Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan.
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan.
Eur Neuropsychopharmacol. 2017 Oct;27(10):1000-1010. doi: 10.1016/j.euroneuro.2017.08.071. Epub 2017 Aug 16.
Dopamine (DA) modulates cognitive functions in the prefrontal cortex (PFC) and hippocampus. Olfactory bulbectomy (OBX) in mice induces cognitive dysfunctions. Recently, we reported that aripiprazole (ARI) normalizes the behavioral hyper-responsivity to DA agonists in OBX mice. However, it remains unclear whether ARI affects OBX-induced cognitive dysfunctions. To address this question we evaluated ARI-treated and untreated OBX mice in a passive avoidance test. Then, we investigated the effects of ARI on cell proliferation in the hippocampal dentate gyrus by immunohistochemistry, and on c-fos levels in the PFC and hippocampus, as well as nerve growth factor (NGF) levels in the hippocampus by western blotting. On the 14th day after surgery OBX mice showed an alteration in passive avoidance and decreases in both cell proliferation and levels of p-ERK, p-CREB and NGF in the hippocampus. The cognitive dysfunctions in OBX mice improved 30min to 24h after the administration of ARI (0.01mg/kg). C-fos levels in the PFC but not in the hippocampus was increased 30min after the administration (early response). This early response was inhibited by the selective D receptor antagonist SCH23390. Cell proliferation and NGF levels in the hippocampus increased 24h after ARI administration (late response), and these effects were also inhibited by SCH23390. The MEK1/2 inhibitor U0126 prevented ARI from improving the behavioral impairment as well as enhancing NGF levels in OBX mice. These findings revealed the potential of ARI to improve cognitive dysfunctions via D receptors with the PFC and hippocampus being affected sequentially.
多巴胺（DA）调节前额叶皮层（PFC）和海马体的认知功能。嗅球切除术（OBX）在小鼠中诱导认知功能障碍。最近，我们报道阿立哌唑（ARI）可使 OBX 小鼠对 DA 激动剂的行为高反应性正常化。然而，ARI 是否影响 OBX 诱导的认知功能障碍仍不清楚。为了解决这个问题，我们在被动回避测试中评估了未处理和处理过的 OBX 小鼠。然后，我们通过免疫组织化学研究了 ARI 对海马齿状回细胞增殖的影响，通过 Western blot 研究了 ARI 对 PFC 和海马中 c-fos 水平以及海马中神经生长因子（NGF）水平的影响。在手术后的第 14 天，OBX 小鼠表现出被动回避改变，以及海马中细胞增殖和 p-ERK、p-CREB 和 NGF 水平降低。在 ARI（0.01mg/kg）给药后 30 分钟至 24 小时，OBX 小鼠的认知功能障碍得到改善。给药后 30 分钟（早期反应），PFC 中的 c-fos 水平增加，但海马体中没有增加。这种早期反应被选择性 D 受体拮抗剂 SCH23390 抑制。给药 24 小时后，海马体中的细胞增殖和 NGF 水平增加（晚期反应），SCH23390 也抑制了这些作用。MEK1/2 抑制剂 U0126 阻止了 ARI 改善 OBX 小鼠的行为障碍以及增强 NGF 水平的作用。这些发现表明 ARI 通过 PFC 和海马体依次受到影响的 D 受体来改善认知功能障碍的潜力。
