2003 Fiscal Year Annual Research Report

中枢興奮薬の逆耐性現象における神経可塑性を標的とした創薬研究

Research Project

Project/Area Number	15650068
Research Institution	Tohoku University
Principal Investigator	福永浩司東北大学, 大学院・薬学研究科, 教授 (90136721)
Co-Investigator(Kenkyū-buntansha)	笠原二郎東北大学, 大学院・薬学研究科, 助手 (10295131)
Keywords	メタンフェタミン / 逆耐性現象 / 統合失調症 / ドパミン受容体 / カルシウム / NF-κB / 覚醒剤中毒 / D2受容体
Research Abstract	メタンフェタミンなどの覚醒剤は連用によって感受性が亢進して、逆耐性現象が発現する。神経化学的研究から、ドパミン系機能亢進によるcAMP依存性リン酸化反応の亢進、NMDA受容体の過剰興奮によるカルシウムシグナル伝達系の亢進がその病態に関わると考えられる。私達は逆耐性モデル動物でのドパミン神経、グルタミン神経系のシグナル伝達系異常を評価する実験系を確立して、覚醒剤中毒による前頭葉機能障害や統合失調症に対する創薬を目指している。本研究では統合失調症に関与するドパミンD2受容体のサズタイプD2LとD2S受容体の細胞内局在、シグナル伝達系の違い、さらにドパミン神経系の活性をモニターするための指標について新しい知見を得た。細胞内第3ループに29アミノ酸の挿入されたD2L受容体は形質膜のみならず、小胞体、ゴルジ装置に局在するのに対してD2Sは形質膜のみに発現している。D2受容体はG_<i/o>蛋白質を介してアデニル酸シクラーゼを抑制するほかに、MAPキナーゼを活性化する。本研究によってD2L受容体はD2S受容体に比べて強いMAPキナーゼ活性化作用を有することを見いだした。特に、D2L受容体刺激後のカルシウムシグナルの活性化がMAPキナーゼの活性化反応に関わることを証明した。さらに、ドパミン神経系の活性をモニターするための指標として転写因子NF-κBが有用であることを見いだした。

Research Products
(20 results)

All Other

All Publications (20 results)

[Publications] Kikukawa, K.: "Acute changes in the axonal cytoskeleton after mild stretching of the rat brachial plexus."J.Orthopaedic Res.. 21. 359-364 (2003)
[Publications] Nomura, K.: "Involvement of calcium/calmodulin-dependent protein kinase II in the induction of mPer1."J.Neurosci.Res.. 72. 384-392 (2003)
[Publications] Takeuchi, Y.: "Differential regulationof NF-κB, SRE and CRE by dopamine D1 and D2 receptors in transfected NG108-15 cells."J.Neurochem.. 85. 729-739 (2003)
[Publications] Nishimura, H.: "Cloning, characterization, and expression of two alternatively splicing isoforms of Ca^<2+>/calmodulin-dependent protein kinase Iγ in the brain."J.Neurochem.. 85. 1216-1227 (2003)
[Publications] Takeuchi, Y.: "Differential subcellular localiztion of two dopamine D2 receptor isoforms in transfected NG108-15 cells."J.Neurochem.. 85. 1064-1074 (2003)
[Publications] Yunoue, S.: "Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GAP function toward Ras."J.Biol.Chem.. 278. 26958-26969 (2003)
[Publications] 福永浩司: "最近の話題:心肥大形成とカルシウムシグナル"日薬理誌. 121. 287 (2003)
[Publications] Sakao, E: "Two-peaked synchronization in day/night expression rhythms of the fibrinogen gene cluster in the mouse liver."J.Biol.Chem.. 278. 30450-30457 (2003)
[Publications] Fukunaga, K.: "Akt is a molecular target for signal transduction therapy in brain ischemic insult."J.Pharmacol.Sci.. 92. 317-327 (2003)
[Publications] Hasegawa, Y.: "Neuroprotective effect of postischemic administration of sodium orthovanadate in rats with transient middle cerebral artery occlusion."J.Cereb.Blood Flow & Metab.. 23. 1040-1051 (2003)
[Publications] 福永浩司: "脳血管障害の新しい創薬ターゲット分子"医学のあゆみ. 207. 61-66 (2003)
[Publications] Jourdan, P.: "CaMKII contributes to activity-dependent filopodia growth and spine formation"J.Neurosci.. 23. 10645-10649 (2003)
[Publications] Takeuchi, Y.: "Different effects of five dopamine receptor subtypes on NF-κB activity in NG108-15 cells and mouse brain."J.Neurochem.. 88. 41-50 (2004)
[Publications] Hashiguchi, A.: "Up-regulation of endothelial nitric oxide synthase via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampus."J.Cereb.Blood Flow & Metab.. 24. 271-279 (2004)
[Publications] Takeuchi, Y.: "Differential subcellular distributions of Ca^<2+>/Calmodulin-Dependent Protein kinase II subunits."J.Neurosci.Res.. (in press). (2004)
[Publications] Takeuchi, Y.: "Dopamine D2 receptor activates extracellular signal-regulated kinase through the specific region in the third cytoplasmic loop."J.Neurochem.. (in press). (2004)
[Publications] Takeuchi, Y.: "Different activation of NF-κB by stimulation of dopamine D2L and D2S receptors through calcineurin activation."J.Neurochem.. (in press). (2004)
[Publications] Iwahana, E.: "Effects of lithium on the circadian rhythms of locomotor activity and GSK-3 protein expression in the mouse suprachiasmatic nuclei."Eur.J.Neurosci. (in press). (2004)
[Publications] Miyazaki, K.: "Cell and Molecular Biology of Endometrial Carcinoma"Springer-Verlag Tokyo. 138 (2003)
[Publications] 大森始紀他: "神経回路の機能発現のメカニズム"共立出版. 500 (2004)

2003 Fiscal Year Annual Research Report

中枢興奮薬の逆耐性現象における神経可塑性を標的とした創薬研究

Principal Investigator

福永 浩司 東北大学, 大学院・薬学研究科, 教授 (90136721)

Research Products

[Publications] Kikukawa, K.: "Acute changes in the axonal cytoskeleton after mild stretching of the rat brachial plexus."J.Orthopaedic Res.. 21. 359-364 (2003)

[Publications] Nomura, K.: "Involvement of calcium/calmodulin-dependent protein kinase II in the induction of mPer1."J.Neurosci.Res.. 72. 384-392 (2003)

[Publications] Takeuchi, Y.: "Differential regulationof NF-κB, SRE and CRE by dopamine D1 and D2 receptors in transfected NG108-15 cells."J.Neurochem.. 85. 729-739 (2003)

[Publications] Nishimura, H.: "Cloning, characterization, and expression of two alternatively splicing isoforms of Ca^<2+>/calmodulin-dependent protein kinase Iγ in the brain."J.Neurochem.. 85. 1216-1227 (2003)

[Publications] Takeuchi, Y.: "Differential subcellular localiztion of two dopamine D2 receptor isoforms in transfected NG108-15 cells."J.Neurochem.. 85. 1064-1074 (2003)

[Publications] Yunoue, S.: "Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GAP function toward Ras."J.Biol.Chem.. 278. 26958-26969 (2003)

[Publications] 福永 浩司: "最近の話題:心肥大形成とカルシウムシグナル"日薬理誌. 121. 287 (2003)

[Publications] Sakao, E: "Two-peaked synchronization in day/night expression rhythms of the fibrinogen gene cluster in the mouse liver."J.Biol.Chem.. 278. 30450-30457 (2003)

[Publications] Fukunaga, K.: "Akt is a molecular target for signal transduction therapy in brain ischemic insult."J.Pharmacol.Sci.. 92. 317-327 (2003)

[Publications] Hasegawa, Y.: "Neuroprotective effect of postischemic administration of sodium orthovanadate in rats with transient middle cerebral artery occlusion."J.Cereb.Blood Flow & Metab.. 23. 1040-1051 (2003)

[Publications] 福永 浩司: "脳血管障害の新しい創薬ターゲット分子"医学のあゆみ. 207. 61-66 (2003)

[Publications] Jourdan, P.: "CaMKII contributes to activity-dependent filopodia growth and spine formation"J.Neurosci.. 23. 10645-10649 (2003)

[Publications] Takeuchi, Y.: "Different effects of five dopamine receptor subtypes on NF-κB activity in NG108-15 cells and mouse brain."J.Neurochem.. 88. 41-50 (2004)

[Publications] Hashiguchi, A.: "Up-regulation of endothelial nitric oxide synthase via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampus."J.Cereb.Blood Flow & Metab.. 24. 271-279 (2004)

[Publications] Takeuchi, Y.: "Differential subcellular distributions of Ca^<2+>/Calmodulin-Dependent Protein kinase II subunits."J.Neurosci.Res.. (in press). (2004)

[Publications] Takeuchi, Y.: "Dopamine D2 receptor activates extracellular signal-regulated kinase through the specific region in the third cytoplasmic loop."J.Neurochem.. (in press). (2004)

[Publications] Takeuchi, Y.: "Different activation of NF-κB by stimulation of dopamine D2L and D2S receptors through calcineurin activation."J.Neurochem.. (in press). (2004)

[Publications] Iwahana, E.: "Effects of lithium on the circadian rhythms of locomotor activity and GSK-3 protein expression in the mouse suprachiasmatic nuclei."Eur.J.Neurosci. (in press). (2004)

[Publications] Miyazaki, K.: "Cell and Molecular Biology of Endometrial Carcinoma"Springer-Verlag Tokyo. 138 (2003)

[Publications] 大森始紀 他: "神経回路の機能発現のメカニズム"共立出版. 500 (2004)

福永浩司東北大学, 大学院・薬学研究科, 教授 (90136721)

[Publications] 福永浩司: "最近の話題:心肥大形成とカルシウムシグナル"日薬理誌. 121. 287 (2003)

[Publications] 福永浩司: "脳血管障害の新しい創薬ターゲット分子"医学のあゆみ. 207. 61-66 (2003)

[Publications] 大森始紀他: "神経回路の機能発現のメカニズム"共立出版. 500 (2004)