Effects of an Anti-estrogen on Neural Estradiol Binding and on Behaviors in Female Rats*

Although the synthetic anti-estrogen, nafoxidine (Upjohn ll,100A), has been very useful in studies of the molecular actions of estradiol in the uterus, little is known about its effects on neural estradiol binding or on estrogen-influenced behaviors. In these studies we first determined the time course of changes in cytoplasmic estradiol-binding sites and in in vivo binding of [3H]estradiol by cell nuclei in the hypothalamus- preoptic area-septum of ovariectomized rats after a single injection of nafoxidine (4 mg ip in saline). We then compared these changes in neural estradiol binding with changes in two estradiol-influenced behavioral responses–female sexual behavior and suppression of eating and body weight. Nafoxidine reduced brain cytoplasmic estradiol binding sites by 80% within 6 h, and these levels remained unchanged for 4 days. One week after nafoxidine, cytoplasmic binding sites were 50% of controls, and recovery was complete by day 15. Inhibition of [3H]estradiol binding in brain cell nuclei paralleled cytoplasmic binding site content. Nafoxidine was fully estrogenic with regard to eating and body weight. Eating was maximally suppressed within 24 h, and return to pretreatment levels closely paralleled cytoplasmic receptor levels. Estradiol + progesterone-induced sexual receptivity was totally inhibited 1 day after nafoxidine. However, lordosis recovered from this inhibition more rapidly than would be predicted from the receptor data, suggesting that after an initial inhibitory period nafoxidine may be weakly estrogenic for lordosis. These results indicate that nafoxidine produces a prolonged inhibition of neural estradiol binding and alterations in estrogen-dependent behaviors. The data are fully consistent with the hypothesis that in the brain estrogens have different molecular mechanisms of action on eating behavior and on female sexual behavior. (Endocrinology102: 245, 1978)