We previously demonstrated that NPY potentiates LHRH-induced LH secretion specifically under endocrine conditions in which preovulatory LH surges are generated. The present study was designed to test the hypothesis that NPY's facilitatory actions are dependent upon preovulatory progesterone secretion. In Exp 1, female rats were fitted with atrial catheters on diestrus. On proestrus, hourly blood samples were collected from 1100-2100 h. At 1230 h, rats received a sc injection of the progesterone receptor antagonist RU486 (6 mg/kg BW) or oil. At 1330 h, rats received pentobarbital (40 mg/kg BW), to block hypothalamic LHRH release, or saline. Every 30 min from 1400-1800 h, pentobarbital-treated rats received iv pulses of LHRH (15 ng/pulse) or saline along with concurrent pulses of NPY (5 micrograms/pulse), or saline. In Exp 2, rats received jugular catheters on diestrus, but were sampled every hour throughout the morning (0700-1600 h), rather than the afternoon, of proestrus. In these morning groups, pentobarbital was injected at 0830 h, and peptides (LHRH or combined LHRH and NPY solutions) were administered as pulses at 30-min intervals between 0900-1300 h. Results from Exp 1 were as follows: administration of RU486 to rats given an ip injection of vehicle at 1330 h and pulses of saline from 1400-1800 h completely blocked the endogenous LH surge. In oil-treated pentobarbital-blocked rats, concurrent administration of NPY with LHRH significantly (P < 0.01) potentiated the ability of LHRH to restore LH surges. However, NPY was without any potentiating effects in animals pretreated with RU486 at 1230 h. RU486 also attenuated the ability of LHRH alone to restore LH surges in pentobarbital-blocked rats. In Exp 2, NPY was without effect on LHRH-induced LH secretion during the morning hours of proestrus. Our results demonstrate that 1) NPY facilitates LHRH-induced LH surges on the afternoon of proestrus; 2) presumptive progesterone receptor blockade by RU486 completely prevents NPY's potentiating effects; and 3) NPY is without effect on the morning of proestrus, before the afternoon surge of progesterone. These findings are entirely consistent with the idea that one function of preovulatory progesterone secretion is to up-regulate pituitary sensitivity to the facilitatory actions of NPY. It is hypothesized that these actions of progesterone together with an increase in NPY neurosecretion mediate the acute increase in pituitary sensitivity to LHRH that occurs just before the LH surge.