DIFFERENTIAL GONADOTROPIN RESPONSES TO N-METHYL-D,L-ASPARTATE IN METESTROUS, PROESTROUS, AND OVARIECTOMIZED RATS

Peripheral administration of N-methyl-D,L-aspartate (NMA), an analogue of the excitatory amino acid aspartate, elicits LH and prolactin (PRL ) release in rats, most likely by increasing endogenous releasing-horm one secretion. These experiments were carried out to assess the degree to which NMA stimulates FSH and to analyze the relationship between e ndocrine status and responsiveness to NMA in female rats, in contrast to male rats, as described in the companion paper [Biol Reprod 48:000- 000]. In experiment 1, estrous rats (n = 10) and diestrous rats (n = 1 0) and in experiment 2, estrous rats (n = 11) and rats ovariectomized (OVX) 8 days previously (n = 10) were fitted with atrial catheters and injected s.c. with 100 mug of an LHRH antagonist or vehicle at 2100 h . Starting at 0900 h the next day (metestrus, proestrus, or Day 9 post -OVX), blood was withdrawn every 10 min for 3 h. Each animal received i.v. 5 mg NMA after the first hour and i.v. 500 ng LHRH after the seco nd hour. NMA significantly increased LH in metestrous and proestrous f emales, and LHRH antagonist blunted the increases. In OVX females, LH decreased after NMA. FSH was not affected by NMA in any group. PRL inc reased after NMA in proestrous and metestrous animals. LHRH caused sur ge-like LH and small FSH increases in vehicle groups; these increases did not differ in amplitude between intact and OVX animals and were bl unted by pretreatment with LHRH antagonist. In experiment 3, 10 diestr ous rats were fitted with atrial catheters and were serially bled at 2 -h intervals from 1200 h on the following day (proestrus) until 0600 h on estrus morning. After the first sample the animals were injected s .c. with 0.2 mg/kg MK801, a noncompetitive NMA receptor antagonist, or with saline. Four of the 5 saline-treated animals exhibited surges of LH and FSH as well as elevated progesterone levels, with LH and proge sterone peaking at 2000 h. Five of 5 MK801-treated animals failed to h ave elevated LH, FSH, or progesterone levels at any time point. These data demonstrate that LHRH mediates the LH response to NMA in rats and that endogenous NMA receptor binding may be necessary for the preovul atory gonadotropin surges. The lack of FSH responses to NMA during per iods of low-level gonadotropin secretion suggests that physiological i ncrements in endogenous LHRH secretion sufficient to induce a pulse of LH are insufficient to stimulate pulse-like FSH release. Comparison o f metestrous and proestrous NMA responses suggests that elevated proes trous estradiol levels do not enhance the releasability of LHRH by NMA , while the suppression of LH levels following NMA in OVX rats suggest s that in the absence of ovarian feedback the inhibitory effects of NM A on LHRH release predominate over its stimulatory effects.