In virgin female rats, atrial distension (an index of blood volume expansion) causes an increase in c-fos expression in the paraventricular nucleus of the lateral hypothalamus. During pregnancy, this response is markedly attenuated. We tested the effects of 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-OH-DHP) on activation of central pathways following stimulation of the atrial volume receptors. Not only does this progesterone metabolite increase during pregnancy, but it has already been implicated in pregnancy-induced changes in the baroreflex. Female rats were prepared with indwelling venous cannulas and intracardiac balloons that, when inflated, caused a discrete localized stimulation of the atrial volume receptors in the absence of changes in cardiac hemodynamics. Seven days later, the rats were infused with 3alpha-OH-DHP dissolved in cyclodextrin and the intracardiac balloons were inflated. One hour later, the rats were killed and fixed by perfusion and the brains were prepared for visualization of c-fos activity. Infusion with 3alpha-OH-DHP significantly reduced the central response to atrial distension, i.e., it mimicked pregnancy. These results are consistent with the suggestion that this metabolite of progesterone may be an important factor in cardiovascular adaptation to pregnancy.