Molecular biological study of mechanism of action of atypical antipsychotic drugs
| Project/Area Number |
13670978
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | HOKKAIDO UNIVERSITY |
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Principal Investigator |
KUSUMI Ichiro Hokkaido Univ. Med. Hospital, Lecturer, 医学部附属病院, 講師 (30250426)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Yoshito Hokkaido Univ. Med. Hospital, Instructor, 医学部附属病院, 助手 (90301902)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2001: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Keywords | Atypical antipsychotic drug / Serotonin-2A receptor / Dopamine-2 receptor / SSRI / Lithium / Working memory / Dopamine-1 receptor / Frontal cortex / セロトニン5-HT2A受容体 / 定型抗精神病薬 / 錐体外路症状 / 遅発性ジスキネジア / citalopram / methamphetamine / ドパミンD_2受容体 / D_2 mRNA / 遺伝子転写速度 |
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| Research Abstract |
The effects of 3-week treatment with haloperidol (HPD 0.1 mg/kg), HPD/fluvoxamine (FLV 25 mg/kg) and risperidone (RIS 0.5mg/kg)/FLV on the binding to D_2 receptors were examined in the rat striatum. Subchronic treatment with HPD/FLV significantly enhanced D_2 receptor up-regulation induced by HPD alone, while no increase was observed with RIS/FLV compared to controls. These findings suggest that 5-HT_<2A> receptor blockade prevents the enhanced D_2 receptor up-regulation induced by coadministration of SSRI with HPD and that the frequency of extrapyramidal symptoms and tardive dyskinesia may be low not only in case of treatment with RIS alone, but also in case of cotreatment with RIS and SSRI.
The effect of long-term treatment with lithium on working memory and referrence memory was examined in the rat using radial maze test. Both working and referrence memory were significantly improved compared to controls on the beginning and one week after oral administration of lithium, respectively. No significant differences were found between the two groups in body weight, locomotor activity and appetite. The D_1 receptor agonist SKF82958-induced locomotor activity was significantly enhanced in the lithium-treated rat compared with controls. The D_1 receptor protein measured by Western blotting was significantly increased in the frontal cortex on 14 days and 28 days after lithium administration, but no changes were observed in the nucleus accurnbens and striatum. The D1 receptor mRNA in frontal cortex was increased on 6, 14 and 28 days, while it was significantly decreased in the nucleus accumbens and striatum on 28 days. It is possible that long-term treatment with lithium may improve cognitive function by the mechanism of enhanced transcription of the D_1 receptor gene in frontal cortex.
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Report
(3 results)
Research Products
(28 results)
