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

孕激素独立和与避孕雌激素相互作用对尼古丁使用的贡献

基本信息

批准号：
10592661
负责人：
Cassandra D Gipson-Reichardt
金额：
$ 20.07万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10592661
关键词：
Acids Adolescence Affect Animals Area Automobile Driving Behavioral Brain region Caring Cells Chronic Contraceptive Agents Contraceptive Usage Data Electrophysiology (science)Estradiol Estrogens Ethinyl Estradiol Ethinyl Estradiol/Levonorgestrel Exposure to Female Formulation Foundations Future Glutamates Goals Hormone use Hormones Intravenous Levonorgestrel Measures Methods Motivation N-Methylaspartate Neurobiology Neurons Nicotine Nicotine Dependence Norethisterone Acetate Nucleus Accumbens Oral Oral Contraceptives Outcome Ovarian Ovarian hormone Ovariectomy Ovary Pathway interactions Periodicity Play Procedures Progesterone Progestins Public Health Publishing Rattus Relapse Research Rewards Role Saline Self Administration Smoke Smoking Substance Use Disorder Synaptic plasticity System Time Toxic effect Translations United States Variant Woman addiction base behavioral economics birth control cigarette craving craving critical period drug reward insight men neural circuit neurobehavioral nicotine reward nicotine use novel patch clamp prevent protective effect receptor reproductive reproductive development resilience reward circuitry smoking cessation xenoestrogen young adult

项目摘要

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.

项目概要/摘要女性比男性更难实现长期戒烟，超过 170,000 名女性在美国，每年因吸烟引起的并发症死亡人数呈周期性变化。与女性吸烟渴望和复吸存在差异性相关，其中 17β-雌二醇 (E2) 和此外，黄体酮分别与成瘾脆弱性和复原力有关。长期维持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，和一种合成的黄体酮，称为“孕激素”。与内源性 E2 相比，其效力和生物利用度更高，女性在关键时期服用 EE 此外，孕激素如左炔诺孕酮在青春期和青年期的生殖发育。（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验这些合成激素对尼古丁的影响女性的神经行为结果会产生细胞适应，例如突触的变化。与药物奖励相关的大脑区域的可塑性，特别是伏隔核核心（NAcore）内。从机制上讲，E2 受体 (ER) 位于 NAcore 内的中型多棘神经元 (MSN) 上，我们发现突触可塑性发生了激素依赖性变化（通过 AMPA 与 NMDA 的比率来测量）尼古丁自我给药（SA）后的电流）此外，我们表明单独使用 EE 可以部分缓解。卵巢切除术导致尼古丁消耗和需求减少，LEVO 减少尼古丁在这里，我们将系统地比较卵巢完整的女性在 SA 期间的消耗量与 EE+LEVO 治疗的情况。评估两种不同孕激素 LEVO 或 NETA 对尼古丁需求和 NAcore 谷氨酸的贡献具体而言，目标 1a 和 1b 将独立或与 EE 相互作用地影响卵巢完整的雌性。重点关注 LEVO，而目标 2a 和 2b 将重点关注 NETA，我们努力争取这两种孕激素。对尼古丁需求和谷氨酸可塑性的影响不同，因此仅 LEVO 就可以减少尼古丁需求并增加 AMPA/NMDA 比率，仅 NETA 就会增加尼古丁需求并减少 AMPA/NMDA 我们认为，当与 EE 结合使用时，LEVO 的保护作用将会被阻断。我们追求EE+NETA将增加尼古丁需求并进一步降低AMPA/NMDA比率，从而这些研究将系统地加剧与尼古丁使用相关的神经行为结果。评估口服避孕药中所含的外源合成激素对尼古丁使用的贡献，以及将揭示对神经回路的未知影响 R21 的发现将为未来奠定基础。 R01应用进一步深入研究各种其他避孕药中所含孕激素的检查总之，这些研究可以提供对影响生殖周期的条件的深入了解。将使人们对女性使用尼古丁的动机有一个机械的理解。