Antipsychotic Potential of Quinazoline ErbB1 Inhibitors in a Schizophrenia Model Established With Neonatal Hippocampal Lesioning

Makoto Mizuno; Yuriko Iwakura; Masako Shibuya; Yingjun Zheng; Takeyoshi Eda; Taisuke Kato; Yohei Takasu; Hiroyuki Nawa

doi:10.1254/jphs.10099FP

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Antipsychotic Potential of Quinazoline ErbB1 Inhibitors in a Schizophrenia Model Established With Neonatal Hippocampal Lesioning

Makoto Mizuno, Yuriko Iwakura, Masako Shibuya, Yingjun Zheng, Takeyoshi Eda, Taisuke Kato, Yohei Takasu, Hiroyuki Nawa

Author information

Makoto Mizuno
Center for Transdisciplinary Research, Niigata University, Japan
Yuriko Iwakura
Molecular Neurobiology, Brain Research Institute, Niigata University, Japan
Masako Shibuya
Molecular Neurobiology, Brain Research Institute, Niigata University, Japan
Yingjun Zheng
Molecular Neurobiology, Brain Research Institute, Niigata University, Japan
Takeyoshi Eda
Molecular Neurobiology, Brain Research Institute, Niigata University, Japan
Taisuke Kato
Molecular Neurobiology, Brain Research Institute, Niigata University, Japan
Yohei Takasu
Molecular Neurobiology, Brain Research Institute, Niigata University, Japan
Hiroyuki Nawa
Center for Transdisciplinary Research, Niigata University, Japan
Molecular Neurobiology, Brain Research Institute, Niigata University, Japan

Keywords: antipsychotic, hippocampal lesion, schizophrenia, epidermal growth factor (EGF), epidermal growth factor receptor (EGFR)

JOURNAL FREE ACCESS

2010 Volume 114 Issue 3 Pages 320-331

DOI https://doi.org/10.1254/jphs.10099FP

View "Advance Publication" version (October 14, 2010).

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Abstract

Hyper-signaling of the epidermal growth factor receptor family (ErbB) is implicated in the pathophysiology of schizophrenia. Various quinazoline inhibitors targeting ErbB1 or ErbB2 – 4 have been developed as anti-cancer agents and might be useful for antipsychotic treatment. In the present study, we used an animal model of schizophrenia established by neonatal hippocampal lesioning and evaluated the neurobehavioral consequences of ErbB1-inhibitor treatment. Subchronic administration of the ErbB1 inhibitor ZD1839 to the cerebroventricle of rats receiving neonatal hippocampal lesioning ameliorated deficits in prepulse inhibition as well as those in the latent inhibition of tone-dependent fear learning. There were no apparent adverse effects on basal learning scores or locomotor activity, however. The administration of other ErbB1 inhibitors, PD153035 and OSI-774, similarly attenuated the prepulse inhibition impairment of this animal model. In parallel, there were decreases in ErbB1 phosphorylation in animals treated with ErbB1 inhibitors. These results indicate an antipsychotic potential of quinazoline ErbB1 inhibitors. ErbB receptor tyrosine kinases may be novel therapeutic targets for schizophrenia or its related psychotic symptoms.

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