Development of the synthetic cannabinoid-dependent mouse and investigation of its formation factor

• Project/Area Number: 15K19272
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Legal medicine
• Research Institution: Nagoya University
• Principal Investigator: Zaitsu Kei 名古屋大学, 医学系研究科, 准教授 (30700546)
• Research Collaborator: HAYASHI Yumi 名古屋大学, 大学院医学系研究科, 助教
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: メタボローム解析 / 遺伝子発現解析 / 合成カンナビノイド / 分析化学 / カンナビノイド受容体作動薬 / エネルギー代謝 / 薬物依存 / 質量分析

Outline of Final Research Achievements

The synthetic cannabinoid AM-2201, which has been abused worldwide, was chronically administered to drug-naive ICR male mice (6-week, n=6) for 7 days. After chronic administration, the cerebrum specimens were collected by dissection under anesthesia, and mass-spectrometry based metabolome analysis and gene expression analysis using real-time qPCR were executed. Metabolome analysis revealed that AM-2201 administered and control groups were unsatisfactory separated in PCA score plots: chronic administration of AM-2201 did not cause energy metabolism disruption, contrary to the acute toxic effect of AM-2201 which has been show to alter energy metabolism in the cerebrum. In addition, four genes related to energy metabolism were not significantly expressed in the chronically administered mice. These results suggests that energy metabolism of the chronically administered mice recovered to their original state by tolerance due to chronic administration of AM-2201.

Research Products

• [Journal Article] Regioisomeric differentiation of the alkyl-substituted synthetic cannabinoids JWH-122 and JWH-210 by GC-EI-MS/MS (2016)
  • Author(s): Kusano M, Yamanaka M, Zaitsu K, Nakayama H, Nakajima J-i, Moriyasu T, Tsuchihashi H, Ishii A
  • Journal Title: Forensic Toxicology Volume: 34 Issue: 2 Pages: 304-315
  • DOI: 10.1007/s11419-016-0317-x
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Development of a mass spectrometric hydroxyl-position determination method for the hydroxyindole metabolites of JWH-018 by GC-MS/MS (2016)
  • Author(s): Maiko Kusano, Kei Zaitsu*, Mayumi Yamanaka, Kazuaki Hisatsune, Tomomi Asano, Kentaro Taki, Yumi Hayashi, Hitoshi Tsuchihashi, Akira Ishii
  • Journal Title: Journal of Mass Spectrometry Volume: 51 Issue: 5 Pages: 8-11
  • DOI: 10.1002/jms.3761
  • Peer Reviewed
• [Journal Article] Application of metabolomics to toxicology of drugs of abuse: a mini review of metabolomics approach to acute and chronic toxicity studies (2016)
  • Author(s): Kei Zaitsu*, Yumi Hayashi, Maiko Kusano, Hitoshi Tsuchihashi, Akira Ishii.
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 31 Issue: 1 Pages: 21-26
  • DOI: 10.1016/j.dmpk.2015.10.002
  • NAID: 50014431237
  • Peer Reviewed
• [Journal Article] Intact endogenous metabolite analysis of mice liver by probe electrospray ionization/triple quadrupole tandem mass spectrometry (PESI/MS/MS) and its preliminary application to in vivo real-time analysis (2016)
  • Author(s): Kei Zaitsu*, Yumi Hayashi, Tasuku Murata, Tomomi Ohara, Kenta Nakagiri, Maiko Kusano, Hiroki Nakajima, Tamie Nakajima, Tetsuya Ishikawa, Hitoshi Tsuchihashi, Akira Ishii
  • Journal Title: Analytical Chemistry Volume: 88(7) Issue: 7 Pages: 3556-3561
  • DOI: 10.1021/acs.analchem.5b04046
  • Peer Reviewed
• [Journal Article] High resolution mass spectrometric determination of the synthetic cannabinoids MAM-2201, AM-2201, AM-2232 and their metabolites in postmortem plasma and urine by LC/Q-TOFMS (2015)
  • Author(s): Kei Zaitsu*, Hiroshi Nakayama, Mayumi Yamanaka, Kazuaki Hisatsune, Kentaro Taki, Tomomi Asano, Tooru Kamata, Munehiro Katagi, Yumi Hayashi, Maiko Kusano, Hitoshi Tsuchihashi, Akira Ishii
  • Journal Title: International Journal of Legal Medicine Volume: 129 Pages: 1233-1245
  • Peer Reviewed
• [Presentation] 1.Direct drug analysis in serum by probe electrospray ionization/tandem mass spectrometry and its preliminary application to a real-time metabolism study (2017)
  • Author(s): Kei Zaitsu, Yumi Hayashi, Maiko Kusano, Kazuaki Hisatsune , Tomomi Ohara, Tasuku Murata, Hiroki Nakajima, Hiroshi Tanihata, Hitoshi Tsuchihashi, Tetsuya Ishikawa, Akira Ishii
  • Organizer: MSACL-US 2017 9th Annual Conference & Exhibits
  • Place of Presentation: Palm Springs (USA)
  • Int'l Joint Research
• [Presentation] Real-time metabolome analysis by probe electrospray ionization-tandem mass Spectrometry (PESI-MS/MS): preliminary challenge to real-time metabolomics (2016)
  • Author(s): Kei Zaitsu, Yumi Hayashi, Tasuku Murata, Hiroki Nakajima, Tamie Nakajima, Maiko Kusano, Hitoshi Tsuchihashi, Tetsuya Ishikawa, Akira Ishii
  • Organizer: Pittcon Conference&EXPO 2016
  • Place of Presentation: Atlanta, GA, USA
  • Year and Date: 2016-03-08
  • Int'l Joint Research
• [Presentation] 質量分析を用いた危険ドラッグの代謝物構造推定 (2016)
  • Author(s): 財津桂
  • Organizer: 平成27年度地方衛生研究所全国協議会東海北陸支部衛生化学部会
  • Place of Presentation: ぎふメディアコスモス、岐阜県岐阜市
  • Year and Date: 2016-02-05
  • Invited
• [Presentation] Intact metabolome analysis of mice biological tissues by probe electrospray (2016)
  • Author(s): Kei Zaitsu, Yumi Hayashi, Tasuku Murata, Hiroki Nakajima, Tetsuya Ishikawa, Maiko Kusano, Hitoshi Tsuchihashi, Akira Ishii
  • Organizer: 64th Conference of American Society for Mass Spectrometry
  • Place of Presentation: San Antonio (USA)
  • Int'l Joint Research
• [Presentation] Ultrafast and direct detection of drugs of abuse in serum by probe electrospray ionization-tandem mass (2016)
  • Author(s): Maiko Kusano, Kei Zaitsu, Yumi Hayashi, Saki Noda, Tomomi Ohara, Hitoshi Tsuchihashi, Akira Ishii
  • Organizer: The 54th Annual Meeting of the International Association of Forensic
  • Place of Presentation: Brisbane (Australia)
  • Int'l Joint Research
• [Presentation] Intact metabolome analysis of mice biological tissues by probe electrospray ionization-tandem mass spectrometry (PESI-MS/MS) and its application to real-time analysis (2016)
  • Author(s): Yumi Hayashi, Kei Zaitsu, Tasuku Murata, Hiroki Nakajima, Maiko Kusano, Hitoshi Tsushihashi, Akira Ishii, Tetsuya Ishikawa
  • Organizer: RSC Tokyo International Conference 2016
  • Place of Presentation: Makuhari Messe (Chiba-city, Chiba)
  • Int'l Joint Research
• [Presentation] Real-time Monitoring of Glutamic Acid in Mouse Brain by Direct Coupling of Microdialysis to Tandem MS with the Newly Developed On-line Desalting System (2016)
  • Author(s): Kei Zaitsu, Yumi Hayashi , Hiroaki Kanayama, Ryosuke Takagi, Saki Noda , Maiko Kusano, Toshikazu Minohata , Jun-ichi Azuma , Nobuhiro Kanayama , Tetsuya Ishikawa , Hitoshi Tsuchihashi, Akira Ishii.
  • Organizer: The Association for Mass Spectrometry:Applications to the Clinical Lab
  • Place of Presentation: Salzburg (Austria)
  • Int'l Joint Research
• [Presentation] Application of Intact Metabolome Analysis by Probe Electrospray Ionization (PESI)/MS/MS to Local Distribution Analysis and in vivo Real-time Monitoring (2016)
  • Author(s): Yumi Hayashi, Kei Zaitsu, Tasuku Murata, Hiroki Nakajima, Maiko Kusano, Hitoshi Tsuchihashi, Akira Ishii, Tetsuya Ishikawa
  • Organizer: The Association for Mass Spectrometry:Applications to the Clinical Lab
  • Place of Presentation: Salzburg (Austria)
  • Int'l Joint Research
• [Presentation] Development of a user-friendly automated drug-quantification system and its application to Forensic Toxicology (2016)
  • Author(s): Kei Zaitsu
  • Organizer: Forensic Toxicology and Drug Analysis Technology Forum of China 2016
  • Place of Presentation: 太原市(中国)
  • Int'l Joint Research / Invited
• [Presentation] マウスを用いた合成カンナビノイドJWH-018およびAM-2201の胆汁排泄の評価 (2016)
  • Author(s): 久恒一晃、財津桂、林由美、瀧健太朗、浅野友美、石場厚、肥田宗政、草野麻衣子、土橋均、石井晃
  • Organizer: 日本法中毒学会35年会
  • Place of Presentation: 大阪産業創造館（大阪市中央区）
• [Presentation] 探針エレクトロスプレー/タンデム質量分析(PESI/MS/MS)によるマウス肝臓内のメタボローム直接分析法（インタクト・メタボローム分析法）の構築 (2015)
  • Author(s): 林 由美、財津 桂、村田 匡、大原倫美、中切雄太、草野麻衣子、那須民江、中島宏樹、石川哲也、土橋 均、石井 晃
  • Organizer: 第40回日本医用マススペクトル学会年会
  • Place of Presentation: アクトシティ浜松 コングレスセンター、静岡県浜松市
  • Year and Date: 2015-09-17
• [Presentation] 質量分析を用いた危険ドラッグの代謝物構造推定および代謝経路の特定 (2015)
  • Author(s): 財津桂
  • Organizer: TMS研究会
  • Place of Presentation: 東京大学、東京文京区
  • Year and Date: 2015-07-30
  • Invited
• [Presentation] セロトニン症候群モデルラットの脳および血漿メタボローム解析 (2015)
  • Author(s): 財津 桂、林 由美、木村 友哉、纐纈 雄太、小崎 朋子、山中麻友美、草野麻衣子、土橋 均、石井 晃
  • Organizer: 第42回 日本毒性学会学術年会
  • Place of Presentation: 石川県立音楽堂、石川県金沢市
  • Year and Date: 2015-06-30
• [Presentation] Intact metabolome analysis of mice liver by probe electrospray ionization-tandem mass spectrometry (PESI-MS/MS). (2015)
  • Author(s): Yumi Hayashi, Kei Zaitsu, Tasuku Murata, Hiroki Nakajima, Hitoshi Tsuchihashi, Akira Ishii, Tetsuya Ishikawa.
  • Organizer: 63rd Conference of American Society for Mass Spectrometry
  • Place of Presentation: St. Louis, MO, USA
  • Year and Date: 2015-06-01
  • Int'l Joint Research
• [Remarks] 名古屋大学大学院医学系研究科 法医生命倫理学ホームページ
  • URL: https://www.med.nagoya-u.ac.jp/legal/
• [Remarks] 名古屋大学研究シーズ集Unite
  • URL: http://www.aip.nagoya-u.ac.jp/unite/jp/detail/0000232.html
• [Patent(Industrial Property Rights)] イオン交換膜電気透析装置 (2016)
  • Inventor(s): 財津桂、林由美、金山伸広、金山裕亮
  • Industrial Property Rights Holder: 財津桂、林由美、金山伸広、金山裕亮
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-165694
  • Filing Date: 2016-08-26
• [Patent(Industrial Property Rights)] 質量分析装置及び該装置を用いた生体試料の分析方法 (2016)
  • Inventor(s): 財津桂、林由美、村田匡
  • Industrial Property Rights Holder: 島津製作所、名古屋大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-03-09