Nicotine addiction is a significant medical and socioeconomic burden on society. Although numeroustreatment strategies have been employed to encourage cessation of smoking, relapse continues to representa major challenge to those efforts. Surprisingly, relatively little is known about gender-specific influences onnicotine use, relapse, and treatment responsiveness. Studies using animal models have provided valuableinformation about biological and environmental factors that contribute to nicotine addiction; however, thesestudies have primarily focused on male subjects. Accordingly, this proposal will focus on identifying sex-related and estrous cycle-dependent differences in nicotine self-administration, vulnerability to relapse, andsensitivity to pharmacotherapies that are clinically used as smoking cessation treatments. More specifically, established mouse models of operant self-administration will be employed to study thereinforcing effects of nicotine, and reinstatement procedures will be used to examine the ability of nicotine,conditioned cues, and stress to trigger reinstatement of nicotine-seeking behavior in male and female mice.Additionally, the effects of pharmacological drugs (buproprion and varenicline) on nicotine self-administration, as well as their ability to block or attenuate reinstatement of nicotine-seeking behavior will beevaluated. To examine estrous cycle-related differences in relapse vulnerability, reinstatement testing will beconducted in separate groups of females to coincide with the estrus and non-estrus phases of the cycle.Similarly, to examine estrous cycle-dependent differences in responsiveness to the pharmacotherapeuticagents, drug treatments will begin at different estrous cycle phases in females. Progesterone levels will bemeasured in females and correlated with behavioral measures of nicotine's reinforcing effects, as well asreinstatement of nicotine-seeking provoked by various trigger stimuli. As such, these studies not only address the overarching theme of the SCOR, but also fill a critical void inthe literature regarding this important clinical issue. This project directly relates (by design) to a clinicalSCOR project focused on investigating the impact of timing of pharmacological treatment within themenstrual cycle on relapse to smoking in women (Project #4). Results from this project will also interfacewith preclinical (Project #1) and clinical (Project #2) SCOR projects that address similar gender-relatedissues regarding cocaine dependence and relapse. Overall, the complementary nature of the preclinical andclinical research components of the MUSC SCOR Center will foster and facilitate translational efforts toguide the development of new and more gender-specific treatment strategies for nicotine (and other) drugaddiction and relapse in women and men.
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