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Development of animal models for Parkinson's desease and new drugs for this desease by the study of synaptic plasticity

通过突触可塑性研究开发帕金森病动物模型及新药

基本信息

批准号：
07672366
负责人：
SHIBATA Shigenobu
金额：
$ 1.47万
依托单位：
Waseda University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07672366/
关键词：
Parkinson dopamine circadian rhythm long-term potentiation plasticity reserpine suprachiasmatic nucleus NMDA Parkinson Circadian rhythm dopamine long-term potentiation plasticity reserpine suprachiasmatic nucleus 学習シナプス可塑性

项目摘要

I tried to develop the model animals for Parkinson's desease by the study of synaptic plasticity. Long-term enhancemnet of dopamine release was obtained by high frequency tetanic stimulation via a N-methyl-D-aspartate (NMDA) receptor-mediated pathyway in rat striatal slices. Haloperidol which produces a catalepsy in the rat apparently reduced the NMDA- and tetanic stimulation-induced dopamine release from the striatum. In addition, NMDA-induced dopamine release was low in the aged animals. These results suggest that tetanic stimulation or NMDA receptor activation caused a synaptic plasticity in the striatum. Therefore, deficit of dopamine release in the striatum by tetanic or NMDA activation may become one of the animal models of Parkinson's desease. Impairment of locomotor activity induced by 6-OHDPAT or reserpine is widely used to evaluate the anti-Parkinson's drugs. In the present experiment, day/night differences of activity rhythm was observed in the reserpine-injected rats. In the next experiment, therefore I examined the effect of bromocriptine and taripexole on reserpine-induced impairment of wheel-running rhythm in the hamster. However, these chemicals did not attenuate the impairment. The present results suggest that dopamine release induced by tetanic stimulation or NMDA receptor activation may be related to the skillfulness of the motor function, and that a deficit of locomotor rhythm in reserpine-injected animals may not be useful to evaluate the anti-Pakinson's drug.

本研究试图通过对突触可塑性的研究来建立帕金森病的动物模型。在大鼠纹状体脑片上，高频强直刺激通过N-甲基-D-天冬氨酸（NMDA）受体介导的通路获得多巴胺释放的长期增强。氟哌啶醇在大鼠中产生僵住症，明显减少NMDA和强直刺激诱导的纹状体多巴胺释放。此外，NMDA诱导的多巴胺释放在老年动物中很低。这些结果表明，强直刺激或NMDA受体激活引起的纹状体突触可塑性。因此，强直刺激或NMDA激活引起的纹状体多巴胺释放障碍可能成为帕金森病的动物模型之一。6-OHDPAT或利血平引起的自发活动损害被广泛用于评价抗帕金森病药物。本实验观察到注射利血平大鼠活动节律的昼夜差异。因此，在接下来的实验中，我检查了溴隐亭和他立哌索对利血平诱导的仓鼠车轮运行节律损伤的影响。然而，这些化学物质并没有减轻损害。目前的结果表明，多巴胺释放引起的强直刺激或NMDA受体激活可能与运动功能的熟练程度，和赤字的运动节奏在利血平注射的动物可能是没有用的，以评估抗帕金森的药物。