Glutamate Receptors of the Non-<i>N</i>-Methyl-D-Aspartic Acid Type Mediate the Increase in Luteinizing Hormone-Releasing Hormone Release by Excitatory Amino Acids<i>in Vitro</i>

Donoso, Alfredo O.; López, Francisco J.; Negro‐Vilar, A.

doi:10.1210/endo-126-1-414

Cited by 149 publications

(71 citation statements)

References 34 publications

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“…For the in vitro studies, animals were killed by decapitation, the brain was rapidly removed from the skull, and arcuate nuclei-ME fragments were dissected under a stereomicroscope with a fine pair of scissors (30). The procedure used for the incubation has been described in detail (31). Briefly, dissected tissue fragments were preincubated for 30 min and then exposed for an additional 30 min to galanin at different concentrations, and the changes in the secretion of LHRH during this period were evaluated.…”

Section: Methodsmentioning

confidence: 99%

Colocalization of galanin and luteinizing hormone-releasing hormone in a subset of preoptic hypothalamic neurons: anatomical and functional correlates.

Merchenthaler

López

Negro‐Vilar

1990

Proc. Natl. Acad. Sci. U.S.A.

134

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Colocalization of neurotransmitters, including neuropeptides and amines, in the same neuron of certain areas or well-defined nuclei of the central and peripheral nervous systems appears to be the rule rather than the exception. The coexistent neurotransmitters can be coreleased and interact at pre-and postsynaptic levels in a synergistic or antagonistic manner. Galanin is a recently isolated and characterized "gut-brain" peptide. It is colocalized with many neurotransmitters in both the central and the peripheral nervous systems. Among other regions in the central nervous system, galanin is present in neuronal perikarya of the septum and the hypothalamus. The dense accumulation of nerve terminals in the external zone of the median eminence suggests that galanin is an important peptide regulating neuroendocrine functions. Although most galanin and luteinizing hormonereleasing hormone (LHRH) neurons have a distinctly different morphology, a subset of galanin-immunoreactive perikarya in the diagonal band of Broca and the medial preoptic area, near the organum vasculosum of the lamina terminalis, have morphological features similar to those of LHRH neurons. By using double-labeling immunocytochemistry, we have found that in the preoptic region of the male rat brain 15-20% of these "LHRH-like" galanin-immunoreactive neurons are also immunopositive for LHRH. Moreover, in the medial preoptic area and the diagonal band of Broca, some of the single-labeled LHRH cells are surrounded with galanin-immunoreactive nerve terminals, suggesting that LHRH perikarya have synaptic contacts with galanin-immunoreactive terminals. Additional studies indicated that galanin can readily enhance in vitro release of LHRH from nerve terminals in the median eminence.The observations that (i) galanin is coexpressed with LHRH, (ii) galanin seems to innervate LHRH-producing neurons, and (iii) galanin acts as a putative neurotransmitter to enhance the release of LHRH suggest that galanin should be considered an important regulator of LHRH-containing neurons and, therefore, of reproductive functions.Galanin is a 29-amino acid peptide originally isolated from porcine intestine (1). It is widely distributed in the central and peripheral nervous systems (2-5), the gastrointestinal tract (2, 6, 7), the urogenital tract (8), and the adrenal medulla (9). Moreover, a widespread distribution of galanin binding sites in the nervous system has also been described (10). Immunocytochemical mapping of galanin-immunoreactive structures in the brain indicated that high galanin concentrations occur in the median eminence (ME); in the paraventricular, the supraoptic, the arcuate, and the dorsomedial nuclei of the hypothalamus; in the locus ceruleus; in the spinal trigeminal nucleus; and in the nucleus of the solitary tract (1-4).Although the precise physiological role of galanin has not yet been established, the presence of a dense accumulation of galanin-immunoreactive nerve terminals in the external zone of the ME suggests that galanin is an important h...

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Section: Methodsmentioning

confidence: 99%

Colocalization of galanin and luteinizing hormone-releasing hormone in a subset of preoptic hypothalamic neurons: anatomical and functional correlates.

Merchenthaler

López

Negro‐Vilar

1990

Proc. Natl. Acad. Sci. U.S.A.

134

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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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“…Glutamergic and noradrenergic terminals stimulate the NOergic neuron to release NO by action on their receptors to increase intracellular free calcium in the NOergic neurons, and the calcium combines with calmodulin that activates neural NO synthase (NOS), causing synthesis and release of NO from the neurons. Previous experiments have shown that LH-RH is released from medial basal hypothalamic explants by membrane depolarization by high potassium concentrations [K ϩ ] (24,25), by the specific stimulant Nmethyl-D-aspartate (NMDA) (26)(27)(28)(29)(30)(31)(32), and by a releaser of NO, nitroprusside (NP) (18,26,30,33), whereas inhibition of NO synthesis with the competitive inhibitor of the enzyme N Gmonomethyl-L-arginine (NMMA) blocked NMDA-induced stimulation of LH-RH release, indicating the crucial role of NO in the response.…”

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confidence: 99%

Ascorbic acid acts as an inhibitory transmitter in the hypothalamus to inhibit stimulated luteinizing hormone-releasing hormone release by scavenging nitric oxide

Karanth

Yu²,

Walczewska³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Because ascorbic acid (AA) is concentrated in synaptic vesicles containing glutamic acid, we hypothesized that AA might act as a neurotransmitter. Because AA is an antioxidant, it might therefore inhibit nitric oxidergic (NOergic) activation of luteinizing hormonereleasing hormone (LH-RH) release from medial basal hypothalamic explants by chemically reducing NO. Cell membrane depolarization induced by increased potassium concentration [K ؉ ] increased medium concentrations of both AA and LH-RH. An inhibitor of NO synthase (NOS), N G -monomethyl-L-arginine (NMMA), prevented the increase in medium concentrations of AA and LH-RH induced by high [K ؉ ], suggesting that NO mediates release of both AA and LH-RH. Calcium-free medium blocked not only the increase in AA in the medium but also the release of LH-RH. Sodium nitroprusside, which releases NO, stimulated LH-RH release and decreased the concentration of AA in the incubation medium, presumably because the NO released oxidized AA to dehydro-AA. AA (10 ؊5 to 10 ؊3 M) had no effect on basal LH-RH release but completely blocked high [K ؉ ]-and nitroprusside-induced LH-RH release. N-Methyl-D-aspartic acid (NMDA), which mimics the action of the excitatory amino acid neurotransmitter glutamic acid, releases LH-RH by releasing NO. AA (10 ؊5 to 10 ؊3 M) inhibited the LH-RH-releasing action of NMDA. AA may be an inhibitory neurotransmitter that blocks NOergic stimulation of LH-RH release by chemically reducing the NO released by the NOergic neurons.is present in high concentrations in the hypothalamus (1-3) but its role in the modulation of hypothalamic hormone release is obscure. The brain accumulates AA from the blood and maintains a relatively high concentration (1.1-1.7 mM), independent of AA ingestion (4-7). Neuronal intracellular AA concentrations are 10 times greater than extracellular AA concentration (6, 7). Neuronal activity was shown to increase extracellular AA in vitro (6,(8)(9)(10)(11)(12) and in vivo as determined by voltametry (13). AA is further concentrated in isolated nerve terminals (14). Synaptic vesicles concentrate AA by active transport (15). AA is present in high concentrations in synaptic vesicles of glutamergic neurons (13) and in adrenal medullary catecholamine secretory granules (16,17).The presence of high concentrations of AA in synaptic vesicles and the evidence that it could be released into the extracellular space by neuronal activity suggested to us that AA might be a neurotransmitter. Since high concentrations of AA are already known to be present in the hypothalamus, we hypothesized that AA might control luteinizing hormone-releasing hormone (LH-RH) release, possibly by its antioxidant properties. LH-RH release is controlled by release of nitric oxide (NO) from NOergic interneurons that release the soluble gas in juxtaposition to the LH-RH terminals (18,19). In the terminals, NO activates guanylyl cyclase, leading to an increase in cyclic guanosine monophosphate (cGMP), cyclooxygenase, resulting in increased concentrations of prostagla...

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Glutamate Receptors of the Non-N-Methyl-D-Aspartic Acid Type Mediate the Increase in Luteinizing Hormone-Releasing Hormone Release by Excitatory Amino Acidsin Vitro

Cited by 149 publications

References 34 publications

Colocalization of galanin and luteinizing hormone-releasing hormone in a subset of preoptic hypothalamic neurons: anatomical and functional correlates.

Colocalization of galanin and luteinizing hormone-releasing hormone in a subset of preoptic hypothalamic neurons: anatomical and functional correlates.

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

Ascorbic acid acts as an inhibitory transmitter in the hypothalamus to inhibit stimulated luteinizing hormone-releasing hormone release by scavenging nitric oxide

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