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
• 负责人: Bryan L. Roth
• 金额: $ 63.95万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10356900
• 关键词: Agonist; Antipsychotic Agents; Arrestins; Basic Science; Behavior; Behavioral; Binding Sites; Brain; CRISPR/Cas technology; Cells; Complex; Disease; Dopamine; Drug abuse; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Goals; Grooming; HTR2A gene; Hallucinations; Hallucinogens; Head; High School Student; Human; Hyperactivity; In Vitro; Individual; Kinetics; Knockout Mice; Lead; Life; Ligand Binding; Lysergic Acid Diethylamide; Mediating; Modeling; Molecular; Mouse Strains; Mus; Mutate; Neurons; Nose; Outcome; Paper; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Population; Prevalence; Psychoses; Receptor Activation; Reporting; Research; Resolution; Role; Science; Serotonin; Serotonin Receptor 5-HT2A; Serotonin Receptor 5-HT2B; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Stereotyping; Structure; Surveys; Testing; Time; Walking; Wild Type Mouse; arrestin 1; behavioral response; behavioral study; beta-arrestin; drug of abuse; experimental study; extracellular; in vivo; insight; molecular modeling; mutant; novel; novel therapeutics; prepulse inhibition; receptor; response; serotonin receptor; side effect

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.

对5-羟色胺-5-羟色胺受体LSD(麦角酸二乙胺)作用的机械论洞察LSD(麦角酸二乙胺)--典型的致幻剂--仍然是一种经常被滥用的拟精神分裂药，在所有接受调查的个人中，终身流行率高达10.9%，在高中生中高达3%。LSD具有复杂的药理作用，与数十个G蛋白偶联受体(GPCRs)有显著的相互作用，并对5-HT2A(5-HT2A)受体起主要作用。各种实验表明，与G蛋白偶联受体(GPCRs)结合的配体可以 激活、抑制或不影响G蛋白依赖的信号通路，而通过β-arrestin(βARR)对G蛋白依赖的信号通路有相似或不同的作用。在大脑中，这些作用可以通过βARR 1和/或2介导。在最近的《科学与细胞》杂志上，Roth实验室报道了LSD是一种有效的βARR偏向的5-HT2a受体激动剂。在对野生型小鼠的初步实验中，我们发现LSD在开阔的田野中产生多动，它扰乱脉冲前抑制，并刺激重复的和刻板的反应(头部抽动、鼻子戳、逆行行走、无人支持的饲养和梳理)。相比之下，在全球βARR2基因敲除小鼠中，多动被钝化，其他行为被取消。然而，更多的生理和行为反应被归因于LSD，可能也涉及G蛋白或βARR1.本研究的总体目标是阐明β受体在体内和体外对5-HT2A型受体的调节作用。我们的中心假设是，βARR通过5-HT2a受体介导的信号将在许多对LSD的反应中发挥主要作用。相关性：我们已经报道了βARR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，迷幻药的一些行为效应至少是通过β受体2介导的。在不同品系的小鼠中，我们将通过5-HT2a受体定义βarr1和βarr2信号的作用，从而揭示这种受体的激活如何导致人类的幻觉。