BIOLOGICAL AND BIOCHEMICAL CHARACTERIZATION OF SIGMA RECEPTORS

这个项目描绘了生化和 Sigma受体及其配体的药理特性。在这 本财年，我们发现抗精神病药物舒必利可以增强 NMDA诱导的细胞内钙离子浓度升高和 舒必利的这种作用反过来又被西格玛配体增强。 此外，还发现舒必利的这一作用被蛋白质阻断。 激酶A抑制剂。结果表明， 抗精神病药物和西格玛配体的作用，并提示该作用 任何一种或两种药物都可能影响细胞内钙离子 信号和蛋白质的磷酸化。在行为上，我们发现一个 合成Sigma配体Pre-084，如神经类固醇孕烯醇酮 硫酸盐和二氢表雄酮，改善学习和记忆 在记忆能力受到ICV损害的小鼠中 注射β-淀粉样肽25-35。此外，所有人的行动 三种化合物被黄体酮阻断，孕酮是一种神经类固醇 它能结合西格玛受体。因此，西格玛受体配体可以 代表了一类用于开发抗记忆药物的新化合物 探员们。

This projects delineates biochemical and pharmacological properties of sigma receptors and ligands. In this fiscal year, we found that a neuroleptic sulpiride can potentiate the NMDA-induced increase in intracellular calcium concentration and that this action of sulpiride is in turn enhanced by sigma ligands. Also, it was found that this action of sulpiride is blocked by protein kinase A inhibitor. The results indicate a relationship between the action of neuroleptics and sigma ligands and suggest that the action of either or both classes of drugs could invlove intracellular calcium signaling and protein hosphorylation. Behaviorally, we found that a synthetic sigma ligand PRE-084, like neurosteroids pregnenolone sulfate and dihydroepiandrosterone, improves learning and memory in mice whose mnemonic capacities were compromized by the icv injection of beta-amyloid peptide 25-35. Further, the action of all three compounds are blocked by progesterone, a neurosteroid which binds sigma receptors. Thus, sigma receptor ligands may represent a new class of compounds for developing antiamnesic agents.