Glutamate Receptors of the Non-N-Methyl-D-Aspartic Acid Type Mediate the Increase in Luteinizing Hormone-Releasing Hormone Release by Excitatory Amino Acidsin Vitro

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Abstract
The present study was designed to analyze in detail the effects of L-glutamate (L-Glu) and its agonists on the release of LHRH from arcuate nucleus-median eminence (AN-ME)fragments in vitro. Fragments from adult male rats were incubated in Krebs-Ringer bicarbonate buffer in the presence of different concentrations of L-Glu, kainate (KA), N-methyl-d-aspartic acid (NMDA), and quisqualate (QA). L-Glu at 10-20 mm evoked a significant increase in basal LHRH release while D-glutamate at similar concentrations was ineffective. Partial depolarization with 14 mm K+ significantly augmentedthe release of LHRH induced by L-Glu-L-induced LHRH release was blunted in a dose-related manner by the specific KA/QA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione. Exposure to KA or QA significantly increased LHRH release at concentrations (1 mm) much lower than those required for L-Glu. In the presence of 14 mm K+ the potencies of KA and QA (0.075 and 0.1 mm, respectively) were significantly enhanced. 6,7-dinitroquinoxaline-2,3-dione blocked KA-induced LHRH release, while AP-7, a competitive NMDA receptor antagonist, was inactive in preventing L-Glu- and KA-induced LHRH release. LHRH secretion from AN-ME fragments was unaffected by NMDA at concentrations up to 10 mm in the different media tested. A significant stimulatory effect of NMDA at 20 mm was observed when fragments were incubated in Mg2+-free medium. These results show the stereoselectivity of L-Glu to enhance LHRH release from AN-ME fragments in vitro. Moreover, in view of the respective potencies of excitatory amino acid agonists (KA = QA > L-Glu > NMDA) and the selective antagonism of excitatory amino acid effects, they provide evidence that non-NMDA receptors primarily mediate the excitatory actions of L-Glu on LHRH release from nerve terminals in the AN-ME.