Fan Shuyuan, Qi Yize, Zhang Fukang, Shi Yatong, Ma Kunfang, Pan Qihang, Jiang Ai, He Luanyue, Zhang Junlong, Ma Tengfei, Zhou Li
Institute for Stem Cell and Neural Regeneration and Key Laboratory of Cardiovascular &Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, PR China.
Department of Anesthesiology, The Second People's Hospital of Lianyungang, Lianyungang, Jiangsu 222023, PR China.
Phytomedicine. 2025 Jan;136:156322. doi: 10.1016/j.phymed.2024.156322. Epub 2024 Dec 14.
Addiction is a chronic brain disease in which the underlying neuronal mechanism is characterized by drug-seeking and use. Flos Daturae (FD) and its components are used to treat addiction. However, the effective ingredients of FD that are linked to the neuronal mechanisms of seeking behavior remain unclear.
We aimed to explore the effect and mechanism of the monomer ingredients of FD on methamphetamine (METH) addiction.
The main chemical constituents and potential targets of FD were screened using LC-MS/MS and bioinformatics method. Molecular docking was used to screen the component of FD associated with the neuronal subtype mechanism. The effectiveness of the targets in related pathways was verified by behavioral experiment, immunofluorescence and Western blot. Electrophysiology was used to identify the functions of the ingredients of FD in D1-tdTomato and D2-eGFP transgenic mice.
There were 125 targets of 25 active components in FD, which included dopamine 1 receptor (D1R)/dopamine 2 receptor (D2R)/cAMP signaling pathway. Furthermore, we identified that pinoresinol (PINL) is a major component of FD targeting this signaling pathway. Moreover, PINL attenuated METH-induced seeking behavior and decreased expression of c-Fos in striatal D1R neurons, but not D2R neurons. Accordingly, PINL functionally reduced the over-excitation of D1R, but not D2R neurons. Finally, we clarified that D1R/PKA pathway is a critical factor mediating the effects of PINL on METH-induced seeking behavior.
We revealed that PINL specifically targeted D1R/PKA signaling in D1R neurons and decreased METH-induced seeking behavior, providing a new strategy to treat addictive diseases.
成瘾是一种慢性脑部疾病，其潜在的神经元机制以觅药和用药为特征。洋金花及其成分被用于治疗成瘾。然而，与觅药行为神经元机制相关的洋金花有效成分仍不清楚。
探讨洋金花单体成分对甲基苯丙胺（METH）成瘾的影响及机制。
采用液相色谱-串联质谱法（LC-MS/MS）和生物信息学方法筛选洋金花的主要化学成分和潜在靶点。利用分子对接筛选与神经元亚型机制相关的洋金花成分。通过行为实验、免疫荧光和蛋白质免疫印迹法验证相关通路中靶点的有效性。采用电生理学方法鉴定洋金花成分在D1-tdTomato和D2-eGFP转基因小鼠中的作用。
洋金花中25种活性成分有125个靶点，其中包括多巴胺1受体（D1R）/多巴胺2受体（D2R）/环磷酸腺苷（cAMP）信号通路。此外，我们确定松脂醇（PINL）是洋金花靶向该信号通路的主要成分。而且，PINL可减弱METH诱导的觅药行为，并降低纹状体D1R神经元而非D2R神经元中c-Fos的表达。相应地，PINL在功能上降低了D1R神经元而非D2R神经元的过度兴奋。最后，我们阐明D1R/蛋白激酶A（PKA）通路是介导PINL对METH诱导的觅药行为影响的关键因素。
我们揭示了PINL特异性靶向D1R神经元中的D1R/PKA信号，并降低了METH诱导的觅药行为，为治疗成瘾性疾病提供了新策略。
