Chronic exposure to anabolic androgenic steroids alters neuronal function in the mammalian forebrain via androgen receptor- and estrogen receptor-mediated mechanisms.
Anabolic androgenic steroids (AAS) can promote detrimental effects on social behaviors for which GABA type A (GABA(A)) receptor-mediated circuits in the forebrain play a critical role. While all AAS bind to androgen receptors (AR), they may also be aromatized to estrogens and thus potentially impart effects via estrogen receptors (ER). Chronic exposure of wild-type male mice to a combination of chemically distinct AAS increased action potential (AP) frequency, selective GABA(A) receptor subunit mRNAs, and GABAergic synaptic current decay in the medial preoptic area (mPOA). Experiments performed with pharmacological agents and in AR-deficient Tfm mutant mice suggest that the AAS-dependent enhancement of GABAergic transmission in wild-type mice is AR-mediated. In AR-deficient mice, the AAS elicited dramatically different effects, decreasing AP frequency, spontaneous IPSC amplitude and frequency and the expression of selective GABA(A) receptor subunit mRNAs. Surprisingly, in the absence of AR signaling, the data indicate that the AAS do not act as ER agonists, but rather suggest a novel in vivo action in which the AAS inhibit aromatase and impair endogenous ER signaling. These results show that the AAS have the capacity to alter neuronal function in the forebrain via multiple steroid signaling mechanisms and suggest that effects of these steroids in the brain will depend not only on the balance of AR- versus ER-mediated regulation for different target genes, but also on the ability of these drugs to alter steroid metabolism and thus the endogenous steroid milieu.
Penatti
Carlos A A
CA
Department of Physiology, Dartmouth Medical School, Hanover, NH 03755, USA.
Porter
Donna M
DM
Henderson
Leslie P
LP
D000200:Action Potentials / Q000187:drug effects; D045930:Anabolic Agents / Q000008:administration & dosage; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000008:administration & dosage; D000818:Animals; D047072:Aromatase Inhibitors / Q000494:pharmacology; D004338:Drug Combinations; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008297:Male; D008777:Methyltestosterone / Q000008:administration & dosage*; D051379:Mice; D008822:Mice, Transgenic; D009277:Nandrolone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077603:Nandrolone Decanoate; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011301:Preoptic Area / Q000166:cytology / Q000187:drug effects*; D011944:Receptors, Androgen / Q000008:administration & dosage / Q000172:deficiency; D011960:Receptors, Estrogen / Q000378:metabolism*; D018079:Receptors, GABA / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D013739:Testosterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism
D045930:Anabolic Agents; D059002:Androgen Receptor Antagonists; D000728:Androgens; D047072:Aromatase Inhibitors; D004338:Drug Combinations; D004967:Estrogens; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D018079:Receptors, GABA; D013739:Testosterone; D004958:Estradiol; D009277:Nandrolone; D000077603:Nandrolone Decanoate; C016131:testosterone 17 beta-cypionate; D008777:Methyltestosterone