DIFFERENTIAL EXPRESSION OF C-FOS AND ZIF268 IN RAT STRIATUM AFTER HALOPERIDOL, CLOZAPINE, AND AMPHETAMINE
DIFFERENTIAL EXPRESSION OF C-FOS AND ZIF268 IN RAT STRIATUM AFTER HALOPERIDOL, CLOZAPINE, AND AMPHETAMINE
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DOI：
10.1073/pnas.89.10.4270
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发表时间：
1992-05-15
影响因子：
11.1
通讯作者：
HYMAN, SE
中科院分区：
文献类型：
--
作者：
NGUYEN, TV;KOSOFSKY, BE;HYMAN, SE
抗精神病药物是单胺受体拮抗剂。然而，这些直接作用转化为治疗效果的机制尚不清楚。候选机制包括受体介导的靶神经元中基因表达的调节。诱导型转录因子，包括某些立即早期基因（IEG），可以介导受体激活的第二信使系统和参与神经元分化功能的基因表达之间的关系。我们研究了几种抗精神病药物急性给药后诱导IEGs c-fos和zif 268的特异性，并进行比较，兴奋剂安非他明，其药理作用相对相反的抗精神病药物。具有强效多巴胺D2受体拮抗剂特性的抗精神病药物，如氟哌啶醇，在尾壳核中诱导c-fos和zif 268 mRNA;然而，非典型抗精神病药物氯氮平在该区域诱导zif 268而不是c-fos mRNA。同样，氟哌啶醇，而不是氯氮平，诱导c-Fos样免疫反应性的尾壳核。相反，这两种药物诱导c-Fos样免疫反应性在丘脑核。像氟哌啶醇，安非他明诱导c-fos和zif 268 mRNA在尾壳核，但诱导c-Fos样免疫反应的两种药物的解剖模式是显着不同的。氟哌啶醇和安非他明诱导的AP-1结合活性的尾壳核的细胞提取物，表明药物诱导的IEG表达的蛋白质产物，可能在调节靶基因的表达。因此，这些数据表明，诱导IEG表达氟哌啶醇，氯氮平，安非他明是具体的，可能是生物学相关的，并建议进一步调查的途径。
Antipsychotic drugs are monoamine receptor antagonists. However, the mechanisms by which these direct actions are translated into therapeutic effects are unknown. Candidate mechanisms include receptor-mediated regulation of gene expression in target neurons. Inducible transcription factors, including certain immediate early genes (IEGs), may mediate between receptor-activated second messenger systems and expression of genes involved in the differentiated functions of neurons. We examined the specificity of induction of the IEGs c-fos and zif268 after acute administration of several antipsychotic drugs and, for comparison, the stimulant amphetamine, which has pharmacologic effects relatively opposite to those of antipsychotics. Antipsychotic drugs with potent dopamine D2 receptor antagonist properties, such as haloperidol, induced both c-fos and zif268 mRNA in the caudate-putamen; however, the atypical antipsychotic drug clozapine induced zif268 but not c-fos mRNA in that region. Similarly, haloperidol, but not clozapine, induced c-Fos-like immunoreactivity in the caudate-putamen. In contrast, both drugs induced c-Fos-like immunoreactivity in the nucleus accumbens. Like haloperidol, amphetamine induced both c-fos and zif268 mRNA in the caudate-putamen, but the anatomic patterns of induction of c-Fos-like immunoreactivity by the two drugs were dramatically different. Haloperidol and amphetamine induced AP-1 binding activity in cell extracts from the caudate-putamen, indicating that drug-induced IEG expression results in protein products that may function in the regulation of target gene expression. Thus these data demonstrate that inductions of IEG expression by haloperidol, clozapine, and amphetamine are specific, may be biologically relevant, and suggest avenues for further investigation.