ドーパミンシグナルを介した精神疾患病態に関するマイクロエンドフェノタイプの解明
Publicly Offered Research
Project Area | Unraveling micro-endophenotypes of psychiatric disorders at the molecular, cellular and circuit levels. |
Project/Area Number |
25116532
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Research Category |
Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
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Allocation Type | Single-year Grants |
Review Section |
Biological Sciences
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Research Institution | Tokyo Metropolitan Institute of Medical Science |
Principal Investigator |
池田 和隆 公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 参事研究員 (60281656)
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Project Period (FY) |
2013-04-01 – 2015-03-31
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Project Status |
Completed (Fiscal Year 2014)
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Budget Amount *help |
¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2013: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
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Keywords | 医療・福祉 / 神経科学 / 生理活性 / 脳・神経 / 薬理学 |
Outline of Annual Research Achievements |
ドーパミンは、快情動、人格、注意など主要な精神活動や運動を制御する極めて重要な脳内物質であり、ドーパミンシグナルの変調は精神疾患病態におけるマイクロエンドフェノタイプであると考えられる。ドーパミン欠乏マウスの解析は、ドーパミンシステムの機能解明において画期的な手法であるが、予備検討により、従来の条件ではドーパミンが脳に残存していることが明らかになった。そこで本研究では、真のドーパミン欠乏マウスを用いることで、ドーパミンシグナル変調というマイクロエンドフェノタイプが精神活動に与える真の影響の解明を目指した。平成26年度は以下の成果を得た。 ドーパミン欠乏マウスに、ドーパミンの前駆体であるL-DOPAを毎日投与することで長期間飼育し、その後3日間のL-DOPA断薬をすることでドーパミン欠乏マウスを準備し実験に用いた。前年度に、クロザピンがドーパミン欠乏マウスの多動を抑制し、クロザピンの多数の作用点の中でムスカリニックアセチルコリン受容体作動効果が主にドーパミン欠乏マウスの異常を抑制したことから、今年度は、マイクロダイアリシス分析により、線条体におけるアセチルコリンの細胞外濃度を測定した。その結果、ドーパミン欠乏マウスは細胞外アセチルコリン量が有意に低下していることが明らかになった。さらに、ドーパミン欠乏マウスの脳を採取し、免疫組織化学的解析、ウェスタンブロット解析、遺伝子発現解析を行ったところ、アセチルコリン合成酵素であるコリンアセチル転移酵素の遺伝子発現および蛋白質量が有意に低下していることが明らかになった。 これらの結果より、ドーパミンが枯渇することによる異常行動にはアセチルコリンシステムが関与していることが分子レベルで明らかとなった。
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Research Progress Status |
26年度が最終年度であるため、記入しない。
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Strategy for Future Research Activity |
26年度が最終年度であるため、記入しない。
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Report
(2 results)
Research Products
(135 results)
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[Journal Article] Association between the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene and postoperative analgesic requirements.2015
Author(s)
Aoki Y, Nishizawa D, Hasegawa J, Kasai S, Yoshida K, Koukita Y, Ichinohe T, Nagashima M, Katoh R, Satoh Y, Tagami M, Hayashida M, Fukuda K, Ikeda K.
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Journal Title
J Pharmacol Sci
Volume: 127
Issue: 3
Pages: 391-393
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Attenuated methamphetamine-induced locomotor sensitization in serotonin transporter knockout mice is restored by serotonin 1B receptor antagonist treatment.2015
Author(s)
Igari M, Shen H, Hagino Y, Fukushima S, Kasahara Y, Lesch K, Murphy D, George R Uhl, Ikeda K, Yaegashi N, Sora I
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Journal Title
Behav Pharmacol
Volume: 26
Issue: 1 and 2 - Special Issue
Pages: 167-179
DOI
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Peer Reviewed
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[Journal Article] Association Between <i>KCNJ6</i> (<i>GIRK2</i>) Gene Polymorphism rs2835859 and Post-operative Analgesia, Pain Sensitivity, and Nicotine Dependence2014
Author(s)
Nishizawa D, Fukuda K, Kasai S, Ogai Y, Hasegawa J, Sato N, Yamada H, Tanioka F, Sugimura H, Hayashida M, Ikeda K.
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Journal Title
Journal of Pharmacological Sciences
Volume: 126
Issue: 3
Pages: 253-263
DOI
NAID
ISSN
1347-8613, 1347-8648
Related Report
Peer Reviewed / Open Access
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[Journal Article] Haplotype analysis of GSK-3beta gene polymorphisms in bipolar disorder lithium responders and non-responders.2014
Author(s)
Iwahashi K, Nishizawa D, Narita S, Numajiri M, Murayama O, Yoshihara E, Onozawa Y, Nagahori K, Fukamauchi F, Ikeda K, Ishigooka J
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Journal Title
Clin Neuropharmacol
Volume: 37
Issue: 4
Pages: 108-110
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Association between genetic polymorphism rs2952768, close to the METTL21A and CREB1 genes, and intellectual ability in healthy subjects2014
Author(s)
Nishizawa D, Ohi K, Hashimoto R, Yamamori H, Yasuda Y, Fujimoto M, Umeda-Yano S, Takeda M, Ikeda K
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Journal Title
Journal of Addiction Research & Therapy
Volume: 5(2)
Issue: 02
Pages: 1000178-1000178
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] 物質関連障害および嗜癖性障害群.2014
Author(s)
宮田久嗣, 樋口進, 廣中直行, 池田和隆, 伊豫雅臣, 小宮山徳太郎, 松本俊彦, 鈴木勉, 高田孝二, 和田清, 齋藤利和
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Journal Title
精神神経学雑誌
Volume: 116(11)
Pages: 950-954
Related Report
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[Journal Article] Haplotype analysis of GSK-3beta gene polymorphisms in bipolar disorder lithium responders and non-responders.2014
Author(s)
Iwahashi K, Nishizawa D, Narita S, Numajiri M, Murayama O, Yoshihara E, Onozawa Y, Nagahori K, Fukamauchi F, Ikeda K, Ishigooka J
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Journal Title
Clinical Neuropharmacology
Volume: -
Related Report
Peer Reviewed
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[Journal Article] Genome-wide association study identifies a potent locus associated with human opioid sensitivity.2014
Author(s)
Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Aoki Y, Nishi A, Saita N, Koukita Y, Nagashima M, Katoh R, Satoh Y, Tagami M, Higuchi S, Ujike H, Ozaki N, Inada T, Iwata N, Sora I, Iyo M, Kondo N, Won MJ, Naruse N, Uehara-Aoyama K, Itokawa M, Koga M, Arinami T, Kaneko Y, Hayashida M, Ikeda K.
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Journal Title
Mol Psychiatry
Volume: 19(1)
Issue: 1
Pages: 55-62
DOI
Related Report
Peer Reviewed
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[Journal Article] Involvement of the N-methyl-D-aspartate receptor GluN2D subunit in phencyclidine-induced motor impairment, gene expression, and increased Fos immunoreactivity2013
Author(s)
Hideko Yamamoto, Etsuko Kamegaya, Wakako Sawada, Ryota Hasegawa, Toshifumi Yamamoto, Yoko Hagino, Yukio Takamatsu, Kazuhide Imai, Hisashi Koga, Masayoshi Mishina and Kazutaka Ikeda
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Journal Title
Molecular Brain
Volume: 6
Issue: 1
Pages: 56-56
DOI
Related Report
Peer Reviewed
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[Journal Article] Functional analysis of deep intronic SNP rs13438494 in intron 24 of PCLO gene2013
Author(s)
Seo S, Takayama K, Uno K, Ohi K, Hashimoto R, Nishizawa D, Ikeda K, Ozaki N, Nabeshima T, Miyamoto Y, Nitta A
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Journal Title
PLoS ONE
Volume: 8(10)
Issue: 10
Pages: e76960-e76960
DOI
Related Report
Peer Reviewed
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[Presentation] Specific regions display altered grey matter volume in mu-opioid receptor knockout mice: mri voxel-based morphometry.2014
Author(s)
Sora I, Sasaki K, Sumiyoshi A, Nonaka H, Kasahara Y, Ikeda K, Hall FS, Uhl GR, Watanabe M, Kawashima R
Organizer
The 53rd Annual Meeting of American College of Neuropsychopharmacology (ACNP 53rd Annual Meeting)
Place of Presentation
Phoenix, USA
Year and Date
2014-12-07 – 2014-12-11
Related Report
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[Presentation] Differences in responsiveness between methamphetamine, nisoxetine and methylphenidate may reflect specific developmental characteristics in juvenile DAT KO mice.2014
Author(s)
Kubo Y, Kasahara Y, Arime Y, Hall FS, Takamatsu Y, Ikeda K, Uhl GR, Sora I, Tomita H
Organizer
Society for Neuroscience 2014
Place of Presentation
Washington DC, USA
Year and Date
2014-11-15 – 2014-11-19
Related Report
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[Presentation] PCLO SNP rs13438494 regulates DA and 5-HT uptake, accompanied with splicing efficiency and dependence-like behaviors in genomic association studies.2014
Author(s)
Uno K, Nishizawa D, Seo S, Sasaki N, Ohi K, Nabeshima T, Hashimoto R, Ozaki N, Ikeda K, Miyamoto Y, Nitta A
Organizer
29th CINP World Congress of Neuropsychopharmacology
Place of Presentation
Vancouver, Canada
Year and Date
2014-06-24
Related Report
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[Presentation] Associations of an orexin (hypocretin) receptor 2 gene polymorphism with nicotine dependence found in genome-wide and following association studies.2014
Author(s)
Nishizawa D, Kasai S, Hasegawa J, Sato N, Tanioka F, Nagashima M, Ujike H, Hashimoto R, Tanaka M, Sugimura H, Ikeda K
Organizer
29th CINP World Congress of Neuropsychopharmacology
Place of Presentation
Vancouver, Canada
Year and Date
2014-06-23
Related Report
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[Presentation] Personalized pain control.2014
Author(s)
Ikeda K, Nishizawa D, Hayashida M, Fukuda K
Organizer
2014 YONSEI BK21 PLUS-IGAKUKEN Joint Symposium
Place of Presentation
Soul, Korea
Year and Date
2014-06-20
Related Report
Invited
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[Presentation] Genome-wide association study identifies a potent locus associated with human opioid sensitivity.2013
Author(s)
Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Nagashima M, Satoh Y, Higuchi S, Ujike H, Arinami T, Hayashida M, Ikeda K
Organizer
XXIst World Congress of Psychiatric Genetics(WCPG2013:第21回精神科遺伝学国際会議)
Place of Presentation
Boston, USA
Related Report
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[Presentation] Genome-wide association study identifies a potent locus associated with human opioid sensitivity.2013
Author(s)
Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Aoki Y, Nishi A, Saita N, Koukita Y, Nagashima M, Katoh R, Satoh Y, Tagami M, Higuchi S, Ujike H, Ozaki N, Inada T, Iwata N, Sora I, Iyo M, Kondo N, Won MJ, Naruse N, Uehara K, Itokawa M, Koga M, Arinami T, Kaneko Y, Hayashida M, Ikeda K
Organizer
European Human Genetics Conference 2013
Place of Presentation
Paris, France
Related Report
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[Presentation] 精神疾患に関連するPCLO SNP rs13438494の分子生物学的検討.
Author(s)
宇野恭介, 徐承姫, 松村祥平, 大井一高, 橋本亮太, 西澤大輔, 池田和隆, 酒井規雄, 鍋島俊隆, 宮本嘉明, 新田淳美
Organizer
第23回日本臨床精神神経薬理学会・第43回日本神経精神薬理学会合同年会
Place of Presentation
宜野湾
Related Report
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[Presentation] A randomized, rater blinded, crossover study of ifenprodil effect on relapse risk in patients with alcohol dependence.
Author(s)
Sugaya N, Ogai Y, Aikawa Y, Yumoto Y, Takahama M, Tanaka M, Haraguchi A, Umeno M, Ikeda K
Organizer
CINP Special Congress on Addiction and Mental Health
Place of Presentation
Kuala Lumpur, Malaysia
Related Report
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[Presentation] Increased regional gray matter volume in the mu-opioid receptor knockout mice determined by mri voxel-based morphometry.
Author(s)
Sasaki K, Sumiyoshi A, Nonaka H, Hall FS, Uhl GR, Watanabe M, Kasahara Y, Ikeda K, Kawashima R, Sora I
Organizer
INRC2013
Place of Presentation
Cairns, Australia
Related Report
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[Presentation] セロトニンおよびドパミントランスポーターを過剰発現させたPC12およびHEK293細胞において、PCLOのSNPはモノアミン取り込みを制御する.
Author(s)
宇野恭介, 高山佳奈子, 徐承姫, 大井一高, 橋本亮太, 西澤大輔, 池田和隆, 酒井規雄, 鍋島俊隆, 宮本嘉明, 新田淳美
Organizer
Neuro2013
Place of Presentation
京都
Related Report
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