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TAAR1激动剂PCC0105004调节杏仁核突触可塑性以减轻大鼠的焦虑样行为。

The TAAR1 Agonist PCC0105004 Regulates Amygdala Synaptic Plasticity to Alleviate Anxiety-Like Behaviors in Rats.

作者信息

Zhang Yingtian, Zhang Wei, Yu Linyao, Shi Yaoqin, Xu Min, Wang Hui, Li Chunmei, Tian Jingwei

机构信息

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, People's Republic of China.

State Key Laboratory of Advanced Drug Delivery and Release Systems, Yantai, Shandong, People's Republic of China.

出版信息

Pharmacol Res Perspect. 2025 Apr;13(2):e70068. doi: 10.1002/prp2.70068.

DOI:10.1002/prp2.70068
PMID:40186385
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11971484/
Abstract

Anxiety disorder is a persistent, widespread, and intractable mood disorder, and the available pharmacotherapies have limited efficacy with significant side effects. Trace amine-associated receptor 1 (TAAR1) is an emerging drug target for neuropsychiatric disorders. This study examined the effects and underlying mechanisms of a novel TAAR1 agonist, PCC0105004, in a rat model of CUMS-induced anxiety-like behavior. The elevated zero maze and open field tests test were employed to evaluate the anti-anxiety-like activity of PCC0105004. PCC0105004 dose-dependently attenuated anxiety-like behaviors in rats without affecting spontaneous activity. Morphologically, PCC0104005 decreased the density of dendritic spines in the amygdala. For the mechanistic studies, whole-genome transcriptomic analysis revealed significant differences in the patterns of amygdala gene expression in the CUMS-induced anxiety rat model. These transcriptomic data were further confirmed by using RT-qPCR and western blotting, further revealing alterations associated with genes (Col1a1, DCN, Ewsr1) known to regulate synaptic plasticity, and PCC0105004 was able to reverse these changes. These results suggest that PCC0105004 is a promising anxiolytic candidate for pharmacotherapy of anxiety and warrants further examination and development.

摘要

焦虑症是一种持续存在、广泛且难以治疗的情绪障碍，现有的药物治疗疗效有限且副作用显著。痕量胺相关受体1（TAAR1）是神经精神疾病中一个新兴的药物靶点。本研究在慢性不可预测轻度应激（CUMS）诱导的焦虑样行为大鼠模型中，研究了新型TAAR1激动剂PCC0105004的作用及其潜在机制。采用高架零迷宫试验和旷场试验评估PCC0105004的抗焦虑样活性。PCC0105004能剂量依赖性地减轻大鼠的焦虑样行为，且不影响自发活动。形态学上，PCC0104005降低了杏仁核中树突棘的密度。在机制研究方面，全基因组转录组分析揭示了CUMS诱导的焦虑大鼠模型中杏仁核基因表达模式存在显著差异。这些转录组数据通过逆转录定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹法进一步得到证实，进一步揭示了与已知调节突触可塑性的基因（Col1a1、DCN、Ewsr1）相关的变化，且PCC0105004能够逆转这些变化。这些结果表明，PCC0105004是一种有前景的用于焦虑症药物治疗的抗焦虑候选药物，值得进一步研究和开发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/4c73efc256b5/PRP2-13-e70068-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/6fd1a8d74d81/PRP2-13-e70068-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/7e9b5c40a6d7/PRP2-13-e70068-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/da495c738e47/PRP2-13-e70068-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/dc0d6d49dc44/PRP2-13-e70068-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/30e1ee826bc3/PRP2-13-e70068-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/6034278f8f6e/PRP2-13-e70068-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/4c73efc256b5/PRP2-13-e70068-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/6fd1a8d74d81/PRP2-13-e70068-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/7e9b5c40a6d7/PRP2-13-e70068-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/da495c738e47/PRP2-13-e70068-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/10dcd81357e7/PRP2-13-e70068-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/2cd5afcd9a2c/PRP2-13-e70068-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/dc0d6d49dc44/PRP2-13-e70068-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/30e1ee826bc3/PRP2-13-e70068-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/6034278f8f6e/PRP2-13-e70068-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e4e/11971484/4c73efc256b5/PRP2-13-e70068-g007.jpg

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