HALLUCINOGENS IN SPECIFIC SIGNALING AND CIRCUITRY

特定信号和电路中的致幻剂

• 批准号: 7298951
• 负责人: STUART C. SEALFON
• 金额: $ 35.22万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7298951
• 关键词: Agonist; Behavioral; Biochemical; Biological Assay; Collaborations; Complex; Cyclic GMP-Dependent Protein Kinases; Data; Drug abuse; Event; Fingerprint; Fluorescent in Situ Hybridization; Gene Expression Profile; Genes; Genetic; Genomics; Hallucinogens; In Vitro; Investigation; Knock-in Mouse; Laboratories; Ligands; Maps; Mediating; Mediator of activation protein; Metabotropic Glutamate Receptors; Molecular; Molecular Target; Mus; Neurobiology; Neurons; Neuropharmacology; Pattern; Phenethylamine; Phenethylamines; Phospholipase C; Proteins; Psychiatry; Receptor Activation; Receptor Signaling; Research; Role; Sampling; Serotonin; Signal Pathway; Signal Transduction; Specificity; Structure; Tertiary Protein Structure; Testing; Tryptamines; Work; base; cellular targeting; drug of abuse; in vivo; insight; mouse model; neurochemistry; neuropsychological; receptor; response; serotonin receptor; trafficking; tryptamine

Why serotonergic hallucinogens such as LSD have unique neuropsychological effects remains a fundamental question for neurobiology relevant to drug abuse, psychiatry and neuropharmacology. The primary target for hallucinogens is the serotonin 5HT2A receptor (5HT2AR). The neuronal signaling events and circuitry responsible for their unique effects in comparison with closely related non-hallucinogens have not been resolved. In vitro, hallucinogens and other 5HT2AR agonists show agonist-directed signal trafficking, i.e.they differentially activate 5HT2AR signaling pathways. We developed a high-throughput quantitative genomics-based approach called transcriptome fingerprinting (TFP) that reflects complex signaling responses, and our studies are consistent with hallucinogen signal trafficking in vivo and in primary cultured neurons. TFP profiles that correlate with behavioral responses in mice in conjunction with cutting- edge computational and genetic approaches developed by the Weinstein and Gingrich laboratories provide the basis to investigate the molecular target, signaling mechanisms and neurons modulated by hallucinogens. In order to elucidate the cellular and molecular mechanisms underlying hallucinogen signaling specificity, we will pursue two aims. We will use in vitro studies to investigate the mediators of hallucinogen-specific signaling in neurons, the role of 5HT2AR structure on hallucinogen-specific signaling and the presence and functional role of 5HT2AR-mGlu2 receptor complexes. In mouse, we will study the identity of hallucinogen-responsive neurons anatomically and will collaboratively study a variety of mouse models to test hypotheses about the target and mechanism of hallucinogens in vivo. These studies will use the unique synergy of this PPG to test and refine specific hypotheses for the mechanism of action of hallucinogens.

为什么像LSD这样的能引起兴奋的致幻剂具有独特的神经心理学效应， 与药物滥用、精神病学和神经药理学相关的神经生物学的基本问题。的 致幻剂的主要目标是5-羟色胺5 HT 2A受体（5 HT 2AR）。神经元信号事件 与密切相关的非致幻剂相比， 没有得到解决。在体外，致幻剂和其他5 HT 2AR激动剂显示激动剂导向信号 它们的作用是通过运输，即它们差异性地激活5 HT 2AR信号传导途径。我们开发了一种高通量的 一种基于定量基因组学的方法，称为转录组指纹（TFP）， 信号反应，我们的研究是一致的致幻剂信号贩运在体内和原发性 培养的神经元TFP谱与小鼠的行为反应相关， 由温斯坦和金里奇实验室开发的边缘计算和遗传方法提供了 为进一步研究其分子靶点、信号转导机制和神经元调控机制奠定基础。 致幻剂为了阐明致幻剂的细胞和分子机制 我们将追求两个目标。我们将使用体外研究来研究 神经元中致幻剂特异性信号传导，5 HT 2AR结构在致幻剂特异性信号传导中的作用 以及5 HT 2AR-mGlu 2受体复合物的存在和功能作用。在小鼠中，我们将研究 从解剖学上鉴定致幻原反应神经元，并将合作研究各种小鼠 模型，以测试有关的目标和机制的迷幻剂在体内的假设。这些研究将使用 这种PPG的独特协同作用，以测试和完善的作用机制的具体假设， 致幻剂