Androgens with activity at estrogen receptor beta have anxiolytic and cognitive-enhancing effects in male rats and mice |
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| Affiliation: | 1. Department of Psychology, The University at Albany-SUNY, USA;2. Department of Biological Sciences, The University at Albany-SUNY, USA;3. The Center for Life Sciences, The University at Albany-SUNY, USA;4. The Center for Neuroscience Research, The University at Albany-SUNY, USA;1. Reproduction, Mother and Youth Health, Centre de recherche CHU de Québec, Québec, QC, Canada;2. Department of Obstetrics/Gynecology & Reproduction, Faculty of Medicine, Université Laval, Québec, QC, Canada;3. Centre de Recherche en Biologie de la Reproduction (CRBR), Faculté de Médecine, Université Laval, Québec, QC, Canada;1. The Institute of Cancer Research, London, UK;2. The Royal Marsden NHS Foundation Trust, London, UK;1. School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK;2. School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK;3. Department of Neuroscience, Physiology and Pharmacology, University College London, London W1E 6BT, UK;4. University College London Hospital, London NW1 2BU, UK;5. Laboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo (USP), 14040-901 Ribeirão Preto, SP, Brazil;6. Instituto de Neurociências e Comportamento—INeC, Campus USP, 14040-901 Ribeirão Preto, SP, Brazil |
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| 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 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. |
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