1 药物成瘾记忆形成及其神经环路机制
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] .1.1 奖赏学习引发药物成瘾记忆的初始形成
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.1.2 药物相关线索与药物奖赏反复匹配形成习惯化成瘾记忆
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.2 药物成瘾记忆维持药物寻求及使用行为
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.3 成瘾记忆的临床干预方法
3.1 成瘾记忆的行为干预方法
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.
3.1.1 消退干预方法
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] .3.1.2 多情境消退干预方法
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.3.1.3 记忆再巩固干预方法
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.3.2 虚拟现实技术在成瘾记忆干预中的应用
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.3.3 神经调控技术抑制成瘾记忆唤醒后诱发的自动化药物寻求及使用行为
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（<1 Hz）减少神经激活，高频刺激增加神经激活（5~20 Hz）[107,108] . 许多关于成瘾的临床研究，利用高频rTMS作用于背外侧前额叶（dorsolateral prefrontal cortex，dlPFC）以恢复PFC的抑制控制功能，这一脑区涉及到认知处理、工作记忆及冲动控制[109,110] . 在可卡因临床研究中发现，通过rTMS刺激dlPFC可降低可卡因渴求[111] . 也有研究显示rTMS无法降低渴求[112] . 尽管利用rTMS刺激脑部进行成瘾治疗的结果并不一致，但rTMS仍有希望恢复成瘾记忆形成后的脑功能损伤，从而抑制自动化药物寻求及使用行为. 未来可发展大样本的双盲随机对照实验来研究脑部刺激方法对于抑制成瘾记忆的唤醒，减少复吸的有效性，并了解其背后的机制.tDCS也是一种非侵入性脑刺激技术，利用电极作用于大脑头皮上的目标区域，通过电极两极的微电流刺激（1~2 mA）调节静息电位以改变皮层的兴奋
性[113] . 研究发现阳极刺激可以增加皮层兴奋性，阴极刺激可以抑制皮层兴奋性[114,115] . 近年来，研究者将tDCS应用于成瘾治疗中，同样发现tDCS刺激dlPFC可以提高成瘾者的执行控制功能，降低成瘾记忆被唤醒后的渴求反应，这一结果在尼古丁[116,117] 、酒精[118,119] 、可卡因[120,121] 、海洛因[122] 、阿片[123] 、冰毒[124] 等不同类型的成瘾研究中均得到了证实. 有研究总结，截至2017年16个应用tDCS刺激dlPFC的成瘾治疗研究中，有8个提示tDCS可降低成瘾者的渴求[113] . 这说明tDCS在成瘾干预中的应用前景，然而也有研究显示tDCS刺激dlPFC没有改变成瘾者的渴求，如一些尼古丁成瘾研究[125,126] ，或者只降低了成瘾者的渴求而未改变吸烟行为[127] . tDCS的疗效差异可能是由于目前成瘾治疗研究设置的电极刺激参数不一致，并且大部分研究样本量过小，无法进一步确定tDCS的长期效果. tDCS刺激在成瘾治疗应用中的有效性有待大样本双盲实验进行长效研究进一步确认. 未来tDCS可结合神经影像学和电生理学理解成瘾记忆的病理生理机制，并确定治疗的刺激参数[113] .4 总结与展望
成瘾记忆在物质成瘾中发挥着重要作用，成瘾行为发展的每一个阶段都有着相应的神经基础，其中PFC及NAc、海马、杏仁核等学习记忆关键脑区，在成瘾记忆形成及成瘾行为维持中发挥着重要作用. 成瘾记忆形成后，药物相关线索唤醒成瘾记忆引发强烈渴求反应，促使成瘾者复吸. 了解成瘾记忆形成过程及背后神经机制，对成瘾记忆的干预有着重要指导意义. 寻求更优的成瘾记忆干预方法，成为目前成瘾临床治疗的重要方向.
消退干预作为干预成瘾记忆的一种基本方法，在人类的成瘾研究中取得了一定的效果及推广，然而在部分临床治疗应用中，成瘾者的复吸并未得到有效的改
善[128] . 消退干预后重建、更新、自发恢复等效应的出现，提示成瘾者是否复吸取决于消退干预过程中新形成的消退记忆与原有成瘾记忆相互竞争的结果[79] . 因此，增强消退记忆或者直接干预原有成瘾记忆，为药物成瘾的临床治疗提供了重要依据和参考.多情境消退被认为可以增强消退记忆，避免或减少消退干预中的情境单一性所带来的更新现象. 然而多情境消退干预中的消退记忆是短期形成的，无法确定增强的消退记忆能否与成瘾记忆进行长期抗衡，较长时间维持干预效果. 因此，研究者提出记忆再巩固干预方法直接从源头干预成瘾记忆，抑制成瘾记忆的再巩固过程. 研究验证了记忆再巩固干预方法较消退干预能更好地干预成瘾记忆，降低渴求反应，维持长期干预效果，并能迁移降低新颖药物相关线索诱发的渴求反
应[83,86] .目前记忆再巩固干预方法在人类药物成瘾治疗中的临床应用有
限[84] ，并且记忆再巩固干预效果可能会由于原有成瘾记忆激活程度的限制而受到影响. 虚拟现实技术可能更好地激活成瘾记忆，促进记忆再巩固过程的完成. 因此，未来可利用虚拟现实技术与记忆再巩固干预方法相结合，对成瘾记忆进行干预，有利于降低线索诱发的渴求反应和减少自动化药物寻求及使用行为，维持长期稳定的干预效果，为成瘾治疗的临床干预提供了新思路和新策略.由于成瘾记忆形成过程对应着神经功能的改变及损伤，无创神经调控技术如rTMS和tDCS可用来调控神经功能. 如干预NAc以降低成瘾者的渴求反应，或恢复PFC等功能；如对自动化药物寻求行为的抑制控制功能. 在恐惧记忆研究中发现，vmPFC在消退干预中发挥着重要作
用[129,130] ，激活vmPFC可以增加消退记忆的表达[131] . 有成瘾动物研究也显示，激活vmPFC可增强消退学习，增加消退干预的效果[132] . 最近有一个人类恐高研究，使用rTMS激活vmPFC，成功促进了消退干预效果[133] . 之后的研究可以使用rTMS激活vmPFC，促进成瘾者的多情境消退干预或者记忆再巩固干预过程中的消退学习过程，加强成瘾记忆的干预效果. 神经调控技术在成瘾治疗的临床干预中有待进一步验证推广，其背后作用机制也有待更多研究探明.总之，未来可利用虚拟现实技术、神经调控技术等结合成瘾记忆干预方法对成瘾记忆进行干预，特别是与记忆再巩固干预方法的结合，为成瘾的临床干预和治疗提供有效方法及可靠依据.
Tel:86-10-64850437, E-mail: liyonghui@psych.ac.cn
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摘要
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.
Abstract
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.
药物成瘾是一种长期持久的复发性脑疾
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
