Animal model of schizophrenia: Dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine

Toshitaka Nabeshima, Akihiro Mouri, Rina Murai, Yukihiro Noda

Research output: Chapter in Book/Report/Conference proceedingConference contribution

55 Citations (Scopus)

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. Ca2+/ 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.

Original languageEnglish
Title of host publicationIntegrated Molecular Medicine for Neuronal and Neoplastic Disorders
PublisherBlackwell Publishing Inc.
Pages160-168
Number of pages9
ISBN (Print)1573316555, 9781573316552
DOIs
Publication statusPublished - 11-2006
Externally publishedYes

Publication series

NameAnnals of the New York Academy of Sciences
Volume1086
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

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All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

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. In Integrated Molecular Medicine for Neuronal and Neoplastic Disorders (pp. 160-168). (Annals of the New York Academy of Sciences; Vol. 1086). Blackwell Publishing Inc.. https://doi.org/10.1196/annals.1377.003