Goldstein M, Fuxe K, Meller E, Seyfried C A, Agnati L, Mascagni F M
Department of Psychiatry, New York University Medical Center, New York.
J Neural Transm. 1987;70(3-4):193-215. doi: 10.1007/BF01253598.
The effects of the dopamine (DA) agonist EMD 23,448 on central normosensitive and supersensitive DA receptors were investigated. EMD 23,448 only slightly inhibits rat striatal DOPA synthesis in vivo and does not inhibit the enhanced striatal DOPA synthesis elicited by acute administration of haloperidol. Also unlike other DA agonists it does not increase striatal acetylcholine levels. However, it inhibits striatal DOPA synthesis in rats with DA receptors rendered supersensitive by chronic treatment with haloperidol. EMD 23,448 also effectively inhibits the enhanced striatal DOPA synthesis elicited by administration of GBL. Furthermore, EMD 23,448 selectively reduces, in a dose-dependant way, DA utilization in nerve terminals of the central caudate and in dotted terminals of the ventral striatum but DA utilization in the substantia nigra is unaffected. The most marked reduction of DA utilization was induced in the anteromedial frontal cortex. These results indicate that EMD 23,448 selectively stimulates presynaptic DA receptors and supersensitive postsynaptic DA receptors. Behavioral experiments in animals with normosensitive and supersensitive DA receptors also indicate that EMD 23,448 effectively stimulates presynaptic and supersensitive postsynaptic DA receptors. Receptor binding studies have shown that EMD 23,448 has a high affinity for the D2 DA receptors, but it ineffectively promotes the coupling of the DA receptors with the guanine nucleotide regulatory protein. However, at supersensitive striatal DA receptors the coupling is shown to be enhanced by EMD 23,448. The selectivity of EMD 23,448 for presynaptic DA receptors might, at least in part, be related to the presence of DA receptor reserves which are sensitive to EMD 23,448. With regard to the selectivity of EMD 23,448 for supersensitive postsynaptic DA receptors an increase in the efficiency of the coupling mechanism upon activation by EMD 23,448 is probably involved.
研究了多巴胺（DA）激动剂EMD 23,448对中枢正常敏感和超敏DA受体的作用。EMD 23,448在体内仅轻微抑制大鼠纹状体多巴合成，且不抑制氟哌啶醇急性给药引起的纹状体多巴合成增强。此外，与其他DA激动剂不同，它不会增加纹状体乙酰胆碱水平。然而，它能抑制经氟哌啶醇慢性处理而使DA受体超敏的大鼠的纹状体多巴合成。EMD 23,448还能有效抑制GBL给药引起的纹状体多巴合成增强。此外，EMD 23,448以剂量依赖的方式选择性降低中枢尾状核神经末梢和腹侧纹状体点状末梢的DA利用率，但黑质中的DA利用率不受影响。DA利用率降低最明显的是在前内侧额叶皮质。这些结果表明，EMD 23,448选择性刺激突触前DA受体和超敏突触后DA受体。对正常敏感和超敏DA受体动物的行为实验也表明，EMD 23,448能有效刺激突触前和超敏突触后DA受体。受体结合研究表明，EMD 23,448对D2 DA受体具有高亲和力，但它不能有效地促进DA受体与鸟嘌呤核苷酸调节蛋白的偶联。然而，在超敏纹状体DA受体处，EMD 23,448可增强偶联。EMD 23,448对突触前DA受体的选择性可能至少部分与对EMD 23,448敏感的DA受体储备的存在有关。关于EMD 23,448对超敏突触后DA受体的选择性，可能涉及EMD 23,448激活后偶联机制效率的提高。
