title: Direct effects of the anabolic/androgenic steroids, stanozolol and 17 alpha-methyltestosterone, on benzodiazepine binding to the. gamma-aminobutyric acid(a) receptor.
abstract: Various exogenous and endogenous steroids have been demonstrated to have both enhancing and inhibiting effects on ligand binding to the gamma-aminobutyric acid(A) receptor (GABAA receptor) in previous studies. In the present study we have explored the possibility that an additional class of synthetic steroidal compounds, anabolic/androgenic steroids (AAS), mediate some of their CNS effects through direct interaction with the GABAa receptor. At micromolar concentrations, two AAS, stanozolol and 17 alpha-methyltestosterone (17 alpha-MT), significantly inhibited 1 nM [3H]flunitrazepam ([3H]Fln) binding to rat brain cerebrocortical membranes. Inhibition of 1 nM [3H]Fln binding by stanozolol was similar for both males and females (approximately 50% inhibition at 50 microM stanozolol). 17 alpha-MT was much less efficacious, but did significantly inhibit 1 nM [3H]Fln binding at concentrations > 10 microM. In equilibrium binding assays, stanozolol (50 microM) raised the apparent KD for [3H]Fln binding. The observed changes in the [3H]Fln binding curve, when analyzed by Rosenthal analysis, reveal complex equilibrium binding behavior. In females, the Rosenthal plot was best fit by a two site binding model. Stanozolol (50 microM) inhibited binding to the higher affinity site in a manner consistent with competitive inhibition, increasing the KD without changing the BMAX. However, the effect of stanozolol on the binding to the low affinity site was more complex, with an increase in the the KD and the BMAX. In males the data were best fit by a single binding site model. This single site exhibited a slight increase in the KD and a decrease in the BMAX in the presence of 50 microM stanozolol.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Center for Avanced Biotechnology and Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway 08854, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Masonis
authors.forename: M P
authors.initials: MP
authors.lastname: McCarthy
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism*; D005260:Female; D005445:Flunitrazepam / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008777:Methyltestosterone / Q000494:pharmacology*; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism*; D012727:Sex Characteristics; D013197:Stanozolol / Q000494:pharmacology*; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D011963:Receptors, GABA-A; D001569:Benzodiazepines; D013197:Stanozolol; D005445:Flunitrazepam; D008777:Methyltestosterone