Lappalainen J, Hietala J, Koulu M, Seppälä T, Sjöholm B, Syvälahti E
Department of Pharmacology, University of Turku, Finland.
J Pharmacol Exp Ther. 1990 Feb;252(2):845-52.
Effects of chronic administration (18 days) with SCH 23390 (0.1 or 0.5 mg/kg/day s.c.) and haloperidol (1 mg/kg/day s.c.) on dopamine and serotonin synthesis and metabolism in discrete dopaminergic and serotonergic nuclei of rat brain were studied. Additionally, the effects of these treatments on dopamine D-1 and D-2 receptor characteristics in rat caudate-putamen were investigated. Chronic administration with both dose regimens of SCH 23390 decreased DA metabolism significantly (basal homovanillic acid concentrations) in nucleus caudatus. In another set of experiments dopamine synthesis (rate of accumulation of 3,4-dihydroxyphenylalanine after 3,4-dihydroxyphenylalanine-decarboxylase inhibition) was reduced significantly only in nucleus accumbens after the higher SCH 23390 dose regimen. In turn, chronic administration with haloperidol decreased basal dopamine metabolism and synthesis in nucleus caudatus and nucleus accumbens. Chronic haloperidol, but not SCH 23390, treatment induced a clear-cut increase in [3H]spiperone binding in caudate-putamen. Interestingly, neither SCH 23390 nor haloperidol treatments affected [3H]SCH 23390 binding in caudate-putamen. SCH 23390 and haloperidol had no significant effects on serotonin synthesis and metabolism in serotonergic and dopaminergic areas. In conclusion, the classical antipsychotic drug, haloperidol, clearly decreases dopamine turnover in nigrostriatal and mesolimbic dopaminergic systems. The D-1 antagonist, SCH 23390, also decreases dopaminergic activity in nigrostriatal and mesolimbic systems although DA synthesis and metabolism are affected to different degrees in nucleus caudatus and nucleus accumbens. Therefore, we suggest that if D-1 antagonists such as SCH 23390 show antipsychotic activity in clinical studies, they may not be free of extrapyramidal side-effects.
研究了SCH 23390（0.1或0.5毫克/千克/天，皮下注射）和氟哌啶醇（1毫克/千克/天，皮下注射）连续给药18天对大鼠脑内离散多巴胺能和5-羟色胺能核团中多巴胺和5-羟色胺合成及代谢的影响。此外，还研究了这些处理对大鼠尾状核-壳核中多巴胺D-1和D-2受体特性的影响。SCH 23390两种剂量方案的连续给药均显著降低了尾状核中的多巴胺代谢（基础高香草酸浓度）。在另一组实验中，仅在较高剂量方案的SCH 23390处理后，伏隔核中的多巴胺合成（3,4-二羟基苯丙氨酸脱羧酶抑制后3,4-二羟基苯丙氨酸的积累速率）才显著降低。相反，氟哌啶醇连续给药降低了尾状核和伏隔核中的基础多巴胺代谢及合成。氟哌啶醇连续给药而非SCH 23390处理导致尾状核-壳核中[3H]司来吉兰结合明显增加。有趣的是，SCH 23390和氟哌啶醇处理均未影响尾状核-壳核中[3H]SCH 23390结合。SCH 23390和氟哌啶醇对5-羟色胺能和多巴胺能区域中的5-羟色胺合成及代谢无显著影响。总之，经典抗精神病药物氟哌啶醇明显降低黑质纹状体和中脑边缘多巴胺能系统中的多巴胺周转。D-1拮抗剂SCH 23390也降低黑质纹状体和中脑边缘系统中的多巴胺能活性，尽管尾状核和伏隔核中的多巴胺合成及代谢受到不同程度的影响。因此，我们认为，如果像SCH 23390这样的D-1拮抗剂在临床研究中显示出抗精神病活性，它们可能无法避免锥体外系副作用。
