Central Mechanisms Subserving the Impaired Growth Hormone Secretion Induced by Persistent Blockade of NMDA Receptors in Immature Male Rats

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 µM), alone or associated with MK-801 (1 µM) 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 immunoreactivity (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.

Testosterone modulates growth hormone secretion at the hypothalamic but not at the hypophyseal level in the adult male rhesus monkey

“…The ability of NMA to evoke a release of GH has been well documented for rats (Mason et al 1983), pigs (Barb et al 1992), sheep (Estienne et al 1989), holstein bulls (Shahab et al 1993) and monkeys (Plant et al 1989, Medhamurthy et al 1992. The excitatory effects of NMA on GH secretion have been shown to be exerted via the discharge of GHRH from the hypothalamus (Cocilovo et al 1992). It has also been suggested that, in primates, parenterally infused NMA excites NMDA receptors on GHRH neurones located in the median eminence (Medhamurthy et al 1992).…”

Gonadal and Age-Related Influences on NMDA-Induced Growth Hormone Secretion in Male Rats

“…These data indicate that the actions of NMDA are exerted through specific receptors and that endogenous EAAs play a stimulatory role in the control of basal GH secretion in prepubertal males, acting through NMDA receptors. This action could explain the growth retardation shown by male and female rats treated with MK-801 during the prepubertal period [10, 24]. …”

“…However, pentobarbital-anesthetized male rats were used in this study and the ineffectiveness of NMDA could be due to the reduction in pituitary GH content [25]. Finally, it has been shown that administration of MK-801 decreases hypothalamic GHRH gene expression, although chronic treatment with MK-801 was not associated with changes in GH secretion [10]. Moreover, the effects of NMDA on GHRH gene expression have not been reported.…”

“…Previous experiments showed that NMDA and KA given systemically increased GH secretion in prepubertal and adult male rats [7, 8, 9]. The abolition of NMDA effect after destruction of GHRH neurons by neonatal administration of monosodium glutamate (MSG) [8], as well as the reduction in hypothalamic GHRH gene expression after administration of MK-801, an NMDA receptor antagonist [10], have supported the hypothesis that NMDA action is mediated through GHRH neurons [8, 10]. …”

Somatotropic Dysfunction in Growth Hormone-Releasing Hormone-Deprived Neonatal Rats: Effect of Growth Hormone Replacement Therapy

“…Filters were hybridized with a rat GHRH cDNA (plasmid prGRF 2, kindly provided by Dr. Kelly E. Mayo, Northwestern University, Evanston, IL) and rat SS cDNA (plasmid pSR-1, kindly provided by Dr. Richard H. Goodman, Oregon Health Center, Portland, OR). Specificity of hybridization of these probes has already been tested (12,13). Both cDNA probes were labeled with [a-"PI~CTP as previously described for GH gene expression.…”