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.

LSD 对 5-HT2A-5-羟色胺受体作用的机制见解 LSD（麦角酰二乙胺）——一种典型的致幻剂——仍然是一种经常被滥用的拟精神病药物，在所有接受调查的个体中，一生中的患病率高达 10.9%。 LSD 在高中生中的比例高达 3%，其药理学复杂，与数十种 G 蛋白偶联受体 (GPCR) 存在显着相互作用，并发挥主要作用。各种实验表明，配体与 G 蛋白偶联受体 (GPCR) 结合可以作用于血清素 2A (5-HT2A) 受体。 激活、抑制或不影响 G 蛋白依赖性信号通路，同时通过 β-arrestin (βARR) 对 G 蛋白独立通路具有相似或不同的作用。在大脑中，这些作用可以通过 βARR 1 和/或进行介导。或 2. 在《Science》和《Cell》最近发表的论文中，Roth 实验室报道 LSD 是一种有效的 βARR 偏向 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 会产生多动症。在开放环境中，它会破坏前脉冲抑制，并刺激重复性和刻板反应（扭头、戳鼻子、逆行、无支撑的站立和梳理毛发），相反，在开放环境中，过度活跃会减弱，其他行为也会被消除。然而，额外的生理和行为反应被归因于 LSD，这些反应也可能涉及 G 蛋白或 βARR1。 βARR 在体外和体内介导 LSD 对 5-HT2A 受体的作用 我们的中心假设是，βARR 介导的通过 5-HT2A 受体的信号传导将在 LSD 的许多反应中发挥重要作用。 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，LSD 的某些作用至少是通过各种菌株的 βARR2 介导的。我们将通过 5-HT2A 受体定义 βARR1 和 βARR2 信号传导在小鼠中的作用，从而揭示该受体的激活如何成为人类幻觉的基础。