# Mechanistic studies of Neurosteroid Analogues

> **NIH NIH P50** · WASHINGTON UNIVERSITY · 2021 · $539,232

## Abstract

Project Summary
Neurosteroids such as allopregnanolone (AlloP) strongly potentiate GABAA receptor function, driving the view
that these effects mediate psychoactive effects of neuroactive steroids (NAS). The rapid antidepressant
actions of AlloP seem to belie a solely GABAergic mechanism. Understanding the additional mechanisms of
NAS will allow evolution of the next generation of treatments. We seek to both understand mechanisms by
which AlloP promotes therapeutic benefit and to improve on these benefits with NAS that possess additional
and/or alternative mechanisms. The Center leverages a unique set of NAS analogues. This project's first Aim
is to evaluate the impact of these analogues on underappreciated ion channel targets of NAS: voltage-gated
Ca2+ channels and NMDA receptors. This aim will work in concert with Project 1 to identify sites of action on
NMDA receptors. In addition, this aim will re-evaluate the GABAA receptor subtype selectivity of NAS in native
cells. The second aim of the study is to limit NAS actions to plasma membrane receptors using novel tethered
ligand approaches. This will reveal NAS effects in the absence of intracellular targets, which we will explore in
Aim 3 with evaluation of compounds' activity on neuroinflammatory cytokines and autophagy pathways. This
aim follows up on preliminary data that suggests that NAS unnatural enantiomers influence the function of
these intracellular targets, and project 1 will explore potential relevant protein targets that mediate these
effects. A final aim is to evaluate the impact of various NAS analogues on functional microcircuitry of ex vivo
brain circuits. This project will identify the most interesting set of compounds for evaluation in project 3, which
explores in vivo physiology and circuitry.

## Key facts

- **NIH application ID:** 10198243
- **Project number:** 1P50MH122379-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** STEVEN J MENNERICK
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $539,232
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198243

## Citation

> US National Institutes of Health, RePORTER application 10198243, Mechanistic studies of Neurosteroid Analogues (1P50MH122379-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10198243. Licensed CC0.

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