Enguix M J, Sánchez L, Villazón M, Brea J, Tristán H, Caruncho H J, Cadavid M I, Loza M I
School of Pharmacy, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
Naunyn Schmiedebergs Arch Pharmacol. 2003 Aug;368(2):79-90. doi: 10.1007/s00210-003-0775-7. Epub 2003 Jul 12.
Most studies of 5-HT(2) receptor regulation have been carried out on the central nervous system (CNS) (which expresses 5-HT(2A) and 5-HT(2C) receptors); very few in vitro studies have addressed the peripheral receptors 5-HT(2A) and 5-HT(2B). The aim of this investigation was to compare the possible short- and long-term processes regulating these peripheral receptors in the rat. The in vitro contractile response elicited by serotonin (5-HT, 10 micro M) in the rat gastric fundus (5-HT(2B) receptor system) was rapid and followed by a partial fade to a steady state, in contrast with the rat thoracic aorta response (5-HT(2A) receptor system), which was more stable, slower and sustained. To characterize drug-receptor interactions, cumulative concentration/response curves (CCRCs) for 5-HT were constructed ex vivo for rat tissues treated with drugs acting at these receptors. Rats were examined 4 or 24 h after a single, i.p. administration of (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(+/-)DOI, 1 or 2.5 mg/kg], clozapine, cyproheptadine or rauwolscine (10 mg/kg), 48 h after a single i.p. administration of (+/-)DOI (2.5 mg/kg), clozapine or cyproheptadine (10 mg/kg) or 24 h after the last of with 15 daily i.p. administrations of (+/-)DOI (1 or 2.5 mg/kg), clozapine, cyproheptadine or rauwolscine (10 mg/kg). In the aorta, E(max) (the maximum response elicited by 5-HT) was unchanged 4 h after a single dose of any of the drugs tested. However, 24 h after a single dose, E(max) was lower in animals treated with (+/-)DOI (2.5 mg/kg), clozapine or cyproheptadine than in controls, whilst 48 h after a single dose of (+/-)DOI (2.5 mg/kg), clozapine or cyproheptadine there was no difference in E(max) between experimental and control animals. After chronic treatment with (+/-)DOI (2.5 mg/kg), clozapine and cyproheptadine, E(max) was lower than in controls. In the gastric fundus, E(max) 4 h after a single dose of each drug was lower than in controls, and the response recovered by 24 or 48 h. Following chronic treatment, E(max) was significantly lower than in controls for each drug used. These findings suggest first, that regulation of peripheral 5-HT(2) receptors (5-HT(2A) and 5-HT(2B)) is a functionally significant phenomenon in vivo, and occurs after administration of both agonists and antagonists. Second, the kinetics of peripheral 5-HT(2) receptor regulation were similar in both in vivo and ex vivo experiments. The 5-HT(2B) receptors in rat gastric fundus are more sensitive to drug-induced regulation than the 5-HT(2A) rat aortic receptors. Finally, long-term regulation of both receptors stabilizes short-term desensitization for longer.
大多数关于5-羟色胺（5-HT）2型受体调节的研究是在中枢神经系统（CNS）中进行的（中枢神经系统表达5-HT2A和5-HT2C受体）；针对外周5-HT2A和5-HT2B受体的体外研究极少。本研究的目的是比较调节大鼠这些外周受体的可能的短期和长期过程。5-羟色胺（5-HT，10微摩尔）在大鼠胃底（5-HT2B受体系统）中引发的体外收缩反应迅速，随后部分消退至稳态，这与大鼠胸主动脉反应（5-HT2A受体系统）不同，后者更稳定、更缓慢且持续时间更长。为了表征药物-受体相互作用，对用作用于这些受体的药物处理过的大鼠组织进行离体构建5-HT的累积浓度/反应曲线（CCRCs）。大鼠在单次腹腔注射（±）1-（2,5-二甲氧基-4-碘苯基）-2-氨基丙烷[（±）DOI，1或2.5毫克/千克]、氯氮平、赛庚啶或萝芙木碱（10毫克/千克）后4或24小时进行检查，在单次腹腔注射（±）DOI（2.5毫克/千克）、氯氮平或赛庚啶（10毫克/千克）后48小时进行检查，或在连续15天每天腹腔注射（±）DOI（1或2.5毫克/千克）、氯氮平、赛庚啶或萝芙木碱（10毫克/千克）的最后一次注射后24小时进行检查。在主动脉中，单次给予任何一种受试药物后4小时，5-HT引发的最大反应（E(max)）未发生变化。然而，单次给药后24小时，用（±）DOI（2.5毫克/千克）、氯氮平或赛庚啶处理的动物的E(max)低于对照组，而单次给予（±）DOI（2.5毫克/千克）、氯氮平或赛庚啶后48小时，实验动物和对照动物之间的E(max)没有差异。用（±）DOI（2.5毫克/千克）、氯氮平及赛庚啶进行慢性处理后，E(max)低于对照组。在胃底，单次给予每种药物后第4小时的E(max)低于对照组，且反应在24或48小时恢复。慢性处理后，所用每种药物的E(max)均显著低于对照组。这些发现首先表明，外周5-HT2型受体（5-HT2A和5-HT2B）的调节在体内是一种功能上重要的现象，并且在给予激动剂和拮抗剂后均会发生。其次，外周5-HT2型受体调节的动力学在体内和体外实验中相似。大鼠胃底中的5-HT2B受体比大鼠主动脉中的5-HT2A受体对药物诱导的调节更敏感。最后，两种受体的长期调节使短期脱敏在更长时间内保持稳定。
Zotero 插件