Walker J M, Matsumoto R R, Bowen W D, Gans D L, Jones K D, Walker F O
Department of Psychology, Brown University, Providence, RI 02912.
Neurology. 1988 Jun;38(6):961-5. doi: 10.1212/wnl.38.6.961.
Haloperidol exhibits a high affinity for a subclass of sigma- "opiate" binding sites which have a unique anatomic distribution and a unique drug selectivity pattern. These binding sites differ from phencyclidine-sensitive sigma-receptors and are found in many brain areas involved in the control of movement. 1,3-Di-o-tolylguanidine (DTG), a highly selective ligand for the haloperidol-sensitive sigma-receptor, produced marked dystonia in rats after microinjection into the red nucleus, a motor area rich in this receptor. Haloperidol and another sigma-ligand [(+)-SKF 10,047] produced similar effects. On the other hand, clozapine, an antipsychotic drug which fails to bind to sigma-receptors and fails to induce movement disorders in humans, failed to induce these dystonic reactions in rats. Phencyclidine was also without effect, as were injections of the active compounds in sites distant to the red nucleus. Microinjections of DTG in the substantia nigra produced vigorous contralateral circling behavior at extremely low doses. These findings suggest that sigma-binding sites represent biologically functional receptors that are active in the neural control of movement. Since haloperidol (and many other antipsychotic drugs) exhibit an affinity for sigma-receptors which is at least equal to its affinity for dopamine receptors, these data raise the further possibility that sigma-receptors are involved in the motor side effects of antipsychotic drugs.
氟哌啶醇对一类西格玛-“阿片样物质”结合位点具有高亲和力，这些结合位点具有独特的解剖分布和独特的药物选择性模式。这些结合位点不同于对苯环己哌啶敏感的西格玛受体，且存在于许多参与运动控制的脑区。1,3-二邻甲苯基胍（DTG）是一种对氟哌啶醇敏感的西格玛受体的高度选择性配体，微量注射到富含该受体的运动区域红核后，可在大鼠中产生明显的肌张力障碍。氟哌啶醇和另一种西格玛配体[（+）-SKF 10,047]产生类似的效果。另一方面，氯氮平是一种抗精神病药物，它不与西格玛受体结合，也不会在人类中诱发运动障碍，在大鼠中也未能诱发这些肌张力障碍反应。苯环己哌啶也没有效果，在红核以外的部位注射活性化合物也无效果。在极低剂量下，向黑质微量注射DTG会产生强烈的对侧转圈行为。这些发现表明，西格玛结合位点代表了在运动神经控制中起作用的生物学功能性受体。由于氟哌啶醇（以及许多其他抗精神病药物）对西格玛受体的亲和力至少与其对多巴胺受体的亲和力相当，这些数据进一步增加了西格玛受体参与抗精神病药物运动副作用的可能性。
