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

项目总结/摘要 情绪障碍（例如，焦虑、压力和抑郁症）与饮酒高度共病 疾病，尤其是女性。情绪障碍的一个核心特征是情感功能障碍， 广义上的概念是：高水平的情绪困扰，对这种困扰的反应增强， 能够利用适应性策略灵活地调节情绪反应和/或维持行为 控制情感功能障碍加剧了对酒精的渴望和奖励（即，正酒精强化）， 在女性中增强的效果，并且是负强化饮酒动机的关键驱动因素（例如， 依赖酒精来减轻痛苦）。卵巢激素（雌二醇、孕酮）是一种新的性别特异性 酒精强化和女性情感功能的生物标志物。酒精似乎可以增强酒精 孕酮低时的强化（即，卵泡早期-中期），雌二醇水平下降， 孕酮增加了情感功能障碍的风险（即，黄体晚期）。因此，频繁 在月经周期中雌二醇和孕酮的波动可能会导致间歇性的 加重负面情绪和痛苦，耗尽适应性情绪调节能力，这可能使 女性尤其容易受到负面强化饮酒的影响。然而，现有的工作几乎 专门关注雌二醇，尽管有强有力的证据表明孕酮在情感功能障碍中的作用， 酒精强化的核心驱动力。此外，现有的研究受到不频繁测量的限制 卵巢激素或依赖月经期作为客观激素测量的代表， 限制了关于卵巢激素变化或波动与酒精影响的知识的精确性 联动因此，拟议的研究是对72名患有重度抑郁症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），未被激素避孕药改变。超过 在整个月经周期的过程中，每天收集唾液样本以直接评估孕酮， 雌二醇，并将与情感功能障碍的每日生态瞬时评估（EMA）配对， 酒精使用和酒精奖励报告在“实时”从女性在其自然环境。的目的 这项研究是为了评估在女性的月经周期中唾液雌二醇和孕酮的每日波动， 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 以探索酒精使用对这些协会的调节作用。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 (i.e.,前馈关联）。这项研究有可能改善女性的治疗决策 在月经周期前后大量饮酒，包括在月经周期中进行干预，最终， 最需要哪些特定干预（例如，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).