The physiological role of N-methyl-D-aspartate (NMDA) receptors in controlling LH secretion and the initiation of puberty was investigated using two specific antagonists, MK-801 and DL-2-amino-5-phosphono valeric acid (AP-5). Single daily sc injections of MK-801 (0.1-0.2 mg/kg BW), a noncompetitive NMDA receptor antagonist, given to prepubertal rats significantly delayed but did not prevent the timing of puberty, as determined by the age at vaginal opening and first ovulation. Infusion of MK-801 (5 μg/h) via osmotic minipumps for 4 days inhibited the postovarieclomy rise of LH secretion in prepubertal rats. Both MK-801 (0.2 mg/kg BW, sc) and AP-5 (4 × 30 mg, iv), a competitive NMDA receptor antagonist, blocked the estradiol-induced LH surge in prepubertal ovariectomized rats. These results demonstrate that blockade of NMDA receptors can prevent the development of enhanced LH secretion in female rats undergoing sexual maturation. Moreover, they support the view that activation of NMDA receptors significantly contributes to the physiological initiation of the pubertal process.