# The Role of Estradiol on Central Dopamine Signaling and its Associations with Cocaine Preference and Exercise

> **NIH NIH F31** · UNIVERSITY OF MISSOURI-COLUMBIA · 2022 · $33,699

## Abstract

Abstract
Historically, women have been underrepresented in addiction research. Given the 7.2 million women affected
by substance use disorder (SUD) in 2018, this lack of research contributes to a lack of effective treatment
options. Exercise has recently been highlighted as a promising non-pharmacological treatment for SUD and
women may be uniquely affected, but mechanisms for this phenomenon are not fully understood. Previous
investigations in humans and rodent models have shown that both physical activity and preference for
psychostimulant drugs (e.g., cocaine) correlate with fluctuations in estradiol (E2) throughout the menstrual
cycle. Specifically, women report greater euphoria, desire, and energy after drug use during the follicular (i.e.,
higher E2) phase of their cycle, while blockade of estrogen receptors in female rats reduces self-administration
of cocaine. In addition, E2-sufficient female rodents are more physically active, while loss of E2 in
postmenopausal women and ovariectomized (OVX) rodents reduces physical activity. One potential
mechanistic explanation for this is the effect of E2 on dopamine (DA) signaling in the nucleus accumbens
(NAc), a brain region associated with reward and addiction. My previous work has shown a strong correlation
between reduced physical activity in E2-depleted female rodents and 6-pyruvoyltetrahydropterin synthase
(Pts), a gene upstream of DA synthesis in the NAc. This proposal seeks to compare the effect of E2 loss on
voluntary wheel-running (VWR) and conditioned place preference (CPP) for cocaine in young (12-16 weeks)
wild-type female C57Bl6/J mice that have undergone OVX operations. To determine mechanism, we propose
to stereotaxically inject E2 directly into the NAc brain region of each group of OVX mice to determine the
rescue effect on both VWR and CPP for cocaine. We will examine the potential mechanism by measuring
changes in DA synthesis and receptor expression in the NAc following OVX and E2 treatment and associating
such changes with each behavior.
Aim 1 will test the hypothesis that OVX will reduce VWR in young female mice, while direct microinjection of
E2 into the NAc will rescue this effect. We will test whether this behavioral change occurs by reduced DA
synthesis and receptor expression in the NAc via a mechanism involving reduction in Pts.
Aim 2 will test the hypothesis that OVX will reduce conditioned preference for cocaine, while direct
microinjection of E2 into the NAc will increase conditioned preference. We will test whether this behavioral
change occurs by a similar mechanism to VWR as tested in Aim 1.
This proposal examines the effect of E2 on rewarding behaviors in female rodents and will test whether the
mechanism involves DA synthesis in the NAc brain region. Furthermore, this project will provide the applicant
valuable training, serving as a foundation for a future career in exercise and addiction research.

## Key facts

- **NIH application ID:** 10534474
- **Project number:** 1F31DA055452-01A1
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Dusti Shay
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $33,699
- **Award type:** 1
- **Project period:** 2022-08-05 → 2024-08-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534474

## Citation

> US National Institutes of Health, RePORTER application 10534474, The Role of Estradiol on Central Dopamine Signaling and its Associations with Cocaine Preference and Exercise (1F31DA055452-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10534474. Licensed CC0.

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