Lidow M S, Elsworth J D, Goldman-Rakic P S
Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
J Pharmacol Exp Ther. 1997 Apr;281(1):597-603.
D2 dopamine receptor antagonism is postulated to be the key to antipsychotic efficacy in the treatment of schizophrenia. Yet the D1 dopamine family of receptors is far more prevalent in the cortical areas of the brain, such as the prefrontal cortex, which have frequently been implicated in schizophrenia. Moreover, the prefrontal cortical D1 sites have recently been shown to be down-regulated by chronic treatment with several commonly used antipsychotic drugs (Lidow and Goldman-Rakic, 1994). To provide further insight into the pharmacological regulation of the D1 class of dopaminergic receptors, we have now used ribonuclease protection assays to examine the regulation of D1 and D5 dopamine receptor mRNAs in the prefrontal cortex and the neostriatum of nonhuman primates after chronic treatment with eight different drugs representing a wide structural and pharmacological spectrum of antipsychotic medications. The medications were administered for 6 months twice daily at doses that fall within the therapeutic range recommended for human patients. The study also included a substituted benzamide, tiapride, which is a D2 antagonist like the eight aforementioned drugs but reportedly lacks antipsychotic activity. Remarkably, all drugs used in this study, including tiapride, down-regulated the levels of both D1 and D5 mRNAs in the prefrontal cortex by 30% to 60% compared with a vehicle control group, whereas mRNAs in the neostriatum were not affected. This observation indicates that a reduction in the levels of prefrontal cortical dopamine receptors of the D1 class may be an obligatory consequence of D2 receptor antagonism and thus may be a pharmacological property of antipsychotic drugs.
D2多巴胺受体拮抗作用被认为是治疗精神分裂症时抗精神病疗效的关键。然而，多巴胺受体的D1家族在大脑皮质区域，如前额叶皮质中更为普遍，而前额叶皮质经常与精神分裂症有关。此外，最近发现，几种常用抗精神病药物的长期治疗会使前额叶皮质的D1位点下调（利多和戈德曼 - 拉基奇，1994年）。为了进一步深入了解D1类多巴胺能受体的药理调节作用，我们现在使用核糖核酸酶保护分析来研究，在用代表广泛结构和药理谱的八种不同抗精神病药物进行长期治疗后，非人类灵长类动物前额叶皮质和新纹状体中D1和D5多巴胺受体mRNA的调节情况。这些药物每天给药两次，持续6个月，剂量在推荐给人类患者的治疗范围内。该研究还包括一种取代苯甲酰胺——硫必利，它与上述八种药物一样是D2拮抗剂，但据报道缺乏抗精神病活性。值得注意的是，与溶剂对照组相比，本研究中使用的所有药物，包括硫必利，都使前额叶皮质中D1和D5 mRNA的水平下调了30%至60%，而新纹状体中的mRNA则未受影响。这一观察结果表明，D1类前额叶皮质多巴胺受体水平的降低可能是D2受体拮抗作用的必然结果，因此可能是抗精神病药物的一种药理特性。
