A Critical Period for Glutamate Receptor‐Mediated Induction of Precocious Puberty in Female Rats

The excitatory amino acid glutamate and especially its NMDA subtype receptor are important components of the neural system that regulates sexual maturation. It is known that multiple daily injections of immature rats and monkeys with NMDA will induce precocious puberty. We have previously reported that a single daily injection of NMDA administered from 27 days of age to the day of vaginal opening (VO) is sufficient to synchronize and slightly accelerate (1-2 days) first ovulation in female rats. We have now optimized this treatment schedule and show that a higher dose of NMDA (20 mg/kg), or the racemic mixture N-methyl-D,L-aspartate (NMA; 30 mg/kg), initiated earlier in development (24 days to VO) significantly advances first ovulation (4 days). Rats induced to ovulate prematurely had normal estrous cycles. We also report that the same degree of precocity can be obtained when injections are discontinued well before first ovulation occurs. For example, NMA administered from day 21 to 25 or from day 24 to 28 accelerates sexual maturation to the same degree as if injections were continued until VO was observed. It is clear that the hypothalamic-pituitary-ovarian (H-P-O) axis is stimulated by daily NMDA treatment as shown by the dose-related luteinizing hormone (LH) release and by an estrogen-dependent rise in uterine weight. However, stimulation of the P-O axis with daily injections of GnRH (5 ng/100 g), which elicits an LH response slightly greater than NMDA (20 mg/kg), does not advance puberty. This suggests that NMDA induces some change in hypothalamic control which is not directly related to LH secretion. Interestingly, there also seems to be a critical period of NMDA effectiveness because daily injections of NMA (30 mg/kg) from day 16 to 20 do not induce precocious puberty. Since the ovaries respond with increased estrogen production (increased uterine weight) to gonadotrophin stimulation at this early age (16 days) we conclude that the hypothalamus may be relatively unresponsive to stimulation with NMDA. Paradoxically the hypothalamus is also hyporesponsive to NMDA in the period preceding spontaneous first ovulation. We now show that an LH dose-response curve for NMDA at age 28 days demonstrates that in NMDA-treated rats the LH response to NMDA is less than in the control group. Further, the hyporesponsiveness is not due to pituitary desensitization since an LH dose-response curve for GnRH at age 28 days is identical in the NMDA-treated and control groups.(ABSTRACT TRUNCATED AT 400 WORDS)