N-methyl-aspartic acid lesions of the arcuate nucleus in adult C57BL/6J mice: a new model for age-related lengthening of the estrous cycle.

We report a new effect of the excitotoxin N-methyl-aspartic acid (NMA) on adult mice. Besides confirming cell loss in the arcuate nucleus of animals treated as adults, we also observed lengthened estrous cycles. Cycling female C57BL/6J mice were treated with subcutaneous injections of NMA and estrous cycles monitored for 30 days. NMA treatment lengthened average estrous cycle length by 1 day, to 5.6 days. The elongated cycles were due to an increase in the frequency of 5- and 6-day cycles at the expense of 4-day cycles. This effect was observed in mice aged 4 and 7 months; however, 10-month-old mice had irregular cycles and a higher mortality rate following NMA, which precluded cycle analysis. NMA caused a region-specific 30-45% cell loss in the rostral portions of the arcuate nucleus; no cell loss was detected in the adjacent ventromedial nucleus. Possible neuronal substates for NMA lesions, as analyzed by in vitro receptor autoradiography for glutamate receptor subtypes, include a high density of kainate receptors in the arcuate nucleus; there was little specific binding of ligands to NMDA and quisqualate receptors. Consistent with the regional pattern of cell loss, little specific binding of any glutamatergic ligand was observed in the VMN. NMA caused weight gain in all age groups. Serum LH and PRL were unaffected by NMA. The transition from 4-day to 5- and 6-day estrous cycles produced by NMA treatment mimics the early age-related changes in estrous cycle patterns in rodents. This new model will be useful in analyzing the contributions of neuroendocrine changes in the arcuate nucleus to reproductive senescence.