Deconvoluting Polypharmacologic Contributions of Rapidly-Acting Antidepressants

项目总结/摘要 多药理学或多个分子靶点的同时参与是一个共同特征 在治疗中枢神经系统疾病的最普遍的治疗剂类别中， 包括抗抑郁药到目前为止，具有理想的支架的鉴定 多药活性主要依赖于无指导的、表型驱动的方法， 由于用于将离散的期望或不期望的结果与 对多个目标同时作用的特定模式。然而，进入机械 理解这种系统药理学方法提供的是一个基本的优先事项，如果 多靶点精神病治疗的合理设计将成为现实。因此 这一系列工作的长期目标是开发和验证抗体介导的， 作为补充的组合神经元系综标记化学神经科学方法 手段，以确定和操纵跨分子的靶向多药理学现象， 细胞和行为水平。更直接的是，该项目旨在使用增量疫苗接种 针对小分子治疗剂，以鉴定（R，S）-氯胺酮和（2 R，6 R）- 羟基去甲氯胺酮以时间协调方式作用于不同的多巴胺能靶点 以快速但持久的方式减少快感缺乏和行为绝望的表达。 此外，它的目的是使用神经元整体激活，标记和消融的存在， 由（R，S）-氯胺酮给药引起的单一或多种化学物质。这将允许 用于鉴定由于多药作用引起的紧急细胞水平效应。总体而言， 该项目不仅将提供关于（R，S）-氯胺酮和（2 R，6 R）- 羟基去甲氯胺酮相互作用以支持重度抑郁症治疗，但也 确定潜在的机械方法，以区分速效止痛药的滥用责任 抗抑郁药的治疗效果

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.