Metabotropic glutamate receptor 5 localized in the limbic forebrain is critical for the development of morphine-induced rewarding effect in mice
Metabotropic glutamate receptor 5 localized in the limbic forebrain is critical for the development of morphine-induced rewarding effect in mice
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DOI：
10.1111/j.1460-9568.2004.03609.x
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发表时间：
2004-09-01
影响因子：
3.4
通讯作者：
Suzuki, T
中科院分区：
文献类型：
--
作者：
Aoki, T;Narita, M;Suzuki, T
本研究的目的是阐明代谢性谷氨酸5 （mGlu5）受体亚型在典型的mu-阿片受体激动剂吗啡诱导的小鼠奖赏效应发展中的作用。在条件位置偏好范式中，脑室内（i.c.v）给予选择性mGlu5受体拮抗剂2-甲基-6-（苯乙基）吡啶（MPEP），可减弱吗啡诱导的奖赏效应。通过免疫印迹分析，我们证实在吗啡条件下的ICR小鼠的边缘前脑中观察到蛋白激酶Cgamma （PKCgamma）异构体的水平升高。本研究首次发现MPEP处理显著抑制小鼠边缘前脑PKCgamma亚型的上调，表现出明显的位置偏好。此外，值得注意的是，吗啡条件小鼠的边缘前脑膜制剂中mGlu5蛋白水平明显高于盐水条件小鼠。在免疫印迹分析结果的基础上，我们利用受体结合实验证明吗啡条件作用显著增加了小鼠边缘前脑中mGlu5受体的数量。目前的数据提供了直接证据，表明与小鼠边缘前脑PKCgamma亚型增加相关的mGlu5受体的激活与吗啡奖励效应的发展有关。
The aim of the present study was to clarify the role of the metabotropic glutamate 5 (mGlu5) receptor subtype in the development of rewarding effect induced by a prototypical mu-opioid receptor agonist morphine in the mouse. In the conditioned place preference paradigm, intracerebroventricular (i.c.v.) administration of a selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), attenuated the morphine-induced rewarding effects. Using immunoblot analysis, we confirmed that the increased level of protein kinase Cgamma (PKCgamma) isoform was observed in the limbic forebrain of ICR mice conditioned with morphine. Here we found for the first time that the treatment with MPEP significantly inhibited the up-regulation of PKCgamma isoform in the limbic forebrain of mice showing the significant place preference. Furthermore, it should be mentioned that the protein level of mGlu5 was significantly increased in membrane preparations of the limbic forebrain obtained from morphine-conditioned mice compared to those from saline-conditioned mice. As well as the result from the immunoblot analysis, we demonstrated using the receptor binding assay that the number of mGlu5 receptors in the mouse limbic forebrain was significantly increased by morphine conditioning. The present data provide direct evidence that the activation of mGlu5 receptor linked to the increased PKCgamma isoform in the mouse limbic forebrain is implicated in the development of rewarding effect of morphine.