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Animal model of schizophrenia: dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine.
Ann N Y Acad Sci 2006; 1086:160-8AN

Abstract

In humans, phencyclidine (PCP), a noncompetitive N-methyl-d-aspartate (NMDA) antagonist, reproduces a schizophrenia-like psychosis such as positive/negative symptoms and cognitive deficits. PCP (10 mg/kg/day for 14 days)-treated mice exhibit the enhanced immobility in a forced swimming test as indexes of negative symptoms and impairment of latent learning in a water finding test as indexes of cognitive deficits. These behavioral deficits remain after withdrawal from repeated PCP treatment and are attenuated by atypical antipsychotics, but not by typical antipsychotics. Since it has been hypothesized that insufficient glutamate neurotransmission is involved in the pathophysiology of schizophrenia, we investigated an involvement of glutamatergic system in emotional and cognitive deficits in mice treated with PCP repeatedly. Ca(2+)/calmodulin kinase II (CaMKII) is markedly phosphorylated after the forced swimming test and the training trial of water finding test in the prefrontal cortex of saline-treated mice but not PCP-treated mice. Facilitation of NMDA receptor function by NMDA receptor glycine-site agonists such as D-cycloserine and glycine is effective on the abnormal intracellular signaling, and emotional and cognitive deficits in mice treated with PCP repeatedly. The repeated PCP treatment impaired NMDA receptor function and decreased levels of spontaneous extracellular glutamate in the prefrontal cortex, indicating that the repeated PCP treatment impairs both pre- and postsynaptic glutamate transmissions. Our findings suggest that abnormal NMDA receptor signaling is involved in the emotional and cognitive deficits in mice treated with PCP repeatedly. Our PCP-treated mice would be a useful model for studying the effect of antipsychotics on emotional and cognitive deficits in schizophrenia.

Authors+Show Affiliations

Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan. tnabeshi@med.nagoya-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

17185514

Citation

Nabeshima, Toshitaka, et al. "Animal Model of Schizophrenia: Dysfunction of NMDA Receptor-signaling in Mice Following Withdrawal From Repeated Administration of Phencyclidine." Annals of the New York Academy of Sciences, vol. 1086, 2006, pp. 160-8.
Nabeshima T, Mouri A, Murai R, et al. Animal model of schizophrenia: dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine. Ann N Y Acad Sci. 2006;1086:160-8.
Nabeshima, T., Mouri, A., Murai, R., & Noda, Y. (2006). Animal model of schizophrenia: dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine. Annals of the New York Academy of Sciences, 1086, pp. 160-8.
Nabeshima T, et al. Animal Model of Schizophrenia: Dysfunction of NMDA Receptor-signaling in Mice Following Withdrawal From Repeated Administration of Phencyclidine. Ann N Y Acad Sci. 2006;1086:160-8. PubMed PMID: 17185514.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Animal model of schizophrenia: dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine. AU - Nabeshima,Toshitaka, AU - Mouri,Akihiro, AU - Murai,Rina, AU - Noda,Yukihiro, PY - 2006/12/23/pubmed PY - 2007/2/14/medline PY - 2006/12/23/entrez SP - 160 EP - 8 JF - Annals of the New York Academy of Sciences JO - Ann. N. Y. Acad. Sci. VL - 1086 N2 - In humans, phencyclidine (PCP), a noncompetitive N-methyl-d-aspartate (NMDA) antagonist, reproduces a schizophrenia-like psychosis such as positive/negative symptoms and cognitive deficits. PCP (10 mg/kg/day for 14 days)-treated mice exhibit the enhanced immobility in a forced swimming test as indexes of negative symptoms and impairment of latent learning in a water finding test as indexes of cognitive deficits. These behavioral deficits remain after withdrawal from repeated PCP treatment and are attenuated by atypical antipsychotics, but not by typical antipsychotics. Since it has been hypothesized that insufficient glutamate neurotransmission is involved in the pathophysiology of schizophrenia, we investigated an involvement of glutamatergic system in emotional and cognitive deficits in mice treated with PCP repeatedly. Ca(2+)/calmodulin kinase II (CaMKII) is markedly phosphorylated after the forced swimming test and the training trial of water finding test in the prefrontal cortex of saline-treated mice but not PCP-treated mice. Facilitation of NMDA receptor function by NMDA receptor glycine-site agonists such as D-cycloserine and glycine is effective on the abnormal intracellular signaling, and emotional and cognitive deficits in mice treated with PCP repeatedly. The repeated PCP treatment impaired NMDA receptor function and decreased levels of spontaneous extracellular glutamate in the prefrontal cortex, indicating that the repeated PCP treatment impairs both pre- and postsynaptic glutamate transmissions. Our findings suggest that abnormal NMDA receptor signaling is involved in the emotional and cognitive deficits in mice treated with PCP repeatedly. Our PCP-treated mice would be a useful model for studying the effect of antipsychotics on emotional and cognitive deficits in schizophrenia. SN - 0077-8923 UR - https://www.unboundmedicine.com/medline/citation/17185514/Animal_model_of_schizophrenia:_dysfunction_of_NMDA_receptor_signaling_in_mice_following_withdrawal_from_repeated_administration_of_phencyclidine_ L2 - https://doi.org/10.1196/annals.1377.003 DB - PRIME DP - Unbound Medicine ER -