Long-Lasting Impairment of Associative Learning Is Correlated with a Dysfunction of N-Methyl-d-aspartate-Extracellular Signaling-Regulated Kinase Signaling in Mice after Withdrawal from Repeated Administration of Phencyclidine
Long-Lasting Impairment of Associative Learning Is Correlated with a Dysfunction of N-Methyl-d-aspartate-Extracellular Signaling-Regulated Kinase Signaling in Mice after Withdrawal from Repeated Administration of Phencyclidine
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DOI：
10.1124/mol.105.011304
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发表时间：
2005-12
影响因子：
3.6
通讯作者：
T. Enomoto;Y. Noda;A. Mouri;E. Shin;Dayong Wang;R. Murai;K. Hotta;H. Furukawa;A. Nitta;Hyoung‐Chun Kim;T. Nabeshima
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文献类型：
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作者：
T. Enomoto;Y. Noda;A. Mouri;E. Shin;Dayong Wang;R. Murai;K. Hotta;H. Furukawa;A. Nitta;Hyoung‐Chun Kim;T. Nabeshima
在人类中，服用苯环利定会导致精神分裂症样症状，在停用苯环利定后会持续几周。我们在这里证明了苯环利定(10 mg/kg/天)预先处理的小鼠。14天)显示出巴甫洛夫恐惧条件反射在苯环利定治疗停止8天后持续损害。生理盐水处理组小鼠杏仁核和海马区细胞外信号调节激酶(ERK)在条件反射后一过性激活。在苯环利定治疗的小鼠中，海马区ERK活性的基础水平升高，而杏仁核和海马区的ERK活性在条件反射后受到抑制。未观察到外源性N-甲基-d-天冬氨酸(NMDA)、甘氨酸和亚精胺诱导的ERK在苯环利定处理的小鼠海马片和杏仁核中的激活。重复奥氮平(3 mg/kg/d，口服)7天)，而不是氟哌啶醇(1 mg/kg/d，P.O.连续7天)，治疗逆转了反复苯环利定治疗的小鼠的联想学习和恐惧条件反射诱导的ERK激活的损害。我们的发现表明，通过NMDA受体的ERK信号异常参与了苯环利定反复治疗引起的认知功能障碍。此外，我们的苯环利定治疗的小鼠将是一个有用的模型，研究抗精神病药物对精神分裂症认知功能障碍的影响。
In humans, the administration of phencyclidine causes schizophrenic-like symptoms that persist for several weeks after withdrawal from phencyclidine use. We demonstrated here that mice pretreated with phencyclidine (10 mg/kg/day s.c. for 14 days) showed an enduring impairment of associative in a Pavlovian fear conditioning 8 days after cessation of phencyclidine treatment. Extracellular signaling-regulated kinase (ERK) was transiently activated in the amygdalae and hippocampi of saline-treated mice after conditioning. In the phencyclidine-treated mice, the basal level of ERK activation was elevated in the hippocampus, whereas the activation was impaired in the amygdala and hippocampus after conditioning. Exogenous N-methyl-d-aspartate (NMDA), glycine, and spermidine-induced ERK activation was not observed in slices of hippocampus and amygdala prepared from phencyclidine-treated mice. Repeated olanzapine (3 mg/kg/day p.o. for 7 days), but not haloperidol (1 mg/kg/day p.o. for 7 days), treatment reversed the impairment of associative learning and of fear conditioning-induced ERK activation in repeated phencyclidine-treated mice. Our findings suggest an involvement of abnormal ERK signaling via NMDA receptors in repeated phencyclidine treatment-induced cognitive dysfunction. Furthermore, our phencyclidine-treated mice would be a useful model for studying the effect of antipsychotics on cognitive dysfunction in schizophrenia.