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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

Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan (T.E., Y.N., A.M., E.-J.S., D.W., R.M., K.H., A.N., T.N.); Division of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, Japan (Y.N.); Neurotoxicology Program, College of Pharmacy, Kangwon National University, Chunchon, South Korea (E.-J.S., H.-C.K.); and Department of Medical Chemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan (H.F.)

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.

Received for publication January 21, 2005.

Accepted for publication September 7, 2005.

Address correspondence to: Drs. Toshitaka Nabeshima and Yukihiro Noda, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurum-cho, Showa-ku, Nagoya 466-8560, Japan. E-mail: tnabeshi{at}med.nagoya-u.ac.jp; y-noda{at}med.nagoya-u.ac.jp

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