HALLUCINOGENS & 5-HT2A RECEPTORS: MECHANISMS AND EFFECTS

迷幻剂是一种滥用药物，具有明显独特的作用机制，会在思维、感知和情绪方面产生干扰。致幻剂的这些作用机制尚不清楚，但它们与5-羟色胺/2 A受体活性的关系由来已久。尽管在表征5-羟色胺能迷幻剂的行为、生理和药理学特性方面取得了相当大的进展，但致幻潜力背后的分子特征仍然难以捉摸。5-HT2A受体在幻觉发生中的确切作用也仍然不清楚。为了消除在知识和理解方面的这些重要差距，该计划项目赠款(PPG)解决了一系列相互关联的问题，涉及迷幻剂在培养细胞和整个动物中表达的人类5-HT/2A受体(h5-HT2AR)的各种突变结构的功能和影响，在3D受体模型和配体结构的共同结构背景下。这里所寻求的对致幻剂作用机制的基本分子水平的理解，也旨在使今后在针对滥用致幻剂的治疗方式的结构/基础设计方面的努力成为可能。PPG将围绕项目1中的综合计算建模、动力学模拟和结构分析与设计进行组织。项目2和3中将利用涉及细胞系统和整个小鼠的转基因结构的药理学、生化和行为方法，对致幻剂影响信号转导、基因表达和行为的不同机制进行功能探索。这三个项目都将以具体的结构性假设为基础。例子包括等同于5-羟色胺和致幻剂(例如，LSD)的作用，改变受体与G蛋白的相互作用(例如，偶联到小分子G蛋白)，以及表现出第二信使产生的非激动剂刺激。项目1还讨论了致幻剂与受体模型相互作用的独特模型的结构-活性考虑，由此产生的干扰将为其他项目的方案中受体结构和配体的选择提供信息。因此，PPG将组织从多学科实验中获得的见解，将迷幻剂的h5-HT/2AR作用与整个动物的作用的分子基础联系起来。

Hallucinogens are drugs of abuse with an apparently unique mechanism of action producing disturbances in thought, perception and mood. The mechanisms for these actions of hallucinogens are unknown, but their association with 5-HT/2A receptor activities is longstanding. Despite considerable progress in characterizing behavioral, physiological and pharmacological properties of serotonergic hallucinogens, the molecular signature underlying the hallucinogenic potential remains elusive. The exact role of the 5-HT2A receptor in hallucinogenesis also remains obscure. To eliminate these important gaps in knowledge and understanding, this Program Project Grant (PPG) addresses a continuum of interrelated questions about function and effects elicits by hallucinogens on various mutant constructs of the human 5-HT/2A receptor (h5-HT2AR) expressed in cultured cells and in whole animals, in a common structural context of 3D receptor models and ligand structures. The fundamental molecular level of understanding sought here for the mechanisms of action of hallucinogens also aims to enable future efforts in structure/based design of therapeutic modalities against their abuse. The PPG is organized around comprehensive computation modeling, dynamics simulation, and structure analysis and design in Project 1. Functional probing for distinct mechanisms in the effects of hallucinogens on signal transduction, gene expression and behavior will be carried out in Projects 2&3 with pharmacological, biochemical and behavioral approaches involving genetically modified constructs in cell systems and whole mice. All three Projects will take the basis of specific structural hypotheses. Examples include one that equalizes the efficacies of 5-HT and hallucinogens (e.g., LSD), one that alters the interaction of the receptor with G proteins (e.g., coupling to small mw G proteins), and one that exhibits agonist-independent stimulation of second messenger production. Structure-activity considerations for distinctive models of interaction of hallucinogens with receptor models are also addressed in Project 1, and resulting interferences will inform choices of receptor constructs and ligands in protocols of the other Projects. The PPG will thus organize insights from multi-disciplinary experiments into a mechanistic understanding relating h5-HT/2AR actions of hallucinogens to a molecular basis for effects in the whole animal.