Vahid-Ansari F, Nakabeppu Y, Robertson G S
Department of Pharmacology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
Eur J Neurosci. 1996 May;8(5):927-36. doi: 10.1111/j.1460-9568.1996.tb01579.x.
We have recently demonstrated that specific neuroanatomical patterns of Fos-like immunoreactivity are predictive of atypical antipsychotic activity. However, the fact that neuroleptics must be administered chronically in order to generate both extrapyramidal side effects and an optimal therapeutic response calls into question the relevance of acute changes in Fos-like immunoreactivity for these slowly developing events. Fos-like immunoreactivity cannot be used to identify neurons activated by chronic neuroleptic administration because the increase in Fos-like immunoreactivity produced by an acute antipsychotic injection is dramatically reduced following repeated neuroleptic administration. In contrast, expression of the immediate-early gene product deltaFosB is persistently elevated in the striatum by chronic haloperidol administration. This suggests that deltaFosB-like immunoreactivity may be used to identify neurons activated by chronic antipsychotic administration. Since typical and atypical neuroleptics elevate Fos-like immunoreactivity in different regions of the forebrain acutely, the purpose of the present study was to determine whether typical (haloperidol) and atypical (clozapine, ICI 204,636) antipsychotics produce distinct patterns of elevated deltaFosB-like immunoreactivity in the forebrain after chronic administration. Administration of haloperidol (2 mg/kg/day) to rats for 19 days induced a homogeneous elevation of neurons which displayed deltaFosB-like immunoreactivity in the ventral, medial and dorsolateral aspects of the striatum. Chronic haloperidol administration did not enhance the deltaFos-like immunoreactivity in the prefrontal cortex and lateral septal nucleus. Repeated administration of clozapine (20 mg/kg/day) and ICI 204,636 (20 mg/kg/day) for 19 days elevated deltaFosB-like immunoreactivity not only in the ventral striatum but also in the prefrontal cortex and lateral septal nucleus. However, these compounds had weak effects on deltaFosB-like immunoreactivity in the dorsolateral striatum. These results suggest that a preferential action on limbic structures such as the prefrontal cortex, ventral striatum and lateral septal nucleus may account for the ability of chronic clozapine and ICI 204, 636 administration to reduce the symptoms of schizophrenia without generating extrapyramidal side effects.
我们最近证实，Fos样免疫反应的特定神经解剖学模式可预测非典型抗精神病药物的活性。然而，抗精神病药物必须长期给药才能产生锥体外系副作用和最佳治疗反应，这使得Fos样免疫反应的急性变化与这些缓慢发展的事件的相关性受到质疑。Fos样免疫反应不能用于识别由慢性抗精神病药物给药激活的神经元，因为急性抗精神病药物注射所产生的Fos样免疫反应的增加在重复给予抗精神病药物后会显著降低。相比之下，慢性给予氟哌啶醇会使纹状体中即早基因产物deltaFosB的表达持续升高。这表明deltaFosB样免疫反应可能用于识别由慢性抗精神病药物给药激活的神经元。由于典型和非典型抗精神病药物在急性给药时会在前脑的不同区域提高Fos样免疫反应，本研究的目的是确定典型（氟哌啶醇）和非典型（氯氮平、ICI 204,636）抗精神病药物在长期给药后是否会在前脑产生不同模式的deltaFosB样免疫反应升高。给大鼠连续19天每天注射氟哌啶醇（2毫克/千克），可诱导纹状体腹侧、内侧和背外侧区域中显示deltaFosB样免疫反应的神经元均匀升高。慢性给予氟哌啶醇并未增强前额叶皮质和外侧隔核中的deltaFos样免疫反应。连续19天重复给予氯氮平（20毫克/千克/天）和ICI 204,636（20毫克/千克/天），不仅会使腹侧纹状体中的deltaFosB样免疫反应升高，还会使前额叶皮质和外侧隔核中的deltaFosB样免疫反应升高。然而，这些化合物对背外侧纹状体中的deltaFosB样免疫反应影响较弱。这些结果表明，对边缘结构如前额叶皮质、腹侧纹状体和外侧隔核的优先作用可能解释了长期给予氯氮平和ICI 204,636能够减轻精神分裂症症状而不产生锥体外系副作用的能力。
