Deconvoluting Polypharmacologic Contributions of Rapidly-Acting Antidepressants

项目摘要/摘要 多重药理学，或同时参与多个分子靶点，是一个共同的特征 在治疗中枢神经系统疾病的最流行的治疗方法中， 包括抗抑郁药。到目前为止，支架的鉴定具有可取的 多元药理活性依赖于一种基本上没有指导的、表型驱动的方法， 由于很少有技术可以将离散期望或不期望结果与 在多个目标上并发操作的特定模式。然而，访问机械式的 理解这种系统药理学方法是一个基本的优先事项，如果 多靶点精神疗法的合理设计将成为现实。因此， 这项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为互补 跨分子识别和操纵有针对性的多元药理现象的手段， 细胞水平和行为水平。更直接的是，这个项目的目标是使用增量疫苗接种 对抗小分子疗法鉴定(R，S)-氯胺酮和(2R，6R)- 羟基去甲氯胺酮对不同谷氨酸能靶点的时间协同作用 以一种快速而持久的方式减少快感缺失和行为绝望的表现。 此外，它的目标是在存在的情况下使用神经元整体激活、标记和消融 由(R，S)-氯胺酮引起的单一或多个化学物种。这将允许 用于识别由于多种药物参与而产生的紧急细胞水平效应。总的来说， 该项目不仅将提供所需的关于(R，S)-氯胺酮和(2R，6R)- 羟基去甲氯胺酮相互作用，支持治疗严重抑郁障碍，但也将 确定潜在的机制方法来分离快速作用谷氨酸能药物的滥用责任 抗抑郁药物的治疗效果。

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.