Deconvoluting Polypharmacologic Contributions of Rapidly-Acting Antidepressants

解卷积速效抗抑郁药的多药理作用

基本信息

批准号：
10343773
负责人：
Cody James Wenthur
金额：
$ 54.05万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343773
关键词：
AMPA Receptors Ablation Acute Address Adverse effects Anesthetics Anhedonia Antibodies Antibody Affinity Antibody Formation Antidepressive Agents Behavior Behavioral Behavioral Model Binding Brain Central Nervous System Diseases Chemicals Clinical Complex Mixtures Disease Management Drug Kinetics Enzyme-Linked Immunosorbent Assay Event FRAP1 gene Face Formulation Glutamates Haptens Hippocampus (Brain)Immunofluorescence Immunologic Individual Ketamine Label LacZ Genes Light Major Depressive Disorder Maps Measures Mediating Mental Depression Mental disorders Metabolic Methods Microscopy Molecular Molecular Target Monoclonal Antibodies Mus Neuronal Plasticity Neurons Neurosciences Outcome Parents Pattern Pharmaceutical Preparations Pharmacology Phenotype Population Protocols documentation Rattus Resolution Risk Role Signal Transduction Source Synaptosomes System Techniques Testing Therapeutic Therapeutic Effect Transcriptional Regulation Treatment Efficacy Vaccination Vaccines Vision Work abuse liability behavioral outcome biological adaptation to stress brain tissue combinatorial design drug maintenance drug reward experimental study improved in vivo preservation prevent rational design recruit scaffold side effect small molecule small molecule therapeutics theories tool treatment-resistant depression

项目摘要

PROJECT SUMMARY / ABSTRACT Polypharmacology, or concurrent engagement of multiple molecular targets, is a common feature of the most prevalent classes of therapeutics for treating disorders of the central nervous system, including antidepressants. To date, the identification of scaffolds with desirable polypharmacologic activity has relied on a largely unguided, phenotypically-driven approach, since there are few techniques for matching a discrete desired or undesired outcome with a specific pattern of concurrent action at multiple targets. Nevertheless, accessing the mechanistic understanding offered by such a systems pharmacology approach is a fundamental priority if the rational design of multi-target psychiatric therapeutics is ever to become a reality. Therefore, the long-term objective of this line of work is to develop and validate antibody-mediated and combinatorial neuronal ensemble tagging chemical neuroscience methods as complementary means to identify and manipulate targetable polypharmacologic phenomena across molecular, cellular, and behavioral levels. More immediately, this project aims to use incremental vaccination against small molecule therapeutics to identify whether (R,S)-ketamine and (2R,6R)- hydroxynorketamine act on differential glutamatergic targets in a temporally coordinated manner to reduce the expression of anhedonia and behavioral despair in a rapid, yet persistent, manner. Furthermore, it aims to use neuronal ensemble activation, tagging, and ablation in the presence of single or multiple chemical species arising from (R,S)-ketamine administration. This will allow for identification of emergent cellular-level effects due to polypharmacologic engagement. Overall, this project will not only provide needed clarity regarding how (R,S)-ketamine and (2R,6R)- hydroxynorketamine interact to support treatment of major depressive disorder, but will also identify potential mechanistic means to separate the abuse liability of rapidly-acting glutamatergic antidepressants from their therapeutic effects.

项目概要/摘要多药理学，或多个分子靶标的同时参与，是一个共同特征用于治疗中枢神经系统疾病的最流行的治疗方法，包括抗抑郁药。迄今为止，已鉴定出具有理想性能的支架多药理学活动很大程度上依赖于一种无指导的、表型驱动的方法，因为很少有技术可以将离散的期望或不期望的结果与针对多个目标同时采取行动的特定模式。尽管如此，访问机械这种系统药理学方法所提供的理解是一个基本的优先事项，如果多目标精神治疗的合理设计将成为现实。因此，该工作的长期目标是开发和验证抗体介导的和组合神经元集成标记化学神经科学方法作为补充是指跨分子识别和操纵可靶向的多药理学现象，细胞水平和行为水平。更直接的是，该项目旨在使用增量疫苗接种针对小分子疗法，以确定是否 (R,S)-氯胺酮和 (2R,6R)- 羟基去甲氯胺酮以时间协调的方式作用于不同的谷氨酸靶标以快速而持久的方式减少快感缺失和行为绝望的表达。此外，它的目标是在存在的情况下使用神经元集成激活、标记和消融 (R,S)-氯胺酮给药产生的单一或多种化学物质。这将允许用于识别由于多药联合作用而产生的紧急细胞水平效应。全面的，该项目不仅将提供有关 (R,S)-氯胺酮和 (2R,6R)- 的必要澄清羟基去甲氯胺酮相互作用以支持重度抑郁症的治疗，但也会确定潜在的机制方法来分离速效谷氨酸的滥用倾向抗抑郁药的治疗作用。