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.

在5-HT2A-苏罗尼蛋白受体LSD（lysergic Aid二乙酰胺）的机械洞察力（原型幻觉剂）（原型致幻剂）中仍然是一种经常被虐待的精神病患者，在所有个人被调查的人中，高达3％的学生的生活时间经常高达10.9％。 LSD具有复杂的药理学，具有与数十种G蛋白偶联受体（GPCR）的显着相互作用，并且在5-羟色胺2A（5-HT2A）受体上发挥主要作用。各种实验表明，配体与G蛋白偶联受体（GPCR）的结合可以 激活，抑制或执行对G蛋白依赖性信号通路的影响，同时对通过β-arrestin（βARR）具有相似或发散的作用相似或发散作用。在大脑中，这些作用可以通过βARR1和/或2介导。在科学和细胞的最近论文中，罗斯实验室报告说，LSD是潜在的βarr偏向5-HT2A受体激动剂。在使用野生型小鼠的初步实验中，我们发现LSD在开放式场中产生多动症，会破坏预硫的抑制作用，并刺激重复性和刻板印象的反应（头缠结，鼻子踢路，鼻子戳，逆行步行，不受支撑的饲养以及grooming）。相比之下，多动症被钝化，其他行为在全球βarr2敲除小鼠中被废除。然而，已经将其他物理和行为反应分配给了可能涉及G蛋白或βARR1的LSD。拟议的研究的总体目标是阐明βARR在体外和体内介导5-HT2A受体在5-HT2A受体上的作用中的作用。我们的中心假设是，通过5-HT2A受体介导的信号传导将在许多对LSD的反应中起主要作用。相关性：我们已经报道了抗精神病药作用βarr偏向多巴胺2受体化合物对行为的施加。我们有证据表明，LSD的某些行为效应至少通过βARR2介导。使用各种小鼠菌株，我们将通过5-HT2A受体来定义βArr1和βarr2信号的作用，从而揭示该受体的激活如何在人类中幻觉。