N-Methyl-D,L-Aspartate Elicits Hypothalamic Gonadotropin-Releasing Hormone Release in Prepubertal Male Rhesus Monkeys (Macaca mulatto)*

Abstract

In higher primates, the protracted delay from infancy to puberty results from an interruption in hypothalamic GnRH release. To determine whether the quiescent hypothalamic GnRH neurons of the prepubertal macaque are capable of discharging the decapeptide in response to a generalized neural depolarization, an excitatory amino acid analog, N-methyl-D,L-aspartate (NMA), was administered systemically to orchidectomized rhesus monkeys between 13 and 20 months of age. GnRH secretion was estimated indirectly by monitoring changes in circulating LH concentrations after the responsivity of pituitary gonadotropes to GnRH had been greatly facilitated by the chronic intermittent iv infusion of GnRH (0.1 microgram/min for 3 min every hour). The iv bolus administration of increasing doses of NMA (1.5, 4.8, and 15.0 mg/kg BW), 10-14 h after termination of the priming infusion of GnRH, elicited distinct discharges of LH, with magnitudes directly related to the amount of the excitant injected. Administration of a higher dose of NMA (48 mg/kg BW), however, failed to induce further LH release. The finding that pretreatment with a long-acting and potent GnRH receptor antagonist [( AcD2Nal1,4ClPhe2,DTrp3,DArg6,DAla10] GnRH-HOAc) abolished the LH-releasing activity of NMA provides compelling evidence for the view that the action of the neural excitant to induce gonadotropin release was exerted at a suprapituitary level. The additional observation that an N-methyl-D-aspartate receptor antagonist (D,L-2-amino-5-phosphono-valeric acid) blocked the NMA-induced release of GnRH suggests that the amino acid analog interacted with the N-methyl-D-aspartate receptor on neurons that synthesize and/or control the release of the hypothalamic hormone. Most interestingly, three sequential GnRH discharges, with a period and an amplitude apparently similar to those generated by the hypothalamus of the adult, were elicited from the brain of prepubertal monkeys by the sequential administration of three injections of NMA at hourly intervals. Taken together these findings demonstrate that the apparent dormancy of hypothalamic GnRH neurons, which is characteristic of prepubertal development in higher primates and underlies the protracted delay in the onset of puberty in these species, may be readily terminated by application of a generalized neural excitation. Plasma FSH, PRL, GH, and cortisol concentrations were also monitored during the course of some of these experiments, and release of each of these four hormones was observed after the iv injection of NMA (15 mg/kg BW).

Luteinizing Hormone Responses to N‐Methyl‐D,L‐Aspartate During a Photoperiodically‐lnduced Reproductive Cycle in the Ram

“…On both occasions NMDA was injected iv in a 10 ml solution at three doses (low: 1 mg/kg: medium: 5 mg/kg; high: 20 mg/kg) and saline was injected as a control. The range of doses was selected to be stirnulatory but not neurotoxic based on studies in the monkey and rat (17,18). All animals received each of the four treatments during 4 consecutive days with one treatment per day in a randomized order.…”

Gonadotropin-Releasing Hormone and NMDA Receptor Gene Expression and Colocalization Change during Puberty in Female Rats

“…Because the GnRH neurosecretory system is already morphologically and functionally mature long before the onset of puberty Goldsmith and Song, 1987), it is probable that changes in inputs to the GnRH system are responsible for the increase in pulsatile GnRH release that ultimately results in the attainment of adult reproductive function. For example, increases in stimulatory inputs from noradrenergic (Advis et al, 1978;Raum et al, 1980;Gore and Terasawa, 1991), neuropeptide Y (Sutton et al, 1988;Minami et al, 1990;Gore et al, 1993;Gruaz et al, 1993), and glutamatergic (Gay and Plant, 1987;Urbanski and Ojeda, 1990) neurons precede the onset of puberty. Similarly, a decrease in inhibition from GABAergic neurons probably also contributes to the timing of puberty (Mitsushima et al, 1994).…”

Release of chicken luteinising hormone-releasing hormone-I (cLHRH-I) by mediobasal hypothalamus in the cockerel: validation of an incubation system and effect of excitatory amino acids

“…Moreover, the necessity of the presence of calcium ions in the incubation medium for a response to occur showed that this release answers to the physiological mechanisms of neural secretion (Smith and Augustine, 1988 (Gay and Plant, 1987;Ondo et al, 1988) and agonists to stimulate the release of LHRH by hypothalamic tissue of rats in vitro (Bourguignon et al, 1989;Lopez et al, 1992 (1989) that NMDA is more potent than KA in eliciting the release of GnRH by incubated hypothalimi in the rat. However, the specificity of these effects in the chicken has to be further documented by the use of antagonists.…”