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)