| Project/Area Number |
09470212
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Psychiatric science
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| Research Institution | National Institute of Radiological Sciences |
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Principal Investigator |
SUHARA Tetsuya National Institute of Radiological Sciences Division of Advanced Technology for Medical Imaging, Senior Researcher, 高度診断機能研究ステーション, 主任研究官 (90216490)
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| Co-Investigator(Kenkyū-buntansha) |
HARADAHIRA Terushi National Institute of Radiological Sciences Division of Advanced Technology for Medical Imaging, Senior Researcher, 高度診断機能研究ステーション, 主任研究官 (50181029)
OKUBO Yoshiro Tokyo Medical and Dental University Faculty of Medicine, School of Allied Health Sciences Department of Clinical Physiology, Professor, 医学部・保健衛生学科機能検査学, 教授 (20213663)
SUZUKI Kazutoshi National Institute of Radiological Sciences Division of Advanced Technology for Medical Imaging, 高度診断機能研究ステーション・第一ユニット, ユニットリーダー (90162932)
NAKAYAMA Kazuhiko The Jikei University School of Medicine Department of Psychiatry, Associate Professor, 精神医学講座, 助教授 (70155878)
MURAYAMA Hideo National Institute of Radiological Sciences Division of Advanced Technology for Medical Imaging, Senior Researcher, 高度診断機能研究ステーション, 主任研究官 (50166310)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥15,300,000 (Direct Cost: ¥15,300,000)
Fiscal Year 1999: ¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 1998: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 1997: ¥5,700,000 (Direct Cost: ¥5,700,000)
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| Keywords | PET / Serotonin Transporter / Antidepressant / Lung / Occupancy / [11C] McN5652-X / [11C] Cyanoimipramine / Intrinsicserotonin / 内在性セロノニン / 5-HT1A受容体,5-HT7受容体 / うつ薬 / 〔11C〕WAY100635 / 5-HTIA受容体 / 代謝 / [11C]McN5652-X / [11C]WAY100635 / SSRI / 抗うつ薬 / 体内動態 / 薬物相互作用 |
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| Research Abstract |
1. Research on antidepressants in pharmacokinetic drug interactions
We have investigated the role of lung in pharmacokinetic drug interactions between tricyclic antidepressants and SSRIs using [ィイD111ィエD1C] cyanoimipramine. A large proportion of the injected [ィイD111ィエD1C] cyanoimipramine (70-80%) was accumulated in the lung. Fifty mg of clomipramine, antidepressant with high affinity for the serotonin transporter, decreased the lung uptake of [ィイD111ィエD1C] cyanoimipramine in approximately 40%. Whole-brain uptake was low in control state but increased significantly after clomipramine administration. The lungs may function as a reservoir for antidepressants with high affinity to the serotonin transporter. The accumulated antidepressants may be displaced by other antidepressants, and this displacement would substantially increase plasma concentrations and thus cause toxic effects.
2. Measurement of serotonin transporter occupancy with antidepressants
We demonstrated the occupancy of serotoni
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n transporters using [ィイD111ィエD1C] McN5652-X. We measured the changes of the specific binding in thalamus using the cerebellum as a non-specific binding site. Approximately 50-70% of serotonin transporter were occupied by clinical dose of clomipramine. Using inactive stereoisomer [ィイD111ィエD1C] (-) McN5652, non-specific binding was reevaluated and it was larger than previous evaluation. Calculated occupancy using [ィイD111ィエD1C] (-) McN5652 as non specific binding was 90 % by 50 mg of clomipramine and 95%, 75% of occupancy was calculated after administration of 50 mg, 25 mg fluboxamine
3. Development of a new method to measure the endogenous serotonin
The bindings of endogenous serotonin were analyzed by using a 5-HT1A receptor agonist, [ィイD111ィエD1C] WAY100635 after administration of fenflramin or reserpine. Endogenous serotonin had no significant effect on [ィイD111ィエD1C] IWAY100635 binding in vivo.
4. Serotonin transporters in mood disorders
The binding potentials of [ィイD111ィエD1C] McN5652-X were 0.89±0.17 (mean±S.D.) in thalamus, 0.93±0.26 in left basal ganglia and 0.87±0.18 in right basal ganglia in patients with mood disorders. In the control group, the binding potentials were 0.77±0.24 in thalamus, 0.88±0.37 in left basal ganglia and 0.92±0.30 in right basal ganglia. There was no significant difference of binding potentials between patients and controls. However, there was a positive correlation between the binding potentials of right basal ganglia and Hamilton depression scores (F=7.90, P=0.20). Less
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