Enhanced cocaine responsiveness and impaired motor coordination in metabotropic glutamate receptor subtype 2 knockout mice
Enhanced cocaine responsiveness and impaired motor coordination in metabotropic glutamate receptor subtype 2 knockout mice
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DOI：
10.1073/pnas.0500914102
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发表时间：
2005-03-15
影响因子：
11.1
通讯作者：
Nakanishi, S
中科院分区：
文献类型：
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作者：
Morishima, Y;Miyakawa, T;Nakanishi, S
最近出现了广泛的药理学研究，表明包含mGluR 2和mGluR 3亚型的第2组代谢型谷氨酸受体（mGluR）与几种神经和精神障碍相关。mGluR 2广泛分布于多种神经元细胞的突触前和突触后，但对mGluR 2在脑功能中的生理作用知之甚少。本研究涉及mGluR 2（-/-）敲除（KO）小鼠的综合行为分析，以探索mGluR 2在脑功能中的生理作用。尽管在一般观察下，mGluR 2（-/-）KO小鼠似乎没有行为异常，但它们在强制和定义的行为测试中表现出几种行为改变。他们显示出与重复可卡因给药相关的运动敏感性和条件性位置偏好显著增加，表明mGluR 2有助于参与可卡因强化和成瘾的行为反应。在可卡因给药后的体内微透析分析中，不仅细胞外多巴胺水平增加，而且mGluR 2（-/-）KO小鼠的延髓核中谷氨酸释放的反应模式也发生了显着变化。mGluR 2（-/-）KO小鼠在加速旋转杆测试中也显示出运动协调的显著损伤，并且当通过旷场和强迫游泳测试评估时，在新的环境和应激条件下表现出过度运动。这些结果表明，抑制性mGluR 2在神经网络的突触调节中起着关键作用。
Extensive pharmacological studies have recently emerged indicating that group 2 metabotropic glutamate receptors (mGluRs) comprising mGluR2 and mGluR3 subtypes are associated with several neurological and psychiatric disorders. mGluR2 is widely distributed both presynaptically and postsynaptically in a variety of neuronal cells, but the physiological role of mGluR2 in brain function is poorly understood. This investigation involves a comprehensive behavioral analysis of mGluR2(-/-) knockout (KO) mice to explore the physiological role of mGluR2 in brain function. Although, under general observation, mGluR2(-/-) KO mice appeared to have no behavioral abnormalities, they exhibited several lines of behavioral alterations in the enforcing and defined behavioral tests. They showed a significant increase in locomotor sensitization and conditioned place preference in association with repeated cocaine administration, indicating that mGluR2 contributes to behavioral responses implicated in reinforcement and addiction of cocaine. Upon in vivo microdialysis analysis after cocaine administration, not only did extracellular levels of dopamine increase but also the response pattern of glutamate release markedly changed in the nucleus accumbens of mGluR2(-/-) KO mice. The mGluR2(-/-) KO mice also showed significant impairment in motor coordination in the accelerating rota-rod test and exhibited hyperlocomotion in novel environmental and stressful conditions, when assessed by the open-field and forced-swim tests. These results indicate that the inhibitory mGluR2 plays a pivotal role in synaptic regulation of glutamatergic transmission in the neural network.