Cyclical alcohol craving is linked with estradiol-based modulation of ventral tegmental area functional connectivity and is blunted by childhood maltreatment

BACKGROUND: Estradiol (E2) is associated with enhanced alcohol-related reward. Childhood maltreatment may potentiate its effects, particularly in women. There is a gap in the literature exploring the mechanistic effects of E on alcohol use and reward neurocircuitry, particularly in trauma-exposed women. We hypothesized that women would show an increase in alcohol use and craving immediately before ovulation, exacerbated by childhood maltreatment, and stronger effects of exogenous E2 on reward circuits. METHODS: Participants were n=91 largely trauma-exposed, naturally cycling women characterized by low alcohol use and craving, recruited from the greater Atlanta area, enrolled in a randomized double-blind within-subjects crossover clinical trial of transdermal E2 as part of the Grady Trauma Project. Participants rated their alcohol use and craving nightly over the course of a full menstrual cycle, using ecological momentary assessment (1,765 responses). Interacting effects of childhood maltreatment and menstrual cycle phase on alcohol use and craving were modeled using zero-inflated Poisson regressions. A subset was then randomized to receive transdermal E2 or placebo during resting state fMRI and crossed over to the other condition on a subsequent cycle (n=49). RESULTS: Findings supported a preovulatory increase in alcohol craving (β=0.63, p=0.03). An increase around ovulation was blunted in women with higher childhood maltreatment, among whom ovulatory alcohol craving decreased (β=-0.05, p=0.02). Exogenous E2 administration produced changes in resting-state functional connectivity between the VTA and insula among participants who exhibited cycle-dependent alcohol craving. CONCLUSIONS: Findings suggest that the endogenous preovulatory E2 peak enhances alcohol craving, but that childhood maltreatment may blunt this effect. Neuroendocrine Risk for PTSD in Women, https://clinicaltrials.gov/study/NCT03973229, NCT03973229.