Contributions of Progestins Independently and Interactively with Contraceptive Estrogen to Nicotine Use

PROJECT SUMMARY/ABSTRACT Long-term smoking cessation is more difficult to achieve in women than men, and more than 170,000 women die of complications related to smoking in the United States each year. Cyclical variations in hormone levels are differentially associated with craving and relapse to smoking in women, with increases in 17β-estradiol (E2) and progesterone being associated with addiction vulnerability and resilience, respectively. Further, women can be chronically maintained on synthetic hormones contained in oral contraceptives, which contain ethinyl estradiol (EE), a synthetic, orally bio-available estrogen, and a synthetic progesterone, termed “progestins”. EE is more potent and bioavailable than the endogenous E2, and women are prescribed EE during critical periods of reproductive development in adolescence and young adulthood. Further, progestins such as levonorgestrel (LEVO) or norethisterone acetate (NETA) can have either beneficial or potentially deleterious effects on women. Despite this, there are no studies to date that have examined the impact of these synthetic hormones on nicotine neurobehavioral outcomes in females. Nicotine produces cellular adaptations such as changes in synaptic plasticity in brain regions associated with drug reward, especially within the nucleus accumbens core (NAcore). Mechanistically, the E2 receptors (ERs) are located on medium spiny neurons (MSNs) within the NAcore, which we show undergo hormone-dependent changes in synaptic plasticity (measured via the ratio of AMPA to NMDA currents) following nicotine self-administration (SA). Further, we show that EE alone partially rescues ovariectomy-induced decreases in nicotine consumption and demand, and LEVO decreases nicotine consumption during SA as compared to EE+LEVO treatment in ovary-intact females. Here, we will systematically evaluate the contributions of two different progestins, LEVO or NETA, to nicotine demand and NAcore glutamate plasticity either independently or interactively with EE in ovary-intact females. Specifically, Aims 1a and 1b will focus on LEVO, whereas Aims 2a and 2b will focus on NETA. We hypothesize that these two progestins will differentially impact nicotine demand and glutamate plasticity, such that LEVO alone will reduce nicotine demand and increase AMPA/NMDA ratios and NETA alone will increase nicotine demand and decrease AMPA/NMDA ratios. We hypothesize that when combined with EE, the protective effects of LEVO will be occluded. Further, we hypothesize that EE+NETA will enhance nicotine demand and further decrease AMPA/NMDA ratios, thus exacerbating the neurobehavioral outcomes associated with nicotine use. These studies will systematically evaluate the contributions of exogenous synthetic hormones contained in oral contraceptives to nicotine use and will uncover unknown consequences on neural circuitry. Findings from this R21 will lay a foundation for a future R01 application to further delve into examination of progestins contained in various other contraceptive formulations. Together, these studies may provide insight into conditions that impact reproductive cycles, which will allow a mechanistic understanding of nicotine use motivation in women.