Involvement of neuroexcitatory amino acids in the control of gonadotropin-releasing hormone release from the hypothalamus of the adult male guinea pig: predominantly inhibitory action of N-methyl-D-aspartate-mediated neurotransmission and its reversal after orchidectomy.

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Excitatory amino acids (EAA) have been implicated in the control of LH secretion through facilitation of GnRH release, although disparate findings of an inhibitory effect of EAA on LH secretion in several species after gonadectomy have been reported. Using a static incubation system, we studied the effects of EAA receptor agonists and antagonists on in vitro GnRH release from the isolated medial basal hypothalamus (MBH) of the male guinea pig. In the presence of 0.4 mM glycine, the N-methyl-D-aspartate (NMDA)-specific receptor agonist N-methyl-D,L-aspartic acid (NMA) exerted a dose-dependent inhibition of GnRH output from the MBH of intact guinea pigs, which was significant (P < or = 0.01) at concentrations of 1 and 50 mM. The NMDA-specific receptor antagonist D,L-2-amino-5-phosphonovaleric acid (AP-5) significantly stimulated GnRH release at 10(-3) and 1 mM (P < or = 0.001) and was ineffective at 10(-6) mM. NMA (50 mM) and AP-5 (1 mM) produced similar effects when tested at a lower glycine concentration of 10 nM. The presence of the two compounds together resulted in overall unchanged GnRH output. The inhibitory effect of 50 mM NMA was also effectively blocked in the presence of 2 mM Mg2+ at both high and low glycine concentrations. When, for comparative purposes, isolated MBHs of 50-day-old intact male rats were exposed to 50 mM NMA, a response opposite to that seen in the intact guinea pig was observed, with a marked increase in GnRH output (P < or = 0.001). When tested at 10 nM glycine, 50 mM kainic acid, a non-NMDA-specific receptor agonist, on the other hand, had a marked stimulatory effect on GnRH output (P < or = 0.01) from intact guinea pig MBHs, an action that was prevented in the presence of the kainate/quisqualate receptor antagonist 6,7-dinitro-quinoxaline-2,3-dione (0.1 mM); 6,7-dinitro-quinoxaline-2,3-dione alone inhibited GnRH release (P < or = 0.01). In a separate series of experiments, the effects of EAA (in the presence of 10 nM glycine) on GnRH release from the MBHs of long term orchidectomized and sham-operated guinea pigs were compared. Orchidectomy led to a dramatic reversal of the NMDA-mediated inhibition of GnRH secretion observed in MBHs of sham-operated animals, with 50 mM NMA producing a marked increase (P < or = 0.0001) and 1 mM AP-5 resulting in a clear inhibition (P < or = 0.0001) of GnRH release. Kainic acid (50 mM), on the other hand, had a similar stimulatory action on GnRH release from the MBHs of both orchidectomized (P < or = 0.0001) and sham-castrated (P < or = 0.001) guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)