The influence of ovarian hormones on the putative mechanisms that promote female nicotine use

Abstract

Nicotine use is driven by pleasurable effects, but following chronic exposure, nicotine use becomes largely driven by the desire need to avoid withdrawal symptoms. Current cessation strategies focusing on alleviating withdrawal, but current cessation interventions are less effective for women than men. Also, hormone fluctuations across the menstrual cycle appear to impact use patterns, withdrawal severity, and treatment efficacy. This raises important questions regarding optimal quit dates and the application of hormone interventions to alleviate withdrawal in women. This review surveys the existing literature assessing the impact of ovarian hormones on nicotine withdrawal severity. This is an important issue because women seeking cessation treatments may be using hormone-based contraceptives or hormone replacement post-menopause. Hormone interventions may also offer a novel treatment avenue that is more effective than current cessation approaches. Future work in this area is important for reducing health disparities produced by excessive nicotine use in women.

Figure 1

Depicts our hypothesis regarding peak increases in nicotine reward and withdrawal overlaid across the female cycle in humans and rodents. We suggest that the rewarding effects of nicotine are heightened during the follicular phase, when estrogen levels peak. Also, we predict that aversive effects that emerge during nicotine withdrawal are heightened during the luteal phase, when progesterone levels are relatively higher than estrogen. Prior work in rodents revealed that estradiol enhances the rewarding effects of nicotine and higher ratios of progesterone to estradiol is associated with greater nicotine withdrawal.

Figure 2

Depicts our hypothesis regarding the mechanisms by which ovarian hormones promote nicotine withdrawal in females. We suggest that chronic nicotine produces a disproportionately greater recruitment of CRF systems and ACh release in the IPN in females versus males. This results in a greater expression of CRF1 receptors and α5 subunits that are anatomically positioned to promote GABA release (inhibitory tone) in the IPN. Given that estrogen and progesterone closely regulate the expression of CRF1 receptors and α5 subunits respectively, it is expected that the peak increases in these hormones promote greater expression of these key targets that facilitate inhibitory tone in the IPN.