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Functional role of nicotinic receptor in striato-nigral dopaminergic pathway using patch clamp method.

使用膜片钳方法研究烟碱受体在纹状体黑质多巴胺能通路中的功能作用。

基本信息

批准号：
11670090
负责人：
MATSUBAYASHI Hiroaki
金额：
$ 2.3万
依托单位：
Hiroshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670090/
关键词：
striato-nigral dopamine pathway nicotine patch clamp nicotinic acetylcholine receptor

项目摘要

In this study, I tried to investigate the functional role of nicotinic acetylcholine receptor in the stiato-nigral dopaminergic system using patch clamp method. Previous in vivo experiments using rats anesthetized with chloral hydrate have revealed that nicotine applied iontophoretically increased firing of striatal neurons receiving exicitatory dopaminergic input from the substantia nigra, and nicotine-induced firing was inhibited by domperidone. Therefore, I performed the patch-clamp study using slice preparations of the rat striatum to elucidate the mechanisms underlying nicotine-induced excitation of striatal neurons. Application of nicotine to the bath did not produce any effect on the resting membrane potential, but did increase the frequency of miniature postsynaptic potentials. Domperidone (a dopamine D2 receptor antagonist) and/or GDEE (a non-selective glutamate receptor antagonist) inhibited this excitatory effect of nicotine. These results suggest that nicotine acts on the nerve terminals to release neurotransmitters such as dopamine and/or glutamate, thereby activating the striatal neurons.On the other hand, a patch-clamp study using slice preparations of the substantia nigra revealed that nicotine induced a dose-dependent depolarization of dopaminergic neurons accompanying by an increase in firing. The nicotine-induced depolarization was observed even in a Ca^<2+>-free / high Mg^<2+> solution. These results suggest that nicotine postsynaptically activates dopaminergic neurons in the substantia nigra to facilitate dopamine release in the striatum beside eliciting presynaptic effects on the dopaminergic terminals.

本研究试图用膜片钳技术研究烟碱型乙酰胆碱受体在纹状体-黑质多巴胺能系统中的功能作用。先前使用水合氯醛麻醉的大鼠进行的体内实验表明，尼古丁通过离子导入增加了接受来自黑质的兴奋性多巴胺能输入的纹状体神经元的放电，而尼古丁诱导的放电被多潘立酮抑制。因此，我进行了膜片钳研究，使用切片制备的大鼠纹状体，以阐明尼古丁诱导的纹状体神经元兴奋的机制。应用尼古丁浴没有产生任何影响的静息膜电位，但增加了微小的突触后电位的频率。多潘立酮（多巴胺D2受体拮抗剂）和/或GDEE（非选择性谷氨酸受体拮抗剂）抑制尼古丁的这种兴奋作用。这些结果表明，尼古丁作用于神经末梢，释放神经递质，如多巴胺和/或谷氨酸，从而激活纹状体神经元。另一方面，使用黑质切片制备的膜片钳研究表明，尼古丁诱导多巴胺能神经元的剂量依赖性去极化，伴随着放电的增加。即使在无Ca^2+/高Mg^2+溶液中也能观察到尼古丁诱导的去极化。这些结果表明，尼古丁突触后激活黑质多巴胺能神经元，促进纹状体多巴胺释放，引发突触前效应的多巴胺能末梢。