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

• 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
• 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

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.

项目摘要/摘要 女性的长期戒烟比男性更难实现，超过170,000名女性 每年与吸烟有关的并发症死亡。激素水平的周期性变化是 与女性吸烟的渴望和继电器有关，在17β-雌二醇（E2）和 孕酮分别与成瘾脆弱性和韧性相关。此外，女人可以 在口服避孕药中包含的合成恐怖片长期维护，其中含有乙基雌二醇 （EE），一种合成的，口服生物可用的雌激素和一种合成孕酮，称为“孕激素”。 EE更多 潜在的和生物利用的E2比内源性E2，在关键时期开处方EE 青少年和成年时期的生殖发展。此外，孕激素（例如左甲虫 （LEVO）或乙酸盐（Neta）可能对妇女产生有益或潜在删除的影响。 尽管如此，迄今为止尚无研究检查这些合成恐怖对尼古丁的影响 女性的神经行为结局。尼古丁会产生细胞适应性，例如突触的变化 与药物奖励相关的大脑区域的可塑性，尤其是在伏隔核（Nacore）中。 从机械上讲，E2受体（ERS）位于纳索尔内的中棘神经元（MSN）上，该神经元（MSN） 我们显示出突触可塑性的依赖性变化（通过AMPA与NMDA的比率测量 电流）尼古丁自我管理（SA）。此外，我们表明单独的EE部分回应 卵巢切除术引起的尼古丁消耗和需求下降，Levo降低了尼古丁 与卵巢直觉女性的EE+LEVO治疗相比，SA期间的消耗。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 可塑性是独立或与卵巢独立雌性中的EE交互式的。具体而言，目标1a和1b将 专注于Levo，而Aims 2A和2B将专注于Neta。我们假设这两个孕激素将 差异影响尼古丁的需求和谷氨酸可塑性，因此仅LEVO将减少尼古丁的需求 并增加AMPA/NMDA比率，仅NETA将增加尼古丁的需求并减少AMPA/NMDA 比率。我们假设在与EE结合使用时，LEVO的受保护作用将被遮挡。更远， 我们假设EE+Neta将增强尼古丁的需求并进一步降低AMPA/NMDA比率，从而 加剧与尼古丁使用相关的神经行为结局。这些研究将系统地 评估口服避孕药中包含的外源合成恐怖的贡献， 将发现对神经回路的未知后果。 R21的发现将为未来奠定基础 R01的应用进一步研究了其他各种避孕药中包含的孕激素 公式。这些研究共同可以洞悉影响复制循环的条件，这是 将允许对女性尼古丁使用动机的机械理解。