Involvement of alpha7 nicotinic acetylcholine receptors and neuroinflammation in the self-medicating effects of smoking in individuals with schizophrenia

• Project/Area Number: 19K08070
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Wakuda Tomoyasu 浜松医科大学, 医学部附属病院, 講師 (80444355)
• Co-Investigator(Kenkyū-buntansha): 横倉 正倫 浜松医科大学, 医学部, 助教 (00529399) ; 間賀田 泰寛 浜松医科大学, 光尖端医学教育研究センター, 教授 (20209399) ; 尾内 康臣 浜松医科大学, 光尖端医学教育研究センター, 教授 (40436978) ; 桑原 斉 埼玉医科大学, 医学部, 教授 (50456117) ; 山末 英典 浜松医科大学, 医学部, 教授 (80436493)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ポジトロン断層法 / 統合失調症 / ニコチン性アセチルコリン受容体 / ニコチン性受容体

Outline of Research at the Start

統合失調症は、20歳代に発病する主要な精神疾患である。症状には陽性症状（幻覚妄想）、陰性症状（感情の平板化など）、認知機能障害（記憶力障害など）があり、陰性症状と認知機能障害に対する治療法は未だ確立されていない。喫煙（ニコチン）が統合失調症の陰性症状や認知機能障害を改善させるという報告を手掛かりに、本研究では、PETを用いて統合失調症者のニコチン受容体と活性化ミクログリア結合能を測定することで、新たな創薬標的を創出することを目指す。

Outline of Final Research Achievements

By FY2022, we recruited 22 subjects with schizophrenia and 22 healthy subjects and completed this study. We analyzed the analyzable data at the time of this report from 18 subjects with schizophrenia and 20 healthy subjects. The schizophrenia group had a mean age of 28.1 years with a male-to-female ratio of 10:8, and the healthy group had a mean age of 25.9 years with a male-to-female ratio of 8:12. The schizophrenia group showed an increase in the binding potential of QAA in the whole brain compared to the healthy group. On the other hand, the binding potential of DPA713 was not significantly different between the schizophrenia and healthy subjects. In the future, we plan to conduct a correlation analysis of the binding potential of QAA with symptom severity and the binding potential of DPA713, as well as an ROI analysis by defining regions of interest, and submit the results to an international journal.

Academic Significance and Societal Importance of the Research Achievements

これまで死後脳研究結果のみであった統合失調症者のα7ニコチン性アセチルコリン受容体の異常が、本研究によりPETを用いてヒト生体内で測定可能となり、さらに、本研究結果から統合失調症者のα7ニコチン性アセチルコリン受容体が健常者と比較して増加している可能性が示された。これまで統合失調症ではα7ニコチン性アセチルコリン受容体が減少している仮説が支持されており、本研究結果は期待に反する結果であったことから、α7ニコチン性アセチルコリン受容体が統合失調症の新規薬剤の標的となり得る学術的意義を検討していく必要があると考えられた。

Research Products

• [Journal Article] Lower Availability of Mitochondrial Complex I in Anterior Cingulate Cortex in Autism: A Positron Emission Tomography Study (2023)
  • Author(s): Kato Yasuhiko、Yokokura Masamichi、Iwabuchi Toshiki、Murayama Chihiro、Harada Taeko、Goto Takafumi、Tamayama Taishi、Kameno Yosuke、Wakuda Tomoyasu、Kuwabara Hitoshi、Benner Seico、Senju Atsushi、Tsukada Hideo、Nishizawa Sadahiko、Ouchi Yasuomi、Yamasue Hidenori
  • Journal Title: American Journal of Psychiatry Volume: 180 Issue: 4 Pages: 277-284
  • DOI: 10.1176/appi.ajp.22010014
  • Peer Reviewed
• [Journal Article] Reduced P-glycoprotein recognition of a radioiodine-labeled phosphonium cation by stilbenylation for mitochondrial membrane potential based-imaging (2023)
  • Author(s): Suzuki Chie、Sakai Toshihiro、Magata Yasuhiro
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 84 Pages: 117260-117260
  • DOI: 10.1016/j.bmc.2023.117260
  • Peer Reviewed
• [Journal Article] Extrastriatal dopamine D2/3 receptor binding, functional connectivity, and autism socio-communicational deficits: a PET and fMRI study (2022)
  • Author(s): Murayama C, Iwabuchi T, Kato Y, Yokokura M, Harada T, Goto T, Tamayama T, Kameno Y, Wakuda T, Kuwabara H, Senju A, Nishizawa S, Ouchi Y, Yamasue H.
  • Journal Title: Mol Psychiatry Volume: - Issue: 4 Pages: 2106-2113
  • DOI: 10.1038/s41380-022-01464-3
  • Peer Reviewed
• [Journal Article] In vivo Illustration of Altered Dopaminergic and GABAergic Systems in Early Parkinson's Disease (2022)
  • Author(s): Takashima Hirotsugu、Terada Tatsuhiro、Bunai Tomoyasu、Matsudaira Takashi、Obi Tomokazu、Ouchi Yasuomi
  • Journal Title: Frontiers in Neurology Volume: 13
  • DOI: 10.3389/fneur.2022.880407
  • Peer Reviewed / Open Access
• [Journal Article] 'Opening doors' for long-term institutionalised patients with schizophrenia in Japan (2021)
  • Author(s): Wakuda T, Takei N.
  • Journal Title: Acta Psychiatr Scand. Volume: 143(3) Issue: 3 Pages: 277-278
  • DOI: 10.1111/acps.13269
  • NAID: 120007191213
  • Peer Reviewed
• [Journal Article] In vivo imaging of dopamine D1 receptor and activated microglia in attention-deficit/hyperactivity disorder: a positron emission tomography study (2020)
  • Author(s): Yokokura Masamichi、Takebasashi Kiyokazu、Takao Akiyo、Nakaizumi Kyoko、Yoshikawa Etsuji、Futatsubashi Masami、Suzuki Katsuaki、Nakamura Kazuhiko、Yamasue Hidenori、Ouchi Yasuomi
  • Journal Title: Molecular Psychiatry Volume: - Issue: 9 Pages: 12-12
  • DOI: 10.1038/s41380-020-0784-7
  • Peer Reviewed / Open Access
• [Journal Article] Coexistence of cerebral hypometabolism and neuroinflammation in the thalamo-limbic-brainstem region in young women with functional somatic syndrome (2020)
  • Author(s): Matsudaira T, Terada T, Obi T, Yokokura M, Takahashi Y, Ouchi Y.
  • Journal Title: EJNMMI Res. Volume: 10(1) Issue: 1 Pages: 29-29
  • DOI: 10.1186/s13550-020-00617-1
  • Peer Reviewed / Open Access
• [Journal Article] Alterations in serotonin transporter and body image-related cognition in anorexia nervosa (2019)
  • Author(s): Yokokura Masamichi、Terada Tatsuhiro、Bunai Tomoyasu、Nakaizumi Kyoko、Kato Yasuhiko、Yoshikawa Etsuji、Futatsubashi Masami、Suzuki Katsuaki、Yamasue Hidenori、Ouchi Yasuomi
  • Journal Title: NeuroImage: Clinical Volume: 23 Pages: 101928-101928
  • DOI: 10.1016/j.nicl.2019.101928
  • Peer Reviewed / Open Access
• [Journal Article] In vivo direct relation of tau pathology with neuroinflammation in early Alzheimer's disease. (2019)
  • Author(s): Terada T, Yokokura M, Obi T, Bunai T, Yoshikawa E, Ando I, Shimada H, Suhara T, Higuchi M, Ouchi Y.
  • Journal Title: J Neurol. Volume: 266(9) Issue: 9 Pages: 2186-2196
  • DOI: 10.1007/s00415-019-09400-2
  • Peer Reviewed
• [Journal Article] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect (2018)
  • Author(s): Ikeda M,Takahashi A,Kamatani Y,Momozawa Y,Saito T,Kondo K,Shimasaki A,Kawase K,Sakusabe T,Iwayama Y,Toyota T,Wakuda T,Kikuchi M,Kanahara N,Yamamori H,Yasuda Y,Watanabe Y,Hoya S,Aleksic B,Kushima I,Arai H,Takaki M,Hattori K,Kunugi H,Okahisa Y,Ohnuma T,Ozaki N,Someya T,Hashimoto R,Yoshikawa T,Kubo M,Iwata N
  • Journal Title: Schizophrenia Bulletin Volume: 印刷中 Issue: 4 Pages: 824-834
  • DOI: 10.1093/schbul/sby140
  • Peer Reviewed / Open Access
• [Presentation] 統合失調症におけるα7ニコチン性アセチルコリン受容体：[11C](R)-MeQAAを用いたPET脳画像の予備的研究 (2019)
  • Author(s): 和久田智靖、横倉正倫、中泉享子、加藤康彦、亀野陽亮、桑原斉、二ツ橋昌実、 吉川悦次、間賀田泰寛、尾内康臣、武井教使、山末英典
  • Organizer: 第115回日本精神神経学会学術総会
• [Presentation] 第1、第2 世代のPET トレーサーを用いた、加齢性変化と認知症におけるミクログリア活性の検討 (2019)
  • Author(s): 横倉正倫、寺田達弘、武内智康、中泉享子、加藤康彦、二ツ橋昌実、吉川悦次、 山末英典、尾内康臣
  • Organizer: 第115回日本精神神経学会学術総会
• [Presentation] 摂食障害患者におけるミクログリア活性について：PET を用いた検討 (2019)
  • Author(s): 横倉正倫、寺田達弘、武内智康、中泉享子、加藤康彦、二ツ橋昌実、吉川悦次、 山末英典、尾内康臣
  • Organizer: 第115回日本精神神経学会学術総会