Kearney J A, Albin R L
Department of Neurology, The University of Michigan, Ann Arbor, MI 48109, USA.
Neuroscience. 2000;95(2):409-16. doi: 10.1016/s0306-4522(99)00439-x.
Metabotropic glutamate receptors are a major class of excitatory amino acid receptors. Eight metabotropic glutamate receptor subtypes have been cloned, and are classified into three groups (I, II and III) based on amino acid sequence identity, effector systems and pharmacological profile. Previous results have shown that unilateral stimulation of metabotropic glutamate receptors in the subthalamic nucleus with the non-subtype-selective metabotropic glutamate receptor agonist 1S,3R-1-amino-1,3-cyclopentane dicarboxylate results in contralateral rotation in rats and Fos expression in the subthalamic nucleus. This suggests that metabotropic glutamate receptor stimulation results in altered subthalamic nucleus activity with consequent altered basal ganglia activity on the injected side. We sought to determine the metabotropic glutamate receptor subtype(s) involved and the functional neuroanatomy underlying the rotational behavior. Unilateral intrasubthalamic nucleus injection of group II or group III metabotropic glutamate receptor agonists induced contralateral rotation. In addition to producing rotation, group II and group III metabotropic glutamate receptor agonists induce toxicity in the subthalamic nucleus and overlying thalamus. Following group II or group III subthalamic nucleus metabotropic glutamate receptor stimulation, there is Fos-like immunoreactivity in the globus pallidus, subthalamic nucleus, substantia nigra pars reticulata and entopeduncular nucleus, suggesting altered activity in subthalamic nucleus target regions. However, examination of [14C]2-deoxyglucose uptake suggests that the alterations in basal ganglia activity are different following group II versus group III metabotropic glutamate receptor stimulation, suggesting that rotation is occurring via different mechanisms. It appears that stimulation of subthalamic nucleus group II metabotropic glutamate receptors induces rotation by increasing subthalamic nucleus activity. These results suggest that group II metabotropic glutamate receptor antagonists may be useful for alleviating subthalamic nucleus overactivity in Parkinson's disease.
代谢型谷氨酸受体是兴奋性氨基酸受体的主要类别。已克隆出8种代谢型谷氨酸受体亚型，并根据氨基酸序列同源性、效应系统和药理学特性分为三组（I、II和III）。先前的研究结果表明，用非亚型选择性代谢型谷氨酸受体激动剂1S,3R-1-氨基-1,3-环戊烷二羧酸单侧刺激丘脑底核中的代谢型谷氨酸受体，会导致大鼠出现对侧旋转以及丘脑底核中Fos表达。这表明代谢型谷氨酸受体刺激会导致丘脑底核活动改变，进而使注射侧的基底神经节活动发生改变。我们试图确定参与其中的代谢型谷氨酸受体亚型以及旋转行为背后的功能性神经解剖学机制。单侧丘脑底核内注射II组或III组代谢型谷氨酸受体激动剂会诱发对侧旋转。除了产生旋转外，II组和III组代谢型谷氨酸受体激动剂还会在丘脑底核和上覆丘脑诱发毒性。在II组或III组丘脑底核代谢型谷氨酸受体受到刺激后，苍白球、丘脑底核、黑质网状部和内囊核中会出现Fos样免疫反应，提示丘脑底核靶区的活动发生了改变。然而，对[14C]2-脱氧葡萄糖摄取的检测表明，II组与III组代谢型谷氨酸受体刺激后基底神经节活动的改变有所不同，这表明旋转是通过不同机制发生的。似乎刺激丘脑底核II组代谢型谷氨酸受体会通过增加丘脑底核活动来诱发旋转。这些结果表明，II组代谢型谷氨酸受体拮抗剂可能有助于减轻帕金森病中丘脑底核的过度活动。
