星形胶质细胞G蛋白偶联受体在药物成瘾中的作用

Alexander K. Zinsmaier ,  Eric J. Nestler ,  Dong Yan

Engineering ›› 2025, Vol. 44 ›› Issue (1) : 269 -280.

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Engineering ›› 2025, Vol. 44 ›› Issue (1) : 269 -280. DOI: 10.1016/j.eng.2024.12.016
研究论文

星形胶质细胞G蛋白偶联受体在药物成瘾中的作用

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Astrocytic G Protein-Coupled Receptors in Drug Addiction

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摘要

了解药物成瘾的细胞机制是当前大脑研究的一项关键任务。虽然在过去三十年中，基于神经元的药物成瘾机制得到了广泛探索，但是最近证据表明，星形胶质细胞（大脑中主要非神经元细胞类型）的参与至关重要。在细胞外刺激下，星形胶质细胞对神经元活动、突触传递和神经网络特性进行调节，协同影响大脑功能。星形胶质细胞表面的G蛋白偶联受体（GPCR）通过激活或抑制信号传导来响应神经元和环境衍生的配体，进而调节相邻神经元及其回路。本文重点介绍了多巴胺D1受体（D1R）和代谢型谷氨酸受体5（mGLUR5或GRM5）作为GPCR在获得和维持成瘾相关行为中的作用。本文简要探讨了星形胶质细胞生物学特征，概述了早期发现的星形胶质细胞在物质使用障碍（SUD）中的作用，并详细讨论了星形胶质细胞D1R和mGLUR5在调节伏隔核（NAc）中的突触和网络连接功能，而伏隔核是调控与成瘾相关的情绪和动机反应的大脑区域。本文为探索星形胶质细胞GPCR与药物成瘾和其他精神疾病之间联系奠定了基础。

Abstract

Understanding the cellular mechanisms of drug addiction remains a key task in current brain research. While neuron-based mechanisms have been extensively explored over the past three decades, recent evidence indicates a critical involvement of astrocytes, the main type of non-neuronal cells in the brain. In response to extracellular stimuli, astrocytes modulate the activity of neurons, synaptic transmission, and neural network properties, collectively influencing brain function. G protein-coupled receptors (GPCRs) expressed on astrocyte surfaces respond to neuron- and environment-derived ligands by activating or inhibiting astrocytic signaling, which in turn regulates adjacent neurons and their circuitry. In this review, we focus on the dopamine D1 receptors (D1R) and metabotropic glutamate receptor 5 (mGLUR5 or GRM5)—two GPCRs that have been critically implicated in the acquisition and maintenance of addiction-related behaviors. Positioned as an introductory-level review, this article briefly discusses astrocyte biology, outlines earlier discoveries about the role of astrocytes in substance-use disorders (SUDs), and provides detailed discussion about astrocytic D1Rs and mGLUR5s in regulating synapse and network functions in the nucleus accumbens (NAc)—a brain region that mediates addiction-related emotional and motivational responses. This review serves as a stepping stone for readers of Engineering to explore links between astrocytic GPCRs and drug addiction and other psychiatric disorders.

关键词

星形胶质细胞 / G蛋白偶联受体 / 伏隔核 / 药物成瘾 / 代谢型谷氨酸受体5 / 多巴胺

Key words

Astrocyte / GPCR / Nucleus accumbens / Addiction / mGLUR5 / Dopamine

引用本文

引用格式 ▾
Alexander K. Zinsmaier,Eric J. Nestler,Dong Yan. 星形胶质细胞G蛋白偶联受体在药物成瘾中的作用[J]. 工程（英文）, 2025, 44(1): 269-280 DOI:10.1016/j.eng.2024.12.016

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1 引言

人类消费精神活性物质的历史可追溯至文明诞生之初。在现代社会，人们经常用咖啡因和尼古丁提高认知和警觉性，使用阿片类药物缓解患者的痛苦，还有大量人群购买大麻和酒精等药物作为娱乐性消遣品。然而，一些人会患上物质使用障碍（SUD），我们对其相关的大脑机制却知之甚少。SUD目前被定义为一种个体不顾负面后果继续寻找和使用精神活性物质的行为状态。针对这种脑部疾病，神经科学研究在很大程度上仍停留在重复寻求药物和服用药物的行为框架内，这种行为源于药物诱发的大脑奖励回路中神经元适应性变化。这种神经适应部分集中在中脑边缘和皮质纹状体投射到伏隔核（NAc）的单个神经递质（如多巴胺和谷氨酸）的活动里。作为关键脑区，NAc汇聚和整合皮层和皮层下输入信号，以调节与奖励和动机相关的行为。多年来，在构成NAc和其他几个与奖励相关的大脑区域的神经元群中已经发现了许多适应性变化。然而，越来越明显的是，神经元并不是药物诱导适应和药物驱动行为的唯一参与者。

除神经元外，中枢神经系统（CNS）还包含几乎等量的神经胶质细胞，它们不仅为相邻神经细胞提供结构和稳态支持，还调节其功能。星形胶质细胞是最丰富的神经胶质细胞，因其在调节突触传递和神经回路功能中的作用而日益受到重视。在哺乳动物大脑中，星形胶质细胞突起位于突触和树突附近，这是一种可能促进神经元和星形胶质细胞之间双向交流的解剖学结构。在过去二十年里，越来越多证据表明，这种串扰是与动机行为相关的学习和记忆过程的基本机制。

谷氨酸能神经传递与多巴胺能神经传递是滥用药物所引发求药和服药行为的两个主要靶点。这些神经递质的代谢受体[即谷氨酸能和多巴胺能G蛋白偶联受体（GPCR）]与药物记忆密切相关。然而，与神经元GPCR相比，人们对这些在星形胶质细胞上表达的GPCR的细胞和行为功能仍知之甚少。本文总结了关于星形胶质细胞的谷氨酸能和多巴胺能GPCR的研究现状，并讨论了星形胶质细胞如何通过这些GPCR与神经元交流，以促进SUD情况下的行为改变。

2 SUD背景下星形胶质细胞简史

自B.F. Skinner提出操作性条件反射箱以来，神经科学家已经能研究啮齿动物反复、自愿使用药物对神经的影响。基于操作性反应的药物自身给药（SA）模型使研究人员可以探究药物使用的奖励和动机，并提供一个受控的实验室环境来测试药物相关行为与药物诱导的神经适应之间的因果关系。早期行为神经科学家使用该模型证明，大鼠反复选择用于发送或接收多巴胺能投射的大脑区域进行电自刺激[1‒2]。此外，使用具有增加或延长多巴胺作用的兴奋剂提高了用电进行自我刺激的频率[3]。随后，研究人员发现，所有导致易感人群成瘾的药物都会增加从中脑腹侧被盖区（VTA）到前脑NAc的多巴胺能传递[4]。因此，成瘾是多巴胺的奖励/强化特性功能失调的结果，这一假设[5‒6]成为神经科学界的主流[7]（深入讨论可参阅早期对SUD中多巴胺能适应的综述[8‒10]）。下文将讨论最近的新发现，NAc星形胶质细胞参与药物适应和多巴胺能传递。

随着时间推移，越来越多的证据也表明，谷氨酸能传递的长期适应性有助于推动成瘾行为的获得和维持[11‒15]。2009年，对药物成瘾情况下谷氨酸稳态的关注扩大到星形胶质细胞（核心作用）。这一假设提出，成瘾起源于由药物引发的皮质纹状体投射中谷氨酸释放/再摄取失衡，终止于NAc [16]。鉴于这些投射而产生习得的行为，以及根据环境不断变化而改变的行为[17]，该假设表明，成瘾可能源于觅药行为的习得和强化、抑制觅药行为的能力减弱，或两者的结合。值得注意的是，许多关于谷氨酸稳态的后续研究都使用了啮齿动物药物复用的恢复模型。因此，一些已确定的适应行为可能只会在断药训练后发生[18]，这是一种强制戒断模式，不再生成之前药物或其配对线索（强化条件刺激）所产生奖励的操作反应[19]。自身给药行为稳定消退后，即使经历长时间戒断，再次接触药物或此前与之相关的线索也会引发觅药行为[20]。

在长期的可卡因自身给药和戒断后，皮质纹状体通路中谷氨酸稳态的失调源于NAc星形胶质细胞周围突触的多重适应性改变[21‒24]。首先，谷氨酸转运体1（GLT1）表达减少，而GLT1负责超过90% 的中枢神经系统突触的谷氨酸清除[25‒31]。其次，xCT（一种胱氨酸/谷氨酸反向转运体）功能受损，xCT调节突触外间隙的环境谷氨酸水平[32‒33]。再次，虽然GLT1降低会有损突触中谷氨酸的清除，但xCT下调会降低突触外谷氨酸水平，而突触外谷氨酸通常通过激活神经末梢上的代谢型谷氨酸受体2和3（mGLUR2/3）来驱动突触前抑制，从而导致增加谷氨酸能传递[34‒35]。最后，戒断训练导致星形胶质细胞突起显著回缩，会阻隔NAc突触[18,36]。这些适应变化共同加剧了谷氨酸从突触间隙溢出到突触外空间的情况[16,24]，从而触发相邻突触的非特异性神经元活动[37‒40]，并促进觅药行为[24,41‒42]。N-乙酰半胱氨酸是一种恢复GLT1和xCT功能的半胱氨酸新型前药，可有效减少在消退或戒断可卡因成瘾模型中线索引发的觅药行为[21,43‒45]，这表明星形胶质细胞可能成为人类患者治疗干预的新希望。截至目前，使用N-乙酰半胱氨酸来刺激xCT介导的谷氨酸清除，在初步临床研究中显示出令人喜忧参半的结果[46]。在一项针对111名可卡因使用障碍患者的双盲安慰剂对照研究中，N-乙酰半胱氨酸仅在一小部分已戒除可卡因的受试者中有效增加了再次给药时间或降低对可卡因的渴望程度，而对正在用药患者戒断率无显著影响[47]。虽然这项研究的结果主要是负面的，但确实有必要进行进一步临床研究，应更好地纳入可卡因戒断者，以深入研究N-乙酰半胱氨酸对预防复吸的作用。

觅药和复用药物通常由压力或强烈的药物渴望引起。在许多情况下，药物渴望是通过使用者遇到与药物相关联的人、地点或物体而引发。在反复服药期间，先前中性（非正面或负面）的提示受到用药经历的限制，可预测是否可获得药物。因此，条件性线索可以强化觅药/服药行为，因为在禁药期间再次接触它们会引发强烈渴望，从而导致持续用药。这种依赖记忆的现象引发一个重要问题：与药物使用相关的记忆如何在大脑中编码？为什么即使长期不用药，仍会引发复用药物等自我破坏行为？星形胶质细胞在SUD中的角色是否超越了稳态维持的功能障碍？实际中，星形胶质细胞究竟能否重塑神经系统以适应和维持这些持久的记忆？

药物滥用作用于大脑区域（如NAc）并利用其与学习和记忆流程相同的细胞机制[17,48‒52]。NAc中的主要神经元是中棘神经元（MSN），它们从多个皮层和皮层下结构接收广泛的谷氨酸能投射[8‒9]。这些投射提供了相关的情境和情感信息，这些信息被整合到NAc层面上，以指导动机行为[53‒54]。NAc有两个子区域：核心区域优先参与寻求奖励相关运动功能的获得和启动，而外壳区域优先影响动机和联想记忆动态[55]。在对NAc外壳区域的几个投射中，可卡因自我给药重新产生独特的谷氨酸能突触群。一些细胞特征使这些突触与其他谷氨酸能突触不同，其中一个突出的特征是缺乏功能稳定的α-氨基-3-羟基-5-甲基-4-异𫫇唑丙酸（AMPA）受体（AMPAR）。起初，这些“沉默AMPAR”突触仅包含功能性N-甲基-D-天冬氨酸受体（NMDAR），但在退出过程中通过募集缺乏GLUA2 AMPAR亚基的非典型、钙离子可渗透的AMPAR（CP-AMPAR）而成熟，一旦成熟，这些突触就会形成可卡因相关记忆，其动态状态能调节可卡因记忆的提取、失稳和再巩固[56‒57]。

这些突触的新发性质以及它们通常使用早期发育的细胞机制，为药物成瘾的神经再生假说提供了支持[58‒59]。在该假设中，反复接触可卡因使通常与发育早期突触形成相关的休眠细胞重新恢复正常运作，以重建大脑奖励回路的突触结构。星形胶质细胞在早期发育突触形成中起重要作用，这一情况引导对星形胶质细胞是否有助于可卡因特异性突触产生的进一步研究。这项工作表明，星形胶质细胞释放的血小板反应蛋白2（TSP2）激活神经元受体α2δ1（CACNΑ2D1；加巴喷丁和相关药物的靶标），进而促进可卡因自身给药后静默突触的产生[60‒61]。TSP表达在早期发育期间最高，随年龄增长而下降到较低水平[62]。这些较低水平的TSP2可在成人NAc [靠近神经元受体（α2δ1）]中检测到[61,63]，尽管TSP下降，但其水平仍然较高。虽然可卡因自身给药不会上调NAc中的TSP2水平，但短发夹RNA（shRNA）介导的TSP2或α2δ1敲除足以阻止静默突触生成[61]，这表明星形胶质细胞中低水平TSP2足以导致突触形成。此外，加巴喷丁对TSP2-α2δ1的药理学抑制足以防止静默突触的产生和NAc树突棘密度的相应增加，并以及减少线索诱导的可卡因觅药行为[61]。因此，与年龄相关的星形胶质细胞衍生信号传导能力下降并不等同于功能丧失。相反，星形胶质细胞介导的发育信号似乎持续到成年，并可在学习过程中主动重塑周围的突触环境。之后将进一步讨论星形胶质细胞在较低表达水平下调控信号通路的能力，其中包括星形胶质细胞生物学特征、GPCR在星形胶质细胞中的作用以及星形胶质细胞GPCR在SUD中的作用。

3 星形胶质细胞生物学特征

单个星形胶质细胞的解剖结构非常复杂，因其末梢突起形成云状外观，常被描述为“海绵状”。典型的原生质星形胶质细胞包括一个中央细胞体、包裹附近脉管系统的1~3个端足、几个较厚的初级分支以及一个由错综复杂的小枝和小叶组成的大网（突触周围突起），这些小枝和小叶接触其区域内的数千个突触[64‒68]。或许因末梢突起的复杂性和尺寸所致（如单个小叶的范围为10~100 nm [69]），星形胶质细胞与相邻细胞的区域重叠极小（小于5%）[70‒72]，而形成高度复杂的平铺排列，即星形胶质细胞突起延伸并覆盖整个中枢神经系统，同时最大限度地减少重叠[73]。平铺式排布是啮齿动物和人类星形胶质细胞的一个显著特征，尽管人类星形胶质细胞显示出更大程度的区域重叠[74‒76]。此外，邻近的星形胶质细胞通过细胞间隙广泛连接，形成大规模的电耦合网状网络，称为合胞体[77‒79]。合胞体结构使偶联的星形胶质细胞能够不断平衡其膜电位并作为单一单位发挥作用[80]。这一特征，加上低膜电阻和高钾渗透性，可以防止膜电位发生大幅偏差[27]，并有助于星形胶质细胞的电生理不可兴奋特性[81]。然而，尽管星形胶质细胞不像神经元那样产生动作电位，但是它们可以通过胞体和突触内的动态细胞内钙离子（Ca2+）波动对神经递质做出反应[82‒83]。

星形胶质细胞同时表达离子型受体和代谢型受体，经研究显示星形胶质细胞对谷氨酸、γ-氨基丁酸（GABA）、三磷酸腺苷（ATP）、多巴胺、血清素、乙酰胆碱、去甲肾上腺素、内源性大麻素和其他递质有反应[84‒85]。虽然对于星形胶质细胞内钙离子波动的下游效应缺乏共识[86‒87]，但很明显这些钙离子活性受到星形胶质细胞上表达的GPCR的严格调控[84,88‒92]。这种钙离子波动（无论在胞体还是分支中），通常由GPCR介导的磷脂酶C（PLC）和三磷酸肌醇（IP3）[93]的激活引发。当IP3与星形胶质细胞中的主要细胞内受体三磷酸肌醇受体2（IP3R2）结合时，会触发内质网（ER）内部储存的钙离子的释放。在末端突起中也检测到不依赖IP3R2的钙离子波动，但这些波动相对较小，且局限于神经元突触附近的微区内[94‒99]。IP3R2非依赖性钙离子波动在体内很常见，并且可能由跨膜钙离子扩散[100]等外部来源引起。体内研究还表明，神经调节剂的大量释放可驱动跨越整个大脑区域的大规模钙离子事件[101‒104]。神经元反应（如突触传递和动作电位放电）发生在毫秒级，而星形胶质细胞的钙离子反应要慢得多，通常持续数百毫秒到几秒[97,103,105]。较长时间的星形胶质细胞钙离子波动可能具有显著的行为相关性。例如，在幼年斑马鱼中，反复尝试逆流而上会产生行为失配信号，导致钙离子在放射状星形胶质细胞中逐渐积累。这些长时程钙离子信号与斑马鱼剧烈游泳尝试间歇期表现出的行为被动性的开始和维持相关，表明星形胶质细胞钙离子的时序动态特征是行为状态转换的中枢神经系统调控的一部分[104]。

有力证据表明，星形胶质细胞和神经元处于持续的交流中，这种相互交流对行为很重要[106‒108]。如前所述，星形胶质细胞表达各种类型的神经递质受体，这些受体使神经元与星形胶质细胞进行信号传递。作为回报，星形胶质细胞可以通过胶质传递过程将信息传递给神经元，该过程部分由星形胶质细胞上GPCR的刺激所驱动[86‒87,97,109]。在实验诱导或神经元刺激下，星形胶质细胞可释放无数神经活性分子，包括ATP/腺苷[110‒121]、谷氨酸[122‒126]、GABA [127‒132]和D-丝氨酸[133‒135]。值得注意的是，单个星形胶质细胞可根据刺激强度和持续时间，以双相方式释放不同的胶质递质（即谷氨酸和ATP/腺苷）[136]，这一特征表明星形胶质细胞可执行复杂的信号整合和处理。

星形胶质细胞具有多种神经胶质传递机制，包括依赖钙离子的胞吐，以及各种形式的非钙离子依赖性递质释放。例如，谷氨酸可通过依赖钙离子的胞吐[137‒138]、骨髓基质细胞抗原1（BST1）阴离子和TREK-1钾通道[139]、半通道[140]、体积调节阴离子通道（VRAC）[141]以及几种转运蛋白、反向转运蛋白和交换蛋白[142]释放。依赖钙离子胞吐在成年星形胶质细胞中的突出地位，一直是星形胶质细胞生物学中持续争论的主题。已发现培养和急性分离的星形胶质细胞都含有钙离子依赖性囊泡胞吐所必需的分子，包括SNARE蛋白小突触泡蛋白Ⅱ、SNAP 23蛋白、囊泡相关膜蛋白（VAMP）2和3、突触融合蛋白（Syntaxin）1，以及几种突触结合蛋白亚型和囊泡型谷氨酸转运蛋白（VGLUT）1和2 [143‒148]。VGLUT 1和2对于将谷氨酸包装成囊泡和谷氨酸的胞吐释放至关重要。例如，免疫金标记和单细胞逆转录聚合酶链反应（RT-PCR）已经验证了从海马体齿状回（DG）培养和急性分离的星形胶质细胞中存在VGLUT 1和2。VGLUT 1和2在弥散分布的囊泡中表达，这些囊泡类似于神经元囊泡，但其融合蛋白的分子组成不同。S-3,5-二羟基苯基甘氨酸（DHPG）是mGLUR1和mGLUR5的强效激动剂，刺激内源性星形胶质细胞GPCR可导致SNARE蛋白介导的囊泡快速融合和谷氨酸释放。重要的是，VGLUT 1和2仅存在于约25%~40%的分离星形胶质细胞中，这表明存在一个特殊的星形胶质细胞亚群，可以进行依赖钙离子的胞吐[138]。然而，难以检测到大量VGLUT 1和2表达水平较低的星形胶质细胞。此外，该研究未检测到星形胶质细胞在化学遗传介导的内部钙离子水平增加而释放谷氨酸的情况[149]。为解决这些相互矛盾的发现，研究人员在DG中证明了钙离子依赖性胞吐后，使用更新的生物信息学和成像方法重新检验了他们的发现[150]。研究揭示了9个含不同分子的星形胶质细胞亚群中，只有一个亚群具备谷氨酸囊泡胞吐所需的机制[150]。虽然结果令人惊讶，但表明星形胶质细胞存在明显的区域和分子异质性，这可能是许多早期实验结果存在不一致的原因，这些不一致引发了关于钙离子信号和胶质传递作用的争论[151‒154]。事实上，其他研究小组发现，对其他大脑区域（如NAc核心和体感皮层）星形胶质细胞的化学遗传学刺激会触发谷氨酸释放[155‒158]。例如，在SUD背景下，星形胶质细胞释放的谷氨酸（可能是经胞吐作用）刺激NAc核心中的神经元mGLUR 2/3，并抑制寻求线索诱导的可卡因、甲基苯丙胺和乙醇复吸行为[155,157‒158]。这些发现突出了星形胶质细胞机制的复杂性和多样性，在解释跨大脑区域和行为背景的积极和消极结果时应考虑这一点。

4 星形胶质细胞GPCR在SUD中的作用

与SUD相关的两种代表性星形胶质细胞GPCR是 mGLUR5和多巴胺D1受体（D1R）。尽管人们已经对神经元mGLUR5和D1R进行了广泛研究，但对星形胶质细胞mGLUR5和D1R贡献知之甚少。在简要讨论GPCR功能后，本节总结了所了解到这些受体在星形胶质细胞上的表达及其对SUD的贡献。

GPCR是一类通过递质结合激活后触发细胞内多步信号级联放大反应的受体。在神经元中，这些信号级联放大反应由Gα亚基与共同构成G蛋白异源三聚体的βγ亚基解离触发[159]。至少有四类G蛋白（Gq、Gi/o、Gs和G12/13）[160‒161]存在。在神经元中，Gq和Gs偶联的第二信使系统的激活通常会增加胞内钙离子浓度并引起神经元的兴奋，而Gi/o通路激活会导致相反的效果。然而，在星形胶质细胞中，这种功能二分法似乎并不明确[156,162]。近期研究表明，由特定设计药物激活的“兴奋性”（Gq偶联）和“抑制性”（Gi/o偶联）人工设计受体（DREADDs）都可提高脑纹状体[106,149]中星形胶质细胞的钙离子水平。研究显示，在海马体中，Gq激活能稳定提升星形胶质细胞钙离子水平[149,156,163]，而Gi/o激活的影响因研究而异：既有研究认为不影响胞内钙离子水平[149,164]，又有研究认为会提高钙离子水平[156]，还有研究认为对钙离子水平有双相作用（最初增加后随后降低）[165]没有影响。尽管这些观察结果背后的确切机制尚不清楚，但这些差异可能是星形胶质细胞GPCR功能的区域和分子异质性的表现。神经元GPCR历来被认为仅与单一G蛋白偶联。然而，现有研究证实GPCR表现出构象可塑性，这使它们能够与多个G蛋白偶联[166‒169]，并以时间依赖性方式依次将其激活[170‒171]。因此，星形胶质细胞GPCRs也可能激活多个信号通路，且这些反应可能呈现区域异质性。

需要重点考虑的是，星形胶质细胞GPCR比神经元GPCR更稀缺且更分散。然而，星形胶质细胞GPCR保有强大的功能，已在内源性大麻素受体（CB1）研究中证明[172‒174]。事实上，星形胶质细胞GPCR表现出一些特征，如信号级联放大、更高的配体结合亲和力和较低脱敏率[84,109]，使其尽管处于低表达水平，仍可在多个突触中对神经元活动进行可靠的采样和整合。

4.1 mGLUR5

在小鼠和人类中，星形胶质细胞中mGLUR5的表达在发育期间达到峰值，然后在进入成年期时下降[149,175‒177]，这一发育期间特征一定程度是受腺苷A2B受体表达增加而驱动[178]。mGLUR2/3 [176,179]表达的同步增加可解释为对成年期mGLUR5功能降低的补偿。尽管处于低表达水平，星形胶质细胞mGLUR5在成年野生型小鼠中仍具有功能[180]，甚至在受到损伤或疾病状态下mGLUR5会有所增加[181‒184]。在星形胶质细胞上，已经在与突触前和突触后末梢相关的精细外周突上观察到mGLUR5，但在胞体上几乎没有表达[119,185]，因此通过光学显微镜难以检测到mGLUR5。然而，最近一项研究检测到mGLUR5蛋白位于成年、中枢神经特异性蛋白（s100β）标记海马体中的星形胶质细胞胞体和一级分支[186]。另一项研究检测到在神经结扎后体感皮层中免疫金标记的mGLUR5与胶质纤维酸性蛋白（GFAP）存在共定位[187]。因此，mGLUR5表达及其相对水平在单个星形胶质细胞内的亚细胞水平，以及不同脑区的星形胶质细胞间的种群水平上都是异质的（图1）。

有趣的是，敲除成年小鼠海马体中mGLUR5会增加星形胶质细胞标志物中枢神经特异性蛋白（s100β）的表达[186]。这一结果表明，星形胶质细胞mGLUR5负向调节成年期星形胶质细胞的增殖和激活。然而，研究人员承认，这一发现与其他mGLUR5在发育过程中正向调节星形胶质细胞分支的发现[188‒189]形成鲜明对比。有必要进行进一步研究，以确定mGLUR5是与中枢神经特异性蛋白（s100β），还是与NAc中的纹状体星形胶质细胞标志物μ-结晶蛋白（μ-crystalline）定位。鉴于此前尝试使用GFAP，将mGLUR5表达定位到该大脑区域的星形胶质细胞[190]，与海马区星形胶质细胞相比，GFAP在纹状体星形胶质细胞中的表达水平非常低[149]。

从功能角度，海马体和纹状体中的星形胶质细胞对mGLUR5和mGLUR2/3激动剂敏感，这两种激动剂在星形胶质细胞突起中都能引发钙离子激活，与mGLUR5激动剂相比，mGLUR2/3激动剂在胞体中引起更大的反应[149,156,179]。虽然研究已深入分析了mGLUR2/3在控制谷氨酸能神经末梢方面的作用，但如上所述，mGLUR3在星形胶质细胞中富集。理论上，星形胶质细胞mGLUR可以由突触释放的谷氨酸或突触外溢出的谷氨酸刺激。几项研究已检验了这些可能性。例如，在年轻大鼠中，海马体CA1区神经元的单次突触刺激后可观察到mGLUR5依赖性反应[119]。这些信号很弱，发生于树突棘的离散亚细胞区室中，这支持星形胶质细胞直接从神经元接收信息的观点。在体内，通过刺激清醒[191]和麻醉[91]成年小鼠的胡须，可观察到星形胶质细胞对突触或异位谷氨酸释放的反应。胡须刺激诱导的星形胶质细胞钙离子反应对AMPAR或NMDAR拮抗剂不敏感，表明它们不是谷氨酸能突触传递到神经元的间接结果[91]（其他情况见参考文献[191]）。此外，这些体内反应被mGLUR5拮抗剂2-甲基-6-（苯乙炔基）吡啶（MPEP）阻断，表明mGLUR5参与这些星形胶质细胞反应。在另一项研究中，成年小鼠NAc核心和壳层的星形胶质细胞亚群对多个谷氨酸能传入的光遗传学刺激有反应。这些反应仍需mGLUR5，并在河豚毒素（TTX）和苦味毒存在的情况下得以保留[192]，这进一步表明星形胶质细胞直接对受刺激的传入做出反应，无需局部神经元参与。

虽然上述结果表明星形胶质细胞mGLUR5在成年期具有功能性作用，但也有证据表示并非如此。在成年小鼠的海马体苔状纤维通路中，电场刺激（EFS）诱发谷氨酸释放到星形胶质细胞上，仅在爆发放电后才增加星形胶质细胞胞体和分支中的钙离子活性，单次刺激后没有明显效果。上述反应依赖IP3R2，mGLUR2/3拮抗剂LY341495（10 μmol∙L-1）和GABAB受体拮抗剂CGP52432（10 μmol∙L-1）的组合可阻止上述反应，但mGlUR5拮抗剂MPEP（50 μmol∙L-1）不能[193]。然而，对单个突触事件的反应与大型传入刺激的反应可能有不同的机制。由于在轻微刺激后可以在树突棘附近观察到显著的钙离子事件，而单次EFS对胞体或分支中的钙离子水平没有影响，我们推测时间或空间整合可能在起作用。

以一项检查成年小鼠的纹状体的研究为例，其中EFS以每秒四次的频率刺激10 s，会选择性地增加星形胶质细胞分支中的钙离子的活性，但未增加胞体中钙离子的活性[179]。该研究中，刺激后约20 s出现了额外且大量的钙离子活动，这种延迟最初被解释为刺激伪迹。然而，这种延迟效应类似于最近证明的星形胶质细胞钙离子信号在体感皮层中的唤起，该信号在外周感觉刺激（后爪刺痛）后约20 s达到峰值[194]。因此，该延迟可被重新解释为星形胶质细胞突起的综合体细胞响应。具体来说，如果mGLUR确实在精细突起处中优先表达，并介导局部钙离子事件[185]，那么只有当来自远端突起的足够强度且时间相关的钙离子信号整合到超阈值的体细胞信号中时，才会发生延迟的体细胞反应。最近在一项体内双光子研究[195]中检测到这样的阈值，该研究监测了小鼠初级体感皮层中星形胶质细胞钙离子对外周感觉刺激的反应。该研究还揭示了星形胶质细胞的钙离子信号起源于精细突起和分支，必须跨越特定的空间阈值才能触发全细胞IP3R2介导的钙离子激增[195]。在脑切片中，ATP诱导的星形胶质细胞刺激会生成缓慢的内电流，这是胶质细胞递质释放的替代标志。一旦突破空间阈值，这种内电流就会在邻近的2/3层皮质神经元中产生[195]。虽然这些发现的意义重大，但空间阈值是否可以在大脑区域和星形胶质细胞表达的GPCR推广仍有待确定。

星形胶质细胞mGLUR5的激活会导致一系列下游效应（图1）。在NAc中，星形胶质细胞mGLUR5调节钙离子动态，导致胶质细胞传递到相邻的MSN上[196]。在背侧纹状体中，星形胶质细胞mGLUR5调节皮质纹状体突触的长时程抑制（LTD）诱导[197]。在体感皮层中，外周疼痛上调星形胶质细胞mGLUR5，导致突触发生信号分子（TSP-1）的释放和新突触连接的产生，这是神经病理性疼痛持续的基础[187,198]。

神经元mGLUR5在SUD中的作用已被广泛研究[199‒202]。尚未有研究直接探讨SUD中的星形胶质细胞mGLUR5的作用，因此我们根据深入的文献分析做出一些推测。mGLUR5的基因缺失可阻断可卡因自身给药，并降低了可卡因引发的运动敏感化[203]。然而，另一项研究表明，尽管阻断了可卡因引发的VTA适应，但mGLUR5的基因缺失并不影响可卡因引发的运动敏感化[204]。这种差异可能源于所使用的小鼠品系不同，因此mGLUR5的缺失在不同神经元或神经胶质细胞群中可能受到不同影响。尽管如此，mGLUR5的药物抑制降低了对可卡因自身给药[203]和几种形式复用药物觅药的依赖，包括线索和可卡因引发的药物复用[205‒208]（其他情况见参考文献[190]）。因此，尽管存在一些差异，但大多数结果表明mGLUR5功能的破坏会减弱服药、觅药或其他成瘾相关行为。

上述讨论的mGLUR5功能破坏通过整体敲除或药物抑制实现，这些方法会影响所有细胞类型（包括神经元和星形胶质细胞）中的mGLUR5。最近针对神经元mGLUR5的一项研究表明，NAc D1型多巴胺受体的中棘神经元（D1-MSN）中选择性敲除mGLUR5对线索引发的恢复寻找可卡因的影响低于非特异性药物抑制，而对自身给药或戒断则没有影响[209]。这些结果提示星形胶质细胞mGLUR5可能与神经元mGLUR5协同作用以调节线索相关药物记忆。此外，在发育过程中，星形胶质细胞mGLUR5调控星形胶质细胞和相邻兴奋性突触的功能成熟度[188]，而星形胶质细胞mGLUR5的上调引发TSP1释放和成年期新兴奋性突触的形成[187,198]。如前所述，星形胶质细胞分泌的TSP2及其神经元α2δ1受体促成NAc中因可卡因相关的突触的形成，这些突触经历动态变化，调节可卡因戒断后线索相关可卡因记忆的演变[61]。有趣的是，可卡因自身给药和戒断增加了NAc核心TSP1和α2δ1的表达，但在恢复用药前服用加巴喷丁并未影响线索引发的觅药行为[63]。这些结果表明，TSP1/2-α2δ1信号通路是线索相关药物记忆形成的必要条件，但不是线索相关药物记忆行为表达所需的条件。根据上述神经再生假说[58]，假设用药经历会重新激活发育机制以产生持久的细胞适应，我们有必要研究星形胶质细胞mGLUR5是否有助于药物引发的突触生成。

4.2 D1R

NAc中D1型和D2型多巴胺受体是调节细胞类型特异性谷氨酸能适应的基础，这些适应与促进药物寻求的药物记忆和线索记忆有关[8‒9]。在NAc [110]、尾状壳核（背侧纹状体）[210]和大脑皮层[210‒213]中检测到不同表达情况的D1R蛋白。在急性NAc切片中，星形胶质细胞通过多个D1R对多巴胺能末梢进行光遗传学刺激而增加内部钙离子水平[110]。然而，在前额叶皮层（PFC），星形胶质细胞似乎并非通过多个D1R，而是通过Gq偶联的α1-肾上腺素能受体对多巴胺做出反应[214]，这表明星形胶质细胞多巴胺D1Rs在不同大脑区域具有异质功能。在神经元中，D1Rs通常被认为是Gs偶联的GPCR，通过激活腺苷酸环化酶来增加环磷酸腺苷活性[215]。然而，星形胶质细胞中D1R介导的钙离子活性依赖于IP3R2，表明Gq信号通路参与其中[110,216‒217]。因此，Gq-Ca2+通路可能是星形胶质细胞D1R信号传导的主要介质。此外，D1Rs不仅能单独发挥作用，还可与星形胶质细胞中的其他GPCR一起作为异二聚体发挥作用。例如，已有研究表明D1R可在细胞培养过程中与肾上腺素能受体形成异二聚体[218‒221]，并在皮质神经元中出现了这些受体的共定位现象[222]。该受体-受体相互作用被认为是星形胶质细胞中多巴胺受体的一个关键特征，但仍有待实验检验[223]。

进行可卡因自身给药后，NAc星形胶质细胞的基础活性水平降低[224]，这可能是可卡因戒断后多巴胺水平失调的结果[225‒226]。在脑切片中，急性多巴胺暴露（通过对VTA末梢的光遗传学刺激或浸泡）增加了NAc星形胶质细胞中钙离子事件的发生概率[61,110]。虽然强有力的证据表明，多巴胺诱导的星形胶质细胞钙离子活性由D1Rs介导，但星形胶质细胞中D1Rs基因敲除提高了钙离子事件的基础水平[110]，这说明星形胶质细胞D1R在NAc中具有复杂的功能。尽管如此，近期研究揭示了D1R引发的星形胶质细胞活性在NAc中的关键性功能意义[110,227]。具体而言，星形胶质细胞D1R-IP3（即多巴胺D1受体-三磷酸肌醇）的信号转导激活引发腺苷释放，进而激活相邻突触前神经末梢上的A1受体，导致谷氨酸能向NAc中MSN传递减弱（图1）。就行为而言，星形胶质细胞IP3R2或D1R功能缺失的小鼠对苯丙胺行为敏感性减弱，表明星形胶质细胞D1R在药物引发的神经可塑性和相关行为的发展中发挥作用。

5 结语

过去数十年来，神经科学领域在星形胶质细胞如何影响行为的整体认知方面已取得巨大进展。在成像技术和星形胶质细胞特异性工具快速发展的助力下，目前已能通过全新视角重新检验和桥接过往成果。随着脑切片和体内操纵星形胶质细胞功能技术日益完善，我们将更深入了解神经元和星形胶质细胞之间基本生物成分（如GPCR）的差异。这些新信息将有助于我们进一步理解SUD等脑部功能紊乱，更将为开发创新疗法开辟道路。

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