# Estrogen receptor regulation of cocaine effects on dopamine terminals

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2022 · $46,752

## Abstract

PROJECT SUMMARY/ABSTRACT:
For many psychiatric disorders, such as substance use disorder, sex is a critical biological variable and women
represent a particularly vulnerable population. For cocaine use disorder women transition to addiction faster,
take more cocaine, experience more adverse consequences, and have more difficulty remaining abstinent.
Previous research has exposed significant sex differences in the mesolimbic dopamine system, a neural circuit
critical in reward learning and motivation, and identified the gonadal hormone 17b-estradiol as a significant
contributor to this vulnerability. The mesolimbic dopamine system - which originates in the ventral tegmental
area and projects to the striatum - has been shown to be involved in the expression of sex-specific behavior
especially as it relates to cocaine reward and motivation. To understand cocaine use disorder in females we
need to understand the fundamental mechanisms by which drug responses are mediated and how this influences
the systems these drugs act on – I focus here on the dopamine system. While substantial work has focused on
sex differences in the anatomy of dopamine neurons and relative dopamine levels between males and females,
an important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated
by local regulatory mechanisms independent of somatic activity. The dopamine system contains a high density
of estrogen receptors (ERa, ERb, and GPER-1 subtypes) that likely serve as important substrates through which
ovarian hormones exert their influence on dopaminergic function. Indeed, there is robust dopamine system
regulation by ovarian hormones where 17β-estradiol (E2) increases dopamine cell activity and release from
dopamine terminals in the striatum. In Aim 1, I will combine analytical chemistry and optical imaging techniques
with pharmacology to isolate dopamine terminals in the nucleus accumbens core and characterize the role of
specific estrogen receptor subtypes in the modulation of presynaptic dopamine release. Further, previous work
from our lab has shown selective increases in cocaine-evoked dopamine release, cocaine potency, and cocaine
affinity for the dopamine transporter in estrus females (with high levels of circulating E2). In Aim 2, I will define
how direct manipulation of estrogen receptors affects dopamine transporter-mediated clearance and potency of
cocaine at terminals in the nucleus accumbens core. This work builds on the foundation set by innovators in the
field to examine the role of estrogen receptors in presynaptic dopamine dynamics, and further proposes to
investigate how these mechanisms modulate cocaine effects at the dopamine transporter. Importantly, this work
provides me with an exceptional training opportunity while simultaneously providing answers to fundamental
questions in the field, which are imperative in developing effective pharmacotherapies for cocaine use disorder.
Together, understandi...

## Key facts

- **NIH application ID:** 10463262
- **Project number:** 1F31DA056202-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Kirsty R. Erickson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463262

## Citation

> US National Institutes of Health, RePORTER application 10463262, Estrogen receptor regulation of cocaine effects on dopamine terminals (1F31DA056202-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10463262. Licensed CC0.

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