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（MUD）存在众所周知的性别差异;女性在较早的年龄开始使用，更快地过渡到依赖，并且比男性表现出更严重的成瘾过程。从历史上看，男性使用甲基苯丙胺（MA）的比例高于女性，但在25岁以下的年轻人中不再如此。数据还显示，近年来，25岁以上妇女使用MA的人数显著增加，与MA相关的过量死亡人数增加了五倍。因此，迫切需要了解为什么女性容易受到MA使用的影响，以改善女性的公共健康。女性性激素的周期性波动是导致MUD性别差异的一个因素;雌激素（E2）促进而孕酮（P4）抑制脑多巴胺系统对多巴胺激动剂（MA）的敏感性。因此，临床研究已经探索了P4作为女性兴奋剂使用障碍的潜在治疗方法的有效性，但结果模棱两可。然而，很少有研究评估合成卵巢激素的影响，孕激素，激素避孕药的活性成分，对刺激性药物奖励的敏感性。这是令人惊讶的，因为大多数美国妇女在生育期的某个时候使用口服避孕药（避孕药，BCP），并且E2和P4对大脑神经生物学和药物作用的影响有充分的记录。这项研究的长期目标是填补合成卵巢激素如何影响MA效果和使用的知识空白。实现这一目标的第一步是在受控的实验室环境中系统地确定合成卵巢激素如何影响MA的奖励和激励作用。本研究的目的是确定BCP如何影响MA的主观经验和动机的MA。其理由是，合成激素如何影响MA滥用潜力的重要数据将为以女性为重点的新型预防和治疗方法提供信息。工作假设是，P4的效果和钝化的MA和动机，以获得MA的奖励主观效果，receistin模仿。该假设基于P4对兴奋剂药物奖励作用的现有临床前和临床数据以及PI实验室的试验数据。具体目标是：1）确定MA的主观奖励效果和动机，以获得MA的妇女使用BCP测试期间积极的药丸周与非积极的药丸周，相比，自然循环的妇女在月经周期的两个阶段测试，2）确定如何循环天然和合成激素与MA的奖励主观效果和动机效果。这项研究意义重大，因为它将为合成卵巢激素如何影响女性对MA的反应提供基础知识。结果将具有临床意义，因为它们适用于目前使用BCP或自然周期的相当大比例的美国女性。这项研究具有创新性，因为它是第一个系统研究天然和合成卵巢激素如何影响MA奖励和动机的研究，并将MUD性别差异的临床研究重点从天然激素的影响转移到合成激素。最后，积极的研究结果，高稳定水平的合成合成的抗氧化剂钝MA奖励将提供一个框架，专注于女性机制的疗法的发展。