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: 9496860
• 负责人: Bryan L. Roth
• 金额: $ 64.68万
• 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/9496860
• 关键词: Adverse effects; 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; Hyperactive behavior; 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; Psychotic Disorders; 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

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。