Deutch A Y, Ongür D, Duman R S
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA.
Neuroscience. 1995 May;66(2):337-46. doi: 10.1016/0306-4522(94)00571-l.
Monitoring expression of c-fos and other immediate-early genes has proven a useful method for determining potential sites of action of antipsychotic drugs. Most studies of the effects of antipsychotic drugs on immediate-early gene expression have focused on the basal ganglia and allied cortical regions. We now report that clozapine administration markedly increases both the number of cells expressing Fos protein-like immunoreactivity and the amount of Fos protein in the thalamic paraventricular nucleus, but not the contiguous mediodorsal thalamic nucleus. Comparable doses of several dopamine D2-like antagonists, including raclopride, sulpiride, remoxipride and haloperidol, did not induce Fos expression in the paraventricular nucleus. However, loxapine and very high doses of haloperidol resulted in a small but significant increase in paraventricular nucleus Fos expression. The dopamine D1 receptor antagonist SCH23390 did not induce Fos in the paraventricular nucleus or alter the magnitude of the clozapine-elicited increase in Fos expression. The serotonergic 5-hydroxytryptamine2a/2c antagonist ritanserin, alone or in combination with sulpiride, did not increase Fos expression in the paraventricular nucleus. Similarly, the 5-hydroxytryptamine2:D2 antagonist risperidone did not change the amount of Fos protein in the paraventricular nucleus. Neither the alpha 1 adrenergic antagonist prazosin nor the muscarinic cholinergic antagonist scopolamine mimicked the effect of clozapine. The key placement of the paraventricular nucleus as an interface between the reticular formation and forebrain dopamine systems suggests that this thalamic nucleus may be an important part of an extended neural network subserving certain actions of antipsychotic drugs.
监测c-fos及其他即刻早期基因的表达已被证明是确定抗精神病药物潜在作用位点的一种有用方法。大多数关于抗精神病药物对即刻早期基因表达影响的研究都集中在基底神经节和相关皮质区域。我们现在报告，给予氯氮平可显著增加丘脑室旁核中表达Fos蛋白样免疫反应性的细胞数量和Fos蛋白的含量，但对相邻的丘脑背内侧核没有影响。几种多巴胺D2类拮抗剂，包括雷氯必利、舒必利、瑞莫必利和氟哌啶醇，给予可比剂量时并未在室旁核诱导Fos表达。然而，洛沙平及非常高剂量的氟哌啶醇导致室旁核Fos表达有小幅但显著的增加。多巴胺D1受体拮抗剂SCH23390并未在室旁核诱导Fos表达，也未改变氯氮平引起的Fos表达增加的幅度。5-羟色胺能5-羟色胺2a/2c拮抗剂利坦色林单独或与舒必利联合使用时，并未增加室旁核的Fos表达。同样，5-羟色胺2:D2拮抗剂利培酮也未改变室旁核中Fos蛋白的含量。α1肾上腺素能拮抗剂哌唑嗪和毒蕈碱胆碱能拮抗剂东莨菪碱均未模拟氯氮平的作用。室旁核作为网状结构与前脑多巴胺系统之间的界面的关键位置表明，这个丘脑核可能是一个扩展神经网络的重要组成部分，该网络参与抗精神病药物的某些作用。
