# Mapping brain glutamate in humans: sex differences in cigarette smokers

> **NIH NIH R03** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $78,000

## Abstract

PROJECT SUMMARY/ABSTRACT
 Smoking is the leading cause of preventable death and disease in the U.S. Women are disproportionately
affected by smoking, as they not only have a higher risk of experiencing some health consequences of smoking,
such as heart disease, but also suffer sex-specific health issues, including cervical cancer. Women have more
difficulty maintaining long-term abstinence from smoking than men, possibly because they experience stronger
withdrawal symptoms and greater relief of these symptoms after resumption of smoking. Despite their enhanced
need for smoking-cessation therapies, current first-line treatments, such as nicotine replacement, are less
effective for women than men. The underlying differences in brain function that drive these sex differences
remain unknown, and understanding them can guide development of personalized smoking cessation therapies.
 Glutamatergic neurotransmission is a promising new target for smoking cessation therapy, but sex
differences in glutamate levels across the brain, which can impact the efficacy of glutamatergic treatments, have
not been investigated in smokers. Our preliminary data using single-voxel magnetic resonance spectroscopy
(MRS), have revealed important sex differences in the relationships of glutamate in the dorsal anterior cingulate
cortex (dACC), a region highly implicated in Tobacco Use Disorder, with sex (males vs. females) and smoking
state (overnight abstinent vs. post-smoking) in smokers. Moreover, glutamate in the dACC is also associated
with circulating estrogen, and possibly progesterone, in women who smoke. However, important relationships
between glutamate in other brain regions and these factors are yet to be explored. Echo-planar spectroscopic
imaging (EPSI), a state-of-the-art technique, permits measurement of glutamate in ~80 percent of the whole
brain in vivo in humans. Given our preliminary results using single-voxel MRS, we now propose to test
replicability of our finding in the dACC and to examine potential extension to other brain regions heavily
implicated in the behavioral states of Tobacco Use Disorder - the anterior insula and thalamus. We will also
perform exploratory analyses of relationships of glutamate across the brain with sex, smoking state, and ovarian
hormones.
 Otherwise healthy, adult daily smokers (30 men and 30 women) will serve as participants for this study. They
will be tested twice, after overnight (~12 h) abstinence from smoking and after smoking their first cigarette of the
day. We will combine EPSI with analysis of circulating ovarian hormones in serum to address two specific aims:
Aim 1. Determine relationships between brain glutamate, sex, and circulating ovarian hormones. Aim 2.
Determine sex differences in acute effects of smoking on brain glutamate. The findings from this study will
provide important empirical information regarding glutamate levels across the brain in smokers and help guide
development of personalized, sex-specific...

## Key facts

- **NIH application ID:** 10376214
- **Project number:** 5R03DA052719-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Jeffry R Alger
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $78,000
- **Award type:** 5
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376214

## Citation

> US National Institutes of Health, RePORTER application 10376214, Mapping brain glutamate in humans: sex differences in cigarette smokers (5R03DA052719-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10376214. Licensed CC0.

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