Neuroendocrine effects of quipazine in man in health state or with neurological disorders

The role of serotonin (5-HT) in the hypothalamic regulation of human growth hormone (GH) was reassessed through the use of fenfluramine, which selectively releases 5-l·lT from presynaptic terminals. Oral administration of L-dopa plus propranolol induced a potent and sustained GH release in the subjects tested (26 ± 6 ng/ml). The administration of fenfluramine (20 mg i.v. as bolus plus 20 mg/30 min i.v.) completely suppressed the L-dopa-induced GH secretion (2 ± 0.5 ng/ml). On the other hand, when arginine (30 g/30 min i.v.) was used as a GH stimulant of medium intensity (12.7 ± 2.8 ng/ml), fenfluramine at the same dose was not able to alter the pattern of pituitary secretion (11.5 ± 4.2 ng/ml). Fenfluramine alone induced a slight nonsignificant decrease in GH values with a parallel and significant increase in prolactin (PRL) secretion in accordance with the proposed serotoninergic activity of the drug. Rat PRLsecretion by pituitaries incubated in vitro was inhibited by dopamine. Fenfluramine added to the system did not counteract the dopaminergic reduction of PRL release, making unlikely the possibility of an antagonism at the dopaminergic receptor as mechanism of action of fenfluramine on PRL secretion. In conclusion, depending on the stimulus under study, serotoninergic activation by fenfluramine either inhibits or does not alter GH secretion in man. No proof of a serotoninergic stimulatory component on GH regulation has been detected in this study. Fenfluramine is a valuable tool in neuroendocrinological studies, dealing with serotoninergic mechanisms.

Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Depending on the Stimulus, Central Serotoninergic Activation by Fenfluramine Blocks or Does not Alter Growth Hormone Secretion in Man

Casanueva¹,

Villanueva²,

Peñalva³

et al. 1984

“…However, a stimulatory role of 5-HT on cGH release has also been suggested, based on the finding that activation of 5-HT neurotransmission with 5-hydroxytryptophan (5-HTP) increases plasma GH levels [31]. Finally, as happened with dogs, based on data obtained in humans, stimulatory, inhibitory or no influence of serotoninergic pathways have been claimed [3, 4, 5, 7, 9, 10, 11]. However, in light of the poor specificity of most of the drugs used in these studies, it was concluded by most authors that no firm conclusions could be reached [1, 2].…”

Section: Discussionmentioning

confidence: 99%

“…Although in the last two decades considerable insight has been gained with regard to the role played by different neurotransmitter pathways, the mechanisms underlying the serotoninergic control of GH secretion are not yet clear, with stimulatory, inhibitory or no effect having been reported [3, 4, 5, 6, 7, 8, 9, 10, 11, 12]. This limitation has mainly been due to the existence of many different receptors that mediate the serotonin (5-HT) actions, and the lack of suitable specific agonist and antagonist drugs.…”

Section: Introductionmentioning

confidence: 99%

Influence of Different Serotonin Receptor Subtypes On Growth Hormone Secretion

Valverde

Peñalva²,

Diéguez

2000

The role of serotonin (5-HT) in the regulation of growth hormone (GH) secretion remains unclear due to the existence of many different receptors that mediate the 5-HT actions, and the lack of suitable specific agonist and antagonist drugs. In the present work we have taken advantage of the recent development of new selective 5-HT drugs in order to clarify the role played by different 5-HT receptor types and subtypes on GH secretion. The experiments were carried out on beagle dogs. GH-releasing hormone (GHRH) increased basal canine GH (cGH) levels from 0.8 ± 0.2 to 8.8 ± 1.7 µg/l at 15 min. Administration of 5-HT_1D receptor agonist sumatriptan (SUM) induced a cGH peak at 30 min of 12.9 ± 2.7 µg/l. The combined administration of GHRH plus SUM strikingly potentiated cGH release with a peak of 36.9 ± 6 µg/l at 30 min (p < 0.05). Pretreatment with the muscarinic receptor antagonist atropine completely abolished the cGH response to SUM, while the cholinergic agonist pyridostigmine (PYR) did not modify this response (15.3 ± 5 µg/l PYR plus SUM vs. SUM alone 12.9 ± 2.7 µg/l). On the other hand, administration of drugs with activity at 5-HT_2A/C receptors showed a stimulatory role for the 5-HT_2C receptor subtype, since LY-53857 (antagonist 5-HT_2A/C) and DOI agonist (5-HT_2A/C) both modified the GH response stimulated by GHRH (AUC 88.5 ± 30.4 and 400 ± 64.6 vs. 267.3 ± 52.6 respectively), while ketanserin (antagonist 5-HT_2A) did not modify this response. The 5-HT₃ antagonist ICS-205–930 failed to modify either basal or GHRH induced GH responses. In conclusion, our data show that 5-HT_1D receptors play a stimulatory role on GH secretion in the dog, possibly by acting through a decrease in hypothalamic somatostatin release. Similarly, the 5-HT_2C receptor subtypes also appear to play a stimulatory role. However, 5-HT_2A and 5-HT₃ receptors do not appear to be involved in the control of basal and GHRH-induced GH secretion.

“…From our current data, we con clude that HPA hormones modulate the spontaneous GH release pattern. This has implications for the interpretation of neuroen docrine studies in patients with depression, where exaggerated HPA activity often concurs with elevated GH secretion during daytime and decreased GH surges during sleep or following pharmacological stimuli.The pulsatile secretion of GH is primarily under control of two hypothalamic peptides, the growth hormone-releasing hor mone (GHRH) [1,2] and the somatotropin release-inhibiting hormone (SR1H) [3], Besides these regulatory hormones, other neurotransmitters [4][5][6] and hormones [7] influence the release of GH from the pituitary in man and intact rats, aj-noradrenergic, dopamine, serotonin and GABA receptor stimulation leads Received: December 11, 1989 Accepted after revision: March 4, 1991 to an increase ofGH secretion [4,5,8,9]. In addition to GHRH and SRIH.…”

mentioning

confidence: 99%

Influence of Human Corticotropin-Releasing Hormone and Adrenocorticotropin upon Spontaneous Growth Hormone Secretion

Wiedemann¹,

Bardeleben²,

Holsboer³

1991

Hormones of the hypothalamo-pituitary-adrenocortical (HPA-) axis are considered to be of physiological and clinical relevance in regulating spontaneous growth hormone (GH) secretion. To further investigate interdependencies between both systems, we studied the effects of adrenocorticotropin [ACTH(1–24)] and human corticotropin-releasing hormone (h-CRH) upon spontaneous GH secretion in 10 male volunteers. Administration of 1 µg ACTH (1–24), 10 µg h-CRH or saline (control: CTL) every hour from 9.00 to 6.00 p.m. resulted in significant differences of cortisol secretion during the entire observation period (8.00 a.m.-3.00 a.m.) between the three groups (p < 0.001, Friedman two-way ANOVA). Mean area under the time course curve (AUC) values (± SEM) for cortisol expressed as ng × 1,000 × min/ml showed also significant differences between the three treatments from 8.00 a.m. to 3.00 a.m.: CTL 64.0 ± 6.4, ACTH(1–24) 178.5 ± 9.4 (p < 0.01, Wilcoxon test), h-CRH 88.5 ± 5.6 (p < 0.01). The main portion of cortisol was released during daytime from 8.00 a.m. to 11.00 p.m., where the most significant differences in the AUC values emerged: CTL 59.6 ± 5.8, ACTH(1–24) 171.5 ± 8.8 (p < 0.01, Wilcoxon test), h-CRH 80.2 ± 5.1 (p < 0.01). With regard to GH secretion, significant differences became obvious between the three treatments during daytime from 8.00 a.m. to 11.00 p.m. and the sleep-related period from 11.00 p.m. to 3.00 a.m. (p < 0.01 and p < 0.02, Friedman two-way ANOVA). The pulse frequency also differed significantly between the treatments during daytime (p < 0.02). Mean AUC values (± SEM) expressed as ng × min/ml for GH from 8.00 a.m. to 11.00 p.m. were: CTL 2,507 ± 614, ACTH(1–24) 3,419 ± 801 (p < 0.02, Wilcoxon test). AUC values for GH from 11.00 p.m. to 3.00 a.m. were: CTL 2,033 ± 368, ACTH(1–24) 1,136 ± 147 (p < 0.02, Wilcoxon test). Also, the number of GH secretory pulses is increased by stimulation with AOΗ(1–24). Stimulation with h-CRH in the same experimental schedule resulted in allusively similar effects, which were less pronounced. While prolonged exposure of somatotrophs to glucocorticoids results in a reduction of GH secretion, short-term exposition to glucocorticoids as resulting from our present stimulation with ACTH(1–24) enhances the amount of GH released. From our current data, we conclude that HPA hormones modulate the spontaneous GH release pattern. This has implications for the interpretation of neuroen-docrine studies in patients with depression, where exaggerated HPA activity often concurs with elevated GH secretion during daytime and decreased GH surges during sleep or following pharmacological stimuli.