Pulsatile Release of Gonadotropin-Releasing Hormone from Hypothalamic Explants Is Restrained by Blockade of<i>N</i>-Methyl-<scp>D</scp>,<scp>L</scp>-Aspartate Receptors*

Bourguignon, Jean-Pierre; Gérard, Arlette; Mathieu, Jacqueline; Simons, Jean; Franchimont, P

doi:10.1210/endo-125-2-1090

Cited by 112 publications

(64 citation statements)

References 15 publications

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“…Male Wistar rats (Janssen Pharmaceutica, Beerse, Belgium) housed in standardized conditions ( 14- Incubation of hypothalamic explants and radioimmunoassay of GnRH. Retrochiasmatic hypothalamic explants were studied by using a procedure described in detail previously ( 18,23). Briefly, 12 animals were studied in each experiment.…”

Section: Methodsmentioning

confidence: 99%

“…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%

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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: Methodsmentioning

confidence: 99%

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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“…However, there have been no studies to confirm whether NMDA rapidly enters these tissues in the sheep, or if NMDA receptors are present. In the rat, NMDA receptors are relatively sparsely distributed in the caudal hypothalamus including the median eminence (7), nevertheless, NMDA will stimulate LHRH secretion from cultured explants of these neural tissues and induction of spontaneous pulsatile LHRH secretion from such explants depends on binding of endogenous ligands to NMDA receptors (20).…”

Section: -mentioning

confidence: 99%

“…NMDA may not act directly on the LHRH cells but indirectly through neural systems which modulate the release of LHRH into the pituitary portal blood system (20). In addition, NMDA is expected to induce the secretion of other peptides from the hypothalamus which may influence LHRH/LH secretion.…”

Section: -mentioning

confidence: 99%

Luteinizing Hormone Responses to N‐Methyl‐D,L‐Aspartate During a Photoperiodically‐lnduced Reproductive Cycle in the Ram

Lincoln

1991

J Neuroendocrinology

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Aspartate and glutamate represent a major class of excitatory amino-acid neurotransmitters in the vertebrate brain, and stimulation of glutaminergic receptors by the specific agonist N-methyl-D,L-aspartate (NMDA) induces luteinizing hormone-releasing hormone (LHRH) and LH secretion. In this study, we used NMDA as a probe to investigate the hypothalamic regulation of LH secretion at different stages of a reproductive cycle in Soay rams induced by exposure to alternating 16-week periods of long and short days. NMDA (20 mg/kg) injected intravenously caused an acute increase in blood plasma concentrations of LH, with a significant increase within 2 to 4 min, and peak levels within 20 min. The magnitude of the response changed markedly during the cycle; it was greatest in the sexually inactive phase under long days (with a linear dose-response over the range 1 to 20 mgikg NMDA) and least in the sexually active phase under short days (only 20 mg/kg NMDA produced a small response). Pituitary responsiveness to a standard dose of LHRH (5.3 ng/kg iv) varied only slightly at the different stages and could not account for the observed changes in the LH response to NMDA. There were the expected changes in the endogenous pattern of LH secretion during the cycle, with high frequency LH pulses occurring during the sexually active phase. There was an inverse relationship between the frequency of LH pulses and the LH response to NMDA. Pretreatment of rams with an LHRH antagonist (36 pg/kg iv; Syntex, RS18286) totally blocked the LH response to both NMDA and LHRH, while in a separate study, treatment with dexamethasone (synthetic glucocorticoid, 133.4 pglkg iv) partially blocked the LH responses. The overall results indicate that NMDA stimulates LHRH secretion in the ram and the response is independent of the activation of the hypothalamo-pituitary-adrenal axis. The variation in the LH response during the reproductive cycle may reflect changes in the releasable stores of LHRH in the median eminence. These appear to be depleted in the sexually active phase, when LHRH is secreted in pulses at high frequency. The variation in the response to NMDA may also reflect changes in release of endogenous excitatory amino-acids, which act via NMDA receptors to form part of the physiological regulation of the reproductive cycle in the ram.The dicarboxylic amino-acids aspartate and glutamate represent a major class of excitatory neurotransmitters in the vertebrate brain ( I ) . These amino-acids have excitatory effects through at least three classes of receptors of which the N-methyl-D,Laspartate (NMDA) receptor class is best characterized, and these receptors are apparently involved in the neural control of reproduction (2). Studies in the rat have shown that the administration of NMDA causes the release of luteinizing hormone (LH) from the anterior pituitary gland by inducing the secretion of LHreleasing hormone (LHRH) from the hypothalamus (3, 4), and there is evidence that both NMDA and non-NMDA excitatory amino-acid receptors are in...

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“…No further changes in GnRH pulsatility occur between 25 and 50 days, during puberty. Because pulsatile GnRH secretion can be blocked by NMDA receptor antagonists, whereas kainate receptor antagonists are not effective in our study conditions (Bourguignon et al 1989), we have concentrated on possible changes in NMDA receptor function at onset of puberty.…”

Section: MD Brown School Of Sport and Exercise Sciences University Omentioning

confidence: 99%

Symposium Proceedings

1995

The Journal of Physiology

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Starting with the earliest in vivo studies of the microcirculation, observers have been impressed with the variability and heterogeneity of microcirculation blood flow. The question I should like to address is how heterogeneity of microvascular perfusion influences transport of diffusible solutes, and how control of heterogeneity may contribute to regulation of blood-tissue exchange. Available exchange vessel surface area and inter-exchange vessel distances are controlled at the arteriolar level by the number of vessels open to the supply of arterial blood. When metabolic requirements are low, only a fraction of the exchange vessels in a vascular network are perfused; as metabolic activity increases, more exchange vessels are recruited. However, the efficiency with which available exchange vessel surface is utilized for diffusion of a given solute depends on the distribution of individual blood flow/permeability surface area ratios (Q/PS) in the network. Maximum efficiency (full utilization of available PS) is achieved when Q/PS is uniform.In vivo observations of red blood cell velocities show wide variation among individual exchange vessels of the same class (capillaries, postcapillary venules); presumably the same is true of plasma velocities. Flow velocity is only one of the factors that determines local transport; the critical parameter is the product of velocity and vessel radius divided by vessel length times solute permeability (v. r/ 1 P). The impression I get from published intra-vital microscope data is that this ratio may vary even more widely than velocity alone. Physiological measurements of solute transport in whole organs provide indirect support for broad heterogeneity of perfusion, at least in low metabolic states. In resting skeletal muscles the apparent (measured) PS products for 86Rb and 51Cr EDTA increase with increasing perfusion rate, approaching limiting values at high flow rates, as predicted for a heterogeneity perfused assemblage of exchange vessels. Estimated coefficients of variation (cv = S.D./mean) of Q/PS or v. r/ 1 P lie in the range 07-09.In heterogeneously perfused organs and tissues, the degree of heterogeneity (cv of Q/PS) and the total blood flow are potentially important secondary regulators of capillary transport, because they determine the efficiency with which the primary controlling factors, total blood flow and available exchange vessel surface area, are utilized (note that blood flow acts both directly and indirectly). Efficiency, defined as the ratio of apparent PS to the maximum PS at uniform perfusion, is inversely related to the degree of heterogeneity and directly related to the mean flow velocity. There is conflicting evidence in the literature concerning the degree to which alteration of Q/PS heterogeneity is involved in adaptive control of diffusion exchange. However, even with constant total PS and fixed heterogeneity, an increase in total blood flow can decrease the influence of heterogeneity on transport and thus contribute substantially to Berlin 33, Ger...

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Pulsatile Release of Gonadotropin-Releasing Hormone from Hypothalamic Explants Is Restrained by Blockade ofN-Methyl-D,L-Aspartate Receptors*

Cited by 112 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.

Luteinizing Hormone Responses to N‐Methyl‐D,L‐Aspartate During a Photoperiodically‐lnduced Reproductive Cycle in the Ram

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