group has little effection than the NY-3 group and the EA group.
4.2 CREB in hippocampal:Compared with the contral group, CREB in hippocampal of the model rats was reduced than the contral group(P<0.01) while CREB in hippocampal of the three treating groups showes no difference(P>0.05). Compared with the model group, CREB in hippocampal of the three treating groups showes great difference(P<0.05,P<0.01,P<0.01) and there is no difference between the three treating groups(P>0.05).
5.Nestin in hippocampal:Compared with the contral group, Nestin in hippocampal of the model rats showes no difference(P>0.05) while the NY-3 group and the EA group also showes no difference(P>0.05). Nestin in hippocampal of the Prozac group was the lest among all the groups (P<0.01).
Conclusions:
1.Cronic stress rat model shows some depression-like psychological symptoms such as movement and curricity reduced helpless, lack of happiness and the ability of learning and study reduced. NY-3 and acupouncture have the recover to reduce these symptoms.
2.Cronic stress could activate the path way of HPA continually and NY-3 and acupouncture could resist it.
3.GR、NMDAR、NR2B which was dropped in the model.NY-3 and acupouncture could enhance the sensitivity of the receptors which was dropped in the model. The reason for this maybe too much of Glu stayed in the synaps for so long time. These cause the back reflact of the HPA weaked.
4. NY-3 and acupouncture could anti the weekness of expression of PKA and CREB in hippocampal in the model.
5. The expression of Nestin in hippocampal of the model rats was reduced but NY-3 and acupouncture could resist the change. The cappable function may have some relationship with the pathway of HPA-Glu-NMDA.
我们的课题小组已经完成了大量的前期工作,我的论文是在这一基础上的延伸与拓展,是一系列有关抑郁症的基础动物实验研究部分,为进一步的临床研究提供前期的工作依据和理论基础。
目的:通过建立慢性应激大鼠模型,一方面围绕若干抑郁症的核心精神症状设立一系列行为学指标的检测,观察中医药方法对这些行为学的影响,并进行系统的动态行为学观察,观察中药和电针的不同起效时段,并进一步探讨建立慢性应激的证侯模型的可能性;另一方面试图进一步发掘抑郁症发病机制的某些新途径,并观察中医药方法是否通过这些新途径来干预抑郁症的发生,以及电针、中药和氟西丁在抗抑郁的过程中各自的作用特点。
方法:采用慢性应激结合孤养的方法建立抑郁大鼠模型;将大鼠随机分为5组,分别为正常组、模型组、氟西丁组、中药组、电针组,每组10只;采用开野实验、强迫游泳实验、“Y”型电迷宫实验,糖水消耗实验等判断模型的可靠程度并观察中药和电针对模型大鼠活动性、绝望程度、学习记忆能力以及快感缺失等行为表现的影响;放免法检测大鼠下丘脑CRF,垂体ACTH、肾上腺CORT;免疫组化方法检测海马内GR、NMDA、NR2B;PKA、CREB;Nestin。
结果:
1.慢性应激结合孤养方法建立抑郁模型大鼠行为学检测:
1.1 Open-Field试验:
1.1.1水平运动结果:与空白组比较,模型大鼠活动总路程显著下降(P<0.01),中药组和电针组总路程与空白组比较也有明显下降(P<0.01),但是与模型组比较差异性仍有显著意义(P<0.01);中药和电针组与氟西丁组比较有显著差异(P<0.05,P<0.01)。实验第10天各组大鼠水平运动的总路程即表现出一定的差异,电针和中药NY-3号都有一定的作用,但电针组起效快,中药组的起效过程较为平稳。
1.1.1垂直运动结果:与空白组比较,造模各组站立次数均显著减少(P<0.01);与模型组比较,中药组和电针组有统计学意义(分别P<0.01,P<0.05);电针组与氟西丁组比较无统计学意义(P>0.05),而中药组与氟西丁组比较有统计学意义(P<0.05);中药组与电针组之间比较有统计学意义(P<0.05)。实验第10天各组大鼠站立次数也开始表现出一定的差异,氟西丁和电针起效较早,中药组作用较为平稳。
1.2强迫游泳试验:
各组大鼠强迫游泳实验成绩显示:与空白组比较,应激使模型大鼠的游泳不动时间显著延长(P<0.01);三个治疗组与模型组比较游泳不动时间也有统计学意义(分别P<0.01,P<0.05)。实验开始后第一周,各造模组游泳不动时间即迅速延长,但治疗各组均表现出一定的拮抗作用。与空白组和模型组比较,三组的游泳不动时间较空白组差距较大,虽然与模型组比较有统计学意义,但仍然距模型组水平比较接近。
1.3“Y”型电迷宫实验:
1.3.1各组大鼠学习成绩显示:与空白组比较,应激使各组造模大鼠的学习能力大幅度下降(P<0.01);与模型组比较,中药组和电针组学习成绩有所提高(P<0.01,P<0.05);与氟西丁组比较,中药组学习成绩有显著差异(P<0.05),电针组无显著差异(P>0.05)。电针组与中药组比较其学习成绩有统计学意义(P<0.05)。
1.3.2各组大鼠记忆成绩结果显示:与空白组比较,应激使各组造模大鼠的记忆能力大幅度下降(P<0.01,P<0.05);与模型组比较,中药组和电针组记忆成绩有所提高(P<0.01);与氟西丁组比较,中药组和电针组的记忆成绩无显著差异(P>0.05)。电针组与中药组比较其学习成绩无统计学意义(P<0.05)。
1.4各组大鼠糖水消耗实验结果:
与空白组比较,应激使各组造模大鼠一小时内糖水摄入量明显减少(P<0.01),但治疗各组与模型组比较能明显增加糖水的摄取量(P<0.05或P<0.01);其中电针组的糖水摄取量多于中药组,结果有显著性意义(P<0.01)。
2.各组大鼠下丘脑CRF,垂体ACTH、肾上腺CORT放免法检测结果:与空白组比较,模型组大鼠下丘脑CRF,垂体ACTH,肾上腺CORT显著升高(P<0.01或P<0.05)。与模型组比较,除中药、电针对垂体ACTH的含量影响没有显著性意义(P>0.05)外,各组治疗组对大鼠HPA轴各激素含量升高都有明显拮抗作用(P<0.01或P<0.05)。在垂体ACTH含量上,电针和中药治疗后仅显示出降低垂体ACTH含量的趋势。
3.各组大鼠海马GR、NMDAR、NR2B免疫组化检测结果:
3.1海马GR:与空白组比较,模型组大鼠海马内GR表达强度有显著差异(P<0.01),而中药组、电针组和氟西丁组均无统计学差异(P>0.05);与模型组比较,氟西丁组差异无显著性(P>0.05),中药组和电针组GR表达强度有显著性意义(P<0.05,P<0.01),三个治疗组之间比较都没有统计学意义(P>0.05),但从秩和和平均秩和的数据来看,电针组比氟西丁组和中药组的作用更接近于正常组。
3.2海马NMDAR:与空白组比较,模型组大鼠海马内GR表达强度有显著差异(P<0.05),而中药组、电针组和氟西丁组均无统计学差异(P>0.05);与模型组比较,氟西丁组未表现出显著差异(P>0.05),而中药和电针组与之比较有显著性差异(P<0.01);三个治疗组之间海马GR表达强度无统计学差异(P>0.05)。
3.3海马NR2B:与空白组比较,模型组和中药组大鼠海马内NR2B表达强度有显著差异(P<0.01),而电针组和氟西丁组均无统计学差异(P>0.05);与模型组比较,氟西丁组和电针组有显著性差异(P<0.01,P<0.05),中药组与之比较无统计学差异(P>0.05);与氟西丁组比较,中药组有显著性差异(P<0.01),电针组差异无显著性(P>0.05);电针组与中药组之间比较也有显著性差异(P<0.01)。
4.各组大鼠海马PKA、CREB免疫组化检测结果:
4.1海马PKA:与空白组比较,模型大鼠海马内PKA阳性表达强度有显著差异(P<0.05),三个治疗组与之比较差异无显著性(P>0.05);与模型组比较,氟西丁组无显著性差异(P>0.05)而中药和电针组差异有显著性(P<0.01);与氟西丁组比较,中药组无显著差异(P>0.05)而电针组有差异有显著性(P<0.01);中药和电针组之间无显著性差异(P<0.05)。
4.2海马CREB:与空白组比较,模型大鼠海马内CREB阳性表达强度有显著差异(P<0.01),三个治疗组与之比较差异无显著性(P>0.05);与模型组比较,三个治疗组都表现出显著性差异(分别P<0.05,P<0.01,P<0.01);三组治疗组之间两两比较也没有显著性差异(P>0.05)。
5.各组大鼠海马Nestin免疫组化检测结果:
与空白组比较,模型大鼠海马内Nestin阳性表达强度差异未表现出显著性(P>0.05),中药和电针组与之比较也没有显著性差异(P>0.05)而氟西丁组与之有显著性差异(P<0.01);与模型组比较,电针组有显著性差异外(P<0.01),其余两个治疗组与之比较差异无显著性(P>0.05);与氟西丁组比较,中药和电针组均有显著性差异(P<0.01),而中药和电针组之间差异无显著性(P<0.01)。
结论:
1.本实验所采用的慢性应激结合孤养的动物模型能够表现出一定的活动性和兴趣降低,快感缺失以及学习记忆能力减退等现象,证明实验在行为学上能够模仿抑郁的某些精神症状的表现。在参考抑郁症的“病”“证”结合研究成果后,我们初步假设本次实验所建立的慢性应激结合孤养的动物模型可能与“肝郁”和“脾气虚”两种证型关系较为密切。实验结果提示中药和电针具有很好的抵抗大鼠活动度和兴趣减低、改善慢性应激大鼠的行为绝望程度、提高学习记忆能力,增加大鼠对奖赏刺激的敏感性、改善大鼠的快感缺失等一系列拟抑郁症精神症状的行为学改变。电针对大鼠的活动性和探究行为的影响起效较快,而氟西丁和中药则表现出较为平稳的疗效。2.慢性应激结合孤养能持续激活脑内HPA轴,提示实验造模能够模仿抑郁发病中的HPA轴持续亢进的状态。中药和电针具有拮抗模型鼠体内异常的HPA轴亢进。3.慢性应激结合孤养大鼠模型的海马GR、NMDAR、NR2B的阳性表达降低,其原因可能是由于Glu的在突触内长期堆积,导致三种受体的敏感性降低。这样可以使HPA轴的负反馈作用降低,导致其过度激活而引发一系列症状。中药和电针具有拮抗模型鼠海马GR、NMDAR、NR2B敏感性降低的作用。
4.慢性应激结合孤养大鼠模型的海马各亚区PKA、CREB降低,这种改变可能进一步通过其下游机制影响学习记忆功能和造成海马神经元的损伤,其下游通路有待进一步探讨。中药和电针具有拮抗模型鼠海马各亚区PKA、CREB降低的作用。
5.慢性应激结合孤养大鼠模型的海马内Nestin的阳性表达有降低趋势,我们认为这种改变可能是HPA轴-GR-NMDA通路的作用结果。中药和电针具有增强海马内Nestin的作用,且其作用机制可能与氟西丁不同。
Depression is a series clinical symptom or states in which was caused by many complex reason and the patients experience a sustained low mood, it is a kind of mood disorders or affective disorders. Depression has bring many serious harm to us and modern chemical medicine have put many efforts on the study of depression, but several hundred years have passed, we still can’t make it fully clarified in the field of modern medicines. Also, in treating depression, there are some bland spots and secondary action in modern medicines.
But, as a matter of fact, Chinese medicine has already been used as a therapy to treat depression for thousands of years. We have our special theory to deal with this disease and it has been confirmed effectiveness in treating both the core and the side symptoms. So how to develop its advantages, clarify its mechanism, and improve its positive effectiveness, has become an urgent and valuable researching topic to the scientific researchers.
This thesis is a foundation research which is a part of a series projects of depression belong to my tutor professor Tu, and this research will supply the basis theory foundation for the clinical research next to it.
Objective: We built some behaviors tests to observe the depression-like symptoms of the chronic stress depression rats model and the influences of Traditional Chinese Medicine on them. At the same time, we try to find some new ways of how depression occurs and whether the anti-depression mechanisms of T.C.M. methods are through this ways.
Methods: The depression rats model was built by chronic stress on them, then they were assigned into 5 groups: the control group, the model group, the Prozac group, the NY-3 group, the EA group, each has 10 rats. To observe the influence of T.C.M. on the behaviors about movements, appetite and learning of them; The expression of GR、NMDA、NR2B、PKA、CREB、Nestin、ChAT and 5-HT in hippocampal tissue was detected by immunohistochemical technology. Results:
1. Behavior results of the chronic stress depression rats models:
1.1 Open-Field test:
1.1.1 Results of plane-moving:The total distance traveled by the model rats was declined compare with the contral group(P<0.01), and which of the EA group and NY-3 group was also declined(P<0.01) but still more than the model rats(P<0.01).While the distance has no significant change in the Prozac group(P>0.05). There is no difference between the NY-3 group and the EA group(P>0.05)。The total distance of each group was changed at the 10th day, the EA group does work faster than the other two treating groups and it’s total distance was the nearest to the control group. But the later effect of EA was not so good.
1.1.1 Results of vertical-moving:Compare with the contral group, the numbers of standup of the model rats was declined significantly(P<0.01) but which of the EA group and NY-3 group were more than the model group(P<0.01,P<0.05). The numbers of standup of the EA group is more than the NY-3 group(P<0.05)。The total distance of each group was changed at the 10th day, the Prozac group does work faster than the other two treating groups and it’s total distance was the nearest to the control group. There is no difference between the NY-3 group and the EA group. In this test, the EA group work well in the first 10 days, but it’s effection dropped in the last 10 days.
1.2 Force swimming test:It showes that the still-swimming time of the model group declined than the contral group(P<0.01), and which of the three treating groups was increased than the model group(P<0.01,P<0.01,P<0.05). The results of stilling-time of this three treating group is not as much as the contral group.
1.3“Y”-mazing test:
1.3.1 Learning results:Compare with the contral group, chronic stress could week the rats‘ability of learning(P<0.01), and the NY-3 group and the EA group can anty this change(P<0.01) while the Prozac group showes no changes(P>0.05).
1.3.2 Memory results:Compare with the contral group, chronic stress could reduce the rats‘ability of memory ability(P<0.01,P<0.05) and the NY-3 group and the EA group could enhance this ability(P<0.01).
1.4 Results of Sugar intake test: Compare with the contral group, the sugar intake a- mount of model group dropped (P<0.01). While the sugar intake amount of all the tresting groups was much more than the model rats(P<0.05或P<0.01); EA group shows significantly differences when compared with the other treating groups(P<0.01).
2.Results of the CRF in hypothalamus, ACTH in pituitary gland, CORT in adrenal gland by RIA method: CRF, ACTH and CORT were increased greatly in the model group (P<0.01, P<0.05)and even the EA and the NY-3 group did not show great effect of decreased the CRF and CORT level significantly but we can see the kind of trend in them.
3.The expression of GR、NMDA、NR2B in hippocampal tissue detected by immunohistochemical technology:
3.1 GR in hippocampal:Compared with the contral group, GR in hippocampal of the model rats was reduced than the contral group(P<0.01) while GR in hippocampal of the three treating groups showes no difference(P>0.05). GR in hippocampal of the EA groups was the nearest to the contral group than the other two.
3.2 NMDAR in hippocampal : Compared with the contral group, NMDAR in hippocampal of the model rats was reduced than the contral group(P<0.05) while the three treating groups showes no difference(P>0.05). There was no difference among the EA ,NY-3 and the Prozac group(P>0.05).
3.3 NR2B in hippocampal:Compared with the contral group, NR2B in hippocampal of the model and NY-3 groups was reduced than the contral group(P<0.01) while the EA and the Prozac groups showes no difference(P>0.05). The NY-3 group shows the weakest effection among the three treating groups. (P<0.01)
4.The expression of PKA、CREB in hippocampal tissue detected by immunohisto- chemical technology:
4.1 PKA in hippocampal:Compared with the contral group, PKA in hippocampal of the model rats was reduced than the contral group(P<0.05) while PKA in hippocampal of the three treating groups showes no difference(P>0.05). In this test, it showes that the Prozac group has little effection than the NY-3 group and the EA group.
4.2 CREB in hippocampal:Compared with the contral group, CREB in hippocampal of the model rats was reduced than the contral group(P<0.01) while CREB in hippocampal of the three treating groups showes no difference(P>0.05). Compared with the model group, CREB in hippocampal of the three treating groups showes great difference(P<0.05,P<0.01,P<0.01) and there is no difference between the three treating groups(P>0.05).
5.Nestin in hippocampal:Compared with the contral group, Nestin in hippocampal of the model rats showes no difference(P>0.05) while the NY-3 group and the EA group also showes no difference(P>0.05). Nestin in hippocampal of the Prozac group was the lest among all the groups (P<0.01).
Conclusions:
1.Cronic stress rat model shows some depression-like psychological symptoms such as movement and curricity reduced helpless, lack of happiness and the ability of learning and study reduced. NY-3 and acupouncture have the recover to reduce these symptoms.
2.Cronic stress could activate the path way of HPA continually and NY-3 and acupouncture could resist it.
3.GR、NMDAR、NR2B which was dropped in the model.NY-3 and acupouncture could enhance the sensitivity of the receptors which was dropped in the model. The reason for this maybe too much of Glu stayed in the synaps for so long time. These cause the back reflact of the HPA weaked.
4. NY-3 and acupouncture could anti the weekness of expression of PKA and CREB in hippocampal in the model.
5. The expression of Nestin in hippocampal of the model rats was reduced but NY-3 and acupouncture could resist the change. The cappable function may have some relationship with the pathway of HPA-Glu-NMDA.
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