Desensitisation of 5-HT autoreceptors upon pharmacokinetically monitored chronic treatment with citalopram
Desensitisation of 5-HT autoreceptors upon pharmacokinetically monitored chronic treatment with citalopram
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DOI：
10.1016/s0014-2999(00)00308-3
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发表时间：
2000-06-02
影响因子：
5
通讯作者：
Wikström, HV
中科院分区：
文献类型：
--
作者：
Cremers, TIFH;Spoelstra, EN;Wikström, HV
采用微型渗透泵长期给大鼠注射选择性5-羟色胺再摄取抑制剂西酞普兰[1-（3-二甲氨基丙基）-1-（4-氟苯基）-5-酞卡硝基]。西酞普兰输注浓度为50 mg/ml，维持约0.3 μ M西酞普兰的稳态血药浓度15天。移除微型泵48小时后，西酞普兰血浆水平降至药理学活性浓度以下。虽然慢性西酞普兰治疗在全身给予5-HT1A受体激动剂8-羟基-2-（二-正丙基氨基）四萘林（8-OH-DPAT）后确实诱导了细胞外5-羟色胺（5-HT）水平的减弱反应，但当局部输注5-HT1B/D受体激动剂舒马曲坦（3-[2-二甲氨基]乙基-n-甲基-1 h -吲哚-5 -甲烷磺胺）评估5-HT1B受体功能时，慢性西酞普兰治疗没有观察到任何影响。有争议的是，全身服用西酞普兰并没有观察到5-羟色胺水平的增加。结论是，尽管长期服用西酞普兰确实会诱导5-HT1A受体脱敏，但西酞普兰对5-羟色胺水平没有增强作用，这表明其他机制弥补了自身受体控制的丧失。(C) 2000 Elsevier Science B.V.版权所有
Rats were chronically treated with the selective serotonin re-uptake inhibitor citalopram [1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phtalancarbonitril], by means of osmotic minipumps. Using an infusion concentration of 50 mg/ml citalopram, steady-state plasma concentrations of approximately 0.3 mu M citalopram were maintained for 15 days. Citalopram plasma levels dropped below pharmacologically active concentrations 48 h after removal of the minipumps. Although chronic treatment with citalopram did induce an attenuated response by extracellular levels of 5-hydroxytryptamine (5-HT) after systemic administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), no effect of chronic citalopram treatment was observed when 5-HT1B receptor function was evaluated with a local infusion of 5-HT1B/D receptor agonist, sumatriptan (3-[2-dimethylamino]ethyl-N-methyl-1 H-indole-5methane sulphonamide). Controversially, no augmentation of the increase of 5-HT levels was observed upon systemic administration of citalopram It is concluded that, although chronic treatment with citalopram does induce desensitisation of 5-HT1A receptors, the absence of augmented effects of citalopram on 5-HT levels indicates that other mechanisms compensate for the loss of autoreceptor control. (C) 2000 Elsevier Science B.V. All rights reserved.