Influence of synthetic sex hormones on methamphetamine effects and self-administration in women

合成性激素对女性甲基苯丙胺效果和自我给药的影响

• 批准号: 10608855
• 负责人: EMMA CHILDS
• 金额: $ 23.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608855
• 关键词: Acute; Address; Age; Area; Biological Availability; Blood specimen; Brain; Clinical Data; Clinical Research; Data; Dependence; Development; Dopamine Agonists; Drug Addiction; Drug Use Disorder; Drug abuse; Drug usage; Estrogens; Ethinyl Estradiol; Ethinyl Estradiol/Levonorgestrel; Exhibits; Female; Goals; Gonadal Steroid Hormones; Hormonal; Hormones; Individual; Knowledge; Laboratories; Levonorgestrel; Life; Luteal Phase; Mediating; Menstrual cycle; Methamphetamine; Methamphetamine use disorder; Midbrain structure; Mission; Motivation; National Institute of Drug Abuse; Neurobiology; Noise; Oral; Oral Contraceptives; Ovarian hormone; Participant; Pharmaceutical Preparations; Phase; Predisposition; Prevention; Prevention approach; Progesterone; Progestins; Psychological reinforcement; Public Health; Research; Rewards; Role; Route; Schedule; Science; Self Administration; Sex Differences; Signal Transduction; Stimulant; Strategic Planning; Study Subject; Synthetic Progestogens; System; Testing; United States National Institutes of Health; Woman; Women' s Health; Work; abuse liability; addiction; antagonist; capsule; clinically significant; dopamine system; drug reward; efficacious treatment; experience; female sex hormone; gender difference; hormonal contraception; improved; innovation; inter-individual variation; interest; men; methamphetamine effect; methamphetamine use; novel; overdose death; pill; pre-clinical; proliferative phase Menstrual cycle; reproductive; response; reward processing; sex; sigma-1 receptor; stimulant use disorder; therapy development; willingness; young adult

There are well-known sex differences in methamphetamine use disorder (MUD); women initiate use at an earlier age, transition to dependence faster, and exhibit a more severe course of addiction than men. Historically, men have used methamphetamine (MA) at higher rates than women, however this is no longer true among young adults under age 25. Data also show significant increases in MA use among women over age 25 and a five-fold increase in MA- associated overdose deaths in recent years. Thus, there is an urgent need to understand why women are vulnerable to MA use to improve women’s public health. Cyclical fluctuations in female sex hormones are one factor that contributes to sex differences in MUD; estrogen (E2) promotes while progesterone (P4) dampens sensitivity of brain dopamine systems to dopamine agonists (MA). So, clinical studies have probed the efficacy of P4 as a potential treatment for stimulant use disorders in women but with equivocal findings. However, few studies have assessed the influence of synthetic ovarian hormones e.g., progestins, the active component of hormonal contraceptive medications, on sensitivity to stimulant drug reward. This is surprising since a majority of US women use oral contraceptives (birth control pill, BCP) at some point in their reproductive life and the effects of E2 and P4 on brain neurobiology and drug effects are well documented. The long-term goal of this research is to fill the knowledge gap of how synthetic ovarian hormones influence MA effects and use. The first step toward this goal is to systematically determine how synthetic ovarian hormones influence the rewarding and motivational effects of MA in a controlled laboratory setting. The objective of this study is to determine how BCP influences MA subjective experiences and motivation for MA. The rationale is that vital data of how synthetic hormones influence the abuse potential of MA will inform novel women-focused prevention and treatment approaches. The working hypothesis is that progestin mimics the effects of P4 and blunts the rewarding subjective effects of MA and motivation to obtain MA. This hypothesis is based upon the existing preclinical and clinical data of P4 effects on stimulant drug reward and also pilot data from the PI’s lab. The specific aims are: 1) To determine the subjective rewarding effects of MA and motivation to obtain MA among women using BCP tested during active pill weeks vs. inactive pill weeks, in comparison to naturally cycling women tested at two phases of the menstrual cycle, 2) To determine how circulating natural and synthetic hormones are related to the rewarding subjective effects and motivational effects of MA. This research is significant because it will provide fundamental knowledge of how synthetic ovarian hormones influence responses to MA in women. The results will be clinically significant as they apply to a substantial proportion of US women who currently use BCP or cycle naturally. This study is innovative because it is the first systematic study of how natural and synthetic ovarian hormones influence MA reward and motivation, and shifts the focus of clinical research on sex differences in MUD from the effects of natural hormones to synthetic hormones. Finally, positive findings that high stable levels of synthetic progestin blunt MA reward will provide a framework for the development of therapies focused on female mechanisms.

甲基苯丙胺使用障碍（泥）存在众所周知的性别差异；妇女在更早的年龄开始使用，过渡到依赖性更快，并且比男性更加严重地成瘾。从历史上看，男性以高于女性的速率使用甲基苯丙胺（MA），但是在25岁以下的年轻人中，这种情况不再是正确的。数据还显示，在25岁以上的女性中，MA使用率显着增加，并且近年来MA相关的过量死亡人数增加了5倍。因此，迫切需要了解为什么妇女容易受到改善妇女公共卫生的影响。女性马匹的周期性波动是导致性别差异的一个因素。雌激素（E2）促进孕酮（P4）会抑制脑多巴胺系统对多巴胺激动剂（MA）的敏感性。因此，临床研究证明了P4作为女性刺激使用障碍的潜在治疗方法，但具有模棱两可的发现。但是，很少有研究评估合成卵巢马的影响，例如孕激素，是激素避孕药的活性成分对刺激药物奖励的敏感性。这是令人惊讶的，因为我们大多数女性在生殖生活中的某个时候使用口服避孕药（BCP），并且有充分的记录E2和P4对脑神经生物学和药物作用的影响。这项研究的长期目标是填补合成卵巢训练如何影响MA效应和使用的知识差距。朝着这一目标迈进的第一步是系统地确定合成卵巢训练如何影响MA在受控实验室环境中的有意义和动机效应。这项研究的目的是确定BCP如何影响MA的主观经验和MA的动机。理由是，合成性人物如何影响MA的滥用潜力的重要数据将为新颖以女性为中心的预防和治疗方法提供信息。工作假设是孕激素模仿了P4的影响，并钝化了MA的主观效果和获得MA的动机。该假设基于P4对刺激药物奖励的影响的现有临床前和临床数据，也基于PI实验室中的PILOT数据。具体目的是：1）确定MA的主观奖励效果和在活跃药物周中使用BCP测试的BCP在几周中测试的BCP的动机的主观奖励效果，而不是在月经周期的两个阶段进行的自然循环妇女，2）以确定与循环的自然和合成骑士的循环自然和合成的骑士有关的主体效果和动力效果与MA的动力效应和动力效应。这项研究很重要，因为它将提供有关合成卵巢激素如何影响女性反应的基本知识。结果将在临床上具有重要意义，因为它们适用于当前使用BCP或自然循环的美国妇女中很大一部分。这项研究具有创新性，因为它是对自然和合成卵巢骑马如何影响MA奖励和动机的首次系统研究，并将临床研究的重点转移到了泥浆中的性别差异的重点从天然骑兵的影响到合成骑马。最后，积极的发现，高稳定水平的合成孕激素钝器MA奖励将为开发专注于女性机制的疗法提供一个框架。