Alterations in the density of neuropeptide Y (NPY)-immunoreactive fibers and of NPY1 receptor gene expression in the hypothalamus of Y1R/LacZ transgenic pregnant mice were investigated. In the paraventricular nucleus of mice on the 18th d of pregnancy NPY immunoreactivity was significantly decreased, and NPY1 receptor gene expression, as measured by histochemical staining of beta-galactosidase and in situ hybridization of NPY1 receptor mRNA, was significantly increased compared with those in estrous mice. Conversely, pregnant transgenic mice displayed a significant induction of NPY immunoreactivity and a reduction of NPY1 receptor gene expression in the ventromedial nucleus. A significant increase in Y1R/LacZ transgene expression and NPY1 receptor mRNA, but no changes in NPY immunoreactivity were observed in the arcuate nucleus of mice on the 18th d of pregnancy. These results suggest that the elevated expression of NPY in the ventromedial nucleus may contribute to the state of leptin resistance that occurs during pregnancy.