Type 2 metabotropic glutamate (mGlu) receptors tonically inhibit transmitter release in rat caudate nucleus: In vivo studies with (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine, a new potent and selective antagonist
Type 2 metabotropic glutamate (mGlu) receptors tonically inhibit transmitter release in rat caudate nucleus: In vivo studies with (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine, a new potent and selective antagonist
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DOI：
10.1111/j.1460-9568.1997.tb01489.x
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发表时间：
1997-07-01
影响因子：
3.4
通讯作者：
Moroni, F
中科院分区：
文献类型：
--
作者：
Cozzi, A;Attucci, S;Moroni, F
以往的解剖、生化和电生理研究表明，皮质-纹状体终末含有丰富的突触前第2组代谢性谷氨酸(MGlu)受体。使用脑片，我们以前已经证明，这些受体抑制去极化诱导的递质释放。利用自由活动大鼠的微透析，我们现在报告了第2组mGlu受体激动剂和拮抗剂对尾状体胞外液中谷氨酸浓度的影响。局部应用mGlu受体激动剂1S，3R-1-氨基环戊烷-1，3-二羧酸或(2S，3S，4S)-α-羧基环丙基-甘氨酸(L-CCG-1)可使尾状核透析液中谷氨酸浓度轻度下降(20-30%)。相反，1型和2型mGlu受体拮抗剂α-甲基-4-羧基苯甘氨酸使透析液中谷氨酸浓度增加3.5倍，其作用可被优先的2型mGlu受体激动剂L-CCG-1阻断。局部应用另一种结构无关、相对选择性和有效的2型mGlu受体拮抗剂(2S，1‘S，2’S，3‘R)-2-(2’-carboxy-3‘-phenylcyclopropyl)glycine，后，纹状体透析液中谷氨酸的产量也显著增加。结果表明，2型mGlu受体强直抑制皮质纹状体终末的递质释放。由于皮质-纹状体通路对很大比例的尾状核神经元的功能有深远的影响，因此有理由预测选择性2型mGlu受体药物的使用将有助于对基底节疾病的生理病理学的科学和治疗研究。
Anatomical, biochemical and electrophysiological studies have previously shown that cortico-striatal terminals contain abundant presynaptic group 2 metabotropic glutamate (mGlu) receptors. Using brain slices we have previously shown that these receptors inhibit depolarization-induced transmitter release. Using microdialysis in freely moving rats, we now report the effects of group 2 mGlu receptor agonists and antagonists on glutamate concentration in the caudate extracellular fluid. A mild decrease (20-30%) in glutamate concentration in caudate dialysates was observed when 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid or (2S,3S,4S)-alpha-carboxycyclopropyl-glycine (L-CCG-1), mGlu receptor agonists, was locally administered. On the contrary, alpha-methyl-4-carboxyphenylglycine, an antagonist of type 1 and type 2 mGlu receptors, increased the glutamate concentration in dialysates by up to 3.5-fold, and its effects were prevented by the simultaneous administration of L-CCG-1, a preferential type 2 mGlu receptor agonist. A significant increase of glutamate output in striatal dialysate was also found after local administration of (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine, another structurally unrelated, relatively selective and potent type 2 mGlu receptor antagonist. The results suggest that type 2 mGlu receptors tonically inhibit transmitter release from corticostriatal terminals. Since the cortico-striatal pathway profoundly affects the function of a large percentage of caudate neurons, it is reasonable to predict that the use of selective type 2 mGlu receptor agents will be helpful for scientific and therapeutic studies on the physiopathology of basal ganglion disorders.