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

众所周知，甲基苯丙胺使用障碍(MUD)存在性别差异；女性开始使用甲基苯丙胺的年龄更早，转化为依赖的速度更快，表现出比男性更严重的成瘾过程。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岁以下的年轻人中则不再是这样。数据还显示，25岁以上女性中使用MA的人数显著增加，近年来与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妇女容易受到使用MA来改善妇女公共健康的影响。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)抑制大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，但结果并不明确。然而，很少有研究评估激素避孕药的活性成分孕激素等合成卵巢激素对刺激性药物奖励敏感性的影响。这很令人惊讶，因为大多数美国女性在生殖生活的某个时候会使用口服避孕药(避孕药，BCP)，而E2和P4对大脑神经生物学和药物效应的影响也得到了很好的证明。这项研究的长期目标是填补关于合成卵巢激素如何影响MA效果和使用的知识空白。迈向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的奖励和激励效应。本研究的目的是确定BCP如何影响移动通信的主观体验和移动通信动机。其基本原理是，合成激素如何影响MA滥用潜力的关键数据将为新的以妇女为重点的预防和治疗方法提供依据。工作假设是，孕激素模仿P4的影响，削弱MA的有益主观影响和获得MA的动机。这一假设是基于现有的P4对兴奋剂药物奖励影响的临床前和临床数据，以及PI实验室的试点数据。研究的具体目的是：1)比较在月经周期的两个阶段测试的自然骑车女性和在积极服药周接受BCP测试的女性，确定MA的主观奖赏效应和获得MA的动机；2)确定循环中的自然和合成激素如何与MA的奖赏主观效应和激励效应相关。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。这一结果将具有临床意义，因为它们适用于目前使用BCP或自然循环的相当大比例的美国女性。这项研究具有创新性，因为它是第一次系统地研究自然和合成卵巢激素如何影响MA的奖励和动机，并将临床研究的重点从天然激素的影响转移到合成激素上。最后，积极的发现是，高稳定水平的合成孕激素钝化MA奖励将为以女性机制为重点的治疗方法的发展提供一个框架。

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.