Examination Of Sex Differences And The Role Of Ovarian Hormones In Modulating Nicotine Withdrawal In Rats

Introduction: Aim 1 characterized sex differences and the role of ovarian hormones in physical signs and negative affective states produced by nicotine withdrawal in female, ovariectomized female (OVX), and male rats. We also compared nicotine withdrawal and corticosterone levels with estradiol (E2) and progesterone across the 4-day estrous cycle. Aim 2 validated the role of ovarian hormones in withdrawal in OVX females that received vehicle, E2, or E2+progesterone. Methods: Female rats received a sham surgery or an ovariectomy procedure. Fifteen days later, all rats were implanted with a pump that delivered nicotine for 14 days. On the test day, separate groups received saline or mecamylamine to precipitate withdrawal. Rats were then examined for physical signs of withdrawal and anxiety-like behavior. After testing, serum levels of corticosterone, E2, and progesterone were assessed. Female rats received vaginal lavage procedures to verify the phase of the estrous cycle on the test day. Results: Intact females displayed greater anxiety-like behavior and higher corticosterone during withdrawal as compared to males and OVX females. Intact females that were tested in estrus (when E2 levels are relatively low) displayed less anxiety-like behavior and corticosterone as compared to all other phases. During withdrawal, anxiety-like behavior and corticosterone were positively correlated with E2 and negatively correlated with progesterone and the progesterone/E2 ratio. Intact females displaying high E2/low progesterone levels displayed greater anxiety-like behavior and corticosterone as compared to females displaying low E2/high progesterone levels. Lastly, OVX rats that received E2 displayed greater anxiety-like behavior as compared to OVX rats that received vehicle. OVX rats that received E2+progesterone displayed less anxiety-like behavior as compared to OVX rats that received E2 alone. Conclusion: These data suggest that E2 promotes, whereas progesterone reduces anxiety-like behavior produced by nicotine withdrawal