Corticosteroidogenesis by isolated human adrenal cells: Effect of serotonin and serotonin antagonists

Summary The direct effect of serotonin and antiserotonin agents on adrenal steroid biosynthesis was studied in isolated adrenal cells derived from patients with Cushing's syndrome. The results indicate that serotonin increases corticosterone production, while the serotonin antagonists cyproheptadine and methysergide depress adrenal steroid-particularly cortisol and aldosterone-biosynthesis.The authors are indebted to Dr. M. Kárteszi, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, for the determination of plasma ACTH by radioimmunoassay in our patients, and to Prof. P. Vecsei, Department of Pharmacology, University of Heidelberg, providing us with highly specific antisera for corticosteroids RIA-s.     

Effect of air ionization of blood serotonin in vitro.

The effect of negative and positive air ionisation on siliconized blood serotonin was studied in vitro. The experiments showed that within 10 min positive ionisation increased serotonin levels in total blood (+40%), plasma (+90%), erythrocytes (+50%) and thrombocytes (+240%). On the other hand, negative ionization (10 min) lowered the serotonin content of total blood (-30%), plasma (-42.5%), erythrocytes (-41.7%) and thrombocytes (-72.3%), thus confirming the 'Krueger Effect' in vitro.     

Circulating serotonin in vertebrates

The role of circulating serotonin is unclear and whether or not serotonin is present in the blood of non-mammalian species is not known. This study provides the first evidence for the presence of serotonin in thrombocytes of birds and three reptilian species, the endothermic leatherback sea turtle, the green sea turtle and the partially endothermic American alligator. Thrombocytes from a fresh water turtle, American bullfrog, Yellowfin tuna, and Chinook salmon did not contain serotonin. Serotonin is a vasoactive substance that regulates skin blood flow, a major mechanism for endothermic body temperature regulation, which could explain why circulating serotonin is present in warm-blooded species. The temperature sensitivity of human blood platelets with concomitant changes in serotonin content further supports a link between circulating serotonin and thermoregulation. Phylogenetic comparison of the presence of circulating serotonin indicated an evolutionary divergence within reptilian species that might coincide with the emergence of endothermy.Received 2 April 2005; received after revision 15 May 2005; accepted 15 June 2005     

Ovarian serotonin content in relation to ovulation

Summary In the mature cyclic female rat, analysis for ovarian serotonin content reveals comparatively high serotonin content. Fluctuation of serotonin content was observed; peak for serotonin was observed at estrus. In gonadotropintreated immature rats, there was no detected ovarian serotonin using this procedure. It was concluded that ovaries from gonadotropin-treated immature rats are physiologically different from ovaries taken from mature cyclic rats.Supported by NIH Grant RR8111.National Institutes of Health, MBS Trainee.     

Heterogeneous responses of canine basilar and middle cerebral arteries to serotonin at normal and high CO2 tension.

The responses of basilar arteries (BAs) to serotonin were attenuated by high PCO2 (86 +/- 1 mm Hg) and the pH matched acidotic solution (PCO2 37 +/- 1 mm Hg), whereas the responses of middle cerebral arteries (MCAs) were not. High PCO2 decreased the basal tone of both arteries, and the changes in basal tone due to high PCO2 were not influenced by 3 x 10(-7) M imipramine, 10(-5) M pargyline or 10(-4) M aspirin. The responses of BAs to serotonin were attenuated by high PCO2 in the presence of imipramine, pargyline and aspirin. The responses of MCAs to serotonin were not influenced by high PCO2 in the presence of pargyline and aspirin, but attenuated by high PCO2 in the presence of imipramine.     

A circannual rhythm in bovine pineal serotonin

Summary Bovine pineal serotonin (5-HT) was analyzed at the time of the solstices and equinoxes from December, 1975 until June, 1978. The highest values of 5-HT were detected at the winter solstices and lowest values at the summer solstices of each year examined. The peaks in bovine pineal 5-HT correspond with a lessened fertility in cattle reported during the winter months.Supported by NSF grant PCM 77-05734.The authors wish to thank Roeglein's Provision Company, Beef Processing Division and especially H. Schmidt, Foreman.     

Ontogeny of the sex steroid and prolactin receptors in the male rat adrenal gland

Cytosolic estrogen and androgen receptors and membrane prolactin-binding sites in the male adrenal glands showed a definite pattern during sexual development. The level of sexual steroid receptors paralleled adrenal growth, whereas prolactin binding reached its maximum value in mature rats.     

Demonstration of high affinity binding of estradiol in adrenal cortex tissue]

Evidence is presented demonstrating the presence of a high affinity (Ka10(8)M-1), limited capacity (3-4 pmoles/mg protein) estradiol binder in the soluble fraction of the Bovine, Rat and Human adrenal cortex. The binding appears specific to the estrogen structure whereas C19 and C21 steroids do not bind. Upon sucrose density gradient centrifugation, the estradiol binder sedimented at 9 S at low ionic strength and was shifted to 4.5 S in the presence of 0.5 M KCl. This demonstration of a receptor-like moiety for estradiol in the adrenal cortex lends biochemical support to previous observations suggesting that adrenal cortex functions may be modulated by a direct effect of gonadal steroid hormones.     

Studies on the serotonin transporter in platelets

[3H]-Imipramine and [3H]-paroxetine label with high affinity a recognition site which is associated with the serotonergic transporter in blood platelets. The pharmacological profile of [3H]-imipramine and [3H]-paroxetine binding is highly correlated with the potency of drugs to inhibit the uptake of serotonin. Dissociation kinetic experiments suggest that the substrate recognition site for serotonin may be different from the modulatory site which is labeled with [3H]-imipramine or [3H]-paroxetine. The existence of an endocoid acting on the imipramine receptor to modulate the serotonin transporter has been proposed by several laboratories. In clinical studies most laboratories have reported a decrease in Bmax of [3H]-imipramine binding in platelets from depressed untreated patients when compared with matched healthy volunteers. The Bmax of [3H]-imipramine binding in platelets appears to be a state-dependent biological marker in depression.     

Hypnotic effect of serotonin administered in the vago-aortic afferent pathway

A minute amount of serotonin injected in the nodose ganglion circulation area develops abrupt myosis and general electrocortical synchronization activity in "encéphale isolé" Cat preparation. This hypnogenic effect of serotonin can still be reproduced after transection of vago-aortic nerves caudally to the nodose ganglia. The same injections become ineffective after rostral transection of the same pathway. These results suggest that serotonin may trigger some signs of sleep through peripheric nervous elements in which are probably localized in the nodose ganglia.     

Role of serotonin in the hepato-gastroIntestinal tract: an old molecule for new perspectives

Beside its role as a neurotransmitter in the central nervous system, serotonin appears to be a central physiologic mediator of many gastrointestinal (GI) functions and a mediator of the brain-gut connection. By acting directly and via modulation of the enteric nervous system, serotonin has numerous effects on the GI tract. The main gut disturbances in which serotonin is involved are acute chemotherapy-induced nausea and vomiting, carcinoid syndrome and irritable bowel syndrome. Serotonin also has mitogenic properties. Platelet-derived serotonin is involved in liver regeneration after partial hepatectomy. In diseased liver, serotonin may play a crucial role in the progression of hepatic fibrosis and the pathogenesis of steatohepatitis. Better understanding of the role of the serotonin receptor subtypes and serotonin mechanisms of action in the liver and gut may open new therapeutic strategies in hepato-gastrointestinal diseases. Received 15 August 2007; received after revision 1 November 2007; accepted 5 November 2007     

Hypothermia induced in mice by enzyme-mediated depletion of serotonin

Injection of a purified serotonin (and tryptophan)-degrading enzyme into mice produced a pronounced hypothermia when the mice were maintained at 22 degrees C, but not at 30 degrees C. Brain levels of serotonin and tryptophan were strikingly depleted, but concentrations of norepinephrine and dopamine remained unchanged.     

Morphological effects of serotonin and ketanserin on embryonic chick skin in vitro

Cell and organotypical cultures are used to study the direct effect of serotonin and of ketanserin, a serotonin antagonist, on dermal and epidermal cells of embryonic chick skin. Ketanserin stimulates the increase in cell number and inhibits the differentiation, whereas serotonin stimulates differentiation and inhibits the increase in cell number.     

Morphological effects of serotonin and ketanserin on embryonic chick skin in vitro

Summary Cell and organotypical cultures are used to study the direct effect of serotonin and of ketanserin, a serotonin antagonist, on dermal and epidermal cells of embryonic chick skin. Ketanserin stimulates the increase in cell number and inhibits the differentiation, whereas serotonin stimulates differentiation and inhibits the increase in cell number.     

NADP-isocitric dehydrogenase of gerbil adrenal mitochondria: support of steroid hydroxylation

In gerbil adrenal cortex the activity of intramitochondrial NADP-linked isocitric dehydrogenase (IDH) is up to 10-fold greater than the NAD-linked IDH. The NADP-IDH, apparent Km 0.58 mM, Vmax 280 nmoles/min/mg mitochondrial protein, appears to be the major source of reducing equivalents to support adrenal mitochondrial steroid 11B- and 19-hydroxylation in this species.     

Capture and fixation of tritiated serotonin by chick embryo notochord]

The 3 day old Chick notochord capacity to fix tritiated serotonin is maximal in its axis and in cephalic region. Our observations permitting us to find, the intracellular serotonin binding sites, contribute to an explanation of the capture mechanism and suggest a special direct role of the notochord on the monoaminergic neuron cytodifferentiation.     

Adrenal gland growth of the ovine fetus in the end of gestation: evolution of DNA and of membrane proteins]

The adrenal weight of the ovine fetus increases dramatically during late pregnancy. This increase is achieved in three periods: one of DNA duplication between two phases of cellular hypertrophy. During cellular hypertrophy an important biosynthesis of membrane proteins is observed. This development concerns essentially the adrenal cortex.     

Hypothermia induced in mice by enzyme-mediated depletion of serotonin

Summary Injection of a purified serotonin (and tryptophan)-degrading enzyme into mice produced a pronounced hypothermia when the mice were maintained at 22°C, but not at 30°C. Brain levels of serotonin and tryptophan were strikingly depleted, but concentrations of norepinephrine and dopamine remained unchanged.This investigation was supported by grants CA-18844 and CA-08748 awarded by the National Cancer Institute, DHEW. We thank Barbara Morelli and Margaret Costello for their technical assistance.     

Suppression of the immune response by drugs interfering with the metabolism of serotonin

The work was based on the assumption that neurohumoral control of the immune response, particularly in stressed animals, involves central serotoninergic mechanisms. Rats immunized with sheep erythrocytes were stressed by repeated restraints and/or treated with a precursor of serotonin (5-hydroxytryptophan, 5-HTP) or with an inhibitor of serotonin synthesis (parachlorophenylalanine, PCPA). As expected, repeated stresses reduced the plaque-forming cell (PFC) response. Treatment with 5-HTP also reduced the PFC response, and potentiated the immunosuppressive effect of stress. This was accompanied by increased metabolism of serotonin in the brain, as indicated by increased concentration of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in cerebral tissue. Treatment with PCPA also suppressed the PFC response, but this suppression was accompanied by decreased levels of brain serotonin and of 5-HIAA. Plasma corticosterone levels were elevated in rats treated with PCPA. It seems that putative central effects of PCPA on serotoninergic regulation of the immune response were outweighed by its effects on corticosterone secretion and/or on lymphoid cells.     

Suppression of the immune response by drugs interfering with the metabolism of serotonin

Summary The work was based on the assumption that neurohumoral control of the immune response, particularly in stressed animals, involves central serotoninergic mechanisms. Rats immunized with sheep erythrocytes were stressed by repeated restraints and/or treated with a precursor of serotonin (5-hydroxytryptophan, 5-HTP) or with an inhibitor of serotonin synthesis (parachlorophenylalanine, PCPA). As expected, repeated stresses reduced the plaque-forming cell (PFC) response. Treatment with 5-HTP also reduced the PFC response, and potentiated the immunosuppressive effect of stress. This was accompanied by increased metabolism of serotonin in the brain, as indicated by increased concentration of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in cerebral tissue. Treatment with PCPA also suppressed the PFC response, but this suppression was accompanied by decreased levels of brain serotonin and of 5-HIAA. Plasma corticosterone levels were elevated in rats treated with PCPA. It seems that putative central effects of PCPA on serotoninergic regulation of the immune response were outweighed by its effects on corticosterone secretion and/or on lymphoid cells.