title: Androgens with activity at estrogen receptor beta have anxiolytic and cognitive-enhancing effects in male rats and mice.
abstract: 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 5alpha-androstane,3alpha,17beta-diol (3alpha-diol) and/or 5alpha-androstane-3beta,17beta-diol (3beta-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 (ERbeta; 3alpha-diol, 3beta-diol), or GABA(A)/benzodiazepine receptors (GBRs; 3alpha-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 ERbeta. Experiment 1: Gonadectomized (GDX) wildtype and ERbeta knockout mice (betaERKO) were subcutaneously (SC) administered 3alpha-diol, 3beta-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 3alpha-diol, 3beta-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 betaERKO 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 ERbeta may be required for T's anxiety-reducing and cognitive-enhancing effects.
authors.affiliation: Department of Psychology, The University at Albany-SUNY, NY 12222, USA. cafrye@albany.edu
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Frye
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Koonce
authors.forename: Kassandra L
authors.initials: KL
authors.lastname: Edinger
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Osborne
authors.forename: Alicia A
authors.initials: AA
authors.lastname: Walf
mesh_terms: D000221:Adaptation, Ocular / Q000187:drug effects / Q000502:physiology; D000223:Adaptation, Psychological / Q000502:physiology; D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology*; D000738:Androsterone / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000503:physiopathology; D001921:Brain / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018697:Nootropic Agents / Q000494:pharmacology*; D010364:Pattern Recognition, Visual / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D014151:Anti-Anxiety Agents; D047629:Estrogen Receptor beta; D018697:Nootropic Agents; D000738:Androsterone
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