2026-10-27 中国科学院（CAS）
＜関連情報＞
- https://english.cas.cn/newsroom/research-news/202610/t20261027_1212588.shtml
- https://www.nature.com/articles/s41593-026-02497-5
5- HT2A受容体-β-アレスチンシグナル伝達を介した幻覚剤の持続的な抗うつ様効果 Sustained antidepressant-like effects of psychedelics through 5-HT2AR–β-arrestin signaling
Licong He, Lingjie Tang, Dongmei Cao, Wenwen Duan, Jing Yu, Pei Zhang, Huiqiong Li, Yumeng Wang, Bing Meng, Huan Wang, Yue Zhou, Wenhao Li, Xiaoyu Li, Zhijie Liu, Lei Zhang, Jianjun Cheng & Sheng Wang
Nature Neuroscience Published:23 October 2026
DOI:https://doi.org/10.1038/s41593-026-02497-5
Abstract
Psychedelics produce long-lasting antidepressant effects, but their hallucinogenic properties limit clinical use. Using structure-guided design of 5-HT2AR–β-arrestin-biased agonists, we identified β-arrestin signaling as a critical driver of prolonged antidepressant-like effects in mice. Here we show that the slow-dissociation kinetics of lysergic acid diethylamide (LSD) enable progressive accumulation of 5-HT2AR engagement during repeated low-dose administration, approaching the receptor occupancy achieved by an acute high dose while avoiding its high peak concentration. This kinetic separation sustains β-arrestin signaling while limiting robust Gαq-mediated Ca2+ responses. Consistent with this framework, repeated low-dose LSD and repeated low-dose psilocybin pretreatment followed by a high-dose psychedelic challenge produced sustained antidepressant-like behavioral effects in mice. In parallel, these regimens produced no detectable psychedelic-associated behavioral disruption in mice and cynomolgus macaques. Together, these findings uncover the signaling basis of sustained psychedelic efficacy and provide a rational framework for developing nonhallucinogenic psychedelic therapies for psychiatric disorders.
