# The role of GPER-1 and addiction

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $324,428

## Abstract

Project Summary/Abstract
Addiction is a major public health concern. Approximately 8.3% of the population needed treatment for addiction
in 2013. Cocaine is one commonly used illicit drug that is abused by 10-12% of the population and is highly
addictive. During adolescents, equivalent numbers of males and females are abusing or dependent on cocaine.
In adults aged 18 and older, the prevalence is double in males compared to females. It is important that we
identify why twice as many males are continuing to use after adolescence, and identify novel potential treatment
targets that can be beneficial to males. While our lab has historically studied sex differences and especially the
characteristics of female drug taking, the studies proposed focus on a novel mechanism that may mitigate drug
taking in males. In the proposed work, we investigate a novel mechanism through which the preference and
motivation for cocaine is differentially affected in males, but not females. Estradiol (E2) is an important hormone
in the brains of both females and males. In males, E2 in the brain is synthesized from testosterone via the
enzyme aromatase. In both sexes, E2 acts by binding to one of three types of E2 receptors (ER)s: alpha (α),
beta (β), or G-protein receptor -1 (GPER-1). Previous studies have found that E2 potentiates cocaine-induced
DA in the dorsal striatum (dSTR) and enhances acquisition of drug taking in females only. The studies proposed
will identify how ER activation of GPER-1 differentially influences preference and motivation for cocaine in male
and female rats. Our preliminary data show that activation of GPER-1 in the dSTR of male rats blocks conditioned
place preference (CPP) for cocaine, but has no effect on CPP in females. Additional preliminary results find that
activating GPER-1 attenuates cocaine-induced DA increases within the dSTR of males, but not females.
Together, these results suggest that GPER-1 activation may have a protective effect against the rewarding
effects of cocaine in male rats, but not females. The experiments proposed will investigate: 1) whether sex
differences in GPER-1 receptor activation in the dSTR are related to the preference for cocaine; 2) the effect of
GPER-1 on cocaine-induced DA release in male and female rats; and 3) the effect of GPER-1 on the motivation
for cocaine in male and female rats during acquisition and after acquisition. Addiction treatment needs targeted
treatment for males and females. This work will open new avenues for prevention and treatment of addiction by
providing a sex-specific understanding of gonadal hormones the neurobiological mechanisms mediating the
rewarding properties of psychostimulants.

## Key facts

- **NIH application ID:** 10455025
- **Project number:** 5R01DA049795-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** JILL B. BECKER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $324,428
- **Award type:** 5
- **Project period:** 2020-09-30 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455025

## Citation

> US National Institutes of Health, RePORTER application 10455025, The role of GPER-1 and addiction (5R01DA049795-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10455025. Licensed CC0.

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