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抑郁癥動物模型的研究進(jìn)展

2017-01-16 07:47張磊陽裘福榮陳文文楊蔣偉
中國比較醫(yī)學(xué)雜志 2017年9期
關(guān)鍵詞:動物模型抗抑郁造模

張磊陽,賀 敏,李 玥,裘福榮,陳文文,吳 雨,楊蔣偉,蔣 健

(上海中醫(yī)藥大學(xué)附屬曙光醫(yī)院臨床藥理科,上海 201203)

研究進(jìn)展

抑郁癥動物模型的研究進(jìn)展

張磊陽,賀 敏,李 玥,裘福榮,陳文文,吳 雨,楊蔣偉,蔣 健*

(上海中醫(yī)藥大學(xué)附屬曙光醫(yī)院臨床藥理科,上海 201203)

近年來抑郁癥發(fā)病率逐年上升,嚴(yán)重危害了人類的身心健康,但是其發(fā)病機(jī)制尚未明確。而動物模型可以模擬人類抑郁癥的疾病狀態(tài),被廣泛運(yùn)用于抑郁癥發(fā)病機(jī)制研究和抗抑郁新藥的研發(fā)。抑郁癥動物模型根據(jù)造模方式不同可以分為以下幾類:應(yīng)激造模,手術(shù)造模,藥物誘發(fā)造模和遺傳造模。這些模型可以從不同的方面來解釋抑郁癥的發(fā)生,比如神經(jīng)遞質(zhì)及其受體和轉(zhuǎn)運(yùn)蛋白、神經(jīng)營養(yǎng)因子、神經(jīng)內(nèi)分泌系統(tǒng)、炎癥假說等,在抑郁癥的研究中發(fā)揮重要作用。該綜述就常用的嚙齒類動物抑郁癥模型進(jìn)行概述和評價,為抑郁癥的研究提供參考。

抑郁癥;嚙齒類;動物模型;發(fā)病機(jī)制

抑郁癥是一種常見的精神障礙性疾病,其核心癥狀為心境低落和興趣減退,同時可伴有認(rèn)知功能損害、意志活動減退、飲食睡眠障礙及各種軀體癥狀。抑郁癥的發(fā)病率逐年增高[1],WHO估計全球患此病者逾億。盡管如此,我們對抑郁癥的病因、發(fā)病機(jī)制仍知之甚少,合理的抑郁癥動物模型是篩選抗抑郁藥物并明確作用機(jī)理的重要手段。本文就目前應(yīng)用較多的嚙齒類動物的抑郁癥模型進(jìn)行介紹與評價,以期為抑郁癥的動物實(shí)驗(yàn)研究提供參考。

1 應(yīng)激造模

應(yīng)激是引起人類及動物抑郁的主要因素之一,而抗抑郁藥物可糾正應(yīng)激引起的抑郁。應(yīng)激是制作抑郁癥動物模型的主要方法之一,目前常用的有以下幾種:

1.1行為絕望模型

主要包括大小鼠強(qiáng)迫游泳模型和小鼠懸尾模型,此類模型屬于急性應(yīng)激模型。

1.1.1 大小鼠強(qiáng)迫游泳實(shí)驗(yàn)(forced swimming test,F(xiàn)ST)

該實(shí)驗(yàn)是將大鼠或小鼠置于一個局限且無法逃脫的空間游泳,當(dāng)多次逃逸無效后,其放棄掙扎而漂浮在水面上呈不動的狀態(tài),這種狀態(tài)被稱為“絕望”狀態(tài)[2]。此法簡單易行,可信度較高,多數(shù)抗抑郁藥能減少動物游泳不動的時間,可用于抗抑郁藥的初篩,且與臨床藥效顯著相關(guān)。該模型也常用于其他抑郁模型建立成功與否的判斷。但此模型有假陽性反應(yīng),一些精神興奮劑如苯丙胺也會降低不動的時間;品系差異也較大,比如檢測氟西汀的抗抑郁效果時NMRI小鼠要比C57BL6小鼠更敏感[3]。此外,對“不動”的判定易帶有主觀性——“不動”可能是疲勞產(chǎn)生的,也可能是鼠保存體力的生存策略。另外,實(shí)驗(yàn)動物易受水溫、水深以及周圍環(huán)境的影響。

1.1.2 小鼠懸尾實(shí)驗(yàn)(tail suspension test,TST)

該實(shí)驗(yàn)將動物頭部向下懸掛,動物為克服不正常體位,經(jīng)多次掙扎仍不能擺脫困境后,出現(xiàn)間斷性不動,顯示“行為絕望”狀態(tài)。該方法是抗抑郁藥物活性篩選中具有高靈敏度的行為學(xué)方法,又因其快速、方便,自1985年提出至今,一直被廣為接受和應(yīng)用。本方法也是評價抑郁癥模型造模成功與否的常用檢驗(yàn)方法。但該模型也有品系差異,如和其他品系的小鼠相比較,C57BL/6J小鼠有更長的不動時間[4],說明C57BL/6J小鼠在無法逃避的情況下易于造成行為絕望,可能更適合用于急性應(yīng)激抑郁模型的建立。

1.2習(xí)得性無助模型(learnedhelplessnessmodel,LH)

該模型由Seligman等提出,常用于抗抑郁藥的篩選及抑郁癥發(fā)病機(jī)制的研究,是眾多抑郁癥病理生理學(xué)理論概念的來源[5, 6]。當(dāng)個體暴露于無法控制的應(yīng)激(如電擊)時,將在之后的學(xué)習(xí)活動中表現(xiàn)出行為欠缺,如逃避行為障礙、自發(fā)活動減少;同時伴有其他的行為改變,如食欲減退、體重減輕、運(yùn)動性活動減少、攻擊性降低等。而這種逃避行為障礙可以通過抗抑郁藥治療逆轉(zhuǎn)。研究表明,在習(xí)得性無助模型中,小鼠海馬區(qū)腦源性神經(jīng)營養(yǎng)因子(brain-derived neurotrophic factor,BDNF)基因表達(dá)受到抑制,致使BDNF水平降低[7];且BDNF在LH模型鼠不同腦區(qū)的作用及含量不同,在內(nèi)側(cè)前額葉皮質(zhì)、海馬CA3區(qū)和海馬齒狀回明顯減少,而在伏隔核卻明顯增加[8]。除此之外,LH大鼠大腦額葉皮質(zhì)及海馬區(qū)ERK1/2信號通路功能降低[9],線粒體內(nèi)18×103轉(zhuǎn)位蛋白表達(dá)減少[10]。

LH模型也存在爭議:動物暴露于無法控制的應(yīng)激時,它們會變得無助,也可能學(xué)會有意不動;并沒有證據(jù)表明抑郁癥患者的臨床癥狀,如抑郁、絕望以及消極的認(rèn)識等是由于習(xí)得性無助這一心理過程所導(dǎo)致的;正常人在無法逃避的時候,并沒有形成習(xí)得性無助;逃避障礙可能僅是因?yàn)榭謶忠?,并非是無助[11]。

1.3社會失敗應(yīng)激模型

也可以稱為定居者與入侵者的測試,該法是運(yùn)用同一物種間引發(fā)沖突進(jìn)而產(chǎn)生精神心理壓力來實(shí)現(xiàn)。當(dāng)一只雄性的嚙齒類動物被重復(fù)多次放入居住著另一只雄性好斗、有支配地位的年長嚙齒類動物的籠子里,入侵者會被攻擊,最終表現(xiàn)出快感缺乏等癥狀[12]。該模型可以引起腦內(nèi)從器質(zhì)到功能的多方面改變,對于抑郁癥及抗抑郁藥的研究具有較大價值。

研究發(fā)現(xiàn)社會失敗應(yīng)激模型鼠的海馬體及內(nèi)側(cè)前額葉皮質(zhì)的體積減少,下丘腦-垂體-腎上腺(hypothalamic-pituitary-adrenal,HPA)軸功能亢進(jìn),皮質(zhì)醇分泌增多,前額葉皮質(zhì)及海馬區(qū)的BDNF表達(dá)下降,BDNF-TrkB通路功能失調(diào)[13, 14];單胺神經(jīng)遞質(zhì)及其轉(zhuǎn)運(yùn)體等均出現(xiàn)了改變[15, 16];小鼠腦內(nèi)的犬尿氨酸通路活性增高[17]。通過轉(zhuǎn)錄組測序技術(shù)發(fā)現(xiàn),模型小鼠的下丘腦和海馬區(qū)的大部分核糖體基因表達(dá)下調(diào)[18]。另外,研究中也發(fā)現(xiàn)模型鼠前腦額葉皮質(zhì)區(qū)的谷氨酸及γ-氨基丁酸的功能異常,海馬區(qū)的糖皮質(zhì)激素受體mRNA表達(dá)下降,前炎性細(xì)胞因子增多[19-21]。

但該模型能同時引起抑郁和焦慮的行為表現(xiàn),可能更適合于具有二者混合特征的機(jī)制研究[22]。

1.4慢性束縛應(yīng)激模型(chronicrestraintstress,CRS)

慢性束縛應(yīng)激模型是將嚙齒類動物重復(fù)地置于束縛管內(nèi),限制其行動自由一段時間而造模。最終嚙齒類動物表現(xiàn)出快感缺失、體重減輕、飲食減少等抑郁樣癥狀,這些均可以被抗抑郁藥所改善。這種模型制作簡便,作為一種非損傷性刺激,與人類的疾病過程有相似性,因此是一種常用的應(yīng)激模型,實(shí)驗(yàn)中經(jīng)常聯(lián)合慢性溫和應(yīng)激模型造模。

該模型廣泛用于研究嚙齒類動物不同腦區(qū)(如海馬、前額葉皮質(zhì)、杏仁核及伏隔核等)形態(tài)、激素水平及行為學(xué)的改變。研究表明,該模型鼠海馬區(qū)及前額葉皮質(zhì)的BDNF表達(dá)及ERK的磷酸化水平均降低,Bcl-2 mRNA表達(dá)下調(diào),Bax mRNA表達(dá)上調(diào),杏仁核的神經(jīng)元異常,腦內(nèi)線粒體功能異常[23-25]。研究也發(fā)現(xiàn)該模型的前炎性細(xì)胞因子增多,抗炎性細(xì)胞因子減少[26]。

1.5慢性不可預(yù)知溫和應(yīng)激模型(chronicunpredictablemildstress,CUMS)

在一定時間內(nèi)讓嚙齒類動物暴露于一系列重復(fù)的不可預(yù)知的溫和刺激下,從而誘導(dǎo)出抑郁相關(guān)的行為,大部分抑郁癥狀可被抗抑郁藥逆轉(zhuǎn)。此模型體現(xiàn)了抑郁癥發(fā)病的多個方面,目前應(yīng)用最為廣泛。模型中應(yīng)激因子較多且應(yīng)激強(qiáng)度低,模型具有高度的有效性,效果可以持續(xù)幾個月,抗抑郁藥治療有效,治療的時間進(jìn)程及效果都與臨床治療情形相似,對研究抗抑郁藥的臨床作用機(jī)制及抑郁癥的病理生理機(jī)制具有一定價值。

研究表明該模型可以誘導(dǎo)持久的快感缺乏,還可使動物記憶受損、社交能力下降、體重減輕、皮質(zhì)醇分泌增多、體溫降低、夜間褪黑素分泌增多,并會引起焦慮樣行為;模型鼠生物鐘基因也發(fā)生改變,前額葉皮質(zhì)Per1和Per2基因的表達(dá)降低[27-29]。此外,該模型還存在p11基因甲基化的表觀遺傳修飾[30],模型鼠海馬區(qū)及前額葉皮質(zhì)的BDNF水平及Na+, K+-ATP酶活性降低[31],HPA軸亢進(jìn),5-HT再攝取增多,NF-κB信號通路活性增強(qiáng),NRG1/ErbB信號通路功能異常[32-34]。

但此模型實(shí)際操作過程的工作量較大,持續(xù)時間較長。

1.6母嬰分離模型(maternalseparation,MS)

早期的生活應(yīng)激刺激會使嚙齒類動物產(chǎn)生持久的生理學(xué)和行為學(xué)的改變,會增加動物成年后情感紊亂的風(fēng)險。母嬰分離屬于早期生活應(yīng)激的一種,短暫的分離能產(chǎn)生積極的影響,使母鼠更關(guān)心幼鼠,重復(fù)多次地把幼鼠和母鼠分離會使幼鼠的生理機(jī)能和行為產(chǎn)生長久的改變,如產(chǎn)生抑郁樣行為、HPA軸活性增強(qiáng),并會改變基因的表達(dá)[35, 36]。雌鼠更容易出現(xiàn)情感的改變,并且在和情緒相關(guān)的腦區(qū)發(fā)現(xiàn)色氨酸-犬尿氨酸代謝途徑紊亂,及產(chǎn)生神經(jīng)炎癥反應(yīng)[37]。有研究表明,母嬰分離后子鼠海馬區(qū)內(nèi)Tlr-4基因及其相關(guān)的信號蛋白基因Myd88表達(dá)增多[38]。該模型主要用于早期應(yīng)激對子鼠成年后病理生理及行為變化的研究。

2 手術(shù)造模

常用的是嗅球切除模型。嗅球位于端腦前端,與邊緣系統(tǒng)功能有關(guān),影響行為、情緒和內(nèi)分泌。大鼠切除雙側(cè)嗅球后嗅覺喪失,被動回避學(xué)習(xí)能力下降,應(yīng)激反應(yīng)增強(qiáng),攻擊行為增強(qiáng),強(qiáng)迫游泳實(shí)驗(yàn)中靜止時間延長。這些行為均可以被抗抑郁藥逆轉(zhuǎn)。模型鼠病變的機(jī)制與抑郁癥患者類似[39]。

該模型的神經(jīng)生化機(jī)制改變包括單胺神經(jīng)遞質(zhì)濃度和谷氨酸受體功能[40-42]。此外,也存在海馬體內(nèi)BDNF水平降低,血清皮質(zhì)酮降低,炎癥因子、凋亡蛋白增多及氧化損傷等現(xiàn)象。

此模型抑郁效果明顯、可靠性好,且抑郁動物的病理生理改變與人類抑郁相似,對檢測抗抑郁劑有較高的選擇價值。常用于抗抑郁藥的次篩以及作用機(jī)制研究。

但對實(shí)驗(yàn)手術(shù)技術(shù)要求高,實(shí)驗(yàn)中動物死亡率較高,模型有品系差異。

3 藥物誘發(fā)造模

此類模型是早期基于藥物之間的相互作用而產(chǎn)生的,主要篩選針對專一靶點(diǎn)的抗抑郁藥。嚴(yán)格來講,這些模型不應(yīng)稱為動物抑郁模型,但可以用來探討抗抑郁藥的藥理作用性質(zhì),或用于初篩未知化合物。

這類模型主要基于抑郁癥的單胺假說,如利血平誘導(dǎo)的抑郁模型,可以非選擇性的耗竭腦內(nèi)的單胺類神經(jīng)遞質(zhì),從而誘導(dǎo)嚙齒類動物體溫下降及運(yùn)動不能癥狀[43]。精神興奮劑的戒斷模型也會誘發(fā)抑郁樣的改變,嚙齒類動物在強(qiáng)迫游泳實(shí)驗(yàn)及懸尾實(shí)驗(yàn)中不動時間延長[44]。

這類模型與人類抑郁癥的發(fā)生機(jī)制之間存在一定的差距,目前使用較少。

4 遺傳型造模

遺傳型抑郁動物模型所使用的動物來自于自然突變或近交系,腦內(nèi)機(jī)制與抑郁患者相似,對抗抑郁藥的反應(yīng)更為良好。主要介紹以下兩種模型。

4.1Flinderssensitiveratline(FSL)大鼠模型

最初選擇性培育FSL大鼠是為了得到抗膽堿酯酶個體[45],后發(fā)現(xiàn)FSL大鼠表現(xiàn)出類似于人類抑郁樣癥狀,還發(fā)生了食欲及精神運(yùn)動功能減退等行為學(xué)方面的改變,晝夜節(jié)律出現(xiàn)異常,五羥色胺、多巴胺、膽堿能及神經(jīng)肽Y均發(fā)生改變,但HPA軸、γ-氨基丁酸水平及認(rèn)知功能正常[46, 47]。此模型大鼠和抑郁癥患者的行為學(xué)表現(xiàn)、神經(jīng)化學(xué)和藥理學(xué)機(jī)制類似,是一種非常有效的檢測抗抑郁藥的動物模型。

4.2Wistar-Kyoto(WKY)大鼠模型

該品系大鼠源自自發(fā)性高血壓大鼠,后來表現(xiàn)出和抑郁癥患者類似的激素水平、行為學(xué)及生理學(xué)的異常,故被作為一種遺傳型的抑郁癥模型[48]。動物在強(qiáng)迫游泳試驗(yàn)中靜止時間長而穩(wěn)定,出現(xiàn)社交回避癥狀,HPA軸功能亢進(jìn),血清皮質(zhì)酮增多[49]。該品系大鼠中縫背核及前額葉皮質(zhì)的五羥色胺水平出現(xiàn)了與抑郁癥患者類似的異常[50],海馬體積減少[51],腦與血清的BDNF含量較低[52],對SSRIs類抗抑郁藥不敏感。

除以上模型外,還有基因敲除模型、操作行為模型——大鼠72 s低頻差式強(qiáng)化程序模型、電刺激小鼠角膜引起的不動狀態(tài)模型、雙側(cè)卵巢切除抑郁模型,等等。這些模型均復(fù)制或模擬了人類抑郁癥的部分特征,可以作為抗抑郁藥及抑郁癥研究的方法。

5 小結(jié)

綜上所述,抑郁癥動物模型無論對于新的抗抑郁藥物開發(fā)還是對于抑郁癥發(fā)病機(jī)制的研究都是一項必不可少的手段。目前建立抑郁癥動物模型有多種方法,慢性不可預(yù)知溫和應(yīng)激模型及行為絕望模型應(yīng)用較多,但各種模型都存在一些局限性,多種模型的聯(lián)合應(yīng)用也許可以提高實(shí)驗(yàn)結(jié)果的可信度,選用敏感度高的品系來造模更是事半功倍。此外,應(yīng)多增加對遺傳性抑郁模型和早期應(yīng)激模型如母嬰分離模型的研究,以解決逐漸增多的青少年抑郁癥問題。抑郁癥動物模型還有待深入研究,以期進(jìn)一步完善模型,為抑郁癥的研究提供更有益的幫助。

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Researchprogressonanimalmodelsofdepression

ZHANG Lei-yang, HE Min, LI Yue, QIU Fu-rong, CHEN Wen-wen, WU Yu, YANG Jiang-wei, JIANG Jian*

(Department of Clinical Pharmacology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China)

The incidence of depression has been increasing over the recent years, which can cause serious physical and mental health problems in humans, but its pathogenesis has not been fully clarified. Animal models can simulate the depression in humans, thus are widely used for studies of the pathogenesis of depression, as well as in research and development of new antidepressants. According to the different ways of modeling, animal models of depression can be divided into the following categories: stress models, surgical models, drug-induced models and genetic models. These models can provide useful tools to explain some pathogenetic aspects of depression, such as neurotransmitters and their receptors/transporters, neurotrophic factors, neuroendocrine systems, inflammatory hypotheses, and so on. This review summarizes and evaluates the commonly used rodent animal models of depression and provides a reference for further research on depression.

Depression; Rodent; Animal models; Pathogenesis

R-33

A

1671-7856(2017) 09-0092-06

10.3969.j.issn.1671-7856.2017.09.018

2016-12-27

上海市進(jìn)一步加快中醫(yī)藥事業(yè)發(fā)展三年行動計劃(編號:ZY3-CCCX-3-2007)。

張磊陽(1991-),女,碩士研究生,研究方向:中醫(yī)郁證的臨床及實(shí)驗(yàn)研究。E-mail: zlyash123@163.com

蔣健(1956-),男,博士,主任醫(yī)師,博士生導(dǎo)師,研究方向:中醫(yī)郁證的臨床及基礎(chǔ)研究。E-mail: jiangjiansg@126.com

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