N‐Methyl‐DL‐Aspartate Receptor Antagonism by D‐2‐Amino‐5‐Phosphonovaleric Acid Delays Onset of Puberty in the Female Rat

Abstract

Abstract To investigate the possible role of N-methyl-DL-aspartate (NMDA) receptor activation in the initiation of puberty, we examined the effects of the selective competitive antagonist 2-amino-5-phosphonovaleric acid (AP5) on the timing of vaginal opening. Paired and weight-matched litter mates of immature female rats were implanted with osmotic minipumps for the intracerebroventricular infusion of DL- or D-AP5 or artificial cerebrospinal fluid from 27 to 30 days of age for 14 days. Each animal was weighed and examined daily for vaginal opening as the indicator of first oestrous. Infusion of 20 or 40 mM DL-AP5 beginning on Day 30 failed to delay vaginal opening. Administration 50mM of the single enantiomer D-AP5 beginning on Day 27 significantly delayed the age of vaginal opening to 40.6+/-1.1 (mean +/- SEM) days compared to the cerebrospinal fluid-infused controls (36.5 +/- 0.6 days). Blockade of NMDA receptors in the D-AP5-treated animals was confirmed on Day 32 by the suppression of luteinizing hormone response to intravenous NMDA (20 mg/kg) while the response to exogenous luteinizing hormone-releasing hormone (50 ng/kg) remained intact. AP5-treated animals had a slower rate of growth (3.1 +/- 0.2 g/day) compared to controls (4.2 +/- 0.2 g/day). However, a similar degree of growth retardation produced by a 75% restricted diet in untreated juvenile animals did not delay vaginal opening. This suggests that the slower growth rate in the D-AP5-treated animals could not account for the delayed onset of puberty. In conclusion, these data suggest that blockade of central NMDA receptors inhibits excitatory mechanisms which may be important in the control of pubertal onset in the female rat.