Gonzalez G M, Werling L L
Department of Pharmacology, The George Washington University Medical Center, Washington, DC 20037, USA.
Naunyn Schmiedebergs Arch Pharmacol. 1997 Oct;356(4):455-61. doi: 10.1007/pl00005076.
Sigma receptors are found in motor and limbic areas in the brains of humans, non-human primates, and rodents. The most extensive pharmacological studies of ligand binding to sigma receptors have utilized brain tissue from guinea pigs, where two subtypes of sigma receptor, designated sigma1 and sigma2, have been identified. Few functional roles for sigma receptors have been described. Their location in guinea pig striatum, a terminal field of dopaminergic projections arising from the substantia nigra, suggested that this tissue would be a logical choice in which to examine physiological properties of sigma receptor activation. We found that sigma1 receptor agonists inhibited N-methyl-D-aspartate-stimulated [3H]dopamine release from guinea pig striatal slices in a concentration-dependent manner. The inhibition by sigma1 receptor agonists was reversed by a selective sigma1 receptor antagonist, as well as by a non-subtype-selective sigma receptor antagonist. The ability of agonists working through sigma1 receptors, but not through sigma2 receptors, to inhibit the stimulated release of catecholamines appears to be a unique characteristic of guinea pig striatum. We have previously reported that in rat striatum and hippocampus, as well as in guinea pig nucleus accumbens, prefrontal cortex, and hippocampus, activation of either sigma receptor subtype inhibits such release. Stimulated release of [3H]dopamine from guinea pig striatum was also inhibited by the phencyclidine receptor agonist dizocilpine, but this inhibition was not reversed by the sigma receptor antagonists. Therefore, the inhibition produced by sigma receptor agonists was not mediated via the phencyclidine binding site within the N-methyl-D-aspartate-operated cation channel. Our findings support the hypothesis that sigma receptor activation provides a mechanism of modulating dopamine release from striatum, and that striatal tissue from guinea pigs appears to be an appropriate model for characterizing sigma1 receptor-mediated effects.
西格玛受体存在于人类、非人灵长类动物和啮齿动物大脑的运动和边缘区域。关于配体与西格玛受体结合的最广泛药理学研究使用了豚鼠的脑组织，在那里已鉴定出两种西格玛受体亚型，分别命名为西格玛1和西格玛2。关于西格玛受体的功能作用描述较少。它们在豚鼠纹状体中的位置，纹状体是黑质多巴胺能投射的终末区域，这表明该组织将是研究西格玛受体激活生理特性的合理选择。我们发现西格玛1受体激动剂以浓度依赖性方式抑制豚鼠纹状体切片中N-甲基-D-天冬氨酸刺激的[3H]多巴胺释放。西格玛1受体激动剂的抑制作用可被选择性西格玛1受体拮抗剂以及非亚型选择性西格玛受体拮抗剂逆转。通过西格玛1受体而非西格玛2受体起作用的激动剂抑制儿茶酚胺刺激释放的能力似乎是豚鼠纹状体的独特特征。我们之前曾报道，在大鼠纹状体和海马体中，以及在豚鼠伏隔核、前额叶皮质和海马体中，任一西格玛受体亚型的激活均会抑制这种释放。豚鼠纹状体中[3H]多巴胺的刺激释放也受到苯环己哌啶受体激动剂地佐环平的抑制，但这种抑制作用不能被西格玛受体拮抗剂逆转。因此，西格玛受体激动剂产生的抑制作用不是通过N-甲基-D-天冬氨酸操作的阳离子通道内的苯环己哌啶结合位点介导的。我们的研究结果支持这样的假设，即西格玛受体激活提供了一种调节纹状体多巴胺释放的机制，并且豚鼠的纹状体组织似乎是表征西格玛1受体介导效应的合适模型。
