BEHAVIORAL-EFFECTS OF 3-ALPHA-ANDROSTANEDIOL .2. HYPOTHALAMIC AND PREOPTIC AREA ACTIONS VIA A GABAERGIC MECHANISM

We investigated whether 5 alpha-androstane-3 alpha,17 beta-diol (3 alp ha-androstanediol; 3 alpha-Diol), a neurosteroid whose effects are pri marily inhibitory to sexual behavior, may act through interactions wit h gamma-aminobutyric acid (GABA) receptor complexes (GBRs) in the medi al basal hypothalamus (MBH) and the preoptic area (POA). In Experiment (Exp.) 1, ovariectomized (ovx) rats were implanted with bilateral gui de cannulae aimed above the MBH and were later treated with 17 beta-es tradiol (E(2), 2 injections of 1 mu g/0.2 ml in 10% ethanol) and eithe r 3 alpha-Diol (3.0 mg/kg, s.c.) or vehicle. Progesterone (0.5 mg, s.c .) was given 24 h after the first E(2) injection and a pre-test for lo rdosis responsiveness was carried out 4 h later. The GABA(A) agonist, muscimol (50 ng), then was infused into the MBH and rats were tested 1 0, 30 and 60 min later. Muscimol infusion facilitated lordosis behavio r in vehicle-treated controls, but 3 alpha-Diol-treated animals failed to show this facilitation. To ascertain whether 3 alpha-Diol would al so prevent muscimol's action in the POA, a site in which muscimol inhi bits, rather than facilitates, sexual receptivity, ovx animals in Exp. 2 were implanted with bilateral guide cannulae aimed above the POA an d were treated with E(2), 3 alpha-Diol, and P and infused and tested a s in Exp. 1. Muscimol and 3 alpha-Diol each significantly inhibited re ceptivity; when they were combined, the inhibition was more pronounced . In Exp. 3, POA infusions of the GABA(A) antagonist, bicuculline, cou nteracted muscimol's and 3 alpha-Diol's inhibition of sexual behavior. In Exp. 4, in vitro treatment of POA and MBH membrane fractions with 3 alpha-Diol (30 mu M) enhanced maximal [H-3]muscimol binding without altering the affinity of the binding sites for the agonist. These data suggest that 3 alpha-Diol inhibits E(2) and progestin-induced lordosi s behavior via actions at the GBR in both the MBH and POA.