Peripubertal Treatment with N-Methyl-D-Aspartic Acid or Neonatally with Monosodium Glutamate Accelerates Sexual Maturation in Female Rats, an Effect Reversed by MK-801

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Abstract
Recent reports from several laboratories have implicated the excitatory neurotransmitter glutamate as a component in the neural regulation of sexual maturation. In the rat we have previously proposed that a hypothalamic opioid restraint mechanism may ultimately be overridden by maturation of an excitatory drive, culminating in first ovulation. We have now investigated whether glutamate may be the excitatory factor. Treatment of immature female rats with single, daily injections of two N-methyl-D-aspartate (NMDA) antagonists – dextrorphan (18 mg/kg) and MK-801 (0.1 mg/kg) – beginning on the 27th postnatal day, significantly delayed the timing of vaginal opening (VO). Interestingly, treated rats reached VO in spite of continued antagonist treatment. The antagonist effect was reversed by preinjection of NMDA, suggesting that endogenous glutamate exerts its effect via an NMDA-subtype glutamate receptor. Injection of NMDA alone (15 mg/kg; once daily) produced a striking synchronization of VO such that all treated rats showed VO over a 24-hour period compared to a normal distribution of several days for control rats. In a model of first ovulation, i.e. rats induced to ovulate by pregnant mare serum, MK-801 (1 mg/kg) arrested treated rats at proestrus. This was readily reversible after discontinuing injections. A lower dose of MK-801 (0.1 mg/kg/day) was ineffective in delaying ovulation. In a second series of experiments we studied the consequences of a neonatal hypothalamic lesion which destroys glutamate-sensitive neurons. Monosodium glutamate (MSG; 4 mg/g), injected on postnatal days 2 and 4, resulted in an acceleration of sexual maturation such that treated rats reached first ovulation on day 30.1 ± 0.2 compared to 34.8 ± 0.4 for control rats. The action of MSG was prevented by co-injection of MK-801. In conclusion, our data demonstrate that: (1) hypothalamic glutamate receptors represent a significant regulatory component of sexual maturation, and (2) the neurotoxin MSG probably removes an inhibitory, possibly opioid, factor which normally restrains the onset of puberty.

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