Activation of N-methyl-D,L-aspartic acid (NMDA) receptors stimulates growth hormone (GH) secretion. The mechanisms involved in this action are still a matter of debate. Present experiments were carried out to assess specifically: (1) the age-related changes in NMDA effects; (2) the physiological role of NMDA in pulsatile GH secretion; (3) the hypothalamic and/or pituitary actions of NMDA, and (4) the influence of gonadal function on NMDA-induced GH release. NMDA (15 mg/kg i.p.) stimulated GH secretion in neonatal, prepubertal and adult males, this effect being blocked by MK-801, a selective antagonist of NMDA receptors. In adult males, pulsatile GH secretion was abolished after administration of MK-801 and AP-5, antagonists of NMDA receptors. The stimulatory effect of NMDA on GH release was exerted at the hypothalamic level, since in vitro GH secretion was slightly inhibited in the presence of NMDA (0.5 mM). The increase in GH release after NMDA treatment cannot be explained through an increase in GHRH release, as the NMDA effect persisted in animals pretreated with GHRH antiserum and in those neonatally injected with mono- sodium glutamate, a drug that destroys GHRH neurons. In addition, NMDA-induced GH secretion was independent of testicular function since it remained after orchidectomy, testosterone replacement as well as after permanent damage of testicular function by neonatal administration of estrogens (500 µg on day 1 of life). We conclude that NMDA receptors play a physiological role stimulating GH secretion through a hypothalamic mechanism that is, at least partially, not GHRH-dependent, and is not modulated by testicular secretion.

Keywords:
Growth hormone, Somatostatin, Growth hormone-releasing hormone, Excitatory amino acid receptors, Excitatory amino acid receptor antagonists, Gonadal steroids, Puberty
1.
Bertherat J, Bluet-Pajot MT, Epelbaum J: Neuroendocrine regulation of growth hormone. Eur J Endocrinol 1995;132:12–24.
2.
Pinilla L, López F, Aguilar E: The effect of orchidectomy on rat pituitary responsiveness to GHRH depends on age. Acta Endocrinol (Copenh) 1990;122:349–353.
3.
Wehrenberg WB, Baird A, Ying SY, Ling N: Effects of testosterone and estrogen on the pituitary growth hormone response to growth hormone-releasing factor. Biol Reprod 1985;32:369–375.
4.
Aguilar E, Tena-Sempere M, Pinilla L: 5-α-Androstane diol stimulates the pituitary growth hormone responsiveness to growth hormone-releasing hormone more effectively than testosterone or dihydrotestosterone in rats. Acta Endocrinol (Copenh) 1992;126:162–166.
5.
Van den Pol A, Waurin J, Dudek F: Glutamate, the dominant excitatory transmitter in neuroendocrine regulation. Science 1990;250:1276–1278.
6.
Brann WD, Mahesh VB: Excitatory amino acids: Evidence for a role in the control of reproduction and anterior pituitary hormone secretion. Endocr Rev 1997;18:678–700.
7.
Mason GA, Bissette G, Nemeroff CB: Effects of excitotoxic amino acids on pituitary hormone secretion in the rat. Brain Res 1983;289:366–369.
8.
Acs Z, Lonart G, Makara GB: Role of hypothalamic factors (growth hormone-releasing hormone and gamma-aminobutyric acid) in the regulation of growth hormone secretion in the neonatal and adult rat. Neuroendocrinology 1990;52:156–160.
9.
Pinilla L, Tena-Sempere M, Gonzalez D, Aguilar E: Positive role of non-N-methyl-D-aspartate receptors in the control of growth hormone secretion in male rats. J Endocrinol Invest 1996;19:353–358.
10.
Cocilovo L, Colonna V, Zoli M, Biagini G, Settembrini BP, Muller EE, Cocci D: Central mechanisms subserving the impaired growth hormone secretion induced by persistent blockade of NMDA receptors in immature male rats. Neuroendocrinology 1992;55:416–421.
11.
Cicero TJ, Meyer ER, Bell RD: Characterization and possible opiod modulation of N-methyl-D-aspartic acid induced increases in serum luteinizing hormone levels in the developing male rat. Life Sci 1988;42:1725–1732.
12.
Bourguignon JP, Gerard A, Mathieu J, Mathieu A, Franchimont P: Maturation of the hypothalamic control of pulsatile gonadotropin-releasing hormone secretion at onset of puberty. I. Increased activation of N-methyl-D-aspartate receptors. Endocrinology 1990;127:873–881.
13.
Brann DW, Mahesh VB: Excitatory amino acid regulation of gonadotropin secretion: Modulation by steroid hormones. J Steroid Biochem Mol Biol 1992;41:847–850.
14.
Luderer U, Strobl FJ, Levine JE, Schwartz NB: Differential gonadotropin responses to N-methyl-D,L-aspartate in metestrous, proestrous, and ovariectomized rats. Biol Reprod 1993;48:857–866.
15.
Pinilla L, Tena-Sempere M, Aguilar E: Effects of LHRH, naloxone and N-methyl-D-aspartic acid on serum gonadotropin concentrations in neonatally estrogenized female rats. Neuroendocrinology Lett 1994;16:233–239.
16.
Pinilla L, Tena-Sempere M, Aguilar E: The role of excitatory amino acid pathways in the control of pituitary function in neonatally oestrogenized male rats. J Endocrinol 1995;147:51–57.
17.
Mallo F, Lamas JA, Casanueva FF, Dieguez C: Effect of retinoic acid deficiency on in vivo and in vitro GH responses to GHRH in male rats. Neuroendocrinology 1992;55:642–647.
18.
Lorenzo MJ, Sanchez-Franco F, de los Frailes MT, Reichlin S, Fernandez G, Cacicedo L: Synthesis and secretion of vasoactive intestinal peptide by rat fetal cerebral cortical and hypothalamic cells in culture. Endocrinology 1989;125:1983–1990.
19.
Benitez L, Mallo F, Alvarez C, Burguera B, Sanchez-Franco F, Dieguez C: Estrogen-dependent effects of bombesin on in vivo growth hormone secretion in the rat. Neuroendocrinology 1990;52:608–611.
20.
Greenwood FC, Hunter WM, Glover JS: The preparation of 131I-labelled human growth hormone of high specific radioactivity. Biochem J 1963;89:114–123.
21.
MacDonald MC, Wilkinson M: Characterization and ontogenesis of N-methyl-D-aspartate evoked luteinizing hormone secretion in immature female rats. J Neuroendocrinol 1992;4:223–229.
22.
Somana R, Visessuwan S, Samridtong A, Holland R: Effect of neonatal androgen treatment and orchidectomy on pituitary levels of growth hormone in the rat. J Endocrinol 1978;79:399–400.
23.
Gabriel SM, Rocancio JR, Ruiz NS: Growth hormone pulsatility and the endocrine milieu during sexual maturation in male and female rats. Neuroendocrinology 1992;56:619–628.
24.
Veneroni O, Cocilovo L, Müller EE, Cocchi D: Delay of puberty and impairment of growth in female rats given a noncompetitive antagonist of NMDA receptors. Life Sci 1990;47:1253–1260.
25.
Arce V, Garcia Barros M, Vara E, Lima L, Tresguerres JAF, Devesa J: Clonidine potentiates the growth hormone response to a growth hormone-releasing hormone challenge in hypothalamic growth hormone-releasing hormone-deficient rats. Neuroendocrinology 1991;61:552–558.
26.
Baht GK, Mahesh VB, Chu ZW, Chorich LP, Zamorano PL, Brann DW: Localization of the N-methyl-D-aspartate R1 receptor subunit in specific anterior pituitary hormone cell types of the female rat. Neuroendocrinology 1995;62:178–186.
27.
Lindström P, Ohlsson L: Effects of N-methyl-D,L-aspartate on isolated rat somatotrophs. Endocrinology 1992;131:1903–1907.
28.
Login IS: Direct stimulation of pituitary prolactin release by glutamate. Life Sci 1990;47:2269–2275.
29.
Sah P, Hestrin S, Nicoll RA: Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons. Science 1989;246:815–818.
30.
Tapia Arancibia L, Astier H: Glutamate stimulates somatostatin release from diencephalic neurons in primary culture. Endocrinology 1988;123:2360–2366.
1999
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