Discriminative stimulus effects of serotonin agonists, neutral antagonists, and inverse agonists in pigeons: perspectives on intrinsic efficacy measurements in vivo.
Discriminative stimulus effects of serotonin agonists, neutral antagonists, and inverse agonists in pigeons: perspectives on intrinsic efficacy measurements in vivo.
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血清素激动剂、中性拮抗剂和反向激动剂对鸽子的区别刺激作用：体内内在功效测量的观点。
DOI：
10.1007/s00213-010-1893-9
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发表时间：
2010
影响因子：
3.4
通讯作者：
Walker,Ellen
中科院分区：
文献类型：
--
作者：
Farrell,Martilias;Rosenzweig-Lipson,Sharon;Walker,Ellen
受体功能的扩展三元络合物理论根据配体优先稳定非活性构象、活性构象或不偏好构象状态的能力，可将其分为反向激动剂、激动剂或中性拮抗剂。目的虽然在体外相应地对5-羟色胺2C(5-HT2C)受体配体进行分类，但尚不清楚在体内是否存在反向激动剂的现象和/或是否具有生理相关性。方法因此，我们测试了一系列建议的激动剂、中性拮抗剂和反向激动剂在三组鸽子中的活性，以区分生理盐水：1.0 mg/kg MK212激动剂；结果根据MK212的替代模式，MK212的区分性刺激作用可能是通过激动剂介导的，而甲基丝氨酸甲酯和米安色林的刺激作用可能是通过拮抗剂介导的。选择性5-HT2B/2C反向激动剂SB206,553(1 mg/kg)阻断MK212辨别刺激线索，并在甲基丝氨酸乙酯和米安色林训练的鸽子中替代(0.32-10 mg/kg)，证实了5-HT2B受体在这些辨别刺激中的作用。完全替代甲基丝氨酸的反向激动剂和中性拮抗剂。除SB206,553外，甲基丝氨酸(0.032~1.0m g/kg)和5-羟色胺激动剂8-OH-DPAT(0.32~1.0m g/kg)完全替代米安色林，提示MK212、甲基丝氨酸和米安色林的鉴别线索是不同的，药物鉴别范式是检验体内内在疗效的有用的功能分析方法。
RationaleThe extended ternary complex theory of receptor function states a ligand can be classified as an inverse agonist, agonist, or neutral antagonist based on its ability to preferentially stabilize the inactive conformation, the active conformation, or to have no preference for conformational state, respectively.ObjectivesWhile serotonin2C(5-HT2C) receptor ligands are classified accordingly in vitro, whether the phenomenon of inverse agonism manifests itself and/or is physiologically relevant in vivo is unknown.MethodsTherefore, we tested a range of proposed agonists, neutral antagonists, and inverse agonists with activity at 5-HT2Creceptors in three groups of pigeons trained to discriminate saline from: 1.0 mg/kg MK212, an agonist; 0.1 mg/kg methysergide, a proposed neutral antagonist; or, 10 mg/kg mianserin, a proposed inverse agonist.ResultsBased on the patterns of substitution, the discriminative stimulus effects of MK212 appear to be mediated through agonist actions and the stimulus effects of methysergide and mianserin appear to be mediated through antagonist actions. Selective 5-HT2B/2Cinverse agonist SB206,553 (1 mg/kg) blocked the MK212 discriminative stimulus cue and substituted (0.32–10 mg/kg) in both methysergide- and mianserin-trained pigeons, confirming a 5-HT2Creceptor role in mediating these discriminative stimuli. Inverse agonists and neutral antagonists fully substituted for methysergide. In addition to SB206,553, methysergide (0.032–1.0 mg/kg) and 5-HT1Aagonist 8-OH-DPAT (0.32–1.0 mg/kg) substituted completely for mianserin suggesting a complex discriminative stimulus profile for this proposed inverse agonist.ConclusionsThese data and the subsequent analyses suggest that the discriminative cues of MK212, methysergide, and mianserin are different and that the drug discrimination paradigm is a useful functional assay to examine intrinsic efficacy in vivo.