Regulation of hypothalamic neuropeptide YY1 receptor gene expression during the estrous cycle: Role of progesterone receptors

Neuropeptide Y (NPY) stimulates the release of GnRH in an estrogen (E-2)-de pendent manner, which is important in generating preovulatory GnRH surges. We tested the hypothesis that E-2 up-regulates NPY's actions by stimulating NPY Y1 receptor (Y1r) gene expression through a mechanism mediated by E-2' s ability to induce progesterone (P) receptors (PRs). In initial experiment s, a specific Y1r antagonist BIBP3226 was used to confirm the involvement o f Y1r in the stimulatory effects of NPY on in vivo GnRH release. Hypothalam ic Y1r messenger RNA (mRNA) levels were then measured using competitive RT- PCR and were found to be significantly increased at 1000, 1200, and 1400 h on proestrus compared with other times of the day or cycle stage. Ovariecto my eliminated these increases, and E-2 treatment restored them. Additional P treatment produced even larger increases in Y1r mRNA levels. To assess th e role of PRs in stimulating Y1r expression, proestrous rats were treated w ith PR antagonist or oil vehicle and killed at 1200 h. Treatment with PR an tagonist completely blocked the proestrous rise in Y1r gene expression. In parallel experiments, the same in vivo PR antagonist treatments also blocke d NPY stimulation of GnRH release in vitro. Together our findings reveal th at 1) Y1r mRNA levels are increased during the late morning and afternoon o f proestrus; 2) Y1r mRNA levels are similarly increased by E-2, and to an e ven greater extent by additional P; and 3) PR antagonism blocks both increa sed Y1r mRNA and induction of GnRH responsiveness to NPY. These observation s support the idea that E-2 up-regulates GnRH neuronal responses to NPY thr ough stimulation of Y1r gene expression, and that E-2's actions are mediate d by the induction and subsequent activation of PRs.