Brain Function and Disease Laboratory, Shantou University Medical College, No. 22 Xinling Road, Shantou, 515041, Guangdong Province, PR China.
Brain Function and Disease Laboratory, Shantou University Medical College, No. 22 Xinling Road, Shantou, 515041, Guangdong Province, PR China.
Biomed Pharmacother. 2021 Jan;133:110962. doi: 10.1016/j.biopha.2020.110962. Epub 2020 Nov 7.
This study aimed at determining the synergistic effects of Yuanhu Zhitong tablets (YHZTP) on alcohol-induced conditioned place preference (CPP) in mice, in addition, the intervention mechanism was preliminarily explored based on traditional Chinese Medicine (TCM) network pharmacology on alcohol addiction.
Alcohol-induced CPP mice were used to evaluate the effects of either YHZTP or levo-tetrahydropalmatine (l-THP) plus imperatorin (IMP) administration on animal behavior. The network pharmacological strategy was used to establish the "compound-target" and "disease-drug-target" network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the shared targets between the compound and the disease. Twelve algorithms on CytoHubba were used to find the hub genes that were verified by qPCR.
Systemic administration (2 g/kg, i.p.) of ethanol (EtOH) to mice was used to induce CPP. YHZTP On its own did not induce CPP or conditioned place aversion (CPA) at the doses of 0.3 g/kg or 0.6 g/kg (i.g.), but attenuated the acquisition and expression of EtOH-induce CPP in mice. In addition, YHZTP (0.3 or 0.6 g/kg) did not exhibit any effect on the motor activity of mice. Acquisition of alcohol-induced CPP was blocked by a combination of l-THP (5 mg/kg, i.g.) + IMP (2.5 mg/kg, i.g.) or l-THP (10 mg/kg, i.g.) + IMP (5 mg/kg, i.g.). However, the combination of l-THP (2.5 mg/kg, i.g.) + IMP (1.25 mg/kg, i.g.) or mono-administration of l-THP and IMP did not exhibit any effect on alcohol-induced CPP. YHZTP was also shown to reverse the up-regulation of Gabra1, Ptgs2, Mapk1, Mapk8, Mapk14, Nr3c, Prkca and Sirt1 genes and the down-regulation of Hhtr2a and Drd2 genes in the prefrontal cortex of EtOH induced CPP mice. These genes were associated with neuroactive ligand-receptor interactions, activation of the sphingolipid, calcium, cAMP, ErbB, NF-kappa B and MAPK signaling pathways.
YHZTP inhibits EtOH-induced CPP behavior in mice while a combination of l-THP and IMP exerts a synergistic effect on the reduction of EtOH-induced CPP. Possible pharmacological mechanisms include inhibition of the expression of inflammatory factors and regulation of neurotransmitter receptor levels. Therefore, YHZTP is a novel candidate for the treatment of alcohol addiction.
本研究旨在确定元胡止痛片（YHZTP）对酒精诱导的条件性位置偏爱（CPP）在小鼠中的协同作用，此外，还基于中药（TCM）网络药理学对酒精成瘾的干预机制进行了初步探讨。
使用酒精诱导的 CPP 小鼠来评估 YHZTP 或左旋四氢巴马汀（l-THP）加白芷素（IMP）给药对动物行为的影响。使用网络药理学策略建立“化合物-靶标”和“疾病-药物-靶标”网络。对化合物与疾病之间的共有靶标进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析。使用 CytoHubba 上的 12 种算法找到关键基因，并通过 qPCR 进行验证。
给小鼠腹腔注射乙醇（EtOH）（2 g/kg）以诱导 CPP。YHZTP 单独使用时，在 0.3 g/kg 或 0.6 g/kg（ig）的剂量下不会引起 CPP 或条件性位置厌恶（CPA），但可减轻小鼠中 EtOH 诱导的 CPP 的获得和表达。此外，YHZTP（0.3 或 0.6 g/kg）对小鼠的运动活动没有影响。l-THP（5 mg/kg，ig）+IMP（2.5 mg/kg，ig）或 l-THP（10 mg/kg，ig）+IMP（5 mg/kg，ig）联合使用可阻断酒精诱导的 CPP 的获得。然而，l-THP（2.5 mg/kg，ig）+IMP（1.25 mg/kg，ig）或单药 l-THP 和 IMP 联合使用对酒精诱导的 CPP 没有影响。YHZTP 还可逆转 EtOH 诱导的 CPP 小鼠前额叶皮质中 Gabra1、Ptgs2、Mapk1、Mapk8、Mapk14、Nr3c、Prkca 和 Sirt1 基因的上调以及 Hhtr2a 和 Drd2 基因的下调。这些基因与神经活性配体-受体相互作用、鞘脂、钙、cAMP、ErbB、NF-kappa B 和 MAPK 信号通路的激活有关。
YHZTP 抑制小鼠中 EtOH 诱导的 CPP 行为，而 l-THP 和 IMP 的组合对减少 EtOH 诱导的 CPP 具有协同作用。可能的药理学机制包括抑制炎症因子的表达和调节神经递质受体水平。因此，YHZTP 是治疗酒精成瘾的一种新的候选药物。
