调控去甲肾上腺素能系统对防治创伤后应激障碍的影响*

王红波 朱湘茹

(河南大学认知与行为研究所, 开封 475001)

1 概述

80%的人一生中至少会遭遇一次创伤事件(de Vries & Olff, 2009), 而约7%的个体在经历创伤后会罹患创伤后应激障碍(posttraumatic stress disorder,PTSD) (de Vries & Olff, 2009; Kessler et al., 2005)。PTSD严重损害患者的社会交往、工作和生活质量,并与抑郁和物质滥用高共病。根据《精神障碍诊断与统计手册》(DSM-Ⅴ) (APA, 2013), PTSD主要临床表现为四大症状簇：创伤再体验、回避创伤相关刺激、情感麻木和高唤醒。当前, 研究者主要依据生物−心理−社会多维度模型研究 PTSD的发病机理和治疗方法, 其中药物治疗是重点。基础和临床研究表明药物治疗 PTSD主要有两种趋向：一种是在创伤经历后即刻施行, 旨在改变创伤记忆的编码、巩固和重整, 以降低患 PTSD的风险; 一种是对已经形成的 PTSD尽力治疗其具体症状(Kapfhammer, 2014)。研究证据表明情绪记忆在 PTSD的病理生理中起着重要作用, 而去甲肾上腺素能系统(noradrenergic system)在情绪记忆的调控中起关键作用(Lonergan, Olivera-Figueroa, Pitman, & Brunet, 2013)。本文将首先阐述去甲肾上腺素能系统与 PTSD形成和维持的关系, 然后再讨论调控去甲肾上腺素能系统对预防和治疗PTSD的影响。

2 去甲肾上腺素能系统与 PTSD形成的关系

应激性经历激活体内的应激系统(自主神经系统和下丘脑−垂体−肾上腺轴), 引起肾上腺释放应激激素包括肾上腺素和糖皮质激素(Joëls & Baram,2009)。早期PTSD的神经生物学研究发现PTSD住院患者 24小时尿液中儿茶酚胺分泌物(如去甲肾上腺素/肾上腺素)含量显著高于 PTSD 门诊患者和正常人(Yehuda, Southwick, Giller, Ma, & Mason, 1992),表明PTSD住院患者自主神经系统的激素持久的处于高水平状态。之后的研究直接考察创伤后早期自主神经系统活动的变化与 PTSD形成的关系, 发现急诊部的病人在住院期间心率越高就越可能患PTSD或表现出PTSD症状, 这表明创伤早期自主神经系统的高活动可能是随后表现出创伤后应激症状的危险因素(Zatzick et al., 2005)。

大量证据表明中枢去甲肾上腺素能系统参与恐惧或焦虑。PTSD患者脑脊液中的去甲肾上腺素(norepinephrine, NE)水平显著高于正常人, 且与PTSD症状的严重性正相关(Geracioti et al., 2001)。蓝斑(locus coeruleus)是中枢 NE的主要来源。有动物研究发现选择性地去除(ablate)蓝斑去甲肾上腺素能神经元, 可增加小鼠在高架十字迷宫开放臂的跑动距离和停留时间, 以及在旷场测试中增加小鼠在中央区的跑动距离和停留时间, 表现出抗焦虑效应。这证明蓝斑是焦虑神经环路的一部分, 去甲肾上腺素能神经元参与焦虑行为(Itoi,2008)。最近, 一个由再体验(reexperiencing, 即闯入性记忆和梦魇)、回避(avoidance, 即回避创伤相关的线索)、麻木(numbing, 即与他人脱离或疏远和兴趣丧失)、不悦性唤起(dysphoric arousal, 即睡眠困难、易激惹或愤怒和注意力问题)及焦虑性唤起(anxious arousal, 即高警觉和过度惊吓)症状组成的5-因素模型为PTSD症状结构提供了精确的表型表征(phenotypic representation) (Armour et al.,2012; Elhai et al., 2011; Pietrzak, Tsai, Harpaz- Rotem,Whealin, & Southwick, 2012)。依据该模型, 以去甲肾上腺素转运体(norepinephrine transporter, NET)为靶点, NET可以促使突触间隙的NE被快速清除从而减弱神经信号, 研究者发现 PTSD患者蓝斑的 NET利用率(availability)显著低于健康被试,而那些经历过创伤但未罹患PTSD的个体其NET的利用率介于 PTSD患者和健康被试的中间, 与两者均无显著差异。在PTSD患者中, 蓝斑的NET利用率越高的个体, 其焦虑性唤醒症状越严重,并且NET利用率只与焦虑性唤醒症状的严重程度正相关, 与 PTSD其它症状簇无关(Pietrzak et al.,2013)。此外, 遗传学研究发现编码去甲肾上腺素能α受体2B亚型(ADRA2B)的基因调节情绪记忆的负性偏向性(Gibbs, Bautista, Mowlem, Naudts,& Duka, 2013)。该基因在编码ADRA2B时, 有时会导致受体上 3个谷氨酸残基的缺失, 这是一种功能性缺失多态性(functional deletion polymorphism),与人的创伤记忆的再体验增加有关。缺失变异型(deletion variant)的携带者会更强烈地受应激性事件的影响。在 PTSD患者中, 缺失变异型的携带者会比非携带者表现出更严重的创伤再体验症状(de Quervain et al., 2007)。这是因为缺失变异型的携带者在编码负性情绪刺激时, 杏仁核被激活的程度较非携带者更高(Cousijn et al., 2010; Rasch et al.,2009)。功能性核磁共振成像(fMRI)研究显示焦虑障碍患者的杏仁核被应激性刺激过度激活(Etkin &Wager, 2007), 而这种激活依赖去甲肾上腺素能神经系统(van Stegeren, 2008)。另外, 杏仁核对刺激的情绪反应受前额叶调控(Maren, 2011), 而PTSD病人的前额叶功能受到损坏(Jovanovic et al., 2013;Tian et al., 2014)。这是因为应激状态下NE水平升高, 通过占用低亲和力的α1和β1肾上腺素受体,快速降低前额叶神经元的放电并加强杏仁核的功能(Arnsten, Raskind, Taylor, & Connor, 2015), 导致前额叶系统对认知和情绪兴奋性的有效调控受到损害(Kapfhammer, 2014)。

综上, 基础和临床研究都表明去甲肾上腺素能系统参与 PTSD症状的形成和维持, 且外周和中枢的 NE水平能预测PTSD的症状严重性。应激后中枢 NE水平升高会通过降低前额叶的神经放电进而损坏前额叶对杏仁核的抑制功能。分布有大量去甲肾上腺素能神经元的蓝斑是焦虑神经环路的一部分, PTSD患者蓝斑的 NET利用率只与焦虑性唤醒症状正相关, 与其它症状无关, 而ADRA2B基因缺失变异型与PTSD患者的创伤再体验症状加重有关。这些将有助于我们理解PTSD的表型异质性(phenotypic heterogeneity)。

3 调控去甲肾上腺素能系统对预防PTSD的影响

创伤经历后形成的条件性恐惧记忆是后来发展为PTSD的重要病理机制(Mineka & Oehlberg,2008)。应激中释放的应激激素相互作用参与情绪记忆的编码, 并且这些激素水平的改变与记忆的异常巩固和随后形成的 PTSD症状有关(Bryant,McGrath, & Felmingham, 2013; Kukolja, Klingmuller,Maier, Fink, & Hurlemann, 2011; Nicholson, Bryant,& Felmingham, 2014; Ostrowski & Delahanty, 2014;Soeter & Kindt, 2011b)。记忆在初始获得后不稳定,需要经历突触可塑性及合成新的蛋白质才变得稳定, 这一过程称为巩固(McGaugh, 2000)。情绪性经历诱发的去甲肾上腺素能系统的高活动会增强对刺激的反应和记忆的巩固(Barsegyan, McGaugh,& Roozendaal, 2014; McGaugh, 2013; O'Donnell,Hegadoren, & Coupland, 2004; Soeter & Kindt,2011b; van Stegeren, 2008)。因此, 抑制创伤经历诱发的去甲肾上腺素能系统的高活动, 可能会减弱对刺激的反应及创伤记忆的过度巩固, 从而阻止PTSD的形成。

有研究发现健康人群在应激性刺激出现前服用β-肾上腺素能受体阻断剂普萘洛尔(propranolol)可降低杏仁核对刺激的反应性(Hurlemann et al.,2010)。PTSD的条件性恐惧动物模型研究也显示,条件性恐惧训练前腹腔注射或往杏仁核外侧核团注射普萘洛尔可损害线索恐惧记忆的获得和保持(Bush, Caparosa, Gekker, & Ledoux, 2010; Kroon& Carobrez, 2009)。然而, 应激后给β-肾上腺素能阻断剂能否降低PTSD的发生率或减轻PTSD症状, 各研究的结果并不一致。早期的临床初步研究发现创伤后立即服用普萘洛尔可以减轻 PTSD症状甚至可能阻止 PTSD的形成(Pitman et al.,2002; Vaiva et al., 2003)。最近的研究报道在植入式心脏除颤器(ICD)放电时服用亲脂性的β受体阻断剂可以显著减轻由ICD不可预测不可控制的放电诱发的PTSD症状(Bhuvaneswar, Ruskin, Katzman,Wood, & Pitman, 2014)。但也有研究报道急性身体损伤如烧伤、手术创伤后的短时间内服用普萘洛尔并没有降低PTSD的发生率或减少其症状(Hoge et al., 2012; McGhee et al., 2009; Stein, Kerridge,Dimsdale, & Hoyt, 2007)。动物研究也发现大鼠在经历天敌气味应激后, 立即被腹腔注射普萘洛尔,不能破坏情境恐惧记忆的巩固(Cohen et al., 2011)。以及在线索条件性恐惧训练后, 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;Dębiec & Ledoux, 2004)注射普萘洛尔, 也不能破坏恐惧记忆的巩固。应激后的β受体阻断剂不能破坏创伤记忆的巩固, 原因有以下几种可能：1、创伤事件发生时间和药物处理时间的间隔所致,上述一些实验的间隔为 1天或更长, 并且服用普萘洛尔需要一段时间才能达到合适的血药浓度,而普萘洛尔对去甲肾上腺素能的阻断作用被限制在一个可能只有几小时的记忆巩固时间窗里(Gazarini,Stern, Carobrez, & Bertoglio, 2013)。2、去甲肾上腺素能系统只参与记忆巩固的后期过程(Sara,Roullet, & Przybyslawski, 1999), 所以应激后立即给药会导致巩固后期的血药浓度较低。3、某些应激太强会诱发出更强的去甲肾上腺素能神经传导,所以可能需要更高剂量的拮抗剂才能破坏巩固(Dębiec & LeDoux, 2004)。4、不同性质(如可控性,可预测性和厌恶性)的创伤事件可能会激活不同的脑区(Wood et al., 2015; Yang & Liang, 2014)和受体(Genro, de Oliveira Alvares, & Quillfeldt, 2012),从而需要不同的药物做干预(Davis, Walker, Miles,& Grillon, 2010; Genro et al., 2012; Santos, Gárgaro,Oliveira, Masson, & Brandão, 2005)。例如, 在抑制性回避任务训练后, 往伏隔核注射利多卡因(lidocaine, 酰胺类局部麻醉药)可以减弱背侧海马或内侧前额叶的 NE对记忆的增强效应; 而在情境条件性恐惧训练后, 伏隔核的利多卡因并不影响背侧海马或内侧前额叶的 NE对记忆的增强效应(Yang & Liang, 2014)。另外, 在强电击训练后向海马注射辣椒素受体(transient receptor potential vanilloid type 1, TRPV1, 在疼痛的传导和调节中发挥重要作用, 其离子通道的功能可作为疼痛感受器)的拮抗剂辣椒平(Capsazepine, 阻断TRPV1通道的激活)能破坏情境条件性恐惧记忆的巩固, 而弱电击训练后的辣椒平则不影响记忆的巩固。当采用抑制性回避模型时, 不管是在强电击还是弱电击的训练条件下, 辣椒平都不影响记忆的巩固(Genro et al., 2012)。5、创伤早期的β受体阻断剂对创伤记忆和 PTSD症状的影响还有性别差异, β受体阻断剂主要影响女性的创伤记忆和 PTSD症状(Krauseneck et al., 2010; Nugent et al., 2010)。尽管应激后立即给予普萘洛尔不总能破坏恐惧记忆的巩固, 但能稳定应激状态下前额叶的神经活动, 减轻应激引起的前额叶损伤(Fitzgerald et al., 2015), 并且能降低恐惧线索进一步的二级条件化(secondorder conditioning, 即原有条件性刺激(S1)获得非条件性刺激的特性后使个体对与 S1相关联的新的中性刺激(S2)也产生条件反应, 是PTSD患者条件性恐惧难以消退的可能原因之一) (Kroon & Carobrez,2009), 这为以后治疗PTSD创造了有利条件。

综上, 应激前的 β受体阻断剂通过破坏条件化学习, 降低条件性恐惧记忆的获得, 从而减弱条件性恐惧记忆, 阻止PTSD的形成。应激后的β受体阻断剂有保护前额叶功能和阻止恐惧线索二级条件化的作用, 对记忆巩固的破坏作用可能受药物处理的时间点、药物剂量、应激强度、创伤事件的性质等因素的影响。

4 调控去甲肾上腺素能系统对治疗PTSD的影响

一旦恐惧记忆巩固导致 PTSD形成, 那么对PTSD的治疗工作主要集中在促进恐惧记忆的消退或破坏恐惧记忆的再巩固以及减轻某些具体症状等方面。

4.1 调控去甲肾上腺素能系统对恐惧记忆消退的影响

治疗焦虑障碍如 PTSD、恐怖症最有效的心理疗法是依靠对恐惧记忆的渐进性消退(Bentz,Michael, de Quervain, & Wilhelm, 2010)。消退是临床暴露疗法的核心原理, 是指在一个安全可控的环境下重复且系统地单独呈现预示恐惧事件的线索刺激而不出现厌恶性后果。经过消退学习后,个体习得曾经的恐惧性线索不再预示着厌恶性后果, 从而降低恐惧反应。由于消退降低恐惧反应只是因为形成了一种新的抑制性记忆而不是破坏原始的创伤记忆(Milad & Quirk, 2012), 且消退记忆相对原始的创伤记忆而言脆弱又依赖环境, 故在多种条件下如重新暴露在非条件刺激(重建)或改变环境(续新)或经过一段时间(自发恢复), 对线索刺激的恐惧反应都可能恢复(Myers & Davis,2007)。消退后的恐惧复发仍是当前临床实践的一个主要难题。因此, 增强消退记忆能更好地抑制恐惧反应以减少症状复发。

消退记忆也是一种情绪记忆, 消退时去甲肾上腺素能系统的高活动将有助于增强消退记忆。动物研究发现, 在消退时刺激迷走神经来激活去甲肾上腺素能通路, 可以加速消退记忆的巩固,从而快速降低恐惧反应(Peña, Engineer, & McIntyre,2013)。对人和动物的研究显示育亨宾(yohimbin,一种α2受体拮抗剂, 促使NE释放)能促进恐惧消退(Cain, Blouin, & Barad, 2004; Holmes & Quirk,2010; Morris & Bouton, 2007; Powers, Smits, Otto,Sanders, & Emmelkamp, 2009)。不过育亨宾促进消退的效应依赖环境, 当消退环境与条件性恐惧习得环境相同时, 育亨宾不能促进消退(Mueller,Olivera-Figueroa, Pine, & Quirk, 2009), 只有当消退环境不同于条件性恐惧习得环境时, 育亨宾才促进消退(Cain et al., 2004; Morris & Bouton, 2007)。环境有助于增加条件刺激(conditioned stimulus, CS)的预测性, 当 CS可预测时, NE对消退的调节效应最大(Mueller & Cahill, 2010)。并且育亨宾增强消退效应是剂量依赖的, 育亨宾只有在最佳浓度下才促进消退(Morris & Bouton, 2007)。此外, 在消退训练前给育亨宾会促进消退, 消退训练后给药则无效。即使是去甲肾上腺素也需要在消退训练后的短时间内(即消退记忆巩固时间窗内)及时注射才能促进消退(Berlau & McGaugh, 2006)。值得注意的是, CS的出现将引发两个相反的过程：消退和再巩固(Lee, Milton, & Everitt, 2006), 而去甲肾上腺素药物既能促进消退记忆的巩固, 也能促进恐惧记忆的再巩固, 所以这两个共存的竞争性行为将影响NE对消退的调节效应。目前, 临床仍在评估去甲肾上腺素能激动剂辅助暴露疗法对PTSD的治疗效果。

内侧前额叶皮层(mPFC)和海马是调控恐惧消退的关键脑区(Orsini, Kim, Knapska, & Maren,2011; Orsini & Maren, 2012)。前额叶边缘下区(infralimbic, IL)β去甲肾上腺素能受体的激活所引发的级联反应是消退的必需条件(Mueller,Porter, & Quirk, 2008)。NE通过β受体激活由蛋白激酶A (PKA)调控的分子级联反应来提高IL神经元的兴奋性, 从而增强消退记忆。所以, 在恐惧消退前, 向 IL区注射普萘洛尔可损害消退记忆(Mueller et al., 2008), 而注射β受体的激动剂异丙肾上腺素(isoproterenol)则可以促进消退记忆的巩固(Do-Monte et al., 2010)。海马去甲肾上腺素能受体激活也可以促进消退学习。消退训练后往背侧海马注射 NE可增强消退记忆的长时保持, 其机制是NE提高了PKA的磷酸化、反应元件结合蛋白(CREB)和细胞膜谷氨酸Ⅰ型受体(GluR1)的水平(Chai et al., 2014)。

总之, 去甲肾上腺素通过激活前额叶和海马的去甲肾上腺素能神经机制来增强消退记忆, 但其增强消退的效应受CS的可预测性、NE释放水平、给药时间和共存的竞争性行为等因素的影响。

4.2 调控去甲肾上腺素能系统对恐惧记忆再巩固的影响

重新激活已经巩固的记忆可以使该记忆回到一种不稳定的状态(Kim et al., 2010), 如果该记忆继续保存就必须再次经历突触可塑性和新蛋白质合成的过程, 即再巩固(Dudai, 2006; Nader, Schafe,& Le Doux, 2000; Reichelt & Lee, 2013; Tronson &Taylor, 2007)。记忆处于再巩固状态时容易被破坏和更改(Dębiec & LeDoux, 2004; Nader & Einarsson,2010), 破坏再巩固相关的突触可塑性将损害特定的被重新激活的记忆。去甲肾上腺素能的神经信号加强突触可塑性, 是情绪记忆编码的必要条件。去甲肾上腺素能系统通过向其受体(α1、α2和β)发送神经信号来调控恐惧记忆的再巩固(Otis,Werner, & Mueller, 2015)。提取恐惧记忆会激活杏仁核的去甲肾上腺素能神经元, 从而增强恐惧记忆的再巩固并抵抗消退, 这可能是 PTSD创伤相关记忆保持和加强的机制(Dębiec, Bush, & LeDoux,2011)。抑制NE激发的CREB磷酸化, 间接地破坏再巩固阶段必需的蛋白合成过程(Thonberg,Fredriksson, Nedergaard, & Cannon, 2002), 可能是去甲肾上腺素能系统阻断剂破坏再巩固的机制。

啮齿类动物的条件性恐惧研究表明在提取记忆前或后, 向腹腔注射 α2受体激动剂可乐定(clonidine, 降低去甲肾上腺素能神经总信号)(Gamache, Pitman, & Nader, 2012)、α1受体拮抗剂哌唑嗪(prazosin) (Do Monte, Souza, Wong, &Carobrez Ade, 2013)、β受体拮抗剂(Muravieva &Alberini, 2010; Schneider et al., 2014)或直接向杏仁核(Dębiec et al., 2011; Dębiec & LeDoux, 2004,2006)注射β受体拮抗剂都可以完全破坏线索诱导的恐惧记忆的再巩固。在以上实验中, 如果缺乏记忆提取以重新激活恐惧记忆的过程, 药物则不影响记忆, 这表明药物破坏恐惧记忆的再巩固依赖于记忆的激活。临床研究表明在提取现实中的创伤记忆后, 服用普萘洛尔可以显著缓解病人的PTSD症状(Brunet et al., 2008, 2011; Menzies,2012), 并降低 PTSD病人的抑郁症状(Poundja,Sanche, Tremblay, & Brunet, 2012)。普萘洛尔通过破坏恐惧记忆的再巩固, 能持久地损害条件性恐惧的表达(Kindt, Soeter, & Vervliet, 2009), 并能阻止恐惧反应的复发(Abrari, Rashidy-Pour, Semnanian,& Fathollahi, 2008; Dębiec & LeDoux, 2004)。元分析研究也证实再巩固期间的普萘洛尔可降低线索诱导的恐惧(Lonergan et al., 2013), 并且只破坏特定的被重新激活的记忆, 而不破坏没有被重新激活的相似的恐惧记忆, 表明普萘洛尔破坏记忆再巩固的效应是记忆特异性的, 并不会泛化到其它记忆(Soeter & Kindt, 2011a)。

然而, 普萘洛尔对记忆再巩固的破坏作用具有个体差异性和记忆差异性。例如, 普萘洛尔不能破坏高特质焦虑个体的恐惧记忆的再巩固, 即个体的特质焦虑水平越高, 普萘洛尔降低恐惧的程度越弱(Soeter & Kindt, 2013)。其原因可能是剂量不足, 高特质焦虑的个体需要更高剂量的药物,抑或是高特质焦虑的个体需要不同的提取方式才能诱导出恐惧记忆的去稳定化。普萘洛尔也不能阻断恐惧记忆的所有方面, 因为 β受体激活只特异性地调控恐惧记忆中情绪成分而不能调控陈述成分。例如, 人在用条件刺激提取恐惧记忆前, 口服普萘洛尔可持久损害条件性恐惧的表达, 却没有破坏条件刺激与非条件刺激匹配联结的陈述性记忆, 表现为当条件刺激出现时, 对厌恶性非条件刺激出现的预期值没有降低, 但条件刺激不再引起恐惧反应(Kindt et al., 2009); 动物在提取恐惧记忆后, 腹腔被注射普萘洛尔虽可以降低线索诱导的僵直行为(freezing)但不影响回避行为(Muravieva& Alberini, 2010), 原因是啮齿类动物的回避行为与僵直行为不同, 被认为是陈述性记忆(Cammarota,Bevilaqua, Medina, & Izquierdo, 2007)。这些都表明提取中或提取后的普萘洛尔破坏的是恐惧记忆的病理情绪性成分而不是陈述性成分。后续的研究进一步证实了这个结论(Kindt, Soeter, & Sevenster,2014; Schwabe, Nader, Wolf, Beaudry, & Pruessner,2012; Sevenster, Beckers, & Kindt, 2012; Soeter &Kindt, 2010, 2011a, 2012a, 2012b)。

总之, 普萘洛尔能长时程地破坏恐惧记忆的再巩固, 但对记忆再巩固的破坏作用具有个体差异性和记忆特异性, 并且有前提条件：记忆提取程序必须能使记忆去稳定化。有研究报道分两个阶段可以较好地破坏创伤记忆的再巩固：首先用N-甲基-D-天冬氨酸(NMDA)受体的局部激动剂环丝氨酸(D-cycloserine)使记忆容易被重新激活处于不稳定状态, 然后再用 α2受体激动剂可乐定阻断再巩固(Gazarini, Stern, Piornedo, Takahashi, &Bertoglio, 2014)。

4.3 调控去甲肾上腺素能系统对治疗PTSD相关梦魇的影响

创伤相关梦魇是 PTSD最常见又痛苦难治的症状之一, 创伤后急性发生率高达 90%(Levin &Nielsen, 2007), PTSD老兵中也有50～70%发生率(Lamarche & De Koninck, 2007), 能对抗常规药物如选择性血清素重摄取抑制剂(SSRIs)的治疗(Nappi, Drummond, & Hall, 2012)。哌唑嗪是一种亲脂性的 α1肾上腺素能拮抗剂, 能进入中枢神经系统内活动(Taylor et al., 2008), 是被美国食品药品监督局批准的降压药。目前有很多研究表明哌唑嗪能有效治疗创伤相关的急慢性 PTSD梦魇(Cain, Maynard, & Kehne, 2012; Germain et al.,2012; Kung, Espinel, & Lapid, 2012; Writer, Meyer,& Schillerstrom, 2014)。哌唑嗪可能通过降低肾上腺素与 α1肾上腺素受体结合的效率, 阻断突触后α1肾上腺素能受体对 NE过度的反应性, 从而减弱中枢去甲肾上腺素能的过度激活, 使 PTSD患者的快速眼动(REM)睡眠正常化(Lamarche & De Koninck, 2007; Levin & Nielsen, 2007)。由于哌唑嗪的降血压作用, 临床上常使用较低剂量(最高每天16 mg), 但低剂量的哌唑嗪通常不能完全解决PTSD相关梦魇。最近有研究报道了两例用高剂量(30和45 mg)哌唑嗪治疗PTSD共病心境障碍患者,发现高剂量的哌唑嗪治疗成年PTSD 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种选择性α1肾上腺素能拮抗剂特拉唑嗪(terazosin)也能有效治疗PTSD梦魇症状(Nirmalani-Gandhy, Sanchez, &Catalano, 2015; Salviati et al., 2013), 故可以作为治疗梦魇的二线药物。

5 总结与展望

应激后去甲肾上腺素能系统的高活动促使创伤记忆过度巩固, 这为 PTSD的形成和维持提供了重要基础。在应激事件出现前用药物如普萘洛尔抑制去甲肾上腺素能系统的活动, 可破坏创伤记忆的习得和保持, 从而预防 PTSD的形成。不过由于创伤事件的不可预测性和不可控制性, 很难在早期对创伤记忆进行及时干预。一旦创伤记忆得到巩固导致 PTSD的形成, 那么在消退过程中通过增强去甲肾上腺素能系统的活动来促进消退记忆的巩固, 可以更好地抑制创伤记忆; 或者重新激活创伤记忆, 使之进入不稳定的再巩固阶段, 通过抑制去甲肾上腺素能系统的活动来阻断再巩固, 也可以破坏创伤记忆。因此, 在创伤记忆的不同阶段都可以通过调控去甲肾上腺素能系统的活动来影响创伤记忆, 达到预防和治疗 PTSD的目的。

β受体阻断剂对创伤记忆巩固的破坏作用可能受药物处理的时间点、药物的剂量、创伤事件的性质和创伤记忆强度等因素的影响, 这需要进一步的实验验证。与其它药物联合使用能否更好地破坏创伤记忆的巩固, 也有待实验研究。另外,α和 β受体都参与情绪记忆的巩固, 尽管甚少有研究发现α1受体阻断剂对恐惧记忆巩固的破坏作用, 但最近的动物研究发现 α2受体激动剂可乐定也能减弱情境恐惧记忆的巩固(Gazarini et al.,2013)。未来临床研究可以考察α2受体在预防和治疗 PTSD中的作用。由于去甲肾上腺素药物增强消退后仍不能阻止续新效应(Lissek, Glaubitz,Günturkün, & Tegenthoff, 2015), 表明消退记忆的环境依赖性独立于去甲肾上腺素能神经机制, 所以在消退过程中联合其它药物或行为方法共同来促进消退, 可能会阻止恐惧反应的续新。目前对普萘洛尔破坏再巩固的研究采用的是总群体样本(不管是啮齿类动物还是人类)。由于个体差异在PTSD形成中起着重要作用, 也是影响药物作用的重要因素, 因此, 不能简单地将对动物和人的平均群体的研究推演到临床实践, 以后的研究需要考虑到个体的差异性, 尤其是高特质焦虑的个体, 需要探索个体差异的神经生物基础是如何影响药物对记忆再巩固的作用, 以解决药物治疗中的个体差异性。

另外, 目前的研究已证实 PTSD患者蓝斑的NET利用率显著低于健康被试(Pietrzak et al.,2013), 但尚不清楚PTSD患者蓝斑的NET利用率在创伤前的水平以及创伤后的变化, 它是否可以成为 PTSD的预测因子, 是否影响后续的药物和认知行为治疗的效果。恐惧或焦虑神经环路中的其它脑区如前额叶、海马和杏仁核中的NET利用率是否与焦虑或恐惧有关, 这些有待进一步的研究。以及ADRA2B基因缺失变异型的携带者在编码负性情绪刺激时, 杏仁核被激活的程度较非携带者更高(Cousijn et al., 2010; Rasch et al., 2009),那么缺失变异型携带者在编码负性情绪刺激时服用抑制去甲肾上腺素能系统的药物如普萘洛尔是否可以降低其杏仁核对刺激的反应, 从而降低创伤再体验, 避免形成PTSD, 也有待研究。

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