Merchant K M, Dobner P R, Dorsa D M
Department of Pharmacology, University of Washington, Seattle 98195.
J Neurosci. 1992 Feb;12(2):652-63. doi: 10.1523/JNEUROSCI.12-02-00652.1992.
A single dose of typical neuroleptic, haloperidol, has been demonstrated to increase the expression of neurotensin/neuromedin N (NT/N) mRNA in the dorsolateral striatum within 1 hr of its administration (Merchant et al., 1991). The present study further investigated neuroleptic-induced regulation of NT/N gene transcription. Levels of NT/N mRNA were examined at various times following a single dose of haloperidol (1 mg/kg, i.p.) or the atypical antipsychotic clozapine (20, 30, or 40 mg/kg, i.p.) by in situ hybridization histochemistry and quantitative solution hybridization. In the dorsolateral striatum, the two drugs had strikingly different effects; haloperidol rapidly (within 30 min) increased the expression of mature NT/N mRNA while virtually no increase was observed in response to nontoxic doses of clozapine at any of the time points examined. Following haloperidol, maximal induction occurred at 7 hr, at which time NT/N mRNA levels were an order of magnitude higher than basal levels. By 20 hr after haloperidol, there was a significant decline in striatal NT/N mRNA levels. In situ hybridization analysis using an intron-derived probe revealed that haloperidol-induced increases in mature NT/N mRNA levels in the striatum were preceded by a transient increase in intron-containing NT/N gene transcripts. These data strongly indicate that acute haloperidol treatment results in transient transcriptional activation of NT/N gene, although a concomitant effect on the stability of NT/N primary transcripts cannot be ruled out. In contrast to their differential effects in the dorsolateral striatum, a single dose of both haloperidol and clozapine induced a small but significant increase in NT/N mRNA expression in the shell sector of the nucleus accumbens. These results raise the possibility that NT neurons in the nucleus accumbens may, at least in part, mediate the antipsychotic effects of classical neuroleptics, whereas NT cells in the dorsolateral region of the striatum may be involved in mediating other effects of typical neuroleptics such as extrapyramidal motor symptoms.
已证实，单次给予典型抗精神病药物氟哌啶醇可在给药后1小时内增加背外侧纹状体中神经降压素/神经介素N（NT/N）mRNA的表达（Merchant等人，1991年）。本研究进一步探讨了抗精神病药物对NT/N基因转录的调控作用。通过原位杂交组织化学和定量溶液杂交技术，在单次给予氟哌啶醇（1mg/kg，腹腔注射）或非典型抗精神病药物氯氮平（20、30或40mg/kg，腹腔注射）后的不同时间点检测NT/N mRNA水平。在背外侧纹状体中，这两种药物产生了截然不同的效应；氟哌啶醇迅速（30分钟内）增加了成熟NT/N mRNA的表达，而在任何检测时间点，无毒剂量的氯氮平均未引起明显增加。给予氟哌啶醇后，最大诱导作用出现在7小时，此时NT/N mRNA水平比基础水平高一个数量级。氟哌啶醇给药20小时后，纹状体中NT/N mRNA水平显著下降。使用内含子衍生探针的原位杂交分析显示，氟哌啶醇诱导纹状体中成熟NT/N mRNA水平增加之前，含内含子的NT/N基因转录本会短暂增加。这些数据强烈表明，急性氟哌啶醇治疗导致NT/N基因的短暂转录激活，尽管不能排除对NT/N初级转录本稳定性的伴随影响。与它们在背外侧纹状体中的不同效应相反，单次给予氟哌啶醇和氯氮平均可诱导伏隔核壳区NT/N mRNA表达出现小幅但显著的增加。这些结果提示，伏隔核中的NT神经元可能至少部分介导了经典抗精神病药物的抗精神病作用，而纹状体背外侧区域的NT细胞可能参与介导典型抗精神病药物的其他效应，如锥体外系运动症状。
