# Ovarian influence on circadian and infradian modulation of nicotine‐seeking in female mice

## TL;DR

Ovarian hormones influence nicotine-seeking behavior in female mice and nicotine use harms ovarian health.

## Contribution

This study reveals a bidirectional relationship between nicotine-seeking behavior and ovarian health in female mice.

## Key findings

- Intact female mice showed nicotine-anticipatory behavior, which was absent in ovariectomized mice.
- Nicotine exposure disrupted the estrous cycle and caused ovarian follicular damage in intact mice.
- Ovarian hormones are critical modulators of nicotine-seeking behavior in female mice.

## Abstract

Sex differences in tobacco intake are closely associated with hormonal fluctuations during the menstrual cycle in women. Elevated estrogen levels have been associated with increased stress, which may lead to a higher likelihood of seeking psychoactive substances. Additionally, tobacco use has been associated with negative effects on reproductive health. Preclinical studies suggested that the estrous cycle significantly influences addictive behaviors, emphasizing the role of ovarian hormones. Furthermore, psychoactive substances entrain circadian rhythms, with animals showing increased locomotor activity 1–2 h before drug administration time, known as anticipatory activity, reflecting seeking behavior. This study aims to evaluate the impact of ovarian hormones on nicotine‐anticipatory behavior. A circadian model of forced administration of nicotine via nebulization was implemented in intact and ovariectomized female mice, exposing them to nicotine at a fixed time (ZT4) for 20 min daily over 14 days. The effects of nicotine intake on ovarian follicle morphology and maturation were also assessed. Daily nicotine exposure successfully entrained a clear anticipatory behavior in intact mice. Notably, this anticipatory activity was completely abolished in ovariectomized females, indicating a critical dependence on ovarian factors. Furthermore, nicotine exposure disrupted the estrous cycle and induced significant ovarian follicular damage in intact females. Our findings suggest that the hormonal state is a primary modulator of nicotine‐anticipatory behavior. Moreover, the observed nicotine‐induced ovarian damage highlights a significant risk to female reproductive health, suggesting a bidirectional relationship between nicotine use and the hypothalamic–pituitary–gonadal axis.