Merchant K M, Dobie D J, Filloux F M, Totzke M, Aravagiri M, Dorsa D M
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.
J Pharmacol Exp Ther. 1994 Oct;271(1):460-71.
Previous studies have shown elevation of neurotensin neuromedin N (NT/N) and c-fos mRNA in the dorsolateral region of the rat neostriatum (DLSt) by acute administration of only typical antipsychotic drugs. However, NT/N mRNA in the nucleus accumbens-shell is enhanced acutely by several clinically efficacious antipsychotic drugs, regardless of their motor side effect liability. In the present study, induction of NT/N mRNA in the DLSt was observed again after 28 days of continuous administration (via osmotic minipumps) of haloperidol, but not clozapine. However, this response was only about 50% of that caused by acute haloperidol and c-fos mRNA levels in the DLSt were not elevated after the chronic treatment. An acute challenge of haloperidol 24 hr after chronic haloperidol treatment did not affect the tolerant response of NT neurons but caused a small increase in c-fos mRNA in the DLSt. Similar to the DLSt, chronic haloperidol (but not clozapine) significantly enhanced NT/N gene expression in the ventrolateral striatum, a region thought to be involved in abnormal oral movements, perhaps related to tardive dyskinesia. Interestingly, dopamine D2 receptor binding using [125I]iodosulpride nearly doubled in all regions of the striatum after chronic haloperidol but not clozapine. In contrast to the lateral neostriatum, NT/N mRNA expression in the nucleus accumbens-shell was elevated similarly by chronic treatment with haloperidol and clozapine to a level observed after acute haloperidol treatment. These results demonstrate further that region-specificity of NT/N mRNA regulation discriminate between typical and atypical antipsychotic drugs.
先前的研究表明，仅急性给予典型抗精神病药物可使大鼠新纹状体背外侧区（DLSt）的神经降压素神经调节素N（NT/N）和c-fos mRNA水平升高。然而，几种临床有效的抗精神病药物均可急性增强伏隔核壳中的NT/N mRNA，无论其运动副作用倾向如何。在本研究中，通过渗透微型泵连续28天给予氟哌啶醇后，DLSt中再次观察到NT/N mRNA的诱导，但氯氮平未出现此现象。然而，这种反应仅约为急性氟哌啶醇引起的反应的50%，慢性治疗后DLSt中的c-fos mRNA水平未升高。慢性氟哌啶醇治疗24小时后急性给予氟哌啶醇，并不影响NT神经元的耐受反应，但导致DLSt中的c-fos mRNA略有增加。与DLSt相似，慢性氟哌啶醇（而非氯氮平）显著增强了腹外侧纹状体中NT/N基因的表达，该区域被认为与异常口腔运动有关，可能与迟发性运动障碍有关。有趣的是，慢性给予氟哌啶醇而非氯氮平后，纹状体所有区域中使用[125I]碘舒必利的多巴胺D2受体结合几乎增加了一倍。与外侧新纹状体相反，氟哌啶醇和氯氮平慢性治疗使伏隔核壳中的NT/N mRNA表达同样升高至急性氟哌啶醇治疗后观察到的水平。这些结果进一步证明，NT/N mRNA调节的区域特异性可区分典型和非典型抗精神病药物。
