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 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.
Frye
Cheryl A
CA
Department of Psychology, The University at Albany-SUNY, NY 12222, USA. cafrye@albany.edu
Koonce
Carolyn J
CJ
Edinger
Kassandra L
KL
Osborne
Danielle M
DM
Walf
Alicia A
AA
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
D000726:Androgen Antagonists; D000728:Androgens; D014151:Anti-Anxiety Agents; D047629:Estrogen Receptor beta; D018697:Nootropic Agents; D000738:Androsterone
Psychoneuroendocrinology. 2005 Jun;30(5):418-30
15721054
Clin Pharm. 1993 Sep;12(9):641-56; quiz 699-701
8306565
Pharmacol Biochem Behav. 2000 Nov;67(3):587-96
11164090
Horm Behav. 1998 Apr;33(2):85-94
9647934
Behav Neurosci. 2004 Dec;118(6):1352-64
15598144
Neuroscience. 2006;138(3):1015-20
16310318
Neurobiol Learn Mem. 2008 May;89(4):513-21
18313947
Horm Res. 2001;56 Suppl 1:86-92
11786693
Steroids. 1987 Oct-Dec;50(4-6):459-74
3332936
Neuropeptides. 2007 Jun;41(3):145-63
17420046
Brain Res. 2002 Nov 29;956(2):285-93
12445697
Neurobiol Learn Mem. 2007 Jan;87(1):78-85
16904920
Endocrinology. 2005 Jan;146(1):147-55
15471969
Neurobiol Learn Mem. 2006 Jul;86(1):35-46
16529958
Psychopharmacology (Berl). 2006 Jun;186(3):312-22
16538472
Neuropsychopharmacology. 2008 Apr;33(5):1049-61
17625503
Behav Neurosci. 2004 Apr;118(2):306-13
15113256
Aging Male. 2006 Dec;9(4):195-9
17178554
Neurobiol Learn Mem. 2008 Jul;90(1):171-7
18455450
Neuropsychopharmacology. 2006 Jun;31(6):1097-111
16554740
J Pharmacol Exp Ther. 2003 Jan;304(1):109-20
12490581
Cogn Affect Behav Neurosci. 2001 Jun;1(2):172-82
12467112
Psychopharmacol Bull. 2003;37(4):133-46
15131523
Horm Behav. 2008 May;53(5):741-52
18067894
Brain Res. 2002 May 10;935(1-2):73-80
12062475
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3996-4001
11891272
J Neuroendocrinol. 2008 Jun;20(6):866-72
18513207
Pharmacol Biochem Behav. 2003 May;75(2):473-9
12873640
Horm Behav. 2002 Dec;42(4):448-60
12488111
Cogn Affect Behav Neurosci. 2001 Dec;1(4):371-81
12467088
Psychiatr Dev. 1987 Spring;5(1):1-23
3601929
Neurobiol Learn Mem. 2006 Mar;85(2):183-91
16326119
Neurosci Lett. 1995 Apr 7;189(1):35-8
7603620
Pharmacol Biochem Behav. 2007 Feb;86(2):407-14
16916539
Mol Cell Neurosci. 1994 Dec;5(6):549-55
7704428
Neuroscience. 2006;138(3):757-64
16310315
Horm Behav. 2006 Aug;50(2):216-22
16631174
Nat Protoc. 2007;2(2):322-8
17406592
Clin Cornerstone. 2005;7 Suppl 4:S8-12
16651207
Steroids. 2008 Oct;73(9-10):997-1007
18342348
Mol Cell Endocrinol. 1986 Mar;44(3):261-70
3956856
Psychoneuroendocrinology. 2001 Oct;26(7):731-50
11500254
Psychoneuroendocrinology. 2005 Sep;30(8):762-70
15919582
Pharmacol Rev. 1998 Jun;50(2):151-96
9647865
Endocrinology. 2007 Jul;148(7):3371-82
17412808
Horm Behav. 1993 Dec;27(4):568-83
8294123
Reproduction. 2005 Jul;130(1):15-28
15985628
Behav Neurosci. 1994 Apr;108(2):325-32
8037876
Horm Behav. 2006 Jan;49(1):123-8
16026788
Behav Neurosci. 1996 Jun;110(3):603-12
8889005
Neuropsychopharmacology. 2005 Sep;30(9):1598-609
15798780
Psychoneuroendocrinology. 2003 Oct;28(7):863-74
12892654
Aging Male. 2002 Mar;5(1):47-51
12040975
Mol Neurobiol. 1988 Winter;2(4):291-317
2855977
Pharmacol Biochem Behav. 2004 Jul;78(3):473-81
15251256
Behav Brain Res. 2001 Aug 27;123(1):65-76
11377730
Biol Reprod. 1987 Oct;37(3):628-33
3676409
Pharmacol Biochem Behav. 2004 Jul;78(3):559-68
15251265
J Neurosci. 2006 Feb 1;26(5):1448-56
16452668