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目的 观察甲基苯丙胺(methamphetamine, Meth)撤药后小鼠的抑郁样行为，阐述色氨酸(TRP)和酪氨酸(TYR)代谢途径神经递质的紊乱。方法 SPF级C57BL/6J小鼠经腹腔注射给与不同浓度的Meth(0、5、10和15 mg/kg·d),连续注射10 d,撤药14 d后，通过悬尾测试，强迫游泳测试，分析小鼠抑郁样改变，并通过超高效液相串联质谱法(LC-MS-MS)检测TRP、TYR途径神经递质代谢的改变。结果 Meth撤药引起小鼠血清中TRP和TYR水平微弱下降，差异无统计学意义(P>0.05),其中TRP代谢途经中五羟色胺(5-HT)水平明显下降(F=8.356,P<0.05),而犬尿氨酸(kynurenine, KYN)水平有上升趋势；TYR代谢途经中，TYR及其代谢产物多巴胺(dopamine, DA)、二羟基苯乙酸(DOPAC)(F=3.130,P<0.05)水平下降；其他神经递质如谷氨酸(GLU),γ-氨基丁酸(GABA)水平亦有降低趋势，但差异无统计学意义(P>0.05)。结论 Meth撤药明显引起小鼠抑郁样改变，导致TRP和TYR等代谢途径中多种神经递质紊乱，因而靶向干预TRP和TYP代谢途径的神经递质有望为Meth撤药引起的抑郁样改变提供干预策略，具有积极的应用价值。
Abstract：Objective To examine the depression-like behaviors and elucidate the role of neurotransmitter metabolic disorders in tryptophan and tyrosine metabolic pathways in methamphetamine-withdrawal mice. Methods SPF C57BL/6J mice were intraperitoneally injected with different concentrations of Meth(0,5,10,15 mg/kg·day) for 10 consecutive days, and after 14 days, tail suspension test and forced swimming test were used to analyze the depression-like changes of the mice. Ultra-high performance liquid chromatography-tandem mass spectrometry(LC-MS-MS) was used to detect the changes of neurotransmitter metabolism in tryptophan(TRP) and tyrosine(TYR) metabolic pathways. Results After Meth withdrawal, the levels of TRP and TYR in serum of mice decreased slightly, besides, the level of 5-hydroxytryptamine(5-HT) in TRP metabolism obviously decreased(F=8.356,P<0.05), while the level of kynurenine(KYN) slightly increased. For the TYR metabolic pathway, the levels of TYR and itsmetabolites dopamine(DA) and dihydroxyphenylacetic acid(DOPAC)(F=3.130,P<0.05) decreased. Similarly, other neurotransmitters such as glutamate(GLU) and γ-aminobutyric acid(GABA) were also displayed decreased tendency. Conclusion Meth withdrawal can significantly cause depression-like changes in mice, contributing to metabolic disturbance of neurotransmitters in TRP, TYR and other metabolic pathways. Therefore, targeting TRP and TYP metabolic pathways may provide deep insight into the interventive strategies for depression-like changes induced by Meth, which has positive application value.
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基本信息:
DOI：10.16421/j.cnki.1002-3127.2025.06.001
中图分类号:R994.3
引用信息:
[1]卫一敏,刘见佳,吴宇轩,等.甲基苯丙胺撤药后产生的抑郁样行为及神经递质的改变[J].毒理学杂志,2025,39(06):397-403.DOI:10.16421/j.cnki.1002-3127.2025.06.001.
基金信息:
国家自然科学基金(82473664); 国家级大学生创新训练计划(202310312025Z,202410312069Z)