Seo Myoung Suk, Kim Se Hyun, Ahn Yong Min, Kim Yeni, Jeon Won Je, Yoon Se Chang, Roh Myoung-Sun, Juhnn Yong-Sung, Kim Yong Sik
Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
Int J Neuropsychopharmacol. 2007 Jun;10(3):359-68. doi: 10.1017/S1461145706006869. Epub 2006 Jun 19.
Repeated administrations of NMDA receptor antagonists induce behavioural changes which resemble the symptoms of schizophrenia in animals. ERK and GSK-3beta associated signalling pathways have been implicated in the pathogenesis of psychosis and in the action mechanisms of various psychotropic agents. Here, we observed the phosphorylations of ERK and GSK-3beta and related molecules in the rat frontal cortex after repeated intraperitoneal injections of MK-801, over periods of 1, 5, and 10 d. Repeated treatment with 0.5, 1, and 2 mg/kg MK-801 increased the phosphorylation levels of the MEK-ERK-p90RSK and Akt-GSK-3beta pathways and concomitantly and significantly increased CREB phosphorylation in the rat frontal cortex. However, single MK-801 treatment did not induce these significant changes. In addition, the immunoreactivities of HSP72, Bax, and PARP were not altered, which suggests that neuronal damage may not occur in the rat frontal cortex in response to chronic MK-801 treatment. These findings suggest that chronic exposure to MK-801 may induce pro-survival and anti-apoptotic activity without significant neuronal damage in the rat frontal cortex. Moreover, this adaptive change might be associated with the psychotomimetic action of MK-801.
反复给予N-甲基-D-天冬氨酸（NMDA）受体拮抗剂会在动物身上诱发行为变化，这些变化类似于精神分裂症的症状。细胞外信号调节激酶（ERK）和糖原合成酶激酶-3β（GSK-3β）相关的信号通路与精神病的发病机制以及各种精神药物的作用机制有关。在此，我们观察了在1、5和10天的时间段内，对大鼠腹腔内反复注射MK-801后，大鼠额叶皮质中ERK、GSK-3β及相关分子的磷酸化情况。用0.5、1和2mg/kg的MK-801反复治疗可提高大鼠额叶皮质中MEK-ERK-p90核糖体S6激酶（RSK）和Akt-GSK-3β信号通路的磷酸化水平，并同时显著增加cAMP反应元件结合蛋白（CREB）的磷酸化。然而，单次给予MK-801并未诱导这些显著变化。此外，热休克蛋白72（HSP72）、促凋亡蛋白Bax和聚（ADP-核糖）聚合酶（PARP）的免疫反应性未改变，这表明慢性给予MK-801可能不会导致大鼠额叶皮质发生神经元损伤。这些发现表明，长期暴露于MK-801可能在大鼠额叶皮质中诱导促存活和抗凋亡活性，而不会造成明显的神经元损伤。此外，这种适应性变化可能与MK-801的拟精神病作用有关。
