抄録
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 phencyclidinetreated 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.
| 元の言語 | English |
|---|---|
| ページ（範囲） | 1765-1774 |
| ページ数 | 10 |
| ジャーナル | Molecular Pharmacology |
| 巻 | 68 |
| 発行部数 | 6 |
| DOI | |
| 出版物ステータス | Published - 01-12-2005 |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Pharmacology
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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. / Enomoto, Takeshi; Noda, Yukihiro; Mouri, Akihiro; Shin, Eun Joo; Wang, Dayong; Murai, Rina; Hotta, Kazuo; Furukawa, Hiroshi; Nitta, Atsumi; Kim, Hyoung Chun; Nabeshima, Toshitaka.
：: Molecular Pharmacology, 巻 68, 番号 6, 01.12.2005, p. 1765-1774.研究成果: Article
TY - JOUR
T1 - 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
AU - Enomoto, Takeshi
AU - Noda, Yukihiro
AU - Mouri, Akihiro
AU - Shin, Eun Joo
AU - Wang, Dayong
AU - Murai, Rina
AU - Hotta, Kazuo
AU - Furukawa, Hiroshi
AU - Nitta, Atsumi
AU - Kim, Hyoung Chun
AU - Nabeshima, Toshitaka
PY - 2005/12/1
Y1 - 2005/12/1
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 phencyclidinetreated 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.
AB - 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 phencyclidinetreated 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.
UR - http://www.scopus.com/inward/record.url?scp=27844483411&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=27844483411&partnerID=8YFLogxK
U2 - 10.1124/mol.105.011304
DO - 10.1124/mol.105.011304
M3 - Article
C2 - 16150934
AN - SCOPUS:27844483411
VL - 68
SP - 1765
EP - 1774
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 6
ER -