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 40.6f 1.1 (mean kSEM) days compared to the cerebrospinal fluid-infused controls (36.5k0.6 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 mglkg) while the response to exogenous luteinizing hormone-releasing hormone (50 nglkg) remained intact. AP5-treated animals had a slower rate of growth (3.1 +0.2 glday) compared to controls (4.2k0.2 glday). 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.Puberty in the female rat can be regarded as a series of maturational events in the CNS associated with the gradual emergence of a s) nchronized pattern of pulsatile luteinizing hormone-releasing hormone (LHRH) secretion culminating in first ovultion (1). Although a decline in opioid-mediated inhibitory control can be demonstrated prepubertally (2, 3), recent evidence suggests that the formation or activation of excitatory neurotransmitter pathwaqs may be important in the control of the onset of puberty. Thus, pulsatile administration of N-methyl-DL-aspartate (NMDA), an agonist at NMDA receptors, is able to advance Pubcrty in juvenile animals (4).There is good evidence that NMDA acts to stimulate LHRH release in hypothalamic neurons; NMDA is without effect on gonadotrophs in v i m (5, 6); NMDA excites release of LHRH from hypothalamic explants in vitro (7) and in vivo NMDAstimulated LH secretion can be blocked by LHRH antagonists (8). That the specific NMDA antagonist, D-2-amino-5-phosphonovaleric acid (D-AP5), suppresses pulsatile LH secretion in adult castrates, at least acutely, suggests a role for endogenous excitatory amino-acid neurotransmitters in the control of LHRH secretion (9). It is therefore important to ascertain whether the endogenous ligands (glutamate and aspartate) are implicated in the mechanisms underlying the onset of pubert...