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树鼩抑郁反应模型的构建及其抗抑郁药物预测效度的评价
其他题名The development of depression models in tree shrews and the evaluation of predict validity by antidepressants
孟肖路
学位类型博士
导师隋南
2014-05
学位授予单位中国科学院研究生院
学位授予地点北京
学位专业心理学
关键词树鼩 抑郁反应模型 预测效度 氟西汀 卡贝缩宫素
摘要动物模型是抑郁症机制研究及药物研发的主要工具。当前抑郁症动物模型主要基于啮齿类,与人类亲缘关系较远,行为模式相对简单,难以模拟心理应激诱发的抑郁样行为;此外,现有模型多基于单一抑郁样行为及单一的抗抑郁药物,难以模拟人类抑郁症状的异质性及药物反应特异性。采用更合适的模式动物构建有效的抑郁症模型是解决上述问题的关键。
树鼩是一种灵长类近缘动物,具有构建应激相关疾病模型——抑郁症模型的先天优势:1)极易应激,且对因争夺领地而产生的心理应激敏感;  2)应激系统相关受体基因与人类高度相似,且激动应激系统糖皮质激素受体的激素为皮质醇,与人类相同。  
本研究拟以树鼩为模式动物,通过梯度性增强不可控不可逃避电击刺激应激强度(2,4,7天)和丰富应激输入类型来构建新型抑郁反应模型。考察的主要抑郁样行为指标如下:表征习得性无助的逃避失败次数和逃避潜伏期;表征动机缺乏的主动觅食糖水断点;表征快感缺失的糖水偏爱水平及表征社交回避的社交区域停留时间。同时,本研究重点考察了选择性 5-HT 重摄取抑制剂氟西汀(fluoxetine,15 mg/kg)和催产素激动剂卡贝缩宫素(carbetocin,6.4 mg/kg,20 mg/kg)两种药物对上述抑郁样行为的疗效。此外,根据标准化后的症状总分分析了不同药物对抑郁总体状况的影响。主要结果如下:
1, 随着应激强度的梯度性增强,当应激天数达到 4天时,树鼩表现出习得性无助,且可维持2周;而当应激天数增加到7天时,除了习得性无助外,树鼩表现出动机缺乏行为,但行为难以维持2周。提示习得性无助行为是抑郁症发生发展的早期症状,行为表现较稳定,可用于抑郁的初步诊断与筛查;动机缺乏行为是抑郁症发展过程中逐渐出现的行为,行为不稳定,不易于发现及诊治。
2, 经历7天应激的树鼩所表现出的习得性无助被 2周氟西汀给药完全逆转,表明7天应激所构建的抑郁反应模型具有较好预测效度。
3, 为了增加应激后树鼩行为输出类型,我们在7 天应激的基础上增加了慢性温和应激以丰富应激输入类型。结果显示,丰富应激输入类型后,树鼩表现出除习得性无助外的快感缺失和社交回避行为。结果提示,与单一应激刺激相比,综合应激刺激会诱发更多的抑郁样行为,快感缺失及社交退缩可能发生在抑郁症较晚时期,可用于抑郁症疾病发展状况考察。
4, 随着给药时间的增长,当给药一周时,氟西汀和高、低剂量卡贝缩宫素处理均减少了树鼩的逃避失败次数;给药两周后,氟西汀组树鼩的习得性无助被完全逆转而快感缺失和社交回避被部分逆转;与氟西汀组相似,高剂量卡贝缩宫素组树鼩的习得性无助行为也被成功逆转且快感缺失被部分逆转, 但社交回避行为未表现出逆转趋势;而低剂量卡贝缩宫素组仅表现出逃避失败次数的减少。给药期间体重的变化显示,氟西汀慢性治疗导致了体重下降,而卡贝缩宫素对体重没有影响。结果提示药物的疗效随时间而变化,氟西汀和高、低剂量卡贝缩宫素均具有一定的疗效;氟西汀和高剂量卡贝缩宫素给药起效早,药效好于低剂量卡贝缩宫素;卡贝缩宫素给药负作用小于氟西汀。
5, 模拟人类症状评分情况,我们将给药前后各抑郁样行为进行标准化并赋分。结果显示氟西汀和高剂量卡贝缩宫素组均表现出症状总分的明显下降,而低剂量卡贝缩宫素组未表现出明显的变化。提示根据抑郁症状总分来判断,氟西汀和高剂量卡贝缩宫素药物处理均具有较好的抗抑郁作用。
综上所述,本研究首次采用梯度性增强应激强度与丰富应激输入类型相结合的方式,构建了树鼩抑郁反应模型,成功诱发了习得性无助、动机缺乏、快感缺失和社交回避等多种抑郁样行为,且氟西汀和卡贝缩宫素对上述抑郁样行为具有不同的疗效,这就为临床试验抑郁症个性化治疗提供了实验依据。
其他摘要Animal models are important tools for  the  screening  of  antidepressants  and  the exploration of mechanisms of depression. However, there are some limitations  in the commonly used rodents’ model. Rats and mice are remote affinity to human and their behaviors are  relatively simple.  It’s difficult to mimic the depression-like behaviors induced by psychological stressors. Moreover, commonly used depression models are usually  based on a single  behavior  or antidepressant, which makes it difficult to explore the heterogeneous in depression syndromes and the specificity in responses to antidepressants. Therefore it’s crucial  to develop an effective depression models with various symptoms in a kind of animals that is more affinitive with human.   
Tree shrews are  the closest relative of primates.  There  are  congenital superiorities  for tree shrews  to  develop depression models.  Firstly, tree shrews are sensitive to stress, especially the social psychological stresses elicited by social defeats  for territory.  Then, their  genes for major stress-regulating receptor proteins,such as  the glucocorticoid and  the mineralocorticoid receptor,  revealed  high homologies to the equivalent human genes. Also, instead of corticosterone in rodents, tree shrew has  cortisol that  activates glucocorticoid receptor, which is identity to human.  
In  our  study, tree shrews were  used to develop  a  new depression model with different stress intensities (uncontrollable and inescapable foot-shocks, 2 days, 4 days and 7  days) and  the abundant type of stress.  There were four depression-like behaviors: learned helplessness represented by the frequency of failure escape and the escape latency, amotiation  represented  by  the  breakpoints  of  self-administration  of sucrose, anhedonia  represented  by  the  sucrose preference, and social  withdrawal represented  by  the  time spent in the  social  interaction  zone.  In addition, two antidepressants, fluoxetine (one of selective serotonin reuptake inhibitors, 15 mg/kg), and  carbetocin  (an agonist of oxytocin  receptors,  6.4  mg/kg, 20  mg/kg), were administrated  after stress for two weeks to investigate  their  curative effects on the behaviors above, as well as  the total scores of depressive behaviors. Main results are listed as followed:
  1, Learned helplessness (escape failure) displayed and persisted for 2 weeks in tree shrews exposed to 4 days of uncontrollable  and inescapable stresses; amotiation appeared  accompany with  learned helplessness when the total stress  extended  to 7 days. However, amotiation did not persist  for 2 weeks. All the results above suggest that learned helplessness appears  after intensive stress experience, so helplessness might be more useful for the preliminary screening and diagnosis.
2, Learned helplessness was completely reversed after the two weeks’  fluoxetine treatments in tree shrews exposed to 7 days’   stresses.  It’s suggested that  the  new depression model maintain a good predictive validity. 3, A series of  chronic mild stresses were added to 7 days’   stresses  to increase more  depression-like behaviors.  Two of depression-like behaviors appeared besides learned helplessness, which were anhedonia and social withdraws.  It suggests that more depression-like behaviors may appear  in tree shrews exposed to more types of stresses. It also suggests that amotiation and social withdrawal may appear at the later stage of depression, so it can represent the development of depression.
4, The  frequency of failure escape was  reduced in all the three groups  (Flu 15, Car 6.4 and Car 20)  after one week’s drug treatments. When the treatments  were extended to two weeks, learned helplessness was totally reversed while anhedonia and social  withdrawal  were partially  cured  in tree shrews in Flu 15;  carbetocin  at 20 mg/kg had shown the same effect,while the social withdrawal was kept unchanged; carbetocin at 6.4 mg/kg could only reduce the frequency of failure escape. The results also had shown that weights of tree shrews in Flu15 decreased accompanied by time,while those in the carbetocin groups did not. All the data above suggest that there are curative effects in all the groups treated with antidepressants, In addition, the onset of antidepressant action of fluoxetine and high dose of carbetocin is faster than low dose of  carbetocin, and more depression-like behaviors were reversed. Also, side effects were fewer in tree shrews treated with carbetocin than fluoxetine.
5,  To mimic clinical diagnosis of depression  in human,  a total scores of depression-like behaviors were calculated as the sum of grade according to  standard z-scores of different kinds of behavior tests. The total scores of tree shrews in Flu 15 and Car 20 were significant decreased, while those in saline and Car 6.4 were not. It suggests that fluoxetine and carbetocin (20 mg/kg) have better antidepressant effects. The present study  for  the first time developed depression models in tree shrews by combining the  gradient  stress intensities and  the enriched  stress types.  Four depression-like behaviors were elicited,  and  differences in the  curative effects of fluoxetine and  carbetocin  were reported.  This study  provided  the  experimental evidence for the individual-based treatment of depression in clinical.  
学科领域医学心理学
语种中文
文献类型学位论文
条目标识符http://ir.psych.ac.cn/handle/311026/19640
专题健康与遗传心理学研究室
作者单位中国科学院心理研究所
推荐引用方式
GB/T 7714
孟肖路. 树鼩抑郁反应模型的构建及其抗抑郁药物预测效度的评价[D]. 北京. 中国科学院研究生院,2014.
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