# Genetic and hormonal contributions to sex differences in vulnerability to drug use

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $419,432

## Abstract

Abstract
Sex differences in drug-related behaviors have been well documented and attributed primarily to differences
in levels of estrogens in adult men versus women. This program advances the field beyond this hypothesis
to examine another important factor, sex chromosome complement, with a focus on X-chromosome genes
that escape X-inactivation which are expressed in greater levels in female versus male brains. The four core
genotype (FCG) mouse model allows separate analysis of gonadal hormones and sex chromosome
complement (XX vs. XY). In Aim 1 these mice will be used to examine combined and separate actions of
estradiol and sex chromosome complement on vulnerability to cocaine addiction using intravenous self-
administration. Rates of acquisition and levels of motivation to obtain the drug will be evaluated. In Aim 2, we
will define the role of two X-chromosome genes that escape inactivation in mouse and human brain, Utx and
Smcx. These genes code for enzymes that demethylate histone modifications, regulating chromatin
accessibility and transcription on a wide basis. This work will be conducted with two lines of inducible, tissue-
specific knockout mice that lack the expression of either gene (Utx or Smcx) in CaMK2α in forebrain, including
neurons in the nucleus accumbens. The mice will be tested as in Aim 1 for cocaine vulnerability and
motivation. In Aim 3 brain tissue from the nucleus accumbens of mice tested in Aims 1 and 2 will be used for
epigenetic analysis. A combination of ATAC (Assay for Transposase Accessible Chromatin-), Pro (Precision
Nuclear Run-On-) and ChIP (Chromatin Immuno-Precipitation-) Sequencing will be used to identify
transcriptionally active and repressed genes associated with chromatin restructuring and important
transcription factors. The long term objective of this work is to reveal new mechanisms that underlie sex
differences in vulnerability to addiction that help clinicians design sex-specific preventions/interventions.

## Key facts

- **NIH application ID:** 10769724
- **Project number:** 5R01DA048638-05
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Wendy Jean Lynch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $419,432
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769724

## Citation

> US National Institutes of Health, RePORTER application 10769724, Genetic and hormonal contributions to sex differences in vulnerability to drug use (5R01DA048638-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10769724. Licensed CC0.

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