CHRONIC ANABOLIC-ANDROGENIC STEROID TREATMENT AFFECTS BRAIN GABA(A) RECEPTOR-GATED CHLORIDE-ION TRANSPORT

Previous research in this laboratory has shown that chronic treatment of adult male rats with an anabolic-androgenic steroid (AAS) produced anxiolytic behavior and increased the functional response of cortical gamma-aminobutyric acid(A) (GABA(A)) receptors. The experiments report ed here were aimed at further characterizing the effect of chronic AAS exposure on cerebral cortical GABA(A) receptors. Adult male rats were injected with dianabol (1,4-androstadien-17 alpha-methyl-17 beta-ol-3 -one; 10 mg/kg/day, SC) for 4 weeks. A significant decrease in ventral prostate gland weight was found after 2 weeks of dianabol, and return ed to control levels 3 and 10 days after steroid discontinuation. Test icular weights decreased throughout the treatment period but reached s tatistical significance only during the withdrawal period. Serum 3 alp ha-androstanediol level was marginally increased after 2 weeks of dian abol injection, and was significantly decreased at 3 and 10 days after withdrawal. GABA-stimulated (36)chloride (Cl-) influx in cortical syn aptoneurosomes was increased in animals treated with dianabol for 2 an d 4 weeks, and remained elevated 3 days after dianabol withdrawal, ret urning to control levels at withdrawal day 10. The increase in recepto r efficacy was associated with a transient increase in receptor sensit ivity (inverse of EC(50)), apparent after 2 weeks of AAS treatment and at withdrawal day 3. In a follow-up experiment, metabolites of dianab ol were tested for the in vitro efficacy in potentiating GABA-stimulat ed Cl- transport. Only 3 alpha-androstanediol and androsterone were fo und to have potent stimulatory effects. The 3 beta-reduced metabolites were inactive, as were metabolites that contained a methyl group at t he 17 alpha position. These results point to significant facilitative effects of dianabol treatment on brain GABA(A) receptors via the metab olic formation of neuroactive steroids.