Development an in vivo real-time analytical system that can predict dependency and rewarding effects of novel compounds

• Project/Area Number: 17K19483
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Pharmaceutical Sciences and related fields
• Research Institution: Nagoya University
• Principal Investigator: Nagai Taku 名古屋大学, 医学部附属病院, 准教授 (10377426)
• Co-Investigator(Kenkyū-buntansha): 伊藤 教道 名古屋大学, 医学部附属病院, 特任助教 (30726310)
• Research Collaborator: Zhu Youyun
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 薬理学 / 可視化 / 薬物反応性

Outline of Final Research Achievements

Behavioral pharmacological tests are carried out to predict dependency and rewarding effects of novel compounds. It is desirable to develop analytical methods that can more easily predict drug dependence and rewarding effects because special techniques and experimental apparatuses are required to perform behavioral tests. The aim of this research project is to develop an in vivo real-time analytical system that can easily visualize and monitor the transcriptional activity in the brain in response to addictive drugs. Cocaine treatment stimulated PKA-mediated signaling pathway in the brain of mice. We generated the mice carrying genes encoding luciferase under the control of transcription response element CRE downstream of PKA, and detected the response to the addictive drugs using these mice.

Academic Significance and Societal Importance of the Research Achievements

依存性は薬物の化学構造で規定されるものではないため、分析機器や試薬反応を応用した検出システムでは予測不能である。本システムは画像として結果を取得でき、感度の高さ、広いダイナミックレンジ、迅速で簡便な定量操作が可能である。医薬品開発において化合物の依存性は重要な問題であり、本研究構想の実現により医薬品開発の日・米・EU 医薬品規制調和国際会議ガイドラインに変革をもたらすことが予想され、前臨床試験の時間的短縮および経済的削減の効果は計り知れない。さらに、本システムは違法ドラッグなどの新規化合物の依存性を検出することに役立ち、乱用薬物の規制にも多大なる貢献をもたらすことが予測される。

Research Products

• [Journal Article] Pharmacological and proteomic analyses of neonatal polyI:C-treated adult mice. (2018)
  • Author(s): Kitagawa, K., Nagai, T., Yamada, K.
  • Journal Title: Neurosci. Res. Volume: - Pages: 39-47
  • DOI: 10.1016/j.neures.2018.10.007
  • Peer Reviewed / Open Access
• [Journal Article] Balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in striatal medium spiny neurons (2018)
  • Author(s): Zhang XJ, Nagai T, Ahammad RU, Kuroda K, Nakamuta S, Nakano T, Yukinawa N, Funahashi Y, Yamahashi Y, Amano M, Yoshimoto J, Yamada K, and Kaibuchi K.
  • Journal Title: Neurochemistry International Volume: 122 Pages: 8-18
  • DOI: 10.1016/j.neuint.2018.10.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Innate immune activation of astrocytes impairs neurodevelopment via upregulation of follistatin-like 1 and interferon-induced transmembrane protein 3. (2018)
  • Author(s): Yamada, S., Itoh, N., Nagai, T., Nakai, T., Ibi, D., Nakajima, A., Nabeshima, T., Yamada, K.
  • Journal Title: J. Neuroinflammation. Volume: 15 Issue: 1 Pages: 295-295
  • DOI: 10.1186/s12974-018-1332-0
  • Peer Reviewed / Open Access
• [Journal Article] Cell type-specific activation of mitogen-activated protein kinase in D1 receptor-expressing neurons of the nucleus accumbens potentiates stimulus-reward learning in mice (2018)
  • Author(s): Bin Saifullah Md. Ali、Nagai Taku、Kuroda Keisuke、Wulaer Bolati、Nabeshima Toshitaka、Kaibuchi Kozo、Yamada Kiyofumi
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 14413-14413
  • DOI: 10.1038/s41598-018-32840-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia. (2018)
  • Author(s): Sobue A, Kushima I, Nagai T, Shan W, Kohno T, Aleksic B, Aoyama Y, Mori D, Arioka Y, Kawano N, Yamamoto M, Hattori M, Nabeshima T, Yamada K, Ozaki N.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 13046-13046
  • DOI: 10.1038/s41598-018-31390-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Administration of molecular hydrogen during pregnancy improves behavioral abnormalities of offspring in a maternal immune activation model. (2018)
  • Author(s): Imai, K., Kotani, T., Tsuda, H., Nakano, T., Ushida, T., Iwase, A., Nagai T,, Toyokuni, S., Suzumura, A., Kikkawa, F.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 9221-9221
  • DOI: 10.1038/s41598-018-27626-4
  • Peer Reviewed / Open Access
• [Journal Article] Repetitive and compulsive-like behaviors lead to cognitive dysfunction in Disc1Δ2-3/Δ2-3 mice (2018)
  • Author(s): Wulaer B, Nagai T, Sobue A, Itoh N, Kuroda K, Kaibuchi K, Nabeshima T, Yamada K
  • Journal Title: Genes Brain Behav Volume: 印刷中 Issue: 8
  • DOI: 10.1111/gbb.12478
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Astroglial major histocompatibility complex class I following immune activation leads to behavioral and neuropathological changes. (2018)
  • Author(s): A Sobue, N Ito, T Nagai, W Shan, K Hada, Nakajima A, Y Murakami, A Mouri, Y Yamamoto, T Nabeshima, K Saito, K Yamada
  • Journal Title: Glia Volume: 66 Issue: 5 Pages: 1034-52
  • DOI: 10.1002/glia.23299
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Repetitive and compulsive-like behaviors lead to cognitive dysfunction in Disc1Δ2-3/Δ2-3 mice. (2018)
  • Author(s): Wulaer, B., Nagai T., Sobue, A., Itoh, N., Kuroda, K., Kaibuchi, K., Nabeshima, T., Yamada, K.
  • Journal Title: Gene Brain Behav. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Neuronal PAS domain protein 4 (Npas4) controls neuronal homeostasis in pentylenetetrazole-induced epilepsy through the induction of Homer1a. (2017)
  • Author(s): 2.Shan W, Nagai T, Tanaka M, Itoh N, Furukawa-Hibi Y, Nabeshima T, Sokabe M, Yamada K.
  • Journal Title: J Neurochem. Volume: - Issue: 1 Pages: 19-33
  • DOI: 10.1111/jnc.14274
  • Peer Reviewed / Open Access
• [Journal Article] Exposure to diphtheria toxin during the juvenile period impairs both inner and outer hair cells in C57BL/6 mice (2017)
  • Author(s): Konishi H, Ohgami N, Matsushita A, Kondo Y, Aoyama Y, Kobayashi M, Nagai T, Ugawa S, Yamada K, Kato M, Kiyama H
  • Journal Title: Neuroscience Volume: 印刷中 Pages: 15-23
  • DOI: 10.1016/j.neuroscience.2017.03.028
  • NAID: 120006331816
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of impaired neuronal migration with cognitive deficits in extremely preterm infants. (2017)
  • Author(s): Kubo, K.I., Deguchi, K., Nagai, T,, Ito, Y., Yoshida, K., Endo, T., Benner, S., Shan, W., Kitazawa, A., Aramaki, M., Ishii, K., Shin, M., Matsunaga, Y., Hayashi, K., Kakeyama, M., Tohyama, C., Tanaka, K.F., Tanaka, K., Takashima, S., Nakayama, M.
  • Journal Title: JCI Insight. Volume: 2 Issue: 10 Pages: 88609-88609
  • DOI: 10.1172/jci.insight.88609
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Valocin-containing protein (VCP) is a novel IQ motif containing GTPase activating protein 1 (IQGAP1) interacting protein. (2017)
  • Author(s): Itoh, N., Nagai, T,, Watanabe, T., Taki, K., Nabeshima, N., Kaibuchi, K., Yamada, K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 493 Issue: 4 Pages: 1384-1389
  • DOI: 10.1016/j.bbrc.2017.09.159
  • Peer Reviewed / Open Access
• [Presentation] ゲノムのコピー数変化から統合失調症の診断治療標的を探る. (シンポジウム). (2019)
  • Author(s): 永井拓, 尾崎紀夫, 山田清文.
  • Organizer: 第92回日本薬理学会年会.
  • Invited
• [Presentation] Striatal phosphorylation signals regulating reward and aversive behaviors. (Symposium). (2019)
  • Author(s): Nagai T.
  • Organizer: The 22nd Japan-Korea Joint Seminar on Pharmacology.
  • Int'l Joint Research / Invited
• [Presentation] ホメオスタシスの観点から考えるてんかん治療の標的分子. (シンポジウム). (2018)
  • Author(s): 永井拓, Shan Wei, 山田清文.
  • Organizer: 日本薬学会第138年会
  • Invited
• [Presentation] Npas4-Homer1a pathway regulates neuronal homeostasis in animal model of epilepsy. (2018)
  • Author(s): Nagai, T., Shan, W., Tanaka, M., Itoh, N., Furukawa-Hibi, Y., Nabeshima, T., Sokabe, M., Yamada, K.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology.
  • Int'l Joint Research
• [Presentation] 免疫活性化によって誘導されるアストロサイト由来MHC class Iの病態生理学的役割. (シンポジウム). (2018)
  • Author(s): 永井拓.
  • Organizer: 第61回日本神経化学会大会・第40回日本生物学的精神医学会.
• [Presentation] 自然免疫系の過剰な活性化はアストロサイト由来主要組織適合抗原I型を介して異常行動を引き起こす. (シンポジウム). (2018)
  • Author(s): 永井拓, 祖父江顕, 山田清文.
  • Organizer: 第34回日本ストレス学会学術総会.
  • Invited
• [Presentation] 統合失調症患者から同定されたReelin遺伝子変異の病態生理学的意義. (シンポジウム). (2018)
  • Author(s): 永井拓, 祖父江顕, 久島周, 尾崎紀夫, 山田清文.
  • Organizer: 第28回日本臨床精神神経薬理学会・第48回日本神経精神薬理学会 合同年会.
  • Invited
• [Presentation] 統合失調症の克服を目指したリバーストランスレーショナルリサーチ. (シンポジウム). (2018)
  • Author(s): 永井拓, 尾崎紀夫, 山田清文.
  • Organizer: 第28回日本医療薬学会年会.
  • Invited
• [Presentation] Role of striatal phosphorylation signaling in emotional behaviors. (ワークショップ). (2018)
  • Author(s): 永井拓, 貝淵弘三.
  • Organizer: 第41回日本分子生物学会年会.
  • Invited
• [Presentation] ホメオスタシスの観点から考えるてんかん治療の標的分子. (2018)
  • Author(s): 永井拓, Shan Wei, 山田清文.
  • Organizer: 日本薬学会第138年会
  • Invited
• [Presentation] ドパミン神経伝達により引き起こされる神経興奮と報酬関連行動の細胞内シグナル. (2017)
  • Author(s): 永井拓, 黒田啓介, 貝淵弘三.
  • Organizer: 第40回日本神経科学会大会
  • Invited
• [Presentation] Npas4 mediates pentylenetetrazole-induced Homer1a expression in the hippocampus. (2017)
  • Author(s): 2.永井拓, Shan Wei, 田中基樹, 鍋島俊隆, 曽我部正博, 山田清文.
  • Organizer: 第60回日本神経化学会大会
• [Presentation] 脳機能を制御するリン酸化シグナルの解明に関する研究. (2017)
  • Author(s): 永井拓
  • Organizer: 第60回日本神経化学会大会
  • Invited
• [Presentation] ペンチレンテトラゾール誘発てんかん発作におけるNpas4の役割. (2017)
  • Author(s): 永井拓, Shan Wei, 田中基樹, 鍋島俊隆, 曽我部正博, 山田清文.
  • Organizer: 第39回日本生物学的精神医学会・第47回日本神経精神薬理学会合同年会
• [Presentation] Phosphorylation signals in reward-motivated behaviors. (2017)
  • Author(s): 永井拓, 貝淵弘三.
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Invited
• [Remarks] 名古屋大学大学院医学系研究科医療薬学研究室
  • URL: https://www.med.nagoya-u.ac.jp/medical_J/laboratory/clinical-pharma/clinical-pharma/neuropsycho-pharmacology/
• [Remarks] 医療薬学研究室ホームページ
  • URL: https://www.med.nagoya-u.ac.jp/medical_J/laboratory/clinical-pharma/clinical-pharma/neuropsycho-pharmacology/