本文選題：注意缺陷多動(dòng)障礙 + 多巴胺D4受體　； 參考：《山東大學(xué)》2012年碩士論文

【摘要】：[背景] 注意缺陷多動(dòng)障礙(attention deficit hyperactivity disorder, ADHD)是一種常見(jiàn)的兒童期起病的神經(jīng)行為障礙,主要表現(xiàn)為與發(fā)育水平不相稱(chēng)的一系列行為異常,如不分場(chǎng)合的多動(dòng)、沖動(dòng)以及注意力分散。ADHD是一種影響終身的慢性疾病,若不早期進(jìn)行干預(yù)治療,隨著年齡的增長(zhǎng),70%的患兒癥狀持續(xù)至青春期,30%的患兒癥狀持續(xù)至成人,對(duì)患者的學(xué)業(yè)、行為調(diào)控、社會(huì)生活等方面產(chǎn)生廣泛而消極的影響。其發(fā)病機(jī)制至今尚未闡明。研究表明,ADHD的發(fā)生與發(fā)展可能與多巴胺D4受體異常表達(dá)有關(guān)。既往對(duì)ADHD發(fā)病機(jī)制的研究主要集中在前額葉皮層,紋狀體和基底節(jié)等腦區(qū)。近年來(lái)研究者對(duì)ADHD患兒的腦部磁共振成像掃描時(shí)發(fā)現(xiàn)其小腦總?cè)萘坑绕涫切∧X蚓部容量比正常兒童顯著減少。并且人們對(duì)小腦在注意力、沖動(dòng)情緒控制、認(rèn)知等方面的作用有了新的認(rèn)識(shí)。這些發(fā)現(xiàn)為深入研究ADHD的發(fā)病機(jī)制提供了新的切入點(diǎn)。本研究選擇最常用的ADHD動(dòng)物模型即自發(fā)性高血壓大鼠(spontaneously hypertensive rat, SHR)作為研究載體,采用選擇性多巴胺D4受體激動(dòng)劑ABT-724進(jìn)行干預(yù),觀察ABT-724對(duì)SHR大鼠認(rèn)知行為及其小腦多巴胺D4受體表達(dá)的影響,探討小腦多巴胺系統(tǒng)功能異常在ADHD發(fā)病機(jī)制中的可能作用,并為尋找治療ADHD的新靶點(diǎn)提供理論依據(jù)。 [方法]： 1.觀察幼年SHR/WKY/SD大鼠的行為學(xué)表現(xiàn)。利用開(kāi)場(chǎng)試驗(yàn)、Morris水迷宮、Lat迷宮三種試驗(yàn)方法,分別觀察SHR/WKY/SD大鼠自發(fā)活動(dòng)水平、空間學(xué)習(xí)和記憶能力、非選擇性注意力。 2.研究選擇性多巴胺D4受體激動(dòng)劑ABT-724對(duì)SHR行為的影響。分別用ABT-724低(0.04mg/kg)、中(0.16mg/kg)、高(0.64mg/kg)三個(gè)劑量及哌甲酯(5mg/kg)干預(yù)SHR,并用未干預(yù)(生理鹽水1ml/kg) SHR作為對(duì)照,利用開(kāi)場(chǎng)試驗(yàn)、Morris水迷宮、Lat迷宮,觀察干預(yù)前后SHR自發(fā)活動(dòng)水平、空間學(xué)習(xí)和記憶能力、非選擇性注意力。 3.探討選擇性多巴胺D4受體激動(dòng)劑ABT-724對(duì)SHR小腦多巴胺D4受體表達(dá)的影響。行為學(xué)測(cè)試結(jié)束后,利用免疫組織化學(xué)及實(shí)時(shí)定量RT-PCR技術(shù)檢測(cè)SHR/WKY/SD大鼠及干預(yù)前后SHR小腦多巴胺D4受體的表達(dá)。 [結(jié)果]： 1.觀察幼年SHR/WKY/SD大鼠的行為學(xué)表現(xiàn)。在開(kāi)場(chǎng)實(shí)驗(yàn)中,SHR穿越格子數(shù)(94.50±22.51)較WKY(6±3.12)和SD大鼠(63.63±22.33)明顯增多(p均0.05)。在Morris水迷宮中,SHR大鼠(21.38±5.01)與SD大鼠(41.13±6.10)相比,空間記憶能力降低(p0.05)；WKY大鼠(24.88±9.31)則表現(xiàn)出明顯的漂浮特征。SHR大鼠在Lat迷宮中直立次數(shù)(138.63±31.89)明顯多于WKY(19.36±17.69)及SD大鼠(76.88±32.80)(p0.05),后二者無(wú)明顯差別(p0.05)。 2.研究選擇性多巴胺D4受體激動(dòng)劑ABT-724對(duì)SHR行為的影響。哌甲酯及ABT-724干預(yù)后的SHR大鼠穿越格子數(shù)(分別為70.67±8.59,76.50±10.75,79.17±10.44,65.67±20.62)較鹽水組大鼠(130.33±11.40)明顯減少(p均0.05)。在Morris水迷宮中,干預(yù)后的SHR大鼠空間記憶能力(分別為52.50±4.04,52.17±2.99,61±8.15,53.83±9.87)與鹽水組大鼠(38.83±7.17)相比明顯提高(p均0.05)。在Lat迷宮中,干預(yù)后的SHR大鼠直立次數(shù)(分別為57.17±5.67,60.83±8.28,55.17±9.45,65.33±9.50)與鹽水組大鼠(78.00±13.84)相比明顯減少(p均0.05)。 3.探討選擇性多巴胺D4受體激動(dòng)劑ABT-724對(duì)SHR小腦多巴胺D4受體表達(dá)的影響。SHR小腦多巴胺D4受體累計(jì)光密度值(IOD)(2016900±494060)及mRNA表達(dá)(0.63±0.12)均較WKY/SD大鼠顯著減低(p均0.05),后二者比較無(wú)明顯差別。ABT-724低、中、高劑量和哌甲酯干預(yù)后SHR小腦多巴胺D4受體IOD及nRNA表達(dá)較鹽水組均顯著升高(p均0.05)。 [結(jié)論]： 1. SHR幼鼠作為ADHD最常用的一種動(dòng)物模型,與WKY、SD大鼠相比較,分別在開(kāi)場(chǎng)試驗(yàn)、Lat迷宮、Morris水迷宮中表現(xiàn)出明顯的多動(dòng)、沖動(dòng),注意力不集中以及認(rèn)知功能障礙。本課題在增加了另一品系大鼠(即SD大鼠)的基礎(chǔ)上,對(duì)SHR的自發(fā)活動(dòng)水平、非選擇性注意力、認(rèn)知功能再次進(jìn)行檢測(cè)、評(píng)估,為進(jìn)一步的研究奠定了理論基礎(chǔ)。 2. ABT-724干預(yù)后的SHR表現(xiàn)出白發(fā)活動(dòng)減低、認(rèn)知功能及非選擇性注意力改善,其效果與哌甲酯干預(yù)后效果相近,提示選擇性多巴胺D4受體激動(dòng)劑ABT-724對(duì)SHR的行為認(rèn)知有明顯的改善作用。 3.在SHR/WKY/SD大鼠小腦多巴胺D4受體表達(dá)的比較中,SHR該腦區(qū)多巴胺D4受體表達(dá)較其兩個(gè)對(duì)照組明顯下降,此結(jié)果為進(jìn)一步的干預(yù)試驗(yàn)提供了理論基礎(chǔ)。ABT-724可引起SHR大鼠小腦多巴胺D4受體表達(dá)增多,此作用與哌甲酯干預(yù)后效果相同,表明多巴胺D4受體激動(dòng)劑的適當(dāng)刺激在改善SHR行為認(rèn)知活動(dòng)的同時(shí)可引起小腦多巴胺D4受體表達(dá)升高。提示了小腦多巴胺D4受體的異常表達(dá)可能與ADHD認(rèn)知功能障礙有關(guān),也為尋找ADHD的新治療靶點(diǎn)提供了理論依據(jù)。
[Abstract]:[background]
Attention deficit hyperactivity disorder (attention deficit hyperactivity disorder, ADHD) is a common onset of childhood neurobehavioral disorders, mainly manifested in a series of behavioral abnormalities disproportionate to the level of development, such as undivided hyperactivity, impulsiveness, and distracted.ADHD, a chronic disease that affects life for life, if not early Intervention treatment, with the age of age, 70% of the children's symptoms continue to puberty, 30% of the children's symptoms continue to adult, the patient's academic, behavioral regulation, social life and other aspects of a wide and negative impact. Its pathogenesis has not yet been clarified. The study shows that the occurrence and development of ADHD may be abnormal with dopamine D4 receptor. Previous studies of the pathogenesis of ADHD were mainly focused on the frontal cortex, striatum, and basal ganglia. In recent years, the researchers found that the total volume of cerebellum, especially the cerebellar vermis, was significantly reduced in the brain magnetic resonance imaging (MRI) scan of children with ADHD. There is a new understanding of the role of control and cognition. These findings provide a new entry point for the in-depth study of the pathogenesis of ADHD. This study selects the most commonly used ADHD animal model, spontaneously hypertensive rat (SHR), as the research carrier and selective dopamine D4 receptor agonist ABT-724. The effects of ABT-724 on the cognitive behavior of SHR rats and the expression of dopamine D4 receptor in the cerebellum were observed. The possible role of the dysfunction of the cerebellar dopamine system in the pathogenesis of ADHD was explored, and the theoretical basis for finding new targets for the treatment of ADHD was provided.
[method]:
1. the behavioral performance of young SHR/WKY/SD rats was observed. Using the open field test, the Morris water maze and the Lat maze, the spontaneous activity level, the spatial learning and memory ability, and the non selective attention of the SHR/WKY/SD rats were observed respectively.
2. study the effect of selective dopamine D4 receptor agonist ABT-724 on the behavior of SHR. Using ABT-724 low (0.04mg/kg), medium (0.16mg/kg), high (0.64mg/kg) three doses and methylphenidate (5mg/kg) intervention SHR, and using non intervention (physiological saline 1ml/kg) SHR as control, using open trial, Morris water maze, labyrinth, observed before and after intervention spontaneously. Activity level, spatial learning and memory ability, and non selective attention.
3. to investigate the effect of selective dopamine D4 receptor agonist ABT-724 on the expression of SHR cerebellar dopamine D4 receptor. After the end of the behavioral test, immunohistochemistry and real-time quantitative RT-PCR technique were used to detect the expression of SHR cerebellar dopamine D4 receptor in SHR/WKY/SD rats.
[results]:
1. the behavior of young SHR/WKY/SD rats was observed. In the opening experiment, the number of SHR crossing lattices (94.50 + 22.51) was more than WKY (6 + 3.12) and SD rats (63.63 + 22.33) significantly increased (P 0.05). In the Morris water maze, the spatial memory ability of SHR rats (21.38 + 5.01) and SD rats (41.13 + 6.10) decreased (P0.05); WKY rats (24.88 + 9.31) The erect frequency of.SHR rats in the Lat maze (138.63 + 31.89) was significantly more than that of WKY (19.36 + 17.69) and SD rats (76.88 + 32.80) (P0.05), and there was no significant difference in the latter two (P0.05).
2. study the effect of selective dopamine D4 receptor agonist ABT-724 on SHR behavior. The number of traversing lattices in SHR rats after methylphenidate and ABT-724 (70.67 + 8.59,76.50 + 10.75,79.17 + 10.44,65.67 + 20.62 respectively) decreased significantly (130.33 + 11.40) in saline group (P 0.05). In Morris water maze, the spatial memory of SHR rats after the dry prognosis The ability (52.50 + 4.04,52.17 + 2.99,61 + 8.15,53.83 + 9.87 respectively) was significantly increased (P 0.05) compared with the saline group (38.83 + 7.17). In the Lat maze, the erect number of SHR rats (57.17 + 5.67,60.83 + 8.28,55.17 + 9.50, respectively) in the Lat maze was significantly lower than that in the saline group (78 + 13.84) (P 0.05).
3. the effect of selective dopamine D4 receptor agonist ABT-724 on the expression of SHR cerebellar dopamine D4 receptor in.SHR cerebellar dopamine D4 receptor accumulative optical density (IOD) (2016900 + 494060) and mRNA expression (0.63 + 0.12) were significantly lower than WKY/SD rats (P 0.05), and the latter two had no significant difference in.ABT-724, middle, high dose and methylphenidate. The prognosis of SHR was significantly higher in cerebellar dopamine D4 receptor IOD and nRNA than in saline group (P 0.05).
[Conclusion]:
1. SHR young mice, as one of the most commonly used animal models of ADHD, compared with WKY and SD rats, showed obvious hyperactivity, impulsiveness, concentration of attention and cognitive dysfunction in the open test, Lat maze, and Morris water maze. This topic was based on the addition of another strain of rat (SD rat), the level of spontaneous activity of SHR. The selective attention and cognitive function were re tested and evaluated, which laid a theoretical foundation for further research.
The prognosis of 2. ABT-724 showed that SHR showed decreased white hair activity, cognitive function and non selective attention improvement, and the effect was similar to that of methylphenidate, suggesting that selective dopamine D4 receptor agonist ABT-724 could significantly improve the behavior cognition of SHR.
3. in the comparison of the expression of dopamine D4 receptor in the cerebellum of SHR/WKY/SD rats, the expression of dopamine D4 receptor in the brain region is significantly lower than that of the two control groups. This result provides a theoretical basis for further intervention test.ABT-724 to induce the increase of the expression of dopamine D4 receptor in the cerebellum of SHR rats, which is the same as that of methylphenidate, and the effect is similar to that of the methylphenidate. The appropriate stimulation of the dopamine D4 receptor agonist can increase the expression of the cerebellar dopamine D4 receptor at the same time in improving the cognitive activity of SHR, suggesting that the abnormal expression of the cerebellar dopamine D4 receptor may be related to the cognitive impairment of ADHD, and provides a theoretical basis for finding new therapeutic targets for ADHD.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類(lèi)號(hào)】：R749.94

【共引文獻(xiàn)】

相關(guān)期刊論文 前1條

1 張傳杰;劉麗娟;趙峰;李敬風(fēng);;腦電生物反饋治療兒童注意缺陷多動(dòng)障礙[J];湖北醫(yī)藥學(xué)院學(xué)報(bào);2011年01期

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本文編號(hào)：2116698