We have evaluated the role of gamma-aminobutyric acid (GABA) in the neuroendocrine control of beta-endorphin (beta-EP) secretion in the rat. Plasma beta-EP and beta-lipotropin (beta-LPH) levels and beta-EP-like immunoreactivity (beta-EPLI) in the anterior pituitary (AP) and neurointermediate lobe (NIL) were determined after administration of GABA antagonist or agonist drugs in male rats under resting conditions or after potent physical stresses. Bicuculline (0.1-0.8 mg/kg BW ip), a GABA receptor antagonist, induced a dose-related rise in plasma beta-EP and beta-LPH levels and a concomitant decrease in beta-EPLI concentrations in the AP but not in the NIL. Muscimol, a potent GABA-mimetic drug, did not alter baseline plasma beta-EP and beta-LPH levels, whether given systemically (1.0-2.0 mg/kg BW ip) or intracerebroventricularly (500 ng/kg BW), but prevented the effect of bicuculline on plasma and AP-beta-EP and beta-LPH concentrations. Administration of foot shock or restraint stress induced a clear-cut activation of the AP-related beta-EP secretion, an effect that was prevented by pretreatment with muscimol. Together, these data show that GABA-ergic mechanisms, probably operating at a central nervous system level, exert an inhibitory action on resting and stimulated beta-EP and beta-LPH secretion. Since no alterations in beta-EP concentrations in the NIL occurred after manipulations with GABA-ergic drugs or stress, and these were detected only in the AP, an interaction between GABA-ergic neurons and CRF neurons is the most likely explanation for the reported findings.
In a previous work, we reported that passive immunization with anti-growth hormone-releasing hormone (GHRH) antibodies (GHRH-Ab) in neonatal rats caused disruption of somatotropic function that was still present 60 d posttreatment. We studied the reversibility of this condition by growth hormone (GH) replacement therapy. Neonatal rats received GHRH-Ab (50 ~U r d t , s.c.) or normal rabbit serum every second day from birth up to postnatal d 10 and received hGH (0.4 &g body weight, s.c., b i d . ) or vehicle in a 2 x 2 factorial design. Animals were studied on d 11 of age. In GHRH-Abtreated rats, GH therapy 1 ) counteracted the reduced body weight and low plasma IGF-I levels; 2) failed to modify the reduced pituitary weight and GH content; 3) further reduced the low plasma GH levels; 4) partially restored the defective GH responsiveness to GHRH; 5) failed to modify the reduced hypothalamic somatostatin and increased GHRH gene expression in the hypothalamus; and 6) reverted the decreased pituitary somatostatin binding. Morphologic and morphometric evaluation of the pituitary gland from GHRH-Ab+GH pups showed that the number of GH-labeled structures was lower than in normal rat serum-GH-treated pups, whereas the total GH immunoreact~ty per unit surface, an index of intracellular hormone concentration, was slightly higher than in vehicle-GH or GHRH-Ab pups. As determined by electron microscopy, somatotropes from GHRH-Ab+GH pups had morphologic features of high cellular activity. It appears that in GHRH-deprived pups GH replacement therapy can normalize most but not all altered indices of the somatotropic function. The effects of GH are mainly directed at the pituitaly, whereas the sensitivity of the hypothalamus to GH replacement is lower. (Pediatr Res 36: 315-322, 1994) Abbreviations GH, growth hormone GHRH, growth hormone-releasing hormone GHRH-Ab, anti-GHRH-antibodies NRS, normal rabbit serum dCTP, deoxycytidine triphosphate PRL, prolactin SS, somatostatin Recent studies by us (1,2) and by other groups (3,4) have shown that rat pups treated with GHRH-Ab may represent a suitable animal model for the study of the human growth disorders caused b y a primary hypothalamic dysfunction. Neonatal administration of GHRH-Ab permanently inhibits the growth rate and alters several indices of the hypophyseal somatotropic function (I). Received November 11, 1993: accepted March 21, 1994. Correspondence and reprint requests: Eugenio E. Muller, MD. Department of Pharmacology. Chemotherapy and Toxicology. University of Milan, via VanviIt is presently unknown whether these changes are due t o the G H R H deficiency itself o r to the consequent reduction of G H secretion. Therefore, we studied the effects of concomitant G H and GHRH-Ab treatment. W e have administered G H daily to GHRH-deprived and control pups from postnatal d 1 to 10 and subsequently evaluated in vivo and in vitro several hypothalamic and pituitary indices of somatotropic activity. METHODStelli 32.
1 Administration of the potent 5-hydroxytryptamine (5-HT) re-uptake inhibitor fluvoxamine (25 mg/kg i.p. for 14 days) to adult cycling female rats did not alter either the number of oestrous episodes or the plasma concentrations of luteinizing hormone determined on days 2, 9 and 14 of treatment. 2 Fluvoxamine (25 mg/kg i.p.) induced in male rats a clear-cut lowering of /3-endorphin-like immunoreactivity from the anterior pituitary, but not the neurointermediate lobe, and increased concomitantly plasma levels of 8-endorphin and ,8-lipotropin.3 Fluvoxamine (12.5 and 25 mg/kg i.p.) stimulated, although not strikingly, prolactin (PRL) secretion in adult male rats, and at 25 mg/kg i.p. potentiated the PRL-releasing effect of 5-hydroxytryptophan (30 mg/kg i.p.). 4 In male rats treated daily with fluvoxamine (25 mg/kg i.p.) the PRL-releasing effect of an additional acute fluvoxamine administration (same dose) was abolished after 4 days maintenance treatment. One week after withdrawal of maintenance, which had been given for 14 days, the challenge dose of fluvoxamine was still unable to raise plasma PRL levels. 5 The endocrine effects of acute fluvoxamine administration are compatible with activation of 5-HT neurotransmission in the central nervous system. The mechanism(s) underlying tolerance to the PRL-releasing action of the drug is presently obscure. Its elucidation should provide insight into the mechanism of action of antidepressant drugs affecting 5-HT function.
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