University of Florida, Department of Medicinal Chemistry, PO Box 1000485, 1600 SW Archer Road, Gainesville, FL 32610-0485, USA.
Neuropharmacology. 2013 Jul;70:112-21. doi: 10.1016/j.neuropharm.2013.01.007. Epub 2013 Jan 23.
There are seemingly conflicting data in the literature regarding the role of serotonin (5-HT) 5-HT2C receptors in the mouse head-twitch response (HTR) elicited by the hallucinogenic 5-HT2A/2B/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Namely, both 5-HT2C receptor agonists and antagonists, regarding 5-HT2C receptor-mediated Gq-phospholipase C (PLC) signaling, reportedly attenuate the HTR response. The present experiments tested the hypothesis that both classes of 5-HT2C receptor compounds could attenuate the DOI-elicited-HTR in a single strain of mice, C57Bl/6J. The expected results were considered in accordance with ligand functional selectivity. Commercially-available 5-HT2C agonists (CP 809101, Ro 60-0175, WAY 161503, mCPP, and 1-methylpsilocin), novel 4-phenyl-2-N,N-dimethyl-aminotetralin (PAT)-type 5-HT2C agonists (with 5-HT2A/2B antagonist activity), and antagonists selective for 5-HT2A (M100907), 5-HT2C (SB-242084), and 5-HT2B/2C (SB-206553) receptors attenuated the DOI-elicited-HTR. In contrast, there were differential effects on locomotion across classes of compounds. The 5-HT2C agonists and M100907 decreased locomotion, SB-242084 increased locomotion, SB-206553 resulted in dose-dependent biphasic effects on locomotion, and the PATs did not alter locomotion. In vitro molecular pharmacology studies showed that 5-HT2C agonists potent for attenuating the DOI-elicited-HTR also reduced the efficacy of DOI to activate mouse 5-HT2C receptor-mediated PLC signaling in HEK cells. Although there were differences in affinities of a few compounds at mouse compared to human 5-HT2A or 5-HT2C receptors, all compounds tested retained their selectivity for either receptor, regardless of receptor species. Results indicate that 5-HT2C receptor agonists and antagonists attenuate the DOI-elicited-HTR in C57Bl/6J mice, and suggest that structurally diverse 5-HT2C ligands result in different 5-HT2C receptor signaling outcomes compared to DOI.
文献中关于血清素（5-HT）5-HT2C 受体在致幻 5-HT2A/2B/2C 受体激动剂 2,5-二甲氧基-4-碘苯丙胺（DOI）诱发的小鼠头部抽动反应（HTR）中的作用似乎存在矛盾。即 5-HT2C 受体激动剂和拮抗剂，关于 5-HT2C 受体介导的 Gq-磷脂酶 C（PLC）信号，据报道均能减弱 HTR 反应。本实验检验了以下假设：两种 5-HT2C 受体化合物都可以在 C57Bl/6J 这一单一品系的小鼠中减弱 DOI 诱发的-HTR。预期结果与配体功能选择性一致。市售的 5-HT2C 激动剂（CP 809101、Ro 60-0175、WAY 161503、mCPP 和 1-甲基-6-羟基色胺）、新型 4-苯基-2-N，N-二甲基-氨基四氢萘（PAT）型 5-HT2C 激动剂（具有 5-HT2A/2B 拮抗剂活性）以及对 5-HT2A（M100907）、5-HT2C（SB-242084）和 5-HT2B/2C（SB-206553）受体选择性的拮抗剂均减弱了 DOI 诱发的-HTR。相反，不同类别的化合物对运动有不同的影响。5-HT2C 激动剂和 M100907 降低运动，SB-242084 增加运动，SB-206553 导致运动呈剂量依赖性双相效应，而 PAT 则不改变运动。体外分子药理学研究表明，5-HT2C 激动剂对减弱 DOI 诱发的-HTR 有很强的作用，同时也降低了 DOI 激活 HEK 细胞中 5-HT2C 受体介导的 PLC 信号的效力。尽管少数化合物在小鼠与人类 5-HT2A 或 5-HT2C 受体的亲和力存在差异，但所有测试的化合物在受体物种方面均保留了对受体的选择性。结果表明，5-HT2C 受体激动剂和拮抗剂在 C57Bl/6J 小鼠中减弱了 DOI 诱发的-HTR，并表明与 DOI 相比，结构多样的 5-HT2C 配体导致不同的 5-HT2C 受体信号转导结果。
