Serotonin Release Research Articles

Current and emerging medications for the management of obesity in adults.

Current and emerging medications for the management of obesity in adults.

Mephedrone – a synthetic derivative of cathinone

Abstract Novel psychoactive substances (NPS) are a very diverse group of recreational drugs that mimic effects of classic drugs of abuse and, at least at the beginning, are not usually prohibited. Representative of this group is mephedrone – a cathinone derivative. It is widely used as a recreational drug, particularly among club guests. Mephedrone`s effects are compared to effects of cocaine and MDMA but are more short-lived and include: psychostimulation, enhanced empathy, reduced feeling of tiredness, euphoria, hallucinations. This drug also exerts adverse effects, such as: anxiety, delusions, paranoia, psychosis, increased body temperature, elevated blood pressure, sleep disturbances. According to surveys performed on mephedrone users, it may be addictive. Those findings confirms a growing number of behavioural and molecular studies on animals. Mephedrone acts mainly via increasing monoamine transmission through increasing release of dopamine, serotonin and noradrenaline into synaptic cleft, inhibiting their re-uptake and reducing their metabolism. However, participation of other transmitters, modulators and pathways are investigated, including glutamate and nitric oxide. Favorable routes of administering mephedrone is intranasal and per os. Moreover, most often drug users use it in a binge way, e.g. taking repeated doses of a drug in a short period of time. According to animal studies, this pattern of mephedrone use leaves more neural injuries than taking it regularly, but in smaller doses. Our aim was to present a short, but essential, overview of the current knowledge on mephedrone, focusing on its effects, mechanism of action, animal studies evaluating its influence on the brain structures, toxicity and pharmacokinetics.

The auditory efferent system in mosquitoes.

Whilst acoustic communication forms an integral component of the mating behavior of many insect species, it is particularly crucial for disease-transmitting mosquitoes; swarming males rely on hearing the faint sounds of flying females for courtship initiation. That males can hear females within the din of a swarm is testament to their fabulous auditory systems. Mosquito hearing is highly frequency-selective, remarkably sensitive and, most strikingly, supported by an elaborate system of auditory efferent neurons that modulate the auditory function - the only documented example amongst insects. Peripheral release of octopamine, serotonin and GABA appears to differentially modulate hearing across major disease-carrying mosquito species, with receptors from other neurotransmitter families also identified in their ears. Because mosquito mating relies on hearing the flight tones of mating partners, the auditory efferent system offers new potential targets for mosquito control. It also represents a unique insect model for studying auditory efferent networks. Here we review current knowledge of the mosquito auditory efferent system, briefly compare it with its counterparts in other species and highlight future research directions to unravel its contribution to mosquito auditory perception.

Galvanic Redox Potentiometry for Fouling‐Free and Stable Serotonin Sensing in a Living Animal Brain

AbstractSerotonin (5‐HT) is a major neurotransmitter broadly involved in many aspects of feeling and behavior. Although its electro‐activity makes it a promising candidate for electrochemical sensing, the persistent generation of fouling layers on the electrode by its oxidation products presents a hurdle for reliable sensing. Here, we present a fouling‐free 5‐HT sensor based on galvanic redox potentiometry. The sensor efficiently minimizes electrode fouling as revealed by in situ Raman spectroscopy, ensuring a less than 3 % signal change in a 2 hour continuous experiment, whereas amperometric sensors losing 90 % within 30 min. Most importantly, the sensor is highly amenable for in vivo studies, permitting real‐time 5‐HT monitoring, and supporting the mechanism associated with serotonin release in brain. Our system offers an effective way for sensing different neurochemicals having significant fouling issues, thus facilitating the molecular‐level understanding of brain function.

Galvanic Redox Potentiometry for Fouling-Free and Stable Serotonin Sensing in a Living Animal Brain.

Serotonin (5-HT) is a major neurotransmitter broadly involved in many aspects of feeling and behavior. Although its electro-active feature renders the electrochemical sensor promising, the persistent generation of fouling layers on electrode by its oxidation products presents a hurdle for reliable sensing. Here, we present a fouling-free 5-HT sensor based on galvanic redox potentiometry. The sensor efficiently minimizes electrode fouling as revealed by in situ Raman spectroscopy, ensuring a less than 3% signal change in a 2-hour continuous experiment, whereas amperometric sensors losing 90% within 30 min. Most importantly, the sensor is highly amenable for in vivo studies, permitting real-time 5-HT monitoring, and supporting the mechanism associated with serotonin release in brain. Our system offers an effective way to sensing different neurochemicals having significant fouling issues, thus facilitating the molecular-level understanding of brain function.

Exocytic machineries differentially control mediator release from allergen-triggered RBL-2H3 cells.

Mast cells utilize SNAREs (soluble-N-ethyl-maleimide sensitive factor attachment protein receptors) and SM (Sec1/Munc18) proteins to secrete/exocytose a variety of proinflammatory mediators. However, whether a common SNARE-SM machinery is responsible remains unclear. Four vesicle/granule-anchored SNAREs (VAMP2, VAMP3, VAMP7, and VAMP8) and two Munc18 homologs (Munc18a and Munc18b) were systematically knocked down or knocked out in RBL-2H3 mast cells and antigen-induced release of β-hexosaminidase, histamine, serotonin, and TNF was examined. Phenotypes were validated by rescue experiments. Immunofluorescence studies were performed to determine the subcellular distribution of key players. The reduction of VAMP8 expression inhibited the exocytosis of β-hexosaminidase, histamine, and serotonin but not TNF. Unexpectedly, however, confocal microscopy revealed substantial co-localization between VAMP8 and TNF, and between TNF and serotonin. Meanwhile, the depletion of other VAMPs, including knockout of VAMP3, had no impact on the release of any of the mediators examined. On the other hand, TNF exocytosis was diminished specifically in stable Munc18bknockdown cells, in a fashion that was rescued by exogenous, RNAi-resistant Munc18b. In line with this, TNF was co-localized with Munc18b (47%) to a much greater extent than with Munc18a (13%). Distinct exocytic pathways exist in mast cells for the release of different mediators.

Kappa Opioid Receptors Reduce Serotonin Uptake and Escitalopram Efficacy in the Mouse Substantia Nigra Pars Reticulata.

The serotonin and kappa opioid receptor (KOR) systems are strongly implicated in disorders of negative affect, such as anxiety and depression. KORs expressed on axon terminals inhibit the release of neurotransmitters, including serotonin. The substantia nigra pars reticulata (SNr) is involved in regulating affective behaviors. It receives the densest serotonergic innervation in the brain and has high KOR expression; however, the influence of KORs on serotonin transmission in this region is yet to be explored. Here, we used ex vivo fast-scan cyclic voltammetry (FSCV) to investigate the effects of a KOR agonist, U50, 488 (U50), and a selective serotonin reuptake inhibitor, escitalopram, on serotonin release and reuptake in the SNr. U50 alone reduced serotonin release and uptake, and escitalopram alone augmented serotonin release and slowed reuptake, while pretreatment with U50 blunted both the release and uptake effects of escitalopram. Here, we show that the KOR influences serotonin signaling in the SNr in multiple ways and short-term activation of the KOR alters serotonin responses to escitalopram. These interactions between KORs and serotonin may contribute to the complexity in the responses to treatments for disorders of negative affect. Ultimately, the KOR system may prove to be a promising pharmacological target, alongside traditional antidepressant treatments.

Modulation of inflammatory mediators involved in the antinociceptive and anti-inflammatory effects of a new thioamide derivative: thiocyanoacetamide.

Inflammatory pain is part of the body's defense mechanism and plays an important role in the healing process. Although some drugs are efficient and intensively used for their potent anti-inflammatory properties, they present problematic side effects. The aim of this study was to evaluate the anti-nociceptive effect of the thiocyanoacetamide (Thm) compared to paracetamol (Para), dexamethasone (Dex) and morphine (Morph) and to study inflammatory mediators on models of acute inflammatory pain in rats using the formalin injection test in the hind paw of rats as chemical stimulus. The obtained results showed significant modulation of pain by Thm pretreatment with a maximum at an effective dose (10mg/kg) proved by the absence of lickingand biting of the affected paw during the early and late phases of inflammation. This effect was comparable to Dex at 10mg/kg, Para at 400mg/kg and less than Morph at 5mg/kg pretreatment doses. The study of anti-inflammatory targets showed that Thm pretreatment maintained plasma serotonin release at normal level compared to the negative control group (T-) and corrected the decrease in the plasma level of prostaglandins after inflammatory induction with no variation in the level of histamine in different groups. The evaluation of inflammation mediators demonstrated that the pretreatment with Thm induced the decrease in the amount of both IL-1 Beta and TNF alpha in plasma and the increase in their amount in the tissue of the injection site. The Thm has been promoted as an anti-nociceptive drug that induces modulation of inflammatory mediators.

Brown Slime Cap Mushroom (Chroogomphus rutilus, Agaricomycetes) Polysaccharide Resists Motion Sickness by Inhibiting the Activity of the Serotonin System in Mice.

Motion sickness (MS) is a disorder of the autonomic nervous system caused by abnormal exercise with symptoms such as nausea, vomiting and drowsiness. More than 90% of the human population has experienced different degrees of MS. At present, anticholinergics, antihistamines, and sympathomimetic drugs are used for treating MS, but these drugs generally have some adverse reactions and are not suitable for all people. Therefore, it is necessary to develop anti-MS drugs that have high efficiency and no adverse effects. Previous studies have found that Chroogomphus rutilus polysaccharide (CRP) is effective at preventing and treating MS in rats and mice. However, its mechanism of action is not clear. To clarify whether the CRP has anti-MS effects in mice, and to clarify its mechanism, we performed behavioral, biochemical, and morphological tests in a Kunming mouse model. Our results indicate that CRPs can significantly relieve the symptoms of MS, and their effect is equivalent to that of scopolamine, a commonly used anti-MS medicine. Our results indicate that CRPs may directly act on the gastrointestinal chromaffin cells to inhibit the synthesis and release of serotonin (5-hydroxytryptamine, or 5-HT) and thus reduce the signal from the gastrointestinal tract.

Raynaud's Phenomenon: A Brush Up!

Raynaud's Phenomenon: A Brush Up!

This Month in Anesthesiology

This Month in Anesthesiology

Serotonin Release Assay: Functional Assay for Heparin- and Vaccine-Induced (Immune) Thrombotic Thrombocytopenia.

The serotonin release assay (SRA) has been the gold-standard assay for detection of heparin-dependent platelet-activating antibodies and integral for the diagnosis for heparin-induced thrombotic thrombocytopenia (HIT). In 2021, a thrombotic thrombocytopenic syndrome was reported after adenoviral vector COVID-19 vaccination. This vaccine-induced thrombotic thrombocytopenic syndrome (VITT) proved to be a severe immune platelet activation syndrome manifested by unusual thrombosis, thrombocytopenia, very elevated plasma D-dimer, and a high mortality even with aggressive therapy (anticoagulation and plasma exchange). While the platelet-activating antibodies in both HIT and VITT are directed toward platelet factor 4 (PF4), important differences have been found. These differences have required modifications to the SRA to improve detection of functional VITT antibodies. Functional platelet activation assays remain essential in the diagnostic workup of HIT and VITT. Here we detail the application of SRA for the assessment of HIT and VITT antibodies.

Construction of a New Protein–Protein Interaction and Molecular Biomarkers Networks in Alzheimer’s Disease Patients by Bioinformatics Screening

This study aimed to construct the molecular biomarkers of autophagy and endoplasmic reticulum stress (ERS), as well as their corresponding protein interaction network in Alzheimer’s disease (AD) patients with different levels of physical activity (PA) by bioinformatics methods. The expression profiles of the genes were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) between AD samples with low, moderate and high levels of PA were studied. The autophagy and ERS-related genes (AERSRGs) were extracted from GeneCards and MsigDB databases. The functional enrichment analysis was conducted to determine the function of DEGs. To explore the proteins, miRNAs and transcription factors (TF) interacting with DEGs, the protein–protein network, mRNA-miRNA network and mRNA-TF network were built using Cytoscape software. Then the receiver operating characteristic (ROC) analysis were conducted to verify the diagnostic performance of hub genes. A total of 533 AERSRGs were identified in Group H and 150 AERSRGs were screened in Group M. Functional enrichment analysis suggested genes of AD play vital roles in some biological process (e.g., cell cycle phase transition, mitochondrion organization, proteasomal protein catabolic process). KEGG enrichment analysis suggested that sarcopenia involves the pathways (e.g., GABA, P2Y receptors, serotonin release cycle). A total of 5 hub genes were screened in Group H and 9 were identified in Group M. ROC analysis suggested that several hub genes exhibited a relatively high sensitivity and specificity in both groups of AD. The hub genes screened in this study are closely correlated with autophagy and ERS in AD and can differentiate AD with different levels of PA. SRC, MAPK3 and MAP2K1 exhibit relatively high sensitivity and specificity in diagnosis in Group H; MCM2, CDC42, HNRNPM, ASF1A, NCBP2, SNRNP70 and MCM6 exhibit relatively high sensitivity and specificity in diagnosis in Group M.

Incidence and severity of thrombocytopenia associated with use of intravascular microaxial ventricular assist devices for treatment of cardiogenic shock.

The use of temporary mechanical circulatory support (MCS) for patients with refractory cardiogenic shock has increased over the past decade. Impella devices (intravascular microaxial ventricular assist devices [VADs]) have become common MCS options but reportedly cause thrombocytopenia. Limited published data regarding the incidence or severity of microaxial VAD-associated thrombocytopenia exists. The goal of this study was to determine the incidence, timing, and severity of thrombocytopenia in a microaxial VAD population. A retrospective multicenter review of electronic medical records identified all patients implanted with microaxial VAD at three US academic teaching hospitals between June 2015 and August 2017. Patients were excluded for short-term procedural microaxial VAD use during percutaneous coronary intervention. Sixty-four patients underwent microaxial VAD insertion (95% for left-sided support) during the observed time period. Support was in place for a median duration of 5.2 (interquartile range [IQR]: 2.4-10.0) days. Within 7 days postinsertion, 98.5% of patients developed thrombocytopenia (platelet count <150,000/μl) and 81.3% of patients experienced a>50% platelet decrease. Average platelet count nadir was 68,200/μl or 63.9% from baseline occurring on median day 3.8 (IQR: 2.4-5.4). Twenty-four patients (38.1%) were tested for heparin-induced thrombocytopeniaby the heparin-dependent antibody (HDA) test. All HDAs were either negative or had serotonin release assay negative confirmation. Postdevice removal, platelet counts returned to baseline or >150,000/μl in 63% of patients by Day 5. Microaxial VAD-associatedthrombocytopenia is common. Practitioners should consider this when evaluating supported patients for other causes of thrombocytopenia. Platelet counts return to preimplantation levels within days of device removal.

Next generation genetically encoded fluorescent sensors for serotonin

We developed a family of genetically encoded serotonin (5-HT) sensors (sDarken) on the basis of the native 5-HT1A receptor and circularly permuted GFP. sDarken 5-HT sensors are bright in the unbound state and diminish their fluorescence upon binding of 5-HT. Sensor variants with different affinities for serotonin were engineered to increase the versatility in imaging of serotonin dynamics. Experiments in vitro and in vivo showed the feasibility of imaging serotonin dynamics with high temporal and spatial resolution. As demonstrated here, the designed sensors show excellent membrane expression, have high specificity and a superior signal-to-noise ratio, detect the endogenous release of serotonin and are suitable for two-photon in vivo imaging.

Lavender oil and its effectiveness in anxiety symptoms

Studies prove that using aromatherapy with lavender oil generates reduction of anxiety, sedative, antidepressant, soothing, antispasmodic, analgesic and healing effects. A fact that occurs due to the inhibitory action of lavender on the hypothalamic-hypophysis-adrenal axis, which results in the reduction in the release of cortisol, the stress hormone. Promoting, on the other hand, the release of serotonin, generating a feeling of pleasure and well-being. Thus, the present study aimed, through an integrative literature review, to describe the effects of the use of lavender oil in the treatment of anxiety. The psychological effects of inhaling lavender oil occur through conscious perception, belief and expectation. Meanwhile, the pharmacological effects occur through the modulation of the cyclic activity of adenosine monophosphate (reduction of cyclic adenosine monophosphate results with sedation) and inhibition of glutamate binding (sedative effects). Thus, the use of oil is considered safe, except for rare allergic reactions, and can be beneficial in patients with anxiety and reduce the use of antipsychotic drugs.

Anatomical background of the sensory function in the urethra: involvement of endocrine paraneurons and afferent nerves in divergent urogenital functions. A review.

The urethra is ontogenetically derived from the cloaca together with distal parts of the large intestine, and serotonin cells are predominant among dispersed endocrine/paracrine cells in the epithelia of both tissues. Analysis of urethral endocrine cells thus helps us to understand the functions of gut endocrine cells and their communication with the nervous system, due to the fact that the urethra is a simple tubular organ, where only urine without microflora rapidly passes through. A certain number of urethral endocrine cells display unique, complicated shapes with dendritic processes, reminiscent of neurons. Characteristically, urethral endocrine cells-often called paraneurons-have direct contact with sensory nerves within the epithelium, unlike gut endocrine cells lacking in direct contact with nerves. These traits encourage us to focus on the urethral paraneurons as ideal endocrine/paracrine cells. A topographical complex of urethral paraneurons and afferent nerve fibers is sensitive to the passage of urine or the distention of the urethral lumen. The urethra-bladder excitatory reflex facilitates micturition via the release of serotonin from the paraneurons, ultimately ensuring complete voiding of the bladder. This reflex may also influence sexual behaviors such as ejaculation or the female orgasm. Urethral brush cells as well as paraneurons are responsible for continuous monitoring of the mucosal surface, especially for pathogens entering via the external urethral orifice.

Assessment of immunological anti‐platelet factor 4 antibodies for vaccine‐induced thrombotic thrombocytopenia (VITT) in a large Australian cohort: A multicenter study comprising 1284 patients

BackgroundVaccine‐induced thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus‐based vaccines aimed to prevent and minimize COVID‐19 and related pathophysiology. ObjectivesTo describe patterns of testing for anti‐platelet factor 4 (PF4) antibodies using various ELISA assays in a large Australian cohort and comparative functional platelet activation assays in a subset. Patients/MethodsAsserachrom HPIA IgG ELISA was performed in 1284 patients over a period of 12 months, supplemented in select cohorts by comparative ELISA using three other methods (n = 78–179), three different functional assays (flow cytometry, serotonin release assay, and/or Multiplate; n = 476), and rapid immunological chemiluminescence anti‐PF4 assay (n = 460), in a multicenter study. ResultsFor first episode presentations, 190/1284 (14.8%) ELISA tests were positive. Conversely, most (445/460; 96.7%) chemiluminescence anti‐PF4 test results were negative. All functional assays showed associations of higher median ELISA optical density with functional positivity and with high rates of ELISA positivity (64.0% to 85.2%). Data also identified functional positivity in 14.8%–36.0% of ELISA negative samples, suggesting false negative VITT by HPIA IgG ELISA in upward of one third of assessable cases. ConclusionTo our knowledge, this is the largest multicenter evaluation of anti‐PF4 testing for investigation of VITT. Discrepancies in test results (ELISA vs. ELISA or ELISA vs. functional assay) in some patients highlighted limitations in relying on single methods (ELISA and functional) for PF4 antibody detection in VITT, and also highlights the variability in phenotypic test presentation and pathomechanism of VITT.

Cycles of addiction and loneliness

In this issue of Neuron, Pomrenze and colleagues1 report a novel mechanism behind sociability deficits in mice during protracted withdrawal from morphine. Dorsal raphe dynorphin neurons terminating in the nucleus accumbens suppress local serotonin release through kappa opioid receptors. These findings likely have important clinical implications.

High-frequency Contactless Sensor for the Detection of Heparin-Induced Thrombocytopenia Antibodies via Platelet Aggregation.

Heparin-induced thrombocytopenia (HIT), a severe autoimmune disorder, occurs in patients undergoing heparin therapy. The presence of platelet-activating antibodies against platelet factor 4/Heparin in the blood confirms patients suffering from HIT. The most widely used methods for HIT diagnosis are immunoassays but the results only suit to rule out HIT as the assays provide only around 50% specificity. To confirm HIT, samples with positive results in immunoassays are retested in functional assays (&gt;98% specificity) that track platelet-activating antibodies via platelet aggregation. However, the protocols in functional assays are either time-consuming (due to the requirement of the detection of serotonin release) or require highly trained staff for the visualization of platelets. Here, we applied a cheap and easy-to-use contactless sensor, which employs high-frequency microwaves to detect the changes in the resonant frequency caused by platelet aggregation/activation. Analysis of change in conductivity and permittivity allowed us to distinguish between HIT-like (KKO) and non-HIT-like (RTO) antibodies. KKO caused a stronger reduction of conductivity of platelet samples than RTO. Our results imply that the high-frequency contactless sensor can be a promising approach for the development of a better and easier method for the detection of HIT.