Mechanistic insights into LSD actions at 5-HT2A serotonin receptors
LSD 对 5-HT2A 血清素受体作用的机制见解
基本信息
- 批准号:9496860
- 负责人:
- 金额:$ 64.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAgonistAntipsychotic AgentsArrestinsBasic ScienceBehaviorBehavioralBinding SitesBrainCRISPR/Cas technologyCellsComplexDiseaseDopamineDrug abuseG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGTP-Binding ProteinsGoalsGroomingHTR2A geneHallucinationsHallucinogensHeadHigh School StudentHumanHyperactive behaviorIn VitroIndividualKineticsKnockout MiceLeadLifeLigand BindingLysergic Acid DiethylamideMediatingModelingMolecularMouse StrainsMusMutateNeuronsNoseOutcomePaperPathway interactionsPharmaceutical PreparationsPharmacologyPhysiologicalPlayPopulationPrevalencePsychotic DisordersReceptor ActivationReportingResearchResolutionRoleScienceSerotoninSerotonin Receptor 5-HT2ASerotonin Receptor 5-HT2BSignal PathwaySignal TransductionSite-Directed MutagenesisStereotypingStructureSurveysTestingTimeWalkingWild Type Mousearrestin 1behavioral responsebehavioral studybeta-arrestindrug of abuseexperimental studyextracellularin vivoinsightmolecular modelingmutantnovelnovel therapeuticsprepulse inhibitionreceptorresponseserotonin receptor
项目摘要
Mechanistic insights into LSD actions at 5-HT2A-serotonin receptors LSD (lysergic acid diethylamide) -- the prototypical hallucinogen -- continues to be a frequently abused psychotomimetic agent with a life-time prevalence as high as 10.9% among all individual surveyed and as high as 3% among high school students. LSD has a complex pharmacology with significant interactions with dozens of G-protein coupled receptors (GPCRs) and it exerts primary actions at serotonin 2A (5-HT2A) receptors. Various experiments have shown that ligand binding to G protein-coupled receptors (GPCRs) can
activate, inhibit, or exert no effects on the G protein-dependent signaling pathway while having similar or diverse actions on a G protein-independent pathway through β-arrestin (βARR). In brain, these actions can be mediated through βARR 1 and/or 2. In recent papers in Science and Cell, the Roth lab has reported that LSD is a potent βARR-biased 5-HT2A receptor agonist. In preliminary experiments with wild-type mice, we find that LSD produces hyperactivity in the open field, it disrupts prepulse inhibition, and stimulates repetitive and stereotyped responses (head-twitch, nose-pokes, retrograde walking, unsupported rearing, and grooming). In contrast, the hyperactivity is blunted and the other behaviors are abrogated in the global βARR2 knockout mice. Nevertheless, additional physiological and behavioral responses have been ascribed to LSD that may also involve G proteins or βARR1. The Overall Goal of the proposed research is to clarify the role of βARR in mediating the actions of LSD at 5-HT2A receptors in vitro and in vivo. Our Central Hypothesis is that βARR-mediated signaling through 5-HT2A receptors will play a major role in many responses to LSD. Relevance: We have already reported on the antipsychotic effects βARR-biased dopamine 2 receptor compounds exert on behavior. We have evidence that some of behavioral effects of LSD are mediated at least through βARR2. With various strains of mice we will define a role for βARR1 and βARR2 signaling through 5-HT2A receptors and, thereby, reveal how activation of this receptor may underlie hallucinations in humans.
LSD(麦角酸二乙基酰胺)-原型致幻剂-仍然是一种经常滥用的拟精神病药物,在所有接受调查的个人中终身患病率高达10.9%,在高中生中高达3%。LSD具有复杂的药理学,与数十种G蛋白偶联受体(GPCR)具有显著的相互作用,并且其主要作用于5-羟色胺2A(5-HT 2A)受体。各种实验表明,配体与G蛋白偶联受体(GPCR)的结合可以
激活、抑制或不影响G蛋白依赖性信号通路,而通过β-arrestin(βARR)对G蛋白非依赖性通路具有相似或不同的作用。在脑中,这些作用可以通过βARR 1和/或2介导。在最近发表在《科学》和《细胞》杂志上的论文中,罗斯实验室报告说,LSD是一种有效的β ARR偏置5-HT 2A受体激动剂。在对野生型小鼠的初步实验中,我们发现LSD在开放视野中产生过度活跃,它破坏了前脉冲抑制,并刺激重复和刻板的反应(头部抽搐,鼻子戳,逆行行走,无支撑的饲养和梳理)。相反,在β ARR 2基因敲除小鼠中,过度活动减弱,其他行为被废除。然而,LSD引起的其他生理和行为反应也可能涉及G蛋白或β ARR 1。本研究的总体目标是阐明βARR在体外和体内介导LSD对5-HT 2A受体的作用。我们的中心假设是,β ARR介导的信号通过5-HT 2A受体将发挥重要作用,在许多反应LSD。相关性:我们已经报道了β ARR偏向的多巴胺2受体化合物对行为的抗精神病作用。我们有证据表明LSD的一些行为效应至少是通过β ARR 2介导的。我们将用不同品系的小鼠来确定β ARR 1和β ARR 2通过5-HT 2A受体进行信号传导的作用,从而揭示这种受体的激活如何成为人类幻觉的基础。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Bryan L. Roth其他文献
A novel ligand selectively visualizes and activates chemogenetic receptors in non-human primates
一种新型配体选择性地可视化和激活非人类灵长类动物的化学遗传受体
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
永井裕司;宮川尚久;Xi-Ping Haung;Samuel T. Slocum;Yan Xiong;堀由紀子;小山佳;季斌;平林敏行;藤本淳;三村喬生;Justin G. English;Jing Liu;井上謙一;熊田勝志;関千江;張明栄;須原哲也;高田昌彦;樋口真人;Jian Jin;Bryan L. Roth;南本敬史;Yuji Nagai - 通讯作者:
Yuji Nagai
236 - Regulation of the internalization of the 5HT<sub>2A</sub> receptor in vitro
- DOI:
10.1016/s0920-9964(97)82244-x - 发表时间:
1997-01-01 - 期刊:
- 影响因子:
- 作者:
Sally A. Berry;Laith Alsayegh;Bryan L. Roth - 通讯作者:
Bryan L. Roth
PS I-10
- DOI:
10.1016/s1734-1140(11)70453-4 - 发表时间:
2011-12-30 - 期刊:
- 影响因子:3.800
- 作者:
Jakub Fichna;Kevin Lewellyn;Feng Yan;Bryan L. Roth;Jordan K. Zjawiony - 通讯作者:
Jordan K. Zjawiony
High-dose olanzapine for treatment-resistant schizophrenia.
高剂量奥氮平治疗难治性精神分裂症。
- DOI:
10.4088/jcp.v69n0201 - 发表时间:
2008 - 期刊:
- 影响因子:0
- 作者:
Bryan L. Roth - 通讯作者:
Bryan L. Roth
Structure-Based Discovery of a NPFF1R Antagonist with Analgesic Activity
基于结构的具有镇痛活性的 NPFF1R 拮抗剂的发现
- DOI:
10.1101/2023.10.25.564029 - 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Brian J. Bender;J. E. Pickett;J. Braz;Hye Jin Kang;Stefan Gahbauer;Karnika Bhardwaj;Sian Rodriguez;Yongfeng Liu;Manish K. Jain;Allan I Basbaum;Bryan L. Roth;B. Shoichet - 通讯作者:
B. Shoichet
Bryan L. Roth的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Bryan L. Roth', 18)}}的其他基金
Mechanistic insights into LSD actions at 5-HT2A serotonin receptors
LSD 对 5-HT2A 血清素受体作用的机制见解
- 批准号:
10550420 - 财政年份:2023
- 资助金额:
$ 64.68万 - 项目类别:
STRUCTURE AND FUNCTION OF MRG-FAMILY RECEPTORS
MRG 家族受体的结构和功能
- 批准号:
10419804 - 财政年份:2022
- 资助金额:
$ 64.68万 - 项目类别:
STRUCTURE AND FUNCTION OF MRG-FAMILY RECEPTORS
MRG 家族受体的结构和功能
- 批准号:
10593175 - 财政年份:2022
- 资助金额:
$ 64.68万 - 项目类别:
Mechanistic insights into LSD actions at 5-HT2A serotonin receptors
LSD 对 5-HT2A 血清素受体作用的机制见解
- 批准号:
10356900 - 财政年份:2018
- 资助金额:
$ 64.68万 - 项目类别:
Mechanistic insights into LSD actions at 5-HT2A serotonin receptors
LSD 对 5-HT2A 血清素受体作用的机制见解
- 批准号:
10112869 - 财政年份:2018
- 资助金额:
$ 64.68万 - 项目类别:
Molecular Details of Psychoactive Drug Actions
精神活性药物作用的分子细节
- 批准号:
10557802 - 财政年份:2017
- 资助金额:
$ 64.68万 - 项目类别:
相似国自然基金
Agonist-GPR119-Gs复合物的结构生物学研究
- 批准号:32000851
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
相似海外基金
S1PR1 agonistによる脳血液関門制御を介した脳梗塞の新規治療法開発
S1PR1激动剂调节血脑屏障治疗脑梗塞新方法的开发
- 批准号:
24K12256 - 财政年份:2024
- 资助金额:
$ 64.68万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
AHR agonistによるSLE皮疹の新たな治療薬の開発
使用 AHR 激动剂开发治疗 SLE 皮疹的新疗法
- 批准号:
24K19176 - 财政年份:2024
- 资助金额:
$ 64.68万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease
特定 LXR/PPAR 激动剂治疗阿尔茨海默病的评估
- 批准号:
10578068 - 财政年份:2023
- 资助金额:
$ 64.68万 - 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
- 批准号:
10933287 - 财政年份:2023
- 资助金额:
$ 64.68万 - 项目类别:
Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor
用松弛素受体小分子激动剂靶向乳腺癌微环境
- 批准号:
10650593 - 财政年份:2023
- 资助金额:
$ 64.68万 - 项目类别:
AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis
AMPKa 激动剂减轻 CPT1A 抑制和酒精性慢性胰腺炎
- 批准号:
10649275 - 财政年份:2023
- 资助金额:
$ 64.68万 - 项目类别:
Investigating mechanisms underpinning outcomes in people on opioid agonist treatment for OUD: Disentangling sleep and circadian rhythm influences on craving and emotion regulation
研究阿片类激动剂治疗 OUD 患者结果的机制:解开睡眠和昼夜节律对渴望和情绪调节的影响
- 批准号:
10784209 - 财政年份:2023
- 资助金额:
$ 64.68万 - 项目类别:
A randomized double-blind placebo controlled Phase 1 SAD study in male and female healthy volunteers to assess safety, pharmacokinetics, and transient biomarker changes by the ABCA1 agonist CS6253
在男性和女性健康志愿者中进行的一项随机双盲安慰剂对照 1 期 SAD 研究,旨在评估 ABCA1 激动剂 CS6253 的安全性、药代动力学和短暂生物标志物变化
- 批准号:
10734158 - 财政年份:2023
- 资助金额:
$ 64.68万 - 项目类别:
A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
- 批准号:
10580259 - 财政年份:2023
- 资助金额:
$ 64.68万 - 项目类别:
Fentanyl Addiction: Individual Differences, Neural Circuitry, and Treatment with a GLP-1 Receptor Agonist
芬太尼成瘾:个体差异、神经回路和 GLP-1 受体激动剂治疗
- 批准号:
10534864 - 财政年份:2023
- 资助金额:
$ 64.68万 - 项目类别: