Blockade of Serotonin Induced GH Secretion in Rats by Melatonin and Cyproheptadine

Abstract

5-Hydroxy-L-tryptophan is a potent stimulus for growth hormone (GH) secretion in normal rats. This stimulus is completely blocked by melatonin and also by the serotonin antagonist, cyproheptadine.Materiala ancl Methods Groups of non-handled male and female Wistar rats 80 days old were injected intraperitoneally with the following drugs or drug combinations dissolved in 0.5 ml physiological saline containing 20% v/v ethanol: 5-hydroxy-L-tryptophan (5-HTP, 10 mg/kg); 5-HTP (10 mg/kg) plus melatonin (80 mg/kg); 5-HTP (10 mg/kg) plus cyproheptadine (10 mg/kg). Thirty minutes later the rats were decapitated and their blood collected. The serum level of radioimmunoassayable (RIA) GH of each rat was determined in the one assay using materials supplied by Dr. A Parlow (NIAMD, Rat Pituitary Hormone Program). The assay had a lower level of sensitivity of 4 ug/ml, a within assay precision (95% confidence limits) at 15 ng/ml of ± 8 ng and at 120 ng/ml ± 42 ng. Data were evaluated statistically using Student's t-test. ResultaThe GH responses and serum GH levels of male and female rats receiving the same treatment were virtually identical and the results for both sexes are combined in the Figure. S-HTP caused a highly signi!icant elevation of RIA GH (p < 0.0005). i l z " i 10 E ~ • • 10 Figure .... •• 10 COilTlIOLI . •• 13 I-NTP + Mn ••• I-NTP + CypThis effect was completely blocked by the simultaneous administration of melatonin (MEL) or cyproheptadine (CYP). 5-HTP Vs 5-HTP+MEL, p < 0.0005 and 5-HTP Vs 5-HTP+CYP, P < 0.0005. The level of GH achieved by 5-HTP+MEL was not signi!icantly different from the controls, but with 5-HTP+CVP the level was significantly lower than controls (p < 0.05). The serum RIA rat GH levels for each test group (± SEM) are shown in the Figure. "n" refers to the number of animals in each group. DiIcussionThe observation that 5-HTP, which elevates brain serotonin levels, is a potent stimulus for rat GH secretion supports the postulate that rat GH is released via serotoninergic pathways (Collu, FralJchini, Visconti and Martini 1972). The data show this stimulus to be blocked by the serotonin antagonist cyproheptadine and more importantly, by melatonin. We propose that the pineal gland is an important regulator of GH secretion, exerting inhibitory (melatonin) control via the hypothalamo-pituitary axis.

Suppression of Human Growth Hormone Secretion by Melatonin and Cyproheptadine

“…Melatonin was selected as a possible inhibitor of brain serotonin receptors in this investigation and in studies on rat GH secretion (7)(8)(9) because it is an 0-methylated derivative of serotonin. We have previously hypothesized (21) and recently shown (22,23) that 0-methylation of dopamine results in derivatives that inhibit the actions of dopamine by competing for its hypothalamic receptor sites.…”

“…Collu, Fraschini, Visconti, and Martini (6) have demonstrated that intraventricular administration of serotonin causes GH release in the rat. Our studies (7)(8)(9) have shown that rat GH secretion is stimulated by intraperitoneal administration of 5-HTP and, furthermore, that it is inhibited by serotoninergic blockade and also by the pineal gland hormone, melatonin, which appears to act by competing with ser-otonin for serotonin receptor sites (9). The GH release observed in humans after the onset of slow-wave sleep (10) has also been suggested to originate via serotoninergic pathways (3,11).…”

The Pharmacology of the Pineal Gland

“…High doses of melatonin (SO mg/kg) reportedly suppress the secretion of growth hormone (GH) (115,116); this action may be related to the effect of melatonin on brain serotonin levels (117). It has also been reported that melatonin decreases the somatomedin-like activity of rat plasma (11S).…”