Skarsfeldt T
Department of Pharmacology, H. Lundbeck A/S, Valby, Denmark.
Life Sci. 1988;42(10):1037-44. doi: 10.1016/0024-3205(88)90558-9.
The effects of repeated treatment (21 days) with different antipsychotic compounds (haloperidol, clozapine, thioridazine and tefludazine) on dopamine (DA) neurones in substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) were studied in rats using single unit recording techniques. A dose-dependent decrease in the number of spontaneously active DA neurones in SNC and in VTA was observed with haloperidol. Clozapine showed no significant effect on the activity in SNC while a dose-dependent decrease in the number of active DA neurones in VTA was observed. Thioridazine showed no or weak effect in SNC while repeated treatment induced a marked inhibitory effect on the DA neurones in VTA. Tefludazine, a potential antipsychotic compound, induced a dose-dependent decrease in both SNC and VTA DA activity. However, the effect on the DA neurones in VTA was more pronounced at all doses. Since the classical neuroleptic haloperidol is equally effective in both regions, while the atypical neuroleptics clozapine and thioridazine have selective or predominant effect in the VTA area it has previously been thought that the inhibition of spontaneously active DA neurones in VTA should indicate an antipsychotic effect of a compound while the inhibition of DA neurones in SNC should account for the development of neurological side effects. The data suggests that the potential antipsychotic compound tefludazine should not induce neurological side effects at lower doses but still has an antipsychotic activity while repeated treatment with higher doses of tefludazine might cause extrapyramidal side effects.
采用单单位记录技术，研究了不同抗精神病化合物（氟哌啶醇、氯氮平、硫利达嗪和替氟哒嗪）对大鼠黑质致密部（SNC）和腹侧被盖区（VTA）多巴胺（DA）神经元的重复治疗（21天）效果。氟哌啶醇可使SNC和VTA中自发活动的DA神经元数量呈剂量依赖性减少。氯氮平对SNC的活性无显著影响，而VTA中活性DA神经元数量呈剂量依赖性减少。硫利达嗪对SNC无或仅有微弱影响，而重复治疗对VTA中的DA神经元有显著抑制作用。潜在的抗精神病化合物替氟哒嗪可使SNC和VTA中的DA活性均呈剂量依赖性降低。然而，在所有剂量下，其对VTA中DA神经元的影响更为明显。由于经典抗精神病药物氟哌啶醇在两个区域的效果相同，而非典型抗精神病药物氯氮平和硫利达嗪在VTA区域具有选择性或主要作用，因此此前人们认为，抑制VTA中自发活动的DA神经元应表明化合物具有抗精神病作用，而抑制SNC中的DA神经元应可解释神经副作用的发生。数据表明，潜在的抗精神病化合物替氟哒嗪在较低剂量时不应引起神经副作用，但仍具有抗精神病活性，而高剂量重复治疗替氟哒嗪可能会导致锥体外系副作用。
