Ghersi Chiara, Bonfanti Andrea, Manzari Benedetta, Feligioni Marco, Raiteri Maurizio, Pittaluga Anna
Sezione di Farmacologia e Tossicologia, Dipartimento di Medicina Sperimentale, Università di Genova, Italy.
Neurochem Int. 2003 Mar;42(4):283-92. doi: 10.1016/s0197-0186(02)00129-8.
Presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptors mediating hippocampal [(3)H]noradrenaline or [(3)H]serotonin release, striatal [(3)H]dopamine release and cortical [(3)H]acetylcholine release were pharmacologically characterized using several AMPA/kainate receptor antagonists. The releases of the four transmitters elicited by exposing synaptosomes to AMPA were antagonized by NBQX, indicating that they reflect AMPA/kainate receptor activation. GYKI52466 did not inhibit the AMPA-induced release of [(3)H]noradrenaline, [(3)H]dopamine or [(3)H]serotonin, while it weakly affected the AMPA-mediated release of [(3)H]acetylcholine. On the contrary, LY300164 and LY303070 were potent antagonists able to discriminate among AMPA/kainate receptor subtypes. Both compounds blocked the AMPA receptors mediating [(3)H]dopamine and [(3)H]acetylcholine release. However, LY303070, but not LY300164, inhibited the AMPA-induced release of [(3)H]noradrenaline, while the AMPA-mediated [(3)H]serotonin release was sensitive to LY300164 but not to LY303070. SYM2206 mimicked LY300164 and prevented the AMPA-induced release of [(3)H]dopamine, [(3)H]acetylcholine and [(3)H]serotonin, but not that of [(3)H]noradrenaline. NS102 failed to antagonize the AMPA-induced release of all four transmitters. LY293558 prevented the AMPA-mediated release of [(3)H]noradrenaline, [(3)H]dopamine, [(3)H]acetylcholine or [(3)H]serotonin. Differently, LY377770 did not inhibit the AMPA-mediated release of [(3)H]noradrenaline and [(3)H]acetylcholine, but it potently blocked the AMPA-induced release of [(3)H]serotonin and, less so, of [(3)H]dopamine. AMOA inhibited the AMPA-induced release of [(3)H]serotonin or [(3)H]acetylcholine, but not that of [(3)H]noradrenaline or [(3)H]dopamine. GAMS prevented the AMPA-mediated release of [(3)H]acetylcholine and, more weakly, that of [(3)H]dopamine, but it failed to inhibit the release of [(3)H]noradrenaline or [(3)H]serotonin elicited by AMPA. gamma-DGG did not affect the AMPA-mediated release of any of the four transmitters studied. In conclusion, based on the antagonist profiles obtained, the four receptors here analyzed all belong to the AMPA-preferring subclass of glutamate receptors; however, they appear to differ from each other, probably due to differences in subunit composition. The compounds LY300164, LY303070, LY377770, AMOA and GAMS may be useful to discriminate among AMPA-preferring receptor subtypes.
使用多种α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）/海人藻酸（kainate）受体拮抗剂，对介导海马体中[³H]去甲肾上腺素或[³H]5-羟色胺释放、纹状体中[³H]多巴胺释放以及皮层中[³H]乙酰胆碱释放的突触前AMPA/kainate受体进行了药理学特性分析。将突触体暴露于AMPA所引发的这四种神经递质的释放，均被NBQX拮抗，这表明它们反映了AMPA/kainate受体的激活。GYKI52466并未抑制AMPA诱导的[³H]去甲肾上腺素、[³H]多巴胺或[³H]5-羟色胺的释放，而它对AMPA介导的[³H]乙酰胆碱释放仅有微弱影响。相反，LY300164和LY303070是能够区分AMPA/kainate受体亚型的强效拮抗剂。这两种化合物均阻断了介导[³H]多巴胺和[³H]乙酰胆碱释放的AMPA受体。然而，LY303070抑制了AMPA诱导的[³H]去甲肾上腺素释放，而LY300164则无此作用；AMPA介导的[³H]5-羟色胺释放对LY300164敏感，但对LY303070不敏感。SYM2206与LY300164类似，可阻止AMPA诱导的[³H]多巴胺、[³H]乙酰胆碱和[³H]5-羟色胺释放，但不能阻止[³H]去甲肾上腺素的释放。NS102未能拮抗AMPA诱导的所有这四种神经递质的释放。LY293558可阻止AMPA介导的[³H]去甲肾上腺素、[³H]多巴胺、[³H]乙酰胆碱或[³H]5-羟色胺的释放。不同的是，LY377770并未抑制AMPA介导的[³H]去甲肾上腺素和[³H]乙酰胆碱的释放，但它能强效阻断AMPA诱导的[³H]5-羟色胺释放，对[³H]多巴胺释放的阻断作用稍弱。AMOA抑制了AMPA诱导的[³H]5-羟色胺或[³H]乙酰胆碱的释放，但不抑制[³H]去甲肾上腺素或[³H]多巴胺的释放。GAMS可阻止AMPA介导的[³H]乙酰胆碱释放，对[³H]多巴胺释放的阻止作用较弱，但它未能抑制AMPA引发的[³H]去甲肾上腺素或[³H]5-羟色胺的释放。γ-DGG对所研究的这四种神经递质中任何一种的AMPA介导释放均无影响。总之，根据所获得的拮抗剂谱，此处分析的这四种受体均属于谷氨酸受体中偏好AMPA的亚类；然而，它们似乎彼此不同，这可能是由于亚基组成的差异所致。化合物LY300164、LY303070、LY377770、AMOA和GAMS可能有助于区分偏好AMPA的受体亚型。
