Karabacak Yasemin, Sase Sunetra, Aher Yogesh D, Sase Ajinkya, Saroja Sivaprakasam R, Cicvaric Ana, Höger Harald, Berger Michael, Bakulev Vasiliy, Sitte Harald H, Leban Johann, Monje Francisco J, Lubec Gert
Department of Pharmaceutical Chemistry, University of Vienna Vienna, Austria.
Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna Vienna, Austria.
Front Behav Neurosci. 2015 Aug 19;9:215. doi: 10.3389/fnbeh.2015.00215. eCollection 2015.
A series of drugs have been reported to increase memory performance modulating the dopaminergic system and herein modafinil was tested for its working memory (WM) enhancing properties. Reuptake inhibition of dopamine, serotonin (SERT) and norepinephrine (NET) by modafinil was tested. Sixty male Sprague-Dawley rats were divided into six groups (modafinil-treated 1-5-10 mg/kg body weight, trained and untrained and vehicle treated trained and untrained rats; daily injected intraperitoneally for a period of 10 days) and tested in a radial arm maze (RAM), a paradigm for testing spatial WM. Hippocampi were taken 6 h following the last day of training and complexes containing the unphosphorylated or phosphorylated dopamine transporter (DAT-CC and pDAT-CC) and complexes containing the D1-3 dopamine receptor subunits (D1-D3-CC) were determined. Modafinil was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked specifically (IC50 = 11.11 μM; SERT 1547 μM; NET 182 μM). From day 8 (day 9 for 1 mg/kg body weight) modafinil was decreasing WM errors (WMEs) in the RAM significantly and remarkably at all doses tested as compared to the vehicle controls. WMEs were linked to the D2R-CC and the pDAT-CC. pDAT and D1-D3-CC levels were modulated significantly and modafinil was shown to enhance spatial WM in the rat in a well-documented paradigm at all the three doses and dopamine reuptake inhibition with subsequent modulation of D1-3-CC is proposed as a possible mechanism of action.
据报道，一系列药物可通过调节多巴胺能系统来提高记忆表现，本文对莫达非尼的工作记忆（WM）增强特性进行了测试。测试了莫达非尼对多巴胺、5-羟色胺（SERT）和去甲肾上腺素（NET）的再摄取抑制作用。将60只雄性Sprague-Dawley大鼠分为六组（分别用1-5-10mg/kg体重的莫达非尼处理，分为训练组和未训练组，以及用赋形剂处理的训练组和未训练组大鼠；每天腹腔注射，持续10天），并在放射状臂迷宫（RAM）中进行测试，这是一种测试空间WM的范式。在训练的最后一天后的6小时采集海马体，测定含有未磷酸化或磷酸化多巴胺转运体（DAT-CC和pDAT-CC）的复合物以及含有D1-3多巴胺受体亚基（D1-D3-CC）的复合物。莫达非尼与DAT结合，但与SERT或NET的结合不显著，并且特异性地阻断了多巴胺再摄取（IC50 = 11.11μM；SERT为1547μM；NET为182μM）。从第8天（1mg/kg体重组为第9天）起，与赋形剂对照组相比，莫达非尼在所有测试剂量下均显著降低了RAM中的WM错误（WMEs）。WMEs与D2R-CC和pDAT-CC相关。pDAT和D1-D3-CC水平受到显著调节，并且在所有三个剂量下，莫达非尼均在一个充分记录的范式中增强了大鼠的空间WM，并且提出多巴胺再摄取抑制以及随后对D1-3-CC的调节是一种可能的作用机制。
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