Pharmacological antagonism of the actions of group II and III mGluR agonists in the lateral perforant path of rat hippocampal slices
Pharmacological antagonism of the actions of group II and III mGluR agonists in the lateral perforant path of rat hippocampal slices
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DOI：
10.1111/j.1476-5381.1996.tb15306.x
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发表时间：
1996-04-01
影响因子：
7.3
通讯作者：
Collingridge, GL
中科院分区：
文献类型：
--
作者：
Bushell, TJ;Jane, DE;Collingridge, GL
1代谢型谷氨酸受体（mGluRs）的生理和病理作用的理解，目前阻碍了缺乏选择性拮抗剂。使用标准细胞外记录技术研究最近报道的mGluR拮抗剂对从12 - 16日龄大鼠获得的海马切片的外侧穿通路径中的激动剂诱导的突触传递抑制的活性。2第III组特异性mGluR激动剂（S）-2-氨基-4-膦酰基丁酸酯（L-AP 4）以可逆和剂量依赖性方式抑制基础突触传递。平均用100 μ M L-AP 4获得的（+/-s.e.平均值）抑制选择性II组mGluR激动剂，（1S，3S）-1-氨基环戊烷-1，3-二羧酸酯（（1S，3S）-ACPD）和（2S，1'R，2'R，3'R）-2-（2'，3'-dicarboxycyclopropyl）glycine（DCG-IV）也以可逆和剂量依赖的方式抑制基础突触传递。用200 μ M（1S，3S）-ACPD获得的平均抑制率为83 +/-8%，IC 50值为12 +/-3 μ M（n = 5）。用1 μ M DCG-IV获得的平均抑制率为73 +/-7%，IC 50值为88 +/-15 nM（n = 4）。4由20 μ M（1S，3S）-ACPD和10 μ M L-AP 4的作用诱导的突触抑制被mGluR拮抗剂（+）-α-甲基-4-羧基苯甘氨酸（（+）-MCPG）拮抗，（S）-2-甲基-2-氨基-4-膦酰基丁酸酯（MAP4），（2S，1 'S，2 'S）-2-甲基-2-（2'-羧基环丙基）甘氨酸（MCCG），（RS）-α-甲基-4-四唑基苯基甘氨酸（MTPG），（RS）-α-甲基-4-磺酰基苯甘氨酸（MSPG）和（RS）-α-甲基-4-膦酰基苯甘氨酸（MPPG）（均在500 μ M下测试）。5（+）-MCPG是L-AP 4和（1S，3S）-ACPD诱导的抑制的弱拮抗剂。MCCG对（1S，3S）-ACPD具有选择性，但其作用的分析因明显的部分激动剂活性而变得复杂。MAP 4对L-AP 4诱导的效应显示出良好的选择性。6针对10 μ M L-AP 4测试的最有效的拮抗剂是MPPG（平均逆转90 +/-3%; n = 4）。相反，对20 μ m（1S，3S）-ACPD诱导的抑郁症最有效的拮抗剂是MTPG（平均逆转率为64 +/-4%; n = 4）。这两种拮抗剂产生的激动剂剂量-反应曲线的平行移动。Schild分析得到的K-D值分别为11.7 μ M和27.5 μ M。这两种拮抗剂对腺苷受体激动剂2-氯腺苷诱导的基础传输或抑郁症都没有任何影响（500nM; n = 3）。7我们得出结论，II组和III组mGluR均可介导由mGluR激动剂在外侧穿通通路中诱导的突触抑制。MPPG和MAP4应该是有用的，在确定第二组和第三组mGluRs在中枢神经系统中的作用。
1 An understanding of the physiological and pathological roles of metabotropic glutamate receptors (mGluRs) is currently hampered by the lack of selective antagonists. Standard extracellular recording techniques were used to investigate the activity of recently reported mGluR antagonists on agonist induced depressions of synaptic transmission in the lateral perforant path of hippocampal slices obtained from 12-16 day-old rats.2 The group III specific mGluR agonist, (S)-2-amino-4-phosphonobutanoate (L-AP4) depressed basal synaptic transmission in a reversible and dose-dependent manner. The mean (+/-s.e.mean) depression obtained with 100 mu M L-AP4 (the maximum concentration tested) was 74+/-3% and the IC50 value was 3 +/- 1 mu M (n=5).3 The selective group II mGluR agonists, (1S,3S)-1-aminocyclopentane-1,3-dicarboxylate ((1S,3S)-ACPD) and (2S, 1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) also depressed basal synaptic transmission in a reversible and dose-dependent manner. The mean depression obtained with 200 mu M (1S,3S)-ACPD was 83+/-8% and the IC50 value was 12+/-3 mu M (n=5). The mean depression obtained with 1 mu M DCG-IV was 73+/-7% and the IC50 value was 88+/-15 nM (n=4).4 Synaptic depressions induced by the actions of 20 mu M (1S,3S)-ACPD and 10 mu M L-AP4 were antagonized by the mGluR antagonists, (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG), (S)-2-methyl-2-amino-4-phosphonobutanoate (MAP4), (2S, 1'S,2'S)-2-methyl-2-(2'-carboxycyclopropyl)glycine (MCCG), (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) (all tested at 500 mu M).5 (+)-MCPG was a weak antagonist of both L-AP4 and (1S,3S)-ACPD-induced depressions. MCCG was selective towards (1S,3S)-ACPD, but analysis of its effects were complicated by apparent partial agonist activity. MAP4 showed good selectivity for L-AP4-induced effects.6 The most effective antagonist tested against 10 mu M L-AP4 was MPPG (mean reversal 90+/-3%; n=4). In contrast, the most effective antagonist tested against 20 mu m (1S,3S)-ACPD induced depressions was MTPG (mean reversal 64+/-4%; n=4). Both antagonists produced parallel shifts in agonist dose-response curves. Schild analysis yielded estimated K-D values of 11.7 mu M and 27.5 mu M, respectively. Neither antagonist had any effect on basal transmission or on depressions induced by the adenosine receptor agonist, 2-chloroadenosine (500 nM; n=3).7 We conclude that both group II and group III mGluRs can mediate synaptic depressions induced by mGluR agonists in the lateral perforant path. The mGluR antagonists MTPG, MPPG and MAP4 should be useful in determining the roles of group II and III mGluRs in the central nervous system.