TY - JOUR
T1 - Co-Administration of a D-Amino Acid Oxidase Inhibitor Potentiates the Efficacy of D-Serine in Attenuating Prepulse Inhibition Deficits After Administration of Dizocilpine
AU - Hashimoto, Kenji
AU - Fujita, Yuko
AU - Horio, Mao
AU - Kunitachi, Shinsui
AU - Iyo, Masaomi
AU - Ferraris, Dana
AU - Tsukamoto, Takashi
N1 - Funding Information:
This study was supported in part by grants from the Minister of Education, Culture, Sports, Science, and Technology of Japan (to KH).
PY - 2009/6/15
Y1 - 2009/6/15
N2 - Background: D-Serine, an endogenous agonist of the N-methyl-D-aspartate (NMDA) receptors, is effective in the treatment of schizophrenia. However, orally administered D-serine is metabolized substantially by D-amino acid oxidase (DAAO), diminishing its oral bioavailability. In this study, we examined the effects of oral D-serine administration with or without a DAAO inhibitor, 5-chloro-benzo[d]isoxazol-3-ol (CBIO), on the prepulse inhibition (PPI) deficits after administration of the NMDA receptor antagonist dizocilpine. Methods: Vehicle or D-serine (30, 300, or 900 mg/kg) with or without CBIO (30 mg/kg) was orally administered to mice 1 hour before administration of dizocilpine (.1 mg/kg), and then the PPI of the acoustic startle response was measured. We measured the extracellular levels of D-serine in the frontal cortex after oral administration of D-serine with or without CBIO. Results: Coadministration of CBIO with D-serine (30 mg/kg), but not D-serine (30 mg/kg) alone, significantly attenuated dizocilpine-induced PPI deficits. Furthermore, coadministration of CBIO significantly increased the extracellular levels of D-serine in the frontal cortex after administration of D-serine. Conclusions: These findings suggest that coadministration of CBIO significantly enhanced the efficacy of D-serine in attenuating PPI deficits by administration of dizocilpine. Therefore, coadministration of D-serine and a DAAO inhibitor has therapeutic potential for the treatment of schizophrenia.
AB - Background: D-Serine, an endogenous agonist of the N-methyl-D-aspartate (NMDA) receptors, is effective in the treatment of schizophrenia. However, orally administered D-serine is metabolized substantially by D-amino acid oxidase (DAAO), diminishing its oral bioavailability. In this study, we examined the effects of oral D-serine administration with or without a DAAO inhibitor, 5-chloro-benzo[d]isoxazol-3-ol (CBIO), on the prepulse inhibition (PPI) deficits after administration of the NMDA receptor antagonist dizocilpine. Methods: Vehicle or D-serine (30, 300, or 900 mg/kg) with or without CBIO (30 mg/kg) was orally administered to mice 1 hour before administration of dizocilpine (.1 mg/kg), and then the PPI of the acoustic startle response was measured. We measured the extracellular levels of D-serine in the frontal cortex after oral administration of D-serine with or without CBIO. Results: Coadministration of CBIO with D-serine (30 mg/kg), but not D-serine (30 mg/kg) alone, significantly attenuated dizocilpine-induced PPI deficits. Furthermore, coadministration of CBIO significantly increased the extracellular levels of D-serine in the frontal cortex after administration of D-serine. Conclusions: These findings suggest that coadministration of CBIO significantly enhanced the efficacy of D-serine in attenuating PPI deficits by administration of dizocilpine. Therefore, coadministration of D-serine and a DAAO inhibitor has therapeutic potential for the treatment of schizophrenia.
KW - Bioavailability
KW - D-Amino acid oxidase
KW - D-Serine
KW - NMDA receptors
KW - prepulse inhibition
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U2 - 10.1016/j.biopsych.2009.01.002
DO - 10.1016/j.biopsych.2009.01.002
M3 - Article
C2 - 19217074
AN - SCOPUS:67349116852
SN - 0006-3223
VL - 65
SP - 1103
EP - 1106
JO - Biological psychiatry
JF - Biological psychiatry
IS - 12
ER -