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Molecular Pharmacology

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Research ArticleArticle

Involvement of a Dysfunctional Dopamine-D1/N-Methyl-d-aspartate-NR1 and Ca2+/Calmodulin-Dependent Protein Kinase II Pathway in the Impairment of Latent Learning in a Model of Schizophrenia Induced by Phencyclidine

Akihiro Mouri, Yukihiro Noda, Akihiro Noda, Tomonobu Nakamura, Takanobu Tokura, Yoshimitsu Yura, Atsumi Nitta, Hiroshi Furukawa and Toshitaka Nabeshima
Molecular Pharmacology June 2007, 71 (6) 1598-1609; DOI: https://doi.org/10.1124/mol.106.032961
Akihiro Mouri
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Yukihiro Noda
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Akihiro Noda
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Tomonobu Nakamura
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Takanobu Tokura
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Yoshimitsu Yura
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Atsumi Nitta
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Hiroshi Furukawa
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Toshitaka Nabeshima
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Abstract

Continuous ingestion of phencyclidine (PCP) in humans produces long-lasting schizophrenic-like cognitive dysfunction. Although a malfunction of dopaminergic and/or glutamatergic neurotransmission is implicated in the etiology of schizophrenia, involvement of the dopaminergic-glutamatergic neurotransmission in the cognitive dysfunction induced by repeated PCP treatment is minor. We demonstrated that mice treated with PCP (10 mg/kg/day s.c.) for 14 days displayed an impairment of latent learning in a water-finding task and of learning-associated phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and NR1 in the prefrontal cortex even after drug withdrawal. The infusion of a CaMKII inhibitor and NR1 antisense oligonucleotide into the prefrontal cortex produced an impairment of latent learning and decrease of learning-associated phosphorylation of CaMKII, which were observed in the PCP-treated mice. Exogenous NMDA-induced CaMKII activation was not observed in slices of the prefrontal cortex prepared from mice treated repeatedly with PCP. The potentiation of NMDA receptor function by the infusion of glycine into the prefrontal cortex ameliorated these impairments in mice treated repeatedly with PCP. The high potassium-stimulated release of dopamine from the prefrontal cortex was less extensive in the PCP-treated than saline-treated mice. The infusion of a dopamine-D1 receptor agonist into the prefrontal cortex attenuated the impairment of latent learning and decrease of learning-associated NR1 phosphorylation in the PCP-treated mice, suggesting a functional linkage between glutamatergic and dopaminergic signaling. These findings indicate that repeated PCP treatment impairs latent learning through a prefrontal cortical dysfunction of NMDA-CaMKII signaling, which is associated with dopaminergic hypofunction.

Footnotes

  • This work was supported, in part, by grants-in-aid for scientific research from the Japan Society for the Promotion of Science (14370031, 15922139, 16922036, and 17390018) and for Scientific Research on Priority Areas on “elucidation of glia-neuron network mediated information processing systems” from the Ministry of Education, Culture, Sports, Science and Technology (16047214), by funds from Integrated Molecular Medicine for Neuronal and Neoplastic Disorders [21st Century COE (Center of Excellence) program], from the Research on Regulatory Science of Pharmaceuticals and Medical Devices, from the Japan Brain Foundation, and from the Mitsubishi Pharma Research Foundation, and by an SRF (Smoking Research Foundation) Grant for Biomedical Research.

  • A.M. and Y.N. contributed equally to this work.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.032961.

  • ABBREVIATIONS: NMDA, N-methyl-d-aspartate; PCP, phencyclidine [1-(1-phenylcyclohexyl) piperidine hydrochloride]; KN93, 2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine; KN92, 2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine; NR1 subunit; N-methyl-d-aspartate receptor ζ subunit; CaMKII, Ca2+/calmodulin-dependent protein kinase II; SKF81297, (±)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; AP, anteroposterior; ML, mediolateral; PKA, protein kinase A; ANOVA, analysis of variance.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received November 23, 2006.
    • Accepted March 7, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (6)
Molecular Pharmacology
Vol. 71, Issue 6
1 Jun 2007
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Research ArticleArticle

Involvement of a Dysfunctional Dopamine-D1/N-Methyl-d-aspartate-NR1 and Ca2+/Calmodulin-Dependent Protein Kinase II Pathway in the Impairment of Latent Learning in a Model of Schizophrenia Induced by Phencyclidine

Akihiro Mouri, Yukihiro Noda, Akihiro Noda, Tomonobu Nakamura, Takanobu Tokura, Yoshimitsu Yura, Atsumi Nitta, Hiroshi Furukawa and Toshitaka Nabeshima
Molecular Pharmacology June 1, 2007, 71 (6) 1598-1609; DOI: https://doi.org/10.1124/mol.106.032961

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Research ArticleArticle

Involvement of a Dysfunctional Dopamine-D1/N-Methyl-d-aspartate-NR1 and Ca2+/Calmodulin-Dependent Protein Kinase II Pathway in the Impairment of Latent Learning in a Model of Schizophrenia Induced by Phencyclidine

Akihiro Mouri, Yukihiro Noda, Akihiro Noda, Tomonobu Nakamura, Takanobu Tokura, Yoshimitsu Yura, Atsumi Nitta, Hiroshi Furukawa and Toshitaka Nabeshima
Molecular Pharmacology June 1, 2007, 71 (6) 1598-1609; DOI: https://doi.org/10.1124/mol.106.032961
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