EFFECTS OF THE ADROGENIC ANABOLIC STEROID STANOZOLOL ON GABA(A) RECEPTOR FUNCTION - GABA-STIMULATED CL-36(-) INFLUX AND [S-35] TBPS BINDING/

We have recently demonstrated that androgenic/anabolic steroids modula te in vitro ligand binding to the benzodiazepine binding site(s) assoc iated with the gamma-aminobutyric acid(A) (GABA(A)) receptor complex ( Masonis and McCarthy, 1995). One androgenic/anabolic steroid in partic ular, stanozolol, appears to stabilize the GABA(A) receptor in a moder ate-affinity state for benzodiazepine binding. In the present study, w e demonstrate the effects of stanozolol on the functional responsivene ss of the GABA(A) receptor. After pre-incubation with stanozolol, we o bserved a decrease in the E(max) and EC(50) values for GABA-stimulated Cl-36(-) influx into cortical synaptoneurosomes. Moreover, in the pre sence of stanozolol, flunitrazepam-enhanced GABA-stimulated Cl-36(-) i nflux was lost, and the GABA(A) receptor was stabilized in a functiona l state that was resistant to further desensitization by agonist. Stan ozolol does not appear to reduce GABA-stimulated Cl-36(-) influx by ac ting as a channel blocker at the well-characterized channel blocker bi nding site, as illustrated by the GABA-sensitive biphasic effects of s tanozolol on [S-35] t-butylbicyclophosphorothionate binding. These res ults demonstrate a novel, nongenomic mechanism for androgenic/anabolic steroidal modulation of CNS function.