Synaptic Actions of Estradiol in the Brain's Reward System: Linking Mechanisms to Behavior and Disease

Sex differences in reward processing contribute to divergent patterns of psychiatric susceptibility, with depression affecting women at twice the rate of men and women showing accelerated progression to substance use disorders (SUDs). Increased risk observed for SUDs in women correlates strongly with periods of significant hormone fluctuation, including puberty, postpartum, and menopause, suggesting a key role of sex hormones in modulating behavior and susceptibility. In this review, we focus on 17β-estradiol (E2) and move beyond its classical roles as a regulator of reproduction and gene expression to highlight E2 as a key neuromodulator of the reward system via membrane-associated signaling to rapidly alter neuron function and synaptic transmission in both sexes. Critically, E2's dose-dependent effects create distinct windows of susceptibility: Low E2 states impair excitatory transmission and blunt dopamine signaling, increasing susceptibility to stress-induced depression, while high E2 states enhance reward sensitivity and impair extinction learning, increasing addiction risk. These opposing effects demonstrate how hormonal fluctuations differentially modulate the risk for depression and SUDs through distinct circuit mechanisms. Understanding E2's circuit-level actions across hormonal states will be critical for developing targeted interventions for psychiatric disorders in both sexes.