Liu Junlin, Yang Xixi, Gao Feifei, Yang Jingsi, Yang Zhuojin, Liao Qi, Shen Mengqing, Yu Dongyu, Zhang Yuxiang, Yan Chunxia
College of Forensic Medicine, Key Laboratory of National Health Commission for Forensic Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
Bio-evidence Science Academy, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xixian New Area 712000, Shaanxi, China.
iScience. 2025 Jul 24;28(9):113208. doi: 10.1016/j.isci.2025.113208. eCollection 2025 Sep 19.
Drug addiction involves pathological learning and memory with serious personal and societal effects. Primary cilia on the cell surface are crucial for signal transduction. The 5-HT6R, highly localized in primary cilia, is linked to cognitive and emotional disorders, but its role in morphine-related reward memory is unclear. Using a morphine-induced conditioned place preference (CPP) model, we found that 5-HT6R in the medial prefrontal cortex was selectively downregulated during early extinction, but unchanged in CPP establishment or reinstatement. Knockdown of 5-HT6R accelerated extinction, while overexpression delayed it. These effects required intact cilia, as cilia shortening or IFT88 knockdown promoted extinction. Mechanistically, ATR was identified as a 5-HT6R-binding protein that regulates cilia structure. ATR knockdown mimicked and enhanced the extinction-promoting effect of 5-HT6R suppression, which was blocked by cilia disruption. These findings reveal a 5-HT6R-ATR-Primary cilia network that controls the extinction of morphine-induced reward memory, suggesting therapeutic targets for opioid addiction.
药物成瘾涉及病理性学习和记忆，会对个人和社会产生严重影响。细胞表面的初级纤毛对于信号转导至关重要。高度定位于初级纤毛的5-羟色胺6受体（5-HT6R）与认知和情绪障碍有关，但其在吗啡相关奖赏记忆中的作用尚不清楚。使用吗啡诱导的条件性位置偏爱（CPP）模型，我们发现内侧前额叶皮质中的5-HT6R在早期消退过程中被选择性下调，但在CPP建立或恢复过程中未发生变化。敲低5-HT6R可加速消退，而过度表达则会延迟消退。这些效应需要完整的纤毛，因为纤毛缩短或IFT88敲低会促进消退。从机制上讲，ATR被鉴定为一种调节纤毛结构的5-HT6R结合蛋白。敲低ATR模拟并增强了5-HT6R抑制的促进消退作用，而这种作用被纤毛破坏所阻断。这些发现揭示了一个控制吗啡诱导奖赏记忆消退的5-HT6R-ATR-初级纤毛网络，为阿片类药物成瘾提供了治疗靶点。
