Repetitive Injections of L-Glutamic Acid, in Contrast to Those of N-Methyl-D,L-Aspartic Acid, Fail to Elicit Sustained Hypothalamic GnRH Release in the Prepubertal Male Rhesus Monkey (Macaca mulatta)

Abstract

The purpose of the present study was to examine whether repetitive intravenous injections of L-glutamic acid (Glu), like those of N-methyl-D, L-aspartic acid (NMA), are able to elicit a sustained train of gonadotropin releasing hormone (GnRH) discharges from the hypothalamus of the prepubertal male monkey. In order to utilize pituitary luteinizing hormone (LH) secretion as a bioassay of hypothalamic GnRH release, the responsiveness of the gonadotroph of the prepubertal animals was enhanced prior to the study with a chronic intermittent intravenous infusion of the synthetic decapeptide (0.1 µg/min for 3 min every h). Sequential intravenous injections of Glu (150 mg/kg BW) were administered at 3-hour intervals for 6 or 24 h. Although the first injection of this acidic amino acid elicited a robust discharge of GnRH, subsequent stimulation with Glu resulted in GnRH discharges with progressively decreasing magnitudes, and by the 9th injection Glu-induced GnRH release was abolished. Peak concentrations of circulating Glu following the 1st and 4th Glu injection were indistinguishable (3,959 ± 437 vs. 4,139 ± 72 nmol/ml, respectively). Interestingly, the failure of repetitive intravenous injections of Glu to sustain pulsatile GnRH release was not associated with a loss of responsiveness to NMA administration, nor was it accompanied by a corresponding decrement in Glu induced growth hormone (GH) discharges. As previously demonstrated, repetitive intravenous administration of NMA (2-5 mg/kg BW) every 3 h for 9 h sustained pulsatile GnRH secretion without decrement. A similar intermittent infusion of kainic acid (KA; 1 mg/kg BW every 3 h for 6 h), however, elicited a GnRH response that mimicked that observed in response to intermittent Glu treatment. These findings are consistent with the notion that Glu administered by intravenous injection fails to reach the central N-methyl-D-aspartic acid (NMDA) receptors that mediate the sustained train of GnRH discharges elicited in response to repetitive intravenous injections of NMA. Instead, circulating Glu appears to activate non-NMDA receptors in the vicinity of the median eminence. Repetitive activation of these non-NMDA receptors, in contrast to that of the NMDA receptor, fails to sustain an intermittent discharge of GnRH. The Glu induced GH release, which occurred without decrement, was therefore presumably mediated by NMDA receptors on GH releasing hormone cells in close proximity to the median eminence.

Testosterone modulates growth hormone secretion at the hypothalamic but not at the hypophyseal level in the adult male rhesus monkey

“…administration of NMA was markedly attenuated in chronically orchidectomized monkeys as compared with intact animals, although no large differences were observed between the mean basal plasma GH concentrations of agonadal and intact animals. The inability of NMA to stimulate a significant increase in GH secretion in orchidectomized adult monkeys is contrary to earlier reports that demonstrated that NMA can elicit a significant increase in GH secretion in orchidectomized prepubertal monkeys (Plant et al 1989, Medhamurthy et al 1992 and in some other mammalian species (Estienne et al 1989, Barb et al 1992.…”

“…administration of the neuroexcitatory amino acid agonist NMA induced a prompt discharge of GH in adult intact male monkeys is not surprising. The ability of NMA to evoke a release of GH has been well documented for rats (Mason et al 1983), pigs (Barb et al 1992), sheep (Estienne et al 1989), holstein bulls (Shahab et al 1993) and monkeys (Plant et al 1989, Medhamurthy et al 1992. The excitatory effects of NMA on GH secretion have been shown to be exerted via the discharge of GHRH from the hypothalamus (Cocilovo et al 1992).…”

“…The excitatory effects of NMA on GH secretion have been shown to be exerted via the discharge of GHRH from the hypothalamus (Cocilovo et al 1992). It has also been suggested that, in primates, parenterally infused NMA excites NMDA receptors on GHRH neurones located in the median eminence (Medhamurthy et al 1992).…”

Glutamate: A Major Excitatory Transmitter in Neuroendocrine Regulation

“…It is known that the dose of kainate and AMPA necessary for LH release (1-2.5 mg/kg BW) are considerably less than those required for NMDA. Interestingly, NMDA has been shown to be able to repeatedly stimulate LH release when administered in a pulsatile manner [60,77], In contrast, kainate failed to stimulate LH release in a repetitive manner since the first kainate injection elevated LH release but subsequent injections did not [60,77], Whether AMPA repetitively stimulates LH release has not been determined.…”

Control of Puberty by Excitatory Amino Acid Neurotransmitters and its Clinical Implications

“…Our in vitro studies indicate that estradiol increased the pulsatile GnRH secretion through a mechanism involving the ERα subtype and the kainate receptor. Although the implication of the glutamatergic system in triggering the onset of puberty is well known, only the NMDA receptor subtype has been involved in this process in vivo in the monkey (60) and in vitro in the rat (61). The participation of the kainate receptor in the estradiol-induced advancement of puberty is interesting and leads to the hypothesis that, during development, as the gonads increase their hormonal secretion, the kainate receptors get activated and are responsible for the estradiol-mediated activation of the GnRH system.…”