# Dopaminergic and Glutamatergic Mechanisms of Cocaine Addiction: Sex Differences

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2022 · $521,319

## Abstract

PROJECT SUMMARY
Substance use disorder (SUD) is a major epidemic, and its impact may be particularly severe for women. One
of the most striking examples is “the telescoping effect” wherein women meet criteria for SUD and/or seek
treatment after fewer years of drug use as compared to men. This effect has been reported for multiple drug
classes, including psychostimulants and opioids. Our data obtained from the previous funding period establish
that a similar phenomenon occurs in a rat model of cocaine use disorder (CUD) with females developing an
addiction-like phenotype sooner during abstinence than males. We have defined an addiction-like phenotype as
an enhanced motivation for cocaine. This feature develops over abstinence following extended-access (ExA,
>6-hr/day) but not short-access (ShA) self-administration, and like SUD in humans, it represents a lasting shift
toward a higher motivational state. Our data show that 7 days of abstinence is sufficient for inducing this
phenotype in females, whereas males require 14 days. Females tested after 7 days of abstinence also display
greater compulsive cocaine use, as measured using a punishment procedure, but by 14 days of abstinence,
males reach the female-level. Our goals with this competitive R01 renewal application are to characterize
molecular shifts that underlie the telescoping effect, and to determine whether, similar to humans, the
telescoping effect also occurs with opioids. Our primary hypothesis is that a shift from nucleus accumbens
(NAc) dopamine D1 receptors (D1R) to glutamate AMPA receptors (AMPAR) occurs sooner during abstinence in
females than males and underlies the telescoping effect. This hypothesis is based on our findings showing that
following the development of an addiction-like phenotype, the mechanisms motivating cocaine use shift in both
males and females from NAc D1R to AMPAR, and that in females, estradiol is necessary for the development of
this phenotype and the shift to a diminished role of NAc D1R. In Aim 1, using site-specific antagonism of NAc
D1R and AMPAR, we will determine mechanistic shifts that occur with the development of an enhanced
motivation for cocaine and compulsive cocaine use. Effects will be examined following ExA self-administration
and 1-day of abstinence, which will not induce an addiction-like phenotype or molecular shift in either sex, or 7-
days of abstinence, which will induce this phenotype and molecular shift in females with estradiol, but not males
or females without estradiol. In Aim 2, we will use RNA- and ChIP-sequencing to test the hypothesis that estrogen
receptors regulate the transcriptional events that accompany the development of an addiction-like phenotype.
Finally, in Aim 3, we will use an ExA fentanyl self-administration procedure optimized for studying sex differences
to test the hypothesis that, similar to humans, female rats develop an opioid addiction-like phenotype sooner
during abstinence than males. These studies will pro...

## Key facts

- **NIH application ID:** 10533488
- **Project number:** 2R01DA024716-11A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Wendy Jean Lynch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $521,319
- **Award type:** 2
- **Project period:** 2008-04-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10533488

## Citation

> US National Institutes of Health, RePORTER application 10533488, Dopaminergic and Glutamatergic Mechanisms of Cocaine Addiction: Sex Differences (2R01DA024716-11A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10533488. Licensed CC0.

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