抑郁行为及不同抑郁亚型的多巴胺机制研究

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	抑郁行为及不同抑郁亚型的多巴胺机制研究
其他题名	The role of dopamine in depression and different depressive subtypes
	李幼虹
	2009-05-26
摘要	现阶段大多数考察抑郁病理机制的基础研究工作，都局限在某一种具体的抑郁行为上，例如快感缺失或者习得性无助。而临床研究表明，同样表现出抑郁症状的个体，具有多种不同的伴随症状，例如部分抑郁患者的焦虑水平显著高于正常对照人群，而部分抑郁患者无明显焦虑症状伴随。“抑郁作为一种异质性疾病”已经成为抑郁研究领域中大多数研究者较为公认的理念。但是，如何从操作层面，探索抑郁的“异质性”，区分出作为这种异质性表现的不同的“抑郁亚型”，并探索其可能存在差异的脑内神经活动，此方面的基础研究工作匮乏。本研究采用国际上通用的“习得性无助”模型定义抑郁行为，从行为层面分离出具有相同抑郁症状——习得性无助但伴随显著不同焦虑水平的动物，即“高焦虑无助动物”和“低焦虑无助动物”，将此作为焦虑性抑郁(anxious depression)和非焦虑性抑郁(non-anxious depression)亚型的操作性区分标准。随后考察不同“抑郁亚型”动物，在内侧前额叶皮层(mPFC)及伏隔核(NAc)内多巴胺不同受体亚型（D1/D2/D3）mRNA表达量的差异。研究发现：（1）不可逃避的应激处理可以诱发习得性无助行为，使整体应激动物表现出显著降低的压杆中断电击的行为。尽管应激动物表现出整体上的“无助效应”，但并非所有动物都出现此行为。这其中只有40%的应激动物表现出明确的无助行为，60%的应激动物并不表现出明确的无助行为。（2）应激诱发的无助动物并非“同质”，其中部分动物呈现出显著高于对照动物的焦虑水平（EPM测试），而部分动物表现出显著低于对照动物的焦虑水平，此研究结果和临床研究类似；且在无助动物中，焦虑水平的分布呈现双峰分布，提示高焦虑无助动物和低焦虑无助动物作为不同抑郁亚型动物的有效性。（3）在整体应激动物 vs. 对照动物，无助动物 vs. 非无助动物，高焦虑无助动物 vs. 低焦虑无助动物的mPFC和NAc中D1/D2/D3受体mRNA表达研究中，实验发现，不可控的电击导致整体应激组动物mPFC和NAc中D3受体mRNA表达量上调；而在两个脑区都未发现D1与D2受体mRNA表达的显著改变。较之对照动物，无助动物和非无助动物都表现出mPFC和NAc的D3受体mRNA表达上调。研究同时发现，非无助动物mPFC的D1/D2受体表达量下调，NAc的D2受体表达量下调，无助动物未发现上述改变。（4）以上mPFC和NAc的D1、D2、D3受体mRNA表达的研究结果提示，mPFC和NAc的D3受体上调，是不可控制的电击处理导致的应激性的普遍效应，D3受体上调是动物出现无助行为的必要条件而非充分条件。其中非无助动物mPFC的D1/D2受体表达量下调，NAc的D2受体表达量下调，成为动物在经历不可逃脱电击后的“代偿机制”，使动物并不表现出无助行为；与此相应，与非无助动物相比，无助动物正是缺少了上述代偿机制，才导致无助行为的发生。（5）研究发现，在无助动物内部，焦虑水平的高低与mPFC中D1受体mRNA的表达量呈现显著负相关。较之对照动物，高焦虑无助动物mPFC的D1受体mRNA表达较低（边缘显著），并且显著低于低焦虑无助动物；而低焦虑无助动物mPFC的D1受体表达和对照组相比无差异。研究提示焦虑性抑郁和非焦虑性抑郁作为不同的抑郁亚型，其机制差异体现在mPFC的D1受体的不同功能改变上，从而提示与mPFC的D1受体表达下调相互关联的其他神经递质系统的改变，很可能和D1系统的改变共同构成了临床上较难治愈的焦虑性抑郁的分子基础。; The conceptualization of “depression” as a heterogenous disease has been widely accepted by most researchers. However, controlled experiments are rather sparse. To date, most studies demonstrated that animals with helplessness, a widely recognized behavioral index of “depression” also show varied comobidity expressions of other emotional behaviors, such as hightened or lightened anxiety level compared with controls. This means that distinct subtypes of “depression” may exist, in which different neural mechanisms may play roles. The present study aims to explore the possibility of behaviorally categorizing two depressive subtypes, referred as anxious helplessness and non-anxious helplessness, respectively. Then, by using RT-PCR, the dopamine D1, D2, D3 receptors mRNA expressions in medial prefrontal cortex (mPFC) and nucleus accubems (NAc) were quantified. The main findings are described as belows: 1. Uncontrollable shock could readily induce helpless behavior in shocked animals as a whole but with salient individual differences. Prior inescaoable shock induces subsuquent helplessness in approximately 40% shocked animals, while the other animals showed no sign of helpless expression, and were classified as non-helplessness. 2. Among helpless animals, the “subtype” of anxious helpless and non-anxious helpless could be identified according to the anxiety level evaluated by elevated plus maze. 3. D3 receptors mRNA expressions in the mPFC and NAc were increased in stressed animals after uncontrollable shock treatment. At the meanwhile, significant lower expressions of D2 receptors in the mPFC and NAc, and much lower expressions of D1 receptors in the mPFC were found in rats that did not become helpless after stress. In contrast, no significant difference between helpless and control animals was found in D1/D2 receptors mRNA expressions. 4. Based on above mentioned results, the up-regulation of D3 receptors in the mPFC and NAc may reflect a generalized effect of exposure to uncontrollalbe shock. While the down-regulation of D1\D2 receptors in the mPFC and decreased expression of D2 receptors in the NAc may be associated with adaptive or protective mechnisms which protecting animals from helplessness after uncontrollable shock treatment. 5. Futhermore, a significant negative relationship was found between anxiety level and D1 receptors expressions in the mPFC in helpless animals. Compared to the non-anxious helpless and control rats, the D1 receptors mRNA of anxious helpless rats were down-regulation in the mPFC. The present study indicated that the D1 dopamine receptor gene is associated with co-morbid depression and anxiety.
关键词	抑郁亚型焦虑性抑郁症非焦虑性抑郁症习得性无助多巴胺
学位类型	硕士
语种	中文
学位授予单位	中国科学院心理研究所
学位授予地点	心理研究所
文献类型	学位论文
条目标识符	http://ir.psych.ac.cn/handle/311026/4686
专题	中国科学院心理研究所回溯数据库(1956-2010)
推荐引用方式 GB/T 7714	李幼虹. 抑郁行为及不同抑郁亚型的多巴胺机制研究[D]. 心理研究所. 中国科学院心理研究所,2009.

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