付 娟 鄭希耕 劉正奎

(1中國(guó)科學(xué)院心理研究所心理健康重點(diǎn)實(shí)驗(yàn)室, 北京 100101)

(2濱州學(xué)院生命科學(xué)系, 山東濱州 256603)

近年來(lái), 隨著自然災(zāi)害(地震、雪災(zāi)、海嘯)、人為災(zāi)害(戰(zhàn)爭(zhēng)、各種礦難、空難、恐怖事件)的不斷發(fā)生, 創(chuàng)傷后應(yīng)激障礙(post-traumatic stress disorder, PTSD)的發(fā)生率明顯增高。所謂PTSD是指?jìng)€(gè)體由于經(jīng)歷對(duì)生命具有威脅的事件或嚴(yán)重的創(chuàng)傷, 導(dǎo)致癥狀長(zhǎng)期持續(xù)的精神障礙(安獻(xiàn)麗, 王文忠, 鄭希耕, 2009)。條件性恐懼(conditioned fear)模型是模擬 PTSD的典型動(dòng)物模型, 主要研究恐懼記憶的獲得、存儲(chǔ)、提取和消退等過(guò)程。該模型以經(jīng)典的巴普洛夫條件反射為基礎(chǔ), 即一個(gè)中性刺激(如聲音或燈光)與一個(gè)傷害性刺激(非條件化刺激, unconditioned stimulus, US, 如電擊(重復(fù)配對(duì)呈現(xiàn)后,中性刺激將轉(zhuǎn)變?yōu)闂l件化刺激(conditioned stimulus, CS)進(jìn)而能夠單獨(dú)引起機(jī)體的恐懼反應(yīng)(條件化反應(yīng), conditioned response,CR), 包括防御反應(yīng)以及相應(yīng)的自主神經(jīng)功能與內(nèi)分泌活動(dòng)的改變。條件化恐懼建立之后, 如果僅 CS重復(fù)呈現(xiàn)而不呈現(xiàn) US, 則 CS引起機(jī)體條件化恐懼反應(yīng)的能力將逐漸減弱乃至喪失, 該過(guò)程即為恐懼消退(Davis, Walker, & Myers, 2003)。目前, 臨床上常用基于消退原理的暴露療法治療創(chuàng)傷后應(yīng)激障礙。但是, 此治療方法也僅能對(duì)部分 PTSD患者產(chǎn)生較好的療效, 并且經(jīng)過(guò)治療的PTSD患者也還有出現(xiàn)創(chuàng)傷癥狀再度惡化的可能,即復(fù)發(fā)現(xiàn)象。Choy等人研究發(fā)現(xiàn), 對(duì)PTSD患者進(jìn)行暴露治療后的 6個(gè)月至 3年半的時(shí)間里, 創(chuàng)傷癥狀再度復(fù)發(fā)的比率可高達(dá) 30%～50% (Choy,Fyer, & Lipsitz, 2007)。提示條件性恐懼的復(fù)發(fā)可能是PTSD治療中的關(guān)鍵問(wèn)題。

1 恐懼復(fù)發(fā)相關(guān)動(dòng)物模型

早在1979年Bouton就已經(jīng)發(fā)現(xiàn)消退學(xué)習(xí)只是能夠抑制條件化恐懼記憶的表達(dá),而不能擦除已獲得的條件化恐懼記憶。即經(jīng)過(guò)消退以后, 原來(lái) CS與 US之間習(xí)得的條件化記憶(conditioned memory)仍然存在, 只是沒(méi)有表現(xiàn)出來(lái), 并且消退訓(xùn)練同時(shí)還形成一種新的消退記憶(extinction memory), 兩種記憶同時(shí)存在, 相互競(jìng)爭(zhēng)(Bouton,García-Gutiérrez, Zilski, & Moody, 2006)。經(jīng)過(guò)消退學(xué)習(xí)后不同的刺激因素會(huì)再次誘發(fā)個(gè)體對(duì)條件刺激的恐懼反應(yīng), 這一現(xiàn)象就是恐懼復(fù)發(fā), 并且復(fù)發(fā)是具有異質(zhì)性的, 下面分別介紹研究較多的幾種恐懼復(fù)發(fā)模型(Bouton & Swartzentruber,1991)。

1.1 重建(Reinstatement)

重建是指恐懼消退以后再次暴露與恐懼訓(xùn)練時(shí)相同的US (非條件化的傷害性刺激, 一般為電擊), 當(dāng)用 CS (為條件化刺激, 恐懼訓(xùn)練時(shí)與 US匹配呈現(xiàn), 一般為聲音或燈光)來(lái)測(cè)試時(shí), 恐懼反應(yīng)增強(qiáng)(即復(fù)發(fā))的現(xiàn)象。因CS伴隨在整個(gè)消退過(guò)程中, 所以重建的獲得在某種程度上也依賴于消退學(xué)習(xí), 屬于創(chuàng)傷刺激誘發(fā)的復(fù)發(fā), 這種形式的復(fù)發(fā)程度受到消退后創(chuàng)傷刺激所在環(huán)境的影響。在臨床上, 經(jīng)治療后的應(yīng)激事件會(huì)破壞已有的治療效果使創(chuàng)傷癥狀再度復(fù)發(fā), 重建模型很好的模擬了這一現(xiàn)象。

1.2 續(xù)新(Renewal)

續(xù)新是以依賴空間背景為主的過(guò)程, 指?jìng)€(gè)體在一種環(huán)境中習(xí)得了恐懼反應(yīng), 而在另一種不同的環(huán)境中進(jìn)行消退訓(xùn)練, 那么, 當(dāng)其再次進(jìn)入第一次習(xí)得恐懼的環(huán)境或者另一個(gè)不同于消退環(huán)境的新的環(huán)境時(shí), 都可能會(huì)出現(xiàn)恐懼反應(yīng)再度復(fù)發(fā)的現(xiàn)象, 屬于情境依賴的復(fù)發(fā)。續(xù)新效應(yīng)表明, 只有當(dāng)條件刺激在消退環(huán)境(暴露治療環(huán)境)中出現(xiàn)時(shí), 才能夠抑制已習(xí)得的條件性恐懼反應(yīng), 而當(dāng)條件刺激在不同于治療環(huán)境的其他環(huán)境中出現(xiàn)時(shí),個(gè)體仍有可能對(duì)條件刺激產(chǎn)生恐懼反應(yīng)。這對(duì)臨床上的治療是一個(gè)極大的挑戰(zhàn), 患者的生活環(huán)境不可能局限于治療室。

1.3 自發(fā)恢復(fù)(Spontaneous recovery)

自發(fā)恢復(fù)是以時(shí)間依賴為主的過(guò)程, 指消退訓(xùn)練的效果會(huì)隨著時(shí)間的推移而降低, 對(duì)已習(xí)得的條件性反應(yīng)進(jìn)行消退訓(xùn)練后立即測(cè)試, 消退效果比較明顯, 如果消退過(guò)后間隔一段時(shí)間再進(jìn)行測(cè)試, 就有可能出現(xiàn)復(fù)發(fā)的現(xiàn)象。這也是臨床治療上的一大難題。

除以上 3種比較經(jīng)典的復(fù)發(fā)模型外, 近期有兩種較新的復(fù)發(fā)模型也受到了關(guān)注：

1.4 閾下二次條件化誘發(fā)的恐懼復(fù)發(fā)

閾下二次條件化(second sub-threshold fear conditioning)誘發(fā)的恐懼復(fù)發(fā)是一種較新的復(fù)發(fā)模型, 它是指無(wú)條件刺激強(qiáng)度很弱以至于與條件刺激配對(duì)不能形成顯著的條件反應(yīng), 也就是說(shuō)單獨(dú)進(jìn)行閾下條件化程序個(gè)體不會(huì)形成條件化反應(yīng)。研究發(fā)現(xiàn)在條件性恐懼消退后給予閾下條件化刺激, 個(gè)體會(huì)再次恢復(fù)對(duì)條件刺激的恐懼反應(yīng),相對(duì)于初次的創(chuàng)傷刺激, 消退后的閾下條件化刺激被稱為閾下二次條件化(Deschaux et al., 2011)。閾下二次條件化引起的恐懼反應(yīng)是一種復(fù)發(fā)現(xiàn)象而不是恐懼學(xué)習(xí)加強(qiáng), 因?yàn)镈eschaux等人發(fā)現(xiàn)當(dāng)閾下二次條件化的發(fā)生環(huán)境或者使用的條件刺激與之前的強(qiáng)條件化不同時(shí), 個(gè)體對(duì)原有的條件刺激的恐懼反應(yīng)就不會(huì)出現(xiàn)。

2 恐懼復(fù)發(fā)相關(guān)的腦區(qū)機(jī)制

復(fù)發(fā)與消退密切相關(guān), 消退是一種新的學(xué)習(xí)記憶鏈接(CS-no US), 而不是對(duì)原有恐懼記憶的遺忘。從記憶加工的角度來(lái)看, 條件性恐懼獲得時(shí)個(gè)體習(xí)得了CS-US的恐懼鏈接, 而消退過(guò)程中個(gè)體又逐漸習(xí)得了CS-no US新的記憶鏈接, 這樣CS就產(chǎn)生了兩個(gè)意義相反的鏈接：可能有厭惡刺激或沒(méi)有厭惡刺激。部分研究者認(rèn)為消退后的情境可能是區(qū)分這兩種記憶并做出合理反應(yīng)的重要因素(Bouton, 2002)。續(xù)新是基于情境特異性的,目前與恐懼復(fù)發(fā)相關(guān)的研究大部分都是針對(duì)續(xù)新效應(yīng)進(jìn)行的。

大量研究表明恐懼消退和復(fù)發(fā)需要多個(gè)皮質(zhì)區(qū)域及皮質(zhì)下結(jié)構(gòu)的參與(Kim & Jung, 2006), 如杏仁核不同亞區(qū)、腹內(nèi)側(cè)前額葉(ventral medial prefrontal cortex, vmPFC)、腹側(cè)及背側(cè)海馬等。解剖上, vmPFC的不同亞區(qū)、杏仁核不同亞區(qū)以及海馬間都有密集的交互纖維投射, 提示三者在功能上緊密相關(guān)。

2.1 腹內(nèi)側(cè)前額葉在消退和復(fù)發(fā)中的作用

已有研究表明腹內(nèi)側(cè)前額葉的兩個(gè)亞區(qū)邊緣前皮層(prelimbic cortex, PL)和邊緣下皮層(infralimbic cortex, IL)參與恐懼消退與復(fù)發(fā), 但二者在消退和復(fù)發(fā)中的功能并不相同, PL是恐懼表達(dá)和復(fù)發(fā)的重要腦區(qū), 但并不參與消退記憶的形成和鞏固;而IL主要負(fù)責(zé)消退記憶的形成和鞏固, 卻不影響恐懼的表達(dá)。大量研究發(fā)現(xiàn)PL是后天習(xí)得恐懼表達(dá)的必要腦區(qū), 恐懼表達(dá)前失活 PL會(huì)降低恐懼表達(dá)(Laurent & Westbrook, 2009), 而微量電刺激PL會(huì)增加恐懼表達(dá)(Vidal-Gonzalez, Vidal-Gonzalez,Rauch, & Quirk, 2006)。Burgos-Robles等人還觀察到PL神經(jīng)元的持續(xù)反應(yīng)與條件性恐懼中“僵直行為”的時(shí)程同步性(Burgos-Robles, Vidal-Gonzalez,& Quirk, 2009)。

解剖上, PL除了接受來(lái)自外側(cè)杏仁核的投射,還接受來(lái)自海馬與聽(tīng)覺(jué)皮層的投射, 杏仁核與海馬的共同投射興奮了 PL區(qū)的神經(jīng)元(Ishikawa &Nakamura, 2003), 提示 PL可能是通過(guò)整合來(lái)自不同區(qū)域的信號(hào)產(chǎn)生一段持續(xù)的反應(yīng)。還有一種可能就是恐懼誘發(fā)了PL區(qū)NE與DA的釋放, 這也增強(qiáng)了PL神經(jīng)元的興奮性, 使得PL對(duì)杏仁核、海馬以及聽(tīng)皮層的輸入反應(yīng)增強(qiáng)(Hugues, Garcia,& Léna, 2007)。因此, PL可能作為一個(gè)整合部位綜合聲音、場(chǎng)景以及應(yīng)激相關(guān)信號(hào)針對(duì)條件化刺激輸出合適的行為反應(yīng)(Corcoran & Quirk, 2007)。但在消退前用 GABA-α激動(dòng)劑蠅蕈醇(muscimol)失活PL只破壞了消退中的恐懼表達(dá), 但并不影響消退記憶的形成(Sierra-Mercado, Padilla- Coreano,& Quirk, 2011)。PL也是消退后續(xù)新復(fù)發(fā)的必要腦區(qū), 續(xù)新與PL的c-Fos高表達(dá)呈正相關(guān)(Knapska& Maren, 2009), 而續(xù)新復(fù)發(fā)前切斷PL-VH通路也會(huì)抑制續(xù)新復(fù)發(fā)(Orsini, Kim, Knapska, & Maren,2011), 不僅說(shuō)明了這兩個(gè)腦區(qū)是續(xù)新復(fù)發(fā)的必要腦區(qū), 而且二者之間的信息傳遞也是續(xù)新復(fù)發(fā)的必要條件。我們最新的研究也表明, PL腦區(qū)參與了閾下二次條件化誘發(fā)的復(fù)發(fā), 且PL-VH通路可能參與了這個(gè)過(guò)程(Fu et al., 2016)。

與PL的功能不同, IL參與了消退記憶的形成和提取。研究發(fā)現(xiàn)在消退記憶提取前失活 IL, 恐懼行為再次出現(xiàn), 這說(shuō)明了IL對(duì)于消退記憶的提取是必要的(Milad & Quirk, 2002)。電生理研究表明, IL神經(jīng)元活動(dòng)選擇性地對(duì)消退后的CS反應(yīng)增強(qiáng)(Santini, Quirk, & Porter, 2008), 消退記憶的提取與IL的神經(jīng)元活動(dòng)增加相關(guān), 另外消退還增加了 IL對(duì)抑制杏仁核細(xì)胞活動(dòng)性的調(diào)節(jié)(Phelps,Delgado, Nearing & LeDoux, 2004), 而Knapska和Maren觀察到在消退記憶提取時(shí)IL的c-Fos表達(dá)顯著增加(Knapska & Maren, 2009)。消退提取失敗可能由于PL腦區(qū)的過(guò)度活動(dòng), 或是IL活動(dòng)減少導(dǎo)致。因此, 恐懼記憶和消退記憶哪一種被提取可能依賴于PL與IL活動(dòng)的平衡性。這種觀點(diǎn)也與臨床上的研究一致, 臨床發(fā)現(xiàn)人類消退記憶的提取依賴于PL和IL, 以及dorsal anterior cingulated(dACC)和vmPFC的活動(dòng)性(Kalisch et al., 2006)。

2.2 杏仁核在恐懼消退和復(fù)發(fā)中的作用

很多研究發(fā)現(xiàn)杏仁核也參與恐懼消退, 各個(gè)亞區(qū)(Ce、Ba和La)與消退記憶的情境性調(diào)節(jié)有關(guān)(Knapska et al., 2012)。Maren實(shí)驗(yàn)室的一系列研究發(fā)現(xiàn)：不管是消退記憶還是續(xù)新記憶的提取都會(huì)使杏仁核的 Cel區(qū)的 c-Fos表達(dá)增加, 而 Cem區(qū)只在續(xù)新時(shí)有c-Fos表達(dá)(Knapska & Maren, 2009),這是因?yàn)镃el區(qū)同時(shí)接受來(lái)自VH、PL和IL的投射, 所以可以確定的是情境依賴性的恐懼的表達(dá)是通過(guò)Ce來(lái)介導(dǎo)的; BA接受PL的興奮性投射,有研究認(rèn)為PL通過(guò)BA驅(qū)動(dòng)了恐懼的表達(dá)(Laviolette,Lipski, & Grace, 2005), PL通過(guò)驅(qū)動(dòng)BA,進(jìn)而通過(guò)輸出核團(tuán) Ce表達(dá)恐懼反應(yīng)(Goosens & Maren,2001)。PL和HIPP到BA的投射在恐懼續(xù)新表達(dá)時(shí)活動(dòng)增加, 如果交叉損毀HIPP到BA的路徑(不管直接路徑還是間接路徑)都會(huì)損害恐懼記憶的續(xù)新效應(yīng)(Orsini et al., 2011)。電生理方面的研究證明, 在 BA中存在兩種神經(jīng)元, 分別介導(dǎo)了消退記憶的提取和續(xù)新的發(fā)生, 而這兩種行為狀態(tài)的轉(zhuǎn)換取決于兩種神經(jīng)元活動(dòng)的平衡性(Herry et al.,2008)。線索性恐懼消退后LA神經(jīng)元也顯示出情境特異性的發(fā)放(Hobin, Goosens, & Maren, 2003),最近Knapska等利用一種可以在樹(shù)突特異性表達(dá)熒光蛋白的轉(zhuǎn)基因大鼠, 結(jié)合示蹤技術(shù)證明在LA也存在兩種神經(jīng)元, IL對(duì)La的輸入選擇性激活介導(dǎo)恐懼消退的神經(jīng)元, 而VH與PL向La的輸入選擇性的激活了介導(dǎo)恐懼續(xù)新的神經(jīng)元, 動(dòng)物的行為表現(xiàn)取決于其所在的情境(Knapska et al.,2012)。對(duì)人的研究結(jié)果也表明, 在線索性恐懼復(fù)發(fā)中杏仁核活動(dòng)也是增強(qiáng)的(Lonsdorf, Haaker, &Kalisch, 2014)。

2.3 海馬在恐懼消退和復(fù)發(fā)中的作用

海馬作為情境信息加工的關(guān)鍵結(jié)構(gòu), 對(duì)于消退記憶的鞏固及消退后的恐懼復(fù)發(fā)是必需的(Fanselow, 2000), 且DH和VH在條件性恐懼記憶的加工中也存在功能差異性。DH主要參與了消退記憶的情境編碼和加工。研究表明在條件性恐懼訓(xùn)練前藥物失活或電毀損 DH并不影響條件性恐懼的獲得和消退, 但破壞了消退記憶提取的情境依賴性(Ji & Maren, 2005), 而在消退前失活 DH則影響了消退的速率, 及消退后情境調(diào)節(jié)的記憶提取, 但并不影響恐懼表達(dá), 這說(shuō)明 DH可能參與了消退記憶的獲得、情境編碼及情境依賴的提取, 但不參與線索性條件恐懼的表達(dá)(Corcoran,Desmond, Frey, & Maren, 2005)。而與 DH 不同, 損毀VH損害了以聲音作為CS的條件性恐懼的獲得和表達(dá), 也損害了場(chǎng)景性恐懼的獲得及表達(dá)(Trivedi & Coover, 2004)。藥物失活VH也得到了類似的結(jié)果(Bast, Zhang, & Feldon, 2001)。解剖上,VH與杏仁核有著廣泛的相互投射, 損傷VH到杏仁核的傳出纖維可以阻礙場(chǎng)景性恐懼條件化(Maren & Fanselow, 1995), 這也提示VH與杏仁核的共同活動(dòng)介導(dǎo)了這一學(xué)習(xí)過(guò)程。

Maren和Holt假設(shè)VH可能作為DH向杏仁核傳輸場(chǎng)景信息的渠道, 按此觀點(diǎn), DH負(fù)責(zé)利用場(chǎng)景信息消除CS的歧義, 而VH負(fù)責(zé)將這個(gè)信息傳輸給下游結(jié)構(gòu), 包括杏仁核。VH腦區(qū)內(nèi)微注射GABAA激動(dòng)劑 muscimol不僅破壞了條件性恐懼消退的續(xù)新效應(yīng), 也破壞了利用場(chǎng)景信息確定CS的意義的能力(Hobin, Ji, & Maren, 2006)。失活DH對(duì)AAB和ABC的續(xù)新有影響, 但是不影響ABA的續(xù)新, 進(jìn)一步說(shuō)明了當(dāng)測(cè)試環(huán)境中CS的意義模糊不清時(shí), DH才發(fā)揮作用(Corcoran & Maren, 2004)。消退后失活海馬可以消除杏仁核對(duì) CS引起的神經(jīng)元發(fā)放的情境性調(diào)節(jié)(Maren & Hobin, 2007),提示海馬到杏仁核的投射介導(dǎo)了場(chǎng)景依賴性的消退過(guò)程(Canteras & Swanson, 1992)。因?yàn)閂H是情境信息傳到杏仁核的最初來(lái)源, 所以這種直接投射可能對(duì)續(xù)新是必需的, 也有實(shí)驗(yàn)證實(shí)在續(xù)新時(shí)從VH投射到杏仁核的神經(jīng)元被激活(Herry et al.,2008)。另外一條途徑是VH可以通過(guò)PL來(lái)影響B(tài)A的活動(dòng), VH到PL有密集的投射, 而PL與BA又有相互的直接投射(Vertes, 2004)。損毀PL消弱了恐懼的表達(dá)(Corcoran & Quirk, 2007), 電刺激PL可以導(dǎo)致恐懼行為并且 BA發(fā)放增多(Likhtik,Pelletier, Paz, & Paré, 2005)。恐懼續(xù)新后 PL 的 c-Fos表達(dá)也增加(Knapska & Maren, 2009)。我們的研究證實(shí), 分別失活DH與VH損害了閾下二次條件化誘發(fā)的恐懼復(fù)發(fā)(Fu et al., 2016)。閾下二次條件化誘發(fā)的恐懼復(fù)發(fā)模型中CS的意義也是不明確的,這一點(diǎn)與 ABC續(xù)新模型相似, 所以結(jié)果是一致的。綜上, VH與PL到BA的共同投射介導(dǎo)了消退后對(duì)于恐懼復(fù)發(fā)的影響(Orsini et al., 2011)。

對(duì)人的研究發(fā)現(xiàn), 在線索性消退記憶的表達(dá)過(guò)程中, 海馬的前部可能發(fā)揮著重要作用(Milad et al., 2009)。最近的一項(xiàng)重建研究結(jié)果表明, 消退記憶表達(dá)時(shí)vmPFC活動(dòng)增強(qiáng), 且不依賴于條件化的模式(包括線索性和場(chǎng)景性); 在場(chǎng)景性恐懼重建后杏仁核被激活, 并且重建后海馬前部的活動(dòng)上調(diào), 這提示海馬前部參與了消除情境歧義或者平衡消退記憶與恐懼記憶之間競(jìng)爭(zhēng)的過(guò)程(Lonsdorf,Haaker, & Kalisch, 2014)。

3 恐懼復(fù)發(fā)的藥理學(xué)干預(yù)

有研究發(fā)現(xiàn)杏仁核內(nèi)微注射 NMDA受體激動(dòng)劑 DCS (D-環(huán)絲氨酸)可以促進(jìn)消退學(xué)習(xí)(Walker,Ressler, Lu, & Davis, 2002)。也有報(bào)道稱DCS可以使消退記憶保持長(zhǎng)久, 不易使恐懼記憶重建(Ledgerwood, Richardson, & Cranney, 2004)。此外,在消退前給予DCS可以促使大鼠在恐懼條件化學(xué)習(xí)時(shí)突觸變化發(fā)生反轉(zhuǎn)(Mao, Lin, & Gean, 2008)。對(duì)于育亨賓的研究發(fā)現(xiàn), 在消退訓(xùn)練前進(jìn)行大體注射可以增加小鼠的長(zhǎng)時(shí)消退記憶(Cain, Blouin,& Barad, 2004), 但是也有相反的結(jié)果, Holmes和Quirk (2010)的研究顯示育賓亨損害了消退學(xué)習(xí)。此外, 臨床上報(bào)道育亨賓可以提高幽閉癥病人暴露治療的效果(Powers, Smits, Otto, Sanders, & Emmelkamp,2009), 所以腎上腺素系統(tǒng)在恐懼消退學(xué)習(xí)中的作用非常復(fù)雜; 又如vmPFC腦內(nèi)微注射哌唑嗪損害了小鼠的恐懼消退過(guò)程(Do-Monte, Allensworth, &Carobrez, 2010), 但在臨床上卻一直用它治療PTSD病人的睡眠障礙(Raskind et al, 2007), 盡管如此, 動(dòng)物實(shí)驗(yàn)的結(jié)果也暴露了它在臨床治療中的局限性。

大麻醇對(duì)消退記憶中的促進(jìn)作用也為臨床上的治療提供了一些潛在的可能性, CB1受體廣泛分布于杏仁核的中間抑制性神經(jīng)元, 在消退學(xué)習(xí)過(guò)程中大麻醇可能起到了調(diào)節(jié)這些神經(jīng)元活動(dòng)的作用(Chhatwal et al., 2009; de Bitencourt, Pamplona,& Takahashi, 2013; Ganon-Elazar & Akirav 2012;Rabinak & Phan, 2014)。大體注射重?cái)z取抑制劑AM404和CB1受體激動(dòng)劑WIN55212-2可以促進(jìn)消退學(xué)習(xí)過(guò)程(Marsicano et al., 2002), 然而慢性給藥WIN55212-2卻損害消退學(xué)習(xí)(Lin, Mao, Chen, &Gean, 2008)。而且, 最近的很多研究提示CB1受體可能不在恐懼消退的長(zhǎng)時(shí)保持中起作用, 而是參與了行為的習(xí)慣化(Plendl & Wotjak, 2010)。這類藥物還未應(yīng)用于臨床, 在暴露療法中是否有效還不清楚。Quirk實(shí)驗(yàn)室報(bào)道恐懼條件化24小時(shí)以后在IL腦區(qū)進(jìn)行微注射BDNF, 測(cè)試時(shí)發(fā)現(xiàn)線索性恐懼反應(yīng)的表達(dá)減少, 并且在成功消退動(dòng)物的海馬中檢測(cè)出 BDNF的水平升高, 海馬內(nèi)微注射BDNF與IL內(nèi)微注射的結(jié)果相同(Peters, Dieppa-Perea, Melendez, & Quirk, 2010), Baker-Andresen,Flavell, Li和Bredy (2013)的研究也得到了類似的結(jié)果。這些結(jié)果可能解釋了為什么編碼BDNF的基因變異會(huì)影響到人的消退學(xué)習(xí)(Soliman et al., 2010)。

還有一些新的藥物靶點(diǎn)正在引起研究者的關(guān)注：一個(gè)單一的左旋多巴可以有效防止大鼠續(xù)新(Haaker et al., 2013); 急性心得安對(duì)防止復(fù)發(fā)也有一定效果(Morris, Westbrook, & Killcross, 2005);低劑量東莨菪堿也可以降低續(xù)新效應(yīng), 可能通過(guò)影響海馬的活動(dòng)破壞了消退記憶的場(chǎng)景依賴性(Zelikowsky et al., 2013); 腦內(nèi)鎂元素水平的升高有利于消退記憶的保持(Abumaria et al., 2011)。綜合以上研究結(jié)果, 藥物干預(yù)與暴露療法相結(jié)合或許可以優(yōu)化臨床上相關(guān)精神障礙的治療策略。

4 小結(jié)

PTSD的研究在國(guó)內(nèi)外備受關(guān)注, 而消退記憶的脆弱使恐懼復(fù)發(fā)成為 PTSD治療中的關(guān)鍵問(wèn)題。綜上所述, 腹內(nèi)側(cè)前額葉的不同亞區(qū)在消退和復(fù)發(fā)中功能不同, PL主要參與了復(fù)發(fā), 而IL重點(diǎn)維持消退記憶; 杏仁核參與了消退記憶的情境性調(diào)節(jié), 并且BA與LA中都有兩種神經(jīng)元分布介導(dǎo)了消退記憶的提取與續(xù)新的發(fā)生; 海馬作為情境信息加工的關(guān)鍵結(jié)構(gòu), 對(duì)于消退記憶的鞏固及消退后的恐懼復(fù)發(fā)也是必需的。藥理學(xué)上對(duì)于復(fù)發(fā)的干預(yù)探索或可以優(yōu)化臨床上基于消退原理的暴露療法。但復(fù)發(fā)因誘發(fā)因素的不同而具有的異質(zhì)性使其神經(jīng)機(jī)制變得更加復(fù)雜。目前研究者多致力于利用多種途徑針對(duì)單一動(dòng)物模型尋找抑制恐懼復(fù)發(fā)的方法, 而各模型之間的交叉研究相對(duì)較少, 但實(shí)際在臨床上 PTSD患者經(jīng)過(guò)暴露治療后很多因素可以誘發(fā)復(fù)發(fā)。我們推測(cè)腹內(nèi)側(cè)前額葉、海馬、杏仁核或構(gòu)成了不同模型的共同神經(jīng)環(huán)路基礎(chǔ), 若能整合不同動(dòng)物模型的研究結(jié)果,找到共同的靶點(diǎn), 將有重大的臨床意義。所以對(duì)多種動(dòng)物模型的綜合研究模式應(yīng)該引起足夠的關(guān)注。

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