Differential effects of neuroexcitatory amino acids on corticotropin-releasing hormone-41 and vasopressin release from rat hypothalamic explants

Alfredo Costa, Sharifah A. Yasin, David Hucks, Mary L. Forsling, G. Michael Besser, Ashley Grossman

Research output: Contribution to journalArticle

Abstract

We have investigated the direct effects of different neuroexcitatory amino acids (EAA) on the secretion of CRH-41 and arginine vasopressin (AVP) from the rat hypothalamus maintained in vitro. CRH-41 and AVP released in the medium were assayed by RIA before and after incubation with N-methyl-D-aspartate (NMDA), N-methyl-D,L-aspartic acid, kainate (KA), and quisqualate in the concentration range 1 nM to 1 mM in either the absence or the presence of 1 mM Mg2+ in the medium. In the case of NMDA, the effect of the addition of glycine (1 and 10 μM) to the incubation medium was also studied. Finally, we investigated whether different periods of exposure (up to 100 min) of hypothalamic explants to NMDA and KA would affect CRH-41 release. While no EAA was able to induce CRH-41 release under any of the above conditions, 20-min incubations with NMDA in the dose range of 1 nM to 1 mM in the absence of added Mg2+ significantly stimulated AVP release in a dose-related fashion; the maximum effect occurred at a concentration of 1 mM [ratio of stimulated collection/basal collection: NMDA, 1.51 ± 0.10, controls, 0.86 ± 0.05 (mean ± SEM); P <0.001]. KA also showed a dose-related stimulatory effect in the dose range of 1 nM to 1 mM, with maximal AVP stimulation at 10 MM (KA, 1.91 ± 0.28; controls, 0.90 ± 0.03; P <0.01). The effects of both NMDA and KA on AVP were completely reversed by the competitive antagonists D,L-2-amino-5-phosponovaleric acid and 6-cyano-7-nitroquinoxaline-2,3 dione, respectively, at doses 10 times higher than those of the agonists. N-Methyl-D,L-aspartic acid stimulated AVP secretion only at a dose of 10 mM (P <0.01), whereas quisqualate was ineffective at any concentration. The addition of 1 mM Mg2+ to the medium blocked the effect of NMDA, while attenuating AVP stimulation induced by KA. The stimulatory effect of KA on AVP was significantly reduced by D-L-2-amino-5-phosponovaleric acid (P <0.05), suggesting that KA may also act through NMDA receptors. Moreover, the presence of glycine in the incubation medium did not result in any effect of NMDA on CRH-41 secretion, nor did it appear to potentiate NMDA-induced AVP release. EAA, therefore, appear to stimulate AVP release directly (while having no effect on CRH-41) by acting on hypothalamic NMDA- and non-NMDA (KA)-binding sites, an observation consistent with the finding that both types of receptors are expressed in the rat hypothalamus. These data also suggest that the hypothalamus may constitute the initial site at which EAA elicit activation of the hypothalamo-pituitary-adrenal axis.

Original languageEnglish
Pages (from-to)2595-2602
Number of pages8
JournalEndocrinology
Volume131
Issue number6
Publication statusPublished - Dec 1992

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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