Ase A R, Amdiss F, Hébert C, Huang N, van Gelder N M, Reader T A
Département de physiologie, Faculté de médecine, Université de Montréal, Québec, Canada.
J Neural Transm (Vienna). 1999;106(1):75-105. doi: 10.1007/s007020050142.
The effects of neuroleptics have been attributed to dopamine (DA) receptor blockade; however, other neurotransmitters, in particular serotonin (5-HT), have also been implicated. In this study, we examined the effects of clozapine and haloperidol on the distribution of DA and 5-HT transporters, on endogenous DA, 5-HT and their major metabolites, and on 5-HT1A receptors. Adult male Sprague-Dawley rats were treated with either haloperidol (1 mg/kg/day, i.p.), clozapine (20 mg/kg/day, i.p.) or saline for 21 days, and following 3 days of withdrawal, the brains were removed. Tissue levels of DA and 5-HT and their metabolites were measured by high-performance liquid chromatography in 16 brain regions, while quantitative autoradiography with [125I]RTI-121, [3H]citalopram and [3H]8-OH-DPAT was employed to label DA transporters, 5-HT transporters and 5-HT1A receptors, respectively. After haloperidol, densities of 5-HT transporters were increased in the dorsal insular cortex and in the ventral half of caudal neostriatum, while 5-HT1A receptors augmented in cingulate cortex but decreased in the entorhinal area. After clozapine, [3H]citalopram labelling was increased in ventral hippocampus, ventral caudal neostriatum and nucleus raphe dorsalis, but decreased in medio-dorsal and latero-dorsal neostriatum as well as in substantia nigra. Binding of [3H]8-OH-DPAT following clozapine was decreased in frontal, parietal, temporal and entorhinal cortices but increased in the CA3 division of Ammon's horn. The changes in 5-HT transporters in nucleus raphe dorsalis and substantia nigra, as well as the 5-HT1A receptor down-regulations caused by clozapine but not by haloperidol, may explain effects obtained with clozapine and other atypical neuroleptics. There were no modifications in densities of DA transporters, nor of tissue DA levels, after the chronic neuroleptic treatments. The results are in line with previous suggestions that a certain degree of tolerance to neuroleptics develops, in spite of profound D1 and D2 receptor changes that persist during the entire chronic treatment with these psychotropic agents.
抗精神病药物的作用被认为与多巴胺（DA）受体阻断有关；然而，其他神经递质，尤其是5-羟色胺（5-HT），也被牵涉其中。在本研究中，我们检测了氯氮平和氟哌啶醇对DA和5-HT转运体分布、内源性DA、5-HT及其主要代谢产物，以及5-HT1A受体的影响。成年雄性Sprague-Dawley大鼠分别用氟哌啶醇（1毫克/千克/天，腹腔注射）、氯氮平（20毫克/千克/天，腹腔注射）或生理盐水处理21天，停药3天后取出大脑。通过高效液相色谱法测定16个脑区中DA和5-HT及其代谢产物的组织水平，同时分别用[125I]RTI-121、[3H]西酞普兰和[3H]8-羟基二丙胺基四氢萘进行定量放射自显影，以标记DA转运体、5-HT转运体和5-HT1A受体。氟哌啶醇处理后，5-HT转运体密度在背侧岛叶皮质和尾状新纹状体腹侧半部增加，而5-HT1A受体在扣带回皮质增加，但在内嗅区减少。氯氮平处理后，[3H]西酞普兰标记在腹侧海马、尾状新纹状体腹侧和中缝背核增加，但在中背侧和外侧背侧新纹状体以及黑质减少。氯氮平处理后，[3H]8-羟基二丙胺基四氢萘结合在额叶、顶叶、颞叶和内嗅皮质减少，但在海马角CA3区增加。中缝背核和黑质中5-HT转运体的变化，以及氯氮平而非氟哌啶醇引起的5-HT1A受体下调，可能解释了氯氮平和其他非典型抗精神病药物的作用。慢性抗精神病药物治疗后，DA转运体密度和组织DA水平均无改变。这些结果与先前的观点一致，即尽管在整个慢性治疗期间，这些精神药物会持续引起深刻的D1和D2受体变化，但对抗精神病药物会产生一定程度的耐受性。
