# Establishing sex-specific mechanisms for estrogen receptor beta in heroin extinction memory recall

> **NIH NIH F30** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $34,438

## Abstract

Opioid use disorder (OUD) is a chronic disorder characterized by the ability of drug-associated cues (triggers) to
persistently motivate drug-seeking behaviors, despite negative consequences. When drugs are associated with
cues, a strong conditioned memory is formed between the drug and the cues. Normally, once these cues no
longer predict a drug reward, this conditioned memory would be overpowered by an extinction memory.
Extinction memory recall (EMR) describes the ability to behaviorally express this extinction memory. EMR deficits
may underly the pathological drug seeking (relapse) seen in those with OUD. Importantly, a brain region involved
in each step of this process (conditioning, extinction and EMR) is the basolateral amygdala (BLA). OUD is also
characterized by distinct sex differences, with females being particularly susceptible to the rewarding effects of
opioids and more reactive to opioid-associated cues. Unfortunately, the lack of females in many prior research
studies on OUD has impaired our ability to describe the mechanisms behind, and thereby address, these
disparities. To resolve this knowledge gap, we conducted preliminary studies to investigate the role of estradiol
(E2) signaling in the BLA on heroin EMR in male and females rodents. In our first study, we found that blocking
E2 synthesis in the BLA during cued extinction training impairs EMR in both sexes. On follow-up, we found that
antagonizing estrogen receptor (ER) subtypes in the BLA led to sex-specific impacts on heroin EMR. Briefly,
females who received an ERβ antagonist had a profound EMR deficit relative to all other groups tested. In
agreement, ERβ agonism enhanced EMR in females only. The goal of this proposal is to evaluate the sex-
specific impacts of ERβ signaling in the BLA on heroin EMR. We hypothesize that modulation of ERβ
signaling in the BLA during extinction will alter EMR in females by changing neuronal function and
plasticity-associated mRNA expression, an effect driven by sex-specific ERβ expression in the BLA. We
will evaluate this hypothesis across 2 Aims. We propose to use pharmacologic and genetic approaches in males
and females to identify alterations in BLA activity and signaling following negative (Aim 1) or positive
(Aim 2) modulation of ERβ during cued extinction. Upon analysis, we expect that negative ERβ modulation
by antagonist or shRNA (Aim 1) will impair heroin EMR, decrease ERβ+ neuronal activity, and decrease
plasticity-associated mRNA expression in females. Contrastingly, positive modulation of ERβ by agonist or
overexpression (Aim 2) will have opposite impacts on these measures in females. The proposed studies may
better describe sex differences underlying heroin reward processing and OUD, allowing for more guided, sex-
specific interventions to successfully prevent and treat this disorder. This fellowship will support my training under
the mentorship of Drs. Carmela Reichel and Christopher Cowan. As outlined in this proposal, I wil...

## Key facts

- **NIH application ID:** 10896928
- **Project number:** 5F30DA057044-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Jordan Scott Carter
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,438
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896928

## Citation

> US National Institutes of Health, RePORTER application 10896928, Establishing sex-specific mechanisms for estrogen receptor beta in heroin extinction memory recall (5F30DA057044-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10896928. Licensed CC0.

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