Deutch A Y, Duman R S
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA.
Neuroscience. 1996 Jan;70(2):377-89. doi: 10.1016/0306-4522(95)00357-6.
The assessment of immediate-early gene induction has proven to be a useful method for delineating the neural systems that subserve antipsychotic drug actions. In order to differentiate the sites and mechanisms of action of typical and atypical antipsychotic drugs, we examined the effects of antipsychotic drugs on Fos protein expression in the medial prefrontal cortex. The atypical antipsychotic drug clozapine selectively increased the number of neurons that expressed Fos-like immunoreactivity in the prefrontal cortex, targeting the deep layers of the infralimbic and prelimbic cortices. Pyramidal cells were the major cell type in which Fos was expressed. A small number of calbindin-like immunoreactive, but not parvalbumin- or reduced nicotinamide adenine dinucleotide phosphate diaphorase-containing, interneurons also expressed Fos after clozapine challenge. Immunoblot studies revealed that clozapine induced Fos protein in the infralimbic and prelimbic cortices. Other antipsychotic drugs that are D2 receptor antagonists, including haloperidol, raclopride, sulpiride, remoxipride and loxapine, did not alter Fos expression. The clozapine-induced increase in Fos expression was also not attributable to actions at the D1 dopamine receptor, nor to serotonin type 2a/2c receptor antagonism or combined serotonin type 2-D2 dopamine receptor antagonism. The ability of clozapine to block alpha 1-adrenergic or muscarinic cholinergic receptors did not contribute to the unique actions of clozapine. Despite the inability of dopamine receptor antagonists other than clozapine to elicit an increase in Fos expression, both the mixed D1-D2 dopamine agonist apomorphine and the D2-like agonist quinpirole increased Fos protein levels in the prefrontal cortex. However, neither pretreatment with sulpiride to block D2/3/4 dopamine receptors or SCH 23390 to block D1/5 dopamine receptors modified the Fos response to clozapine. Since dopamine receptor antagonist pretreatments did not attenuate the clozapine-elicited Fos expression, but D2 agonists increased cortical Fos expression, clozapine may act in the prefrontal cortex on an as yet undefined dopamine receptor. In contrast to the nucleus accumbens shell, where all antipsychotic drugs increase Fos expression, only clozapine induced Fos in the medial prefrontal cortex. These observations suggest that the ability of clozapine to treat schizophrenic patients who are resistant to the therapeutic benefits of conventional antipsychotic drugs may occur through actions in the prefrontal cortex.
事实证明，评估即刻早期基因诱导是描绘介导抗精神病药物作用的神经系统的一种有用方法。为了区分典型和非典型抗精神病药物的作用部位和机制，我们研究了抗精神病药物对内侧前额叶皮质中Fos蛋白表达的影响。非典型抗精神病药物氯氮平选择性地增加了前额叶皮质中表达Fos样免疫反应性的神经元数量，其作用靶点为边缘下皮质和边缘前皮质的深层。锥体细胞是表达Fos的主要细胞类型。少量表达钙结合蛋白样免疫反应性但不表达小白蛋白或含还原型烟酰胺腺嘌呤二核苷酸磷酸黄递酶的中间神经元在氯氮平激发后也表达Fos。免疫印迹研究表明，氯氮平可诱导边缘下皮质和边缘前皮质中的Fos蛋白。其他D2受体拮抗剂类抗精神病药物，包括氟哌啶醇、雷氯必利、舒必利、瑞莫必利和洛沙平，均未改变Fos表达。氯氮平诱导的Fos表达增加也不归因于对D1多巴胺受体的作用，也不归因于对5-羟色胺2a/2c受体的拮抗作用或5-羟色胺2-D2多巴胺受体联合拮抗作用。氯氮平阻断α1-肾上腺素能或毒蕈碱胆碱能受体的能力与其独特作用无关。尽管除氯氮平外的多巴胺受体拮抗剂无法引起Fos表达增加，但混合性D1-D2多巴胺激动剂阿扑吗啡和D2样激动剂喹吡罗均能增加前额叶皮质中的Fos蛋白水平。然而，预先用舒必利阻断D2/3/4多巴胺受体或用SCH 23390阻断D1/5多巴胺受体均不能改变对氯氮平的Fos反应。由于多巴胺受体拮抗剂预处理并未减弱氯氮平引起的Fos表达，但D2激动剂可增加皮质Fos表达，因此氯氮平可能在前额叶皮质作用于一种尚未明确的多巴胺受体。与伏隔核壳不同，所有抗精神病药物均可增加伏隔核壳中的Fos表达，而只有氯氮平可在内侧前额叶皮质诱导Fos表达。这些观察结果表明，氯氮平治疗对传统抗精神病药物治疗无反应的精神分裂症患者的能力可能是通过在前额叶皮质的作用实现的。
