A study to clarify the role of emotional stress for the pathogenesis of mood disorders

• Project/Area Number: 24591673
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Hokkaido University
• Principal Investigator: INOUE TAKESHI 北海道大学, 医学(系)研究科(研究院), 准教授 (70250438)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 気分障害 / 恐怖条件付け / 情動ストレス / mirtazapine / 正中縫線核 / 扁桃体 / neurotensin受容体1 / retinoic acid受容体α / 側坐核 / ドパミン / うつ病モデル / α2受容体 / 母子分離 / 慢性ストレス誘発モデル / ストレス / マイクロアレイ

Outline of Final Research Achievements

We clarified the mechanism of the anxiolytic action of mirtazapine, a new antidepressant, by using an animal model of emotional stress. We showed that the anxiolytic effect of mirtazapine is mediated by the α2 antagonism in the median raphe nucleus and that subchronic lithium enhances the anxiolytic effect of mirtazapine. We developed the new unique animal model of depression that consists of maternal separation and chronic mild stress and conducted behavioral and molecular biological experiments in this model. Our results showed that maternal separation decreased the mRNA expression of neurotensin receptor 1 in the adult amygdala and retinoic acid receptor α in the adult dentate gyrus-derived neural precursor cells.

Research Products

• [Journal Article] Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic acid receptor gene promoter (2015)
  • Author(s): Boku S, Toda H, Nakagawa S, Kato A, Inoue T, Koyama T, Hiroi N, Kusumi I
  • Journal Title: Biol Psychiatry Volume: 77 Issue: 4 Pages: 335-344
  • DOI: 10.1016/j.biopsych.2014.07.008
  • NAID: 120005553679
  • Peer Reviewed
• [Journal Article] Subchronic lithium treatment increases the anxiolytic-like effect of mirtazapine on the expression of contextual conditioned fear (2015)
  • Author(s): An Y, Inoue T, Kitaichi Y, Nakagawa S, Wang C, Chen C, Song N, Kusumi I
  • Journal Title: Eur J Pharmacol Volume: 747 Pages: 13-17
  • DOI: 10.1016/j.ejphar.2014.11.009
  • NAID: 120005572426
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Local infusion of citalopram into the amygdala decreased conditioned fear of rats through increasing extracellular serotonin levels (2014)
  • Author(s): Kitaichi Y, Inoue T, Nakagawa S, Omiya Y, Song N, An Y, Chen C, Kusumi I, Koyama T
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry Volume: 54 Pages: 216-222
  • DOI: 10.1016/j.pnpbp.2014.05.018
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The effect of dopamine on adult hippocampal neurogenesis (2014)
  • Author(s): Takamura N, Nakagawa S, Masuda T,Boku S, Kato A, Song N, An Y, Kitaichi Y, Inoue T, Koyama T, Kusumi I
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry Volume: 50 Pages: 116-124
  • DOI: 10.1016/j.pnpbp.2013.12.011
  • NAID: 120005411146
  • Peer Reviewed
• [Journal Article] Effect of the co-administration of citalopram with mirtazapine or atipamezole on rat contextual conditioned fear (2014)
  • Author(s): Masuda T, Inoue T, An Y, Takamura N, Nakagawa S, Kitaichi Y, Koyama T, Kusumi I
  • Journal Title: Neuropsych. Dis. Treat Volume: 10 Pages: 289-295
  • DOI: 10.2147/ndt.s55507
  • NAID: 120005411141
  • Peer Reviewed
• [Journal Article] Maternal separation enhances conditioned fear and decreases the mRNA levels of the neurotensin receptor 1 gene with hypermethylation of this gene in the rat amygdala (2014)
  • Author(s): Toda H, Boku S, Nakagawa S, Inoue T, Kato A , Takamura N, Song N, Nibuya M, Koyama T, Kusum I
  • Journal Title: PLoS One Volume: in press
  • NAID: 120005537461
  • Peer Reviewed
• [Journal Article] Tricyclic antidepressant amitriptyline indirectly increases the proliferation of adult dentate gyrus-derived neural precursors : an involvement of astrocytes. (2013)
  • Author(s): Boku S, Hisaoka-Nahashima K, Nakagawa S, Kato A, Kaiitani N, Inoue T, Kusumi I, Takebayashi M
  • Journal Title: PLoS One Volume: 8 Issue: 11 Pages: 116-124
  • DOI: 10.1371/journal.pone.0079371
  • Peer Reviewed
• [Journal Article] Anxiolytic-like effect of mirtazapine mediates its effect in the median raphe nucleus (2013)
  • Author(s): An Y, Inoue T, Kitaichi Y, Izumi T, Nakagawa S, Song N, Chen C, Li X, Koyama T, Kusumi I
  • Journal Title: Eur J Pharmacol Volume: 720 Issue: 1-3 Pages: 192-197
  • DOI: 10.1016/j.ejphar.2013.09.078
  • NAID: 120005367409
  • Peer Reviewed
• [Journal Article] Valproate recovers the inhibitory effect of dexamethasone on the proliferation of the adult dentate gyrus-derived neural precursor cells via GSK-3β and β-catenin pathway (2013)
  • Author(s): Boku S, Nakagawa S, Masuda T, Nishikawa H, Kato A, Takamura N, Omiya Y, Kitaichi Y, Inoue T, Kusuimi I
  • Journal Title: Eur J Pharmacol Volume: 723 Pages: 425-430
  • DOI: 10.1016/j.ejphar.2013.10.060
  • Peer Reviewed
• [Journal Article] GDNF facilitates differentiation of the adult dentate gyrus-derived neural precursor cells into astrocytes via STAT3 (2013)
  • Author(s): Boku S, Nakagawa S, Takamura N,Kato A, Takebayashi M, Hisaoka-Nakashima K, Omiya Y,Inoue T, Kusumi I
  • Journal Title: Biochem. Biophys Res Commun Volume: 434 Issue: 4 Pages: 779-784
  • DOI: 10.1016/j.bbrc.2013.04.011
  • NAID: 120005460238
  • Peer Reviewed
• [Journal Article] ROCK2 regulates bFGF-induced proliferation of SH-SY5Y cells through GSK-3β and β-catenin pathway. (2013)
  • Author(s): Boku S, Nakagawa S, Toda H, Kato A, Takamura N, Omiya Y, Inoue T, Koyama T
  • Journal Title: Brain research Volume: 1492 Pages: 7-17
  • DOI: 10.1016/j.brainres.2012.11.034
  • NAID: 120005228253
  • Peer Reviewed
• [Journal Article] Involvement of CaMKIV in neurogenic effect with chronic fluoxetine treatment (2013)
  • Author(s): Song N, Nakagawa S, Izumi T, Toda H, Kato A, Boku S, Inoue T, Sakagami H, Li X, Koyama T
  • Journal Title: Int J Neuropsychopharmacol Volume: 16(4) Issue: 4 Pages: 803-812
  • DOI: 10.1017/s1461145712000570
  • Peer Reviewed
• [Journal Article] Effect of triiodothyronine (T(3)) augmentation of acute milnacipran administration on monoamine levels: an in vivo microdialysis study in rats. (2012)
  • Author(s): Kitaichi Y, Inoue T, Nakagawa S, Boku S, Kato A, Kusumi I, Koyama T
  • Journal Title: Neuropsychiatric disease and treatment Volume: 8 Pages: 501-507
  • DOI: 10.2147/ndt.s36906
  • NAID: 120004979568
  • Peer Reviewed
• [Journal Article] The effects of the co-administration of the α1-adrenoreceptor antagonist prazosin on the anxiolytic effect of citalopram in conditioned fear stress in the rat. (2012)
  • Author(s): Takamura N, Masuda T, Inoue T, Nakagawa S, Koyama T
  • Journal Title: Progress in neuro-psychopharmacology & biological psychiatry Volume: 39 Issue: 1 Pages: 107-111
  • DOI: 10.1016/j.pnpbp.2012.05.017
  • Peer Reviewed
• [Presentation] 難治性うつ病はなぜ難治なのか？その解決法について (2014)
  • Author(s): 井上 猛
  • Organizer: 第24回日本臨床精神神経薬理学会・第44回日本神経精神薬理学会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2014-11-22
• [Presentation] 不安障害と気分障害の併存 (2014)
  • Author(s): 井上 猛
  • Organizer: 第110回 日本精神神経学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-05-27
• [Presentation] Subchronic lithium carbonate potentiates the effect of mirtazapine treatment on the conditioned fear. (2012)
  • Author(s): 安 燕、井上 猛、北市雄士、中川 伸、泉 剛、宋 寧、小山 司
  • Organizer: 第３４回日本生物学的精神医学会
  • Place of Presentation: 神戸国際会議場（兵庫）
• [Presentation] 子供の時のストレスとうつ (2012)
  • Author(s): 井上 猛
  • Organizer: 第22回日本臨床精神神経薬理学会・第42回日本神経精神薬理学会 合同年会
  • Place of Presentation: 栃木県総合文化センター（栃木）
  • Invited
• [Presentation] 不安障害の病態生理：動物モデルによる神経科学的解明
  • Author(s): 井上 猛
  • Organizer: 第109回 日本精神神経学会学術総会
  • Place of Presentation: 福岡サンパレスホテル＆ホール（福岡市）
• [Presentation] 恐怖条件付けにおけるmirtazapineの抗不安効果とそのリチウム増強効果は正中縫線核への効果を介している
  • Author(s): 安 燕 、井上 猛、北市雄士、中川 伸、泉 剛、宋 寧、陳 沖、小山 司
  • Organizer: Neuro2013
  • Place of Presentation: 国立京都国際会館（京都市）
• [Presentation] Anxiolytic effects of mirtazapine microinjection in the median raphe nucleus and subchronic lithium carbonate enhances this effect
  • Author(s): An Y, Inoue T, Kitaichi Y, Izumi T, Nakagawa D, Song N, Chen C, Li XB, Kusumi I
  • Organizer: 3rd Congress of The Asian College of Neuropsychopharmacology
  • Place of Presentation: China National Convention Center (Beijing, China)
• [Presentation] Involvement of CaMKIV in antidepressant actions
  • Author(s): Nakagawa S, Song N, Kato A, An Y, Inoue T, Li XB, Kusumi I
  • Organizer: 42nd Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego Convention Center (San Diego, USA)
• [Book] 不安障害診療のすべて＜精神科臨床エキスパート＞ (2013)
  • Author(s): 井上 猛
  • Total Pages: 308
  • Publisher: 医学書院
• [Remarks] 北海道大学大学院医学研究科精神医学分野
  • URL: http://www.hucc.hokudai.ac.jp/~e20529/univ/index.html