Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Prog Neuropsychopharmacol Biol Psychiatry. 2010 Aug 16;34(6):888-94. doi: 10.1016/j.pnpbp.2010.04.010. Epub 2010 Apr 18.
Intracerebroventricular (ICV) injection of ouabain, a specific Na-K ATPase inhibitor, induces behavioral changes in rats resembling the manic phenotypes of bipolar disorder. The binding of ouabain to the Na-K ATPase affects signal events in vitro including Akt, a possible molecular target of mood disorders. However, the effects of ouabain on Akt in the brain need further clarification. In this study, we investigated changes in the phosphorylation state of Akt in the rat brain after ICV injection of ouabain. Consistent with our previous report, the locomotor activity of rats within 30 min after ouabain ICV injection changed according to the dose with higher doses of ouabain, 0.5 and 1 mM, inducing significant hyperactivity. In addition, ouabain administration induced a dose-dependent increase in the immunoreactivity of p-Akt (Ser473) in the frontal cortex, striatum, and hippocampus after 30 min, and reached statistical significance with 1mM of ouabain. Phosphorylation of GSK-3beta (Ser9), FOXO1 (Ser256), and eNOS (Ser1177), which are downstream molecules of Akt, was also increased in a dose-dependent manner within the same brain regions. Moreover, hyperactivity was seen for 8h after a single 1mM injection of ouabain and increased phosphorylation of Akt (Ser473), GSK-3beta (Ser9), FOXO1 (Ser256), and eNOS (Ser1177) was also observed in the cortex, striatum, and hippocampus. Thus, intrabrain injection of ouabain induces activation of Akt signaling accompanied by hyperactivity, suggesting the possible role of Akt in ouabain rat model of mania.
脑室（ICV）注射哇巴因，一种特定的钠-钾 ATP 酶抑制剂，会导致大鼠出现类似于双相情感障碍躁狂表型的行为变化。哇巴因与钠-钾 ATP 酶的结合会影响体外的信号事件，包括 Akt，这是情绪障碍的一个可能的分子靶点。然而，哇巴因对大脑中 Akt 的影响需要进一步澄清。在这项研究中，我们研究了脑室注射哇巴因后大鼠大脑中 Akt 磷酸化状态的变化。与我们之前的报告一致，哇巴因脑室注射后 30 分钟内大鼠的运动活性根据剂量发生变化，较高剂量的哇巴因（0.5 和 1mM）会导致明显的多动。此外，哇巴因给药诱导了 30 分钟后前额皮质、纹状体和海马中 p-Akt（Ser473）免疫反应的剂量依赖性增加，并且在 1mM 哇巴因时达到统计学意义。Akt 的下游分子 GSK-3β（Ser9）、FOXO1（Ser256）和 eNOS（Ser1177）的磷酸化也在相同的脑区呈剂量依赖性增加。此外，单次 1mM 哇巴因注射后 8 小时出现多动，并且在皮质、纹状体和海马中也观察到 Akt（Ser473）、GSK-3β（Ser9）、FOXO1（Ser256）和 eNOS（Ser1177）的磷酸化增加。因此，脑室内注射哇巴因诱导 Akt 信号通路的激活，伴随着多动，表明 Akt 可能在哇巴因大鼠躁狂模型中发挥作用。
