Dissecting the neuronal mechanisms of pinoresinol against methamphetamine addiction based on network and experimental pharmacology.

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2024-12-14 DOI:10.1016/j.phymed.2024.156322

Shuyuan Fan, Yize Qi, Fukang Zhang, Yatong Shi, Kunfang Ma, Qihang Pan, Ai Jiang, Luanyue He, Junlong Zhang, Tengfei Ma, Li Zhou

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引用次数: 0

Abstract

Background: 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.

Objective: We aimed to explore the effect and mechanism of the monomer ingredients of FD on methamphetamine (METH) addiction.

Methods: 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.

Results: 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.

Conclusion: 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.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.