# Neuroactive steroids as novel psychiatric treatments: mechanistic studies

> **NIH NIH P50** · WASHINGTON UNIVERSITY · 2021 · $2,535,717

## Abstract

CONTE CENTER SUMMARY
Neuroactive steroids (NAS) offer novel directions for psychiatric therapeutics. The prototypical NAS is
allopregnanolone (AlloP), which under the formulation of brexanolone, has recently been approved by FDA
for treatment of women with postpartum depression; a second, orally-active NAS has had a successful
Phase 3 study for postpartum depression and a Phase 2B study for men and women with major depression.
While AlloP is a potent and effective enhancer of GABAA receptors (GABAARs), it is not presently clear that
the antidepressant effects of NAS are mediated solely by GABAergic effects, and recent data indicate that
other mechanisms including effects on cellular stress and inflammatory pathways could also be involved.
Members of our center have extensive experience studying the medicinal chemistry and mechanisms
underlying the effects of AlloP-like NAS. In this Conte Center proposal we will leverage novel NAS
compounds to probe varied molecular, synaptic, network and behavioral effects of NAS as clues to their
therapeutic mechanisms and potential. Our center proposal is driven by unique NAS analogues
synthesized in our Chemistry Core and involves three complementary and intertwined projects that will
pursue three specific goals. First, we will test the hypothesis that selective actions of NAS on a class of
GABAARs underlies effects on hippocampal electrical activity, network function and behavior in novel
mouse lines and mouse models of postpartum and major depression. Second, we will examine the role of
non-GABAA ion channels in mediating hippocampal and behavioral effects of NAS focusing on novel NAS
that modulate NMDA glutamate receptors and low voltage activated calcium channels. These studies will
use unique photoaffinity labeling approaches to elucidate sites of actions of NAS on NMDA receptors and
other targets. Other studies will examine effects of NAS analogues on cellular function, neural network
function, and behavior. Third, we will test the role of intracellular targets engaged by NAS on hippocampal
circuits and behavior, focusing on the roles of neuroinflammation and cellular stress pathways. Our center
is uniquely positioned to traverse the exploration of antidepressant NAS from molecules to sites of action
and effects on dysfunctional circuits to identify potentially novel agents and targets for psychiatric
therapeutic development.

## Key facts

- **NIH application ID:** 10198240
- **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:** $2,535,717
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198240

## Citation

> US National Institutes of Health, RePORTER application 10198240, Neuroactive steroids as novel psychiatric treatments: mechanistic studies (1P50MH122379-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10198240. Licensed CC0.

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