{"title":"5-羟色胺2C/1A受体调节DOM诱导的小鼠头部抽搐反应和运动活动的双相剂量反应。","authors":"Huili Zhu, Longyu Wang, Xiaoxuan Wang, Yishan Yao, Peilan Zhou, Ruibin Su","doi":"10.1007/s00213-024-06635-4","DOIUrl":null,"url":null,"abstract":"<p><strong>Rationale: </strong>The phenylalkylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) exhibits an inverted U-shaped dose-response curve for both head twitch response (HTR) and locomotor activity in mice. Accumulated studies suggest that HTR and locomotor hyperactivity induced by DOM are mainly caused by the activation of serotonin 5-hydroxytryptamine 2 A receptor (5-HT<sub>2A</sub> receptor). However, the mechanisms underlying the biphasic dose response of HTR and locomotor activity induced by DOM, particularly at high doses, remain unclear.</p><p><strong>Objectives: </strong>The primary objective of this study is to investigate the modulation of 5-HT<sub>2A/2C/1A</sub> receptors in HTR and locomotor activity, while also exploring the potential receptor mechanisms underlying the biphasic dose response of DOM.</p><p><strong>Methods: </strong>In this study, we employed pharmacological methods to identify the specific 5-HT receptor subtypes responsible for mediating the biphasic dose-response effects of DOM on HTR and locomotor activity in C57BL/6J mice.</p><p><strong>Results: </strong>The 5-HT<sub>2A</sub> receptor selective antagonist (R)-[2,3-di(methoxy)phenyl]-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (M100907) (500 µg/kg, i.p.) fully blocked the HTR at every dose of DOM (0.615-10 mg/kg, i.p.) in C57BL/6J mice. M100907 (50 µg/kg, i.p.) decreased the locomotor hyperactivity induced by a low dose of DOM (0.625, 1.25 mg/kg, i.p.), but had no effect on the locomotor hypoactivity induced by a high dose of DOM (10 mg/kg) in C57BL/6J mice. The 5-HT<sub>2C</sub> antagonist 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) (0.3, 1 mg/kg, i.p.) reduced the HTR induced by a dose of 2.5 mg/kg DOM, but did not affect the response to other doses. SB242084 (1 mg/kg, i.p.) significantly increased the locomotor activity induced by DOM (0.615-10 mg/kg, i.p.) in mice. The 5-HT<sub>1A</sub> antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY100635) (1 mg/kg, i.p.) increased both HTR and locomotor activity induced by DOM in mice. The 5-HT<sub>1A</sub> agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) significantly reduced both the HTR and locomotor activity induced by DOM in mice. Additionally, pretreatment with the Gα<sub>i/o</sub> inhibitor PTX (0.25 µg/mouse, i.c.v.) enhanced the HTR induced by DOM and attenuated the effect of DOM on locomotor activity in mice.</p><p><strong>Conclusions: </strong>Receptor subtypes 5-HT<sub>2C</sub> and 5-HT<sub>1A</sub> are implicated in the inverted U-shaped dose-response curves of HTR and locomotor activity induced by DOM in mice. The biphasic dose-response function of HTR and locomotor activity induced by DOM has different mechanisms in mice.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2315-2330"},"PeriodicalIF":3.5000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"5-hydroxytryptamine 2C/1A receptors modulate the biphasic dose response of the head twitch response and locomotor activity induced by DOM in mice.\",\"authors\":\"Huili Zhu, Longyu Wang, Xiaoxuan Wang, Yishan Yao, Peilan Zhou, Ruibin Su\",\"doi\":\"10.1007/s00213-024-06635-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Rationale: </strong>The phenylalkylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) exhibits an inverted U-shaped dose-response curve for both head twitch response (HTR) and locomotor activity in mice. Accumulated studies suggest that HTR and locomotor hyperactivity induced by DOM are mainly caused by the activation of serotonin 5-hydroxytryptamine 2 A receptor (5-HT<sub>2A</sub> receptor). However, the mechanisms underlying the biphasic dose response of HTR and locomotor activity induced by DOM, particularly at high doses, remain unclear.</p><p><strong>Objectives: </strong>The primary objective of this study is to investigate the modulation of 5-HT<sub>2A/2C/1A</sub> receptors in HTR and locomotor activity, while also exploring the potential receptor mechanisms underlying the biphasic dose response of DOM.</p><p><strong>Methods: </strong>In this study, we employed pharmacological methods to identify the specific 5-HT receptor subtypes responsible for mediating the biphasic dose-response effects of DOM on HTR and locomotor activity in C57BL/6J mice.</p><p><strong>Results: </strong>The 5-HT<sub>2A</sub> receptor selective antagonist (R)-[2,3-di(methoxy)phenyl]-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (M100907) (500 µg/kg, i.p.) fully blocked the HTR at every dose of DOM (0.615-10 mg/kg, i.p.) in C57BL/6J mice. M100907 (50 µg/kg, i.p.) decreased the locomotor hyperactivity induced by a low dose of DOM (0.625, 1.25 mg/kg, i.p.), but had no effect on the locomotor hypoactivity induced by a high dose of DOM (10 mg/kg) in C57BL/6J mice. The 5-HT<sub>2C</sub> antagonist 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) (0.3, 1 mg/kg, i.p.) reduced the HTR induced by a dose of 2.5 mg/kg DOM, but did not affect the response to other doses. SB242084 (1 mg/kg, i.p.) significantly increased the locomotor activity induced by DOM (0.615-10 mg/kg, i.p.) in mice. The 5-HT<sub>1A</sub> antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY100635) (1 mg/kg, i.p.) increased both HTR and locomotor activity induced by DOM in mice. The 5-HT<sub>1A</sub> agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) significantly reduced both the HTR and locomotor activity induced by DOM in mice. Additionally, pretreatment with the Gα<sub>i/o</sub> inhibitor PTX (0.25 µg/mouse, i.c.v.) enhanced the HTR induced by DOM and attenuated the effect of DOM on locomotor activity in mice.</p><p><strong>Conclusions: </strong>Receptor subtypes 5-HT<sub>2C</sub> and 5-HT<sub>1A</sub> are implicated in the inverted U-shaped dose-response curves of HTR and locomotor activity induced by DOM in mice. The biphasic dose-response function of HTR and locomotor activity induced by DOM has different mechanisms in mice.</p>\",\"PeriodicalId\":20783,\"journal\":{\"name\":\"Psychopharmacology\",\"volume\":\" \",\"pages\":\"2315-2330\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Psychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00213-024-06635-4\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/25 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Psychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00213-024-06635-4","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/25 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
摘要
理论依据：苯烷基胺致幻剂(-)-2,5-二甲氧基-4-甲基苯丙胺（DOM）对小鼠头部抽搐反应（HTR）和运动活动均表现出倒置的U形剂量反应曲线。大量研究表明，DOM诱导的HTR和运动亢进主要是由5-羟色胺2 A受体（5-HT2A受体）激活引起的。然而，DOM诱导的HTR和运动活性的双相剂量反应，尤其是在高剂量下的双相剂量反应的机制仍不清楚：本研究的主要目的是研究 5-HT2A/2C/1A 受体在 HTR 和运动活性中的调节作用，同时探索 DOM 双相剂量反应的潜在受体机制：在这项研究中，我们采用药理学方法确定了负责介导 DOM 对 C57BL/6J 小鼠 HTR 和运动活动双相剂量反应效应的特定 5-HT 受体亚型：结果：5-HT2A受体选择性拮抗剂(R)-[2,3-二(甲氧基)苯基]-[1-[2-(4-氟苯基)乙基]哌啶-4-基]甲醇(M100907)(500 µg/kg，i.p.)完全阻断了C57BL/6J小鼠在各种剂量DOM(0.615-10 mg/kg，i.p.)下的HTR。M100907（50微克/千克，静注）可降低低剂量DOM（0.625、1.25毫克/千克，静注）诱导的C57BL/6J小鼠运动机能亢进，但对高剂量DOM（10毫克/千克）诱导的C57BL/6J小鼠运动机能减退没有影响。5-HT2C 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]吲哚啉（SB242084）（0.3、1 毫克/千克，静注）可降低 2.5 毫克/千克 DOM 剂量诱导的 HTR，但不影响对其他剂量的反应。SB242084（1 毫克/千克，静注）可显著提高 DOM（0.615-10 毫克/千克，静注）诱导的小鼠运动活性。5-HT1A 拮抗剂 N-[2-[4-（2-甲氧基苯基）-1-哌嗪基]乙基]N-（2-吡啶基）环己烷甲酰胺马来酸盐（WAY100635）（1 毫克/千克，静注）可增加 DOM 诱导的小鼠 HTR 和运动活性。5-HT1A 激动剂 8-羟基-2-（二正丙基氨基）四氢呋喃（8-OH-DPAT）（1 毫克/千克，静注）可显著降低 DOM 诱导的小鼠 HTR 和运动活性。此外，Gαi/o抑制剂PTX（0.25微克/只小鼠，静注）可增强DOM诱导的HTR，并减轻DOM对小鼠运动活动的影响：结论：5-HT2C 和 5-HT1A 受体亚型与 DOM 诱导的小鼠 HTR 和运动活性的倒 U 型剂量反应曲线有关。在小鼠体内，DOM诱导的HTR和运动活性的双相剂量反应函数具有不同的机制。
5-hydroxytryptamine 2C/1A receptors modulate the biphasic dose response of the head twitch response and locomotor activity induced by DOM in mice.
Rationale: The phenylalkylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) exhibits an inverted U-shaped dose-response curve for both head twitch response (HTR) and locomotor activity in mice. Accumulated studies suggest that HTR and locomotor hyperactivity induced by DOM are mainly caused by the activation of serotonin 5-hydroxytryptamine 2 A receptor (5-HT2A receptor). However, the mechanisms underlying the biphasic dose response of HTR and locomotor activity induced by DOM, particularly at high doses, remain unclear.
Objectives: The primary objective of this study is to investigate the modulation of 5-HT2A/2C/1A receptors in HTR and locomotor activity, while also exploring the potential receptor mechanisms underlying the biphasic dose response of DOM.
Methods: In this study, we employed pharmacological methods to identify the specific 5-HT receptor subtypes responsible for mediating the biphasic dose-response effects of DOM on HTR and locomotor activity in C57BL/6J mice.
Results: The 5-HT2A receptor selective antagonist (R)-[2,3-di(methoxy)phenyl]-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (M100907) (500 µg/kg, i.p.) fully blocked the HTR at every dose of DOM (0.615-10 mg/kg, i.p.) in C57BL/6J mice. M100907 (50 µg/kg, i.p.) decreased the locomotor hyperactivity induced by a low dose of DOM (0.625, 1.25 mg/kg, i.p.), but had no effect on the locomotor hypoactivity induced by a high dose of DOM (10 mg/kg) in C57BL/6J mice. The 5-HT2C antagonist 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) (0.3, 1 mg/kg, i.p.) reduced the HTR induced by a dose of 2.5 mg/kg DOM, but did not affect the response to other doses. SB242084 (1 mg/kg, i.p.) significantly increased the locomotor activity induced by DOM (0.615-10 mg/kg, i.p.) in mice. The 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY100635) (1 mg/kg, i.p.) increased both HTR and locomotor activity induced by DOM in mice. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) significantly reduced both the HTR and locomotor activity induced by DOM in mice. Additionally, pretreatment with the Gαi/o inhibitor PTX (0.25 µg/mouse, i.c.v.) enhanced the HTR induced by DOM and attenuated the effect of DOM on locomotor activity in mice.
Conclusions: Receptor subtypes 5-HT2C and 5-HT1A are implicated in the inverted U-shaped dose-response curves of HTR and locomotor activity induced by DOM in mice. The biphasic dose-response function of HTR and locomotor activity induced by DOM has different mechanisms in mice.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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