| Project/Area Number |
14570935
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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 | (Miyazaki Medical College) University of Miyazaki |
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Principal Investigator |
ISHIDA Yasushi University of Miyazaki, Professor, 医学部, 教授 (20212897)
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| Co-Investigator(Kenkyū-buntansha) |
ABE Hiroshi University of Miyazaki, Assistant, 医学部, 助手 (20344848)
HASHIGUCHI Hiroyuki University of Miyazaki, Assistant, 医学部, 講師 (40305090)
TAKEDA Ryuichiro University of Miyazaki, Assistant, 医学部, 助手 (90336298)
NISHIMORI Toshikazu Miyazaki Medical College, Professor, 医学部, 教授 (20112211)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | dopamine / 6-hydroxydopamine / basal ganglia / antisense / oligodeoxynucleotide / transplantation / transcriptional factor / phosphorylated glutamate receptor / immunohistochemistry / 6-ヒドロキンドーパミン(6-OHDA) |
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| Research Abstract |
1)Double immunostaining for Fos and γ-aminobutyric acid (GABA) was used in a previously established animal model of striatal dysfunction to examine whether GABA-immunoreactive neurons in the globus pallidus (GP) and entopeduncular nucleus (EP) are activated to express Fos immunoreactivity by intraperitoneal injection of amphetamine. Striatal efferent activity was suppressed by intrastriatal infusions of antisense oligodeoxynucleotide targeted to the messenger RNA of the immediate early gene, c-fos. This suppression produced robust rotational behavior and an atypical expression of Fos in the ipsilateral GP and EP following amphetamine challenge. Quantitative analysis revealed that a majority of the amphetamine-activated neurons in the GP and EP express GABA. The present results suggest an inhibition by projection neurons of the two nuclei that are regulated by striatal output activity.
2)To elucidate the morphological changes in immunopositive cells of ionotropic glutamate receptors with
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in intrastriatal "developing" grafts of fetal ventral mesencephalon (VM) in 6-hydroxydopamine-lesioned rats, immunohistochemistry was performed to detect cells expressing N-methyl-D-aspartate (NMDA) receptor subunit 1 (NR1), the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunits (GluR1, GluR2/3, and GluR4), or tyrosine hydroxylase (TH) in the intrastriatal VM grafts at 1, 4, and 12 weeks following transplantation. The results suggest that the ionotropic glutamate receptors have differential roles during the developmental period of the intrastriatal VM grafts.
3)We studied the PET tracer distributions of ligands for dopamine D_1 receptors ([^<11>C]SCH23390) and D_2 receptors ([^<11>C]raclopride) and of the dopamine precursor analog 6-[^<18>F]fluoro-L-3,4-dihydroxyphenylalanine ([^<18>F]FDOPA) as a measurement of presynaptic dopaminergic function, in the brain after 6-hydroxydopamine lesions of the medial forebrain bundle in rats. The unilateral lesions were confirmed behaviorally by methamphetamine-induced rotation at 2 weeks postlesion, and the brains were analyzed by tissue dissection following i.v. bolus of each tracer at 3 weeks postlesion. [^<11>C]Raclopride, but not [^<11>C]SCH23390, showed a higher accumulation in the striatum on the lesion side compared with that on the non-lesioned (intact) side. On the other hand, a lower accumulation of [^<18>F]FDOPA was found in the striatum and cerebral cortex on the lesion side. Our studies demonstrate upregulation in dopamine D_2 receptors in the striatum and a decrease in FDOPA uptake in both the striatum and cerebral cortex ipsilateral to the 6-hydroxydopamine lesions. Therefore the combination of a D_2 antagonist and FDOPA may provide a potentially useful method for assessing the effects of dopamine depletion in Parkinson's disease. Less
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