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, Toshitaka Nabeshima

Research output: Contribution to journalArticle

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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 learningassociated 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 PCPtreated 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.

Original languageEnglish
Pages (from-to)1598-1609
Number of pages12
JournalMolecular Pharmacology
Volume71
Issue number6
DOIs
Publication statusPublished - 01-06-2007
Externally publishedYes

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Phencyclidine
N-Methylaspartate
Prefrontal Cortex
Dopamine
Schizophrenia
Learning
Phosphorylation
Synaptic Transmission
Dopamine D1 Receptors
Antisense Oligonucleotides
Dopamine Agonists
Protein Kinase Inhibitors
N-Methyl-D-Aspartate Receptors
Glycine
Potassium
Eating
Water
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "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",
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 learningassociated 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 PCPtreated 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.",
author = "Akihiro Mouri and Yukihiro Noda and Akihiro Noda and Tomonobu Nakamura and Takanobu Tokura and Yoshimitsu Yura and Atsumi Nitta and Hiroshi Furukawa and Toshitaka Nabeshima",
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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. / Mouri, Akihiro; Noda, Yukihiro; Noda, Akihiro; Nakamura, Tomonobu; Tokura, Takanobu; Yura, Yoshimitsu; Nitta, Atsumi; Furukawa, Hiroshi; Nabeshima, Toshitaka.

In: Molecular Pharmacology, Vol. 71, No. 6, 01.06.2007, p. 1598-1609.

Research output: Contribution to journalArticle

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T1 - 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

AU - Mouri, Akihiro

AU - Noda, Yukihiro

AU - Noda, Akihiro

AU - Nakamura, Tomonobu

AU - Tokura, Takanobu

AU - Yura, Yoshimitsu

AU - Nitta, Atsumi

AU - Furukawa, Hiroshi

AU - Nabeshima, Toshitaka

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AB - 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 learningassociated 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 PCPtreated 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.

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