HALLUCINOGENIC MECHANISMS IN VIVO: GENETICS AND BEHAVIOR

具有明显独特的作用机制的滥用药物， 心情致幻剂的这些作用的机制尚不清楚，但它们与5-HT 2A受体的关系 活动由来已久。尽管在表征行为、生理和 的药理学特性，致幻剂的分子特征， 潜力仍然渺茫。5-HT 2A致幻的确切作用也仍然不清楚。消除这些 在知识和理解的重要差距，这个计划项目补助金（PPG）解决了一个连续的 关于致幻剂对人类5- HT 2A受体（h5-HT 2AR）在培养细胞和整个动物中表达，在3D的共同结构背景下 受体模型和配体结构。在这里寻求的基本分子水平的理解， 致幻剂的作用机制也旨在使未来的努力，在结构为基础的设计治疗 防止其滥用的方式。PPG围绕三个组成部分项目组织： 研究将项目2中的实验方法与全面的计算建模、动力学 仿真、结构分析与设计。功能性探讨不同机制的影响， 迷幻剂对信号传导、基因表达和行为的影响将在项目2和3中进行， 涉及细胞系统中的遗传修饰构建体的药理学、生物化学和行为学方法， 全麦所有三个项目都将利用设计的相同突变h5-HT 2AR构建体， 在项目1和2合作的基础上，具体的结构假设。例如， 使5-HT和致幻剂的效力相等（例如，LSD），一种表现出激动剂非依赖性刺激， 第二信使的产生。致幻剂不同作用模式的构效关系 与受体模型也在项目1中讨论，由此产生的推论将告知受体的选择 其他项目方案中的构建体和配体。因此，PPG将组织来自多学科的见解， 将实验转化为机械的理解 h-5 HT 2AR的作用是致幻剂在整个动物中作用的分子基础。

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-HT2A 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 hallucinogenesis also remains obscure. To eliminate these important gaps in knowledge and understanding , this Program Project Grant (PPG) addresses a continuum of interrelated questionsabout function and effects elicited by hallucinogens on various mutant constructs of the human 5- HT2A 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 three component Projects: Structure-related investigations link experimental approaches in Project 2 with comprehensive computational 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 mcie. All three Projects will take advantage of the same mutant h5-HT2AR constructs designed and characterized in Project 1&2 collaborations on the basis of specific structural hypothesis. Examples include one that equalizes the efficacies of 5-HT and hallucinogens (e.g., LSD), one that exhibits agonist-independent stimulation of second messenger production. Structure-activity considerations for distinctive modes of interaction of hallucinogens with receptor models are also addressed in Projects 1, and resulting inferences will inform choices of receptor constructs and ligands in protocols of the other Projects. The PPG will thus organize insights from multidisciplinary experiments into a mechanistic understanding relating h-5HT2AR actions of hallucinogens to a molecular basis for effects in the whole animal.