奖励系统

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奖励系统是一组神经结构，负责激励显著性（即动机和“想要”，渴望或渴望获得奖励），联想学习（主要是积极强化和经典条件反射），以及积极效应的情绪，特别是它将快乐作为核心组成部分（例如，欢乐，欣快和狂喜）。[1] [6]奖励是刺激的吸引力和动机属性，诱导食欲行为，也称为接近行为和完成行为。[1]在对奖励刺激（即“奖励”）的描述中，对奖励神经科学的评论指出，“任何有可能使我们接近并消费它的刺激，对象，事件，活动或情况是定义的奖励。“[1]在操作条件反射中，奖励刺激作为积极的强化物; [1]然而，相反的说法也是正确的：积极强化者是有益的。[1]

初级奖励是一类奖励刺激，促进自我和后代的生存，包括稳态（例如，可口的食物）和生殖（例如，性接触和父母投资）奖励。[1] [7]内在奖励是无条件的奖励，具有吸引力并激励行为，因为它们本身就是令人愉快的。[1]外在奖励（例如，金钱或看到一个人最喜欢的运动队赢得一场比赛）是有条件的奖励，这些奖励具有吸引力和激励行为，但本身并不令人愉快。[1] [8]外在奖励是由于学习的关联（即条件反射）与内在奖励而产生的动机价值。[1]在经典的内在奖励条件下，外在奖励也可以引发快乐（例如，在彩票中赢得大量金钱的兴奋）。[1]

大多数动物物种的生存取决于最大化与有益刺激的接触并最小化与有害刺激的接触。奖励认知通过引起联想学习，引出方法和完成行为以及触发积极效果的情绪来增加生存和繁殖的可能性。[1]因此，奖励是一种进化的机制，有助于提高动物的适应性。[9]


水


食物


性


父母照顾

成瘾和依赖词汇表[2] [3] [4] [5]
成瘾 - 一种脑功能紊乱，其特点是尽管有不良后果，但仍有强迫性参与奖励刺激
令人上瘾的行为 - 一种既有益又有益的行为
令人上瘾的药物 - 一种既有益又有益的药物
依赖性 - 在停止反复接触刺激（例如药物摄入）后与戒断综合征相关的适应性状态
药物致敏或反向耐受 - 在给定剂量下重复给药导致药物升高的作用
停药 - 停止反复使用药物后出现的症状
身体依赖 - 涉及持续的身体 - 躯体戒断症状的依赖（例如，疲劳和谵妄震颤）
心理依赖 - 涉及情绪 - 动机戒断症状的依赖（例如，烦躁不安和快感缺乏症）
强化刺激 - 刺激，增加重复行为的可能性
奖励刺激 - 大脑解释为内在积极和可取的刺激或接近的刺激
致敏 - 对反复接触刺激引起的刺激的放大反应
物质使用障碍 - 使用物质导致临床和功能上显着的损害或痛苦的情况
耐受性 - 在给定剂量下重复给药导致的药物减少效果

目录
1 定义
2 解剖
2.1 娱乐中心
2.2 需求
2.3 动物与人类
3 学习
4 历史
5 临床意义
5.1 成瘾
5.2 动机
5.2.1 情绪障碍
5.2.2 精神分裂症
6 参考

定义
在神经科学中，奖励系统是大脑结构和神经通路的集合，负责与奖励相关的认知，包括联想学习（主要是经典调节和操作强化），激励突显（即动机和“想要”，欲望或渴望获得奖励）和积极的价值情绪，特别是涉及快乐的情绪（即享乐“喜欢”）。[1] [6]

通常用于描述与奖励的“缺乏”或欲望组成部分相关的行为的术语包括食欲行为，接近行为，预备行为，工具行为，预期行为和寻求。[10]通常用于描述与奖励的“喜欢”或愉悦成分相关的行为的术语包括完成行为和采取行为。[10]

奖励的三个主要功能是：

产生联想学习（即经典条件反射和操作强化）; [1]
影响决策和诱导接近行为（通过将动机显着性分配给奖励刺激）; [1]
引起积极的情感，特别是快乐。[1]

解剖学
构成奖励系统的大脑结构主要位于皮质 - 基底神经节 - 丘脑 - 皮质环内; [11]环的基底神经节部分驱动奖励系统内的活动。[11]连接奖励系统内结构的大多数途径是谷氨酸能中间神经元，GABA能中型多刺神经元（MSNs）和多巴胺能投射神经元，[11] [12]尽管其他类型的投射神经元有贡献（例如，食欲素投射神经元）。奖励系统包括腹侧被盖区域，腹侧纹状体（即伏隔核和嗅结节），背侧纹状体（即尾状核和壳核），黑质（即，压缩和网状），前额皮质，前扣带皮层，岛叶皮层，海马，下丘脑（特别是下丘脑外侧的orexinergic核），丘脑（多核），丘脑底核，苍白球（外部和内部），腹侧苍白球，臂旁核，杏仁核，以及扩展杏仁核的其余部分。[6] [11] [13] [14] [15]中缝背核和小脑似乎调节某些形式的奖赏相关认知（即联想学习，动机显着性和积极情绪）和行为。[16] [17] [18]后侧背节核（LTD），小脑桥脑核（PPTg）和侧缰（LHb）（直接和间接通过内侧肌腱核）也能够通过它们对腹侧被盖区域的投射诱导厌恶显着性和激励显着性（ VTA）。[19] LDT和PPTg都向多巴胺能神经元突触的VTA发送谷氨酸能神经投射，这两者都可以产生激励显着性。 LHb发送谷氨酸能神经元投射，其中大部分是突触GABAergic RMTg神经元，反过来驱动多巴胺能VTA神经元的抑制，尽管一些LHb预测终止于VTA中间神经元。这些LHb预测既可以通过厌恶刺激激活，也可以通过没有预期的奖励激活，激发LHb可以诱发厌恶。[20] [21] [22]

突出于腹侧被盖区域的大多数多巴胺途径（即使用神经递质多巴胺与其他神经元通信的神经元）是奖励系统的一部分; [11]在这些途径中，多巴胺作用于D1样受体或D2样受体刺激（D1样）或抑制（D2样）cAMP的产生。[23]纹状体的GABAergic中型多刺神经元也是奖励系统的组成部分。[11]丘脑底核，前额叶皮层，海马，丘脑和杏仁核中的谷氨酸能投射核通过谷氨酸途径连接到奖励系统的其他部分。[11]内侧前脑束是一组调节脑刺激奖励的许多神经通路（即来自外侧下丘脑的直接电化学刺激的奖励），也是奖励系统的一个组成部分。[24]

关于伏隔核的活动和生成喜欢和想要的两种理论存在。抑制（或超极化）假说提出伏隔核对下腹部结构如腹侧苍白球，下丘脑或腹侧被盖区域施加强直抑制作用，并且在抑制伏隔核（NAcc）中的MSN中，这些结构被激发，“发布“奖励相关行为”。虽然GABA受体激动剂能够引起伏隔核中的“喜欢”和“缺乏”反应，但来自基底外侧杏仁核，腹侧海马和内侧前额叶皮质的谷氨酸能输入可以激发诱因显着。此外，虽然大多数研究发现NAcc神经元减少了对奖励的反应，但许多研究发现相反的反应。这导致了去抑制（或去极化）假设的提议，该假设提出激发或NAcc神经元，或至少某些子集，驱动奖励相关行为。[6] [25] [26]

经过近50年的脑刺激奖励研究，专家们已经证实，大脑中的数十个部位将维持颅内自我刺激。区域包括外侧下丘脑和内侧前脑束，其特别有效。那里的刺激激活了形成上升通路的纤维;上行通路包括中脑边缘多巴胺通路，其从腹侧被盖区突出到伏隔核。关于为什么中脑边缘多巴胺途径是介导奖赏的电路的核心，有几种解释。首先，当动物参与颅内自我刺激时，中脑边缘通路中的多巴胺释放明显增加。[9]其次，实验一致表明，脑刺激奖励刺激通常由自然奖励激活的通路的强化，药物奖励或颅内自我刺激可以发挥更强大的中央奖励机制激活，因为它们直接激活奖励中心而不是通过周围神经。[9] [27] [28]第三，当给动物服用成瘾药物或从事自然有益的行为时，例如喂养或性活动，伏隔核内的多巴胺有明显的释放。[9]然而，多巴胺不是大脑中唯一的奖励化合物。

游乐中心
快乐是奖励的一个组成部分，但并非所有奖励都是令人愉快的（例如，除非这种反应受到限制，否则金钱不会引起快乐）。[1]自然愉悦且因此具有吸引力的刺激被称为内在奖励，而有吸引力且激发接近行为但不具有内在愉悦感的刺激被称为外在奖励。[1]外在奖励（例如金钱）是由于学会了与内在奖励的关联而得到回报。[1]换句话说，外在奖励作为激励磁铁起作用，引起“缺乏”，但一旦被获得就不会“喜欢”反应。[1]

奖励系统包含快乐中心或享乐热点 - 即，介导快乐或从内在奖励中“喜欢”反应的大脑结构。截至2017年10月，已经在伏隔核壳，腹侧苍白球，臂旁核，眶额皮质（OFC）和岛叶皮层的子室中发现了特征性热点。[6] [15] [29]伏隔核壳内的热点位于内侧壳的背斜象限，而快感的冷点位于更后部的区域。后腹侧苍白球还含有特征性热点，而前腹侧苍白球则含有特征性的感冒。阿片类药物，内源性大麻素和食欲素的微量注射能够增强这些热点的喜好。[6]位于OFC前部和后岛叶的特征性热点已被证实对食欲素和阿片类药物有反应，前岛叶和后OFC的重叠享乐感冒也是如此。[29]另一方面，仅有证实臂旁核热点对苯二氮卓受体激动剂有反应[6]。

特征性热点在功能上是相关的，因为一个热点的激活导致其他热点的募集，如通过立即早期基因的c-Fos的诱导表达所指示的。 此外，抑制一个热点会导致激活另一个热点的效果变钝。[6] [29] 因此，奖励系统内每个特征热点的同时激活被认为是产生强烈欣快感的必要条件。[30]

需求
主要文章：激励显著性


调整伏核中的食欲和防御反应。 （上图）AMPA封锁需要D1功能，以产生动机行为，无论价格如何，D2功能产生防御行为。另一方面，GABA激动不需要多巴胺受体功能。（下图）在压力下产生防御行为的解剖区域的扩展，以及由AMPA拮抗作用产生的家庭环境中的食欲行为。 GABA激动作用下这种灵活性不太明显。[25]
激励显着性是“缺乏”或“欲望”属性，其包括一个激励成分，由伏隔核壳（NAcc shell）分配给奖励刺激。[1] [31] [32]从中脑边缘通路进入NAcc壳的多巴胺神经传递程度与奖励刺激的激励显着程度高度相关。[31]

伏隔核的背腹侧区域的激活与想要的增加相关，而没有同时增加的喜好。[33]然而，伏隔核外壳中的多巴胺能神经传递不仅对于奖励刺激的食欲动机显著性（即激励显著性）负责，而且还对厌恶动机显著性负责，这种突显性指导行为远离不良刺激。[34] [35] [36] ]在背侧纹状体中，表达D1的MSN的激活产生食欲激励显著性，而表达D2的MSN的激活产生厌恶。在NAcc中，这种二分法并不是那么明确，D1和D2 MSN的激活足以增强动力，[37] [38]可能通过抑制腹侧苍白球来抑制VTA [39] [40]。

罗宾逊和贝里奇的激励致敏理论（1993）提出，奖励包含可分离的心理成分：想要（激励）和喜欢（快乐）。为了解释与巧克力等特定刺激物的接触增加，有两个独立的因素在起作用 - 我们渴望获得巧克力（想要）和巧克力的喜悦效果（喜欢）。根据罗宾逊和贝里奇的说法，想要和喜欢是同一过程的两个方面，所以奖励通常是想要和喜欢的程度相同。然而，在某些情况下，想要和喜欢也会独立变化。例如，在接受多巴胺（经历对食物的欲望丧失）后不进食的大鼠表现得好像他们仍然喜欢食物。在另一个例子中，大鼠外侧下丘脑中的激活的自我刺激电极增加食欲，但也引起对诸如糖和盐的味道的更多不良反应;显然，刺激增加了想要但不喜欢。这些结果表明我们的奖励系统包括独立的想要和喜欢的过程。想要的成分被认为是由多巴胺能通路控制，而喜欢的成分被认为是由阿片 - 苯二氮卓系统控制的。[9]

动物与人类
动物很快学会按压棒，直接注射到中脑tegmentum或伏隔核中。如果中脑边缘通路的多巴胺能神经元失活，则相同的动物不能获得阿片类药物。从这个角度来看，动物和人类一样，会参与增加多巴胺释放的行为。

情感神经科学研究员肯特贝里奇发现甜味（喜欢）和苦味（不喜欢）的口味产生了明显的口面表达，这些表达同样由人类新生儿，猩猩和大鼠表现出来。这证明了快乐（特别是喜欢）具有客观特征，并且在各种动物物种中基本相同。大多数神经科学研究表明，奖励释放的多巴胺越多，奖励就越有效。这被称为享乐效应，可以通过奖励和奖励本身的努力来改变。 Berridge发现阻断多巴胺系统似乎并没有改变对甜食的积极反应（通过面部表情来衡量）。换句话说，享乐的影响并没有根据糖的量而改变。这打破了多巴胺介导快乐的传统假设。即使有更强烈的多巴胺改变，数据似乎仍然保持不变。[41]然而，从2019年1月开始的一项临床研究评估了多巴胺前体（左旋多巴），拮抗剂（利培酮）和安慰剂对音乐奖励反应的影响 - 包括音乐发冷期间的愉悦程度，通过电子皮肤的变化来衡量活动以及主观评价 - 发现多巴胺神经传递的操纵双向调节人类受试者的快感认知（特别是音乐的快感影响）。[42] [需要非主要来源]这项研究表明增加的多巴胺神经传递作用对人类音乐产生愉悦的享乐反应的必要条件。[42] [需要非主要来源]

Berridge提出了激励显著性假设来解决奖励的缺乏方面。它解释了吸毒成瘾者强迫使用药物，即使药物不再产生欣快感，甚至在个体完成戒断后也会出现这种渴望。一些成瘾者对某些涉及药物引起的神经变化的刺激作出反应。大脑中的这种致敏作用类似于多巴胺的作用，因为发生了想要和喜欢的反应。人类和动物的大脑和行为在奖励系统方面经历了类似的变化，因为这些系统非常突出。[41]

学习
更多信息：联想学习
奖励刺激可以以经典调节（巴甫洛夫调理）和操作调节（器乐调节）的形式推动学习。在经典条件反射中，奖励可以作为无条件刺激，当与条件刺激相关时，导致条件刺激引发肌肉骨骼（以简单方法和避免行为的形式）和植物反应。在操作性条件反射中，奖励可以作为强化者，因为它增加或支持导致自身的行为。[1]学习过的行为可能会或可能不会对他们所导致的结果的价值敏感;对行动表现的结果的偶然性敏感的行为以及结果价值是目标导向的，而对意外事件或价值不敏感的引发行为则称为习惯。[43]这种区别被认为反映了两种学习形式，即模型自由和基于模型。模型免费学习涉及简单的缓存和值更新。相比之下，基于模型的学习涉及存储和构建事件的内部模型，其允许推理和灵活预测。虽然通常认为pavlovian条件是无模型的，但对于条件刺激的激励显着性在内部动机状态的变化方面是灵活的。[44]

不同的神经系统负责学习刺激和结果，行为和结果，刺激和反应之间的关联。尽管经典条件反射不仅限于奖励系统，但是通过刺激（即，巴甫洛夫 - 乐器转移）增强乐器演奏需要伏隔核。习惯性和目标导向的器械学习分别取决于外侧纹状体和内侧纹状体。[43]

在仪器学习期间，AMPA与NMDA受体和磷酸化ERK比率的相反变化分别发生在构成直接和间接途径的D1型和D2型MSN中[45] [46]。突触可塑性和伴随学习的这些变化取决于纹状体D1和NMDA受体的激活。由D1受体激活的细胞内级联涉及蛋白激酶A的募集，并且通过DARPP-32的磷酸化，抑制使ERK失活的磷酸酶。 NMDA受体通过不同但相互关联的Ras-Raf-MEK-ERK途径激活ERK。单独的NMDA介导的ERK活化是自限性的，因为NMDA活化也抑制PKA介导的ERK失活磷酸酶的抑制。然而，当D1和NMDA级联共激活时，它们协同作用，ERK的激活以脊柱重组，AMPA受体转运，CREB调节和通过抑制Kv4.2增加细胞兴奋性的形式调节突触可塑性。 [47] [48] [49]

历史


斯金纳盒子
大脑中存在奖励系统的第一个线索是詹姆斯·奥尔兹和彼得·米尔纳于1954年发现的现象。他们发现老鼠会执行诸如按压棒的行为，对特定的电刺激进行短暂的爆发他们的大脑中的网络。这种现象称为颅内自我刺激或脑刺激奖励。通常，老鼠每小时会按下杠杆数百或数千次来获得这种大脑刺激，只有当它们筋疲力尽时才会停止。在试图教老鼠如何解决问题和运行迷宫时，刺激发现刺激的大脑某些区域似乎给动物带来了快乐。他们尝试与人类相同的事情，结果是相似的。动物为什么参与对自身或物种的生存没有价值的行为的解释是，大脑刺激正在激活奖励制度。[50]

在1954年的一项基本发现中，研究人员詹姆斯·奥尔兹和彼得·米尔纳发现，大鼠大脑某些区域的低压电刺激可以作为教导动物运行迷宫并解决问题的奖励。[51] [52] ]似乎刺激大脑的那些部分给了动物快乐，[51]并且在后来的工作中，人类报告了这种刺激带来的愉悦感觉。当大鼠在Skinner盒中进行测试时，他们可以通过按下杠杆来刺激奖励系统，老鼠按压了几个小时。[52]在接下来的二十年中的研究表明，多巴胺是这些地区帮助神经信号传导的主要化学物质之一，多巴胺被认为是大脑的“快感化学物质”。[53]

伊万巴甫洛夫是一名心理学家，他使用奖励系统来研究经典调理。巴甫洛夫在听到钟声或其他刺激声之后，通过奖励狗的食物奖励系统。巴甫洛夫奖励这些狗，以便狗与食物，奖励，铃铛，刺激物相关联。[54] Edward L. Thorndike使用奖励系统来研究操作性条件反射。他开始把猫放在一个拼图盒里，把食物放在盒子外面让猫想要逃跑。这些猫努力摆脱拼图盒来获取食物。虽然猫在逃离盒子后吃了食物，但是桑迪克得知猫试图在没有食物奖励的情况下逃离盒子。桑代克利用食物和自由的奖励来刺激猫的奖励系统。桑迪克用这个来看看猫是如何学会逃离这个盒子的。[55]

临床意义
成瘾
主要文章：成瘾
ΔFosB（DeltaFosB） - 一种基因转录因子 - 在伏隔核的D1型中型多刺神经元中的过表达是导致成瘾相关行为的几乎所有形式的成瘾（即行为成瘾和药物成瘾）中的关键共同因素。神经可塑性。[3] [56] [57] [58]特别是，ΔFosB促进自我管理，奖励致敏，并奖励特定成瘾药物和行为之间的交叉致敏作用。[3] [56] [57] [59] [60]在脑的特定区域中，组蛋白蛋白质尾部（即组蛋白修饰）的某些表观遗传修饰也已知在成瘾的分子基础中起关键作用。[58] [61] [62] [63]

由于它们对多巴胺奖赏途径的影响，成瘾药物和行为是有益的和加强的（即上瘾）。[14] [64]

外侧下丘脑和内侧前脑束是最常被研究的脑刺激奖励部位，特别是在研究药物对脑刺激奖励的影响方面。[65]最明确的滥用药物习惯形成行为的神经递质系统是中脑边缘多巴胺系统，其伏隔核及其局部GABAergic传入的传出靶标。苯丙胺和可卡因的奖赏相关作用是伏隔核和内侧前额叶皮质的多巴胺能突触。大鼠还学会通过杠杆压力将可卡因注射到内侧前额叶皮质中，这可以通过增加伏隔核中的多巴胺转换来起作用[66] [67]。直接注入伏核中的尼古丁也会增强局部多巴胺的释放，可能是由于该区域多巴胺能末端的突触前作用。烟碱受体定位于多巴胺能细胞体和局部尼古丁注射增加多巴胺能细胞的发射，这对于烟碱奖励至关重要。[68] [69]尽管激活多巴胺能预测，一些额外的形成习惯的药物也可能减少中型多刺神经元的输出。对于鸦片制剂，奖励效应的最低阈值位点涉及对腹侧被盖区域中GABA能神经元的作用，腹侧被盖区域是对伏核的中等多刺输出神经元的鸦片剂奖赏动作的次要部位。因此，以下形成了目前表征的药物奖励电路的核心; GABAergic传入中脑边缘多巴胺神经元（鸦片剂奖赏的主要底物），中脑边缘多巴胺神经元本身（精神运动兴奋剂奖励的主要基质），以及中脑边缘多巴胺神经元的GABAergic传出（鸦片剂奖励的次要部位）。[65]

动机
主要文章：励志显著性
功能失调的动机显著性出现在许多精神症状和障碍中。 Anhedonia，传统上被定义为减少感受到快感的能力，因为大多数的渐近人群都表现出完整的“喜欢”，因此被重新审视为反映迟钝的激励显著性。[70] [71]另一方面，针对特定刺激而缩小的激励突显性是行为和吸毒成瘾的特征。在恐惧或偏执的情况下，功能障碍可能在于厌恶的突然性。[72]

与快感缺乏相关的诊断的神经影像学研究报告，OFC和腹侧纹状体的活动减少。[73]一项meta分析报告，在断尾核，壳核，伏隔核和内侧前额叶皮层（mPFC）中，急性心肌炎与神经反应减少有关。

情绪障碍
抑郁与动机减少有关，正如通过奖励努力的意愿所评估的那样。这些异常暂时与纹状体区域的活动减少有关，虽然假设多巴胺能异常发挥作用，但大多数研究探测抑郁症中的多巴胺功能已报告不一致的结果。[75] [76]虽然尸检和神经影像学研究发现奖励系统的许多区域存在异常，但很少有研究结果得到一致反复。一些研究报道在与奖赏或阳性刺激相关的任务期间，NAcc，海马，内侧前额叶皮质（mPFC）和眶额皮质（OFC）活动减少，以及基底外侧杏仁核和亚扣带皮质（sgACC）活动升高。这些神经影像学异常可以通过很少的验尸研究来证实，但是很少有研究表明mPFC中的兴奋性突触减少了。[77]在奖励相关任务期间，mPFC中的活性降低似乎局限于更多的背部区域（即，前期扣带皮层），而腹侧sgACC在抑郁症中过度活跃[78]。

试图研究动物模型中潜在的神经回路也产生了相互矛盾的结果。两种范式通常用于模拟抑郁症，慢性社交失败（CSDS）和慢性轻度压力​​（CMS），尽管存在许多范例。 CSDS降低了对蔗糖的偏好，减少了社交相互作用，并增加了强迫游泳测试中的不动性。 CMS通过尾部悬浮和强迫游泳测试评估，同样降低了蔗糖偏好和行为绝望。对CSDS敏感的动物表现出增加的阶段性VTA发作，并且VTA-NAcc预测的抑制减弱了由CSDS诱导的行为缺陷[79]。然而，抑制VTA-mPFC预测会加剧社交退缩。另一方面，CMS相关的蔗糖偏好和不动性的降低分别通过VTA激发和抑制而减弱和加剧[80] [81]。虽然这些差异可能归因于不同的刺激方案或不良的翻译范式，但可变结果也可能存在于奖励相关区域的异质功能中。[82]

整个mPFC的光遗传学刺激产生抗抑郁作用。这种效应似乎局限于pgACC（前肢皮质）的啮齿动物同源物，因为对sgACC（infralimbic cortex）的啮齿动物同源物的刺激不产生行为效应。此外，被认为具有抑制作用的infralimbic皮层中的深部脑刺激也产生抗抑郁作用。这一发现与下肢内侧皮质的药理学抑制减弱抑郁行为的观察结果一致。[82]

精神分裂症
精神分裂症与动机缺陷有关，通常归入其他消极症状，如自发性言语减少。虽然结果可能特定于某些刺激，例如金钱奖励，但“喜欢”的经历经常被报道为完整的[83]，无论是行为上还是神经上的。[84]此外，精神分裂症中的内隐学习和简单的奖励相关任务也是完整的。[85]相反，奖励系统中的缺陷存在于认知复杂的奖励相关任务中。这些缺陷与纹状体异常和OFC活动以及与背外侧前额皮质（dlPFC）等认知功能相关的区域异常有关[86]。

另见：
Abusive power and control
Carrot and stick
Child grooming
Compliance (psychology)
Frisson
Motivation
Norm of reciprocity
Palatability
Pavlovian-instrumental transfer
Psychological manipulation

参考：
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Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.
Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
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Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
Berridge KC, Kringelbach ML (May 2015). "Pleasure systems in the brain". Neuron. 86 (3): 646–664. doi:10.1016/j.neuron.2015.02.018. PMC 4425246. PMID 25950633. In the prefrontal cortex, recent evidence indicates that the [orbitofrontal cortex] OFC and insula cortex may each contain their own additional hot spots (D.C. Castro et al., Soc. Neurosci., abstract). In specific subregions of each area, either opioid-stimulating or orexin-stimulating microinjections appear to enhance the number of liking reactions elicited by sweetness, similar to the [nucleus accumbens] NAc and [ventral pallidum] VP hot spots. Successful confirmation of hedonic hot spots in the OFC or insula would be important and possibly relevant to the orbitofrontal mid-anterior site mentioned earlier that especially tracks the subjective pleasure of foods in humans (Georgiadis et al., 2012; Kringelbach, 2005; Kringelbach et al., 2003; Small et al., 2001; Veldhuizen et al., 2010). Finally, in the brainstem, a hindbrain site near the parabrachial nucleus of dorsal pons also appears able to contribute to hedonic gains of function (Söderpalm and Berridge, 2000). A brainstem mechanism for pleasure may seem more surprising than forebrain hot spots to anyone who views the brainstem as merely reflexive, but the pontine parabrachial nucleus contributes to taste, pain, and many visceral sensations from the body and has also been suggested to play an important role in motivation (Wu et al., 2012) and in human emotion (especially related to the somatic marker hypothesis) (Damasio, 2010).
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Yager LM, Garcia AF, Wunsch AM, Ferguson SM (August 2015). "The ins and outs of the striatum: Role in drug addiction". Neuroscience. 301: 529–541. doi:10.1016/j.neuroscience.2015.06.033. PMC 4523218. PMID 26116518. [The striatum] receives dopaminergic inputs from the ventral tegmental area (VTA) and the substantia nigra (SNr) and glutamatergic inputs from several areas, including the cortex, hippocampus, amygdala, and thalamus (Swanson, 1982; Phillipson and Griffiths, 1985; Finch, 1996; Groenewegen et al., 1999; Britt et al., 2012). These glutamatergic inputs make contact on the heads of dendritic spines of the striatal GABAergic medium spiny projection neurons (MSNs) whereas dopaminergic inputs synapse onto the spine neck, allowing for an important and complex interaction between these two inputs in modulation of MSN activity ... It should also be noted that there is a small population of neurons in the [nucleus accumbens] NAc that coexpress both D1 and D2 receptors, though this is largely restricted to the NAc shell (Bertran- Gonzalez et al., 2008). ... Neurons in the NAc core and NAc shell subdivisions also differ functionally. The NAc core is involved in the processing of conditioned stimuli whereas the NAc shell is more important in the processing of unconditioned stimuli; Classically, these two striatal MSN populations are thought to have opposing effects on basal ganglia output. Activation of the dMSNs causes a net excitation of the thalamus resulting in a positive cortical feedback loop; thereby acting as a 'go’ signal to initiate behavior. Activation of the iMSNs, however, causes a net inhibition of thalamic activity resulting in a negative cortical feedback loop and therefore serves as a 'brake’ to inhibit behavior ... there is also mounting evidence that iMSNs play a role in motivation and addiction (Lobo and Nestler, 2011; Grueter et al., 2013). For example, optogenetic activation of NAc core and shell iMSNs suppressed the development of a cocaine CPP whereas selective ablation of NAc core and shell iMSNs ... enhanced the development and the persistence of an amphetamine CPP (Durieux et al., 2009; Lobo et al., 2010). These findings suggest that iMSNs can bidirectionally modulate drug reward. ... Together these data suggest that iMSNs normally act to restrain drug-taking behavior and recruitment of these neurons may in fact be protective against the development of compulsive drug use.
Taylor SB, Lewis CR, Olive MF (2013). "The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans". Subst Abuse Rehabil. 4: 29–43. doi:10.2147/SAR.S39684. PMC 3931688. PMID 24648786. Regions of the basal ganglia, which include the dorsal and ventral striatum, internal and external segments of the globus pallidus, subthalamic nucleus, and dopaminergic cell bodies in the substantia nigra, are highly implicated not only in fine motor control but also in [prefrontal cortex] PFC function.43 Of these regions, the [nucleus accumbens] NAc (described above) and the [dorsal striatum] DS (described below) are most frequently examined with respect to addiction. Thus, only a brief description of the modulatory role of the basal ganglia in addiction-relevant circuits will be mentioned here. The overall output of the basal ganglia is predominantly via the thalamus, which then projects back to the PFC to form cortico-striatal-thalamo-cortical (CSTC) loops. Three CSTC loops are proposed to modulate executive function, action selection, and behavioral inhibition. In the dorsolateral prefrontal circuit, the basal ganglia primarily modulate the identification and selection of goals, including rewards.44 The [orbitofrontal cortex] OFC circuit modulates decision-making and impulsivity, and the anterior cingulate circuit modulates the assessment of consequences.44 These circuits are modulated by dopaminergic inputs from the [ventral tegmental area] VTA to ultimately guide behaviors relevant to addiction, including the persistence and narrowing of the behavioral repertoire toward drug seeking, and continued drug use despite negative consequences.43–45
Grall-Bronnec M, Sauvaget A (2014). "The use of repetitive transcranial magnetic stimulation for modulating craving and addictive behaviours: a critical literature review of efficacy, technical and methodological considerations". Neurosci. Biobehav. Rev. 47: 592–613. doi:10.1016/j.neubiorev.2014.10.013. PMID 25454360. Studies have shown that cravings are underpinned by activation of the reward and motivation circuits (McBride et al., 2006, Wang et al., 2007, Wing et al., 2012, Goldman et al., 2013, Jansen et al., 2013 and Volkow et al., 2013). According to these authors, the main neural structures involved are: the nucleus accumbens, dorsal striatum, orbitofrontal cortex, anterior cingulate cortex, dorsolateral prefrontal cortex (DLPFC), amygdala, hippocampus and insula.
Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 365–366, 376. ISBN 978-0-07-148127-4. The neural substrates that underlie the perception of reward and the phenomenon of positive reinforcement are a set of interconnected forebrain structures called brain reward pathways; these include the nucleus accumbens (NAc; the major component of the ventral striatum), the basal forebrain (components of which have been termed the extended amygdala, as discussed later in this chapter), hippocampus, hypothalamus, and frontal regions of cerebral cortex. These structures receive rich dopaminergic innervation from the ventral tegmental area (VTA) of the midbrain. Addictive drugs are rewarding and reinforcing because they act in brain reward pathways to enhance either dopamine release or the effects of dopamine in the NAc or related structures, or because they produce effects similar to dopamine. ... A macrostructure postulated to integrate many of the functions of this circuit is described by some investigators as the extended amygdala. The extended amygdala is said to comprise several basal forebrain structures that share similar morphology, immunocytochemical features, and connectivity and that are well suited to mediating aspects of reward function; these include the bed nucleus of the stria terminalis, the central medial amygdala, the shell of the NAc, and the sublenticular substantia innominata.
Richard JM, Castro DC, Difeliceantonio AG, Robinson MJ, Berridge KC (November 2013). "Mapping brain circuits of reward and motivation: in the footsteps of Ann Kelley". Neurosci. Biobehav. Rev. 37 (9 Pt A): 1919–1931. doi:10.1016/j.neubiorev.2012.12.008. PMC 3706488. PMID 23261404.
Figure 3: Neural circuits underlying motivated 'wanting' and hedonic 'liking'.
Luo M, Zhou J, Liu Z (August 2015). "Reward processing by the dorsal raphe nucleus: 5-HT and beyond". Learn. Mem. 22 (9): 452–460. doi:10.1101/lm.037317.114. PMC 4561406. PMID 26286655.
Moulton EA, Elman I, Becerra LR, Goldstein RZ, Borsook D (May 2014). "The cerebellum and addiction: insights gained from neuroimaging research". Addict. Biol. 19 (3): 317–331. doi:10.1111/adb.12101. PMC 4031616. PMID 24851284.
Caligiore D, Pezzulo G, Baldassarre G, Bostan AC, Strick PL, Doya K, Helmich RC, Dirkx M, Houk J, Jörntell H, Lago-Rodriguez A, Galea JM, Miall RC, Popa T, Kishore A, Verschure PF, Zucca R, Herreros I (February 2017). "Consensus Paper: Towards a Systems-Level View of Cerebellar Function: the Interplay Between Cerebellum, Basal Ganglia, and Cortex". Cerebellum. 16 (1): 203–229. doi:10.1007/s12311-016-0763-3. PMC 5243918. PMID 26873754.
Ogawa, SK; Watabe-Uchida, M (2 May 2017). "Organization of dopamine and serotonin system: Anatomical and functional mapping of monosynaptic inputs using rabies virus". Pharmacology Biochemistry and Behavior. doi:10.1016/j.pbb.2017.05.001. PMID 28476484.
Morales, M; Margolis, EB (February 2017). "Ventral tegmental area: cellular heterogeneity, connectivity and behaviour". Nature Reviews. Neuroscience. 18 (2): 73–85. doi:10.1038/nrn.2016.165. PMID 28053327.
Lammel, S; Lim, BK; Malenka, RC (January 2014). "Reward and aversion in a heterogeneous midbrain dopamine system". Neuropharmacology. 76 Pt B: 351–9. doi:10.1016/j.neuropharm.2013.03.019. PMC 3778102. PMID 23578393.
Nieh, EH; Kim, SY; Namburi, P; Tye, KM (20 May 2013). "Optogenetic dissection of neural circuits underlying emotional valence and motivated behaviors". Brain Research. 1511: 73–92. doi:10.1016/j.brainres.2012.11.001. hdl:1721.1/92890. PMC 4099056. PMID 23142759.
Trantham-Davidson H, Neely LC, Lavin A, Seamans JK (2004). "Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex". The Journal of Neuroscience. 24 (47): 10652–10659. doi:10.1523/jneurosci.3179-04.2004. PMC 5509068. PMID 15564581.
You ZB, Chen YQ, Wise RA (2001). "Dopamine and glutamate release in the nucleus accumbens and ventral tegmental area of rat following lateral hypothalamic self-stimulation". Neuroscience. 107 (4): 629–639. doi:10.1016/s0306-4522(01)00379-7. PMID 11720786.
Castro, DC; Cole, SL; Berridge, KC (2015). "Lateral hypothalamus, nucleus accumbens, and ventral pallidum roles in eating and hunger: interactions between homeostatic and reward circuitry". Frontiers in Systems Neuroscience. 9: 90. doi:10.3389/fnsys.2015.00090. PMC 4466441. PMID 26124708.
Carlezon WA, Jr; Thomas, MJ (2009). "Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis". Neuropharmacology. 56 Suppl 1: 122–32. doi:10.1016/j.neuropharm.2008.06.075. PMC 2635333. PMID 18675281.
Wise RA, Rompre PP (1989). "Brain dopamine and reward". Annual Review of Psychology. 40: 191–225. doi:10.1146/annurev.ps.40.020189.001203. PMID 2648975.
Wise RA (October 2002). "Brain reward circuitry: insights from unsensed incentives". Neuron. 36 (2): 229–240. doi:10.1016/S0896-6273(02)00965-0. PMID 12383779.
Castro, DC; Berridge, KC (24 October 2017). "Opioid and orexin hedonic hotspots in rat orbitofrontal cortex and insula". Proceedings of the National Academy of Sciences of the United States of America. 114 (43): E9125–E9134. doi:10.1073/pnas.1705753114. PMC 5664503. PMID 29073109. Here, we show that opioid or orexin stimulations in orbitofrontal cortex and insula causally enhance hedonic “liking” reactions to sweetness and find a third cortical site where the same neurochemical stimulations reduce positive hedonic impact.
Kringelbach ML, Berridge KC (2012). "The Joyful Mind" (PDF). Scientific American. 307 (2): 44–45. Bibcode:2012SciAm.307b..40K. doi:10.1038/scientificamerican0812-40. Retrieved 17 January 2017. So it makes sense that the real pleasure centers in the brain – those directly responsible for generating pleasurable sensations – turn out to lie within some of the structures previously identified as part of the reward circuit. One of these so-called hedonic hotspots lies in a subregion of the nucleus accumbens called the medial shell. A second is found within the ventral pallidum, a deep-seated structure near the base of the forebrain that receives most of its signals from the nucleus accumbens. ...
     On the other hand, intense euphoria is harder to come by than everyday pleasures. The reason may be that strong enhancement of pleasure – like the chemically induced pleasure bump we produced in lab animals – seems to require activation of the entire network at once. Defection of any single component dampens the high.
     Whether the pleasure circuit – and in particular, the ventral pallidum – works the same way in humans is unclear.
Berridge KC (April 2012). "From prediction error to incentive salience: mesolimbic computation of reward motivation". Eur. J. Neurosci. 35 (7): 1124–1143. doi:10.1111/j.1460-9568.2012.07990.x. PMC 3325516. PMID 22487042. Here I discuss how mesocorticolimbic mechanisms generate the motivation component of incentive salience. Incentive salience takes Pavlovian learning and memory as one input and as an equally important input takes neurobiological state factors (e.g. drug states, appetite states, satiety states) that can vary independently of learning. Neurobiological state changes can produce unlearned fluctuations or even reversals in the ability of a previously learned reward cue to trigger motivation. Such fluctuations in cue-triggered motivation can dramatically depart from all previously learned values about the associated reward outcome. ... Associative learning and prediction are important contributors to motivation for rewards. Learning gives incentive value to arbitrary cues such as a Pavlovian conditioned stimulus (CS) that is associated with a reward (unconditioned stimulus or UCS). Learned cues for reward are often potent triggers of desires. For example, learned cues can trigger normal appetites in everyone, and can sometimes trigger compulsive urges and relapse in addicts.
Cue-triggered 'wanting’ for the UCS
A brief CS encounter (or brief UCS encounter) often primes a pulse of elevated motivation to obtain and consume more reward UCS. This is a signature feature of incentive salience.
Cue as attractive motivational magnets
When a Pavlovian CS+ is attributed with incentive salience it not only triggers 'wanting’ for its UCS, but often the cue itself becomes highly attractive – even to an irrational degree. This cue attraction is another signature feature of incentive salience ... Two recognizable features of incentive salience are often visible that can be used in neuroscience experiments: (i) UCS-directed 'wanting’ – CS-triggered pulses of intensified 'wanting’ for the UCS reward; and (ii) CS-directed 'wanting’ – motivated attraction to the Pavlovian cue, which makes the arbitrary CS stimulus into a motivational magnet.
Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147–148, 367, 376. ISBN 978-0-07-148127-4. VTA DA neurons play a critical role in motivation, reward-related behavior (Chapter 15), attention, and multiple forms of memory. This organization of the DA system, wide projection from a limited number of cell bodies, permits coordinated responses to potent new rewards. Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). In this example, dopamine modulates the processing of sensorimotor information in diverse neural circuits to maximize the ability of the organism to obtain future rewards. ...
The brain reward circuitry that is targeted by addictive drugs normally mediates the pleasure and strengthening of behaviors associated with natural reinforcers, such as food, water, and sexual contact. Dopamine neurons in the VTA are activated by food and water, and dopamine release in the NAc is stimulated by the presence of natural reinforcers, such as food, water, or a sexual partner. ...
The NAc and VTA are central components of the circuitry underlying reward and memory of reward. As previously mentioned, the activity of dopaminergic neurons in the VTA appears to be linked to reward prediction. The NAc is involved in learning associated with reinforcement and the modulation of motoric responses to stimuli that satisfy internal homeostatic needs. The shell of the NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear to have a greater effect on dopamine release in the shell than in the core of the NAc.
Berridge KC, Kringelbach ML (1 June 2013). "Neuroscience of affect: brain mechanisms of pleasure and displeasure". Current Opinion in Neurobiology. 23 (3): 294–303. doi:10.1016/j.conb.2013.01.017. PMC 3644539. PMID 23375169. For instance, mesolimbic dopamine, probably the most popular brain neurotransmitter candidate for pleasure two decades ago, turns out not to cause pleasure or liking at all. Rather dopamine more selectively mediates a motivational process of incentive salience, which is a mechanism for wanting rewards but not for liking them .... Rather opioid stimulation has the special capacity to enhance liking only if the stimulation occurs within an anatomical hotspot
Salamone JD, Correa M (8 November 2012). "The mysterious motivational functions of mesolimbic dopamine". Neuron. 76 (3): 470–485. doi:10.1016/j.neuron.2012.10.021. ISSN 1097-4199. PMC 4450094. PMID 23141060.
Calipari, ES; Bagot, RC; Purushothaman, I; Davidson, TJ; Yorgason, JT; Peña, CJ; Walker, DM; Pirpinias, ST; Guise, KG; Ramakrishnan, C; Deisseroth, K; Nestler, EJ (8 March 2016). "In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward". Proceedings of the National Academy of Sciences of the United States of America. 113 (10): 2726–31. Bibcode:2016PNAS..113.2726C. doi:10.1073/pnas.1521238113. PMC 4791010. PMID 26831103.
Baliki, MN; Mansour, A; Baria, AT; Huang, L; Berger, SE; Fields, HL; Apkarian, AV (9 October 2013). "Parceling human accumbens into putative core and shell dissociates encoding of values for reward and pain". The Journal of Neuroscience. 33 (41): 16383–93. doi:10.1523/JNEUROSCI.1731-13.2013. PMC 3792469. PMID 24107968.
Soares-Cunha, C; Coimbra, B; Sousa, N; Rodrigues, AJ (September 2016). "Reappraising striatal D1- and D2-neurons in reward and aversion". Neuroscience and Biobehavioral Reviews. 68: 370–386. doi:10.1016/j.neubiorev.2016.05.021. PMID 27235078. Evidence strongly suggests that the canonical view of striatal D1R signalling as pro-reward/reinforcing and D2R signalling as pro-aversive is too simplistic. It is naïve to assume that D1R- and D2R-expressing neurons play completely independent (and con- trasting) roles.
Bamford, NS; Wightman, RM; Sulzer, D (7 February 2018). "Dopamine's Effects on Corticostriatal Synapses during Reward-Based Behaviors". Neuron. 97 (3): 494–510. doi:10.1016/j.neuron.2018.01.006. PMC 5808590. PMID 29420932. Soares-Cunha and coworkers showed that op- togenetic activation of D1R- or D2R-containing SPNs in dorsal striatum both enhance motivation in mice (Soares-Cunha et al., 2016b). Consistent with this, optogenetic inhibition of D2R-con- taining neurons decreases motivation. This study, in agreement with the results obtained with microiontophoresis, suggests that D2R-containing SPNs play a more prominent role in promoting motivation than originally anticipated.
Soares-Cunha, C; Coimbra, B; David-Pereira, A; Borges, S; Pinto, L; Costa, P; Sousa, N; Rodrigues, AJ (23 June 2016). "Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation". Nature Communications. 7: 11829. Bibcode:2016NatCo...711829S. doi:10.1038/ncomms11829. PMC 4931006. PMID 27337658.
Soares-Cunha, Carina; Coimbra, Bárbara; Domingues, Ana Verónica; Vasconcelos, Nivaldo; Sousa, Nuno; Rodrigues, Ana João (19 April 2018). "Nucleus Accumbens Microcircuit Underlying D2-MSN-Driven Increase in Motivation". eNeuro. 5 (2): ENEURO.0386–18.2018. doi:10.1523/ENEURO.0386-18.2018. PMC 5957524. PMID 29780881. Importantly, optogenetic activation of D2-MSN terminals in the VP was sufficient to recapitulate the motivation enhancement. In summary, our data suggests that optogenetic stimulation of NAc D2-MSNs indirectly modulates VTA dopaminergic activity, contributing for increased motivation.
Berridge KC, Kringelbach ML (2008). "Affective neuroscience of pleasure: reward in humans and animals" (PDF). Psychopharmacology. 199 (3): 457–480. doi:10.1007/s00213-008-1099-6. ISSN 0033-3158. PMC 3004012. PMID 18311558. Retrieved 20 October 2012.
Ferreri L, Mas-Herrero E, Zatorre RJ, Ripollés P, Gomez-Andres A, Alicart H, Olivé G, Marco-Pallarés J, Antonijoan RM, Valle M, Riba J, Rodriguez-Fornells A (January 2019). "Dopamine modulates the reward experiences elicited by music". Proceedings of the National Academy of Sciences of the United States of America. doi:10.1073/pnas.1811878116. PMID 30670642. Lay summary – Neuroscience News (24 January 2019). Listening to pleasurable music is often accompanied by measurable bodily reactions such as goose bumps or shivers down the spine, commonly called “chills” or “frissons.” ... Overall, our results straightforwardly revealed that pharmacological interventions bidirectionally modulated the reward responses elicited by music. In particular, we found that risperidone impaired participants’ ability to experience musical pleasure, whereas levodopa enhanced it. ... Here, in contrast, studying responses to abstract rewards in human subjects, we show that manipulation of dopaminergic transmission affects both the pleasure (i.e., amount of time reporting chills and emotional arousal measured by EDA) and the motivational components of musical reward (money willing to spend). These findings suggest that dopaminergic signaling is a sine qua non condition not only for motivational responses, as has been shown with primary and secondary rewards, but also for hedonic reactions to music. This result supports recent findings showing that dopamine also mediates the perceived pleasantness attained by other types of abstract rewards (37) and challenges previous findings in animal models on primary rewards, such as food (42, 43).
Yin, HH; Ostlund, SB; Balleine, BW (October 2008). "Reward-guided learning beyond dopamine in the nucleus accumbens: the integrative functions of cortico-basal ganglia networks". The European Journal of Neuroscience. 28 (8): 1437–48. doi:10.1111/j.1460-9568.2008.06422.x. PMC 2756656. PMID 18793321.
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Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822.
The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. ...
Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a molecular switch (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.
Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."
Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers"
Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Ann. Agric. Environ. Med. 19 (3): 491–496. PMID 23020045. For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken ... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription
Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". The Journal of Neuroscience. 33 (8): 3434–3442. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity
Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM (February 2016). "Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats". Neuropharmacology. 101: 154–164. doi:10.1016/j.neuropharm.2015.09.023. PMID 26391065.
Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
Figure 4: Epigenetic basis of drug regulation of gene expression
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Bucci, P; Galderisi, S (May 2017). "Categorizing and assessing negative symptoms". Current Opinion in Psychiatry. 30 (3): 201–208. doi:10.1097/YCO.0000000000000322. PMID 28212174. They also provide a separate assessment of the consummatory anhedonia (reduced experience of pleasure derived from ongoing enjoyable activities) and anticipatory anhedonia (reduced ability to anticipate future pleasure). In fact, the former one seems to be relatively intact in schizophrenia, whereas the latter one seems to be impaired [32 – 34]. However, discrepant data have also been reported [35].
Young & 2018 215a,"Several recent reviews (e.g., Cohen and Minor, 2010) have found that individuals with schizophrenia show relatively intact self-reported emotional responses to affect-eliciting stimuli as well as other indicators of intact response...A more mixed picture arises from functional neuroimaging studies examining brain responses to other types of pleasurable stimuli in schizophrenia (Paradiso et al., 2003)"
Young & 2018 215b,"As such it is surprising that behavioral studies have suggested that reinforcement learning is intact in schizophrenia when learning is relatively implicit (though, see Siegert et al., 2008 for evidence of impaired Serial Reaction Time task learning), but more impaired when explicit representations of stimulus-reward contingencies are needed (see Gold et al., 2008). This pattern has given rise to the theory that the striatally mediated gradual reinforcement learning system may be intact in schizophrenia, while more rapid, on-line, cortically mediated learning systems are impaired."
Young & 2018 216, "We have recently shown that individuals with schizophrenia can show improved cognitive control performance when information about rewards are externally presented but not when they must be internally maintained (Mann et al., 2013), with some evidence for impairments in DLPFC and striatal activation during internal maintenance of reward information being associated with individuals’ differences in motivation (Chung and Barch, 2016)."