Contraceptive hormone impacts on the primary reinforcing and reward-enhancing effects of nicotine - PROJECT SUMMARY/ABSTRACT Nicotine is the primary addictive agent driving chronic smoking/vaping. Women experience greater nicotine use vulnerability, insofar that they become addicted to nicotine faster than men and exhibit higher smoking relapse rates. Women are also at greater risk of smoking-related heart attacks, cancers, and mortality. Hormonal contraceptives typically contain a synthetic estrogen (e.g., ethinyl estradiol or EE) and/or a progestin (e.g., levonorgestrel or LEVO), and are taken by 50% of premenopausal smokers. Contraceptive hormones are associated with higher smoking rates, enhanced nicotine reward, and a greater risk of smoking-related illness and mortality. Hormonal contraceptives are thus clearly linked with the public health burden of smoking. A better understanding of factors driving enhanced nicotine use vulnerability amongst women, and how hormonal contraceptives work to augment that vulnerability, would be of enormous benefit. The reinforcing effects of nicotine are weak compared to the tenacious addiction that nicotine maintains, leading the field to seek other factors involved in the development of nicotine use disorder. Indeed, environmental stimuli that commonly co- occur with nicotine (e.g., smell, taste, or sight of cigarettes/vapes) have been found to play a large role in smoking/vaping maintenance, particularly for women smokers. The enhanced import of environmental factors in nicotine intake extends to female rats, suggesting this sex-linked disparity may be rooted in biology more generally, or perhaps sex hormones more specifically. One such environmental factor is the enhancement by nicotine of the reinforcing value of other rewarding stimuli. In rats, the species studied here, our lab and others have found that responding for nicotine infusions alone was not reliably above saline suggesting a lack of primary reinforcement by nicotine. However, when nicotine infusions co-occurred with weakly reinforcing visual stimuli (e.g., a brief light presentation), nicotine-maintained responding increased up to eight-fold. This synergistic effect of nicotine reward-enhancement on nicotine intake was more prominent in female rats. Using a preclinical model of the role of reward-enhancement in nicotine intake, the proposed studies will test whether contraceptive hormones alter nicotine intake via the direct primary reinforcing effects of nicotine, or rather via augmenting the role of reward-enhancement in nicotine self-administration. The Specific Aims will examine the separate effects of EE (Aim 1) and LEVO (Aim 2) on the role of reinforcement and reward-enhancement in an intravenous nicotine self-administration task. To this end, separate groups of ovary-intact female rats will respond for nicotine or saline infusions and will receive daily EE (Aim 1) or LEVO (Aim 2) injections before self- administration sessions. Each rat will undergo separate conditions with access to infusions alone or infusions delivered with a moderately reinforcing visual stimulus. We hypothesize that EE will increase and LEVO will decrease nicotine self-administration and do so via modulating the role of reward-enhancement in nicotine self- administration.
