# Influence of the natural hormonal milieu on perfusion fMRI smoking cue responses

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $397,752

## Abstract

Cigarette smoking is the number one cause of preventable death in the U.S. however, despite the known
health consequences of smoking, 1 in 5 Americans continues to smoke. Most smokers desire to quit but
success rates are low. Women have greater difficulty quitting smoking and suffer greater smoking-related
health consequences than men. Greater knowledge of relapse vulnerabilities in women could help to identify
treatment targets and result in interventions that improve health and save lives. The guiding hypothesis for this
proposal is that fluctuations in gonadal sex hormones [estradiol (E) and progesterone (P)] over the course of the
menstrual cycle (MC) may greatly impact relapse vulnerability through their actions on a powerful relapse
motivator, smoking-related cue (SC) exposure. This hypothesis arises from animal studies showing that gonadal
sex hormones dramatically affect reward systems and reward-related behavior. Specifically, E elevates ventral
striatal dopamine and accelerates both drug-cued and drug-primed reinstatement, while P has opposite effects
on drug-seeking behavior. Correspondingly, when women have high E levels, such as those occurring during
the late follicular phase of the MC, they may find drugs more rewarding and drug-related cues more motivating,
which could markedly undermine women's success in quitting smoking at that time. Our preliminary
neuroimaging results show enhanced responses to SCs in the medial orbitofrontal cortex, a region known to be
involved in the coding of reward magnitude, in women during the follicular compared to the luteal phase, but
the direct effects of the hormonal milieu on neural responses to SCs remains untested, divesting us of critical,
treatment-relevant information. Thus, the overarching goal of this proposal is to characterize the influence of
the natural hormonal milieu on brain and behavioral responses to SCs. Specifically, in AIM 1, to link hormonal
status to the brain responses to SCs, over the course of 3 monthly MCs, in a repeated measures counter-
balanced design, we will compare the brain responses to highly appetitive SCs in a group of healthy, naturally-
cycling females who are chronic smokers at 3 distinct time points within their natural MC. Given that the early
follicular phase is associated with extremely low levels of both E and P, it offers a natural and ideal comparator
condition. Sessions will be carefully timed to occur during high E, which corresponds to the late follicular phase,
during high P, which corresponds to the mid-luteal phase, and during the time of the MC when both E and P
are low (LEP). E/P concentrations will be used to verify conditions and as covariates to examine their
associations with brain responses. In AIM 2, to link hormonal status and brain responses to the behavioral
biases to SCs, in synchrony with the imaging sessions, women from Aim 1 will also participate in 3 laboratory
sessions consisting of a neuro-behavioral battery that includes tasks ...

## Key facts

- **NIH application ID:** 9893853
- **Project number:** 5R01DA040670-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Reagan R Wetherill
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,752
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893853

## Citation

> US National Institutes of Health, RePORTER application 9893853, Influence of the natural hormonal milieu on perfusion fMRI smoking cue responses (5R01DA040670-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9893853. Licensed CC0.

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