Robertson G S, Tetzlaff W, Bedard A, St-Jean M, Wigle N
Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ontario, Canada.
Neuroscience. 1995 Jul;67(2):325-44. doi: 10.1016/0306-4522(95)00049-o.
The ubiquitous inducibility of the immediate-early gene c-fos in the central nervous system has led to the search for downstream genes which are regulated by its product, Fos. Recent evidence suggests that c-fos induction by a single injection of the classical antipsychotic haloperidol may contribute to the subsequent increase in neurotensin gene expression in the rodent striatum. Consistent with this proposal, in the present study haloperidol-induced Fos-like immunoreactivity and neurotensin/neuromedin N messenger RNA were found to be expressed by the same population of striatal neurons. Moreover, inhibition of haloperidol-induced c-fos expression by intrastriatal injection of antisense phosphorothioate oligodeoxynucleotides complimentary either to bases 109-126 or 127-144 of c-fos attenuated the subsequent increase in neurotensin/neuromedin N messenger RNA. However, injection of a sense phosphorothioate oligodeoxynucleotide corresponding to bases 127-144 of c-fos did not reduce haloperidol-induced c-fos or neurotensin/neuromedin N expression. Furthermore, constitutive expression of Jun-like immunoreactivity in the striatum was not reduced by either the sense or antisense phosphorothioate oligodeoxynucleotides. Similarly, the sense and antisense phosphorothioate oligodeoxynucleotide failed to reduce proenkephalin messenger RNA, which is located in the same striatal neurons that express haloperidol-induced neurotensin/neuromedin N messenger RNA, which is located in the same striatal neurons that express haloperidol-induced neurotensin/neuromedin N messenger RNA. Lastly, haloperidol-induced increases in nerve growth factor I-A-, JunB- and FosB-like immunoreactivity and fosB messenger RNA were not decreased by intrastriatal injection of either the sense or antisense phosphorothioate oligodeoxynucleotides. These results indicate that the antisense phosphorothioate oligodeoxynucleotides attenuated haloperidol-induced neurotensin/neuromedin N expression by selectively reducing c-fos expression and emphasize the potential importance of immediate-early gene induction in the mechanism of action of this antipsychotic drug.
即刻早期基因c-fos在中枢神经系统中普遍存在的可诱导性，促使人们寻找受其产物Fos调控的下游基因。最近的证据表明，单次注射经典抗精神病药物氟哌啶醇诱导c-fos表达，可能促使啮齿动物纹状体中神经降压素基因表达随后增加。与这一观点一致的是，在本研究中发现，氟哌啶醇诱导的Fos样免疫反应性和神经降压素/神经介素N信使核糖核酸由同一群纹状体神经元表达。此外，通过纹状体内注射与c-fos的109 - 126或127 - 144碱基互补的硫代磷酸酯反义寡脱氧核苷酸，抑制氟哌啶醇诱导的c-fos表达，减弱了随后神经降压素/神经介素N信使核糖核酸的增加。然而，注射与c-fos的127 - 144碱基对应的有义硫代磷酸酯寡脱氧核苷酸，并没有降低氟哌啶醇诱导的c-fos或神经降压素/神经介素N的表达。此外，纹状体中Jun样免疫反应性的组成型表达，未被有义或反义硫代磷酸酯寡脱氧核苷酸降低。同样，有义及反义硫代磷酸酯寡脱氧核苷酸未能降低脑啡肽原信使核糖核酸，脑啡肽原信使核糖核酸位于表达氟哌啶醇诱导的神经降压素/神经介素N信使核糖核酸的同一群纹状体神经元中。最后，纹状体内注射有义或反义硫代磷酸酯寡脱氧核苷酸，并没有降低氟哌啶醇诱导的神经生长因子I-A、JunB和FosB样免疫反应性及fosB信使核糖核酸的增加。这些结果表明，硫代磷酸酯反义寡脱氧核苷酸通过选择性降低c-fos表达，减弱了氟哌啶醇诱导的神经降压素/神经介素N表达，并强调了即刻早期基因诱导在这种抗精神病药物作用机制中的潜在重要性。
