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

项目摘要/摘要 女性比男性更难实现长期戒烟，超过17万女性 每年在美国死于与吸烟有关的并发症。激素水平的周期性变化是 在女性中，17β-雌二醇(E_2)和17-雌二醇(E_2)的升高与渴望和复吸有不同的关系 黄体酮分别与成瘾易感性和韧性有关。此外，女性还可以 长期依赖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用雌激素，以及一种被称为“孕激素”的合成孕酮。Ee是更多 强效和生物利用度高于内源性E2，女性在关键时期服用EE 青春期和青春期的生殖发育。此外，孕激素，如左旋诺孕酮 (LEVO)或乙酸炔诺酮(NETA)对女性既有有益的影响，也有潜在的有害影响。 尽管如此，到目前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，如突触的变化 与药物奖赏相关的大脑区域的可塑性，特别是伏隔核核心(NAcore)。 从机制上讲，E2受体(ER)位于NAcore内的中等棘神经元(MSN)上，NAcore内的MSN 我们发现在突触可塑性中经历了激素依赖性的改变(通过AMPA/NMDA的比率来测量 电流)后，尼古丁自我给药(SA)。进一步地，我们证明了单独的EE部分地拯救了 卵巢切除导致尼古丁消费和需求减少，Levo减少尼古丁 卵巢完整的女性在SA和EE Levo治疗期间的消耗量比较。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 在卵巢完整的雌性中，可塑性与EE独立或交互作用。具体而言，目标1a和1b将 专注于Levo，而目标2a和2b将专注于Neta。我们假设这两种孕激素会 对尼古丁需求和谷氨酸可塑性有不同的影响，因此Levo本身将减少尼古丁需求 增加AMPA/NMDA比率和单独使用NTA将增加尼古丁需求，降低AMPA/NMDA 比率。我们推测，当与EE结合时，Levo的保护作用将被阻断。此外， 我们假设EE Neta将增加尼古丁需求，并进一步降低AMPA/NMDA比率，因此 加剧与尼古丁使用相关的神经行为后果。这些研究将系统地 评估口服避孕药中含有的外源合成激素对尼古丁使用的贡献 将揭示神经回路上的未知后果。R21的发现将为未来奠定基础 R01申请进一步深入检查各种其他避孕药中所含的孕激素 配方。总之，这些研究可能提供对影响生殖周期的条件的洞察，这些条件 将允许对女性使用尼古丁的动机进行机械性的理解。

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.