脳内神経伝達物質の長期効果に関する分子生物学的研究

1993 Fiscal Year Annual Research Report

• Project/Area Number: 04044143
• Research Institution: The Open University of Japan
• Principal Investigator: 鬼頭 昭三 放送大学, 教養学部, 教授 (00010140)
• Co-Investigator(Kenkyū-buntansha): 仙波 純一 放送大学, 教養学部, 助教授 (30183429) ; BARNARD Elic Royal Free Hospital School of Medicine, Professor ; VENTER Graig National Institute of Health, Chief Prof ; JOH Tong H Cornell University Medical College, Professor ; 三好 理絵 東京女子医科大学, 助手 (80209965) ; 遠山 正彌 大阪大学, 医学部, 教授 (40028593) ; 佐藤 公道 京都大学, 薬学部, 教授 (80025709) ; OLSEN Richar UCLA School of Medicine, Professor
• Keywords: steroid hormon / dexamethasone / in vivo microdialysis / estrogen / glutamate / 海馬 / Ca^<2+> / 扁桃核

Research Abstract

ステロイドホルモンは、核内または、細胞質内の受容体を介して、genomicな長期効果を持つ他に、近年は、細胞膜の特異的結合部位を介して、non-genomicな短期効果を持つことが知られている。長期効果と短期効果のクロストークを明らかにすることが本研究の目的である。一方、ステロイドホルモンは神経細胞に対し毒性を示す可能性が私達によって明らかされ、そのメカニズムを探ることによって上記の研究目的を達することにしている。
すなわち、dexamethasoneは海馬培養神経細胞にたいするカイニン酸の毒性を用量依存的に増強する。一方、dexamethasoneは単独では毒性を示さない。このメカニズムを探る目的でin vivo microdialysisによって、ラット海馬における神経伝達物質の放出に対するdexamethasoneの影響を観察した。その結果dexamethasoneはラット海馬からのglutamateの放出を増強することを認めた。genomicな作用としては海馬の神経細胞が傷害されたときに修複機転として働くHGF遺伝子の発現をdexamethasoneが抑制することが考えられたが、この点について確認の実験を継続中である。
更に、estrogenが扁桃核培養神経細胞に対して、単独で高濃度で障害作用を示すことがみられた。このメカニズムを探るために扁桃核にestrogenを加えることにより細胞内Ca^<2+>imagingの実験を行った。その結果10分間、もしくはそれ以上にわたってCa^<2+>濃度の上昇をきたすことを認めた。Ca^<2+>濃度の上昇は短い潜時で急激な立ち上がりを示す場合と、徐々に上昇する場合とが見られた。これらのメカニズムについてさらに検討を続けている。

Research Products

• [Publications] Miyoshi,R.: "Effect of caerulein on expression of the immediate-early genes c-fos and zif/268 in the rat brain." Neuroscience Letters. 145. 205-208 (1992)
• [Publications] Miyoshi,R.: "Effect of estrogen on immediate early gene exprssion in the rat brain." Society for Neuroscience Abstracts. 18. 57.1 (1992)
• [Publications] Kito,S.: "Effect of glucocorticoid on in vivo release of neurotransmitters from the rat hippocampus." Society for Neuroscience Abstracts. 18. 57.4 (1992)
• [Publications] Shimoyama,M.: "Effect of mineralcorticoid on in vivo release of neurotransmitters from the rat hippocampus." Society for Neuroscience Abstracts. 18. 57.3 (1992)
• [Publications] Kito,S.: "A cytoprotective effect of nicotine on hippocampal neurons." Society for Neuroscience Abstracts. 19. 772.15 (1993)
• [Publications] Miyoshi,R.: "Effect of nicotine on neurotransmitter release from the rat hippocampus." Society for Neuroscience Abstracts. 19. 384.6 (1993)
• [Publications] Kito,S.: "Effect of glucocorticoid on hippocampal neurons:in vivo and in vitro studies." Neurochemical Research. 18. 801-860 (1993)
• [Publications] Kokka,N.: "The kindling model of alcohol dependence:similar persistent reduction in seizure threshold to pentylenetetrazol in animals receiving chronic ethanol" Alcohol clin.Exp.Res.17. 525-531 (1993)
• [Publications] Kokka,N.: "The kindling model of alcohol dependence:similar persistent reduction in seizure threshold to pentylenetetrazol in animals receiving chronic ethanol" Alcohol clin.Exp.Res.17. 525-531 (1993)"or chronic pentylenetrazol"
• [Publications] Longoni,B.: "Enhancement of gamma-aminobutyric acidA receptor function and binding by the volatile anesthetic halothane" J.Pharmacol.Exp.Ther.266. 153-159 (1993)
• [Publications] Browning,M.D.: "Phosphorylation of the GABAA receptor by CAMP-dependent protein kinase and by protein kinase C:analysis of the substrate domain" Neurochem.Res.18. 95-100 (1993)
• [Publications] Maeda,T.: "Bidirectional modulation of long-term potentiation by carbachol via M_1 and M_2 muscarinic receptors in guinea pig hippocampal mossy liber‐CA3 synapses." Brain Research Biophysical Research Communications. 619. 324-330 (1993)
• [Publications] Ozaki,M.: "A vaccinia virus vector for efficiently introducing into hippocampal slices." Biochemical and. 193. 653-660 (1993)
• [Publications] Nakamura,S.: "Potentiation of a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)-selective glutamate receptor function by a nootropic drug.idebenone." Biol.Pharm.Bull.17. 70-73 (1994)
• [Publications] Masana Y: "Localization of trkB mRNA in postnatal brain development." J Neurosci Res. 35. 468-79 (1993)
• [Publications] Yoshimura R: "Localization of oxytocin receptor messenger ribonucleic acid in the rat brain." Endocrinology. 133. 1239-46 (1993)
• [Publications] Takatsuji K: "Differential effects on substance P immunoreactivity in rat suprachiasmatic and olivary pretectal nuclei." Neuroreport. 4. 647-50 (1993)
• [Publications] Kito,S.: "A cytoprotective effect of nicotine on hippocampal neurons." Society for Neuroscience Abstracts. 19. 772.15 (1993)
• [Publications] Miyoshi,R.: "Effect of nicotine on neurotransmitter release from the rat hippocampus." Society for Neuroscience Abstracts. 19. 384.6 (1993)
• [Publications] Kito,S.: "Effect of glucocorticoid on hippocampal neurons:in vivo and in vitro studies." Neurochemical Research. 18. 801-860 (1993)
• [Publications] Weiser,M.: "Differntial spatial and temporal gene expression in response to axotomy and differentation following transection of the medial forebrain bundle" J.Neurosci.13. 3472-3484 (1993)
• [Publications] Kim,K.S.: "Both the basal and inducible transcription of the tyrosine hydroxylase gene are dependent upon a cAMP response element" J.Biol.Chem.268. 15689-15695 (1993)
• [Publications] Weiser,M.: "Axotomy-induced differential gene induction in neurons of the locus ceruleus and substantia nigra." Brain Res.Mol.Brain Res.17. 319-327 (1993)
• [Publications] Fraser,C.M.: "Beta-adrenergic and muscarinic cholinergic receptors:relationship between primary structure,receptor function and regulation" American Review of Respiratory Disease. 141. (1990)
• [Publications] Venter,J.C.: "Isolation,purification and molecular biology of cell membrane receptors" Comprehensive Medicinal Chemistry. 3. (1990)
• [Publications] Venter,J.C.: "Genome sequencing conference I:Summary" Genomics. 8. (1990)
• [Publications] Usherwood,P.N.: "Channels formed:by M2 peptides of a putative glutamate receptor subunit of locust." EXS. 63. 241-249 (1993)
• [Publications] Kerry,C.J.: "Reconstitution of glutamate receptor proteins purified from xenopus central nervous system into artificial bilayers." Mol.Pharmacol.44. 142-152 (1993)
• [Publications] Webb,T.E.: "Cloning and functional expression of a brain G-proteincoupled ATP receptor." FEBS Lett.324. 219-225 (1993)
• [Publications] Semba,J.: "Antiepileptic drug phrmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid:milacemide." Br.J.Pharmacol.108. 1117-1124 (1993)
• [Publications] Semba,J.: "Milacemide effcts on the temporal interrelationship of amino acids and monoamine metabolites in rat cerebrospinal fluid." European Journal of Pharmacology. 230. 321-326 (1993)