Serotonin Syndrome Complicating Migraine Pharmacotherapy

Serotonin syndrome, a condition with numerous clinical neurological manifestations, is the result of central serotonergic hyperstimulation. Features of the syndrome include mental status and behavioral changes (agitation, excitement, hypomania, obtuniation), motor system involvement (myoclonus, hemiballismus, tremor, hyperreflexia, motor weakness, dysarthria, ataxia) and autonomic symptoms (fever, chills, diarrhea). Serotonin syndrome has been reported exclusively in patients on medications for psychiatric illness and Parkinsonism, despite the fact that the putative action of many antimigraine agents also involves the serotonin system. We herein report six patients with migraine who developed symptoms suggestive of the serotonin syndrome. Five were taking one or more serotomimetic agents for migraine prophylaxis (sertraline, paroxetine, lithium, imipramine, amitriptyline). In each case the symptoms and signs developed in close temporal proximity with use of a migraine abortive agent known to interact with serotonin receptors. In three instances the agent was subcutaneous sumatriptan and, in three, intravenous dihydroergotamine. In each instance the symptoms were transiers and there was full recovery. With the ever increasing use of migraine medications active at serotonin receptor sites, cases of serotonin syndrome will likely occur more frequently. It is important that physicians creating migraine are aware of the serotonin syndrome and are able to recognize its varying presentations.

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Living-Cell Diffracted X-ray Tracking Analysis Confirmed Internal Salt Bridge Is Critical for Ligand-Induced Twisting Motion of Serotonin Receptors

International Journal of Molecular Sciences ◽

10.3390/ijms22105285 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5285

Author(s):

Kazuhiro Mio ◽

Shoko Fujimura ◽

Masaki Ishihara ◽

Masahiro Kuramochi ◽

Hiroshi Sekiguchi ◽

...

Keyword(s):

Serotonin Receptors ◽

Serotonin Receptor ◽

Frame Rate ◽

Receptor Subtype ◽

Transmembrane Segment ◽

Hek 293 ◽

Gold Nanocrystals ◽

X Ray ◽

Time Dynamics ◽

Analytical Technique

Serotonin receptors play important roles in neuronal excitation, emotion, platelet aggregation, and vasoconstriction. The serotonin receptor subtype 2A (5-HT2AR) is a Gq-coupled GPCR, which activate phospholipase C. Although the structures and functions of 5-HT2ARs have been well studied, little has been known about their real-time dynamics. In this study, we analyzed the intramolecular motion of the 5-HT2AR in living cells using the diffracted X-ray tracking (DXT) technique. The DXT is a very precise single-molecular analytical technique, which tracks diffraction spots from the gold nanocrystals labeled on the protein surface. Trajectory analysis provides insight into protein dynamics. The 5-HT2ARs were transiently expressed in HEK 293 cells, and the gold nanocrystals were attached to the N-terminal introduced FLAG-tag via anti-FLAG antibodies. The motions were recorded with a frame rate of 100 μs per frame. A lifetime filtering technique demonstrated that the unliganded receptors contain high mobility population with clockwise twisting. This rotation was, however, abolished by either a full agonist α-methylserotonin or an inverse agonist ketanserin. Mutation analysis revealed that the “ionic lock” between the DRY motif in the third transmembrane segment and a negatively charged residue of the sixth transmembrane segment is essential for the torsional motion at the N-terminus of the receptor.

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Role of some types of serotonin receptors in murine hypophyseal-testicular complex activation induced by the presence of a female

Problems of Endocrinology ◽

10.14341/probl11792 ◽

2003 ◽

Vol 49 (6) ◽

pp. 53-56

Author(s):

T. G. Amstislavskaya ◽

N. K. Popova

Keyword(s):

Serotonin Receptors ◽

Receptor Agonist ◽

Serotonin Receptor ◽

Receptive Female ◽

Plasma Testosterone ◽

Blood Levels ◽

Inhibitory Effects ◽

Sexual Activation ◽

Different Types

Placement of a sexually receptive female mouse behind a partition that prevents physical contacts, but permits it to see and smell caused an increase in the blood levels of testosterone in male mice. The selective 5-HTIA-serotonin receptor agonist 08-OH- DPAT (0.1 mg/kg) and the mixed 5-HTIA/IB agonist eltoprazine, 3.0 and 10.0 mg/kg, blocked the activating effect of female exposure on the male pituitary-testicular system. The 5-HT/-receptor agonist p-MPPI (0.2 mg/kg) prevented the inhibitory effects of 8-OH-DPATand eltoprazine. The 5-HT/B-receptor agonist CGS- 12066A (1.0 and 2.0 mg/kg) exerted no effect while the mixed 5-HTIB/2C-receptor agonist TFMPP (5.2 mg/kg) inhibited a female-induced increase in the levels of male blood testosterone. The 5-HT/-receptor agonist keranserin (1.0 and 2.0 mg/kg) prevented a female-induced increase in the levels of testosterone. The 5-HT3-receptor agonist ondansetron (0.05 and 0.1 mg/kg) elevated the baseline level of plasma testosterone, but blocked receptive female-induced activation of the male hypothalamic-pituitary-testicular system (HPTS). It is concluded that 5-HTIA-receptors are involved in the control of male sexual activation. At the same time different types and even subtypes of the same type of 5-HT-receptors produce varying inhibitory and activating effects on the receptive female-induced activation of HPTS. Blocking of the female-induced activation of HPTS seems to be realized by involving 5-HTu- and 5-HT2C-receptors and its activation occurs with the participation of 5-HT^- and 5- HT3-receptors.

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Serotonin syndrome due to duloxetine and tramadol use in an older patient

International Journal of Basic & Clinical Pharmacology ◽

10.18203/2319-2003.ijbcp20202953 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1124

Author(s):

Olayinka A. Ogundipe

Keyword(s):

Older Patients ◽

Serotonin Syndrome ◽

Case Review ◽

Clinical Reminder ◽

Concurrent Use ◽

Underlying Causes ◽

High Index Of Suspicion ◽

Opiate Agonist ◽

Symptoms And Signs ◽

Suspected Adverse Drug Reactions

This case report describes a 92-year old woman presenting with acute confusion and agitation. She was initially diagnosed as having a hyperactive delirium. However, based on the presence of additional and evolving features of twitchiness, reduced coordination, palpitations and headaches, the diagnosis was re-evaluated. The clinical presentation was subsequently recognised as being that of the serotonin syndrome. In this instance, the serotonin syndrome was judged to have arisen from the concurrent use of duloxetine and tramadol. Duloxetine is an antidepressant with serotonergic properties. Tramadol is an analgesic agent with weak opiate agonist receptor effects, and also exerts reuptake inhibition of noradrenaline and serotonin. The patient’s polypharmacy was reviewed, and alongside other general supportive care measures, her symptoms and signs resolved within 48 hours. This report serves as a clinical reminder on the potential pitfalls of polypharmacy in older patients. Delirium is a common presentation in older patients, and on occasions, clearly establishing the underlying causes or risk factors may prove challenging or even elusive. The report prompts clinicians to bear in mind that the presentation and diagnosis of the serotonin syndrome requires a high index of suspicion, and that patients may present atypically. In support of pharmacovigilance reporting, two scales of causality assessment are employed in this case review. The application of these systems exemplifies their potential in promoting and enhancing objectivity when clinicians report suspected adverse drug reactions (ADRs) noted in routine clinical practice.

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Withanone Ameliorates Stress Symptoms in Caenorhabditis Elegans by Acting through Serotonin Receptors

Pharmacopsychiatry ◽

10.1055/a-1349-3870 ◽

2021 ◽

Author(s):

Janine Naß ◽

Thomas Efferth

Keyword(s):

Caenorhabditis Elegans ◽

In Silico ◽

Serotonin Receptors ◽

New Drugs ◽

Potential Candidate ◽

Human Beings ◽

Wild Type ◽

C Elegans ◽

Stress Symptoms ◽

Serotonin System

Abstract Introduction Depression is responsible for 800 000 deaths worldwide, a number that will rise significantly due to the COVID-19 pandemic. Affordable novel drugs with less severe side effects are urgently required. We investigated the effect of withanone (WN) from Withania somnifera on the serotonin system of wild-type and knockout Caenorhabditis elegans strains using in silico, in vitro, and in vivo methods. Methods WN or fluoxetine (as positive control drug) was administered to wild-type (N2) and knockout C. elegans strains (AQ866, DA1814, DA2100, DA2109, and MT9772) to determine their effect on oxidative stress (Trolox, H2DCFDA, and juglone assays) on osmotic stress and heat stress and lifespan. Quantitative real-time RT-PCR was applied to investigate the effect of WN or fluoxetine on the expression of serotonin receptors (ser-1, ser-4, ser-7) and serotonin transporter (mod-5). The binding affinity of WN to serotonin receptors and transporter was analyzed in silico using AutoDock 4.2.6. Results WN scavenged ROS in wild-type and knockout C. elegans and prolonged their lifespan. WN upregulated the expression of serotonin receptor and transporter genes. In silico analyses revealed high binding affinities of WN to Ser-1, Ser-4, Ser-7, and Mod-5. Limitations Further studies are needed to prove whether the results from C. elegans are transferrable to mammals and human beings. Conclusion WN ameliorated depressive-associated stress symptoms by activating the serotonin system. WN may serve as potential candidate in developing new drugs to treat depression.

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Stress exposure and psychopathology alter methylation of the serotonin receptor 2A (HTR2A) gene in preschoolers

Development and Psychopathology ◽

10.1017/s0954579417001274 ◽

2017 ◽

Vol 29 (5) ◽

pp. 1619-1626 ◽

Cited By ~ 12

Author(s):

Stephanie H. Parade ◽

Andrew M. Novick ◽

Justin Parent ◽

Ronald Seifer ◽

Samantha J. Klaver ◽

...

Keyword(s):

Child Protection ◽

Life Stress ◽

Serotonin Receptor ◽

Stress Reactivity ◽

Psychiatric Symptoms ◽

Stress Exposure ◽

Negatively Associated ◽

Cpg Sites ◽

Serotonin System ◽

Serotonin Receptor 2A

AbstractSerotonin signaling pathways play a key role in brain development, stress reactivity, and mental health. Epigenetic alterations in the serotonin system may underlie the effect of early life stress on psychopathology. The current study examined methylation of the serotonin receptor 2A (HTR2A) gene in a sample of 228 children including 119 with child welfare documentation of moderate to severe maltreatment within the last 6 months. Child protection records, semistructured interviews in the home, and parent reports were used to assess child stress exposure, psychiatric symptoms, and behavior. The HTR2A genotype and methylation of HTR2A were measured at two CpG sites (–1420 and –1224) from saliva DNA. HTR2A genotype was associated with HTR2A methylation at both CpG sites. HTR2A genotype also moderated associations of contextual stress exposure and HTR2A methylation at site –1420. Contextual stress was positively associated with –1420 methylation among A homozygotes, but negatively associated with –1420 methylation among G homozygotes. Posttraumatic stress disorder and major depressive disorder symptoms were negatively associated with methylation at –1420, but positively associated with methylation at –1224. Results support the view that the serotonin system is sensitive to stress exposure and psychopathology, and HTR2A methylation may be a mechanism by which early adversity is biologically encoded.

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The 1,3,5-Triazine Derivatives as Innovative Chemical Family of 5-HT6 Serotonin Receptor Agents with Therapeutic Perspectives for Cognitive Impairment

International Journal of Molecular Sciences ◽

10.3390/ijms20143420 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3420 ◽

Cited By ~ 13

Author(s):

Gniewomir Latacz ◽

Annamaria Lubelska ◽

Magdalena Jastrzębska-Więsek ◽

Anna Partyka ◽

Małgorzata Anna Marć ◽

...

Keyword(s):

Cognitive Impairment ◽

Serotonin Receptors ◽

Serotonin Receptor ◽

Molecular Mechanisms ◽

Binding Properties ◽

Piperazine Derivatives ◽

Behavioral Studies ◽

Triazine Derivatives

Among serotonin receptors, the 5-HT6 subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HT6R ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient “druglikeness” properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family of potent 5-HT6R ligands. For the most active triazine 5-HT6R agents found (1–4), a wider binding profile and comprehensive in vitro evaluation of their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were investigated within this work. Results indicated the most promising pharmacological/druglikeness profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) and 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (4), which displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative (4) seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and non-sulfone structure with the best 5-HT6R binding properties.

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Different Serotonin Receptor Agonists Have Distinct Effects on Sound-Evoked Responses in Inferior Colliculus

Journal of Neurophysiology ◽

10.1152/jn.00046.2006 ◽

2006 ◽

Vol 96 (5) ◽

pp. 2177-2188 ◽

Cited By ~ 31

Author(s):

Laura M. Hurley

Keyword(s):

Inferior Colliculus ◽

Auditory Processing ◽

Serotonin Receptors ◽

Serotonin Receptor ◽

Frequency Tuning ◽

Receptor Subtypes ◽

Tuning Curves ◽

Wide Range ◽

Selective Agonists ◽

Auditory Nucleus

The neuromodulator serotonin has a complex set of effects on the auditory responses of neurons within the inferior colliculus (IC), a midbrain auditory nucleus that integrates a wide range of inputs from auditory and nonauditory sources. To determine whether activation of different types of serotonin receptors is a source of the variability in serotonergic effects, four selective agonists of serotonin receptors in the serotonin (5-HT) 1 and 5-HT2 families were iontophoretically applied to IC neurons, which were monitored for changes in their responses to auditory stimuli. Different agonists had different effects on neural responses. The 5-HT1A agonist had mixed facilitatory and depressive effects, whereas 5-HT1B and 5-HT2C agonists were both largely facilitatory. Different agonists changed threshold and frequency tuning in ways that reflected their effects on spike count. When pairs of agonists were applied sequentially to the same neurons, selective agonists sometimes affected neurons in ways that were similar to serotonin, but not to other selective agonists tested. Different agonists also differentially affected groups of neurons classified by the shapes of their frequency-tuning curves, with serotonin and the 5-HT1 receptors affecting proportionally more non-V-type neurons relative to the other agonists tested. In all, evidence suggests that the diversity of serotonin receptor subtypes in the IC is likely to account for at least some of the variability of the effects of serotonin and that receptor subtypes fulfill specialized roles in auditory processing.

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Serotonin Receptors in Hippocampus

The Scientific World JOURNAL ◽

10.1100/2012/823493 ◽

2012 ◽

Vol 2012 ◽

pp. 1-15 ◽

Cited By ~ 68

Author(s):

Laura Cristina Berumen ◽

Angelina Rodríguez ◽

Ricardo Miledi ◽

Guadalupe García-Alcocer

Keyword(s):

Limbic System ◽

Immune Cells ◽

Serotonin Receptors ◽

Serotonin Receptor ◽

Functional Network ◽

Receptor Subtypes ◽

Postsynaptic Receptors ◽

Molecular Signal ◽

Almost All

Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system.

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Analysis of pre- and postsynaptic factors of the serotonin system in rabbit retina.

The Journal of Cell Biology ◽

10.1083/jcb.100.1.64 ◽

1985 ◽

Vol 100 (1) ◽

pp. 64-73 ◽

Cited By ~ 38

Author(s):

C K Mitchell ◽

D A Redburn

Keyword(s):

Serotonin Receptor ◽

Amacrine Cells ◽

Uptake System ◽

Rabbit Retina ◽

Binding Studies ◽

High Affinity ◽

Serotonin System ◽

Significant Difference

[3H]Serotonin is accumulated by a specific set of amacrine cells in the rabbit retina. These cells also accumulate the neurotoxin, 5,7-dihydroxytryptamine, and show signs of necrosis within 4 h of in vivo exposure to the drug. Biochemical analysis of [3H]serotonin uptake reveal a sodium- and temperature-dependent, high affinity uptake system with a Km of 0.94 microM and Vmax of 1.08 pmol/mg protein/min. [3H]Tryptophan is also accumulated in rabbit retinal homogenates by a high affinity process. Accumulated [3H]serotonin is released in response to potassium-induced depolarization of intact, isolated retinas. In vitro binding studies of rabbit retinal homogenate membranes demonstrate specific sets of binding sites with characteristics of the postsynaptic serotonin receptor. These data strongly suggest that rabbit retina contains virtually all of the molecular components required for a functional serotonergic neurotransmitter system. The only significant difference between the serotonin system in rabbit retina and that in the well-established serotonin transmitter systems in nonmammalin retinas and in brains of most species is the relatively low concentration of endogenous serotonin in rabbit retinas, as demonstrated by high-performance liquid chromatography, histofluorescence, or immunocytochemistry.

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Increased release of serotonin from rat primary isolated adult cardiac myofibroblasts

Scientific Reports ◽

10.1038/s41598-021-99632-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Emiri Tarbit ◽

Indu Singh ◽

Jason Nigel Peart ◽

Svetlana Bivol ◽

Roselyn Barbara Rose’Meyer

Keyword(s):

Heart Failure ◽

Protein Expression ◽

Western Blot ◽

Serotonin Receptors ◽

Serotonin Receptor ◽

Cardiac Fibroblasts ◽

Cardiac Fibroblast ◽

Receptor Protein ◽

Receptor System ◽

Cardiac Myofibroblasts

AbstractElevated blood serotonin levels have been observed in patients with heart failure and serotonin has a role in pathological cardiac function. The serotonin receptor system was examined in adult rat isolated cardiac fibroblast and myofibroblast cells. This is one of the first studies that has investigated serotonin receptors and other proteins involved in the serotonin receptor system in rat cardiac fibroblast and myofibroblast cells. Rat primary cardiac fibroblasts were isolated and transformed into myofibroblasts using 5 ng/ml TGF-β1. Transformation of cells to myofibroblasts was confirmed with the presence of α-smooth muscle actin using Western blot. Serotonin metabolism and receptor protein expression was assessed using Western blot techniques and serotonin levels measured using ELISA. The 5-HT1A, 5-HT2A and 5-HT2B receptors were found to be present in both rat cardiac fibroblasts and myofibroblast cells, however no significance in protein expression between the two cell types was found (P > 0.05). In this study a significant increase in the serotonin transporter (SERT), tryptophan hydroxylase 1 and extracellular serotonin levels was observed in rat cardiac myofibroblasts when compared to fibroblasts (P < 0.05). These results suggest that serotonin levels may rise in parallel with cardiac myofibroblast populations and contribute to the pathogenesis of heart failure via serotonin receptors.

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