Zhang S P, Connell T A, Price T, Simpson G M, Zhou L W, Weiss B
Department of Pharmacology, Medical College of Pennsylvania/EPPI, Philadelphia 19129, USA.
Biol Psychiatry. 1995 Apr 15;37(8):496-503. doi: 10.1016/0006-3223(94)00185-6.
The biochemical mechanisms involved in the actions of the atypical antipsychotic clozapine are still unclear. Because elevated levels of enkephalin in certain areas of the central nervous system may be necessary for antipsychotic activity, we have examined the effect of clozapine on certain receptors and mRNA transcripts involved in the opioid peptidergic system. Clozapine was infused continuously into mice for 21 days and the density of mu and delta opioid receptors was measured in the brains by quantitative receptor autoradiography, and the level of proenkephalin mRNA and dopamine D1 and D2 receptor mRNA were measured by in situ hybridization histochemistry. The results showed that continuous infusion of clozapine increased the density of D1 but not D2 receptors. However, it failed to alter the levels of either D1 or D2 dopamine receptor mRNA. By contrast, clozapine increased the density of mu and delta opioid receptors and increased the levels of proenkephalin mRNA. These results indicate that continuous treatment with clozapine increases opioid peptidergic activity in mouse brain and suggest that alteration of peptidergic activity as well as alteration of dopaminergic activity may be involved in its antipsychotic action.
非典型抗精神病药物氯氮平作用的生化机制仍不清楚。由于中枢神经系统某些区域脑啡肽水平升高可能是抗精神病活性所必需的，我们研究了氯氮平对阿片肽能系统中某些受体和mRNA转录本的影响。将氯氮平连续注入小鼠体内21天，通过定量受体放射自显影法测量脑中μ和δ阿片受体的密度，并通过原位杂交组织化学法测量前脑啡肽mRNA以及多巴胺D1和D2受体mRNA的水平。结果显示，连续注入氯氮平可增加D1受体的密度，但不会增加D2受体的密度。然而，它未能改变D1或D2多巴胺受体mRNA的水平。相比之下，氯氮平增加了μ和δ阿片受体的密度，并增加了前脑啡肽mRNA的水平。这些结果表明，氯氮平连续治疗可增加小鼠脑中的阿片肽能活性，并提示肽能活性的改变以及多巴胺能活性的改变可能都参与了其抗精神病作用。
