Vahid-Ansari F, Robertson G S
Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ontario, Canada.
Eur J Neurosci. 1996 Dec;8(12):2605-11. doi: 10.1111/j.1460-9568.1996.tb01555.x.
The pattern of neurons which display haloperidol-induced Fos-like immunoreactivity closely matches the distribution of striatal D2 dopamine receptors, whereas clozapine-induced Fos-like immunoreactivity occurs primarily in regions that contain high levels of the D3 dopamine receptor. These neuroanatomical correlations suggest that haloperidol and clozapine may elevate Fos-like immunoreactivity by blocking D2 and D3 receptors respectively. In order to test this hypothesis, the abilities of prior administration of the D3 receptor-preferring agonist 7-hydroxy-N,N'-di-n-propyl-2-aminotetraline (7-OH-DPAT) to competitively reverse haloperidol- and clozapine-induced increases in Fos-like immunoreactivity were compared. Administration of 7-OH-DPAT (0.05 mg/kg, s.c.) 30 min before clozapine (20 mg/kg, s.c.) produced a 60% reduction in the number of neurons that displayed clozapine-induced Fos-like immunoreactivity in the major island of Calleja, nucleus accumbens and medial aspect of the striatum, while prior administration of 0.5 mg/kg (s.c.) of 7-OH-DPAT completely reversed these increases in Fos-like immunoreactivity. In contrast, the increases in Fos-like immunoreactivity in the major island of Calleja, nucleus accumbens and striatum (medial and dorsal aspects) induced by haloperidol (0.1 mg/kg, s.c.) were only reduced by the high dose of 7-OH-DPAT (0.5 mg/kg, s.c.). Hence, clozapine-induced increases in Fos-like immunoreactivity were more readily reversed by 7-OH-DPAT than elevations in Fos-like immunoreactivity produced by haloperidol. These results suggest that D3 receptor blockade plays a larger role in mediating clozapine- than haloperidol-induced increases in Fos-like immunoreactivity.
显示氟哌啶醇诱导的Fos样免疫反应性的神经元模式与纹状体D2多巴胺受体的分布密切匹配，而氯氮平诱导的Fos样免疫反应性主要发生在含有高水平D3多巴胺受体的区域。这些神经解剖学相关性表明，氟哌啶醇和氯氮平可能分别通过阻断D2和D3受体来提高Fos样免疫反应性。为了验证这一假设，比较了预先给予D3受体偏好激动剂7-羟基-N,N'-二正丙基-2-氨基四氢萘（7-OH-DPAT）竞争性逆转氟哌啶醇和氯氮平诱导的Fos样免疫反应性增加的能力。在氯氮平（20mg/kg，皮下注射）前30分钟给予7-OH-DPAT（0.05mg/kg，皮下注射），在Calleja主岛、伏隔核和纹状体内侧显示氯氮平诱导的Fos样免疫反应性的神经元数量减少了60%，而预先给予0.5mg/kg（皮下注射）的7-OH-DPAT则完全逆转了这些Fos样免疫反应性的增加。相比之下，氟哌啶醇（0.1mg/kg，皮下注射）诱导的Calleja主岛、伏隔核和纹状体（内侧和背侧）Fos样免疫反应性的增加仅被高剂量的7-OH-DPAT（0.5mg/kg，皮下注射）所降低。因此，7-OH-DPAT比氟哌啶醇诱导的Fos样免疫反应性增加更能轻易地逆转氯氮平诱导的Fos样免疫反应性增加。这些结果表明，D3受体阻断在介导氯氮平诱导的Fos样免疫反应性增加中比氟哌啶醇发挥更大的作用。
