調(diào)控去甲腎上腺素能系統(tǒng)對防治創(chuàng)傷后應(yīng)激障礙的影響*

王紅波 朱湘茹

(河南大學(xué)認(rèn)知與行為研究所, 開封 475001)

1 概述

80%的人一生中至少會遭遇一次創(chuàng)傷事件(de Vries & Olff, 2009), 而約7%的個體在經(jīng)歷創(chuàng)傷后會罹患創(chuàng)傷后應(yīng)激障礙(posttraumatic stress disorder,PTSD) (de Vries & Olff, 2009; Kessler et al., 2005)。PTSD嚴(yán)重?fù)p害患者的社會交往、工作和生活質(zhì)量,并與抑郁和物質(zhì)濫用高共病。根據(jù)《精神障礙診斷與統(tǒng)計手冊》(DSM-Ⅴ) (APA, 2013), PTSD主要臨床表現(xiàn)為四大癥狀簇：創(chuàng)傷再體驗、回避創(chuàng)傷相關(guān)刺激、情感麻木和高喚醒。當(dāng)前, 研究者主要依據(jù)生物?心理?社會多維度模型研究 PTSD的發(fā)病機理和治療方法, 其中藥物治療是重點。基礎(chǔ)和臨床研究表明藥物治療 PTSD主要有兩種趨向：一種是在創(chuàng)傷經(jīng)歷后即刻施行, 旨在改變創(chuàng)傷記憶的編碼、鞏固和重整, 以降低患 PTSD的風(fēng)險; 一種是對已經(jīng)形成的 PTSD盡力治療其具體癥狀(Kapfhammer, 2014)。研究證據(jù)表明情緒記憶在 PTSD的病理生理中起著重要作用, 而去甲腎上腺素能系統(tǒng)(noradrenergic system)在情緒記憶的調(diào)控中起關(guān)鍵作用(Lonergan, Olivera-Figueroa, Pitman, & Brunet, 2013)。本文將首先闡述去甲腎上腺素能系統(tǒng)與 PTSD形成和維持的關(guān)系, 然后再討論調(diào)控去甲腎上腺素能系統(tǒng)對預(yù)防和治療PTSD的影響。

2 去甲腎上腺素能系統(tǒng)與 PTSD形成的關(guān)系

應(yīng)激性經(jīng)歷激活體內(nèi)的應(yīng)激系統(tǒng)(自主神經(jīng)系統(tǒng)和下丘腦?垂體?腎上腺軸), 引起腎上腺釋放應(yīng)激激素包括腎上腺素和糖皮質(zhì)激素(Jo?ls & Baram,2009)。早期PTSD的神經(jīng)生物學(xué)研究發(fā)現(xiàn)PTSD住院患者 24小時尿液中兒茶酚胺分泌物(如去甲腎上腺素/腎上腺素)含量顯著高于 PTSD 門診患者和正常人(Yehuda, Southwick, Giller, Ma, & Mason, 1992),表明PTSD住院患者自主神經(jīng)系統(tǒng)的激素持久的處于高水平狀態(tài)。之后的研究直接考察創(chuàng)傷后早期自主神經(jīng)系統(tǒng)活動的變化與 PTSD形成的關(guān)系, 發(fā)現(xiàn)急診部的病人在住院期間心率越高就越可能患PTSD或表現(xiàn)出PTSD癥狀, 這表明創(chuàng)傷早期自主神經(jīng)系統(tǒng)的高活動可能是隨后表現(xiàn)出創(chuàng)傷后應(yīng)激癥狀的危險因素(Zatzick et al., 2005)。

大量證據(jù)表明中樞去甲腎上腺素能系統(tǒng)參與恐懼或焦慮。PTSD患者腦脊液中的去甲腎上腺素(norepinephrine, NE)水平顯著高于正常人, 且與PTSD癥狀的嚴(yán)重性正相關(guān)(Geracioti et al., 2001)。藍斑(locus coeruleus)是中樞 NE的主要來源。有動物研究發(fā)現(xiàn)選擇性地去除(ablate)藍斑去甲腎上腺素能神經(jīng)元, 可增加小鼠在高架十字迷宮開放臂的跑動距離和停留時間, 以及在曠場測試中增加小鼠在中央?yún)^(qū)的跑動距離和停留時間, 表現(xiàn)出抗焦慮效應(yīng)。這證明藍斑是焦慮神經(jīng)環(huán)路的一部分, 去甲腎上腺素能神經(jīng)元參與焦慮行為(Itoi,2008)。最近, 一個由再體驗(reexperiencing, 即闖入性記憶和夢魘)、回避(avoidance, 即回避創(chuàng)傷相關(guān)的線索)、麻木(numbing, 即與他人脫離或疏遠和興趣喪失)、不悅性喚起(dysphoric arousal, 即睡眠困難、易激惹或憤怒和注意力問題)及焦慮性喚起(anxious arousal, 即高警覺和過度驚嚇)癥狀組成的5-因素模型為PTSD癥狀結(jié)構(gòu)提供了精確的表型表征(phenotypic representation) (Armour et al.,2012; Elhai et al., 2011; Pietrzak, Tsai, Harpaz- Rotem,Whealin, & Southwick, 2012)。依據(jù)該模型, 以去甲腎上腺素轉(zhuǎn)運體(norepinephrine transporter, NET)為靶點, NET可以促使突觸間隙的NE被快速清除從而減弱神經(jīng)信號, 研究者發(fā)現(xiàn) PTSD患者藍斑的 NET利用率(availability)顯著低于健康被試,而那些經(jīng)歷過創(chuàng)傷但未罹患PTSD的個體其NET的利用率介于 PTSD患者和健康被試的中間, 與兩者均無顯著差異。在PTSD患者中, 藍斑的NET利用率越高的個體, 其焦慮性喚醒癥狀越嚴(yán)重,并且NET利用率只與焦慮性喚醒癥狀的嚴(yán)重程度正相關(guān), 與 PTSD其它癥狀簇?zé)o關(guān)(Pietrzak et al.,2013)。此外, 遺傳學(xué)研究發(fā)現(xiàn)編碼去甲腎上腺素能α受體2B亞型(ADRA2B)的基因調(diào)節(jié)情緒記憶的負(fù)性偏向性(Gibbs, Bautista, Mowlem, Naudts,& Duka, 2013)。該基因在編碼ADRA2B時, 有時會導(dǎo)致受體上 3個谷氨酸殘基的缺失, 這是一種功能性缺失多態(tài)性(functional deletion polymorphism),與人的創(chuàng)傷記憶的再體驗增加有關(guān)。缺失變異型(deletion variant)的攜帶者會更強烈地受應(yīng)激性事件的影響。在 PTSD患者中, 缺失變異型的攜帶者會比非攜帶者表現(xiàn)出更嚴(yán)重的創(chuàng)傷再體驗癥狀(de Quervain et al., 2007)。這是因為缺失變異型的攜帶者在編碼負(fù)性情緒刺激時, 杏仁核被激活的程度較非攜帶者更高(Cousijn et al., 2010; Rasch et al.,2009)。功能性核磁共振成像(fMRI)研究顯示焦慮障礙患者的杏仁核被應(yīng)激性刺激過度激活(Etkin &Wager, 2007), 而這種激活依賴去甲腎上腺素能神經(jīng)系統(tǒng)(van Stegeren, 2008)。另外, 杏仁核對刺激的情緒反應(yīng)受前額葉調(diào)控(Maren, 2011), 而PTSD病人的前額葉功能受到損壞(Jovanovic et al., 2013;Tian et al., 2014)。這是因為應(yīng)激狀態(tài)下NE水平升高, 通過占用低親和力的α1和β1腎上腺素受體,快速降低前額葉神經(jīng)元的放電并加強杏仁核的功能(Arnsten, Raskind, Taylor, & Connor, 2015), 導(dǎo)致前額葉系統(tǒng)對認(rèn)知和情緒興奮性的有效調(diào)控受到損害(Kapfhammer, 2014)。

綜上, 基礎(chǔ)和臨床研究都表明去甲腎上腺素能系統(tǒng)參與 PTSD癥狀的形成和維持, 且外周和中樞的 NE水平能預(yù)測PTSD的癥狀嚴(yán)重性。應(yīng)激后中樞 NE水平升高會通過降低前額葉的神經(jīng)放電進而損壞前額葉對杏仁核的抑制功能。分布有大量去甲腎上腺素能神經(jīng)元的藍斑是焦慮神經(jīng)環(huán)路的一部分, PTSD患者藍斑的 NET利用率只與焦慮性喚醒癥狀正相關(guān), 與其它癥狀無關(guān), 而ADRA2B基因缺失變異型與PTSD患者的創(chuàng)傷再體驗癥狀加重有關(guān)。這些將有助于我們理解PTSD的表型異質(zhì)性(phenotypic heterogeneity)。

3 調(diào)控去甲腎上腺素能系統(tǒng)對預(yù)防PTSD的影響

創(chuàng)傷經(jīng)歷后形成的條件性恐懼記憶是后來發(fā)展為PTSD的重要病理機制(Mineka & Oehlberg,2008)。應(yīng)激中釋放的應(yīng)激激素相互作用參與情緒記憶的編碼, 并且這些激素水平的改變與記憶的異常鞏固和隨后形成的 PTSD癥狀有關(guān)(Bryant,McGrath, & Felmingham, 2013; Kukolja, Klingmuller,Maier, Fink, & Hurlemann, 2011; Nicholson, Bryant,& Felmingham, 2014; Ostrowski & Delahanty, 2014;Soeter & Kindt, 2011b)。記憶在初始獲得后不穩(wěn)定,需要經(jīng)歷突觸可塑性及合成新的蛋白質(zhì)才變得穩(wěn)定, 這一過程稱為鞏固(McGaugh, 2000)。情緒性經(jīng)歷誘發(fā)的去甲腎上腺素能系統(tǒng)的高活動會增強對刺激的反應(yīng)和記憶的鞏固(Barsegyan, McGaugh,& Roozendaal, 2014; McGaugh, 2013; O'Donnell,Hegadoren, & Coupland, 2004; Soeter & Kindt,2011b; van Stegeren, 2008)。因此, 抑制創(chuàng)傷經(jīng)歷誘發(fā)的去甲腎上腺素能系統(tǒng)的高活動, 可能會減弱對刺激的反應(yīng)及創(chuàng)傷記憶的過度鞏固, 從而阻止PTSD的形成。

有研究發(fā)現(xiàn)健康人群在應(yīng)激性刺激出現(xiàn)前服用β-腎上腺素能受體阻斷劑普萘洛爾(propranolol)可降低杏仁核對刺激的反應(yīng)性(Hurlemann et al.,2010)。PTSD的條件性恐懼動物模型研究也顯示,條件性恐懼訓(xùn)練前腹腔注射或往杏仁核外側(cè)核團注射普萘洛爾可損害線索恐懼記憶的獲得和保持(Bush, Caparosa, Gekker, & Ledoux, 2010; Kroon& Carobrez, 2009)。然而, 應(yīng)激后給β-腎上腺素能阻斷劑能否降低PTSD的發(fā)生率或減輕PTSD癥狀, 各研究的結(jié)果并不一致。早期的臨床初步研究發(fā)現(xiàn)創(chuàng)傷后立即服用普萘洛爾可以減輕 PTSD癥狀甚至可能阻止 PTSD的形成(Pitman et al.,2002; Vaiva et al., 2003)。最近的研究報道在植入式心臟除顫器(ICD)放電時服用親脂性的β受體阻斷劑可以顯著減輕由ICD不可預(yù)測不可控制的放電誘發(fā)的PTSD癥狀(Bhuvaneswar, Ruskin, Katzman,Wood, & Pitman, 2014)。但也有研究報道急性身體損傷如燒傷、手術(shù)創(chuàng)傷后的短時間內(nèi)服用普萘洛爾并沒有降低PTSD的發(fā)生率或減少其癥狀(Hoge et al., 2012; McGhee et al., 2009; Stein, Kerridge,Dimsdale, & Hoyt, 2007)。動物研究也發(fā)現(xiàn)大鼠在經(jīng)歷天敵氣味應(yīng)激后, 立即被腹腔注射普萘洛爾,不能破壞情境恐懼記憶的鞏固(Cohen et al., 2011)。以及在線索條件性恐懼訓(xùn)練后, 立即向大鼠腹腔(Fitzgerald, Giustino, Seemann, & Maren, 2015; Kroon& Carobrez, 2009)或直接往杏仁核(Bush et al., 2010;D?biec & Ledoux, 2004)注射普萘洛爾, 也不能破壞恐懼記憶的鞏固。應(yīng)激后的β受體阻斷劑不能破壞創(chuàng)傷記憶的鞏固, 原因有以下幾種可能：1、創(chuàng)傷事件發(fā)生時間和藥物處理時間的間隔所致,上述一些實驗的間隔為 1天或更長, 并且服用普萘洛爾需要一段時間才能達到合適的血藥濃度,而普萘洛爾對去甲腎上腺素能的阻斷作用被限制在一個可能只有幾小時的記憶鞏固時間窗里(Gazarini,Stern, Carobrez, & Bertoglio, 2013)。2、去甲腎上腺素能系統(tǒng)只參與記憶鞏固的后期過程(Sara,Roullet, & Przybyslawski, 1999), 所以應(yīng)激后立即給藥會導(dǎo)致鞏固后期的血藥濃度較低。3、某些應(yīng)激太強會誘發(fā)出更強的去甲腎上腺素能神經(jīng)傳導(dǎo),所以可能需要更高劑量的拮抗劑才能破壞鞏固(D?biec & LeDoux, 2004)。4、不同性質(zhì)(如可控性,可預(yù)測性和厭惡性)的創(chuàng)傷事件可能會激活不同的腦區(qū)(Wood et al., 2015; Yang & Liang, 2014)和受體(Genro, de Oliveira Alvares, & Quillfeldt, 2012),從而需要不同的藥物做干預(yù)(Davis, Walker, Miles,& Grillon, 2010; Genro et al., 2012; Santos, Gárgaro,Oliveira, Masson, & Brand?o, 2005)。例如, 在抑制性回避任務(wù)訓(xùn)練后, 往伏隔核注射利多卡因(lidocaine, 酰胺類局部麻醉藥)可以減弱背側(cè)海馬或內(nèi)側(cè)前額葉的 NE對記憶的增強效應(yīng); 而在情境條件性恐懼訓(xùn)練后, 伏隔核的利多卡因并不影響背側(cè)海馬或內(nèi)側(cè)前額葉的 NE對記憶的增強效應(yīng)(Yang & Liang, 2014)。另外, 在強電擊訓(xùn)練后向海馬注射辣椒素受體(transient receptor potential vanilloid type 1, TRPV1, 在疼痛的傳導(dǎo)和調(diào)節(jié)中發(fā)揮重要作用, 其離子通道的功能可作為疼痛感受器)的拮抗劑辣椒平(Capsazepine, 阻斷TRPV1通道的激活)能破壞情境條件性恐懼記憶的鞏固, 而弱電擊訓(xùn)練后的辣椒平則不影響記憶的鞏固。當(dāng)采用抑制性回避模型時, 不管是在強電擊還是弱電擊的訓(xùn)練條件下, 辣椒平都不影響記憶的鞏固(Genro et al., 2012)。5、創(chuàng)傷早期的β受體阻斷劑對創(chuàng)傷記憶和 PTSD癥狀的影響還有性別差異, β受體阻斷劑主要影響女性的創(chuàng)傷記憶和 PTSD癥狀(Krauseneck et al., 2010; Nugent et al., 2010)。盡管應(yīng)激后立即給予普萘洛爾不總能破壞恐懼記憶的鞏固, 但能穩(wěn)定應(yīng)激狀態(tài)下前額葉的神經(jīng)活動, 減輕應(yīng)激引起的前額葉損傷(Fitzgerald et al., 2015), 并且能降低恐懼線索進一步的二級條件化(secondorder conditioning, 即原有條件性刺激(S1)獲得非條件性刺激的特性后使個體對與 S1相關(guān)聯(lián)的新的中性刺激(S2)也產(chǎn)生條件反應(yīng), 是PTSD患者條件性恐懼難以消退的可能原因之一) (Kroon & Carobrez,2009), 這為以后治療PTSD創(chuàng)造了有利條件。

綜上, 應(yīng)激前的 β受體阻斷劑通過破壞條件化學(xué)習(xí), 降低條件性恐懼記憶的獲得, 從而減弱條件性恐懼記憶, 阻止PTSD的形成。應(yīng)激后的β受體阻斷劑有保護前額葉功能和阻止恐懼線索二級條件化的作用, 對記憶鞏固的破壞作用可能受藥物處理的時間點、藥物劑量、應(yīng)激強度、創(chuàng)傷事件的性質(zhì)等因素的影響。

4 調(diào)控去甲腎上腺素能系統(tǒng)對治療PTSD的影響

一旦恐懼記憶鞏固導(dǎo)致 PTSD形成, 那么對PTSD的治療工作主要集中在促進恐懼記憶的消退或破壞恐懼記憶的再鞏固以及減輕某些具體癥狀等方面。

4.1 調(diào)控去甲腎上腺素能系統(tǒng)對恐懼記憶消退的影響

治療焦慮障礙如 PTSD、恐怖癥最有效的心理療法是依靠對恐懼記憶的漸進性消退(Bentz,Michael, de Quervain, & Wilhelm, 2010)。消退是臨床暴露療法的核心原理, 是指在一個安全可控的環(huán)境下重復(fù)且系統(tǒng)地單獨呈現(xiàn)預(yù)示恐懼事件的線索刺激而不出現(xiàn)厭惡性后果。經(jīng)過消退學(xué)習(xí)后,個體習(xí)得曾經(jīng)的恐懼性線索不再預(yù)示著厭惡性后果, 從而降低恐懼反應(yīng)。由于消退降低恐懼反應(yīng)只是因為形成了一種新的抑制性記憶而不是破壞原始的創(chuàng)傷記憶(Milad & Quirk, 2012), 且消退記憶相對原始的創(chuàng)傷記憶而言脆弱又依賴環(huán)境, 故在多種條件下如重新暴露在非條件刺激(重建)或改變環(huán)境(續(xù)新)或經(jīng)過一段時間(自發(fā)恢復(fù)), 對線索刺激的恐懼反應(yīng)都可能恢復(fù)(Myers & Davis,2007)。消退后的恐懼復(fù)發(fā)仍是當(dāng)前臨床實踐的一個主要難題。因此, 增強消退記憶能更好地抑制恐懼反應(yīng)以減少癥狀復(fù)發(fā)。

消退記憶也是一種情緒記憶, 消退時去甲腎上腺素能系統(tǒng)的高活動將有助于增強消退記憶。動物研究發(fā)現(xiàn), 在消退時刺激迷走神經(jīng)來激活去甲腎上腺素能通路, 可以加速消退記憶的鞏固,從而快速降低恐懼反應(yīng)(Pe?a, Engineer, & McIntyre,2013)。對人和動物的研究顯示育亨賓(yohimbin,一種α2受體拮抗劑, 促使NE釋放)能促進恐懼消退(Cain, Blouin, & Barad, 2004; Holmes & Quirk,2010; Morris & Bouton, 2007; Powers, Smits, Otto,Sanders, & Emmelkamp, 2009)。不過育亨賓促進消退的效應(yīng)依賴環(huán)境, 當(dāng)消退環(huán)境與條件性恐懼習(xí)得環(huán)境相同時, 育亨賓不能促進消退(Mueller,Olivera-Figueroa, Pine, & Quirk, 2009), 只有當(dāng)消退環(huán)境不同于條件性恐懼習(xí)得環(huán)境時, 育亨賓才促進消退(Cain et al., 2004; Morris & Bouton, 2007)。環(huán)境有助于增加條件刺激(conditioned stimulus, CS)的預(yù)測性, 當(dāng) CS可預(yù)測時, NE對消退的調(diào)節(jié)效應(yīng)最大(Mueller & Cahill, 2010)。并且育亨賓增強消退效應(yīng)是劑量依賴的, 育亨賓只有在最佳濃度下才促進消退(Morris & Bouton, 2007)。此外, 在消退訓(xùn)練前給育亨賓會促進消退, 消退訓(xùn)練后給藥則無效。即使是去甲腎上腺素也需要在消退訓(xùn)練后的短時間內(nèi)(即消退記憶鞏固時間窗內(nèi))及時注射才能促進消退(Berlau & McGaugh, 2006)。值得注意的是, CS的出現(xiàn)將引發(fā)兩個相反的過程：消退和再鞏固(Lee, Milton, & Everitt, 2006), 而去甲腎上腺素藥物既能促進消退記憶的鞏固, 也能促進恐懼記憶的再鞏固, 所以這兩個共存的競爭性行為將影響NE對消退的調(diào)節(jié)效應(yīng)。目前, 臨床仍在評估去甲腎上腺素能激動劑輔助暴露療法對PTSD的治療效果。

內(nèi)側(cè)前額葉皮層(mPFC)和海馬是調(diào)控恐懼消退的關(guān)鍵腦區(qū)(Orsini, Kim, Knapska, & Maren,2011; Orsini & Maren, 2012)。前額葉邊緣下區(qū)(infralimbic, IL)β去甲腎上腺素能受體的激活所引發(fā)的級聯(lián)反應(yīng)是消退的必需條件(Mueller,Porter, & Quirk, 2008)。NE通過β受體激活由蛋白激酶A (PKA)調(diào)控的分子級聯(lián)反應(yīng)來提高IL神經(jīng)元的興奮性, 從而增強消退記憶。所以, 在恐懼消退前, 向 IL區(qū)注射普萘洛爾可損害消退記憶(Mueller et al., 2008), 而注射β受體的激動劑異丙腎上腺素(isoproterenol)則可以促進消退記憶的鞏固(Do-Monte et al., 2010)。海馬去甲腎上腺素能受體激活也可以促進消退學(xué)習(xí)。消退訓(xùn)練后往背側(cè)海馬注射 NE可增強消退記憶的長時保持, 其機制是NE提高了PKA的磷酸化、反應(yīng)元件結(jié)合蛋白(CREB)和細胞膜谷氨酸Ⅰ型受體(GluR1)的水平(Chai et al., 2014)。

總之, 去甲腎上腺素通過激活前額葉和海馬的去甲腎上腺素能神經(jīng)機制來增強消退記憶, 但其增強消退的效應(yīng)受CS的可預(yù)測性、NE釋放水平、給藥時間和共存的競爭性行為等因素的影響。

4.2 調(diào)控去甲腎上腺素能系統(tǒng)對恐懼記憶再鞏固的影響

重新激活已經(jīng)鞏固的記憶可以使該記憶回到一種不穩(wěn)定的狀態(tài)(Kim et al., 2010), 如果該記憶繼續(xù)保存就必須再次經(jīng)歷突觸可塑性和新蛋白質(zhì)合成的過程, 即再鞏固(Dudai, 2006; Nader, Schafe,& Le Doux, 2000; Reichelt & Lee, 2013; Tronson &Taylor, 2007)。記憶處于再鞏固狀態(tài)時容易被破壞和更改(D?biec & LeDoux, 2004; Nader & Einarsson,2010), 破壞再鞏固相關(guān)的突觸可塑性將損害特定的被重新激活的記憶。去甲腎上腺素能的神經(jīng)信號加強突觸可塑性, 是情緒記憶編碼的必要條件。去甲腎上腺素能系統(tǒng)通過向其受體(α1、α2和β)發(fā)送神經(jīng)信號來調(diào)控恐懼記憶的再鞏固(Otis,Werner, & Mueller, 2015)。提取恐懼記憶會激活杏仁核的去甲腎上腺素能神經(jīng)元, 從而增強恐懼記憶的再鞏固并抵抗消退, 這可能是 PTSD創(chuàng)傷相關(guān)記憶保持和加強的機制(D?biec, Bush, & LeDoux,2011)。抑制NE激發(fā)的CREB磷酸化, 間接地破壞再鞏固階段必需的蛋白合成過程(Thonberg,Fredriksson, Nedergaard, & Cannon, 2002), 可能是去甲腎上腺素能系統(tǒng)阻斷劑破壞再鞏固的機制。

嚙齒類動物的條件性恐懼研究表明在提取記憶前或后, 向腹腔注射 α2受體激動劑可樂定(clonidine, 降低去甲腎上腺素能神經(jīng)總信號)(Gamache, Pitman, & Nader, 2012)、α1受體拮抗劑哌唑嗪(prazosin) (Do Monte, Souza, Wong, &Carobrez Ade, 2013)、β受體拮抗劑(Muravieva &Alberini, 2010; Schneider et al., 2014)或直接向杏仁核(D?biec et al., 2011; D?biec & LeDoux, 2004,2006)注射β受體拮抗劑都可以完全破壞線索誘導(dǎo)的恐懼記憶的再鞏固。在以上實驗中, 如果缺乏記憶提取以重新激活恐懼記憶的過程, 藥物則不影響記憶, 這表明藥物破壞恐懼記憶的再鞏固依賴于記憶的激活。臨床研究表明在提取現(xiàn)實中的創(chuàng)傷記憶后, 服用普萘洛爾可以顯著緩解病人的PTSD癥狀(Brunet et al., 2008, 2011; Menzies,2012), 并降低 PTSD病人的抑郁癥狀(Poundja,Sanche, Tremblay, & Brunet, 2012)。普萘洛爾通過破壞恐懼記憶的再鞏固, 能持久地?fù)p害條件性恐懼的表達(Kindt, Soeter, & Vervliet, 2009), 并能阻止恐懼反應(yīng)的復(fù)發(fā)(Abrari, Rashidy-Pour, Semnanian,& Fathollahi, 2008; D?biec & LeDoux, 2004)。元分析研究也證實再鞏固期間的普萘洛爾可降低線索誘導(dǎo)的恐懼(Lonergan et al., 2013), 并且只破壞特定的被重新激活的記憶, 而不破壞沒有被重新激活的相似的恐懼記憶, 表明普萘洛爾破壞記憶再鞏固的效應(yīng)是記憶特異性的, 并不會泛化到其它記憶(Soeter & Kindt, 2011a)。

然而, 普萘洛爾對記憶再鞏固的破壞作用具有個體差異性和記憶差異性。例如, 普萘洛爾不能破壞高特質(zhì)焦慮個體的恐懼記憶的再鞏固, 即個體的特質(zhì)焦慮水平越高, 普萘洛爾降低恐懼的程度越弱(Soeter & Kindt, 2013)。其原因可能是劑量不足, 高特質(zhì)焦慮的個體需要更高劑量的藥物,抑或是高特質(zhì)焦慮的個體需要不同的提取方式才能誘導(dǎo)出恐懼記憶的去穩(wěn)定化。普萘洛爾也不能阻斷恐懼記憶的所有方面, 因為 β受體激活只特異性地調(diào)控恐懼記憶中情緒成分而不能調(diào)控陳述成分。例如, 人在用條件刺激提取恐懼記憶前, 口服普萘洛爾可持久損害條件性恐懼的表達, 卻沒有破壞條件刺激與非條件刺激匹配聯(lián)結(jié)的陳述性記憶, 表現(xiàn)為當(dāng)條件刺激出現(xiàn)時, 對厭惡性非條件刺激出現(xiàn)的預(yù)期值沒有降低, 但條件刺激不再引起恐懼反應(yīng)(Kindt et al., 2009); 動物在提取恐懼記憶后, 腹腔被注射普萘洛爾雖可以降低線索誘導(dǎo)的僵直行為(freezing)但不影響回避行為(Muravieva& Alberini, 2010), 原因是嚙齒類動物的回避行為與僵直行為不同, 被認(rèn)為是陳述性記憶(Cammarota,Bevilaqua, Medina, & Izquierdo, 2007)。這些都表明提取中或提取后的普萘洛爾破壞的是恐懼記憶的病理情緒性成分而不是陳述性成分。后續(xù)的研究進一步證實了這個結(jié)論(Kindt, Soeter, & Sevenster,2014; Schwabe, Nader, Wolf, Beaudry, & Pruessner,2012; Sevenster, Beckers, & Kindt, 2012; Soeter &Kindt, 2010, 2011a, 2012a, 2012b)。

總之, 普萘洛爾能長時程地破壞恐懼記憶的再鞏固, 但對記憶再鞏固的破壞作用具有個體差異性和記憶特異性, 并且有前提條件：記憶提取程序必須能使記憶去穩(wěn)定化。有研究報道分兩個階段可以較好地破壞創(chuàng)傷記憶的再鞏固：首先用N-甲基-D-天冬氨酸(NMDA)受體的局部激動劑環(huán)絲氨酸(D-cycloserine)使記憶容易被重新激活處于不穩(wěn)定狀態(tài), 然后再用 α2受體激動劑可樂定阻斷再鞏固(Gazarini, Stern, Piornedo, Takahashi, &Bertoglio, 2014)。

4.3 調(diào)控去甲腎上腺素能系統(tǒng)對治療PTSD相關(guān)夢魘的影響

創(chuàng)傷相關(guān)夢魘是 PTSD最常見又痛苦難治的癥狀之一, 創(chuàng)傷后急性發(fā)生率高達 90%(Levin &Nielsen, 2007), PTSD老兵中也有50～70%發(fā)生率(Lamarche & De Koninck, 2007), 能對抗常規(guī)藥物如選擇性血清素重攝取抑制劑(SSRIs)的治療(Nappi, Drummond, & Hall, 2012)。哌唑嗪是一種親脂性的 α1腎上腺素能拮抗劑, 能進入中樞神經(jīng)系統(tǒng)內(nèi)活動(Taylor et al., 2008), 是被美國食品藥品監(jiān)督局批準(zhǔn)的降壓藥。目前有很多研究表明哌唑嗪能有效治療創(chuàng)傷相關(guān)的急慢性 PTSD夢魘(Cain, Maynard, & Kehne, 2012; Germain et al.,2012; Kung, Espinel, & Lapid, 2012; Writer, Meyer,& Schillerstrom, 2014)。哌唑嗪可能通過降低腎上腺素與 α1腎上腺素受體結(jié)合的效率, 阻斷突觸后α1腎上腺素能受體對 NE過度的反應(yīng)性, 從而減弱中樞去甲腎上腺素能的過度激活, 使 PTSD患者的快速眼動(REM)睡眠正?；?Lamarche & De Koninck, 2007; Levin & Nielsen, 2007)。由于哌唑嗪的降血壓作用, 臨床上常使用較低劑量(最高每天16 mg), 但低劑量的哌唑嗪通常不能完全解決PTSD相關(guān)夢魘。最近有研究報道了兩例用高劑量(30和45 mg)哌唑嗪治療PTSD共病心境障礙患者,發(fā)現(xiàn)高劑量的哌唑嗪治療成年P(guān)TSD 患者是安全有效的(Koola, Varghese, & Fawcett, 2014)。另外,在使用哌唑嗪效果不佳后采用另一種選擇性α1腎上腺素能拮抗劑特拉唑嗪(terazosin)也能有效治療PTSD夢魘癥狀(Nirmalani-Gandhy, Sanchez, &Catalano, 2015; Salviati et al., 2013), 故可以作為治療夢魘的二線藥物。

5 總結(jié)與展望

應(yīng)激后去甲腎上腺素能系統(tǒng)的高活動促使創(chuàng)傷記憶過度鞏固, 這為 PTSD的形成和維持提供了重要基礎(chǔ)。在應(yīng)激事件出現(xiàn)前用藥物如普萘洛爾抑制去甲腎上腺素能系統(tǒng)的活動, 可破壞創(chuàng)傷記憶的習(xí)得和保持, 從而預(yù)防 PTSD的形成。不過由于創(chuàng)傷事件的不可預(yù)測性和不可控制性, 很難在早期對創(chuàng)傷記憶進行及時干預(yù)。一旦創(chuàng)傷記憶得到鞏固導(dǎo)致 PTSD的形成, 那么在消退過程中通過增強去甲腎上腺素能系統(tǒng)的活動來促進消退記憶的鞏固, 可以更好地抑制創(chuàng)傷記憶; 或者重新激活創(chuàng)傷記憶, 使之進入不穩(wěn)定的再鞏固階段, 通過抑制去甲腎上腺素能系統(tǒng)的活動來阻斷再鞏固, 也可以破壞創(chuàng)傷記憶。因此, 在創(chuàng)傷記憶的不同階段都可以通過調(diào)控去甲腎上腺素能系統(tǒng)的活動來影響創(chuàng)傷記憶, 達到預(yù)防和治療 PTSD的目的。

β受體阻斷劑對創(chuàng)傷記憶鞏固的破壞作用可能受藥物處理的時間點、藥物的劑量、創(chuàng)傷事件的性質(zhì)和創(chuàng)傷記憶強度等因素的影響, 這需要進一步的實驗驗證。與其它藥物聯(lián)合使用能否更好地破壞創(chuàng)傷記憶的鞏固, 也有待實驗研究。另外,α和 β受體都參與情緒記憶的鞏固, 盡管甚少有研究發(fā)現(xiàn)α1受體阻斷劑對恐懼記憶鞏固的破壞作用, 但最近的動物研究發(fā)現(xiàn) α2受體激動劑可樂定也能減弱情境恐懼記憶的鞏固(Gazarini et al.,2013)。未來臨床研究可以考察α2受體在預(yù)防和治療 PTSD中的作用。由于去甲腎上腺素藥物增強消退后仍不能阻止續(xù)新效應(yīng)(Lissek, Glaubitz,Günturkün, & Tegenthoff, 2015), 表明消退記憶的環(huán)境依賴性獨立于去甲腎上腺素能神經(jīng)機制, 所以在消退過程中聯(lián)合其它藥物或行為方法共同來促進消退, 可能會阻止恐懼反應(yīng)的續(xù)新。目前對普萘洛爾破壞再鞏固的研究采用的是總?cè)后w樣本(不管是嚙齒類動物還是人類)。由于個體差異在PTSD形成中起著重要作用, 也是影響藥物作用的重要因素, 因此, 不能簡單地將對動物和人的平均群體的研究推演到臨床實踐, 以后的研究需要考慮到個體的差異性, 尤其是高特質(zhì)焦慮的個體, 需要探索個體差異的神經(jīng)生物基礎(chǔ)是如何影響藥物對記憶再鞏固的作用, 以解決藥物治療中的個體差異性。

另外, 目前的研究已證實 PTSD患者藍斑的NET利用率顯著低于健康被試(Pietrzak et al.,2013), 但尚不清楚PTSD患者藍斑的NET利用率在創(chuàng)傷前的水平以及創(chuàng)傷后的變化, 它是否可以成為 PTSD的預(yù)測因子, 是否影響后續(xù)的藥物和認(rèn)知行為治療的效果?？謶只蚪箲]神經(jīng)環(huán)路中的其它腦區(qū)如前額葉、海馬和杏仁核中的NET利用率是否與焦慮或恐懼有關(guān), 這些有待進一步的研究。以及ADRA2B基因缺失變異型的攜帶者在編碼負(fù)性情緒刺激時, 杏仁核被激活的程度較非攜帶者更高(Cousijn et al., 2010; Rasch et al., 2009),那么缺失變異型攜帶者在編碼負(fù)性情緒刺激時服用抑制去甲腎上腺素能系統(tǒng)的藥物如普萘洛爾是否可以降低其杏仁核對刺激的反應(yīng), 從而降低創(chuàng)傷再體驗, 避免形成PTSD, 也有待研究。

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