ABSTRACT
Recently, we have reported in immature female rats that short-term blockade of glutamate receptors of the N-methyl-D-aspartic acid (NMDA) subtype by the noncompetitive antagonist MK-801 induced a reduction of growth rate, basal and stimulated growth hormone (GH) release and plasma somatomedin C levels. In the present study, we investigated in immature male rats the mechanism(s) through which agonists and antagonists of glutamate receptors affect GH secretion. In 21-day-old male rats, administration of MK-801 (0.2 mg/kg i.p.b.i.d.) for 10 days induced a significant impairment of growth rate, which was unrelated to a significant reduction of food intake. GH secretion from anterior pituitary fragments of MK-801-treated rats was not significantly reduced under basal conditions but was significantly less under stimulation by 40 mM K+. Incubation of dispersed pituitary cells of 31-day-old rats with N-methyl-aspartic acid (1 and 100 microM), alone or associated with MK-801 (1 microM) did not change GH secretion. Semi quantitative densitometric analysis of hypothalami of MK-801-treated rats evidenced a clearcut decrease in the intensity of GHRH-like immuno-reactivity (LI) staining in the median eminence (ME), whereas no difference was observed in the ME-somatostatin (SS)-LI. Finally, GHRH mRNA but not SS-mRNA, evaluated by slot-blot hybridization, was reduced in the hypothalamus of MK-801-treated rats. These and our previous data would demonstrate that NMDA glutamate receptors play an important role in the neuroendocrine control of GH secretion in the rat, and suggest an action mediated by GHRH-secreting neurons.
Subject(s)
Dizocilpine Maleate/pharmacology , Growth Hormone/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Cells, Cultured , Gene Expression , Growth Hormone-Releasing Hormone/genetics , Growth Hormone-Releasing Hormone/metabolism , Hypothalamus/metabolism , Insulin-Like Growth Factor I/metabolism , Male , Pituitary Gland, Anterior/drug effects , Pituitary Gland, Anterior/metabolism , Potassium/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Inbred Strains , Receptors, N-Methyl-D-Aspartate/physiology , Somatostatin/genetics , Somatostatin/metabolismABSTRACT
Reportedly, excitatory amino acids are involved in the control of gonadotropin secretion of rats and non-human primates. The aim of this study was to investigate the effect of chronic blockade of NMDA (N-methyl-D-aspartic acid) receptors by the non competitive receptor antagonist MK-801 on gonadotropin secretion and the onset of puberty in female rats. Moreover, since in humans alterations of the timing of puberty frequently coexist with disturbances of body growth, suggesting a common etiology for both events, we evaluated the effect of MK-801 also on the neural mechanisms controlling growth hormone (GH) secretion. Twenty-one-day-old female rats were treated with MK-801 (0.2 mg/kg ip, bid) or placebo for 10 days and were killed after 7 days of withdrawal. Administration of MK-801 induced a significant impairment of growth rate without altering food intake, and a delay in vaginal opening. Pituitaries from rats treated with MK-801 had a reduced luteinizing hormone (LH) content, and secreted in vitro lower amounts of LH both under basal and LHRH-stimulated conditions. MK-801 treated rats had a lower pituitary GH content and basal and GHRH-stimulated GH release and reduced plasma insulin-like growth factor-I levels. These data indicate that blockade of NMDA receptors in a critical period of the female rat life-span: 1) delays puberty by reducing gonadotropin secretion; 2) impairs growth rate by reducing GH secretion, with a mechanism still to be clarified.