Androgens with activity at estrogen receptor beta have anxiolytic and cognitive-enhancing effects in male rats and mice

Testosterone (T) and its metabolites may underlie some beneficial effects for anxiety and cognition, but the mechanisms for these effects are unclear. T is reduced to dihydrotestosterone (DHT), which can be converted to 5α-androstane,3α,17β-diol (3α-diol) and/or 5α-androstane-3β,17β-diol (3β-diol). Additionally, T can be converted to androstenedione, and then to androsterone. These metabolites bind with varying affinity to androgen receptors (ARs; T and DHT), estrogen receptors (ERβ; 3α-diol, 3β-diol), or GABAA/benzodiazepine receptors (GBRs; 3α-diol, androsterone). Three experiments were performed to investigate the hypothesis that reduced anxiety-like and enhanced cognitive performance may be due in part to actions of T metabolites at ERβ. Experiment 1: Gonadectomized (GDX) wildtype and ERβ knockout mice (βERKO) were subcutaneously (SC) administered 3α-diol, 3β-diol, androsterone, or oil vehicle at weekly intervals, and tested in anxiety tasks (open field, elevated plus maze, light–dark transition) or for cognitive performance in the object recognition task. Experiment 2: GDX rats were administered SC 3α-diol, 3β-diol, androsterone, or oil vehicle, and tested in the same tasks. Experiment 3: GDX rats were androsterone- or vehicle-primed and administered an antagonist of ARs (flutamide), ERs (tamoxifen), or GBRs (flumazenil), or vehicle and then tested in the elevated plus maze. Both rats and wildtype mice, but not βERKO mice, consistently had reduced anxiety and improved performance in the object recognition task. Androsterone was only effective at reducing anxiety-like behavior in the elevated plus maze and this effect was modestly reduced by flumazenil administration. Thus, actions at ERβ may be required for T's anxiety-reducing and cognitive-enhancing effects.