The Mechanism of Secretion and Metabolism of Gut-Derived 5-Hydroxytryptamine

Serotonin, also known as 5-hydroxytryptamine (5-HT), is a metabolite of tryptophan and is reported to modulate the development and neurogenesis of the enteric nervous system, gut motility, secretion, inflammation, sensation, and epithelial development. Approximately 95% of 5-HT in the body is synthesized and secreted by enterochromaffin (EC) cells, the most common type of neuroendocrine cells in the gastrointestinal (GI) tract, through sensing signals from the intestinal lumen and the circulatory system. Gut microbiota, nutrients, and hormones are the main factors that play a vital role in regulating 5-HT secretion by EC cells. Apart from being an important neurotransmitter and a paracrine signaling molecule in the gut, gut-derived 5-HT was also shown to exert other biological functions (in autism and depression) far beyond the gut. Moreover, studies conducted on the regulation of 5-HT in the immune system demonstrated that 5-HT exerts anti-inflammatory and proinflammatory effects on the gut by binding to different receptors under intestinal inflammatory conditions. Understanding the regulatory mechanisms through which 5-HT participates in cell metabolism and physiology can provide potential therapeutic strategies for treating intestinal diseases. Herein, we review recent evidence to recapitulate the mechanisms of synthesis, secretion, regulation, and biofunction of 5-HT to improve the nutrition and health of humans.     

Prolonged alterations in the serotonin neural system following the cessation of adolescent anabolic-androgenic steroid exposure in hamsters (Mesocricetus auratus).

In hamsters (Mesocricetus auratus), anabolic-androgenic steroid (AAS) exposure during adolescence facilitates offensive aggression that is modulated, in part, by serotonin (5-HT) signaling and development and by signaling and expression of 5-HT1B receptors. To examine whether these effects are persistent or reversible, the authors administered AAS to hamsters, then examined them for aggression at 1, 4, 11, 18, or 25 days following cessation of AAS treatment. Then, 1 day later, hamsters were killed by transcardial perfusion and examined for 5-HT afferents to and 5-HT1B receptor-containing neuronal puncta and somata in areas of the brain altered by AAS, namely, the anterior hypothalamus, ventrolateral hypothalamus, and medial amygdala. Although aggression resulting from AAS exposure returned to control, nonaggressive levels by 18 days following cessation of AAS treatment, alterations in 5-HT afferent innervation and 5-HT1B receptor localization were observed throughout the extended time period examined. These data suggest that adolescent AAS exposure may have long-term, irreversible effects on 5-HT neural systems and that return to nonaggressive behavioral phenotypes following adolescent AAS exposure may not be a function of plasticity in central 5-HT systems. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The BDNF Val66Met polymorphism is associated with rumination in healthy adults.

This study examined associations between the tendency to ruminate and 2 polymorphisms: the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4). Participants were a homogeneous group of healthy, unmedicated, never depressed individuals with few current symptoms of depression (N = 71). Results indicated that met heterozygotes of the BDNF allele were significantly more likely to ruminate than individuals homozygous for the val BDNF allele. There was no association between rumination and the 5-HTTLPR polymorphism. Furthermore, the interaction between the 5-HTTLPR and BDNF polymorphisms did not predict rumination. Results suggest that variation in the BDNF gene may contribute to the tendency to ruminate. Because this association exists in healthy adults, it may represent a susceptibility factor for affective disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serotonin transporter genotype and depressive symptoms moderate effects of nicotine on spatial working memory.

Smokers may use nicotine to self-medicate for situation-specific or person-specific cognitive or affective deficits. Although evidence suggests that nicotine replacement therapy (NRT), relative to placebo, enhances spatial working memory (SWM) in smoking-abstinent smokers with schizophrenia, the extent to which NRT may be helpful in attenuating abstinence-related SWM in other groups with deficits in SWM is unknown. Depressive symptoms are associated with both tobacco smoking and deficits in SWM. Previous studies have found that smoking abstinence increases depressive affect and depression-related hemispheric asymmetries in brain activation. Although the serotonin neurotransmitter system is closely associated with depression and the effects of nicotine, the authors are not aware of any studies that have evaluated the possible role of individual differences in serotonin transporter (5-HTT) genotype and depressive symptoms as moderators of the effects of NRT on SWM. Thus, the current study assessed the effects of NRT (nicotine patch) on SWM in relation to: (1) depressive traits and (2) 5-HTT genotype. Smoking-deprived habitual smokers (N = 64) completed the dot recall test of SWM during counterbalanced and double-blind nicotine and placebo testing sessions. There was a marginal overall effect of NRT on SWM. More importantly, NRT enhanced SWM in 5-HTT short allele carriers, relative to those with two long alleles, and this enhancement in short-allele carriers was greater for individuals with higher levels of depressive symptoms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serotonin levels influence patterns of repetition priming.

Repetition priming in a word-stem completion task was examined in a group of control subjects and in a group of experimental subjects under conditions of acute tryptophan depletion (T-) and tryptophan augmentation (T+). Experimental subjects ingested amino acid compounds that depleted or loaded the body with tryptophan, and word-stem completion priming performance was measured. Results indicate differential effects of T- and T+ manipulations on word-stem completion priming. In the control group, both specific-visual and amodal priming were observed. Conversely, in the T+ condition, specific-visual priming, but no amodal priming, was observed, whereas in the T- condition, amodal priming, but no specific-visual priming, was observed. The authors conclude that serotonin (5-hydroxytryptamine) plays a critical role in repetition priming by helping to modulate which neural systems contribute to priming effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serotonin—Its Synthesis and Roles in the Healthy and the Critically Ill

Serotonin (5-hydroxytryptamine, 5-HT) plays two important roles in humans—one central and the other peripheral—depending on the location of the 5-HT pools of on either side of the blood-brain barrier. In the central nervous system it acts as a neurotransmitter, controlling such brain functions as autonomic neural activity, stress response, body temperature, sleep, mood and appetite. This role is very important in intensive care, as in critically ill patients multiple serotoninergic agents like opioids, antiemetics and antidepressants are frequently used. High serotonin levels lead to altered mental status, deliria, rigidity and myoclonus, together recognized as serotonin syndrome. In its role as a peripheral hormone, serotonin is unique in controlling the functions of several organs. In the gastrointestinal tract it is important for regulating motor and secretory functions. Apart from intestinal motility, energy metabolism is regulated by both central and peripheral serotonin signaling. It also has fundamental effects on hemostasis, vascular tone, heart rate, respiratory drive, cell growth and immunity. Serotonin regulates almost all immune cells in response to inflammation, following the activation of platelets.     

Human umbilical artery smooth muscle exhibits a 2-apb- sensitive capacitative contractile response evoked by vasoactive substances and exprsses mrnas for stim,orai and trpc channelsa

After depletion of intracellular Ca²⁺ stores the capacitative response triggers an extracellular Ca²⁺ influx through store-operated channels (SOCs) which refills these stores. Our objective was to explore if human umbilical artery smooth muscle presented this response and if it was involved in the mechanism of serotonin- and histamine-induced contractions. Intracellular Ca²⁺ depletion by a Ca²⁺-free extracellular solution followed by Ca²⁺ readdition produced a contraction in artery rings which was inhibited by the blocker of Orai and TRPC channels 2-aminoethoxydiphenyl borate (2-APB), suggesting a capacitative response. In presence of 2-APB the magnitude of a second paired contraction by serotonin or histamine was significantly less than a first one, likely because 2-APB inhibited store refilling by capacitative Ca²⁺ entry. 2-APB inhibition of sarcoplasmic reticulum Ca²⁺ release was excluded because this blocker did not affect serotonin force development in a Ca²⁺-free solution. The PCR technique showed the presence of mRNAs for STIM proteins (1 and 2), for Orai proteins (1, 2 and 3) and for TRPC channels (subtypes 1, 3, 4 and 6) in the smooth muscle of the human umbilical artery. Hence, this artery presents a capacitative contractile response triggered by stimulation with physiological vasoconstrictors and expresses mRNAs for proteins and channels previously identified as SOCs.     

Appetite‐Inducing Effects of Homoeriodictyol: Two Randomized,Cross‐Over Interventions

1 Scope

Anorexia of aging, characterized by a decrease in appetite and/or food intake, is a major risk factor of under‐nutrition and adverse health outcomes in elderly people. Recent in vitro evidence suggests homoeriodictyol (HED), a naturally occurring, bitter‐masking flavanone, as a promising agent to increase appetite and food intake.

2 Methods and results

In two cross‐over intervention trials, 30 mg NaHED, either solely (n = 10, Study I) or in combination with a 75 g glucose load (n = 17, study II) were administered to healthy adult subjects. Ratings of hunger were assessed at fasting and either 30 min (Study I) or 120 min (Study II) post intervention. Ad libitum energy intake from a standardized breakfast and plasma changes in hunger‐/satiety‐associated hormones PYY, GLP‐1, ghrelin and serotonin were determined after blood drawings. Effects were more pronounced when NaHED was administered in combination with 75 g glucose since ad libitum energy (+ 9.52 ± 4.60%) and protein (+ 7.08 ± 7.97%) intake as well as plasma ΔAUC ghrelin values increased in study II solely, whereas plasma serotonin concentrations decreased after both interventions.

3 Conclusions

NaHED demonstrated appetizing effects in healthy adults when administered with a glucose load. Long‐term intervention studies are warranted to verify these effects in compromised subjects.