ICI 182,780 is one of a new class of steroidal antiestrogens that differs from nonsteroidal antiestrogens, such as tamoxifen, in a number of respects. 1) It is bound by estrogen receptors with a high affinity, similar to that for estradiol. 2) It is a "pure" antiestrogen in that it does not mimic any of the effects of estradiol. 3) This class of antiestrogens does not seem to be bound by antiestrogen binding sites. 4) ICI 182,780 may not be active in the brain after peripheral administration. Indeed, ICI 182,780 blocked in vivo cell nuclear binding of [3H]estradiol in uterus, pituitary, and adipose tissue but not in hypothalamus-preoptic area. In vitro, ICI 182,780 competed for binding by neural estrogen receptors with an affinity comparable with that for estradiol. When given to ovariectomized rats, ICI 182,780 did not mimic any of the actions of estradiol. Instead, ICI 182,780 treatment completely blocked the uterotrophic effects of estradiol and attenuated the actions of estradiol on linear growth, carcass fat content, fat pad weight, and sexual receptivity. Treatment with ICI 182,780 also attenuated the estrogenic effects of tamoxifen on food intake, body weight and composition, linear growth, and uterine weight. These findings support the concept that, in addition to its actions in the brain, estradiol can act peripherally to modulate regulatory behaviors, energy balance, and estrous behavior. They are also consistent with the hypothesis that nonsteroidal antiestrogens, such as tamoxifen, affect energy balance via estrogen receptors, rather than antiestrogen binding sites.

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Vaginal-cervical stimulation induces a number of physiological and behavioral events, including the facilitation of mating behavior. Although the facilitation of one component of mating behavior, lordosis, by vaginal-cervical stimulation does not require the presence of progesterone, it appears to be mediated by neural progestin receptors. Abundant evidence suggests that dopamine may play a role in the neural circuitry activated by vaginal-cervical stimulation, including the mating-induced release of dopamine in progestin receptor-containing areas of the brain, changes in the activational state of progestin receptors because of dopamine D1 receptor stimulation, facilitation of lordosis by D1 receptor stimulation in estradiol-primed rats via progesterone-independent events, and D1 agonist-induced neuronal responses in progestin receptor-containing areas and cells. We tested the hypothesis that vaginal-cervical stimulation induces phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein (DARPP-32; Mr = 32,000), a protein phosphorylated predominantly in response to the stimulation of D1 receptors. At 9 d after ovariectomy, female rats were injected subcutaneously with a behaviorally effective dose of estradiol benzoate. At 48 hr later they received vaginal-cervical or control (perineal) stimulation, and they were perfused 1 hr later. Vaginal-cervical stimulation increased the number of cells expressing pDARPP-32 immunoreactivity by 92% in the medial preoptic nucleus, 134% in the caudal ventromedial hypothalamic nucleus, 123% in the posterodorsal medial amygdala, and 103% in the bed nucleus of the stria terminalis. These results suggest that some of the neuronal effects of vaginal-cervical stimulation, and perhaps other social or environmental stimuli, are mediated by phosphorylation of DARPP-32, perhaps via stimulation of D1 receptors, within progestin receptor-containing areas.