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 poten cies of different endogenous and excitatory amino acid (EAA) selective analogs on EAA-induced neuropeptide secretion as well as to analyze t he receptor subtypes involved. For this purpose, different glutamate a gonists were tested for their ability to evoke release of the hypothal amic neuropeptide LHRH from arcuate nucleus-median eminence (AN-ME) fr agments 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 i n vitro. Further evaluation of the range of activity of several of the se compounds, both in terms of the dose inducing a half-maximal respon se and the LHRH-releasing effect at that particular dose, indicated th at AMPA > HCA > QUIN > PYR, suggesting that non-NMDA receptors are pri marily involved in EAA-induced LHRH release at the level of the AN-ME. Evaluation of the receptor types involved using two specific antagoni sts for NMDA and non-NMDA receptors, D,L-2-amino-7-phosphoheptanoic ac id and 6,7-cyanoquinoxaline-2,3-dione, respectively, showed that the e ffects 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 w ere abolished by both receptor blockers. The metabotropic receptor ago nist trans-1-amino-cyclopentyl-1,1,3-dicarboxylic acid was not active in eliciting LHRH secretion. The data indicate that endogenous substan ces active at EAA receptor sites, such as HCA, QUIN, and PYR, can sign ificantly increase the secretion of the neuropeptide LHRH and, thus, m ay participate in the physiological regulation of the activity of this important neuroendocrine neuronal system. In addition, the results su ggest that non-NMDA receptor sites may be preferentially activated at lower ligand concentrations, although NMDA receptors may also be invol ved in the response to certain endogenous agonists.