Endogenous excitatory amino acids and glutamate receptor subtypes involved in the control of hypothalamic luteinizing hormone-releasing hormone secretion.

These studies were designed to evaluate the actions and relative potencies of different endogenous and excitatory amino acid (EAA) selective analogs on EAA-induced neuropeptide secretion as well as to analyze the receptor subtypes involved. For this purpose, different glutamate agonists were tested for their ability to evoke release of the hypothalamic neuropeptide LHRH from arcuate nucleus-median eminence (AN-ME) fragments incubated in vitro. Different glutamate agonists, i.e. 3-amino-3-hydroxy-5-methyl-isoxazole-4-propionic (AMPA), kainic, quisqualic, homocysteic (HCA), quinolinic (QUIN), N-methyl-D-aspartic (NMDA), and pyroglutamic (PYR) acids, elicited LHRH release from AN-ME fragments in vitro. Further evaluation of the range of activity of several of these compounds, both in terms of the dose inducing a half-maximal response and the LHRH-releasing effect at that particular dose, indicated that AMPA greater than HCA greater than QUIN greater than PYR, suggesting that non-NMDA receptors are primarily involved in EAA-induced LHRH release at the level of the AN-ME. Evaluation of the receptor types involved using two specific antagonists for NMDA and non-NMDA receptors, D,L-2-amino-7-phosphoheptanoic acid and 6,7-cyanoquinoxaline-2,3-dione, respectively, showed that the effects of AMPA and HCA on LHRH release can be completely blocked by 6,7-cyanoquinoxaline-2,3-dione, whereas QUIN activity was blocked by D,L-2-amino-7-phosphoheptanoic acid. The effects of PYR on LHRH release were abolished by both receptor blockers. The metabotropic receptor agonist trans-1-amino-cyclopentyl-1,1,3-dicarboxylic acid was not active in eliciting LHRH secretion. The data indicate that endogenous substances active at EAA receptor sites, such as HCA, QUIN, and PYR, can significantly increase the secretion of the neuropeptide LHRH and, thus, may participate in the physiological regulation of the activity of this important neuroendocrine neuronal system. In addition, the results suggest that non-NMDA receptor sites may be preferentially activated at lower ligand concentrations, although NMDA receptors may also be involved in the response to certain endogenous agonists.