Effects of aging on N-methyl-D-aspartate (NMDA)-induced GnRH and LH release in female rats

In order to evaluate if the changes of the hypothalamic-pituitary-ovary axis that induce a decrease in fertility and modifications in the sexual cycles during senescence involve modifications in the regulatory action of excitatory amino acid neurotransmission on GnRH neurons, we measured the in vitro effects of NMDA on GnRH release by the anterior preoptic and medial basal hypothalamic areas (APOA-MBH) of castrated aging (18 months old) and young (90 days of age) rats. In a second series of experiments the in vivo LH release response to intrahypothalamic (push-pull) administration of NMDA to aged and young castrated female rats was also determined. A similar rate of basal GnRH release was observed in old and young rats during the incubation time. The addition of NMDA to the medium significantly increased GnRH release in both groups; nevertheless, the GnRH release response to NMDA was significantly lower in old (P < 0.01) than in young rats (Young: Basal: 50 +/- 10; NMDA 15': 410 +/- 63, 22,5': 1,469 +/- 300; Old: Basal: 47 +/- 10; NMDA 15': 210 +/- 30; 22,5': 350 +/- 65 ng/GnRH/mg.protein). The LH levels measured throughout the in vivo experiments indicated that basal LH concentrations were significantly lower in the aged group. The mean LH concentrations (fractions 1 to 6) was significantly lower in the aged group (Young: 3.9 +/- 0.07, Old: 2.4 +/- 0.03 ng/ml, P < 0.01). The LH release response to NMDA measured 10 min after the intrahypothalamic administration of the glutamate agonist was significantly lower in aged rats (4.2 +/- 1.6 ng/ml) as compared to young animals (18.0 +/- 6.1 ng/ml; P < 0.05). LH levels in young rats increased to 580% vs., and only 47% in aged rats as compared to previous basal values. In conclusion, present results demonstrate that the GnRH responses to NMDA neurotransmission, which has a predominantly excitatory effects on GnRH neurons, is significantly decreased in old rats, these data give further support to the hypothesis that a decrease in the excitatory inputs to GnRH neurons could be directly involved in the reduction of the hypothalamic-pituitary-ovary axis activity observed during aging.