# Deconvoluting Polypharmacologic Contributions of Rapidly-Acting Antidepressants

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $382,418

## Abstract

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.

## Key facts

- **NIH application ID:** 10130002
- **Project number:** 5R01MH122742-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Cody James Wenthur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,418
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130002

## Citation

> US National Institutes of Health, RePORTER application 10130002, Deconvoluting Polypharmacologic Contributions of Rapidly-Acting Antidepressants (5R01MH122742-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10130002. Licensed CC0.

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