2004 Fiscal Year Final Research Report Summary
Mechanisms of the developmert of L-DOPA-induced dyskinesias
| Project/Area Number |
15591506
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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 |
Cerebral neurosurgery
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| Research Institution | HIROSAKI UNIVERSITY |
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Principal Investigator |
TOMIYAMA Masahiko Hirosaki University, Hospital, Assistant, 医学部附属病院, 助手 (40311542)
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| Co-Investigator(Kenkyū-buntansha) |
WAKABAYASHI Ko-ichi Hirosaki University, School of Medicine, Professor, 医学部, 教授 (50240768)
KANNARI Kazuya Hirosaki University, Hospital, Lecturer, 医学部附属病院, 講師 (20241466)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Parkinson's disease / L-DOPA / dyskinesia / medial globus pallidus / GABA |
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| Research Abstract |
We have demonstrated that the medial globus pallidus (MGP) becomes hypertrophied in the lesioned side of 6-OHDA-lesioned rats intermittently treated with L-DOPA. Firstly, to confirm the specific relevance of the hypertrophy to L-DOPA-induced dysinesia (LID), we measured the volume of the MGP in 6-OHDA-lesioned rats treated with L-DOPA and L-DOPA plus an antidyskinesic drug, 8-OH-DPAT. The 6-OHDA-lesioned rats treated with L-DOPA displayd marked dyskinesia and hypertrophy of the MGP, whereas dyskinesia and the hypertrophy was attenuated in those treated with L-DOPA plus 8-OH-DPAT. This finding indicates that the hypertrophy is a neuropathological change that is specific to LID.
Secondly, to characterize the hypertrophy of the MGP, we performed immunohistochemical, electronmicroscopic and immunoelectronmicroscopic examinations. In the MGP of 6-OHDA-lesioned rats displaying LID. Fibers Immunoreactive for vesicular GABA transporter (VGAT) were densely distributed in the hypertrophied MGP, w
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hereas immunoreactivity for vesicular glutamate transporter 1 (VGluT1) was sparse in the hypertrophied MGP. No increase of GFAP immunoreactivity was seen in the hypertrophied MGP. These immunohistochemical observations suggest that the neuropil, putative GABAergic projection, was enlarged in the hypertrophied MGP. Electronmicroscopic examinations revealed that axon terminals surrounding dendrites of neurons became enlarged in the hypertrophied MGP. The enlarged axon terminals was immunoreactive for VGAT, but not for VGluT1. These findings indicate that the enlargement of axon terminals of GABAergic projections contributes to the hypertrophy of the MGP.
There are two GABAergic projections to the MGP, one from the striatum and the other from the lateral globus pallidus (LGP). Thirdly, to determine which GABAergic projection contributes to the hypertrophy, we conducted a tracer study using anterograde tracer, biotylated dextran amine (BDA). We injected BDA into the bilateral striatum or LGP of the dyskinesia model rats, and measured the size of synaptic boutons in the intact and lesioned side MGP. The size of boutons of rats that received BDA injection into the LGP was not different between intact and lesioned side MGP, whereas that of rats that received BDA injection into the striatum was significantly greater in the lesioned side. These results suggest that enlargement of axon terminals of the GABAergic striatum-MGP projection primarily contribute the hypertrophy of the MGP. Less
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Research Products
(7 results)
