Interaction of 5-HT2A and 5-HT2C Receptors in R(-)-2,5-Dimethoxy-4-iodoamphetamine-Elicited Head Twitch Behavior in Mice
Interaction of 5-HT2A and 5-HT2C Receptors in R(-)-2,5-Dimethoxy-4-iodoamphetamine-Elicited Head Twitch Behavior in Mice
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DOI：
10.1124/jpet.110.172247
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发表时间：
2010-12-01
影响因子：
3.5
通讯作者：
Woods, J. H.
中科院分区：
文献类型：
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作者：
Fantegrossi, W. E.;Simoneau, J.;Woods, J. H.
药物引起的头部抽搐行为是研究小鼠中5-HT 2A受体的致幻剂活性的有用模型。在该测定中具有活性的化学多样性化合物产生双相剂量-效应曲线，但是对于这些功能的“下降”部分没有令人信服的解释。设计了一组实验来检验以下假设：头部抽动行为的诱导是由5-HT 2A受体的激动剂作用介导的，而在较高剂量下观察到的头部抽动行为的抑制是由5-HT 2C受体的竞争性激动剂活性引起的。苯乙胺致幻剂R（-）-2，5-二甲氧基-4-碘苯丙胺（DOI）对小鼠头部抽搐行为的影响在一定剂量范围内进行了研究，产生了特征性的双相剂量反应曲线。选择性5-HT 2A拮抗剂（+）预处理-（2，3-二甲氧基苯基）-1-[2-（4-氟苯基乙基）]-4-哌啶-甲醇（M100907）仅移动DOI剂量-效应函数的上升分支，而用非选择性5-HT 2A/2C拮抗剂3-{2-[4-（4-氟苯甲酰基）哌啶-1-基]乙基}喹唑啉-2，4（1H，3 H）-二酮（酮色林）在DOI剂量-反应曲线中产生向右的平行移动。5-HT 2C激动剂S-2-（氯-5-氟-吲哚-L-基）-1-甲基乙胺（Ro 60-0175）给药在整个剂量效应函数中非竞争性抑制DOI诱导的头部抽搐行为。最后，用选择性5-HT 2C拮抗剂6-氯-5-甲基-1-[（2-[2-甲基吡啶-3-基氧基]吡啶-5基）氨基甲酰基]二氢吲哚（SB 242084）或8-[5-（2，4-二甲氧基-5-（4-三氟甲基苯基磺酰氨基）苯基-5-氧代戊基]-1，3，8-三氮杂螺[4，5]癸烷-2，4-二酮盐酸盐（RS 102221）未改变DOI诱导的剂量-反应曲线上升段的头部抽搐行为，但使DOI剂量-反应函数的下降段向右移动。这些实验的结果提供了强有力的证据，即DOI引起的头部抽搐行为是5-HT 2A激动剂介导的效应，随后头部抽搐行为的抑制是由竞争性5-HT 2C激动剂活性驱动的。
Drug-elicited head-twitch behavior is a useful model for studying hallucinogen activity at 5-HT2A receptors in the mouse. Chemically diverse compounds active in this assay yield biphasic dose-effect curves, but there is no compelling explanation for the "descending" portion of these functions. A set of experiments was designed to test the hypothesis that the induction of head-twitch behavior is mediated by agonist actions at 5-HT2A receptors, whereas the inhibition of head-twitch behavior observed at higher doses results from competing agonist activity at 5-HT2C receptors. The effects of the phenethylamine hallucinogen R(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) on head-twitch behavior were studied over a range of doses in the mouse, generating a characteristic biphasic dose-response curve. Pretreatment with the selective 5-HT2A antagonist (+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907) shifted only the ascending limb of the DOI dose-effect function, whereas pretreatment with the nonselective 5-HT2A/2C antagonist 3-{2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl}quinazoline-2,4(1H,3H)-dione (ketanserin) produced a parallel shift to the right in the DOI dose-response curve. Administration of the 5-HT2C agonist S-2-(chloro-5-fluoro-in-dol-L-yl)-1-methylethylamine (Ro 60-0175) noncompetitively inhibited DOI-elicited head-twitch behavior across the entire dose-effect function. Finally, pretreatment with the selective 5-HT2C antagonists 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3-yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) or 8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione hydrochloride (RS 102221) did not alter DOI-elicited head-twitch behavior on the ascending limb of the dose-response curve but shifted the descending limb of the DOI dose-response function to the right. The results of these experiments provide strong evidence that DOI-elicited head-twitch behavior is a 5-HT2A agonist-mediated effect, with subsequent inhibition of head-twitch behavior being driven by competing 5-HT2C agonist activity.