Hypothalamic site of action for N-methyl-D-aspartate (NMDA) on LH secretion

Ondo, J.G.; Wheeler, D. D.; Dom, Richard M.

doi:10.1016/0024-3205(88)90422-5

Cited by 102 publications

(46 citation statements)

References 15 publications

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“…These agonists have obvious excitatory effects in vivo ( 1,2,14) and in vitro ( 15,16) whereas an inhibition is obtained by using specific antagonists to NMDA receptors such as AP-5 or MK-801 (17,18). Based on all these data, it was hypothesized that the NMDA receptors involved in GnRH secretion would be increasingly activated from the time of onset of puberty.…”

Section: Introductionmentioning

confidence: 99%

Neuroendocrine mechanism of onset of puberty. Sequential reduction in activity of inhibitory and facilitatory N-methyl-D-aspartate receptors.

et al. 1992

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In humans and in several animal species, puberty results from changes in pulsatile gonadotropin-releasing hormone (GnRH) secretion in the hypothalamus. In particular, the frequency of pulsatile GnRH secretion increases at the onset of puberty, as can be shown by using hypothalamic explants of male rats of 15 and 25 d. Previous observations from us and others suggested that the initiation of puberty could involve a facilitatory effect of excitatory amino acids mediated through N-methyl-D-aspartate (NMDA) receptors. We found that GnRH secretion could be activated through NMDA receptors only around the time of onset of puberty (25 d). The aim of this study was to clarify why this activation did not occur earlier (at 15 d) and could no longer be observed by the end of puberty (at 50 d). We studied GnRH secretion in the presence of MK-801, a noncompetitive antagonist of NMDA receptors or AP-5, a competitive antagonist. We showed that, in the hypothalamus of immature male rats (15 d), a highly potent inhibitory control of pulsatile GnRH secretion in vitro was mediated through NMDA receptors. These data were confirmed in vivo because administration of the antagonist MK-801 (0.001 mg/kg) to immature male rats resulted in early pubertal development. Onset of puberty (25 d) was characterized by the disappearance of that NMDA receptor-mediated inhibition, thus unmasking a facilitatory effect also mediated through NMDA receptors. During puberty, there was a reduction in activity of this facilitatory control which was no longer opposed by its inhibitory counterpart. We conclude that a sequential reduction in activity of inhibitory and facilitatory NMDA receptors provides a developmental basis for the neuroendocrine mechanism of onset of puberty. (J. Clin. Invest. 1992. 90:1736-1744.) Key words: AP-5 * MK-801-neuroexcitatory amino acids puberty * pulsatile gonadotropinreleasing hormone secretion * N-methyl-D-as~artate

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Section: Introductionmentioning

confidence: 99%

Neuroendocrine mechanism of onset of puberty. Sequential reduction in activity of inhibitory and facilitatory N-methyl-D-aspartate receptors.

et al. 1992

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“…Evidence supporting this contention is derived form the following observations: (1) injection of NMDA or kainate into the third ventricle or preoptic area stimulates LH release whereas direct injection of gluta mate into the anterior pituitary has no effect on LH release [59,65]: (2) administration of a GnRH antagonist blocks EAA induced LH release in a variety of species [63, 64. 67], and (3) EAAs stimulate GnRH release from the POA and from ARC-ME fragments in vitro [74,[82][83][84][85][86][87][88].…”

Section: Eaas and Gnrii Secretionmentioning

confidence: 99%

Glutamate: A Major Excitatory Transmitter in Neuroendocrine Regulation

1995

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Excitatory amino acids (EAAs), such as glutamate and aspartate, are found in large concentrations in presynaptic boutons of a variety of important hypothalamic nuclei, including the arcuate nucleus, supraoptic nucleus, suprachiasmatic nucleus, paraventricular nucleus, organum vasculosa of the lamina terminalis (OVLT) and preoptic area (POA). Likewise, the different ionotropic/metabotropic EAA receptor subtypes are found in the same regions of the hypothalamus although there are differences in their individual patterns of localization. Furthermore, there is evidence supporting the presence of ionotropic N-methyl-D-aspartate (NMDA) receptors and non-NMDA (kainate and AMPA) receptors in the anterior lobe, intermediate lobe and posterior lobe of the pituitary. The majority of work to date has focused on the role of EAAs in the control of LH secretion. Administration of glutamate, NMDA, kainate or AMPA leads to rapid LH release mediated through the stimulation of hypothalamic GnRH release. The major site of NMDA action appears to be the OVLT/preoptic area – where GnRH cell bodies reside, whereas AMPA and kainate have been suggested to act primarily at the arcuate nucleus/median eminence – the site of GnRH nerve terminals. There is evidence that some of the effects of glutamate on GnRH release may involve activation of the novel neurotransmitter nitric oxide and possibly catecholamines. The physiological importance of EAAs in the control of LH surge expression is evidenced by the findings that the steroid-induced LH surge in ovariectomized animals and the preovulatory LH surge in cycling animals and in PMSG-primed animals is blocked by treatment with specific NMDA receptor antagonists, or non-NMDA receptor antagonists. EAAs also appear to be important in regulating the normal pulsatile pattern of LH release as evidenced by the finding that both the NMDA antagonist, AP5, and the AMPA/kainate antagonist, DNQX, lower mean LH levels, LH pulse amplitude and LH pulse frequency in the adult ovariectomized rat. A role for NMDA receptors in the achievement of puberty has been suggested since activation of NMDA receptors has been shown to advance the time of vaginal opening in the immature female rat, while kainate and DNQX were without effect. Steroids have been reported not to affect NMDA receptor binding in the hypothalamus; however, steroids appear to up-regulate AMPA receptor GluRi subunit levels and non-NMDA receptor binding in the hypothalamus. Steroids also increase the release rates of glutamate and aspartate in the POA during the steroid-induced LH surge in the ovariectomized adult rat. Evidence also exists supporting a role for EAAs in the release of other pituitary hormones such as ACTH, growth hormones, prolactin, oxytocin and vasopressin which will also be discussed. Taken as a whole, the studies described herein provide extensive and convincing evidence that EAA transmitters play a pivotal role in the neuroendocrine regulation of a variety of hormonal systems.

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“…Evidence supporting a role for glutamate in the control of GnRH secretion has come from in vivo studies where administration of glutamate, NMDA, kainate and AMPA has been shown to cause a rapid increase in hypothalamic GnRH secretion and/or serum LH levels [1, 2, 3, 4, 5, 6, 7, 8, 9, 10]. The stimulatory effects of glutamate and its agonists on GnRH or LH release can be blocked by using specific antagonists for each glutamate receptor subtype [1, 5, 6, 11, 12, 13].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Ionotropic Glutamate Receptors in Rat Hypothalamus, Pituitary and Immortalized Gonadotropin-Releasing Hormone (GnRH) Neurons (GT1-7 Cells)

Mahesh¹,

Zamorano²,

Sevilla³

et al. 1999

Neuroendocrinology

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Evidence from various sources suggested that the Gonadotropin-Releasing Hormone (GnRH) neuron does not contain glutamate receptors. Northern analysis of the hypothalamus showed the presence of NMDAR1, GluR1, GluR4 and GluR6 mRNA, while the pituitary showed the presence of NMDAR1, GluR1 and GluR6 mRNA. Western blot analysis also showed the presence of NMDAR1 and GluR1 protein. Since there are relatively few GnRH neurons in the hypothalamus, and GT1-7 cells have been considered to be a GnRH neuronal cell line, GT1-7 cells were studied in detail. GT1-7 cells contained NMDAR1 mRNA levels as shown by Northern analysis but did not contain GluR1, GluR4, or GluR6 mRNA. They did not show the presence of NMDAR1 and GluR1 protein by Western analysis. In addition, GT1-7 cells showed no NMDA receptor binding using the competitive inhibitor CGP-39563 and the noncompetitive inhibitor MK-801. Likewise, no binding was detected for kainate receptors. However, a small amount of binding for AMPA receptors was found in GT1-7 cells. GT1-7 cells did not exhibit glutamate toxicity and NMDA failed to elicit inward currents using patch-clamp techniques, although GABA did induce currents in the cells. As a whole, these studies suggest that GT1-7 cells lack or possess only low levels of ionotropic glutamate receptors.

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Hypothalamic site of action for N-methyl-D-aspartate (NMDA) on LH secretion

Cited by 102 publications

References 15 publications

Neuroendocrine mechanism of onset of puberty. Sequential reduction in activity of inhibitory and facilitatory N-methyl-D-aspartate receptors.

Neuroendocrine mechanism of onset of puberty. Sequential reduction in activity of inhibitory and facilitatory N-methyl-D-aspartate receptors.

Glutamate: A Major Excitatory Transmitter in Neuroendocrine Regulation

Characterization of Ionotropic Glutamate Receptors in Rat Hypothalamus, Pituitary and Immortalized Gonadotropin-Releasing Hormone (GnRH) Neurons (GT1-7 Cells)

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