Effects of D-Amino Acid Oxidase Inhibitor on the Extracellular D-Alanine Levels and the Efficacy of D-Alanine on Dizocilpine-Induced Prepulse Inhibition Deficits in Mice



Mao Horio1, Yuko Fujita1, Tamaki Ishima1, Masaomi Iyo2, Dana Ferraris3, Takashi Tsukamoto3, Kenji Hashimoto*, 1
1 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan
2 Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan and
3 Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan and Eisai Research Institute, Baltimore, MD 21224, USA


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© 2009 Horio et al;

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana Chiba 260-8670, Japan; Tel: +81-43-226-2147; Fax: +81-43-226-2150; E-mail: hashimoto@faculty.chiba-u.jp


Abstract

D-Alanine, one of D-amino acids present in the mammalian brain, is a selective and potent agonist at the Nmethyl- D-aspartate (NMDA) receptors. Like D-serine, D-alanine is reported to be effective in the treatment of schizophrenia. However, orally given D-alanine is metabolized substantially by D-amino acid oxidase (DAAO), diminishing its oral bioavailability. In this study, we studied the effects of oral D-alanine administration with or without the novel DAAO inhibitor, 5-chloro-benzo[d]isoxazol-3-ol (CBIO), on the extracellular D-alanine levels in the brain and on the prepulse inhibition (PPI) deficits after administration of the NMDA receptor antagonist dizocilpine. Co-administration of CBIO (30 mg/kg) with D-alanine (100 mg/kg), but not D-alanine (100 mg/kg) alone, significantly attenuated dizocilpine (0.1 mg/kg)-induced PPI deficits in mice. The in vivo microdialysis study of the conscious and free moving mice revealed that co-administration of CBIO (30 mg/kg) significantly increased extracellular levels of D-alanine in the frontal cortex after oral administration of D-alanine (100 mg/kg). These findings suggest that co-administration of CBIO can increase the bioavailability of D-alanine after oral administration of D-alanine, and that co-administration of CBIO can enhance the efficacy of D-alanine on dizocilpine-induced PPI deficits. Therefore, combination of D-alanine and a DAAO inhibitor such as CBIO offers new therapeutic potential for treatment of schizophrenia.

Keywords: D-Alanine, D-amino acid oxidase, NMDA receptors, Prepulse inhibition, Schizophrenia, Bioavailability.