# Neural Substrates of Cigarette Craving, Withdrawal, and Relief: Male-Female Differences

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $415,311

## Abstract

Smoking is the leading cause of preventable death and disease in the U.S., and women disproportionately
suffer some health consequences of smoking, such as heart disease and cervical cancer. Compared to men,
women experience stronger withdrawal symptoms and have more difficulty maintaining long-term abstinence from
smoking, and smoking-cessation treatments are not equally helpful to men and women. The underlying differences
in brain function that drive these male-female differences remain unknown, and understanding them can guide
development of personalized smoking-cessation therapies.
 Glutamatergic neurotransmission is a promising target for smoking cessation therapy, but male-female
differences that can impact the efficacy of glutamatergic treatments have not been investigated. Reducing
glutamate levels within the Salience Network, especially in the dorsal anterior cingulate cortex (dACC) may facilitate
smoking cessation. Smokers have higher glutamate (Glu) in the dACC than nonsmokers and exhibit a positive
correlation of dACC Glu with reactivity within the default-mode network to smoking-related cues. Given these
findings and sex differences in brain glutamate levels in healthy individuals, it is important to test for male-female
differences in the influence of dACC Glu on craving and negative states during withdrawal and their relief after
smoking, as well as the neural substrates that underlie these states.
 We will combine self-report measures with magnetic resonance spectroscopy (MRS) and functional magnetic
resonance imaging (fMRI) to address three specific aims: Aim 1. Determine male-female differences in the
association of Glu signal in the dACC with cigarette craving and negative states during abstinence (negative affect,
psychological withdrawal, and anxiety). Aim 2. Determine male-female differences in the association of Glu in the
dACC with smoking-induced relief of craving and negative states (i.e., negative reinforcement); and Aim 3.
Determine male-female differences in the association of Glu in the dACC with resting-state functional connectivity
(rsFC) within and between large-scale neural networks. The aims of this project focus on pre-smoking assessments
of Glu in the dACC and rsFC of neural networks; however, pre- and post-smoking assessments (self-report, fMRI,
and MRS) will be completed in 60 smokers (30 men and 30 women) after overnight (~12h) abstinence. Women will
complete these assessments on 2 separate days, during the follicular and luteal phases, to allow evaluation of
menstrual-cycle and ovarian hormone effects.
 The findings can help advance development of personalized, sex-specific smoking cessation therapies.
RELEVANCE (See instructions):
Glutamatergic neurotransmission is a promising target for smoking cessation therapy, but male-female differences,
which can impact the efficacy of glutamatergic treatments, have not been investigated. We will combine self-report
measures with magnetic resonance spectroscopy and ...

## Key facts

- **NIH application ID:** 10259663
- **Project number:** 5R37DA044467-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Edythe Danick London
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $415,311
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259663

## Citation

> US National Institutes of Health, RePORTER application 10259663, Neural Substrates of Cigarette Craving, Withdrawal, and Relief: Male-Female Differences (5R37DA044467-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10259663. Licensed CC0.

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