TY - JOUR T1 - Long-Lasting Impairment of Associative Learning Is Correlated with a Dysfunction of <em>N</em>-Methyl-<span class="sc">d</span>-aspartate-Extracellular Signaling-Regulated Kinase Signaling in Mice after Withdrawal from Repeated Administration of Phencyclidine JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1765 LP - 1774 DO - 10.1124/mol.105.011304 VL - 68 IS - 6 AU - Takeshi Enomoto AU - Yukihiro Noda AU - Akihiro Mouri AU - Eun-Joo Shin AU - Dayong Wang AU - Rina Murai AU - Kazuo Hotta AU - Hiroshi Furukawa AU - Atsumi Nitta AU - Hyoung-Chun Kim AU - Toshitaka Nabeshima Y1 - 2005/12/01 UR - http://molpharm.aspetjournals.org/content/68/6/1765.abstract N2 - 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. ER -