Behavioral effects of 3α-androstanediol I: modulation of sexual receptivity and promotion of GABA-stimulated chloride flux

Pregnane neurosteroids may initiate sexual receptivity not only via actions at intracellular receptors, but by affecting gamma-aminobutyric acid (GABA) receptor complexes (GBRs). To investigate whether GBR-mediated actions of an androgenic neurosteroid 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-androstanediol; 3 alpha-Diol) may influence the expression of sexual behavior, ovariectomized (ovx) rats received daily injections of 3 alpha-Diol (0.6, 3.0, 6.0 and 7.5 mg/kg) or vehicle (10% (v/v) ethanol in propylene glycol) at 10.00 h, and s.c. injections of estradiol-17 beta (E2: 1 microgram/0.2 ml in 10% ethanol) at 13.00 h and 19.00 h. Progesterone (P: 0.5, 1.0, 2.0 and 4.0 mg/kg) or sesame-oil vehicle was given at 12.30 h on the day following two days of 3 alpha-Diol and E2 treatment. In Expt. 1, levels of sexual receptivity were measured at 18.00-19.00 h, 56-57 h after the first injection of 3 alpha-Diol and 4 h after P or vehicle injection. 3 alpha-Androstanediol (6.0 mg/kg) attenuated sexual behavior (lordosis quotient, lordosis rating) and facilitated aggressive/rejection behaviors following 0.0, 1.0, 2.0 and 4.0 mg/kg P. The highest dosage of 3 alpha-Diol (7.5 mg/kg) facilitated sexual behavior and inhibited aggression behaviors following 0.0, 1.0, 2.0 and 4.0 mg/kg P. In Expt. 2, GABA-stimulated chloride flux was greater in cortical synaptoneurosomes of animals that received hormone treatments associated with inhibited receptivity (E2 + P + 3 alpha-Diol 3.0 mg/kg) than following treatments that facilitated receptivity (E2 + P and E2 + P + 3 alpha-Diol 7.5 mg/kg) or unreceptive ovx animals. In Expt. 3, circulating concentrations of 3 alpha-Diol resulting from the 0.0, 3.0 and 7.5 mg/kg s.c. doses administered to E2- and P-primed animals was measured by radioimmunoassay. Circulating levels of 3 alpha-Diol at the completion of behavioral testing were comparable to those previously ascertained across the estrous cycle. These data indicate that 3 alpha-Diol influences the expression of E2 and P-induced receptivity, and suggest that 3 alpha-Diol, like other neurosteroids, may exert its effects on sexual behavior by actions at GBRs.