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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.