2006 Fiscal Year Final Research Report Summary
Development of nobel pharmacotherapy for schziphrenia targeted at the NMDA receptor-D-serine system
| Project/Area Number |
17390317
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Psychiatric science
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
NISHIKAWA Toru Tokyo Medical and Dental University, Graduate School, Professor, 大学院医歯学総合研究科, 教授 (00198441)
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| Co-Investigator(Kenkyū-buntansha) |
KURUMAJI Akeo Tokyo Medical and Dental University, Graduate School, Associate Professor, 大学院医歯学総合研究科, 助教授 (00251504)
YAMAMOTO Naoki Tokyo Medical and Dental University Medical Hospital, Psychiatry, Assistant Professor, 医学部附属病院, 講師 (70312296)
ISHII Sumikazu Tokyo Medical and Dental University Medical Hospital, Psychiatry, Research Assistant, 医学部, 教務職員 (20106660)
OSHIMA Kazunari Tokyo Medical and Dental University Medical Hospital, Psychiatry, Research Associate, 医学部附属病院, 助手 (60345288)
SHIMAZU Dai Tokyo Medical and Dental University Graduate School, Psychiatry and Behavioral Sciences, Research Associate, 大学院医歯学総合研究科, 助手 (90436642)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Schizophrenia / Glutamate / D-Serine / NMDA receptor / Antipsychotic-resistant symptoms / Neocortex / D-Cycloserine / Glia |
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| Research Abstract |
In this research project, we are trying to develop a novel class of anti-schizophrenic drugs that ameliorate the conventional antipsychotic-resistant symptoms of schizophrenia by facilitating the N-methyl-D-aspartate (NMDA) type glutamate receptor functions. To this end, we studied the molecular and cellular basis of the D-serine signaling in the brain that has been considered to maintain the physiological activation of the NMDA receptor. Also, we planned the clinical test to evaluate the effects of the oral application of D-cycloserine, a partial agonist of the glutamate receptor, on the negative symptoms of schizophrenic patients that are refractory to antipsychotics.
A body of evidence has been accumulated indicating that D-serine is an endogenous coagonist for the NMDA receptor in the mammalian brain. Thus, D-serine facilitates the functions of the NMDA receptor by selectively stimulating its glycine site and is present in the tissue and extracellular fluid at high contents througho
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ut life with an NR2B subunit-like distribution. The stimulation of the glycine modulatory site is required for the glutamate-induced neurotransmission. Moreover, the selective elimination of D-serine by application of D-amino acid oxidase or D-serine deaminase has been reported to reduce the NMDA-mediated cGMP formation and long-term potentiation in the rat hippocampus. These findings suggest that extracellular D-serine may play a pivotal role in the regulation of the NMDA receptor. Our previous observations that depolarization stimuli including veratrin and a high concentration of potassium ion or cessation of impulse flow by tetrodotoxin failed to increase or decrease the extracellular D-serine contents, respectively, are consistent with the view that D-serine could be liberated into the extracellular fluid in a manner different from classical neurotransmitters. To get further insight into the cellular and molecular mechanisms of the regulation of extracellular D-serine release, we have investigated the effects of a gliotoxin, fluorocitrate, on the extracellular contents of D-serine in the medial frontal cortex of the rats by using HPLC with fluorometric detection. The intra-cortical infusion of the gliotoxin at the concentration of 1 mM caused a decrease in the cortical extracellular contents of D-serine by peaking at 40 min by -25% but produced an increase in those of glycine and L-serine. The attenuated glial activity by fluorocitrate was verified by a marked reduction in the extracellular glutamine contents. The present findings suggest that a group of glial cells such as a population of the protoplasmic astrocytes could, at least in part, participate differently in the regulation of the extracellular release of D-serine and another NMDA coagonist glycine in the medial frontal cortex of the rat. A double-blind randomized crossover trial of D-cycloserine in schizophrenic patients treated with conventional antipsychotic drugs has currently been under investigation. Less
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Research Products
(47 results)
