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

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).