Linkages between ovarian hormones and affective dysfunction with alcohol use, reward and reinforcement

项目概要/摘要 情绪障碍（例如焦虑、压力和抑郁症）与饮酒高度共存 障碍，尤其是女性。情绪障碍的一个核心特征是情感功能障碍，这可能是 广泛地概念化为：高度的情绪困扰、对这种痛苦的反应性增强以及有限的 能够利用适应性策略灵活调节情绪反应和/或维持行为 控制。情感功能障碍会增加对酒精的渴望和奖励（即积极的酒精强化）， 这种效应在女性中增强，并且是负强化饮酒动机的关键驱动因素（例如， 依赖酒精来缓解痛苦）。卵巢激素（雌二醇、黄体酮）是一种新型的性别特异性激素 女性酒精强化和情感功能的生物标志物。雌二醇似乎可以增强酒精含量 当黄体酮较低时（即早中期卵泡期），以及雌二醇和雌激素水平下降时，会加强 黄体酮会增加情感功能障碍（即黄体期晚期）的风险。于是，频繁 月经周期期间雌二醇和孕酮的波动可能会导致间歇性月经周期 加剧负面情绪和痛苦，并耗尽适应性情绪调节能力，这可能会使 女性特别容易受到负强化饮酒的影响。然而，现有的工作几乎已经 尽管有强有力的证据表明黄体酮在情感功能障碍中的作用，但仅关注雌二醇， 酒精强化的核心驱动力。此外，现有研究因测量不频繁而受到限制 卵巢激素或依赖月经阶段作为客观激素测量的代理，这 限制了关于卵巢激素的变化或波动如何与情感酒精相关的知识的精确性 联系。因此，拟议的研究是对 72 名患有重度重度血脂的生物学女性进行的观察性受试者内测试。 饮酒（18-40 岁），月经周期正常（25-35 天），未因激素避孕药改变。结束 在整个月经周期的过程中，每天将收集唾液样本以直接评估黄体酮和 雌二醇，并将与情感功能障碍的每日生态瞬时评估（EMA）配对， 女性在自然环境中“实时”报告的饮酒情况和酒精奖励。的目标 这项研究的目的是评估女性在生育过程中唾液雌二醇和黄体酮的每日波动 完整的月经周期及其对 (a) 日常情感过程和 (b) 酒精强化的影响 探讨饮酒对这些关联的调节作用。另一个探索性目标是 探索情感过程是否介导卵巢激素和酒精强化之间的联系 （即前馈关联）。这项研究有可能改善女性的治疗决策 在月经周期期间大量饮酒，包括在月经周期进行干预时，最终导致 最需要特定干预的人（例如患有情绪障碍的女性）。

PROJECT SUMMARY/ABSTRACT Emotional disorders (e.g., anxiety, stress, and depressive disorders) are highly comorbid with alcohol use disorder, particularly in females. A core feature of emotional disorders is affective dysfunction, which can be broadly conceptualized as: high levels of emotional distress, heightened reactivity to this distress, and limited ability to utilize adaptive strategies to flexibly modulate the emotional response and/or maintain behavioral control. Affective dysfunction heightens alcohol craving and reward (i.e., positive alcohol reinforcement), effects that are potentiated in females, and is a key driver of negative-reinforcement drinking motivation (e.g., reliance on alcohol to alleviate distress). Ovarian hormones (estradiol, progesterone) are a novel sex-specific biomarker of alcohol reinforcement and affective functioning in females. Estradiol appears to enhance alcohol reinforcement when progesterone is low (i.e., early-mid follicular phase), and declining levels of estradiol and progesterone increase risk for heighted affective dysfunction (i.e., late luteal phase). Thus, frequent fluctuations in estradiol and progesterone during the menstrual cycle may contribute to intermittent periods of exacerbated negative affect and distress, and deplete adaptive emotion regulation abilities, which may make females especially vulnerable to negative-reinforcement drinking. However, existing work has almost exclusively focused on estradiol, despite robust evidence for the role of progesterone in affective dysfunction, a core driver of alcohol reinforcement. Moreover, existing studies have been limited by infrequent measurement of ovarian hormones or reliance of menstrual phases as a proxy for objective hormone measurement, which limits precision in knowledge about how changes or fluctuations in ovarian hormones relate to affect-alcohol linkages. Thus, the proposed study is an observational within-subjects test of 72 biological females with heavy drinking (ages 18-40) with a normal menstrual cycle (25-35 days), not altered by hormonal contraceptive. Over the course of a full menstrual cycle, daily saliva samples will be collected to directly assess progesterone and estradiol, and will be paired with daily ecological momentary assessment (EMA) of affective dysfunction, alcohol use, and alcohol reward reported in “real-time” from females in their natural environments. The aims of this study are to evaluate daily fluctuations in salivary estradiol and progesterone over the course of a female’s complete menstrual cycle and its effect on (a) daily affective processes and (b) alcohol reinforcement as well as to explore the moderating role of alcohol use on these associations. An additional exploratory aim is to explore whether affective processes mediate the link between ovarian hormones and alcohol reinforcement (i.e., feed-forward associations). This study has the potential to improve treatment decision-making for females with heavy drinking around their menstrual cycle, including when in their cycle to intervene, and eventually, for whom specific intervention is most needed (e.g., women with emotional disorders).