伏隔核中的胆碱能中枢控制阿片奖励学习

伏隔核中的胆碱能中枢控制阿片奖励学习

作者： 小柯机器人 发布时间：2026/8/6 15:31:30

本期文章：《自然》：Online/在线发表

杜克大学Michael R. Tadross团队的一项最新研究开发出伏隔核中的胆碱能中枢控制阿片奖励学习。该项研究成果发表在2026年8月5日出版的《自然》上。

在这里，研究小组表明，即使在伏隔核多巴胺水平升高的情况下，联想阿片奖励学习也可能被阻断。研究小组开发了naloxoneDART，一种临床阿片受体拮抗剂naloxone的细胞类型特异性类似物，并将其递送到遗传定义的伏隔胆碱能中间神经元，选择性地使这些细胞对吗啡不敏感。吗啡条件下的位置偏好习得以目标参与依赖的方式被消除，没有证据表明环境或运动损伤：生理盐水习惯化在会话之间增强，在会话内保持不变，而吗啡诱发的运动过度、致敏和急性镇痛保持不变。

微透析显示，胆碱能神经元间特异性纳洛酮DART可阻止吗啡诱导的乙酰胆碱减少，而不会明显改变伏隔核中多巴胺的增加。这些发现确定了联合阿片-奖励学习的胆碱能门，支持了新兴的多巴胺-乙酰胆碱可塑性理论，并激发了阿片-胆碱能策略的探索，该策略可能在限制早期联合奖励学习的同时保留急性镇痛。

据了解，有益的和不适应的阿片效应很难分离，部分原因是多巴胺信号传导参与了这两种效应类型。

附：英文原文

Title: A cholinergic hub in the nucleus accumbens gates opioid-reward learning

Author: Yousefzadeh, S. Aryana, Yan, Haidun, Kwak, Seung-Hwa, Oh, Yunju, Jeong, Pyeonghwa, Pogorelov, Vladimir, Ravenel, J. Russell, Lim, Shaun S. X., Roach, James M., Shields, Brenda C., Rodriguiz, Ramona M., Wetsel, William C., Hong, Jiyong, Tadross, Michael R.

Issue&Volume: 2026-08-05

Abstract: Beneficial and maladaptive opioid effects are difficult to dissociate1,2,3, partly because dopamine signalling contributes to both these effect types4,5,6,7,8,9,10,11,12,13. Here we show that associative opioid-reward learning can be blocked even under conditions that elevate dopamine in the nucleus accumbens. We developed naloxoneDART, a cell-type-specific analogue of the clinical opioid receptor antagonist naloxone14,15, and delivered it to genetically defined accumbal cholinergic interneurons, selectively rendering these cells morphine-insensitive. Acquisition of morphine conditioned place preference was abolished in a target-engagement-dependent manner, without evidence of contextual or locomotor impairment: saline habituation was enhanced between sessions and unchanged within sessions, whereas morphine-evoked hyperlocomotion, sensitization and acute analgesia remained intact. Microdialysis revealed that cholinergic interneuron-specific naloxoneDART prevented morphine-induced acetylcholine reductions without detectably altering dopamine increases in the accumbens. These findings identify a cholinergic gate for associative opioid-reward learning, support an emerging dopamine–acetylcholine plasticity theory16,17, and motivate exploration of opioid–cholinergic strategies that may preserve acute analgesia while limiting early associative reward learning18,19,20,21,22,23,24,25.

DOI: 10.1038/s41586-026-10887-9

Source: https://www.nature.com/articles/s41586-026-10887-9

主题：伏隔核中