DL-2-Amino-5-Phosphonopentanoic Acid, a Specific N-Methyl-D-Aspartic Acid Receptor Antagonist, Suppresses Pulsatile LH Release in the Rat

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Abstract
To determine whether neuroexcitatory amino acids may play a role in generating intermittent hypothalamic GnRH release, the effect of H-methyl-D-aspartate (NMDA) receptor blockade on pulsatile LH secretion was examined in male rats. The ability of the NMDA receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (AP5), to inhibit activation of the hypothalamic-pituitary gonadotroph axis that follows peripheral administration of NMDA, was first established in intact rats. Subsequently, acutely castrated rats (n = 12) bearing venous catheters received four consecutive intravenous injections of AP5 (3.75 mg/injection/rat; approx. 13.6 mg;kg BW/injection) at 15-min intervals. Blood samples were collected at 10-min intervals for 1 h before and 2 h after initiation of AP5 treatment, and plasma LH concentrations were determined by RIA. For control purposes, norvaline, an amino acid structurally related to AP5, was administered to a second group of animals (n = 7) in a quantity (2.25 mg/injection/rat; approx. 8.2 mg/kg BW/injection) equimolar to that of the NMDA receptor antagonist. A third group of animals (n = 8) received only saline, the vehicle employed to inject AP5 and norvaline. AP5, but not norvaline, resulted in a marked suppression of pulsatile LH secretion. These findings suggest that neuroexcitatory amino acids acting at the NMDA receptor may play a physiological role in generating the intermittent mode of hypothalamic GnRH release.