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

项目总结/摘要 长期戒烟在女性比男性更难实现，超过17万女性 在美国，每年有1000人死于与吸烟有关的并发症。激素水平的周期性变化 不同程度地与女性吸烟的渴望和复发相关，17 β-雌二醇（E2）和 孕酮分别与成瘾脆弱性和恢复力相关。此外，妇女可以 长期服用口服避孕药中含有的合成激素，其中含有乙炔雌二醇 (EE)一种合成的口服生物可利用的雌激素，和一种合成的孕酮，称为“孕激素”。EE更多 比内源性E2更有效且生物利用度更高，女性在生育的关键时期服用EE 青春期和青年期的生殖发育。此外，孕激素如左炔诺孕酮 （LEVO）或醋酸炔诺酮（NETA）可能对女性产生有益或潜在的有害影响。 尽管如此，迄今为止还没有研究检查这些合成激素对尼古丁的影响 女性的神经行为结果。尼古丁产生细胞适应性变化，如突触 与药物奖励相关的大脑区域的可塑性，特别是在核内的神经元核心（NAcore）。 从机制上讲，E2受体（ER）位于NAcore内的中型棘神经元（MSN）上， 我们发现，在突触可塑性方面，（通过AMPA与NMDA的比率测量） 电流）。此外，我们表明，EE单独部分拯救 卵巢切除导致尼古丁消耗和需求减少，LEVO降低尼古丁 在卵巢完整雌性中，与EE + LEVO治疗相比，SA期间的消耗量。在这里，我们将系统地 评估两种不同的孕激素，LEVO或NETA，对尼古丁需求和NAcore谷氨酸的贡献 可塑性，无论是独立或交互与EE卵巢完整的女性。具体而言，目标1a和1b将 目标2a和2b将侧重于NETA。我们假设这两种孕激素 差异影响尼古丁需求和谷氨酸可塑性，因此LEVO单独使用将降低尼古丁需求 增加AMPA/NMDA比值，单独使用NETA会增加尼古丁需求，降低AMPA/NMDA比值， 比率。我们假设，当与EE联合使用时，LEVO的保护作用将被阻断。此外，本发明还 我们假设EE + NETA将增加尼古丁需求，并进一步降低AMPA/NMDA比值， 加剧与尼古丁使用相关的神经行为结果。这些研究将系统地 评价口服避孕药中所含的外源性合成激素对尼古丁使用的影响， 将揭示对神经回路的未知影响这次R21的发现将为未来奠定基础 R01申请进一步研究多种其他避孕药所含的孕激素 制剂。总之，这些研究可以提供对影响生殖周期的条件的深入了解， 将允许对女性尼古丁使用动机的机械理解。

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.