Effects of MK-801 on the expression of serine racemase and d-amino acid oxidase mRNAs and on the D-serine levels in rat brain.
We have investigated the acute effects of the increasing doses of non-competitive N-methyl-d-aspartate receptor antagonist MK-801 (0.2-1.6 mg/kg) on the expression of serine racemase and d-amino acid oxidase (DAO) mRNAs in several brain areas of rats. We have also evaluated the effects of the chronic administration of MK-801 (0.4 mg/kg) on the gene expression of serine racemase and DAO and on the d-serine concentrations. A dose-dependent augmentation of the expression of serine racemase mRNA was seen in most brain areas at both 1 and 4 h after the administration. In contrast, a drastic decline in the expression of DAO mRNA was observed in most brain areas 1 h after the MK-801 administration, whereas a dose-dependent elevation in the expression of DAO mRNA was observed in most brain areas 4 h after the administration. The chronic MK-801 administration produced a significant increase in the expression of serine racemase mRNA in almost all brain areas, whereas no significant changes were found in the level of DAO mRNA in most brain areas. In addition, the chronic administration caused a slight but significant elevation in the concentrations of d-serine in the cortex and striatum. These present findings indicate that increasing the serine racemase mRNA and no changes in the DAO mRNA after the chronic administration could contribute to the elevation of the d-serine level in the forebrain, and that serine racemase and DAO could play an important role in the regulation of N-methyl-d-aspartate receptors via the d-serine metabolism.
Hashimoto
Atsushi
A
Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan. hashimot@is.icc.u-tokai.ac.jp
Yoshikawa
Masanobu
M
Andoh
Hidehiro
H
Yano
Hiroshi
H
Matsumoto
Hideo
H
Kawaguchi
Mitsuru
M
Oka
Tetsuo
T
Kobayashi
Hiroyuki
H
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003605:D-Amino-Acid Oxidase / Q000235:genetics*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D019998:Racemases and Epimerases / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012694:Serine / Q000378:metabolism; D000099300:Serine Racemase
D003605:D-Amino-Acid Oxidase; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D012333:RNA, Messenger; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D000099300:Serine Racemase