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 alpha-androstanediol; 3 alpha-Diol), a neurosteroid whose effects are primarily inhibitory to sexual behavior, may act through interactions with gamma-aminobutyric acid (GABA) receptor complexes (GBRs) in the medial basal hypothalamus (MBH) and the preoptic area (POA). In Experiment (Exp.) 1, ovariectomized (ovx) rats were implanted with bilateral guide cannulae aimed above the MBH and were later treated with 17 beta-estradiol (E(2), 2 injections of 1 mu g/0.2 ml in 10% ethanol) and either 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 lordosis responsiveness was carried out 4 h later. The GABA(A) agonist, muscimol (50 ng), then was infused into the MBH and rats were tested 10, 30 and 60 min later. Muscimol infusion facilitated lordosis behavior in vehicle-treated controls, but 3 alpha-Diol-treated animals failed to show this facilitation. To ascertain whether 3 alpha-Diol would also prevent muscimol's action in the POA, a site in which muscimol inhibits, rather than facilitates, sexual receptivity, ovx animals in Exp. 2 were implanted with bilateral guide cannulae aimed above the POA and were treated with E(2), 3 alpha-Diol, and P and infused and tested as in Exp. 1. Muscimol and 3 alpha-Diol each significantly inhibited receptivity; when they were combined, the inhibition was more pronounced. In Exp. 3, POA infusions of the GABA(A) antagonist, bicuculline, counteracted 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 lordosis behavior via actions at the GBR in both the MBH and POA.