Ma Jin, Long Li-Hong, Hu Zhuang-Li, Zhang Hai, Han Jun, Ni Lan, Wang Fang, Chen Jian-Guo, Wu Peng-Fei
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China.
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Wuhan City, Hubei 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan City, Hubei 430030, China; The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China.
Brain Res. 2015 Jul 30;1615:71-79. doi: 10.1016/j.brainres.2015.04.030. Epub 2015 Apr 23.
Dopamine, a key neurotransmitter mediating the rewarding effects, exerts some of its effects by modulating neuronal excitability of striatal medium spiny neurons. A D1-like dopamine receptor-dependent phosphatidylinositol signal pathway exists in the striatum, however little is known about its role in the dopaminergic modulation of striatal neuronal excitability. 3-Methyl-6-chloro-7, 8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is a selective D1 receptor agonist with high-affinity. Here, we observed its effect on the voltage-gated sodium channels (VGSCs) in primary cultured striatal neurons by whole cell patch-clamp technique. We found that SKF83959 induced an inhibition on VGSCs in a dose-dependent manner in striatal neurons (IC50 value: 3.31 ± 0.39 μM), which could be prevented by antagonist of D1 receptor, but not that of D2, α1 adrenergic, or cholinoceptor. The effect of SKF83959 on VGSCs was also prevented by pretreatment with inhibitors of phospholipase C (PLC) and protein kinases C (PKC), but the inositol-1,4,5-phosphate 3 (IP3) antagonist did not occlude SKF83959 (1μM)-induced reduction of VGSCs. These data indicate that SKF83959 inhibits VGSCs in cultured striatal neurons via D1-like receptor-phosphatidylinositol-PKC pathway, which may underlie the dopaminergic modulation on striatal neuronal excitability.
多巴胺是介导奖赏效应的关键神经递质，它通过调节纹状体中等棘状神经元的神经元兴奋性来发挥一些作用。纹状体中存在一种D1样多巴胺受体依赖性磷脂酰肌醇信号通路，然而其在多巴胺能调节纹状体神经元兴奋性中的作用却知之甚少。3-甲基-6-氯-7,8-二羟基-1-(3-甲基苯基)-2,3,4,5-四氢-1H-3-苯并氮杂卓（SKF83959）是一种具有高亲和力的选择性D1受体激动剂。在此，我们通过全细胞膜片钳技术观察了其对原代培养的纹状体神经元电压门控钠通道（VGSCs）的影响。我们发现SKF83959对纹状体神经元中的VGSCs具有剂量依赖性抑制作用（IC50值：3.31±0.39μM），这种抑制作用可被D1受体拮抗剂阻断，但不能被D2、α1肾上腺素能或胆碱能受体拮抗剂阻断。SKF83959对VGSCs的作用也可被磷脂酶C（PLC）和蛋白激酶C（PKC）抑制剂预处理所阻断，但肌醇-1,4,5-三磷酸（IP3）拮抗剂并不能消除SKF83959（1μM）诱导的VGSCs减少。这些数据表明，SKF83959通过D1样受体-磷脂酰肌醇-PKC途径抑制培养的纹状体神经元中的VGSCs，这可能是多巴胺能调节纹状体神经元兴奋性的基础。
