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

Abstract

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 LHand 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.

Melatonin, hydroxyl radical‐mediated oxidative damage, and aging: A hypothesis

“…Treatments will only become available if processes that trigger neuronal degeneration and death are understood and the endogenous compounds that prevent nerve cells from dying are identified [Peruche and Kreigelstein, 1993;Reiter et al, 19931. The recent neuropharmacological work on the actions of the major excitatory neurotransmitter in the CNS, the acidic amino acid L-glutamate, has contributed to the understanding of excitotoxic processes that finally lead to neuronal death [Dykens et al, 1987;Marani and Rietveld, 1987;May et al, 1989;Murphy et al, 1989;Pellegrini-Giampietro et al, 1990;Joseph et al, 1991;Wolf et al, 1991;Wozniak et al, 1991;Braun and Mahesh, 1992;Cheramy et al, 1992;Dawson and Wallace, 1992;Delbarre et al, 1992b;Kato et al, 1992;Kitamura et al, 1992;Pazdernik et al, 1992;Wenk et al, 1992;Zawia et al. 1992;ZS.-Nagy, 1992;Hall et al, 1993;Peruche and Kriegelstein, 19931. Melatonin and excitatory amino acids seem to have opposing roles regarding the developmental and aging processes [Marani and Rietveld, 1987;May et al, 1989;Braun and Mahesh, 1992;Reiter, 1992;Reiter et al, 19931.…”

“…The recent neuropharmacological work on the actions of the major excitatory neurotransmitter in the CNS, the acidic amino acid L-glutamate, has contributed to the understanding of excitotoxic processes that finally lead to neuronal death [Dykens et al, 1987;Marani and Rietveld, 1987;May et al, 1989;Murphy et al, 1989;Pellegrini-Giampietro et al, 1990;Joseph et al, 1991;Wolf et al, 1991;Wozniak et al, 1991;Braun and Mahesh, 1992;Cheramy et al, 1992;Dawson and Wallace, 1992;Delbarre et al, 1992b;Kato et al, 1992;Kitamura et al, 1992;Pazdernik et al, 1992;Wenk et al, 1992;Zawia et al. 1992;ZS.-Nagy, 1992;Hall et al, 1993;Peruche and Kriegelstein, 19931. Melatonin and excitatory amino acids seem to have opposing roles regarding the developmental and aging processes [Marani and Rietveld, 1987;May et al, 1989;Braun and Mahesh, 1992;Reiter, 1992;Reiter et al, 19931. Excitatory amino acids act as sculptures and destroyers of neuronal networks, while melatonin seems to counteract these effects by preserving plasticity and protecting against over-stimulation of neurons, which leads to irreversible excitotoxicity and neuronal death due to oxidative stress [Marani and Rietveld, 1987;May et al, 1989;Joseph et al , 199 1 ;Naranjo-Rodriguez et al, 1991;Braun and Mahesh, 1992;Reiter et al, 19931.…”

“…1992;ZS.-Nagy, 1992;Hall et al, 1993;Peruche and Kriegelstein, 19931. Melatonin and excitatory amino acids seem to have opposing roles regarding the developmental and aging processes [Marani and Rietveld, 1987;May et al, 1989;Braun and Mahesh, 1992;Reiter, 1992;Reiter et al, 19931. Excitatory amino acids act as sculptures and destroyers of neuronal networks, while melatonin seems to counteract these effects by preserving plasticity and protecting against over-stimulation of neurons, which leads to irreversible excitotoxicity and neuronal death due to oxidative stress [Marani and Rietveld, 1987;May et al, 1989;Joseph et al , 199 1 ;Naranjo-Rodriguez et al, 1991;Braun and Mahesh, 1992;Reiter et al, 19931. While melatonin retards both pubertal development and reproductive senescence, these processes are triggered by the major excitatory neuromediator in the CNS, glutamate [Marani and Rietveld, 1987;May et al, 1987;Trentini et al, 1991;Braun and Mahesh, 1992;Reiter, 19921. In general, melatonin and glutamate possess antagonistic properties regarding the neuroendocrine regulation of reproduction [Braun and Mahesh, 19921. Much evidence suggests that the decline in hypothalamic catecholaminergic input with age leads to a reduction in neuroendocrine regulatory function and results, finally, in a decreased reproductive and maintenance capability, a decline in immune function, an enhanced cancer rate, and disturbances in the regulation of cardiovascular physiology.…”

Altered Luteinizing Hormone and Prolactin Responses to Excitatory Amino Acids during Lactation

“…Recent autoradiographic stud ies suggest that kainate receptors are more abundant than NMDA receptors in the hypothalamus, and they have a different distribution. Most of the kainate binding sites are in the arcuate nucleus-median eminence region [5][6][7], while NMDA sites appear to be localized in the preoptic area [8]. These results are supported by data showing that non-NMDA receptor agonists are more effective at stimu lating GnRH release from arcuate nucleus-median emi nence fragments [9], while NMA is more potent at stimu lating release from the medial basal hypothalamus [ 10], In this study, we compare NMA and kainate responses dur ing lactation.…”

Repetitive Injections of L-Glutamic Acid, in Contrast to Those of N-Methyl-D,L-Aspartic Acid, Fail to Elicit Sustained Hypothalamic GnRH Release in the Prepubertal Male Rhesus Monkey (Macaca mulatta)

“…On the other hand, NMDA receptors in the monkey hypothalamus, as revealed autoradiographically by MK801 labelling, are diffusely and less densely distributed throughout the medial basal hypo thalamus [22]. A similar distribution of NMDA and non- 664 Medhamurthy/Gay/Plant Glutamate Receptors and GnRH Release NMDA receptor binding in rodent hypothalamus has previously been reported [23][24][25]. In this regard, it is of interest to note that in vitro studies with hypothalamic fragments from rat have demonstrated KA induced GnRH release [26,27], and that a decrease in GnRH re sponsiveness to intermittent intravenous administration of KA, similar to that reported here for the monkey, has also been recently observed in the adult female rat [Abbud and Smith, unpubl.…”