药物成瘾记忆的神经生物机制及临床干预方法

药物成瘾者戒断后的持久复吸是治疗药物成瘾的难点. 成瘾者出现持续复吸的重要原因是由于成瘾记忆的长期存在. 成瘾物质的长期反复使用导致前额叶-边缘多巴胺系统结构和功能的适应性改变，这种改变是成瘾记忆形成的神经基础. 本文从学习记忆的角度来理解成瘾形成，介绍了成瘾记忆的初始形成阶段、习惯化阶段和成瘾行为维持阶段及其相应的神经基础. 回顾了近年来成瘾记忆的临床干预方法，包括消退干预方法、增强消退干预的多情境干预方法，以及直接干预消除成瘾记忆的记忆再巩固干预方法，并总结了虚拟现实、神经调控技术在成瘾记忆干预中的应用. 对记忆再巩固干预方法与虚拟现实、神经调控技术相结合干预成瘾记忆进行展望，为药物成瘾的临床干预和治疗提供了新方法、新思路.

Relapse behavior after long-term abstinence is the key problem of addiction treatment. A major factor to induce relapse is the persistence of maladaptive drug-associated memories. Persistent changes in structure and function of prefrontal cortex-mesolimbic dopamine system caused by chronic drug abusing, lead to the formation of pathological drug-associated memories. This article reviews addiction with a focus on how it can be conceptualised as a disorder of maladaptive memory, considering the neural basis of drug-associated memories during the initial phase, the habituation phase and the maintenance phase of addictive behavior. The present review summarizes the clinical intervention methods of drug-associated memories in recent years including extinction training, extinction in multiple contexts to facilitate extinction and reconsolidation intervention to disrupt drug-associated memories directly, and the application of virtual reality technology and neuromodulation methods in addiction intervention. The intervention methods combined memory reconsolidation with virtual reality technology or neuromodulation methods are prospected to target drug-associated memories, providing new methods and new ideas to treat addiction in future clinical researches.

成瘾记忆；神经生物机制；消退干预；记忆再巩固干预；虚拟现实；神经调控

drug-associated memories; neurobiological mechanism; extinction training; memory reconsolidation; virtual reality; neuromodulation

药物成瘾是一种长期持久的复发性脑疾病[1,2]，成瘾者表现出不顾及负性后果的反复强迫性药物使用行为[3,4]. 复吸一直是成瘾治疗中的关键难题. 成瘾者在长时间戒断后，尽管急性戒断症状已得到明显缓解，仍旧会保持复吸行为[4]. 持续使用药物可能不仅是因为严重的药物戒断反应[5]，以心理渴求为核心的精神依赖也是导致毒品滥用，成瘾者持续用药和复吸的重要原因.

成瘾记忆的持久存在是成瘾者产生渴求、维持精神依赖及持续复吸行为的关键[6]. 成瘾记忆形成后，即使经过长期戒断，一旦成瘾者暴露于药物相关线索中，其成瘾记忆即被唤醒，促使成瘾者产生一系列生理心理的渴求反应，导致自动化的药物寻求及使用行为，引发复吸[6]. 成瘾者脑功能持久的神经适应性改变是成瘾记忆长期存在的神经基础[7]. 阐明成瘾记忆形成的机制，有利于理解成瘾复吸行为，为成瘾治疗及干预指出潜在方向. 因此，本文从适应不良的学习记忆角度理解成瘾形成过程，分别从奖赏学习阶段、习惯化形成阶段和成瘾复吸行为的维持阶段介绍病理性成瘾记忆的形成与巩固，及其相应的神经基础. 继而，本文总结了近年来针对成瘾记忆的临床干预方法，如消退干预、多情境消退干预以及记忆再巩固干预等方法，并介绍了虚拟现实和神经调控等新技术在成瘾干预中的应用. 进一步展望了虚拟现实、神经调控等技术与成瘾记忆干预方法结合的可能，为成瘾及复吸的临床干预及治疗提供了重要指导意义和有效干预手段.

药物成瘾被认为是一个异常的学习过程，成瘾行为形成的各个阶段和学习记忆有着共享的机制[3,4,5,6]. 学习记忆的关键脑区如海马、杏仁核、前额叶（prefrontal cortex，PFC）等，同属于中脑边缘多巴胺系统，是成瘾行为形成过程中的重要脑区，参与奖赏动机行为的调节. 在成瘾记忆形成过程中，中脑腹侧被盖区（ventral tegmental area，VTA）的多巴胺（dopamine，DA）神经元投射至皮层及皮层下边缘系统，包括PFC、前扣带回（anterior cingutate cortex，ACC）、伏隔核（nucleus accumbens，NAc）、海马、下丘脑和杏仁核[7,8,9,10]，这些结构通过彼此之间的兴奋和抑制投射形成功能网络来调控药物寻求及复吸行为[11,12].

在药物成瘾发展的初始阶段，奖赏学习扮演着关键性角色. 使用成瘾药物为个体带来正性奖赏体验. 个体使用成瘾药物致使中脑边缘多巴胺系统的兴奋性递质增加，DA释放增多[13]. VTA投射到NAc的DA浓度增加[14]，个体产生主观欣快感[15]. 这种欣快感，强化了药物使用行为，将药物使用与正性奖赏形成连接. 为追寻正性奖赏（欣快感）[16]体验，个体产生药物寻求及使用的冲动，成瘾记忆初始形成. 成瘾初期，急性戒断后出现的负性状态，如易激惹、痛苦情感、焦虑、烦躁、压力等情形，也是成瘾过程中促使成瘾记忆形成的重要因素. 动物研究发现，急性戒断后，中脑边缘多巴胺系统的激活降低，其杏仁核和NAc中的其他兴奋性递质也降低[17]. 人类影像学研究同样发现戒断期间多巴胺D2受体减少（反映多巴胺能功能下调）和眶额叶-边缘下区皮层系统的激活减退[18]. 这使个体产生了负性状态，负强化了个体的药物寻求及使用行为. 为避免负性刺激（压力、戒断后的负性情绪）[19,20,21]，个体出现强迫性的药物寻求及使用行为[22]，成瘾记忆的初始形成得到促进.

随着成瘾的发展，药物使用行为增多，药物相关线索（条件性刺激，conditioned stimulus，CS）如药物使用时的环境、工具、动作等与药物奖赏（非条件性刺激，unconditioned stimulus，US）如药物本身、药物使用后的感受、反应等反复匹配，产生自动化连接[23,24]，巩固形成成瘾记忆. 长期药物使用使药物相关线索成为药物使用的预测信号，药物相关线索逐渐取代药物本身，产生奖赏预期，诱发成瘾者的渴求反应，促使成瘾者自动化的药物寻求及使用行为[24]. 这种对药物相关线索的动机敏化现象在尼古丁成瘾者[25,26]、阿片成瘾者[27,28]以及可卡因成瘾者[29]，甚至安非他命成瘾者中[30]都有观察到. 这是由于药物使用促使DA水平升高，同时伴随的主观欣快感会使多巴胺神经元在奖赏预期中激活[31]. 因而即使在个体没有使用药物时，预示奖赏的药物相关线索仍会促使DA释放[31,32]. 药物相关线索与DA释放反复匹配，成瘾者对药物相关线索与药物奖赏之间的连接学习增强，促使成瘾者形成异常的条件化反应[33].

反复的药物使用过程中，中脑边缘多巴胺系统的各个记忆关键脑区对药物相关线索的反应均被敏化，药物相关线索的价值得到重新编码，药物相关线索与药物的连接记忆得到增强. 成瘾药物的使用使NAc中产生过量的多巴胺信号，眶额叶和PFC等其他区域多巴胺的释放增加. PFC中大量的多巴胺信号，使个体产生对药物相关线索的过度学习，从而提高个体对药物相关线索的奖赏价值编码[34,35]. VTA与学习记忆的关键脑区海马相互投射，对药物相关线索的动机和强化信号进行编码[36]. 而基底杏仁核（basolateral nucleus of amygdale，BLA）则对药物相关线索的动机和情绪信号进行编码[33].

成瘾发展产生的神经重塑在各研究中都得以证实，为药物成瘾记忆的形成提供了细胞层面的依据. DA调节皮层及皮层下结构的谷氨酸能和氨基丁酸能突触活动，使杏仁核、NAc以及PFC等区域发生长期的突触改变，出现细胞突触长时程增强（long-term potentiation，LTP）或长时程抑制现象（long-term depression，LTD），这是记忆存储的突触模型. 通过LTP和LTD，药物相关线索-药物之间的连接得以巩固[37,38]. 至此，药物相关线索逐渐取代最初的正性和负性强化刺激，与药物奖赏形成直接连接[7,39,40,41]，习惯化成瘾记忆形成.

成瘾记忆形成后，一旦成瘾者暴露于药物相关线索下，成瘾记忆便会被唤醒，促使成瘾者复吸[1]. 首先，药物相关线索出现时，杏仁核和海马等感知信息输入的脑区会对药物相关线索进行加工. 海马对药物相关线索的环境成分进行感知，与药物相关环境引发的复吸有关[1]. 药物相关线索引发的情绪感受由管理重要情绪性记忆的杏仁核进行处理，杏仁核与情绪诱发的复吸有关[33]. 杏仁核和海马对药物相关线索的信息进行加工后，投射到NAc的壳部和核部. NAc的壳和核均参与环境和线索或压力诱发的复吸[42,43,44,45]. NAc壳和核在调节药物寻求行为中的作用尚存在一定争议. 一般认为，NAc核部接收来自背内侧前额叶（dorsomedial prefrontal cortex，dmPFC）的投射，促进药物寻求，而NAc壳部接收来自腹内侧前额叶（ventromedial prefrontal cortex，vmPFC）的投射，抑制药物寻求[46]. 而最近研究证据提示，vmPFC-NAc通路和dmPFC-NAc通路均会促使复吸行为[47]. 这一不同的结果可能源于各研究中成瘾物质的不同，如激活vmPFC到NAc壳部的谷氨酸能投射会促进海洛因寻求行为[48]，抑制vmPFC则会削弱海洛因寻求[49]，反之，抑制vmPFC会促进可卡因寻求[50].

PFC在成瘾记忆被唤醒后的复吸中发挥着重要作用. 长期药物使用使PFC形成病理性适应，其对于行为自上而下的调节控制功能受到损害[51,52]. 有许多神经影像学研究证明成瘾药物的使用会降低PFC的激活[51,53]. 这使得PFC更少地去抑制药物相关线索引发的自动化行为反应，促进了自动化的药物寻求及使用行为.

综上，PFC、NAc、杏仁核、海马等学习记忆重要脑区在成瘾记忆初始形成的奖赏学习阶段、药物相关线索-药物的习惯化反应阶段以及成瘾行为维持阶段发挥着关键作用. 药物相关线索唤醒成瘾记忆，诱发成瘾者产生渴求反应，促使自动化药物寻求及使用行为，是由于成瘾记忆的持久存在及其带来的神经适应性改变[1]. 因此，从成瘾记忆角度对成瘾者进行临床干预，为成瘾治疗提供了新思路. 本文从行为干预层面总结了现有的成瘾记忆干预方法以及虚拟现实技术、神经调控技术在成瘾干预中的应用.

从临床转化应用的角度考虑，改变甚至消除成瘾记忆，降低成瘾相关线索诱发的反应强度等针对成瘾记忆的有效行为干预方法应该得到推广应用. 现有的成瘾记忆行为干预方法包括：基本的消退干预方法、增强消退记忆的多情境消退干预方法、直接干预成瘾记忆再巩固过程的记忆再巩固干预方法.

消退干预，也即线索暴露治疗（cue exposure therapy，CET），是指让成瘾者长时间暴露于药物相关线索中，而不给予药物奖赏，形成新的“药物相关线索-无药物奖赏”（CS-no US）连接的消退记忆，以抑制原有成瘾记忆的过程[54]. 其原理可视为成瘾记忆形成的反向学习过程，通过反复呈现药物相关线索，而不匹配强化物，消退成瘾者对药物相关线索的条件化渴求反应，最终减少复吸的发生[55]. 消退干预可以反转长期药物使用所带来的中脑边缘系统的可塑性改变. 消退干预过程中涉及到BLA、NAc壳部和vmPFC的激活[56,57]，如NAc壳部的谷氨酸能激活[58,59]和BLA中的谷氨酸能激活均参与成瘾记忆的消退过程[60]. 这些脑区在消退干预过程中的激活，为新的消退记忆形成提供了神经层面的依据.

消退干预被认为能有效抑制成瘾记忆[61]，研究者常通过想象、图片、视频、仿真器具等线索呈现方式对成瘾者实施消退干预，目前在尼古丁[62]、酒精[63]、可卡因[64]等成瘾研究中得到了广泛的应用，并取得一定程度的成功. 但在以下几种情境中，即使经过消退干预，药物相关线索仍会重新引发渴求反应和药物寻求及使用行为，如在消退后个体再次接触或使用药物（重建，reinstatement），个体暴露于不同于消退过程的药物相关环境中（更新，renewal），或者是在消退干预很长一段时间后个体再次面对药物相关线索（自发恢复，spontaneous recovery）[65,66]. 这些现象提示，消退过程中形成的消退记忆可能并没有成功抑制原本的成瘾记忆，成瘾记忆并没有发生改变或消失. 因此，为了更好地降低线索诱发渴求反应，降低复吸风险，可从两方面着手对牢固而持久的成瘾记忆进行干预. a. 加强消退学习以巩固强化消退记忆，使消退记忆更好地抑制原有成瘾记忆[67]；b. 直接干预成瘾记忆，抑制成瘾记忆中药物相关线索-药物奖赏连接的再巩固过程，从而消除成瘾记忆[68].

伴随成瘾记忆形成的药物相关环境线索往往是复杂而非单一的[69]. 消退干预后，新形成的消退记忆通常只在原来的消退环境中才能被提取，从而抑制原有的成瘾记忆；一旦面临不同于消退过程的新环境，消退记忆难以被提取唤醒，而原有的成瘾记忆则会表达[68,70]，出现更新效应，这大部分可归结于消退时环境的单一性[71]. 多情境消退干预是增强消退学习、增加消退效果、应对更新效应的重要方法[72,73]. 多情境消退干预过程中，成瘾者在多个不同药物相关线索情境中持续暴露，形成更强的消退记忆，使消退记忆更有可能在新颖环境中被唤醒，提高了抑制复吸的可能性. 目前，多情境消退大多应用于恐惧记忆的研究中，通过多种图片或者视频进行反复消退，研究结果验证了多情境消退可降低更新效应的出现[74,75].

尽管多情境消退干预增强消退记忆的效果在许多记忆研究中得以检验，但这一现象在一些成瘾研究中并未能得到重复，如在一个酒精成瘾研究中，多情境消退并没有比单一消退更好地降低更新中的渴求反应[76]. 这可能是由于方法学方面的原因，如有限的线索呈现方式，也有可能固有成瘾记忆过于顽固，以至于增强的消退记忆也并不一定能很好地抑制成瘾记忆. 未来研究可以利用其他线索呈现方式结合多情境消退，加强消退记忆.

在消退干预中，利用多情境复合线索消退干预方法可增强消退记忆，但增强的消退记忆仍会与原有成瘾记忆进行拮抗，并不能确定消退后，药物相关线索会唤醒消退记忆还是成瘾记忆. 从直接干预消除成瘾记忆的角度出发，记忆再巩固干预被认为通过抑制原有成瘾记忆的再巩固过程，可以修饰或改变原有成瘾记忆，降低记忆唤醒后的渴求反应，减少用药行为[77]. 记忆再巩固过程是指记忆在经过提取激活后，趋于稳定重新储存原有记忆的过程，这一过程加强了药物相关线索-药物的连接，维持和巩固了原有成瘾记忆[77,78]. 记忆再巩固干预通过对原有成瘾记忆进行提取（对成瘾者进行简短的药物相关线索暴露），使成瘾记忆激活至不稳定可更改的状态，在有效时间窗内（10 min ~ 6 h）对其进行干预，如实施消退干预，以改变或消除原有记忆连接，从而重新巩固形成新记忆[79]. 记忆再巩固干预直接影响原始记忆痕迹，有可能克服消退干预的潜在局限性，更好地应对重建、更新及自发恢复等效应[80,81].

近年来，记忆再巩固干预从恐惧记忆研究中被迁移应用于药物成瘾领域中，取得了比消退干预更好的效果. 在成瘾的动物研究中，Ma等[82]2011年发现记忆提取-消退干预可以有效降低吗啡成瘾大鼠的条件性位置偏爱. 这一结果在2012年得到重复验证，利用记忆提取-消退干预方法对可卡因和吗啡成瘾大鼠进行干预，发现记忆再巩固干预组在自发恢复测试和重建测试中的条件性位置偏爱反应较对照组明显降低，这表明记忆再巩固干预能比单一消退干预更好地降低成瘾动物的渴求[83]. 记忆再巩固干预不仅可以更好地干预条件性位置偏爱训成的成瘾记忆，也可以干预自身给药模型训成的成瘾记忆. 有研究采用自身给药模型训成可卡因和海洛因成瘾的大鼠，发现记忆再巩固干预会减少成瘾大鼠在重建、更新以及自发恢复测试中的药物寻求行为，并且其干预效果要优于单纯的消退干预[83]. 这些研究说明，记忆再巩固干预在成瘾的动物研究中取得了比消退干预更好的效果，能降低消退干预后出现的重建、更新、自发恢复等效应.

但记忆再巩固干预效应不一定每次都会出现，在一些成瘾的动物研究中，记忆再巩固干预并没有表现出比消退干预更优的干预效果. 如Ma等[82]在吗啡成瘾研究中，并没有在干预4 w后的重建测试中发现记忆再巩固干预效应. Millan等[84]在酒精成瘾研究中发现，记忆再巩固干预组的成瘾大鼠较对照组获取酒精的动机增强. 记忆再巩固干预在成瘾动物研究中不一致的结果，可能是由于特定实验条件的限制，导致原有记忆无法激活，记忆再巩固过程没有发生，记忆再巩固干预失败. 记忆再巩固干预的关键在于原有记忆是否被激活到不稳定状态[85]. 记忆激活的方式如药物相关线索的呈现方式，可能导致成瘾记忆唤醒程度的不同，从而影响原有记忆的提取激活，最终影响记忆再巩固干预效果[78]. 在未来研究中可进一步探索更好的方法以激活原有成瘾记忆，转化应用于人类成瘾治疗的临床干预中.

目前，记忆再巩固干预在人类成瘾干预研究和临床治疗中的应用有限，但取得了一定的效果. Xue等[83]利用记忆再巩固干预海洛因成瘾者，记忆再巩固干预组线索诱发的渴求反应较单一消退组明显降低，这种降低效果维持到30 d和180 d后的检测中. Germeroth等[86]在尼古丁成瘾人群中重复了此研究，并且进一步检验了记忆再巩固干预可降低新颖药物相关线索诱发的渴求反应，减少尼古丁使用行为. 这些研究表明，记忆再巩固干预可以比消退干预更好地维持干预效果，应对自发恢复，并且更好地应对更新效应，是一种有前景的成瘾记忆干预方法. 在未来研究中可进一步结合新技术新方法更好地激活原有成瘾记忆，确保记忆再巩固过程能够完成，促进记忆再巩固干预方法在成瘾临床治疗与干预中的发展和应用.

虚拟现实（virtual reality，VR）技术以计算机技术为基础，在相应设备中生成一个在视、听、触感等方面与真实环境高度相似的三维立体环境，人们可以在环境中移动，同时与环境进行充分交互，产生身临其境的感受和体验[87]. 通过VR可以向成瘾者呈现药物相关的复合线索. 由于VR良好的生效度和可操纵性，相较于传统的药物相关线索呈现方式，如图片[87]、视频[88,89]等，它能够诱发成瘾者产生更强的渴求反应. 这提示VR可以从方法层面提高记忆再巩固过程中成瘾记忆的激活程度，从而确保记忆再巩固干预效果的实现. 有研究利用VR结合记忆再巩固干预对恐惧记忆进行治疗，发现恐惧的生理反应能得到良好的抑制[90]. 这提示运用VR有助于激活记忆再巩固干预过程中的成瘾记忆，达到消除或改变成瘾记忆的目的.

其次，VR可以增强消退干预效果，VR诱发的渴求反应越明显，成瘾者持续暴露于VR呈现的药物相关线索后，其渴求反应降低越明显，复吸可能性越低. 目前，VR结合成瘾记忆的消退干预方法在成瘾的治疗中已取得一定效果. 如Lee等[91,92]在尼古丁成瘾和酒精成瘾研究中发现，结合VR的消退干预，可减少尼古丁成瘾者的吸烟数量，降低酒精成瘾者的主观渴求和酒精成瘾程度. Girard等[93]也在尼古丁成瘾研究中重复验证VR结合消退干预降低渴求的效果. 有研究报道，利用VR对尼古丁、酒精等物质成瘾者进行单一药物相关情境的消退干预，成瘾者的渴求反应明显降低[94,95]. 也有研究将VR与多情境消退干预方法相结合，对尼古丁成瘾者进行不同情境的逐级暴露，发现成瘾者的主观渴求降低，吸烟行为减少[96]. Choi和Lee[97]将VR与厌恶疗法相结合对酒精成瘾者进行干预，内隐测试及眼动反应等结果显示，酒精相关线索诱发的渴求反应明显降低. 这些研究说明，VR有助于成瘾记忆的行为干预，增强消退干预效果，并且VR有可能更好地激活成瘾记忆，提高记忆再巩固干预的效果，是一种极具潜力的成瘾干预技术. 但目前为止，借助VR来增强成瘾干预效果的研究有限[79]，随着VR技术的飞速发展，未来研究可以结合VR与记忆再巩固干预方法对成瘾记忆进行干预.

药物成瘾记忆形成后，成瘾者大脑神经系统发生适应性的病理变化，如NAc中谷氨酸能和多巴胺能递质的改变，促进了成瘾记忆唤醒后的复吸行为[8,98]. 同时，中脑边缘神经环路系统出现功能失调，其中PFC功能受损，导致成瘾者自动化的药物寻求及使用行为不受控制[99,100]. 成瘾记忆形成过程中的脑功能改变提示，可以通过刺激脑区调节神经激活，来抑制成瘾记忆唤醒后的药物寻求及使用行为. 深部脑刺激（deep brain stimulation，DBS）和经颅磁刺激（repetitive transcranial magnetic stimulation，rTMS）、经颅直流电刺激（transcranial direct current stimulation，tDCS）被认为是成瘾治疗中有应用前景的三大神经调控技术. DBS是指通过外科手术将电极埋入特定的皮层下脑区，利用脉冲发射器传输高频刺激去极化或超极化特定神经元[101]，对脑环路进行同步或去同步化，以恢复受损伤的脑功能[102]. 个案研究显示，DBS在酒精、尼古丁及海洛因的成瘾治疗中初见成效. 一个酒精成瘾研究中，利用DBS双侧刺激成瘾者的NAc，5位被试均报告渴求降低，其中2位保持长期戒断[103]. 尼古丁成瘾研究发现，经过DBS治疗的吸烟者其戒断率在30个月后远高于未参与治疗的群体（30% vs 8.7%）[104]. 对海洛因成瘾者的NAc进行DBS治疗后，被试自我报告海洛因成瘾行为完全缓解[105]. 综上，DBS极有可能抑制成瘾记忆维持的复吸行为，然而DBS的有效机制并不清楚. DBS作为一种侵入性干预方法，目前不能确定是否可以改变成瘾记忆的神经可塑性，对药物寻求及使用行为进行调节.

不同于DBS，rTMS是一种非侵入脑刺激技术，通过在颅骨上方的线圈生成电磁场发射磁脉冲，激活（高频）或者抑制（低频）特定脑区的神经活动[106]. rTMS的作用因频率而异，低频刺激（

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