【作者】 郑兴东；

【导师】 路长林；

【作者基本信息】 第二军医大学 ， 神经生物学， 2001， 博士

【摘要】 CRH、ACTH、NPY和GAL在抑郁症发病中作用 及其机制的研究 抑郁症（depression），又称单相情感性障碍（minor depression），是以显著而 持久的抑郁情感或心境改变为主要特征的一组疾病，也是与应激密切相关的一类 精神病。部队指战员无论平时还是战时都处于不同程度的应激状态，其抑郁症的 发病率高于一般群体。抑郁症已严重威胁指战员身心健康，是造成部队非战斗减 员的重要因素之一。随着社会竞争的日益加剧，在日常生活、学习和工作中，人 们承受的生理、心理压力越来越大，抑郁症的发病率有不断升高的趋势。因此， 加强对应激尤其是军事应激所致抑郁症的研究，在平战时都具有十分重要的意义。 抑郁症发病机理的研究，虽然过去建立与发展了许多学说，但由于对抑郁症发 病机理没有彻底搞清，对抑郁症的诊断和治疗还存在许多问题。目前对抑郁症发 病机理的研究，以及筛选敏感而稳定的抑郁症早期诊断和疗效评价指标等，仍然 是研究的热点。 本研究应用行为测定、放射免疫分析、免疫组化、原位杂交等技术和方法，对 促肾上腺皮质激素释放激素（CRH）、促肾上腺皮质激素（ACTH）、甘丙肽（GAL） 和神经肽 Y（NPY）在抑郁症发病中的作用和机制，进行了较为系统的研究。首先 弄清抑郁症病人血浆中CRH、ACTH、GAL和NPY含量的变化。在此基础上，利用大 鼠抑郁症模型，研究这四种神经肽在抑郁症发病中的作用，并观察GAL和NPY受 体的效应分子GIRK在抑郁症时的变化。旨在观察抑郁症时神经肽CRH、ACTH、GAL 和NPY的变化规律，探讨平战时抑郁症早期诊断、疗效判断及预后评价的指标， 并进一步阐明神经肽参与抑郁症发病的可能机制，为临床抑郁症的诊断和防治提 供新的途径和实验依据。本研究的主要结果和讨论： 一、抑郁症患者血浆CRH、ACTH、GAL和NPY含量的变化 一 与正常人群相比，中度和重度抑郁症患者血浆AC＊含量显著升高中＜0刀5入 重度抑郁症患者血浆＊PY含量显著降低中0刀1人所有抑郁症患者血浆0＊L含 量均显著升高巾功刀 1），并且有随着抑郁症状加重而升高的趋势。 二、大鼠抑郁症撞型的建立 利用长期电击足底应激，制备大鼠抑郁症模型。结果发现，本模型动物表现出 的抑郁状态、兴趣丧失、快感缺乏与抑郁症临床表现中的精神运动改变、兴趣或 快感的丧失有一定程度的相似性。实验表明，这是较为理想的抑郁症动物模型。 三、实验性抑郁症大鼠血桨和备脑区神经肚含量的变化 1．血浆和各脑区 CRH含量的变化 与对照组相比，抑郁症大鼠血浆CRH含 量无明显变化，下丘脑和垂体前叶CRH含量显著升高，海马、顶叶和额叶显著降 低。CRH神经元在脑内主要位于下丘脑。垂体前叶的CRH主要来源于下丘脑，提 示抑郁时垂体前叶CRH含量的升高很可能是下丘脑CRH合成增加的结果。抗抑 郁药盐酸氟西汀对血浆、海马、颖叶和顶叶的CRH水平无明显影响，但可显著降 低垂体前叶CRH的含量。表明抑郁症时，CRH含量在各脑区的变化不一致，抗抑 郁药对各脑区CRH含量的影响也有差异，提示CRH在不同的脑区可能有不同的 作用，其机制还有待于进一步研究。 2．血浆和各脑区ACTH含量的变化 与对照组相比，实验性抑郁症大鼠血浆 ACTH含量无明显变化，下丘脑AC＊含量显著下降，其次是海马和顶叶，而在 其它脑区未发现明显变化。与生理盐水组相比，盐酸氟西汀组大鼠海马的ACTH 含量有所上升，提示海马可能与盐酸氟西汀的抗抑郁作用有关。 3．血浆和各脑区 GAL含量的变化 与对照组相比，实验性抑郁症大鼠血浆GAL 的含量显著下降，与抑郁症患者血浆GAL含量显著升高正好相反，这可能是由于 人和鼠GAL的种属差异较大造成的。实验性抑郁症大鼠下丘脑、海马、额叶、顶 叶和前脑的GAL含量均显著下降，提示抑郁症时大鼠血浆GAL的含量下降，可能 是由于脑内这些区域GAL含量下降所致。给予抗抑郁治疗可显著升高抑郁症大鼠 海马和前脑GAL的含量，提示盐酸氟西汀可能通过影响这两个脑区GAL神经元而 改善抑郁症状，也表明海马和前脑在抑郁症发病中可能起着重要作用。 4．血浆和各脑区NPY fi的变化 与对照组相比，实验性抑郁症大鼠血浆的 NPY含量均显著降低，给予抗抑郁药治疗后，抑郁症大鼠血浆的NPY含量显著升高，更多还原

【Abstract】 The Study on the Principle of CRH, ACTH, NPY andGAL in Depression and its Mechanism Depression is a series of disease characterized by remarkable and permanent depressive mood or mental changes. The incidence of depression has increased progressively for more and more social challenge these years. Depression has become a major health concern not only because of personal distress, excess mortality, impaired interpersonal relationships, and restriction of work activities but also because of the economic burden it imposes. So it is very important to pay more attention to the study of depression. Although there were many hypothesis and theories, the mechanism of depression remains confusing and has attracted considerable attention. in this study we explored the role of neuropeptides CRH, ACTH, GAL and NPY in the development of depression using R1A, immunohistochemistry, and in situ hybndyzation. First, we examined the alteration of the contents of these neuropeptides in plasma of depression patients. Then, we established a model of depression rats. Thereafter, we investigated the alteration of the contents of these neuropeptides in plasma and different brain regions of depression rats and studied the differences of expression of GIRK mRNAs, the effector of these neuropeptides, in depression rats and in normal rats. This study would clarify the mechanism of participation in depression of neuropeptides and contribute to early diagnosis and judgement of prognosis of depression. The main results are as follows: 1. The alteration of contents of neuropeptldes CRH, ACTH, GAL and NPY in plasma of depression patients. The contents of plasma ACTH markedly increased in moderate and heavy depression patients (p<O.05), a the contents of plasma NPY remarkably decreased (p<O.O1). In plasma of all the depression patients the contents of GAL obviously nsed and parrelleled with degree of depression. 2. Establlshm nt of exp rim ntal d pressl n mod I The d pr ssion model was established by chronic unpredictable mild stress. The animalappeared depressiv b havioF, loss of int6rest and anhedonia, which were simiIar to thediagnosis StandaFd of clinicaI depression. So it was an ideal depression modeI.3.The changes of cont6nta of neuropeptldes in pIasma and dlff6rent brainregions Of depression rata.(1 ) CRH ln depression rats the cont6nts of CRH obviously increased in thehypathalamus and anterior pitUitory a decreased in the hippocampus, parietaI Iobe andt6mporal lobe of cerebraI cortex. CRH-positive neurons mainly diStribut6 in thehypothalamus. So CRH in ant6rior pituitary came bom hypothaIamus. This suggest6d the.increase of CRH in ant6rior pituitary of depression ratS was the results of the increase ofCRH synthesis in hypothalamus. FIuox6tine hydroChIoride had no eff6Ct on the cont6nts OfCRH in pIasma, hippacampus, pari6tal Iobe and t6mporal lobe Of cerebral cort6x, butdecreased the cont6ntS Of CRH in the ant6rior pituitery and increas6d that in the fOrebrain.The dfferent changes of CRH in diff6rent brain regions in depression rats and differentetheCtS Of fluoxehne hydrachloride on the cont8ntS Of CRH in different brain regions indicat6dCRH had diff6rent fUnCtions in different brain regions. The mechanism remains obscure.(2) ACTH The cont6ntS Of ACTH of depression rats decreas6d more obviousIy inhypothalamus than in the hippacampus and pariet8l Iobe of cerebraI cort6x, and f8iled toaIt6r in other brain mpions. Aff6r adminiStration Of ffuox8tine hydrochloride the cont6nts ofACTH in the hippacampus and pari6taI lobe of cerebraI cort6x of ratS increased. ThissuggeSted hippaca更多还原