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

52 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 - 01-01-2006
Externally publishedYes

Publication series

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

Fingerprint

Phencyclidine
N-Methyl-D-Aspartate Receptors
Schizophrenia
Animals
Animal Models
Antipsychotic Agents
Glutamic Acid
Glycine
Cycloserine
Calcium-Calmodulin-Dependent Protein Kinases
Water
Prefrontal Cortex
N-Methylaspartate
Neurobehavioral Manifestations
Animal Model
Mouse
Synaptic Transmission
Psychotic Disorders
Learning
Emotion

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
Nabeshima, Toshitaka ; Mouri, Akihiro ; Murai, Rina ; Noda, Yukihiro. / Animal model of schizophrenia : Dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine. Integrated Molecular Medicine for Neuronal and Neoplastic Disorders. Blackwell Publishing Inc., 2006. pp. 160-168 (Annals of the New York Academy of Sciences).
@inproceedings{615e1223ab2f452cbb8f18a14c634361,
title = "Animal model of schizophrenia: Dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine",
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.",
author = "Toshitaka Nabeshima and Akihiro Mouri and Rina Murai and Yukihiro Noda",
year = "2006",
month = "1",
day = "1",
doi = "10.1196/annals.1377.003",
language = "English",
isbn = "1573316555",
series = "Annals of the New York Academy of Sciences",
publisher = "Blackwell Publishing Inc.",
pages = "160--168",
booktitle = "Integrated Molecular Medicine for Neuronal and Neoplastic Disorders",

}

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. Annals of the New York Academy of Sciences, vol. 1086, Blackwell Publishing Inc., pp. 160-168. https://doi.org/10.1196/annals.1377.003

Animal model of schizophrenia : Dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine. / Nabeshima, Toshitaka; Mouri, Akihiro; Murai, Rina; Noda, Yukihiro.

Integrated Molecular Medicine for Neuronal and Neoplastic Disorders. Blackwell Publishing Inc., 2006. p. 160-168 (Annals of the New York Academy of Sciences; Vol. 1086).

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

TY - GEN

T1 - Animal model of schizophrenia

T2 - 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 - 2006/1/1

Y1 - 2006/1/1

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. 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=34447525394&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34447525394&partnerID=8YFLogxK

U2 - 10.1196/annals.1377.003

DO - 10.1196/annals.1377.003

M3 - Conference contribution

SN - 1573316555

SN - 9781573316552

T3 - Annals of the New York Academy of Sciences

SP - 160

EP - 168

BT - Integrated Molecular Medicine for Neuronal and Neoplastic Disorders

PB - Blackwell Publishing Inc.

ER -

Nabeshima T, Mouri A, Murai R, Noda Y. 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. Blackwell Publishing Inc. 2006. p. 160-168. (Annals of the New York Academy of Sciences). https://doi.org/10.1196/annals.1377.003