Guo N, Klitenick M A, Tham C S, Fibiger H C
Department of Psychiatry, University of British Columbia, Vancouver, Canada.
Neuroscience. 1995 Apr;65(3):747-56. doi: 10.1016/0306-4522(94)00552-g.
The atypical antipsychotic clozapine produces distinctly different regional patterns of c-fos expression in rat forebrain than does the prototypical neuroleptic haloperidol. While haloperidol-induced c-fos expression appears to be mediated by its D2 dopamine receptor antagonist properties, the mechanisms by which clozapine increases c-fos expression remain uncertain. Using a combination of brain lesion, pharmacological and immunohistochemical techniques, the present study sought to determine the receptor mechanisms by which clozapine increases the number of Fos-like immunoreactive neurons in various regions of the forebrain. To test whether serotonergic and/or noradrenergic systems are involved in clozapine-induced c-fos expression, rats received either 5,7-dihydroxytryptamine lesions of the medial forebrain bundle or 6-hydroxydopamine lesions of the dorsal noradrenergic bundle two weeks prior to clozapine (20 mg/kg) injections. Neither type of lesion affected clozapine-induced c-fos expression in the rat forebrain, suggesting that neither serotonergic nor noradrenergic mechanisms are involved in this action of clozapine. In another experiment, the 5-hydroxytryptamine2 receptor antagonist ritanserin (5 mg/kg), either alone or in combination with haloperidol (1 mg/kg), failed to mimic the pattern of c-fos expression produced by clozapine. This suggests that clozapine's antagonist actions at 5-hydroxytryptamine2 receptors cannot explain the unique pattern of regional c-fos expression produced by this compound. To determine whether the blockade of subtypes of the D2 dopamine receptor family may contribute to clozapine's effects, the dopamine receptor agonists quinpirole and 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) were injected 15 min prior to clozapine. Quinpirole produced a small but significant decrease in clozapine-induced c-fos expression in the medial prefrontal cortex, had larger effects in the lateral septum, and blocked clozapine's actions in the nucleus accumbens and major island of Calleja. Pretreatment with 7-OH-DPAT attenuated clozapine-induced c-fos expression in the nucleus accumbens and lateral septum, completely blocked the expression in the major island of Calleja, but was without effect in the medial prefrontal cortex. Given the different affinities of quinpirole and 7-OH-DPAT for D2, D3 and D4 receptors, these data suggest that clozapine-induced increases in c-fos expression in the nucleus accumbens, major island of Cajella and lateral septal nucleus are due to antagonist actions of this antipsychotic at D3 dopamine receptors. They also indicate that while antagonist actions at D4 receptors may contribute, the primary mechanisms by which clozapine increases c-fos expression in the medial prefrontal cortex remain to be determined.
与典型抗精神病药物氟哌啶醇相比，非典型抗精神病药物氯氮平在大鼠前脑诱导出截然不同的c-fos表达区域模式。虽然氟哌啶醇诱导的c-fos表达似乎是由其D2多巴胺受体拮抗剂特性介导的，但氯氮平增加c-fos表达的机制仍不确定。本研究结合脑损伤、药理学和免疫组织化学技术，试图确定氯氮平增加前脑各区域Fos样免疫反应性神经元数量的受体机制。为了测试5-羟色胺能和/或去甲肾上腺素能系统是否参与氯氮平诱导的c-fos表达，在注射氯氮平（20mg/kg）前两周，对大鼠进行内侧前脑束的5,7-二羟基色胺损伤或背侧去甲肾上腺素能束的6-羟基多巴胺损伤。两种损伤均未影响氯氮平诱导的大鼠前脑c-fos表达，这表明5-羟色胺能和去甲肾上腺素能机制均不参与氯氮平的这一作用。在另一项实验中，5-羟色胺2受体拮抗剂利坦色林（5mg/kg）单独或与氟哌啶醇（1mg/kg）联合使用，均未能模拟氯氮平产生的c-fos表达模式。这表明氯氮平对5-羟色胺2受体的拮抗作用无法解释该化合物产生的独特区域c-fos表达模式。为了确定D2多巴胺受体家族亚型的阻断是否可能有助于氯氮平的作用，在注射氯氮平前15分钟注射多巴胺受体激动剂喹吡罗和7-羟基-N,N-二正丙基-2-氨基四氢萘（7-OH-DPAT）。喹吡罗使氯氮平诱导的内侧前额叶皮质c-fos表达略有但显著下降，对外侧隔区有更大影响，并阻断了氯氮平在伏隔核和Calleja主岛的作用。用7-OH-DPAT预处理可减弱氯氮平诱导的伏隔核和外侧隔区c-fos表达，完全阻断Calleja主岛的表达，但对内侧前额叶皮质无影响。鉴于喹吡罗和7-OH-DPAT对D2、D3和D4受体的亲和力不同，这些数据表明氯氮平诱导的伏隔核、Cajella主岛和外侧隔核中c-fos表达增加是由于该抗精神病药物对D3多巴胺受体的拮抗作用。它们还表明，虽然对D4受体的拮抗作用可能有贡献，但氯氮平增加内侧前额叶皮质c-fos表达的主要机制仍有待确定。
