# Combined mGluR5 PET and fMRI imaging of Sex Differences during Cocaine Withdrawal

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $693,042

## Abstract

Project Summary
There is compelling preclinical, epidemiological and clinical evidence of greater vulnerability in females for
cocaine effects, including reward magnitude and positive subjective effects, rate of development of cocaine
use disorder (CUD), and relapse risk following cocaine abstinence. Preclinical studies have demonstrated
opposing effects of estradiol (activating) and progesterone (dampening) on behavioral and neurological
responses to cocaine. The glutamate (Glu) system plays a central role in cocaine use, contributing to
development and maintenance of regular use, withdrawal, and reinstatement following abstinence. Importantly,
recent brain imaging studies have shown significant reductions in mGluR5 binding potential (BPND) during
cocaine abstinence. To date, however, CUD human brain imaging studies have enrolled only male subjects or
have included too few female subjects to permit analyses as a function of sex. The proposed research will
examine sex differences in mGluR5 BPND during cocaine withdrawal as a function of gonadal hormones in
women and men with cocaine use disorder and in a comparison group of healthy controls. In response to
reviewer concerns, this revised application adds fMRI scans to broaden examination of sex differences in
neurocircuitry that is activated in parallel with the targeted glutamate system during cocaine withdrawal. fMRI
procedures will include both resting state functional connectivity scans (rsFC) as well as cocaine cue-induced
event-related scans (CC) to occur within-subject during cocaine abstinence. We are specifically adding cueing
procedures because it is known that women are more sensitive to craving and other associated effects of
cocaine cues, during the follicular phase of menses. We will enroll 20 female and 20 male non-treatment
seeking CUD participants. On day 1, CUD subjects undergo cocaine infusion, complete positron emission
tomography (PET) imaging using [18F]FPEB to quantify mGluR5 BPND, followed by rsFC and CC fMRI. Women
will be in the luteal phase of their menstrual cycle. During the 15-day CRU stay, bloods will be collected for
measurement of hormones, and subjects will complete measures of withdrawal severity, craving and mood. On
day 15, subjects will undergo a second set of [18F]FPEB PET and fMRI scans. This proposal will be the first
to: characterize mGluR5 in women and men with CUD; examine the relationship of mGluR5 to resting state
and cocaine cued brain function and to key behavioral measures of cocaine withdrawal and craving. Most
importantly, the potential role of sex hormones in these effects will be studied. Despite over three decades of
research, there are no efficacious pharmacotherapies approved for cocaine treatment. Thus, there is a
pressing need to identify new neurotransmitter targets for medication development and to address gender-
specific treatment needs. Findings may inform personalized, sex specific interventions for cocaine treatment.

## Key facts

- **NIH application ID:** 9897512
- **Project number:** 5R01DA042094-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** MARY E MCCAUL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $693,042
- **Award type:** 5
- **Project period:** 2017-06-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897512

## Citation

> US National Institutes of Health, RePORTER application 9897512, Combined mGluR5 PET and fMRI imaging of Sex Differences during Cocaine Withdrawal (5R01DA042094-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9897512. Licensed CC0.

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