Effects of circulating estradiol on physiological, behavioural, and subjective correlates of anxiety: A double-blind, randomized, placebo-controlled trial.

Anxiety-related behaviours as well as the prevalence of anxiety disorders show a large sex difference in humans. Clinical studies in humans as well as behavioural studies in rodents suggest that estradiol may have anxiolytic properties. In line with this, anxiety symptoms fluctuate with estradiol levels along the menstrual cycle. However, the influence of estradiol on subjective, behavioural, as well as physiological correlates of anxiety has never been systematically addressed in humans. We ran a double-blind, randomized, placebo-controlled study (N = 126) to investigate the effects of estradiol on anxiety in men and women. In healthy volunteers, circulating estradiol levels were elevated through estradiol administration over two consecutive days to simulate the rise in estradiol levels around ovulation. Subjective, behavioral, as well as, physiological correlates of anxiety were assessed using a virtual reality elevated plus-maze (EPM). Estradiol treatment reduced the physiological stress response with blunted heart rate response and lower cortisol levels compared to placebo treatment in both sexes. In contrast, respiration frequency was only reduced in women after estradiol treatment. Behavioural measures of anxiety as well as subjective anxiety on the EPM were not affected by estradiol treatment. In general, women showed more avoidance and less approach behavior and reported higher subjective anxiety levels on the EPM than men. These results highlight the limited anxiolytic properties of circulating levels of estradiol in humans, which influence physiological markers of anxiety but not approach and avoidance behaviour or subjective anxiety levels.

An elevated plus-maze in mixed reality for studying human anxiety-related behavior.

BACKGROUND: A dearth of laboratory tests to study actual human approach-avoidance behavior has complicated translational research on anxiety. The elevated plus-maze (EPM) is the gold standard to assess approach-avoidance behavior in rodents. METHODS: Here, we translated the EPM to humans using mixed reality through a combination of virtual and real-world elements. In two validation studies, we observed participants' anxiety on a behavioral, physiological, and subjective level. RESULTS: Participants reported higher anxiety on open arms, avoided open arms, and showed an activation of endogenous stress systems. Participants' with high anxiety exhibited higher avoidance. Moreover, open arm avoidance was moderately predicted by participants' acrophobia and sensation seeking, with opposing influences. In a randomized, double blind, placebo controlled experiment, GABAergic stimulation decreased avoidance of open arms while alpha-2-adrenergic antagonism increased avoidance. CONCLUSION: These findings demonstrate cross-species validity of open arm avoidance as a translational measure of anxiety. We thus introduce the first ecologically valid assay to track actual human approach-avoidance behavior under laboratory conditions.