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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Negative allosteric modulators of AMPA-preferring receptors inhibit ((3)H)GABA release in rat striatum.
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Negative allosteric modulators of AMPA-preferring receptors inhibit ((3)H)GABA release in rat striatum.

机译：AMPA优先受体的负变构调节剂抑制大鼠纹状体中的（（3）H）GABA释放。

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摘要

The effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), a selective glutamate receptor agonist, on the release of previously incorporated [(3)H]GABA was examined in superfused striatal slices of the rat. The slices were loaded with [(3)H]GABA in the presence of beta-alanine (1 mM) and superfused with Krebs-bicarbonate buffer containing nipecotic acid (0.1 mM) and aminooxyacetic acid (0.1 mM) to inhibit GABA uptake and metabolism. AMPA (0.01 to 3 mM) increased basal [(3)H]GABA outflow and nipecotic acid potentiated this effect. The [(3)H]GABA releasing effect of AMPA was an external Ca(2+)-dependent process in the absence but not in the presence of nipecotic acid. Cyclothiazide (0.03 mM), a positive modulator of AMPA receptors, failed to evoke [(3)H]GABA release by itself, but it dose-dependently potentiated the [(3)H]GABA releasing effect of AMPA. The AMPA (0.3 mM)-induced [(3)H]GABA release was antagonized by NBQX (0.01 mM) in a competitive fashion (pA(2) 5.08). The negative modulator of AMPA receptors, GYKI-53784 (0.01 mM) reversed the AMPA-induced [(3)H]GABA release by a non-competitive manner (pD'(2) 5.44). GYKI-53784 (0. 01-0.1 mM) also decreased striatal [(3)H]GABA outflow on its own right, this effect was stereoselective and was not influenced by concomitant administration of 0.03 mM cyclothiazide. GYKI-52466 (0. 03-0.3 mM), another negative modulator at AMPA receptors, also inhibited basal [(3)H]GABA efflux whereas NBQX (0.1 mM) by itself was ineffective in alteration of [(3)H]GABA outflow.The present data indicate that AMPA evokes GABA release from the vesicular pool in neostriatal GABAergic neurons. They also confirm that multiple interactions may exist between the agonist binding sites and the positive and negative modulatory sites but no such interaction was detected between the positive and negative allosteric modulators. Since GYKI-53784, but not NBQX, inhibited [(3)H]GABA release by itself, AMPA receptors located on striatal GABAergic neurons may be in sensitized state and phasically controlled by endogenous glutamate. It is also postulated that these AMPA receptors are located extrasynaptically on GABAergic striatal neurons.
机译：选择性谷氨酸受体激动剂α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）对先前掺入的[（3）H] GABA释放的影响在超融合的纹状体切片中进行了检查。鼠。在存在β-丙氨酸（1 mM）的情况下，在切片上加载[（3）H] GABA，并与含有乳糜酸（0.1 mM）和氨氧基乙酸（0.1 mM）的Krebs-碳酸氢盐缓冲液进行融合，以抑制GABA的摄取和代谢。 AMPA（0.01至3 mM）增加了基础[（3）H] GABA的流出量，而乳酸酸增强了这种作用。 AMPA的[（3）H] GABA释放作用是外部Ca（2+）依赖过程，而在没有乳酸菌的情况下不存在。 Cyclothiazide（0.03 mM），一种AMPA受体的正调节剂，自身未能引起[（3）H] GABA的释放，但剂量依赖性地增强了AMPA的[（3）H] GABA的释放作用。 NBQX（0.01 mM）以竞争方式拮抗AMPA（0.3 mM）诱导的[（3）H] GABA释放（pA（2）5.08）。 AMPA受体的负调节剂GYKI-53784（0.01 mM）通过非竞争性方式逆转了AMPA诱导的[（3）H] GABA释放（pD'（2）5.44）。 GYKI-53784（0. 01-0.1 mM）本身也减少了纹状体[（3）H] GABA流出，这种作用是立体选择性的，不受0.03 mM环噻嗪的同时给药的影响。 GYKI-52466（0. 03-0.3 mM）是AMPA受体的另一种负调节剂，也抑制了基础[[3）H] GABA外排，而NBQX（0.1 mM）本身对[[3）H] GABA的改变无效。目前的数据表明，AMPA引起新纹状体GABA能神经元从囊泡池释放GABA。他们还证实，激动剂结合位点与正负调节位点之间可能存在多种相互作用，但在正负变构调节剂之间未检测到这种相互作用。由于GYKI-53784（而不是NBQX）本身抑制[（3）H] GABA的释放，位于纹状体GABA能神经元上的AMPA受体可能处于敏化状态，并受内源性谷氨酸阶段性控制。还假定这些AMPA受体突触位于GABA能的纹状体神经元上。

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