ArticleLiterature Review

Serotonin and the Orchestration of Energy Balance

December 2007
Cell Metabolism 6(5):352-61

December 2007
6(5):352-61

DOI:10.1016/j.cmet.2007.09.012

Source
PubMed

Authors:

The phylogenetically ancient signaling molecule serotonin is found in all species that possess nervous systems and orchestrates diverse behavioral and physiological processes in the service of energy balance. In some instances, the manner in which serotonin signaling influences these processes appears comparable among invertebrate and vertebrate species. Within mammalian species, central nervous system serotonergic signaling influences both behavioral and physiological determinants of energy balance. Within the gastrointestinal tract, serotonin mediates diverse sensory, motor, and secretory functions. Further examinations of serotonergic influences on peripheral organ systems are likely to uncover novel functions consistent with an apparently pervasive association between serotonergic signaling and physiological substrates of energy balance.

Straw as an Alternative to Grass Forage in Horses—Effects on Post-Prandial Metabolic Profile, Energy Intake, Behaviour and Gastric Ulceration

Article

Full-text available

Jul 2021

Straw’s low energy content means it is a roughage option for horses with low energy requirements. Previously, in a field study, straw was associated with an increased risk for gastric ulcers. This study evaluated the effect on gastric ulcers, metabolic profile and behaviour of replacing, in a forage-only ration, 50% of the daily allowance with wheat straw. Six equines were studied in a 2 × 21-day cross-over design. The control diet (CON: 100% grass forage) and the straw diet (S: 50% grass forage and 50% straw [DM basis]) were iso-energetic. Gastroscopy was performed prior to the study and on day 21 and blood samples were collected and behavioural observations were performed. Diet did not affect squamous or glandular gastric ulcer scores (p > 0.05). Feed intake time was longer (p < 0.05) plus energy intake and plasma insulin concentrations were lower on diet S compared to CON (p < 0.0001). Plasma serotonin concentrations tended to be higher on diet S compared to CON (p = 0.05). The results suggest that good hygienic quality wheat straw can be included for up to 50% of the diet without causing gastric ulcers and that it can extend feeding time and promote a metabolic profile more suitable for overweight horses.

Serotonergic Neurons Translate Taste Detection into Internal Nutrient Regulation

Preprint

Full-text available

May 2021

The nervous and endocrine systems coordinately monitor and regulate nutrient availability to maintain energy homeostasis. Sensory detection of food regulates internal nutrient availability in a manner that anticipates food intake, but sensory pathways that promote anticipatory physiological changes remain unclear. Here, we identify serotonergic (5-HT) neurons as critical mediators that transform gustatory detection by sensory neurons into the activation of insulin-producing cells and enteric neurons in Drosophila. One class of 5-HT neurons responds to gustatory detection of sugars, excites insulin-producing cells and limits consumption, suggesting that they anticipate increased nutrient levels and prevent overconsumption. A second class of 5-HT neurons responds to gustatory detection of bitter compounds and activates enteric neurons to promote gastric motility, likely to stimulate digestion and increase circulating nutrients when food quality is poor. These studies demonstrate that 5-HT neurons relay acute gustatory detection to divergent pathways for longer-term stabilization of circulating nutrients.

Leptin activation of dorsal raphe neurons inhibits feeding behavior

Preprint

Apr 2023

Leptin is a homeostatic regulatory element that signals the presence of energy stores -in the form of adipocytes-which ultimately reduces food intake and increases energy expenditure. Similarly, serotonin (5-HT), a signaling molecule found in both the central and peripheral nervous systems, also regulates food intake. Here we use a combination of pharmacological manipulations, optogenetics, retrograde tracing, and in situ hybridization, combined with behavioral endpoints to physiologically and anatomically identify a novel leptin-mediated pathway between 5-HT neurons in the dorsal raphe nucleus (DRN) and hypothalamic arcuate nucleus (ARC) that controls food intake. In this study, we show that microinjecting leptin directly into the DRN reduces food intake in male Sprague-Dawley rats. This effect is mediated by leptin-receptor expressing neurons in the DRN as selective optogenetic activation of these neurons at either their ARC terminals or DRN cell bodies also reduces food intake. Anatomically, we identified a unique population of serotonergic raphe neurons expressing leptin receptors that send projections to the ARC. Finally, by utilizing in vivo microdialysis and high-performance liquid chromatography, we show that leptin administration to the DRN increases 5-HT efflux into the ARC. Overall, this study identifies a novel circuit for leptin-mediated control of food intake through a DRN-ARC pathway, utilizing 5-HT as a mechanism to control feeding behavior. Characterization of this new pathway creates opportunities for understanding how the brain controls eating behavior, as well as opens alternative routes for the treatment of eating disorders. Significance Leptin and serotonin both play a vital role in the regulation of food intake, yet there is still uncertainty in how these two molecules interact to control appetite. The purpose of this study is to further understand the anatomical and functional connections between leptin receptor expressing neurons in the dorsal raphe nucleus, the main source of serotonin, and the arcuate nucleus of the hypothalamus, and how serotonin plays a role in this pathway to reduce food intake. Insight gained from this study will contribute to a more thorough understanding of the networks that regulate food intake, and open alternative avenues for the development of treatments for obesity and eating disorders.

Symbiont-regulated serotonin biosynthesis modulates tick feeding activity

Article

Sep 2021
CELL HOST MICROBE

Ticks are obligate hematophagous arthropods. Blood feeding ensures that ticks obtain nutrients essential for their survival, development, and reproduction while providing routes for pathogen transmission. However, the effectors that determine tick feeding activities remain poorly understood. Here, we demonstrate that reduced abundance of the symbiont Coxiella (CHI) in Haemaphysalis longicornis decreases blood intake. Providing tetracycline-treated ticks with the CHI-derived tryptophan precursor chorismate, tryptophan, or 5-hydroxytryptamine (5-HT; serotonin) restores the feeding defect. Mechanistically, CHI-derived chorismate increases tick 5-HT biosynthesis by stimulating the expression of aromatic amino acid decarboxylase (AAAD), which catalyzes the decarboxylation of 5-hydroxytryptophan (5-HTP) to 5-HT. The increased level of 5-HT in the synganglion and midgut promotes tick feeding. Inhibition of CHI chorismate biosynthesis by treating the colonized tick with the herbicide glyphosate suppresses blood-feeding behavior. Taken together, our results demonstrate an important function of the endosymbiont Coxiella in the regulation of tick 5-HT biosynthesis and feeding.

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

Article

Full-text available

May 2021
INT J MOL SCI

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.

Plasma and milk metabolomics profiles in dairy cows with subclinical and clinical ketosis

Article

Full-text available

Apr 2024
J DAIRY SCI

Ketosis, a commonly observed energy metabolism disorder in dairy cows during the peripartal period, is distinguished by increased concentrations of β-hydroxybutyrate (BHB) in blood. This condition has a negative impact on milk production and quality, causing financial losses. An untargeted metabolomics approach was performed on plasma samples from cows between 5 and 7 DIM diagnosed as controls (CON, BHB <1.2 mM, n = 30), subclinically ketotic (SCK, 1.2 < BHB <3.0 mM, n = 30), or clinically ketotic (CK, BHB >3.0 mM, n = 30). Cows were selected from a commercial farm of 214 Holstein cows (average 305-d yield in the previous lactation of 35.42 ± 7.23 kg/d; parity, 2.41 ± 1.12; body condition score, 3.1 ± 0.45). All plasma and milk samples (n = 90) were subjected to Liquid Chromatography-Mass Spectrometry (LC-MS)-based metabolomic analysis. Statistical analyses was performed using the Graph Pad Prism 8.0, MetaboAnalyst 4.0 and R packages (version 4.1.3). Compared with the CON group, both SCK and CK groups had greater milk fat, freezing point, and fat-to-protein ratio and lower milk protein, lactose, solids-nonfat, and milk density. Within 21 d after calving, compared with CON, the SCK group experienced a reduction of 2.65 kg/d in milk yield, while the CK group experienced a decrease of 7.7 kg/d. Untargeted metabolomics analysis facilitated the annotation of a total of 5,259 and 8,423 metabolites in plasma and milk. Differentially affected metabolites were screened in CON vs. SCK, CON vs. CK, and SCK vs. CK (unpaired t-test, False discovery rate <0.05; and absolute value of log(2)-fold change >1.5). A total of 1,544 and 1,888 differentially affected metabolites were detected in plasma and milk. In plasma, glycerophospholipid metabolism, pyrimidine metabolism, tryptophan metabolism, sphingolipid metabolism, amino sugar and nucleotide sugar metabolism, phenylalanine metabolism, steroid hormone biosynthesis were identified as significant pathways. Weighted gene co-expression network analysis (WGCNA) indicated that tryptophan metabolism is a key pathway associated with the occurrence and development of ketosis. Increases in 5-Hydroxytryptophan and decreases in kynurenine and 3-indoleacetic acid in SCK and CK were suggestive of an impact at the gut level. The decrease of most glycerophospholipids indicated that ketosis is associated with disordered lipid metabolism. For milk, pyrimidine metabolism, purine metabolism, pantothenate and CoA biosynthesis, amino sugar and nucleotide sugar metabolism, nicotinate and nicotinamide metabolism, sphingolipid metabolism, fatty acid degradation were identified as significant pathways. The WGCNA indicated that purine and pyrimidine metabolism in plasma was highly correlated with milk yield during the peripartal period. Alterations in purine and pyrimidine metabolism characterized ketosis, with lower levels of these metabolites in both milk and blood underscoring reduced efficiency in nitrogen metabolism. Our results may help to establish a foundation for future research investigating mechanisms responsible for the occurrence and development of ketosis in peripartal cows.

Sertraline Promotes Health and Longevity in Caenorhabditis elegans

Article

Full-text available

Jan 2024
GERONTOLOGY

Introduction: While several antidepressants have been identified as potential geroprotectors, the effect and mechanism of sertraline on healthspan remain to be elucidated. Here, we explored the role of sertraline in lifespan and healthspan of Caenorhabditis elegans (C. elegans). Methods: The optimal effect concentration of sertraline was first screened in wild-type N2 worms under heat stress conditions. Then, we examined the effects of sertraline on lifespan, reproduction, lipofuscin accumulation, mobility, and stress resistance. Finally, the expression of the 5-HT signaling and aging-related genes was investigated to explore the underlying mechanism, and the lifespan assays were performed in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants. Results: Sertraline extended lifespan in C. elegans with concomitant extension of healthspan as indicated by increasing mobility and reducing fertility and lipofuscin accumulation, as well as enhanced resistance to different abiotic stresses. Mechanistically, ser-7 orchestrated sertraline-induced longevity via the regulation of insulin and AMPK pathways, and sertraline-induced lifespan extension in nematodes was abolished in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants. Conclusion: Sertraline promotes health and longevity in C. elegans through ser-7-insulin/AMPK pathways.

Evaluation of Anorexia in Cancer and Its Association with Autonomic Nervous System Activity Assessed by Heart Rate Variability

Article

Full-text available

Nov 2023

Alterations in the central nervous system in cancer patients are pivotal in determining appetite dysregulation and body weight loss (BWL). Autonomic nervous system activity was tested by measuring heart rate variability (HRV) in cancer patients presenting with anorexia. We considered inpatients with different types of cancer and investigated anorexia using their FAACT scores. HRV was evaluated by a three-channel Holter ECG. The domains of low frequencies (LF, sympathetic activity) and high frequencies (HF, parasympathetic activity) were calculated. Also, SDNN (autonomic activity) and RMSSD (parasympathetic activity) were assessed. We enrolled 56 patients with cancer and 23 controls. In cancer patients, RMSSD and SDNN were lower than in controls (p < 0.001 and p = 0.009). Sympathetic activity (LF nu) was lower in cancer patients than in controls (p = 0.023), including sympathovagal balance (LF/HF nu ratio) (p = 0.025). RMSSD was reduced in anorexic (p < 0.001) and non-anorexic (p = 0.003) cancer patients compared to controls. The SDNN was lower in anorexic cancer patients than in non-anorexic cancer patients (p = 0.025), and it was lower in anorexic cancer patients than in controls (p = 0.001). LF nu was lower in anorexic cancer patients than in controls (p = 0.015), as was LF/HF (p = 0.031). SDNN was negatively correlated with BWL in the cancer group (rho = −0.40; p = 0.007). Our data support the hypothesis that autonomic nervous system dysregulation exists in patients with cancer presenting with anorexia, with implications for its diagnosis and treatment.

Unraveling the periprandial changes in brain serotonergic activity and its correlation with food intake-related neuropeptides in rainbow trout Oncorhynchus mykiss

Article

Full-text available

Aug 2023

This study explored changes in brain serotonin content and activity together with hypothalamic neuropeptide mRNA abundance around feeding time in rainbow trout, as well as the effect of one-day fasting. Groups of trout fed at two (ZT2) and six (ZT6) hours after lights on were sampled from 90 minutes before to 240 minutes after feeding, while additional groups of non-fed trout were also included in the study. Changes in brain amine and metabolite contents were measured in hindbrain, diencephalon and telencephalon, while in the diencephalon the mRNA abundance of tryptophan hydroxylase ( tph1 , tph2 ), serotonin receptors (5htr1a , 5htr1b and 5htr2c ) and several neuropeptides ( npy , agrp1 , cartpt , pomca1 , crfb ) involved in the control of food intake were also assessed. The results showed changes in the hypothalamic neuropeptides that were consistent with the expected role for each in the regulation of food intake in rainbow trout. Serotonergic activity increased rapidly at the time of food intake in the diencephalon and hindbrain and remained high for much of the postprandial period. This increase in serotonin abundance was concomitant with elevated levels of pomca1 mRNA in the diencephalon, suggesting that serotonin might act on brain neuropeptides to promote a satiety profile. Furthermore, serotonin synthesis and neuronal activity appear to increase already before the time of feeding, suggesting additional functions for this amine before and during food intake. Exploration of serotonin receptors in the diencephalon revealed only small changes for gene expression of 5htr1b and 5htr2c receptors during the postprandial phase. Therefore, the results suggest that serotonin may play a relevant role in the regulation of feeding behavior in rainbow trout during periprandial time, but a better understanding of its interaction with brain centers involved in receiving and processing food-related signals is still needed.

Constitutive Serotonin Tone as a Modulator of Brown Adipose Tissue Thermogenesis: A Rat Study

Article

Full-text available

Jun 2023

Brown adipose tissue (BAT), an important regulator of thermogenic and metabolic processes, is considered a promising target to combat metabolic disorders. The neurotransmitter and hormone serotonin (5HT) is a major modulator of energy homeostasis, with its central and peripheral pools acting in opposing ways. To better understand how individual variations in 5HT homeostasis influence the thermogenic functionality of BAT, we used a rat model consisting of two sublines with constitutively increased (high-5HT) or decreased (low-5HT) whole-body 5HT tone, developed by selective breeding for platelet 5HT parameters. We have shown that animals with constitutively low 5HT activity maintained at a standard housing temperature (22 °C) have greater interscapular BAT (iBAT) mass and higher iBAT metabolic activity (as evidenced by measurements of iBAT temperature and glucose uptake), accompanied by increased iBAT mRNA expression of key thermogenic genes, compared to animals with high 5HT tone. In response to further thermogenic challenges—intermittent cold exposure or treatment with a β3-adrenergic agonist—5HT sublines show several functional and molecular differences linking constitutively low endogenous 5HT tone to higher BAT activity/capacity. Overall, the results support a role of 5-HT in the control of BAT thermogenesis They also suggest that individuals with lower 5HT activity may be more sensitive to β3-adrenergic drugs.

Serotonin Receptors and Their Involvement in Melanization of Sensory Cells in Ciona intestinalis

Article

Full-text available

Apr 2023

Serotonin (5-hydroxytryptamine (5-HT)) is a biogenic monoamine with pleiotropic functions. It exerts its roles by binding to specific 5-HT receptors (5HTRs) classified into different families and subtypes. Homologs of 5HTRs are widely present in invertebrates, but their expression and pharmacological characterization have been scarcely investigated. In particular, 5-HT has been localized in many tunicate species but only a few studies have investigated its physiological functions. Tunicates, including ascidians, are the sister group of vertebrates, and data about the role of 5-HTRs in these organisms are thus important for understanding 5-HT evolution among animals. In the present study, we identified and described 5HTRs in the ascidian Ciona intestinalis. During development, they showed broad expression patterns that appeared consistent with those reported in other species. Then, we investigated 5-HT roles in ascidian embryogenesis exposing C. intestinalis embryos to WAY-100635, an antagonist of the 5HT1A receptor, and explored the affected pathways in neural development and melanogenesis. Our results contribute to unraveling the multifaceted functions of 5-HT, revealing its involvement in sensory cell differentiation in ascidians.

THE STUDY OF PREDICTION OF BODY MASS INDEX THROUGH GENETIC POLYMORPHISM OF SEROTONIN TRANSPORTER GENE (SLC6A4) 5-HTTLPR IN RAKMHSU STUDENTS

Article

Full-text available

Apr 2021

Introduction: In recent years obesity has become a major health problem and life style changes, habits aggravated the prevalence of obesity in young children. Many studies have suggested that serotonin has been linked with the occurrence of obesity along with various other factors. Based on these facts we aimed to study the relation of serotonin allele’s expression with BMI of university students. Materials and Methods: The study was a case control involving 66 participants done in Biochemistry department, RAK Medical and Health Sciences University, Ras Al Khamiah. A standardized diet history questionnaire used to calculate the calorie intake. The saliva was collected and using the manufactures guidelines the DNA has been extracted using DNA Genotek kit. The polymerase chain reaction used to detect the polymorphism in the subjects. Finally DNA gel electrophoresis done to detect the alleles in different subjects. Results: The study results showed that BMI, Waist circumference and body weight percentage was significant in overweight and obese subjects. The most common alleles in normal subjects was SS when compared with overweight and obese showing SL, LL. Discussion and Conclusion: Our study was in accordance with other studies which showed L allele associate with obesity. We suggest that, L allele associate is a risk and can be used to assess/predict the obesity. Key words: Obesity, Polymorphism, Overweight, Body mass index, Polymerase chain reaction

Serotonergic control of feeding microstructure in Drosophila

Article

Full-text available

Jan 2023

To survive, animals maintain energy homeostasis by seeking out food. Compared to freely feeding animals, food-deprived animals may choose different strategies to balance both energy and nutrition demands, per the metabolic state of the animal. Serotonin mediates internal states, modifies existing neural circuits, and regulates animal feeding behavior, including in humans and fruit flies. However, an in-depth study on the neuromodulatory effects of serotonin on feeding microstructure has been held back for several technical reasons. Firstly, most feeding assays lack the precision of manipulating neuronal activity only when animals start feeding, which does not separate neuronal effects on feeding from foraging and locomotion. Secondly, despite the availability of optogenetic tools, feeding in adult fruit flies has primarily been studied using thermogenetic systems, which are confounded with heat. Thirdly, most feeding assays have used food intake as a measurement, which has a low temporal resolution to dissect feeding at the microstructure level. To circumvent these problems, we utilized OptoPAD assay, which provides the precision of optogenetics to control neural activity contingent on the ongoing feeding behavior. We show that manipulating the serotonin circuit optogenetically affects multiple feeding parameters state-dependently. Food-deprived flies with optogenetically activated and suppressed serotonin systems feed with shorter and longer sip durations and longer and shorter inter-sip intervals, respectively. We further show that serotonin suppresses and enhances feeding via 5-HT1B and 5-HT7 receptors, respectively.

Olanzapine-induced lipid disturbances: A potential mechanism through the gut microbiota-brain axis

Article

Full-text available

Aug 2022

Objective: Long-term use of olanzapine can induce various side effects such as lipid metabolic disorders, but the mechanism remains to be elucidated. The gut microbiota-brain axis plays an important role in lipid metabolism, and may be related to the metabolic side effects of olanzapine. Therefore, we explored the mechanism by which olanzapine-induced lipid disturbances through the gut microbiota-brain axis. Methods: Sprague Dawley rats were randomly divided into two groups, which underwent subphrenic vagotomy and sham surgery. Then the two groups were further randomly divided into two subgroups, one was administered olanzapine (10 mg/kg/day) by intragastric administration, and the other was administered normal saline by intragastric administration (4 ml/kg/day) for 2 weeks. The final changes in lipid parameters, gut microbes and their metabolites, and orexin-related neuropeptides in the hypothalamus were investigated among the different groups. Results: Olanzapine induced lipid disturbances as indicated by increased weight gain, elevated ratio of white adipose tissue to brown adipose tissue, as well as increased triglyceride and total cholesterol. Olanzapine also increased the Firmicutes/Bacteroides (F/B) ratio in the gut, which was even aggravated by subphrenic vagotomy. In addition, olanzapine reduced the abundance of short-chain fatty acids (SCFAs) metabolism related microbiome and 5-hydroxytryptamine (5-HT) levels in the rat cecum, and increased the gene and protein expression of the appetite-related neuropeptide Y/agouti-related peptide (NPY/AgRP) in the hypothalamus. Conclusion: The abnormal lipid metabolism caused by olanzapine may be closely related to the vagus nerve-mediated gut microbiota-brain axis.

Understanding the effects of serotonin in the brain through its role in the gastrointestinal tract

Article

Jul 2022

The neuromodulatory arousal system imbues the nervous system with the flexibility and robustness required to facilitate adaptive behaviour. While there are well understood mechanisms linking dopamine, noradrenaline and acetylcholine to distinct behavioural states, similar conclusions have not been as readily available for serotonin. Fascinatingly, despite clear links between serotonergic function and cognitive capacities as diverse as reward processing, exploration, and the psychedelic experience, over 95% of the serotonin in the body is released in the gastrointestinal tract, where it controls digestive muscle contractions (peristalsis). Here, we argue that framing neural serotonin as a rostral extension of the gastrointestinal serotonergic system dissolves much of the mystery associated with the central serotonergic system. Specifically, we outline that central serotonin activity mimics the effects of a digestion/satiety circuit mediated by hypothalamic control over descending serotonergic nuclei in the brainstem. We review commonalities and differences between these two circuits, with a focus on the heterogeneous expression of different classes of serotonin receptors in the brain. Much in the way that serotonin-induced peristalsis facilitates the work of digestion, serotonergic influences over cognition can be reframed as performing the work of cognition. Extending this analogy, we argue that the central serotonergic system allows the brain to arbitrate between different cognitive modes as a function of serotonergic tone: low activity facilitates cognitive automaticity, whereas higher activity helps to identify flexible solutions to problems, particularly if and when the initial responses fail. This perspective sheds light on otherwise disparate capacities mediated by serotonin, and also helps to understand why there are such pervasive links between serotonergic pathology and the symptoms of psychiatric disorders.

Protective effects of epigallocatechin‐3‐o‐gallate combined with organic selenium against transforming growth factor‐beta 1‐induced fibrosis in LX‐2 cells

Article

Full-text available

May 2022
J FOOD BIOCHEM

In this study, we investigated the protective effects and possible mechanism of epigallocatechin‐3‐o‐gallate (EGCG) combined with organic selenium in transforming growth factor (TGF)‐β1‐activated LX‐2 cells. After 12 h of starvation, LX‐2 cells were treated with 10 ng/ml of recombinant TGF‐β1 and different concentrations of EGCG, L‐selenomethionine (L‐SeMet), or L‐selenomethylcysteine (L‐SeMC) for 24 h. We found that 100 and 200 μM EGCG combined with 1 mM L‐SeMet or L‐SeMC showed a synergistic effect in decreasing the survival rate of activated LX‐2 cells. In addition, the combination of 100 mM EGCG and 1 mM L‐SeMet or L‐SeMC promoted the apoptosis of activated LX‐2 cells. Compared with the EGCG treatment group, the combination intervention group had significantly suppressed levels of hepatic stellate cell activation markers including alpha‐smooth muscle actin, collagen type I alpha 1, collagen type III alpha 1, 5‐hydroxytryptophan (5‐HT), and 5‐HT receptors 2A and 2B. Moreover, interleukin‐10 levels were decreased, while TGF‐β1 levels were increased after TGF‐β1 activation in LX‐2 culture medium, whereas the combin1ation intervention reversed this phenomenon. The combination treatment had a more pronounced effect than any single treatment at the same dose. These results demonstrated that the combination of EGCG and organic selenium synergistically improves the TGF‐β1‐induced fibrosis of LX‐2 cells to some extent by promoting apoptosis and inhibiting cell activation. Practical applications Here, we found that the effects of epigallocatechin‐3‐o‐gallate (EGCG) + L‐selenomethionine or L‐selenomethylcysteine were more pronounced than those of EGCG alone. Future studies should investigate the protective effects of green tea and selenium‐enriched green tea against hepatic fibrosis and explore the differences in their molecular mechanisms. The results of this study will be helpful for the development and utilization of selenium‐enriched tea for food processing and health supplement production.

Decreased serum S100A10 levels in patients with both schizophrenia and metabolic syndrome

Article

Jan 2020

Bold Behavior Is Associated with Genes That Regulate Energy Use but Does Not Covary with Body Condition in Food-Restricted Snails

Article

Nov 2021
PHYSIOL BIOCHEM ZOOL

Theoretical models about the relationship between food restriction and individual differences in risk-taking behavior (i.e., boldness) have led to conflicting predictions: some models predict that food restriction increases boldness, while other models predict that food restriction decreases boldness. This discrepancy may be partially attributable to an underappreciation for animals' complex physiological responses to food restriction. To understand the proximate mechanisms mediating state-dependent boldness, we used freshwater snails (Helisoma trivolvis) to examine the relationships among food availability, body condition, boldness (latency to reemerge from shell and exploration), and mRNA expression of three genes (adenosine monophosphate-activated protein kinase [AMPK], molluscan insulin-like peptide [MIP], and serotonin receptor [5-HT]) involved in maintaining energy homeostasis during periods of moderate food restriction. Latency to reemerge and exploratory behavior decreased over time, but fed snails were bolder than fasted snails, suggesting that food restriction reduces bold behavior. Although food restriction decreased body condition, there was not a relationship between body condition and latency to reemerge from shell. However, expression of MIP was positively correlated with latency to reemerge from shell. Furthermore, AMPK was positively correlated with MIP and negatively correlated with body condition and 5-HT. Therefore, individual differences in physiological responses to food restriction, not overall body condition per se, appear to be more closely associated with state-dependent bold behavior. Finally, snails that experienced a novel assay environment returned to their initial "shy" behavior, suggesting that habituation to the assay environment may contribute to snails expressing bolder behavior over time.

Towards Drug Repurposing in Cancer Cachexia: Potential Targets and Candidates

Article

Full-text available

Oct 2021

As a multifactorial and multiorgan syndrome, cancer cachexia is associated with decreased tolerance to antitumor treatments and increased morbidity and mortality rates. The current approaches for the treatment of this syndrome are not always effective and well established. Drug repurposing or repositioning consists of the investigation of pharmacological components that are already available or in clinical trials for certain diseases and explores if they can be used for new indications. Its advantages comparing to de novo drugs development are the reduced amount of time spent and costs. In this paper, we selected drugs already available or in clinical trials for non-cachexia indications and that are related to the pathways and molecular components involved in the different phenotypes of cancer cachexia syndrome. Thus, we introduce known drugs as possible candidates for drug repurposing in the treatment of cancer-induced cachexia.

Metabolomics in Bariatric Surgery: Towards Identification of Mechanisms and Biomarkers of Metabolic Outcomes

Article

Full-text available

Oct 2021
OBES SURG

Bariatric surgery has been widely performed for the treatment of obesity and type 2 diabetes. Efforts have been made to investigate the mechanisms underlying the metabolic effects achieved by bariatric surgery and to identify candidates who will benefit from this surgery. Metabolomics, which includes comprehensive profiling of metabolites in biological samples, has been utilized for various disease entities to discover pathophysiological metabolic pathways and biomarkers predicting disease progression or prognosis. Over the last decade, metabolomic studies on patients undergoing bariatric surgery have identified significant biomarkers related to metabolic effects. This review describes the significance, progress, and challenges for the future of metabolomics in the area of bariatric surgery. Graphical abstract

Central 5-HTR2C in the Control of Metabolic Homeostasis

Article

Full-text available

Jul 2021

The 5-hydroxytryptamine 2C receptor (5-HTR2C) is a class G protein-coupled receptor (GPCR) enriched in the hypothalamus and the brain stem, where it has been shown to regulate energy homeostasis, including feeding and glucose metabolism. Accordingly, 5-HTR2C has been the target of several anti-obesity drugs, though the associated side effects greatly curbed their clinical applications. Dissecting the specific neural circuits of 5-HTR2C-expressing neurons and the detailed molecular pathways of 5-HTR2C signaling in metabolic regulation will help to develop better therapeutic strategies towards metabolic disorders. In this review, we introduced the regulatory role of 5-HTR2C in feeding behavior and glucose metabolism, with particular focus on the molecular pathways, neural network, and its interaction with other metabolic hormones, such as leptin, ghrelin, insulin, and estrogens. Moreover, the latest progress in the clinical research on 5-HTR2C agonists was also discussed.

Histological and transcriptomic analysis of adipose and muscle of dairy calves supplemented with 5-hydroxytryptophan

Article

Full-text available

May 2021

In mammals, peripheral serotonin is involved in regulating energy balance. Herein, we characterized the transcriptomic profile and microstructure of adipose and muscle in pre-weaned calves with increased circulating serotonin. Holstein bull calves (21 ± 2 days old) were fed milk replacer supplemented with saline (CON, 8 mL/day n = 4) or 5-hydroxytryptophan (5-HTP, 90 mg/day, n = 4) for 10 consecutive days. Calves were euthanized on d10 to harvest adipose and muscle for RNA-Sequencing and histological analyses. Twenty-two genes were differentially expressed in adipose, and 33 in muscle. Notably, Interferon gamma inducible protein-47 was highly expressed and upregulated in muscle and adipose (avg. log FC = 6.5). Enriched pathways in adipose tissue revealed serotonin’s participation in lipid metabolism and PPAR signaling. In muscle, enriched pathways were related to histone acetyltransferase binding, Jak-STAT signaling, PI3K-Akt signaling and cell proliferation. Supplementation of 5-HTP increased cell proliferation and total cell number in adipose and muscle. Adipocyte surface area was smaller and muscle fiber area was not different in the 5-HTP group. Manipulating the serotonin pathway, through oral supplementation of 5-HTP, influences signaling pathways and cellular processes in adipose and muscle related to endocrine and metabolic functions which might translate into improvements in calf growth and development.

Appetite Problem In Cancer Patients: Pathophysiology, Diagnosis, and Treatment

Article

Full-text available

Feb 2021

AimThis study aims to review the current evidence regarding appetite problem in cancer patients, mainly focusing on pathophysiology, diagnosis, and treatment. IntroductionAnorexia is the common symptom of malnutrition in cancer patients. Recently, the understanding of the pathophysiological mechanism of the appetite problem in cancer patients has been increasing that give impact to rigorous research to find the therapies for improving appetite in cancer patients. DiscussionThe development of anorexia in cancer patients is a complex process that involves many cytokines, receptors, chemical mediators/ substances, hormones, and peptides. Growth and differentiation factor-15 (GDF-15) and toll-like receptor (TLR-4) have recently been found to be implicated in the pathogenesis of anorexia. To help diagnose the appetite problem in cancer patients, several questionnaires can be used, starting from well-known questionnaires such as Functional Assessment of Anorexia Cachexia Therapy (FAACT), Visual Analog Scale (VAS), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ30). Several drugs with different mechanisms of action have been studied to help in improving appetite in cancer patients. New repurposed agents such as anamorelin, mirtazapine, thalidomide, and eicosapentaenoic acid (EPA) have shown a beneficial effect in improving appetite and quality of life in cancer patients, however more phase 3 clinical trial studies is still needed. ConclusionThe pathophysiology of appetite problems in cancer patients is a complex process that involves many factors. Several drugs that target those factors have been studied, however more phase 3 clinical trial studies are needed to confirm the findings from previous studies

Nanomaterials Based Electrochemical Sensors for Serotonin Detection: A Review

Article

Full-text available

Jan 2021

The present review deals with the recent progress made in the field of the electrochemical detection of serotonin by means of electrochemical sensors based on various nanomaterials incorporated in the sensitive element. Due to the unique chemical and physical properties of these nanomaterials, it was possible to develop sensitive electrochemical sensors with excellent analytical performances, useful in the practice. The main electrochemical sensors used in serotonin detection are based on carbon electrodes modified with carbon nanotubes and various materials, such as benzofuran, polyalizarin red-S, poly(L-arginine), Nafion/Ni(OH)2, or graphene oxide, incorporating silver-silver selenite nanoparticles, as well as screen-printed electrodes modified with zinc oxide or aluminium oxide. Also, the review describes the nanocomposite sensors based on conductive polymers, tin oxide-tin sulphide, silver/polypyrole/copper oxide or a hybrid structure of cerium oxide-gold oxide nanofibers together with ruthenium oxide nanowires. The presentation focused on describing the sensitive materials, characterizing the sensors, the detection techniques, electroanalytical properties, validation and use of sensors in lab practice.

Differential effects of citalopram on the intake of high fat or high carbohydrates diets in female and male rats

Article

Full-text available

Jan 2021

Chronic administration of selective serotonin reuptake inhibitors (SSRI), usually prescribed as antidepressants, decreases total energy intake; however, at present the differential effect on the intake of distinct macronutrients and on female vs. male organisms is not clear. On this basis, female and male adult Wistar rats were exposed to two types of diets: (1) a standard balanced diet (BD); or (2) two types of diets simultaneously, (a) one high in carbohydrates (HC); the other (b) high in fat (HF). Both study groups were given a dose of 10 mg/kg/day i.p. of citalopram or a vehicle for 21 days. Food and water consumption and body weight were recorded daily at baseline (BL), during treatment (TX), and post-treatment (PTx1-PTx2). The male rats exposed to BD reduced total energy consumption during treatment with citalopram, but body weight gain decreased both females and males compared to BL. During exposure to the two types of diets, citalopram treatment reduced fat consumption with respect to BL and PTx1 only in the male group. This group also decreased its total energy consumption during TX compared to PTx1. Finally, the females gained less body weight in TX than PTx1, while weight gain in the males during TX decreased with respect to BL and PTx1. Results show a differential effect of citalopram on females vs. males that was dependent on the type of macronutrient administered.

Co-option of neurotransmitter signaling for inter-organismal communication in C. elegans

Preprint

Sep 2018

Biogenic amine neurotransmitters play a central role in metazoan biology, and both their chemical structures and cognate receptors are evolutionarily conserved. Their primary roles are in intra-organismal signaling, whereas biogenic amines are not normally recruited for communication between separate individuals. Here, we show that in C. elegans , a neurotransmitter-sensing G protein-coupled receptor, TYRA-2, is required for avoidance responses to osas#9, an ascaroside pheromone that incorporates the neurotransmitter octopamine. Neuronal ablation, cell-specific genetic rescue, and calcium imaging show that tyra-2 expression in the nociceptive neuron ASH is necessary and sufficient to induce osas#9 avoidance. Ectopic expression in the AWA neuron, which is generally associated with attractive responses, reverses the response to osas#9, resulting in attraction instead of avoidance behavior, confirming that TYRA-2 partakes in sensing osas#9. The TYRA-2/osas#9 signaling system thus represents an inter-organismal communication channel that evolved via co-option of a neurotransmitter and its cognate receptor.

Interplay between Peripheral and Central Inflammation in Obesity-Promoted Disorders: The Impact on Synaptic Mitochondrial Functions

Article

Full-text available

Aug 2020
INT J MOL SCI

The metabolic dysfunctions induced by high fat diet (HFD) consumption are not limited to organs involved in energy metabolism but cause also a chronic low-grade systemic inflammation that affects the whole body including the central nervous system. The brain has been considered for a long time to be protected from systemic inflammation by the blood–brain barrier, but more recent data indicated an association between obesity and neurodegeneration. Moreover, obesity-related consequences, such as insulin and leptin resistance, mitochondrial dysfunction and reactive oxygen species (ROS) production, may anticipate and accelerate the physiological aging processes characterized by systemic inflammation and higher susceptibility to neurological disorders. Here, we discussed the link between obesity-related metabolic dysfunctions and neuroinflammation, with particular attention to molecules regulating the interplay between energetic impairment and altered synaptic plasticity, for instance AMP-activated protein kinase (AMPK) and Brain-derived neurotrophic factor (BDNF). The effects of HFD-induced neuroinflammation on neuronal plasticity may be mediated by altered brain mitochondrial functions. Since mitochondria play a key role in synaptic areas, providing energy to support synaptic plasticity and controlling ROS production, the negative effects of HFD may be more pronounced in synapses. In conclusion, it will be emphasized how HFD-induced metabolic alterations, systemic inflammation, oxidative stress, neuroinflammation and impaired brain plasticity are tightly interconnected processes, implicated in the pathogenesis of neurological diseases.

Feeding, hunger, satiety and serotonin in invertebrates

Article

Full-text available

Aug 2020

Aj Tierney

The serotonergic modulation of feeding behaviour has been intensively studied in several invertebrate groups, including Arthropoda, Annelida, Nematoda and Mollusca. These studies offer comparative information on feeding regulation across divergent phyla and also provide general insights into the neural control of feeding. Specifically, model invertebrates are ideal for parsing feeding behaviour into component parts and examining the underlying mechanisms at the levels of biochemical pathways, single cells and identified neural circuitry. Research has found that serotonin is crucial during certain phases of feeding behaviour, especially movements directly underlying food intake, but inessential during other phases. In addition, while the serotonin system can be manipulated systemically in many animals, invertebrate model organisms also allow manipulations at the level of single cells and molecules, revealing limited and precise serotonergic actions. The latter highlight the importance of local versus global modulatory effects of serotonin, a potentially significant consideration for drug and pesticide design.

Peripheral serotonin regulates glucose and insulin metabolism in Holstein dairy calves

Article

Jul 2020
DOMEST ANIM ENDOCRIN

5-Hydroxytryptophan Suppresses the Abdominal Fat Deposit and Is Beneficial to the Intestinal Immune Function in Broilers

Article

Full-text available

Jun 2020

Background Serotonin (5-HT), a monoaminergic neurotransmitter, involves in the regulation of many physiological functions. In the present study, the effects of 5-hydroxytryptophan (5-HTP), the precursor of 5-HT, on lipid metabolism and intestinal immune function in broiler chickens were investigated in chickens.Methods Two hundred broilers were divided randomly into two groups and fed separately with a corn-soybean basal diet (CD) or the basal diet supplemented with 0.2% 5-HTP.ResultsThe results showed that 5-HTP reduced (P < 0.05) feed intake and the abdominal fat pad weight. 5-HTP treatment tended to upregulate the mRNA level of adiponectin receptor 1 (ADP1R) and ADP2R in abdominal fat but had no significant influence on their protein levels (P > 0.05). In 5-HTP-chickens, lipopolysaccharide exposure decreased secretory immunoglobulin A (sIgA) concentrations in serum and the duodenal contents. Expression of mRNA encoding interleukin (IL), tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) decreased after 5-HTP treatment; however, LPS increased expression significantly in 5-HTP-treated chickens compared with CD chickens. In 5-HTP-chickens, the phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) were reduced, but the phosphorylation of ribosomal p70S6 kinase (p70S6K) was increased in the duodenum.Conclusion In summary, the result suggests that dietary 5-HTP supplementation reduces accumulation of abdominal fat and is beneficial to intestinal immune function.

NRF2 deficiency increases obesity susceptibility in a mouse menopausal model

Article

Full-text available

Feb 2020
PLOS ONE

The risk of metabolic abnormalities in menopausal women increases significantly due to the decline in estrogen level. Nuclear factor E2-related factor 2 (NRF2) is an important oxidative stress sensor that plays regulatory role in energy metabolism. Therefore, an ovariectomized menopausal model in Nrf2-knockout (KO) mice was applied to evaluate the effect of Nrf2 deficiency on metabolism in menopausal females. The mice were divided into four groups according to their genotypes and treatments. Blood samples and bodyweights were obtained preoperatively and in the first to ninth postoperative weeks after overnight fasting. Serum levels of triglycerides (TG), total cholesterol (T-CHO), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and glucose (GLU) were measured at postoperative weeks 0, 1, 3, 5, 7, and 9. Neurotransmitter dopamine (DA) and serotonin (5-HT) was analyzed in brain tissues after sacrifice at postoperative week 9. The results demonstrated that, compared with the corresponding wild-type (WT) mice, KO ovariectomized mice had a greater bodyweight gain (P<0.01). Serum analysis showed that the serum GLU, T-CHO, and TG were significantly lower (P<0.05) but LDL was significantly higher (P<0.05) in the KO control mice than that in WT control mice. However, different from the WT counterparts, an increase in blood GLU level (P<0.05), unchanged T-CHO, TG, and HDL levels, and a significant reduction in LDL (P<0.01) was found in the KO ovariectomized mice. In addition, the level of 5-HT was significantly reduced (P<0.05) in the KO mice after ovariectomy. In conclusion, the combination of Nrf2 deletion and a decline in estrogen level induced a significant increase in bodyweight, which may be associated with their altered glucose and LDL metabolism and decreased 5-HT levels. From a clinical perspective, women with antioxidant defense deficiency may have an increased risk of metabolic abnormalities after menopause.

Gut dysbiosis and serotonin: Intestinal 5-HT as a ubiquitous membrane permeability regulator in host tissues, organs, and the brain

Article

Full-text available

Feb 2020

The microbiota and microbiome and disruption of the gut-brain axis were linked to various metabolic, immunological, physiological, neurodevelopmental, and neuropsychiatric diseases. After a brief review of the relevant literature, we present our hypothesis that intestinal serotonin, produced by intestinal enterochromaffin cells, picked up and stored by circulating platelets, participates and has an important role in the regulation of membrane permeability in the intestine, brain, and other organs. In addition, intestinal serotonin may act as a hormone-like continuous regulatory signal for the whole body, including the brain. This regulatory signal function is mediated by platelets and is primarily dependent on and reflects the intestine's actual health condition. This hypothesis may partially explain why gut dysbiosis could be linked to various human pathological conditions as well as neurodevelopmental and neuropsychiatric disorders.

Comparative morphology of serotonin-immunoreactive neurons innervating the central complex in the brain of dicondylian insects

Article

Jul 2023
J COMP NEUROL

Serotonin (5-hydroxytryptamine) acts as a widespread neuromodulator in the nervous system of vertebrates and invertebrates. In insects, it promotes feeding, enhances olfactory sensitivity, modulates aggressive behavior, and, in the central complex of Drosophila, serves a role in sleep homeostasis. In addition to a role in sleep-wake regulation, the central complex has a prominent role in spatial orientation, goal-directed locomotion, and navigation vector memory. To further understand the role of serotonergic signaling in this brain area, we analyzed the distribution and identity of serotonin-immunoreactive neurons across a wide range of insect species. While one bilateral pair of tangential neurons innervating the central body was present in all species studied, a second type was labeled in all neopterans but not in dragonflies and firebrats. Both cell types show conserved major fiber trajectories but taxon-specific differences in dendritic targets outside the central body and axonal terminals in the central body, noduli, and lateral accessory lobes. In addition, numerous tangential neurons of the protocerebral bridge were labeled in all studied polyneopteran species except for Phasmatodea, but not in Holometabola. Lepidoptera and Diptera showed additional labeling of two bilateral pairs of neurons of a third type. The presence of serotonin in systems of columnar neurons apparently evolved independently in dragonflies and desert locusts. The data suggest distinct evolutionary changes in the composition of serotonin-immunolabeled neurons of the central complex and provides a promising basis for a phylogenetic study in a wider range of arthropod species.

Neural Stem Cell-based Regenerative Therapy: A New Approach to Diabetes Treatment

Article

May 2023

Diabetes mellitus (DM) is the most common metabolic disorder that occurs due to the loss, or impaired function of insulin‐secreting pancreatic beta cells, which are of two types - type 1 (T1D) and type 2 (T2D). To cure DM, the replacement of the destroyed pancreatic beta cells of islet of Langerhans is the most widely practiced treatment. For this, isolating neuronal stem cells and cultivating them as a source of renewable beta cells is a significant breakthrough in medicine. The functions, growth, and gene expression of insulin-producing pancreatic beta cells and neurons are very similar in many ways. A diabetic patient's neural stem cells (obtained from the hippocampus and olfactory bulb) can be used as a replacement source of beta cells for regenerative therapy to treat diabetes. The same protocol used to create functional neurons from progenitor cells can be used to create beta cells. Recent research suggests that replacing lost pancreatic beta cells with autologous transplantation of insulin-producing neural progenitor cells may be a perfect therapeutic strategy for diabetes, allowing for a safe and normal restoration of function and a reduction in potential risks and a long-term cure.

Emerging role of substance and energy metabolism associated with neuroendocrine regulation in tumor cells

Article

Full-text available

Mar 2023

Cancer is the second most common cause of mortality in the world. One of the unresolved difficult pathological mechanism issues in malignant tumors is the imbalance of substance and energy metabolism of tumor cells. Cells maintain life through energy metabolism, and normal cells provide energy through mitochondrial oxidative phosphorylation to generate ATP, while tumor cells demonstrate different energy metabolism. Neuroendocrine control is crucial for tumor cells’ consumption of nutrients and energy. As a result, better combinatorial therapeutic approaches will be made possible by knowing the neuroendocrine regulating mechanism of how the neuroendocrine system can fuel cellular metabolism. Here, the basics of metabolic remodeling in tumor cells for nutrients and metabolites are presented, showing how the neuroendocrine system regulates substance and energy metabolic pathways to satisfy tumor cell proliferation and survival requirements. In this context, targeting neuroendocrine regulatory pathways in tumor cell metabolism can beneficially enhance or temper tumor cell metabolism and serve as promising alternatives to available treatments.

Diet Supplementation of Luteolin Before Fatty Liver Formation Improves Hepatic Steatosis in Obese Mice by Inhibiting Visceral Adipose Tissue Lipolysis

Article

Feb 2023
MOL NUTR FOOD RES

Scope: Serotonin (5-HT)-induced visceral adipocyte lipolysis is essential for the development of obesity-related complications. Diet supplementation of luteolin prevents high-fat diet (HFD)-fed mice against obesity and associated fatty liver. However, independent of the body weight loss, whether dietary luteolin can substantially reduce hepatic steatosis remains unclear. Methods and results: In differentiated 3T3-L1 cells, 5-HT treatment promotes adipocyte lipolysis, while luteolin significantly inhibits 5-HT-induced lipolysis, Ca2+ -PKG cascade, and SIRT1/FoxO1/AMPKα signaling through binding to 5-HT receptor HTR2B. Further, 5-week-old mice are fed with an HFD for 16 weeks. At the 6th, 8th, or 10th weeks of HFD feeding, some mice are switched to a luteolin-containing HFD, respectively. In all HFD-fed mice, body weight gain and body component are unaffected by dietary luteolin. However, diet supplementation of luteolin at the 6th or 8th, rather than at the 10th weeks, alleviates hepatic steatosis. Meanwhile, dietary luteolin reduces epididymal adipose tissue (EAT) lipolysis, and represses the level of lipolytic enzyme, the expression of Htr2b, and the activation of PKG and SIRT1/FoxO1/AMPKα signaling in EAT. Conclusions: Diet supplementation of luteolin before the formation of fatty liver protects HFD-fed mice against ectopic lipid deposition in liver by inhibiting visceral adipocyte lipolysis. This article is protected by copyright. All rights reserved.

Computation with Serotonergic Modulation

Chapter

Jun 2022

Matthew Lewis

Serotonin

Chapter

Sep 2022

Serotonin (5-hydroxytryptamine or 5-HT) is a local hormone (autacoid) and a principal neurotransmitter in the central nervous system (CNS) and peripheral nervous system (PNS). Serotonin modulates both the behavioral and neuropsychological processes such as anger, aggression, mood, reward, perception, attention, memory, appetite, and sexual behavior. The serotonergic neurons form the most complex and largest efferent system in the CNS. The serotonin receptors regulate the release of numerous neurotransmitters such as dopamine, epinephrine, norepinephrine, GABA, glutamate, and acetylcholine. Serotonin is synthesized from the essential amino acid l-tryptophan. Serotonin exerts its physiological functions through 14 distinct receptor subtypes, which are categorized into seven receptor families. Various 5-HT receptor agonists or antagonists are used as anti-emetic drugs, for the treatment of migraine, IBS, and neuropsychiatric disorders.

Metabolic interactions between disease-transmitting vectors and their microbiota

Article

May 2022
Trends Parasitol

Disease-transmitting vectors are living organisms that pass infectious agents from one animal/human to another. The epidemiologically important vectors are usually hematophagous arthropods, including mosquitoes, ticks, triatome bugs, sand flies, and tsetse flies. All of them harbor an endogenous microbiota that functionally complements their host’s biology. Different arthropod vectors are ecologically and behaviorally distinct, and as such, their relationships with symbiotic microbes vary. In this review, we summarize the recent discoveries that reveal how bacterial metabolic activities influence development, nutrition, and pathogen defense in mosquitoes, ticks, triatome bugs, and sand flies. These studies provide a foundation for a systematic understanding of vector–microbiota interactions and for the development of integrated approaches to control vector-borne diseases.

Improved Serotonin Measurement with Fast-Scan Cyclic Voltammetry: Mitigating Fouling by SSRIs

Article

Full-text available

Apr 2022
J ELECTROCHEM SOC

Selective serotonin reuptake inhibitors (SSRIs) have been used for decades to treat disorders linked to serotonin dysregulation in the brain. Moreover, SSRIs are often used in studies aimed at measuring serotonin with fast-scan cyclic voltammetry (FSCV) in living tissues. Here, we show that three different SSRIs – fluoxetine, escitalopram, and sertraline – significantly diminish the faradaic oxidation current of serotonin when employing the commonly used Jackson waveform. Coating CFMs with Nafion resulted in further degradation of peak current, increased response times, and decreased background charging currents compared to bare CFMs. To decrease fouling, we employed a recently published extended serotonin waveform, which scans to a maximum positive potential of +1.3 V, rather than +1.0 V used in the Jackson waveform. Use of this waveform with bare CFMs alleviated the decrease in faradaic current, indicating decreased electrode fouling. Collectively, our results suggest that fouling considerations are important when designing FSCV experiments that employ SSRIs and that they can be overcome by using the appropriate waveform.

Serotonergic fast lane from taste detection to preparatory digestive actions

Article

Mar 2022
NEURON

Nutrient detection through the taste system triggers various physiological changes in the body. In this issue of Neuron, Yao and Scott (2022) identify two distinct classes of serotonergic neurons in Drosophila that transform sweet and bitter taste signals into endocrine and digestive responses.

Dynamic functional connectivity in the static connectome of Caenorhabditis elegans

Article

Apr 2022
CURR OPIN NEUROBIOL

A hallmark of adaptive behavior is the ability to flexibly respond to sensory cues. To understand how neural circuits implement this flexibility, it is critical to resolve how a static anatomical connectome can be modulated such that functional connectivity in the network can be dynamically regulated. Here, we review recent work in the roundworm Caenorhabditis elegans on this topic. EM studies have mapped anatomical connectomes of many C. elegans animals, highlighting the level of stereotypy in the anatomical network. Brain-wide calcium imaging and studies of specified neural circuits have uncovered striking flexibility in the functional coupling of neurons. The coupling between neurons is controlled by neuromodulators that act over long timescales. This gives rise to persistent behavioral states that animals switch between, allowing them to generate adaptive behavioral responses across environmental conditions. Thus, the dynamic coupling of neurons enables multiple behavioral states to be encoded in a physically stereotyped connectome.

In‐depth analysis of proteomic and genomic fluctuations during the time course of human embryonic stem cells directed differentiation into beta cells

Article

Jan 2022

Pluripotent stem cells (PSC) endocrine differentiation at a large scale allows sampling of transcriptome and proteome with phosphoproteome (proteoform) at specific time points. We describe the dynamic time course of changes in cells undergoing directed beta-cell differentiation and show target proteins or previously unknown phosphorylation of critical proteins in pancreas development, NKX6-1, and Chromogranin A (CHGA). We describe fluctuations in the correlation between gene expression, protein abundance, and phosphorylation, following differentiation protocol perturbations at all stages to identify proteoform profiles. Our modeling recognizes outliers on a phenomic landscape of endocrine differentiation, and we describe new biological pathways involved. We have validated our proteomic data by analyzing independent single-cell RNAseq datasets for in-vitro pancreatic islet production and corroborated our findings for several proteins suggestive as targets for future research. The single-cell analysis combined with proteoform data places new protein targets within the specific time point and at the specific pancreatic lineage of differentiating stem cells. We suggest that non-correlating proteins abundances or new phosphorylation motifs of NKX6.1 and CHGA point to new signaling pathways that may play an essential role in beta-cell development. We present our findings for the research community's use to improve endocrine differentiation protocols and developmental studies.

Nutrition, anxiety and hormones. Why sex differences matter in the link between obesity and behavior

Article

Jan 2022
PHYSIOL BEHAV

Obesity and mood disorders are two of the most serious health issues of modern times. These health conditions are often linked, with obesity acting both as a cause and consequence of anxiety and depression. Although sex differences in the relationship between obesity and mood disorders are observed in clinical populations, the relative influence of biology versus societal conditioning is unclear. In part, this is because sex effects are rarely examined in the animal models used to derive our understanding of basic biological mechanisms. Due to the perceived confounding nature of hormonal fluctuations in females, rodent studies examining nutritional effects on behavioral responses are typically restricted to males. Yet, hormones play an important role in mediating effects of diet on behavior. In this mini-review, we outline interactions between obesity, hormones and the brain to illustrate the importance of considering sex-specific effects in studies of nutritional effects on behavior. We highlight the need for a more nuanced understanding of how dietary factors influence these relationships, arguing that such knowledge will help improve clinical health outcomes in the management of both obesity and mood disorders.

Serotonergic neurons translate taste detection into internal nutrient regulation

Article

Full-text available

Jan 2022
NEURON

The nervous and endocrine systems coordinately monitor and regulate nutrient availability to maintain energy homeostasis. Sensory detection of food regulates internal nutrient availability in a manner that anticipates food intake, but sensory pathways that promote anticipatory physiological changes remain unclear. Here, we identify serotonergic (5-HT) neurons as critical mediators that transform gustatory detection by sensory neurons into the activation of insulin-producing cells and enteric neurons in Drosophila. One class of 5-HT neurons responds to gustatory detection of sugars, excites insulin-producing cells, and limits consumption, suggesting that they anticipate increased nutrient levels and prevent overconsumption. A second class of 5-HT neurons responds to gustatory detection of bitter compounds and activates enteric neurons to promote gastric motility, likely to stimulate digestion and increase circulating nutrients upon food rejection. These studies demonstrate that 5-HT neurons relay acute gustatory detection to divergent pathways for longer-term stabilization of circulating nutrients.

Protective Effect of Selenium-Enriched Green Tea on Carbon Tetrachloride-Induced Liver Fibrosis

Article

Jul 2021

The major pathogenic feature of liver fibrosis is that oxidative stress motivation of hepatic stellate cells (HSCs) alters the balance between the synthesis and degradation of extracellular matrix (ECM) and HSCs into proliferative myofibroblasts. Green tea and selenium (Se) can protect the liver from damage; however, the precise mechanism of green tea and the action of Se in green tea on hepatic fibrosis remain unclear. Several studies have demonstrated the profibrogenic role of 5-hydroxytryptamine (5-HT) and 5-hydroxytryptamine receptor (5-HTR) 2A/2B in the liver. The current study aimed to investigate the protective effects and possible mechanisms of selenium-enriched green tea on carbon tetrachloride (CCl4)-induced liver fibrosis in male C57BL/6 J mice. After a 4-week intervention with tea solution, histological analysis of the liver showed that green tea interventions alleviated hepatic fibrosis, which was supported by the changes in collagen type I, collagen type III, and α-smooth muscle actin in the liver. Tea interventions significantly inhibited the CCl4-provoked increase of duodenal 5-HT and tryptophan hydroxylase and hepatic 5-HT and 5-HTR2A/2B levels. All of them were lower in the selenium-enriched green tea group than in regular green tea group. Se-enriched green tea had a more pronounced improvement in liver ECM deposition and scar formation and peripheral 5-HT signals than regular green tea. Thus, green tea, especially those enriched with selenium, can improve liver fibrosis through intestinal 5-HT-hepatic 5-HTR signaling.

Peripheral Selective Oxadiazolylphenyl Alanine Derivatives as Tryptophan Hydroxylase 1 Inhibitors for Obesity and Fatty Liver Disease

Article

Jan 2021

Tryptophan hydroxylase 1 (TPH1) has been recently suggested as a promising therapeutic target for treating obesity and fatty liver disease. A new series of 1,2,4-oxadiazolylphenyl alanine derivatives were identified as TPH1 inhibitors. Among them, compound 23a was the most active in vitro, with an IC50 (half-maximal inhibitory concentration) value of 42 nM, showed good liver microsomal stability, and showed no significant inhibition of CYP and hERG. Compound 23a inhibited TPH1 in the peripheral tissue with limited BBB penetration. In high-fat diet-fed mice, 23a reduced body weight gain, body fat, and hepatic lipid accumulation. Also, 23a improved glucose intolerance and energy expenditure. Taken together, compound 23a shows promise as a therapeutic agent for the treatment of obesity and fatty liver diseases.

Obestatin and Its Fragments: A New Approach to the Regulation of Body Weight under Normal and Pathological Conditions

Article

Apr 2020

Serotonin in Plant Signalling and Communication

Chapter

Full-text available

Sep 2020

Serotonin (5-hydroxytryptamine; 5-HT) is an indoleamine neurotransmitter deriving from tryptophan and is present in almost every single living being on earth such as humans, animals and plants, and regulates numerous physiological functions. It is considered as a vital signalling molecule in plants and animals. 5-HT modulates both growth and developmental processes in plants through different mechanisms. This chapter focuses on the interaction of 5-HT with the signalling pathways known to modulate various aspects of growth and developmental processes in plants such as root architecture, shoot organogenesis, flowering and reproduction as well as pigmentation, senescence and defence responses. Special emphasis has been given to calcium signalling, auxin phytohormones interaction, antioxidant activity and reactive oxygen species signalling. Moreover, we also highlight the different techniques that are currently employed for the analysis, detection and quantification of 5-HT in plants. A brief overview of the history and biosynthesis of 5-HT is also presented.

Low vitamin D diet lowers cerebral serotonin concentration in mature female mice

Article

Jul 2020
NUTR RES

Low circulating 25-hydroxyvitamin D (25OHD) is commonly found in obese individuals and is often attributed to a volume dilution effect of adipose tissue. However, low vitamin D (LD) intake may contribute to the obesity itself. In this study, we examine whether low vitamin D status contributes to increased food intake and weight gain and can be explained by altered brain serotonin metabolism in 8 month-old female C57BL/6 J mice. In a first experiment, mice were fed a 45% high fat diet (HFD) containing different amounts of vitamin D at low (100 IU/kg), normal (1000 IU/kg) or high (10 000 IU/kg) intake. After 10 weeks, mice fed LD had greater energy intake, weight gain, total and hepatic fat than the higher vitamin D groups (P < .05). In a second experiment, mice were examined for the central serotonin regulation of food intake after a 10% normal-fat diet (NFD) or 45% HFD containing low (100 IU/kg) or normal (1000 IU/kg) vitamin D. After 10 weeks, both HFD and LD diets attenuated circulating 25OHD concentration. Additionally, LD intake lowered cortical serotonin level, regardless of dietary fat intake (P < .05). In the arcuate and raphe nuclei, gene expression of vitamin D 1α-hydroxylase was lower due to LD during HFD feeding (P < .05). Tryptophan hydroxylase-2 and serotonin reuptake transporter gene expression was not altered due to LD. Overall, these findings suggest that a LD diet alters peripheral 25OHD, reduces central serotonin, and may contribute to weight gain in an obesogenic environment.

Serotonin-like immunoreactivity in the taste bud of the mouse circumvallate papilla

Article

Full-text available

Jan 1985

Takashi Uchida

Serotonin-like immunoreactivity in the circumvallate taste buds of untreated and serotoninor 5-hydroxytryptophan (5-HTP, a precursor of serotonin)-treated mice were investigated by a modified PAP method with light microscopy and protein A-colloidal gold method with electron microscopy. As a control, supraependymal nerve plexus was immunostained by the same metho. In both untreated and serotonin-treated mice, no specific immunostaining was seen in the taste bud, whereas supraependymal nerve plexuses of the lateral and third ventricles contained nerve fibers showing a distinct serotonin-like immunoreactivity. After intraperitoneal injection of 5-HTP, some taste bud cells showed serotonin-like immunoreactivity. Under electron microscopy, colloidal gold particles representing serotonin-like immunoreactivity were seen in the cytoplasm, nucleus and dense-cored vesicles in the type III cell. Positive immunoreaction of the taste bud and supraependymal nerve plexus disappeared by preincubation of the anzi-serotonin serum with serotonin-creatinine sulfate. Immunostaining was not affected by preincubation of the antiserum with 5-HTP. Functional significance of 5-HTP uptake and serotonin synthesis in the type III cell was discussed with particular refernce to taste sensation.

Changes in haemolymph serotonin levels associated with feeding in the blood-sucking bug, Rhodnius prolixus

Article

Full-text available

Dec 1989
J INSECT PHYSIOL

The concentration of serotonin in the haemolymph of fifth-instar larvae of Rhodnius prolixus increase quickly after the onset of feeding. In insects fed on either blood or artificial diet the haemolymph serotonin concentration increases from approx. 7 nM in unfed insects to over 100 nM by 5 min after the onset of feeding whereafter it decreases again to low levels at 20 min. If insects are interrupted after 1 or 2 min of feeding the haemolymph serotonin concentration declines rather than following the predictable pattern of increase achieved when feeding is allowed to continue. One source of serotonin appears to be neurohaemal areas lying upon the abdominal nerves, since the intensity of serotonin-like immunoreactivity is greatly reduced in these areas following 15 min of feeding.We conclude that serotonin is a neurohormone in Rhodnius and that feeding is the natural stimulus responsible for its release and subsequent elevated concentration in the haemolymph.

Evolution and Function in Serotonergic Systems

Article

Full-text available

Dec 2006

Rhanor Gillette

Serotonergic systems of invertebrate and vertebrate central nervous systems (CNS) are functionally similar in multiple characters. Serotonin (5-HT) neurons dispersed throughout the CNS of lophotrochozoan invertebrates (molluscs and leeches) are analogous to vertebrate 5-HT neurons concentrated in the raphe nuclei of mid- and hindbrain: they innervate specific central pattern generators and other circuits of the CNS, receive feedback from them, and support general behavioral arousal. In both groups 5-HT regulates excitatory gain of CNS circuitry and uses similarly diverse 5-HT receptors. Marked contrast, however, exists for roles of 5-HT in regulation of appetite. Where invertebrate 5-HT neurons promote an appetitive state, this role is supplanted in the vertebrates by a peptidergic network centered around orexins/hypocretins, to which the role of 5-HT in arousal is subordinate. In the vertebrates, 5-HT has appetite-suppressant properties. This is paralleled by differing complexities of mechanisms that bring about satiety. Lophotrozoans appear to rely on simple stretching of the gut, with no obvious feedback from true nutrient stores. In contrast, vertebrate appetite is regulated by hypothalamic sensitivity to hormonal signals reporting separately on the status of fat cells and digestive activity, and to blood glucose, in addition to gut stretch. The simple satiety mechanism of a mollusc can be used in value-based foraging decisions that integrate hunger state, taste, and experience (Gillette and others 2000). For vertebrates, where appetite and arousal are regulated by signals from long-lived nutrient stores, decisions can be based on resource need going far beyond simple gut content, enabling value estimation and risk assessment in the longer-term. Thus, connection of nutrient storage depots to CNS circuitry mediating appetite may supply critical substrate for evolving complexity in brain and behavior. This hypothesis may be tested in expanded comparative studies of 5-HT and peptidergic functions in appetite and arousal.

Modulation of Neural Networks for Behavior

Article

Full-text available

Feb 1991

A unique serotonin receptor in choroid plexus linked to phosphatidylinositol turnover

Article

Full-text available

Jul 1986

A novel serotonergic binding site, the 5-HT1C site, has been characterized recently in choroid plexus and several brain regions. The biochemical and physiological roles of this site have not been previously described. In this report we show that serotonin (5-hydroxytryptamine, 5-HT) stimulates phosphatidylinositol turnover in rat choroid plexus. The pharmacology of serotonin-stimulated phosphatidylinositol hydrolysis in choroid plexus was compared to the pharmacology in cerebral cortex, where this response is mediated by the serotonin 5-HT2 receptor. Serotonin increased phosphatidylinositol turnover in choroid plexus by 6-fold and in cerebral cortex by 2.5-fold. Serotonin was greater than 10-fold more potent in choroid plexus (EC50 = 46 nM) than in cerebral cortex (EC50 = 540 nM). The serotonin antagonists ketanserin, mianserin, and spiperone inhibited the response in the two tissues with different potencies. In cerebral cortex all three exhibited nanomolar affinities consistent with their potencies at the 5-HT2 site. In choroid plexus, however, the rank order (mianserin greater than ketanserin much greater than spiperone) and absolute potencies were consistent with binding to the 5-HT1C site. These data suggest that the 5-HT1C site in choroid plexus is a functional receptor that utilizes phosphatidylinositol turnover as its biochemical effector system.

Ingestive Behaviour and Physiology of the Medicinal Leech

Article

Full-text available

Aug 1988

Ingestion lasts 25 min in Hirudo medicinalis and is characterized by pharyngeal peristalsis which fills the crop. This peristalsis has an initial rate of 2·4 Hz which decays smoothly to 1·2 Hz at termination of ingestion. During ingestion, the leech body wall undergoes peristalsis which appears to aid in filling the crop diverticula. Body peristalsis begins at a rate of 10 min−1 and decreases linearly to 2 min−1 at termination. The body also undergoes dorsoventral flexions when blood flow is occluded. Blood meal size increases slightly with leech size: 8·4 g for 1-g leeches and 9·7 g for 2-g leeches. However, relative meal size decreases markedly with increasing animal size; from 8·15 times body mass for 1-g to 4·80 times for 2-g leeches. When intact leeches were exposed to micromolar concentrations of serotonin, there was an increase in the rate of pharyngeal peristalsis and the size of the blood meals. Leeches excrete the plasma from their ingested blood meals. Excretion is activated during ingestion, which increases feeding efficiency by increasing the proportion of blood cells in the ingestate. Excretion continues for 4–6 days following ingestion, removing all the remaining plasma from the ingestate. Leech ingestion comprises stereotyped muscular movements, secretion of saliva and excretion of plasma. A strikingly similar feeding physiology is seen in the bloodsucking insect Rhodnius, and we suggest that efficient sanguivory may require the convergent evolution of similar ingestive mechanisms.

125I-Lysergic acid diethylamide binds to a novel serotonergic site on rat choroid plexus epithelial cells

Article

Full-text available

Jan 1986

125I-Lysergic acid diethylamide (125I-LSD) binds with high affinity to serotonergic sites on rat choroid plexus. These sites were localized to choroid plexus epithelial cells by use of a novel high resolution stripping film technique for light microscopic autoradiography. In membrane preparations from rat choroid plexus, the serotonergic site density was 3100 fmol/mg of protein, which is 10-fold higher than the density of any other serotonergic site in brain homogenates. The choroid plexus site exhibits a novel pharmacology that does not match the properties of 5-hydroxytryptamine-1a (5-HT1a), 5-HT1b, or 5-HT2 serotonergic sites. 125I-LSD binding to the choroid plexus site is potently inhibited by mianserin, serotonin, and (+)-LSD. Other serotonergic, dopaminergic, and adrenergic agonists and antagonists exhibit moderate to weak affinities for this site. The rat choroid plexus 125I-LSD binding site appears to represent a new type of serotonergic site which is located on non-neuronal cells in this tissue.

The 5-HT1B Receptor Agonist CP-94,253 Reduces Food Intake and Preserves the Behavioural Satiety Sequence

Article

Aug 1996

Jason C G Halford

Parabrachial infusion of d-fenfluramine reduces food intake

Article

Apr 2002
PHARMACOL BIOCHEM BE

Systemic administration of the serotonin (5-HT) releaser/reuptake inhibitor, d-fenfluramine decreases consumption of food in mammals. This hypophagic action involves loci at several levels of the neuraxis. Indirect evidence implicates the parabrachial nucleus (PBN) of the pons as one of these regions. Consistent with this hypothesis, unilateral infusion of d-fenfluramine (200, 280, and 400 nmol/0.5 μl) directly into the lateral PBN (LPBN) of male rats reduced food intake by 33%, 56%, and 66% from baseline (7.3±0.7 g) during a 30-min test with chow. Infusions lateral, medial, and dorsal to the PBN were ineffective. Stimulating 5-HT1B receptors in the PBN also reduces feeding. Administration of the selective 5-HT1B agonist CP-93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one) (0, 0.625, 2.5, and 10 nmol/0.5 μl) into the PBN reduced food intake by 25–79%. The selective 5-HT1B antagonist SB-216641 (N-[3-[3-(dimethylamino(ethoxy]-4-methoxyphenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-carboxamide) (2.5 nmol) completely blocked the hypophagic action of the approximate ED50 doses of CP-93,129 (2.5 nmol) and d-fenfluramine (280 nmol). These data strongly suggest that directly or indirectly activating 5-HT1B receptors in the LPBN inhibits feeding and implicates this pontine region in the serotonergic regulation of eating and satiation.

An insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans

Article

Jan 1997

Fan, W. , Boston, B. A. , Kesterson, R. A. , Hruby, V. J. & Cone, R. D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165-168

Article

Jan 1997

DOMINANT alleles at the agouti locus (A) cause an obesity syndrome in the mouse, as a consequence of ectopic expression of the agouti peptide1–6. This peptide, normally only found in the skin, is a high-affinity antagonist of the melanocyte-stimulating hormone receptor (MC1-R)7, thus explaining the inhibitory effect of agouti on eumelanin pigment synthesis. The agouti peptide is also an antagonist of the hypothalamic melanocortin-4 receptor (MC4-R)7–9. To test the hypothesis that agouti causes obesity by antagonism of hypothalamic melanocortin receptors7, we identified cyclic melanocortin analogues10 that are potent agonists or antagonists of the neural MC3 (refs 11, 12) and MC4 receptors. Intracerebroventricular administration of the agonist, MTII, inhibited feeding in four models of hyperphagia: fasted C57BL/6J, ob/ob, and AY mice, and mice injected with neuropeptide Y. Co-administration of the specific melanocortin antagonist and agouti-mimetic SHU9119 completely blocked this inhibition. Furthermore, administration of SHU9119 significantly enhanced nocturnal feeding, or feeding stimulated by a prior fast. Our data show that melanocortinergic neurons exert a tonic inhibition of feeding behaviour. Chronic disruption of this inhibitory signal is a likely explanation of the agouti obesity syndrome.

Localization of serotonin in taste buds: A comparative study in four vertebrates

Article

Mar 1995
J COMP NEUROL

To investigate monoaminergic synaptic mechanisms in taste buds, we examined taste buds of mice, rats, rabbits, and mudpuppies for the presence of the neurotransmitter candidate, serotonin. Immunocytochemistry revealed serotonin-like immunostaining in cells in mammalian taste buds and Merkel-like basal cells in taste buds of mudpuppies. In untreated mudpuppies and in mammals injected with the precursor to serotonin, L-tryptophan, certain taste cells showed serotonin-like immunoreactivity, although in mammalian taste buds the immunostaining was relatively weak. After pretreating mammals with 5-hydroxytryptophan (5-HTP), the intermediate precursor between L-tryptophan and serotonin, several taste cells showed strong immunoreactivity for serotonin. These findings indicate that mammalian taste cells normally contain serotonin and that taste cells can take up 5-HTP and convert it to serotonin. Immunocytochemistry on wholemount preparations demonstrated that serotonergic cells of mudpuppies (i.e., Merkel-like basal cells) were disposed in a ring at the periphery of taste buds. Similarly, serotonergic cells in mammalian taste buds tended to be located at the periphery of taste buds. Based on the position of serotonergic cells in the taste bud and on recent physiological studies on the actions of serotonin in taste buds, we postulate that serotonin functions as a neuromodulator or neurotransmitter in vertebrate taste buds. © 1995 Wiley-Liss, Inc.

Rogers PJ, Blundell JE. Effect of anorexic drugs on food intake and the micro-strucure of eating in human subjects. Psychopharmacology (Berl) 66, 159-165

Article

Nov 1979

Human volunteer subjects of normal weight received oral doses of (+)amphetamine (10 mg) or ()fenfluramine (30 mg and 60 mg) together with a placebo control according to a within-subjects design. The effects of these treatments were monitored by measuring food intake in a test meal, subjective ratings of hunger motivation and the micro-structure of eating behaviour abstracted from videotaped recordings of the test meal. Various measures of the rate of feeding were computed from these recordings. Amphetamine and fenfluramine (60 mg) showed generally similar effects on food intake and on the subjective experience of hunger, but displayed differing actions on the fine structure of eating. Amphetamine increased latency to initiation of eating and increased the rate of food ingestion, whilst fenfluramine slowed the local rate of eating and eliminated the characteristic decline in the rate of feeding across the course of a meal. These findings display certain resemblance to the results of animal experiments involving similar pharmacological manipulations and emphasise the importance of measuring rate of feeding in animal and human studies. The results of this study suggest that the micro-analysis of feeding behaviour not only provides a tool for understanding systems involved in the modulation of food consumption but also reveals information which may be helpful for the use of drugs in the treatment of obesity.

Geyer MA, Puerto A, Menkes DB, Segal DS, Mandell AJ. Behavioral studies following lesions of the mesolimbic and mesostriatal serotonergic pathways. Brain Res 106: 257-269

Article

May 1976
BRAIN RES

The behavior of rats with selective lesions of either the dorsal (B7), median (B8), or lateral (B9) raphe nuclei was compared to that of sham-lesioned controls in a variety of experimental situations. As described previously17, the extent of damage to the midbrain raphe nuclei was determined by fluorescence histochemistry, and the tryptophan hydroxylase and tyrosine hydroxylase activities of 6 forebrain regions were measured for each rat. None of the lesions affected tyrosine hydroxylase activity. Lesions of B7, which reduced tryptophan hydroxylase in the striatum, thalamus, cortex, and hypothalamus, had no significant effect on any of the behavioral measures. Lesions of B9, although twice as large, neither reduced forebrain tryptophan hydroxylase significantly nor affected any of the behavioral variables. However, B8 lesions, which reduced hippocampal, septal, cortical, and hypothalamic tryptophan hydroxylase, had behavioral effects similar to those reported after combined raphe lesions or parachlorophenylalanine. Median raphe-lesioned rats were hyperactive when placed in a novel environment and throughout the dark phase of the light/dark cycle. With respect to locomotor activity, B8-lesioned rats were also hyper-responsive to amphetamine. When placed in a stabilimeter and subjected to repeated air puff stimuli, rats with B8 lesions exhibited larger startle responses. Furthermore, only B8-lesioned animals perseverated when given two unreinforced trials in a Y-maze. All these histologic, biochemical, and behavioral variables were assessed individually for all 39 animals, and a multivariate correlational analysis incorporating the data of this and the preceding paper17 is presented here. These experiments suggest that the mesolimbic serotonergic pathway originating in B8 subserves some of the inhibition necessary to dampen behavioral responsivity.

Male and female 5-HT1B receptor knockout mice have higher body weights than wildtypes

Article

Jan 2001
PHYSIOL BEHAV

5-HT1B receptors have a regulatory role in serotonergic activity and influence feeding behavior and body weight. Because the absence of 5-HT1B receptors may cause changes in this regulation, body weight was measured in male and female 5-HT1B receptor knockout (5-HT1B KO) and wildtype (WT) mice from weaning until the age of 30 weeks. In both genders, 5-HT1B KO mice had a higher body weight than WT mice (17% and 9%, respectively). Body weight was significantly higher for males over the entire period and for females from Week 18 onwards. Absolute food and water consumption were related to body weight. However, relative to body weight, males consumed more than females. 5-HT1B KO males drank strikingly more water. Housing mice singly reduced food and water intake in males, but not in females. Plasma leptin levels and most organ weights did not differ between genotypes, indicating that higher body weight in 5-HT1B KO mice is not related to obesity. Relative to body weight, brains and adrenals were larger in females, while heart and liver were smaller. Kidneys were smaller in females, but larger in 5-HT1B KO mice, while lungs showed opposite effects. Spleen and testes were smaller in 5-HT1B KO mice. Although 5-HT1B KO males are more aggressive, testosterone levels were not different from WT mice. Basal corticosterone levels were similar in all groups and increased in response to mild stress, particularly in females. Lifelong absence of 5-HT1B receptors in mice resulted in clear phenotypic differences in body weights and food and water intake. Lacking this receptor increases body growth, without signs of obesity. A potential genetic background effect influencing this phenotype is discussed.

Retzius cells retain functional membrane properties following ‘ablation’ by the neurotoxin 5,7-DHT

Article

Jun 1984
BRAIN RES

The neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) is generally believed to selectively ablate serotonergic neurons. Serotonin-containing Retzius cells (RZ) in the leech appear ablated by 5,7-DHT treatment. However, these brown, mis-shapen, non-fluorescent neurons retain their synaptic inputs, action potentials, electronic outputs, a membrane receptor, and axonal projections.

Fenfluramine administered systemically or locally increases extracellular serotonin in the lateral hypothalamus as measured by microdialysis

Article

Apr 1989
BRAIN RES

Microdialysis was used to monitor serotonin, 5-hydroxyindoleacetic acid (5-HIAA) and the metabolites of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the perifornical lateral hypothalamus (PFH) of freely moving rats. Systemically administered d-fenfluramine (d-FEN) increased extracellular serotonin, DOPAC and HVA, while decreasing serotonin's metabolite 5-HIAA. Local application of d-FEN directly to the hypothalamic terminal region caused large increases in extracellular serotonin and had a tendency to decrease all 3 metabolites. This effect was confirmed when d-FEN was infused locally by reverse dialysis. These results provide direct evidence that the anorectic drug d-FEN can increase extracellular serotonin in the hypothalamus in vivo and suggest a serotonergic action in the perifornical region. This finding is consistent with our report that a meal also increases serotonin in this region.

The effect of 5 hydroxytryptophan on food intake and on the anorexic action of amphetamine and fenfluramine

Article

Feb 1975

5-Hydroxytryptophan (5-HTP), amphetamine and fenfluramine suppressed food intake in normal rats and in aminals with lesions of the lateral hypothalamus. The anorexic effect of amphetamine was reduced in lesioned animals compared with controls while the effect of 5-HTP like that of fenfluramine was increased. When administered in conjunction with anorexic drugs, 5-HTP markedly potentiated the anorexic effect of amphetamine in both control and lesioned animals. However, 5-HTP potentiated fenfluramine anorexia only in lesioned rats. These findings provide further evidence for the role of 5-hydroxytryptamine (5-HT,in the anorexic effect of fenfluramine, and suggest that a 5-HT mechanism, inhibitory for feeding, produces particulary severe suppression of food intake in rats with lateral hypothalamic lesions.

Hyperphagia and Increased Growth in Rats After Intraventricular Injection of 5,7-Dihydroxytryptamine

Article

May 1976

Juvenile male rats given intracerebroventricular injections of 5,7-dihydroxytryptamine, following treatment with desmethylimipramine, maintained body weight gains of 5 to 6 grams per day into adulthood and grew much larger than control rats. Biochemical analyses of brain tissue obtained 50 to 140 days after the injections revealed 60 to 86% depletions of telencephalic 5-hydroxytryptamine, with catecholamine levels unchanged. Hyperphagia did not develop despite comparable losses of 5-hydroxytryptamine when the pretreatment was withheld, perhaps because substantial depletions of norepinephrine occurred as well.

Molecular characterization of the mouse Agouti locus

Article

Jan 1993
CELL

The agouti (a) locus acts within the microenvironment of the hair follicle to regulate coat color pigmentation in the mouse. We have characterized a gene encoding a novel 131 amino acid protein that we propose is the one gene associated with the agouti locus. This gene is normally expressed in a manner consistent with a locus function, and, more importantly, its structure and expression are affected by a number of representative alleles in the agouti dominance hierarchy. In addition, we found that the pleiotropic effects associated with the lethal yellow (Ay) mutation, which include pronounced obesity, diabetes, and the development of neoplasms, are accompanied by deregulated overexpression of the agouti gene in numerous tissues of the adult animal.

Centrally active 5-HT receptor agonists and antagonists

Article

Feb 1992
NEUROSCI BIOBEHAV R

Eleven subtypes of central 5-HT receptor have so far been postulated, four of which have been cloned (5-HT1A, 5-HT1C, 5-HT1D and 5-HT2) and a fifth (the 5-HT3 receptor) purified. The present review discusses the agonists and antagonists which act at these subtypes with respect to their degree of selectivity and in vivo potency. Selective agonists exist for the 5-HT1A, 5-HT1B and 5-HT3 receptors and selective antagonists for the 5-HT2 and 5-HT3 receptors.

The hypothalamic paraventricular and lateral parabrachial nuclei receive collaterals from raphe nucleus neurons: A combined double retrograde and immunocytochemical study

Article

Apr 1992

Retrograde tracer injections of fluorescein- and rhodamine-labelled latex microspheres centered in the parvicellular zone of the hypothalamic paraventricular nucleus and pontine lateral parabrachial nucleus revealed that 36% of the labelled neurons in the dorsal raphe nucleus send collaterals to both structures. These cells were organized in a well-distinguishable cluster within the dorsal raphe nucleus. By combining retrograde tracing with immunocytochemistry, it was found that less than 8% of the double-labelled cells stained positively for serotonin. Of the remaining raphe nuclei that were examined, only the median raphe nucleus contributed a minor nonserotoninergic projection to the paraventricular or lateral parabrachial nuclei. Few of the retrogradely labelled cells in the median raphe nucleus contained both tracers. These results suggest that nonserotoninergic and serotoninergic neurons in the dorsal raphe nucleus, via collateral branching, may simultaneously influence the activity of two central nervous system nuclei involved in autonomic control.

Role of 5-HT receptors in the effect of d-fenfluramine on feeding patterns in the rat

Article

Apr 1992
EUR J PHARMACOL

The effect of d-fenfluramine, 1.5 mg/kg i.p., on meal patterns was studied in rats treated i.p. with 1 mg/kg metergoline or 0.5 mg/kg ritanserin or s.c. with 3 mg/kg (+/-)cyanopindolol. d-Fenfluramine significantly reduced eating rate, meal size and total intake in the first 4 h of testing and the effects were antagonized by metergoline. (+/-)Cyanopindolol reduced total intake and the effect of d-fenfluramine on this measure; the effect of d-fenfluramine on meal size (but not on eating rate) was also reduced by (+/-)cyanopindolol. Ritanserin only reduced the rate of eating and the effect of d-fenfluramine on this measure. The results suggest that 5-HT1 receptors, possibly of the 5-HT1B type, are involved in the ability of d-fenfluramine to cause satiety in freely feeding rats.

Excitation of neurons in the medullary raphe increases gastric acid and pepsin production in cats

Article

Feb 1991
Am J Physiol

The nucleus raphe obscurus (NRO) has recently emerged as an important nucleus for excitation of gastric motor activity through projections to the dorsal motor nucleus of the vagus (DMV) [P. J. Hornby, C. D. Rossiter, R. L. White, W. P. Norman, D. H. Kuhn, and R. A. Gillis. Am. J. Physiol. 258 (Gastrointest. Liver Physiol. 21): G91-G96, 1990; and M. J. McCann, G. E. Herman, and R. C. Rogers. Brain Res. 486: 181-184, 1989]. A neurotransmitter thought to be involved in this NRO-DMV pathway is thyrotropin-releasing hormone (TRH), a peptide that excites gastric activity when microinjected into the DMV. The purpose of the present study was to determine whether gastric acid and pepsin secretion were altered by 1) activation of neurons in the NRO by microinjection of kainic cid and 2) microinjection of TRH into the DMV in chloralose-anesthetized cats. Microinjection of kainic acid into the NRO increased gastric acid secretion [baseline was 6 +/- 2 (mu eq) H+/15 min (n = 7) and increased to 8 +/- 2, 26 +/- 11 (P less than 0.05), and 21 +/- 7 mu eq/15 min (P less than 0.05) during the first, second, and third 15-min periods after microinjection, respectively]. Pepsin output also increased from a baseline of 287 +/- 67 pepsin units (PU) (n = 4) to 507 +/- 126 PU 15 min postinjection, 541 +/- 118 PU 30 min after injection (P less than 0.05), 608 +/- 92 PU 45 min after injection (P less than 0.05), and 700 +/- 156 PU 60 min postinjection (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Potencies of antagonists indicate that 5-HT1C receptors mediate mCPP-induced hypophagia

Article

Sep 1991

1–3(Chlorophenyl)piperazine (mCPP) (5 mg kg ⁻¹ , i.p.) inhibited 2 h food intake in rats previously deprived of food for one day. Ten 5‐hydroxytryptamine (5‐HT) antagonists given s.c. opposed this hypophagic response. Calculated ID 50 values correlated significantly with reported affinities ( r = 0.81, n = 10, P < 0.01) for 5‐HT 1C but not for 5‐HT 2 , 5‐HT 1A , 5‐HT 1B or 5‐HT 1D receptors. ID 50 values of the ten antagonists against 5‐hydroxytryptophan (5‐HTP) + carbidopa‐induced head shakes (a 5‐HT 2 ‐mediated response) correlated significantly ( r = 0.81, n = 10, P < 0.01) with their affinities for 5‐HT 2 , but not for 5‐HT 1A , 5‐HT 1B , 5‐HT 1C or 5‐HT 1D receptors. ID 50 values for inhibition of hypophagia and head shakes did not correlate significantly with each other. Ratios of ID 50 values against hypophagia and 5‐HT 2 ‐mediated head shakes gave indices of relative in vivo potencies independent of differences in drug metabolism and disposition. These ratios correlated highly significantly ( r = 0.91, n = 10, P < 0.001) with the ratios of the affinities of the drugs for 5‐HT 1C (but not for 5‐HT 1A , 5‐HT 1B or 5‐HT 1B or 5‐HT 1D receptors) and with their affinities for 5‐HT 2 receptors. These results strongly support the hypothesis that mediation of mCPP‐induced hypophagia is by stimulation of 5‐HT 1C receptors and the mediation of 5‐HTP‐induced head twitches by 5‐HT 2 receptors.

Serotonin in the leech central nervous system: anatomical correlates and behavioral effects

Article

Mar 1991

1. Serotonin is sequestered by a limited population of identified neurons in the 32 ganglia of the leech nervous system. A major fraction of the serotonin in each ganglion is contained in the paired Retzius cells, colossal effector neurons whose size varies longitudinally. The 5 other classes of identified serotonin-containing neurons, one effector cell and 4 interneurons, are approximately twice as numerous in anterior as in posterior ganglia. 2. We dissected 6 longitudinal samples from the ventral nerve cords of hungry Hirudo medicinalis, and measured their serotonin content using high pressure liquid chromatography with electrochemical detection. A consistent neurochemical pattern emerged in which segmental ganglia 2-4 had the highest quantity of serotonin: 18.51 pmol per ganglion. The anterior cerebral ganglion contained 14.78 pmol, and the content of the 4 posterior samples, segmental ganglia 7-10, 12-15, 17-20 and the caudal ganglion, decreased continuously from 16.35, 15.08, 10.75 to 2.51 pmol per ganglion, respectively. Morphometric analyses indicated that this pattern of ganglionic serotonin correlated primarily with longitudinal variations in the number of serotonin neurons per ganglion and secondarily with volume of the Retzius cells. Retzius cell volume correlated highly with the mass of their innervated body segments both of which are largest in mid-body domains. 3. Serotonin expresses leech feeding, and its ganglionic levels are a potentially useful index of behavioral state. We measured serotonin in the ganglionic samples from hungry and satiated leeches. The samples from recently fed animals contained 28% less serotonin than those from hungry ones. The amounts of serotonin in the cerebral and all the segmental samples from satiated leeches were significantly lower than equivalent samples of hungry animals. A similar pattern of depletion was seen in leeches which fed for a prolonged period (90 to 120 min) rather than the normal period of 30 min. 4. The effects of ingestion on serotonin-containing neurons was examined with the glyoxylic acid-induced histochemical fluorescence. The levels of fluorescence in all serotonin neurons in fed leeches were consistently lower than those in equivalent neurons in hungry animals, corroborating the ganglionic decrease in serotonin in satiated leeches. 5. To examine effects of body wall distension on serotonin levels, hungry leeches were fed to satiation, and half of them were relaxed by removing their distending blood meals. After 6 weeks, ganglionic serotonin in leeches with relaxed bodies was 21% higher than in those with distended bodies. 6. Ingestive behavior depletes serotonin from leech neurons and body wall distension appears to interfere with its synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Medial hypothalamic nuclei mediate serotonin's inhibitory effect on feeding behavior

Article

Jan 1991
PHARMACOL BIOCHEM BE

Previous studies have demonstrated that injection of serotonin (5-HT) into the paraventricular nucleus (PVN), specifically at the onset of the active feeding cycle, causes a strong and selective suppression of carbohydrate intake, while producing no change in fat intake and, in some cases, enhancing protein consumption. The purpose of the present investigation was to determine whether this selective inhibitory effect of 5-HT on macronutrient ingestion is localized to a specific brain region, perhaps the PVN, or whether it can also occur in other sites throughout the hypothalamus or in regions outside this structure. A total of 7 hypothalamic and 5 extrahypothalamic areas were examined in brain-cannulated, freely feeding rats maintained on pure macronutrient diets of protein, carbohydrate and fat. The effect of 5-HT, a selective suppression (-55%) of carbohydrate feeding, was replicated in the PVN with a relatively low dose of 2.5 nmoles. Tests in 11 other brain sites demonstrated that this action of 5-HT is not unique to the PVN but is anatomically localized to the medial nuclei of the hypothalamus. Sites outside the hypothalamus, namely, the amygdala, nucleus accumbens, septum, diagonal band of Broca and nucleus reuniens dorsal to the PVN, failed to exhibit any response to 5-HT injection. Within the hypothalamus, the ventromedial (VMN) and suprachiasmatic (SCN) nuclei each responded to 5-HT in a manner similar to the PVN, producing a suppression of carbohydrate intake (-50% to -70%) with little or no change in either protein, fat or total kcal intake. The dorsomedial nucleus showed a somewhat smaller response relative to these other medial hypothalamic areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of starvation and neuroactive drugs on feeding inCaenorhabditis elegans

Article

Mar 1990

Caenorhabditis elegans concentrates its food, bacteria, by pharyngeal pumping. The rate of pumping is affected by the presence of bacteria. Using a new assay that allows measurement of pumping rate in a population of worms suspended in liquid by measuring their uptake of microscopic iron particles, we have confirmed and quantitated this effect. Furthermore, we demonstrated that starvation stimulates pumping. Worms that had been deprived of bacteria for more than 4 hours pumped in the absence of bacteria under conditions in which well-fed worms did not. Furthermore, starved worms responded to lower amounts of bacteria than did fed worms. The assay was also useful for measuring effects of drugs on pumping. Of about 30 chemicals screened, 5 had clear effects. The neurotransmitter serotonin and the serotonin uptake inhibitor imipramine stimulated pumping, while the serotonin antagonist gramine inhibits. Imipramine stimulation is greatly decreased in cat-1 and cat-4 mutants, which have low levels of serotonin. Muscimol, an agonist for the neurotransmitter GABA, and ivermectin, whose site of action may also be the GABA receptor, both inhibit pumping. Qualitative observations suggested a role for acetylcholine in the regulation of pumping.

Serotonin- and Substance P-containing projections to the nucleus tractus solitarri of the rat

Article

Nov 1987

The objective of the present study was to determine the location of the neurons that give rise to serotonin- and substance P-containing terminals in the nucleus tractus solitarii. This was done by injecting rhodamine-filled latex microspheres into the nucleus tractus solitarii of rats to retrogradely label neuronal cell bodies and by processing sections from the brains of these animals to determine whether the labelled neurons contained serotonin or substance P immunoreactivity. Serotonin-immunoreactive neurons that projected to the nucleus tractus solitarii were found in the nucleus raphe magnus, nucleus raphe obscurus, nucleus raphe pallidus, and in the ventral medulla, lateral to the pyramidal tract. Substance P-immunoreactive neurons that projected to the nucleus tractus solitarii were found in similar areas but were proportionately less numerous in the nucleus raphe magnus and proportionately more numerous in the nucleus raphe pallidus. It is concluded that neurons in the medullary raphe nuclei, some of which presumably utilize serotonin or substance P as a neurotransmitter, could regulate autonomic function via direct projections to the nucleus tractus solitarii.

Evidence that d-fenfluramine anorexia is mediated by 5-HT

Article

Feb 1989

The effects of eight serotonin (5-HT) receptor antagonists on the anorectic effect of d-fenfluramine (3.0 mg/kg, IP) were examined in a test of sweet mash consumption, using non-deprived male rats. d-Fenfluramine's effect was attenuated by the mixed 5-HT1/5-HT2 receptor antagonists, methiothepin and metergoline; by the 5-HT2 receptor antagonist ritanserin; and by (+/-)cyanopindolol, a mixed 5-HT1A/5-HT1B receptor antagonist. In contrast, d-fenfluramine's effect was not antagonised by the 5-HT2 receptor antagonists ketanserin and ICI 169 369; the 5-HT3 receptor antagonist ICS 205 930; or by xylamidine, a peripheral 5-HT receptor antagonist. In this feeding model, none of the 5-HT antagonists, when tested alone, had any effect to increase palatable food consumption. The pattern of results obtained strongly suggest that central 5-HT1 receptors play an important role in the mediation of d-fenfluramine-induced anorexia.

Distribution of serotonin 5-HT1C receptor mRNA in adult rat Brain

Article

May 1989

Based on in situ hybridization histochemistry (ISHH), we describe the anatomical distribution of the serotonin 5-HT1C receptor mRNA. In addition to the very high levels in epithelial cells of the choroid plexus, 5-HT1C receptor mRNA is found throughout the limbic system, in catecholaminergic cells and in serotonergic neurons. Receptor transcripts are also present in the hypothalamus, numerous motor nuclei and the subthalamus. Our results correlate well with serotonin (5-HT) innervation and receptor binding. Receptor mRNA is present in many brain structures in addition to regions previously shown to have 5-HT1C receptor binding. The distribution of this receptor mRNA suggests that the 5-HT1C receptor may mediate a number of the central effects of 5-HT.

Food intake in baboons: Effects of a long-acting cholecystokinin analog

Article

May 1989

Food intake of four adult male baboons (Papio c. anubis) was monitored during daily experimental sessions lasting 22h. Food was available under a two-component operant schedule. Following completion of the first "procurement component" response requirement, access to food, i.e. a meal, became available under the second "consumption component" during which each response produced a 1-g food pellet. After a 10-min interval in which no response occurred, the consumption component was terminated. A long-acting cholecystokinin (CCK) analog U-67827E (U-67: 0.80-3.2 micrograms/kg) was administered, in the thigh muscle, at 1100 hrs immediately prior to the start of the daily session on Tuesdays and Fridays. U-67 significantly reduced intake during the first 8-h of the session, and intake during the entire 22-h session. The decreased intake was due to a significant decrease in the size of the first meal of the session as a consequence of decreased duration of feeding without a change in response rate. U-67 also produced dose-dependent increases in latency to the first meal of up to 2.5 h. These results demonstrate that a long-acting CCK analog decreases food intake over a prolonged period of time in a naturalistic feeding situation. In addition, the effects of U-67 were limited to the consumption component, suggesting that this CCK analog affected food intake by interacting with physiological mechanisms specifically associated with feeding.

Evidence that hypophagia induced by mCPP and TFMPP requires 5-HT1C and 5-HT1B receptors; hypophagia induced by RU 24969 only requires 5-HT1B receptors

Article

Feb 1988

Male Sprague-Dawley rats deprived of food for 18 h were injected with the 5-HT agonists RU 24969, 1-(3-chlorophenyl)piperazine (mCPP) or 1-[3-(trifluoromethyl)phenyl)]piperazine (TFMPP) and 20 min later presented with their normal diet. Food intake was determined 1, 2 and 4 h later. All three drugs reduced intake over 1 and 2 h. Three out of four drugs with high affinity for 5-HT1C receptors (metergoline, mianserin, and mesulergine but not cyproheptadine) opposed hypophagia caused by mCPP. Another drug reported to have high affinity for the 5-HT1C site, 1-naphthyl-piperazine (1-NP), also blocked the hypophagic response to mCPP at doses which attenuated mCPP-induced hypolocomotion. Only one of the above drugs (metergoline) which also has high affinity for other 5-HT sites opposed hypophagia caused by RU 24969. Two out of three 5-HT1B receptor antagonists [(+/-) cyanopindolol, (-) propranolol, but not (-) pindolol)] which oppose hypophagia caused by RU 24969 (Kennett et al. 1987) also opposed hypophagia caused by mCPP. The 5-HT2 antagonists ketanserin and ritanserin, the 5-HT3 antagonist ICS 205-930 and the alpha 2 adrenoceptor antagonist idazoxan did not oppose the hypophagic effect of mCPP. In agreement with results for mCPP, hypophagia caused by TFMPP was opposed by both, mianserin and (+/-) cyanopindolol. Given alone, mianserin 1-NP and cyproheptadine but not ICS 205-930 increased food consumption of normally fed rats. The results suggest that RU 24969-induced hypophagia depends on 5-HT1B receptors but not on 5-HT1C receptors, while mCPP (and TFMPP)-induced hypophagia may depend on both receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Infusion of the 5-hydroxytryptamine agonists RU24969 and TFMPP into the paraventricular nucleus of the hypothalamus causes hypophagia

Article

Feb 1988

The 5-HT1B agonist RU24969 when given either systemically (1 mg/kg SC) or by infusion (0.5, 1.0, 2.0 micrograms) into the region of the paraventricular nucleus of the hypothalamus caused dose-dependent hypophagia in rats previously deprived of food for 18 h. Similar results were obtained at the above dosages of 1-[3-(trifluoromethyl) phenyl] piperazine (TFMPP), which acts on 5-HT1B and possibly also on 5-HT1C receptors. Neither drug significantly affected locomotion following central administration. Food intake was significantly decreased when the 5-HT1A agonist 8-OH-DPAT was given systemically (1 mg/kg SC) to rats previously deprived of food but was unaffected when 8-OH-DPAT (1 microgram) was infused into the paraventricular nucleus of both food-deprived and free feeding rats. Therefore, hypophagia occurs when hypothalamic 5-HT1B (and possibly 5-HT1C) but not 5-HT1A receptors are activated.

Molecular Characterization of a Functional cDNA Encoding the Serotonin 1c Receptor

Article

Aug 1988

Neurons that release serotonin as a neurotransmitter project to most regions of the central and peripheral nervous system and mediate diverse neural functions. The physiological effects of serotonin are initiated by the activation of multiple, distinct receptor subtypes. Cloning in RNA expression vectors was combined with a sensitive electrophysiological assay in Xenopus oocytes in order to isolate a functional cDNA clone encoding the 5HTlc serotonin receptor. Injection of RNA transcribed in vitro from this clone into Xenopus oocytes elicits serotonin sensitivity. Mouse fibroblasts transformed with this clone bind serotonin agonists and antagonists and exhibit an increase in intracellular Ca2+ concentrations in response to serotonin. The sequence of the 5HTlc receptor reveals that it belongs to the family of G protein-coupled receptors, which are thought to traverse the cytoplasmic membrane seven times. Moreover, in situ hybridization and RNA blot analysis indicate that the 5HTlc receptor is expressed in neurons in many regions of the central nervous system and suggest that this subclass of receptor may mediate many of the central actions of serotonin.

Evidence that MCPP may have behavioural effects mediated by central 5-HT1C receptors

Article

Jun 1988

The effects of 1‐(3‐chlorophenyl)piperazine (mCPP) and 1‐[3‐(trifluoromethyl)phenyl] piperazine (TFMPP) on activity of rats in a novel cage, and on the rotorod and elevated bar co‐ordination tests was examined. Peripherally administered mCPP and TFMPP dose‐dependently reduced locomotion, rearing, and feeding scores but not grooming of freely fed rats placed in a novel observation cage. Yawning behaviour was increased. Similar effects were also observed after injection of mCPP into the 3rd ventricle. Co‐ordination on a rotating drum of both untrained and trained rats was impaired following mCPP but co‐ordination on an elevated bar was not. The hypoactivity induced by mCPP was opposed by three antagonists with high affinity for the 5‐hydroxytryptamine (5‐HT 1C ) site; metergoline, mianserin, cyproheptadine and possibly also by a fourth antagonist mesulergine. Metergoline, mianserin and cyproheptadine also opposed the reduction in feeding scores. However, neither effect of mCPP was antagonized by the 5‐HT 2 ‐receptor antagonists ketanserin or ritanserin, the 5‐HT 3 ‐receptor antagonist ICS 205–930, the 5‐HT 1A and 5‐HT 1B ‐receptor antagonists (—)‐pindolol, (—)‐propranolol and (±)‐cyanopindolol or the 5‐HT 1A ‐, 5‐HT 2 ‐ and dopamine receptor antagonist spiperone. The specific α 2 ‐adrenoceptor antagonist idazoxan was also without effect. Hypoactivity induced by TFMPP was similarly antagonized by mianserin but unaffected by (±)‐cyanopindolol. These results suggest that the hypoactivity is mediated by central 5‐HT 1C ‐receptors and that mCPP and possibly TFMPP may be 5‐HT 1C ‐receptor agonists. As mianserin, cyproheptadine and mesulergine in the absence of mCPP did not increase locomotion but increased the number of feeding scores, the activation of 5‐HT 1C ‐receptors may be of physiological importance in the control of appetite. The possible relevance of these results to the therapeutic and side‐effects of clinically used antidepressants (particularly trazodone and mianserin) and anorexigenic drugs is discussed.

Neurobiology of an anorectic drug: Fenfluramine

Article

Feb 1986
PROG NEUROBIOL

Hypothalamic serotonin in the control of meal patterns and macronutrient selection

Article

Dec 1986
BRAIN RES BULL

Serotonin (5-HT) is believed to have an inhibitory influence over feeding behavior. The present experiments were designed to investigate the effects of hypothalamic 5-HT on spontaneously motivated feeding and appetite regulation. Freely-feeding rats were injected with 5-HT or norfenfluramine (NORFENF) directly into the paraventricular hypothalamus (PVN), and precise changes in feeding behavior were monitored by a computer. Following PVN 5-HT or NORFENF injection, animals exhibited a marked suppression in food intake, associated with a decrease in meal size, duration and eating rate, and no change in the frequency of meals consumed. This suggests that brain 5-HT may influence primarily the induction of satiety rather than the suppression of hunger. The effect of drugs presumed to affect brain 5-HT transmission on diet selection was also investigated in groups of rats injected centrally with 5-HT or NORFENF or peripherally with either fenfluramine, quipazine or cyproheptadine. In a series of 2-diet tests, rats centrally injected with 5-HT or NORFENF exhibited a selective suppression of the carbohydrate-rich diets. In animals provided with three pure macronutrient diets, protein, carbohydrate, and fat, systemic administration of serotonergic agents had its greatest impact on fat and carbohydrate ingestion, as compared to protein consumption. These findings support a role for hypothalamic 5-HT in modulating meal patterns and appetite for particular macronutrients.

Serotonergic modulation of the feeding behavior of the medicinal leech

Article

Jul 1985
BRAIN RES BULL

Charles M. Lent

Hungry medicinal leeches, Hirudo medicinalis, bite warm surfaces and ingest blood meals averaging 890% of their weight. Satiation lasts 12-18 months during which leeches avoid warm surfaces and will not bite. The segmental nervous system of the leech is distinguished by a population of neurons which contain serotonin (5-Hydroxytryptamine, 5-HT) at high concentrations. Some of these identified 5-HT neurons directly activate the effectors responsible for three physiological components of feeding: salivary secretion, bite-like movements and pharyngeal peristalsis. A localized warming of the lip is sufficient to initiate ingestion and synaptically excites anterior 5-HT cells into high frequency impulses or bursts. Distension of the body wall terminates ingestion and also hyperpolarizes these 5-HT neurons. Serotonin treatment produces hyperphagic behavior by the leech, while a specific pharmacological lesion of its 5-HT cell produces the anorexic behavior of satiation. This anorexia is transiently reversed by 5-HT treatment. Serotonin plays an obligatory role in the initiation and expression of leech feeding behavior by its differential modulation of central neuronal networks and peripheral glands and muscles.

The binding of serotonergic ligands to the porcine choroid plexus: Characterization of a new type of serotonin recognition site

Article

Dec 1984
EUR J PHARMACOL

The kinetic and pharmacological characteristics of the binding of [3H]5-HT (serotonin), [3H]8-OH-DPAT (8-OH-2-di-n-propylaminotetraline), [3H]LSD, [3H]ketanserin and [3H]mesulergine to membranes from frontal cortex, hippocampus and choroid plexus of pig brain were studied. The binding of these ligands to frontal cortex and hippocampus demonstrated the presence of 5-HT1 and 5-HT2 sites in both tissues, although hippocampus was richer in 5-HT1 (subtype 5-HT1A) sites. [3H]5-HT, [3H]mesulergine and [3H]LSD labeled the pig choroid plexus with high affinity. The pharmacological profiles of [3H]5-HT and [3H]mesulergine binding to this tissue were closely comparable. Ligands reported as selective for 5-HT1A, 5-HT1B or 5-HT2 subtypes did not show high affinity for these binding sites. Therefore, these 5-HT binding sites in pig choroid plexus could be named 5-HT1C. Other drugs with a high affinity for these sites were methysergide and mianserine. In pig frontal cortex, [3H]5-HT labeled the different subtypes of 5-HT1 sites. In contrast, [3H]mesulergine bound in pig frontal cortex to a small population of sites with pharmacological properties similar to those of the choroid plexus 5-HT1C sites. Possible physiological functions in which these sites might be involved are discussed.

Serotonin and Octopamine in the Nematode Caenorhabditis elegans

Article

Jun 1982

The biogenic amines serotonin and octopamine are present in the nematode Caenorhabditis elegans. Serotonin, detected histochemically in whole mounts, is localized in two pharyngeal neurons that appear to be neurosecretory. Octopamine, identified radioenzymatically in crude extracts, probably is also localized in a few neurons. Exogenous serotonin and octopamine elicit specific and opposite behavioral responses in Caenorhabditis elegans, suggesting that these compounds function physiologically as antagonists.

Advances in Experimental Medicine and Biology

Article

Feb 1981
ADV EXP MED BIOL

The localization and distribution of serotonin (5-HT) has in the rat brain been studied with the indirect immunofluorescence technique of Coons (1958) using a newly developed, specific antibody to 5-HT. This paper contains a detailed description of the distribution of 5-HT in the hypothalamus and hypophyis and a brief report on the localization of 5-HT containing cell bodies. Principally, 5-HT perikarya were present in neuron systems with a distribution similar to that revealed by the mapping of Dahlström & Fuxe (1964) with the formaldehyde-induced-fluorescence technique (FIF). However, in addition to the nine areas originally described, several other areas in the mesencephalon and rhombencephalon appeared to contain 5-HT cell bodies. In the hypothalamus no 5-HT positive neuronal perikarya could be observed. However, in the infundibulum and in the median eminence some 5-HT positive tanycytes and mast cells were observed. Serotonergic fibers and terminals are present throughout the hypothalamus. Particularly dense plexus of the fibers and terminals have been observed in the lateral hypothalamic area, nucleus mamillaris medialis, the nucleus perifornicalis, the nucleus suprachiasmaticus and the nucleus ventromedialis hypothalami. All remaining hypothalamic areas demonstrate various densities of 5-HT immunoreactive nerve fibers. In the pituitary 5-HT-like immunoreactivity have been found in the pars nervosa.

Comparative anatomy of the serotoninergic systems

Article

Feb 1981

A Parent

A brief survey of our knowledge of the morphological organization of central 5-HT neuronal systems across phylogeny has revealed the following facts: 1. The 5-HT neurons seem to have occurred early in phylogeny. These neurons are already well-developed in the brain of cyclostomes (lampreys) and other primitive living vertebrates. 2. A similar pattern of topographical distribution of 5-HT cell bodies has been found in most vertebrates. These neurons are particularly abundant within the raphe region of the brain stem, whereas the catecholamine cells are more laterally located. In birds and mammals, where the 5-HT systems are strikingly well-developed, a certain degree of lateralization of the 5-HT systems has been noticed. This lead to a close intermingling of 5-HT and CA elements in these vertebrates. 3. The 5-HT neurons may act as an important informative link between the CSF and the neural tissue. In all nonmammalian vertebrates, a multitude of 5-HT cells was seen to be in direct contact with the CSF through short, club-like processes. The dense supraependymal plexus of 5-HT fibers disclosed in the rat brain could be the mammalian counterpart of these typical CSF-contacting cells. 4. The central 5-HT systems appear to be widespread and highly collateralized in all vertebrates. A single 5-HT raphe neuron may send divergent axon collaterals to various remote forebrain areas and, thus, could exert a rather diffuse influence over vast neuronal populations in all species. 5. The terminal arborizations of the 5-HT systems display patterns which are strikingly constant from one vertebrate class to another. Such a constancy in the structural organization of the 5-HT neurons strongly suggests that these neuronal systems are indeed phylogenetically ancient and subserve similar fundamental brain functions in all vertebrates.

Stimulation of tryptophan uptake into enteric neurons by 5-hydroxytryptamine: A novel form of neuromodulation

Article

Mar 1980
BRAIN RES

Effects of d-amphetamine and fenfluramine on feeding pattens and activity of obese and lean Zucker rats

Article

Mar 1980
PHARMACOL BIOCHEM BE

The effects of two doses of d-amphetamine and fenfluramine on male Zucker rats maintained ad lib on solid and liquid diets were investigated using the technique of meal pattern analysis. Amphetamine-induced anorexia was of short duration in both obese and lean rats. In the lean rats, anorexia was followed by rebound feeding resulting in little or no reduction in total daily intake. The drug reduced meal sizes of obese but not lean rats and caused a transient decrease in meal frequency. Increased spontaneous activity paralleled the decreased food intake. In contrast, anorexia following fenfluramine was greater, more prolonged and of equivalent magnitude in obese and in lean rats. No rebound feeding was observed. Reduction in intake was achieved primarily by changes in meal size rather than in meal frequency. These data demonstrate that food intakes of genetically obese Zucker rats are more susceptible to the action of d-amphetamine than those of lean rats, and are consistent with reports of differential neurotransmitter levels in the obese and lean rats.

Saper, C.B. & Loewy, A.D. Efferent connections of the parabrachial nucleus in the rat. Brain Res. 197, 291-317

Article

Oct 1980
BRAIN RES

The efferent connections of the parabrachial nucleus have been analyzed in the rat using the anterograde autoradiographic method. Fibers originating from the lateral parabrachial nucleus (PBI) ascend in the periventricular system, the dorsal tegmental bundle and the central tegmental tract. The PBl projects to the dorsal raphe nucleus, the superior central raphe nucleus, and the Edinger-Westphal nucleus. It also innervates the intralaminar (centromedian, centrolateral, paracentral, parafascicular), the midline (paraventricular, reuniens), and the ventromedial basal (VMb) thalamic nuclei as well as much of the hypothalamus, including the dorsomedial, the ventromedial, the arcuate and the paraventricular nuclei, the lateral hypothalamic and the lateral preoptic areas. The PBl sends fibers via the ansa peduncularis into the amygdala, innervating the anterior, the central, the medial, the basomedial, and the posterior basolateral nuclei. In addition, it projects to the lateral part of the bed nucleus of the stria terminalis. Descending PBl fibers travel mainly through the ventrolateral medulla, passing through the region of the A1 and A5 catecholamine cell groups, the ventrolateral reticular formation and the region that contains parasympathetic preganglionic neurons. A small component travels in Probst's bundle to the ventral part of the nucleus of the solitary tract. Only a few PBl axons continue caudally into the lateral funiculus of the spinal cord, but these could not be followed beyond the first few cervical segments.

Caudal raphe-dorsal vagal complex peptidergic projections: Role in gastric vagal control

Article

Feb 1995
PEPTIDES

Subpopulations of raphe pallidus (Rpa) and raphe obscurus (Rob) neurons containing TRH, serotonin (5-HT), and substance P contribute projections to the dorsal vagal complex (DVC). Activation of Rpa and Rob neurons induces a vagal cholinergic-dependent stimulation of gastric secretory and motor function and modulates resistance of the gastric mucosa to gastric injury in rats and cats. The caudal raphe nuclei-DVC pathways containing TRH/5-HT are involved in mediating cold-induced vagal stimulation of gastric function and erosion formation. These results suggest that Rpa/Rob-DVC projections containing TRH/5-HT may be an important pathways in the medullary regulation of vagal activity to the viscera.

An immunocytoehemieal and autoradiographic investigation of the serotonergic innervation of trigeminal mesencephalic and motor nuclei in the rabbit

Article

May 1993
NEUROSCIENCE

The results of a previous experiment suggest that the cell bodies of many jaw closing muscle spindle afférents in the trigeminal mesencephalic nucleus of the rabbit are phasically inhibited during fictive mastication. The aim of this study was to investigate one possible neurotransmitter system that could be involved in this modulation, serotonin, by use of receptor autoradiography techniques and immunofluorescence combined with retrograde labelling of masseteric spindle afférents and motoneurons. A second objective was to compare the serotonin innervation of neurons in the trigeminal mesencephalic nucleus with that of masseteric motoneurons.

Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors

Article

May 1995

Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that is believed to modulate numerous sensory, motor and behavioural processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signalling system and the paucity of selective drugs have made it difficult to define specific roles for 5-HT receptor subtypes, or to determine how serotonergic drugs modulate mood and behaviour. To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin. Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite. Mutant animals are also prone to spontaneous death from seizures, suggesting that 5-HT2C receptors mediate tonic inhibition of neuronal network excitability.

Comparative localization of serotonin(1A, 1C) and 2 receptor subtype mRNAs in rat brain

Article

Jan 1995

Serotonin (5-HT) mediates its effects on neurons in the central nervous system through a number of different receptor types. To gain better insight as to the localization of 5-HT responsive cells, the distribution of cells expressing mRNAs encoding the three 5-HT receptor subtypes 1A, 1C, and 2 was examined in rat brain with in situ hybridization using cRNA probes. 5-HT1A receptor mRNA labeling was most pronounced in the olfactory bulb, anterior hippocampal rudiment, septum, hippocampus (dentate gyrus and layers CA1-3), entorhinal cortex, interpeduncular nucleus, and medullary raphe nuclei. 5-HT1C receptor mRNA labeling was the most abundant and widespread of the three 5-HT receptor subtypes examined. Hybridization signal was densest in the choroid plexus, anterior olfactory nucleus, olfactory tubercle, piriform cortex, septum, subiculum, entorhinal cortex, claustrum, accumbens nucleus, striatum, lateral amygdala, paratenial and paracentral thalamic nuclei, subthalamic nucleus, substantia nigra, and reticular cell groups. 5-HT2 receptor mRNA was localized to the olfactory bulb, anterior hippocampal rudiment, frontal cortex, piriform cortex, entorhinal cortex, claustrum, pontine nuclei, and cranial nerve motor nuclei including the oculomotor, trigeminal motor, facial, dorsal motor nucleus of the vagus, and hypoglossal nuclei. The distributions of mRNAs for the three different 5-HT receptor subtypes overlap with regions that bind various 5-HT receptor-selective ligands and are present in nearly all areas known to receive serotonergic innervation. The results of this study demonstrate that neurons which express these 5-HT receptor subtypes are very widespread in the central nervous system, yet possess unique distributions within the rat brain. Moreover, previously unreported regions of 5-HT receptor subtype expression were observed, particularly with the 5-HT2 receptor riboprobe in the brainstem. Finally, several brain areas contain multiple 5-HT receptor subtype mRNAs, which leads to the possibility that individual cells may express more than one 5-HT receptor subtype.

Serotonin and the Orchestration of Energy Balance

Abstract

No full-text available

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