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.
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.
Enomoto
Takeshi
T
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurum-cho, Showa-ku, Nagoya 466-8560, Japan.
Noda
Yukihiro
Y
Mouri
Akihiro
A
Shin
Eun-Joo
EJ
Wang
Dayong
D
Murai
Rina
R
Hotta
Kazuo
K
Furukawa
Hiroshi
H
Nitta
Atsumi
A
Kim
Hyoung-Chun
HC
Nabeshima
Toshitaka
T
D000679:Amygdala / Q000187:drug effects; D000818:Animals; D003213:Conditioning, Psychological; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis / Q000378:metabolism*; D005239:Fear; D006624:Hippocampus / Q000187:drug effects; D007859:Learning Disabilities / Q000139:chemically induced* / Q000188:drug therapy; D020935:MAP Kinase Signaling System; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology*; D010622:Phencyclidine / Q000008:administration & dosage / Q000633:toxicity*; D013375:Substance Withdrawal Syndrome
D016202:N-Methylaspartate; D048049:Extracellular Signal-Regulated MAP Kinases; D010622:Phencyclidine