REGULATION OF GONADOTROPIN-RELEASING-HORMONE AND LUTEINIZING-HORMONE SECRETION BY AMPA RECEPTORS - EVIDENCE FOR A PHYSIOLOGICAL-ROLE OF AMPA RECEPTORS IN THE STEROID-INDUCED LUTEINIZING-HORMONE SURGE

Recent work has demonstrated that glutamate functions as a major trans mitter involved in the regulation of gonadotropin-releasing hormone (G nRH) and luteinizing hormone (LH) secretion in female animals, althoug h the specific receptors and mechanisms mediating its effects have not been completely worked out. The purpose of the present study, therefo re, was to examine the role of the AMPA lpha-amino-3-hydroxy-5-methyli soxazole-4-acid)type glutamate receptor in the control of GnRH and LH secretion in female animals. Toward this end, the dose-and steroid-dep endent effects of AMPA on GnRH and LH secretion in female rats were in vestigated using both in vitro and in vivo approaches, and the role of AMPA receptors in the production of the steroid-induced LH surge was also assessed. The results of the study revealed that central administ ration of AMPA resulted in a stimulation of LH release in the estrogen -primed ovariectomized adult rat. AMPA was also found to potently stim ulate GnRH release in vitro from mediobasal hypothalamic (MBH) fragmen ts obtained from estrogen-primed ovariectomized adult rats, and this e ffect was blocked by the selective AMPA receptor antagonist, NBQX. The mechanism of action of AMPA appeared to differ from that of N-methyl- D-aspartate (NMDA) as AMPA, in contrast to NMDA, failed to elevate nit ric oxide synthase activity in the hypothalamus. The effect of AMPA on LH secretion was demonstrated to be steroid dependent, as central adm inistration of AMPA stimulated LH release in estrogen-primed ovariecto mized rats, but was inhibitory to LH release in non-estrogen-primed ov ariectomized rats. In contrast, AMPA stimulated GnRH release equally w ell from MBH fragments obtained from estrogen-primed or non-estrogen-p rimed ovariectomized rats. The different effects of AMPA on LH release may be due to different pituitary sensitivities between the two model s, or alternatively, AMPA may stimulate the release of LH inhibitory f actors in the ovariectomized rat in the absence of estrogen. Finally, a physiological role for AMPA receptors in the production of the stero id-induced LH surge was suggested, based on the finding that central a dministration of the selective AMPA receptor antagonist, NBQX, into th e third cerebroventricle significantly attenuated the steroid-induced LH surge in the ovariectomized adult female rat.