Kearney J A, Becker J B, Frey K A, Albin R L
Neuroscience Program, Department of Neurology, University of Michigan, Ann Arbor 48109, USA.
Neuroscience. 1998 Dec;87(4):881-91. doi: 10.1016/s0306-4522(98)00193-6.
Metabotropic glutamate receptors are a major class of excitatory amino acid receptors. Eight metabotropic glutamate receptors subtypes have been cloned and have been classified into three groups based on their amino acid sequence homology, effector systems, and pharmacological profile. Previous results have shown that striatal group I metabotropic glutamate receptor stimulation produces vigorous contralateral rotation in intact rats, thought to be due to increased striatal dopamine release. Examination of FOS-like immunoreactivity and local cerebral glucose metabolism suggests that this occurs secondary to activation of the subthalamic nucleus. We sought to determine the contribution of dopamine by examining metabotropic glutamate receptor agonist-induced rotation in rats following acute dopamine depletion by reserpine/alpha-methyl-para-tyrosine treatment, or chronic dopamine depletion by 6-hydroxydopamine treatment. In unilateral 6-hydroxydopamine lesioned rats, the group I metabotropic glutamate receptor agonist (RS)-3,5-dihydroxyphenylglycine induced contralateral rotation with a coincident increase in striatal 3,4-dihydroxyphenylacetic acid. The rotation was attenuated by the group I antagonist 1-aminoindan-1,5-dicarboxylate. Examination of FOS-like immunoreactivity and [14C]2-deoxyglucose uptake in chronically dopamine depleted rats also revealed similar patterns to those seen previously in intact rats. However, acutely dopamine depleted rats do not exhibit metabotropic glutamate receptor agonist-induced rotation and show a different pattern of [14C]2-deoxyglucose uptake, with no increase in glucose utilization in the intermediate and deep layers of the superior colliculus. These results suggest that there are compensatory changes under conditions of chronic dopamine denervation which permit metabotropic glutamate receptor agonist-induced rotation to occur, which may include dopamine receptor supersensitivity, increased dopamine turnover, and/or changes in sensitivity of striatal group I metabotropic glutamate receptors. The group III metabotropic glutamate receptor agonist L-(+)-2-amino-4-phosphonobutyrate induced contralateral rotation in 6-hydroxydopamine lesioned rats, while it had no effect in intact rats. Additionally, examination of FOS-like immunoreactivity revealed a distinct pattern following L-(+)-2-amino-4-phosphonobutyrate administration in 6-hydroxydopamine lesioned versus intact rats. These results suggest that there is a change in the effect of striatal group III stimulation under conditions of dopamine depletion.
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，并根据其氨基酸序列同源性、效应系统和药理学特性分为三组。先前的研究结果表明，纹状体I组代谢型谷氨酸受体受刺激会使完整大鼠产生强烈的对侧旋转，据认为这是由于纹状体多巴胺释放增加所致。对FOS样免疫反应性和局部脑葡萄糖代谢的研究表明，这种情况继发于丘脑底核的激活。我们试图通过研究在利血平/α-甲基-对酪氨酸治疗导致急性多巴胺耗竭或6-羟基多巴胺治疗导致慢性多巴胺耗竭后，代谢型谷氨酸受体激动剂诱导的大鼠旋转，来确定多巴胺的作用。在单侧6-羟基多巴胺损伤的大鼠中，I组代谢型谷氨酸受体激动剂（RS）-3,5-二羟基苯甘氨酸诱导对侧旋转，同时纹状体3,4-二羟基苯乙酸增加。这种旋转被I组拮抗剂1-氨基茚满-1,5-二羧酸减弱。对慢性多巴胺耗竭大鼠的FOS样免疫反应性和[14C]2-脱氧葡萄糖摄取的研究也揭示了与先前在完整大鼠中观察到的类似模式。然而，急性多巴胺耗竭的大鼠不表现出代谢型谷氨酸受体激动剂诱导的旋转，并且显示出不同的[14C]2-脱氧葡萄糖摄取模式，上丘中间层和深层的葡萄糖利用没有增加。这些结果表明，在慢性多巴胺去神经支配的情况下存在代偿性变化，这使得代谢型谷氨酸受体激动剂诱导的旋转得以发生，这可能包括多巴胺受体超敏反应、多巴胺周转增加和/或纹状体I组代谢型谷氨酸受体敏感性的变化。III组代谢型谷氨酸受体激动剂L-(+)-2-氨基-4-膦酰丁酸在6-羟基多巴胺损伤的大鼠中诱导对侧旋转，而在完整大鼠中没有作用。此外，对FOS样免疫反应性的研究揭示了在6-羟基多巴胺损伤的大鼠与完整大鼠中给予L-(+)-2-氨基-4-膦酰丁酸后不同的模式。这些结果表明，在多巴胺耗竭的情况下，纹状体III组刺激的效应发生了变化。
