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Drugs Jun 2020Akathisia is one of the most prevalent and distressing adverse effects associated with antipsychotic drug treatment. Propranolol, a non-selective beta-adrenergic... (Review)
Review
Akathisia is one of the most prevalent and distressing adverse effects associated with antipsychotic drug treatment. Propranolol, a non-selective beta-adrenergic receptor antagonist, is currently considered a first-line treatment for antipsychotic-induced akathisia (AIA). Surprisingly, the evidence for its anti-akathisia effect is modest. Propranolol's side effects (e.g. orthostatic hypotension, bradycardia), contraindications (e.g. asthma) and increased complexity in titration schedules limit its use in some patients. Anticholinergic agents and benzodiazepines merely provide symptomatic relief in patients with AIA. Effective and well-tolerated treatment remains a major unmet need in akathisia and warrants a search for new anti-akathisia agents. Accumulating evidence during the last two decades indicates that agents with marked postsynaptic serotonin 5-HT receptor antagonism (ritanserin, cyproheptadine, trazodone, mianserin, mirtazapine) may represent a new class of potential anti-akathisia remedies. Among these agents, low-dose mirtazapine (7.5 mg or 15 mg once daily) has demonstrated the most compelling evidence for therapeutic efficacy. In this narrative review we highlight the clinical significance of AIA, outline major approaches for its management and propose a practical algorithm for its treatment.
Topics: Akathisia, Drug-Induced; Algorithms; Antipsychotic Agents; Humans; Propranolol; Psychomotor Agitation; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists
PubMed: 32385739
DOI: 10.1007/s40265-020-01312-0 -
Medicinal Research Reviews Sep 2020Serotonin (5-hydroxytryptophan [5-HT]) is a biologically active amine expressed in platelets, in gastrointestinal (GI) cells and, to a lesser extent, in the central... (Review)
Review
Serotonin (5-hydroxytryptophan [5-HT]) is a biologically active amine expressed in platelets, in gastrointestinal (GI) cells and, to a lesser extent, in the central nervous system (CNS). This biogenic compound acts through the activation of seven 5-HT receptors (5-HT Rs). The 5-HT R is a ligand-gated ion channel belonging to the Cys-loop receptor family. There is a wide variety of 5-HT R modulators, but only receptor antagonists (known as setrons) have been used clinically for chemotherapy-induced nausea and vomiting and irritable bowel syndrome treatment. However, since the discovery of the setrons in the mid-1980s, a large number of studies have been published exploring new potential applications due their potency in the CNS and mild side effects. The results of these studies have revealed new potential applications, including the treatment of neuropsychiatric disorders such as schizophrenia, depression, anxiety, and drug abuse. In this review, we provide information related to therapeutic potential of 5-HT R antagonists on GI and neuropsychiatric disorders. The major attention is paid to the structure, function, and pharmacology of novel 5-HT R modulators developed over the past 10 years.
Topics: Gastrointestinal Diseases; Humans; Nausea; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin Antagonists
PubMed: 32115745
DOI: 10.1002/med.21666 -
Expert Opinion on Therapeutic Patents Jul 2020Numerous chemotypes have been described over time in order to generate potent and selective 5-HTR ligands. Both agonists and antagonists have demonstrated their interest... (Review)
Review
INTRODUCTION
Numerous chemotypes have been described over time in order to generate potent and selective 5-HTR ligands. Both agonists and antagonists have demonstrated their interest in several disease models. This culminates with the FDA approval of tegaserod and prucalopride in the recent years.
AREAS COVERED
This review summarizes the patent applications from 2014 to present, dedicated to the use or the description of novel 5-HTR modulators. Several novel ligands and scaffolds have been industrially protected mainly in the field of central nervous system (CNS) pathologies as well as gastrointestinal disorders, including the combination with other drugs or for veterinary uses.
EXPERT OPINION
The therapeutic potential of 5-HTR modulators has been explored for several years in animal models, but also linked to potential safety issues with initial ligands. The current use of prucalopride in humans demonstrates that its toxicity is not linked to the target and that 5-HTR modulators are safe in humans. Therefore, an important number of studies and patents has continued in the recent years to expand the use of 5-HTR modulators, not only to treat gastrointestinal disorders, but also for CNS pathologies. This article details current efforts in this development.
Topics: Animals; Central Nervous System Diseases; Drug Development; Gastrointestinal Diseases; Humans; Ligands; Patents as Topic; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists
PubMed: 32400221
DOI: 10.1080/13543776.2020.1767587 -
International Journal of Developmental... Apr 2021A survey of the literature indicates that the developmental disruptions in serotonin (5-HT) levels can influence the brain development and the function. To the best of...
A survey of the literature indicates that the developmental disruptions in serotonin (5-HT) levels can influence the brain development and the function. To the best of our knowledge, so far, there are a few studies about the effects of developmental period 5-HT depletion on cognition and behavior of adult male and female rats. Therefore, in the present study, we examined the effects of postnatal days (PND 10-20) administration of para-chlorophenylalanine (PCPA, 100 mg/kg, s.c) a 5-HT synthesis inhibitor, on anxiety-related behaviors, pain sensitivity, short-term recognition memory, and hippocampal and prefrontal cortex (PFC) brain-derived neurotrophic factor (BDNF) mRNA expression in adult male and female rats. Novel object recognition memory (NORM) and behavioral parameters (anxiety-like behaviors and pain sensitivity) were evaluated in early adulthood and after that, the hippocampi and PFC of the rat's brain were removed for the determination of BDNF mRNA expression. Our results indicated that the postnatal period administration of PCPA impaired short-term NORM. The postnatal developmental period treatment with PCPA also increased anxiety-like behaviors in the open field and elevated plus maze (EPM) tests. Postnatal PCPA treatment increased pain sensitivity in the hot plate test in both male and female rats, especially in female animals. In addition, postnatal days serotonin depletion decreased BDNF level in the hippocampus and PFC of both male and female rats. These findings demonstrate that serotonin plays the main role in neurodevelopment, cognitive functions, and behavior. Therefore, serotonergic system dysregulation during the developmental periods may have more adverse influences on the brain development of rats.
Topics: Animals; Anxiety; Brain; Brain-Derived Neurotrophic Factor; Cognition; Female; Fenclonine; Male; Rats; Recognition, Psychology; Serotonin; Serotonin Antagonists; Sex Factors
PubMed: 33404066
DOI: 10.1002/jdn.10087 -
Identification and Pharmacological Characterization of Two Serotonin Type 7 Receptor Isoforms from .International Journal of Molecular... Dec 2022Serotonin (5-hydroxytryptamine, 5-HT) is an important neuroactive molecule, as neurotransmitters regulate various biological functions in vertebrates and invertebrates...
Serotonin (5-hydroxytryptamine, 5-HT) is an important neuroactive molecule, as neurotransmitters regulate various biological functions in vertebrates and invertebrates by binding and activating specific 5-HT receptors. The pharmacology and tissue distribution of 5-HT receptors have been investigated in several model insects, and these receptors are recognized as potential insecticide targets. However, little is known about the pharmacological characterization of the 5-HT receptors in important agricultural pests. In this study, we investigated the sequence, pharmacology, and tissue distribution of receptors from oriental armyworm (Walker) (Lepidoptera: Noctuidae), an important migratory and polyphagous pest species. We found that the receptor gene encodes two molecularly distinct transcripts, and , by the mechanism of alternative splicing in . Msep5-HT7S differs from Msep5-HT7L based on the deletion of 95 amino acids within the third intracellular loop. Two Msep5-HT7 receptor isoforms were activated by 5-HT and synthetic agonists α-methylserotonin, 8-hydroxy-DPAT, and 5-methoxytryptamine, resulting in increased intracellular cAMP levels in a dose-dependent manner, although these agonists showed much poorer potency and efficacy than 5-HT. The maximum efficacy of 5-HT compared to the two 5-HT isoforms was equivalent, but 5-HT exhibited 2.63-fold higher potency against the Msep5-HT7S than the Msep5-HT7L receptor. These two isoforms were also blocked by the non-selective antagonist methiothepin and the selective antagonists WAY-100635, ketanserin, SB-258719, and SB-269970. Moreover, two distinct mRNA transcripts were expressed preferentially in the brain and chemosensory organs of adults, as determined by qPCR assay. This study is the first comprehensive characterization of two splicing isoforms of 5-HT7 receptors in , and the first to demonstrate that alternative splicing is also the mechanism for producing multiple 5-HT7 isoforms in insects. Pharmacological and gene expression profiles offer important information that could facilitate further exploration of their function in the central nervous system and peripheral chemosensory organs, and may even contribute to the development of new selective pesticides.
Topics: Animals; Serotonin; Serotonin Antagonists; Receptors, Serotonin; Moths; Protein Isoforms
PubMed: 36614100
DOI: 10.3390/ijms24010655 -
Cell Host & Microbe Jul 2020The gut-brain axis is crucial to microbial-host interactions. The neurotransmitter serotonin is primarily synthesized in the gastrointestinal (GI) tract, where it is...
The gut-brain axis is crucial to microbial-host interactions. The neurotransmitter serotonin is primarily synthesized in the gastrointestinal (GI) tract, where it is secreted into the lumen and subsequently removed by the serotonin transporter, SERT. Here, we show that serotonin decreases virulence gene expression by enterohemorrhagic E. coli (EHEC) and Citrobacter rodentium, a murine model for EHEC. The membrane-bound histidine sensor kinase, CpxA, is a bacterial serotonin receptor. Serotonin induces dephosphorylation of CpxA, which inactivates the transcriptional factor CpxR controlling expression of virulence genes, notably those within the locus of enterocyte effacement (LEE). Increasing intestinal serotonin by genetically or pharmacologically inhibiting SERT decreases LEE expression and reduces C. rodentium loads. Conversely, inhibiting serotonin synthesis increases pathogenesis and decreases host survival. As other enteric bacteria contain CpxA, this signal exploitation may be engaged by other pathogens. Additionally, repurposing serotonin agonists to inhibit CpxA may represent a potential therapeutic intervention for enteric bacteria.
Topics: Animals; Bacterial Proteins; Citrobacter rodentium; Disease Models, Animal; Enterobacteriaceae Infections; Enterohemorrhagic Escherichia coli; Escherichia coli Proteins; Female; Gastrointestinal Tract; Gene Expression Regulation, Bacterial; HeLa Cells; Host-Pathogen Interactions; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Phosphoproteins; Protein Kinases; Serotonin; Serotonin Antagonists; Transcriptome; Virulence Factors
PubMed: 32521224
DOI: 10.1016/j.chom.2020.05.004 -
Archives of Toxicology Aug 2021The consumption of contaminated shellfish with okadaic acid (OA) group of toxins leads to diarrhoeic shellfish poisoning (DSP) characterized by a set of symptoms...
The consumption of contaminated shellfish with okadaic acid (OA) group of toxins leads to diarrhoeic shellfish poisoning (DSP) characterized by a set of symptoms including nausea, vomiting and diarrhoea. These phycotoxins are Ser/Thr phosphatase inhibitors, which produce hyperphosphorylation in cellular proteins. However, this inhibition does not fully explain the symptomatology reported and other targets could be relevant to the toxicity. Previous studies have indicated a feasible involvement of the nervous system. We performed a set of in vivo approaches to elucidate whether neuropeptide Y (NPY), Peptide YY (PYY) or serotonin (5-HT) was implicated in the early OA-induced diarrhoea. Fasted Swiss female mice were administered NPY, PYY(3-36) or cyproheptadine intraperitoneal prior to oral OA treatment (250 µg/kg). A non-significant delay in diarrhoea onset was observed for NPY (107 µg/kg) and PYY(3-36) (1 mg/kg) pre-treatment. On the contrary, the serotonin antagonist cyproheptadine was able to block (10 mg/kg) or delay (0.1 and 1 mg/kg) diarrhoea onset suggesting a role of 5-HT. This is the first report of the possible involvement of serotonin in OA-induced poisoning.
Topics: Animals; Cyproheptadine; Diarrhea; Enzyme Inhibitors; Female; Mice; Neuropeptide Y; Okadaic Acid; Peptide Fragments; Peptide YY; Serotonin; Serotonin Antagonists; Shellfish Poisoning; Time Factors
PubMed: 34148100
DOI: 10.1007/s00204-021-03095-z -
International Review of Neurobiology 2023Nicotine abuse is frequent worldwide leading to about 8 millions people die every year due to tobacco related diseases. Military personnel often use nicotine smoking... (Review)
Review
Nicotine neurotoxicity exacerbation following engineered Ag and Cu (50-60 nm) nanoparticles intoxication. Neuroprotection with nanowired delivery of antioxidant compound H-290/51 together with serotonin 5-HT3 receptor antagonist ondansetron.
Nicotine abuse is frequent worldwide leading to about 8 millions people die every year due to tobacco related diseases. Military personnel often use nicotine smoking that is about 12.8% higher than civilian populations. Nicotine smoking triggers oxidative stress and are linked to several neurodegenerative diseases such as Alzheimer's disease. Nicotine neurotoxicity induces significant depression and oxidative stress in the brain leading to neurovascular damages and brain pathology. Thus, details of nicotine neurotoxicity and factors influencing them require additional investigations. In this review, effects of engineered nanoparticles from metals Ag and Cu (50-60 nm) on nicotine neurotoxicity are discussed with regard to nicotine smoking. Military personnel often work in the environment where chances of nanoparticles exposure are quite common. In our earlier studies, we have shown that nanoparticles alone induces breakdown of the blood-brain barrier (BBB) and exacerbates brain pathology in animal models. In present investigation, nicotine exposure in with Ag or Cu nanoparticles intoxicated group exacerbated BBB breakdown, induce oxidative stress and aggravate brain pathology. Treatment with nanowired H-290/51 a potent chain-breaking antioxidant together with nanowired ondansetron, a potent 5-HT3 receptor antagonist significantly reduced oxidative stress, BBB breakdown and brain pathology in nicotine exposure associated with Ag or Cu nanoparticles intoxication. The functional significance of this findings and possible mechanisms of nicotine neurotoxicity are discussed based on current literature.
Topics: Animals; Humans; Ondansetron; Antioxidants; Serotonin 5-HT3 Receptor Antagonists; Nicotine; Neuroprotection; Brain Edema; Neuroprotective Agents; Brain; Nanoparticles
PubMed: 37833012
DOI: 10.1016/bs.irn.2023.07.002 -
CNS Drugs Sep 2020Schizophrenia is a major mental illness associated with profound disability. Current treatments for schizophrenia (antipsychotics) all have a similar mechanism of action... (Review)
Review
Schizophrenia is a major mental illness associated with profound disability. Current treatments for schizophrenia (antipsychotics) all have a similar mechanism of action and are primarily dopamine type 2 receptor (DR) antagonists. Antipsychotics are not fully effective for the majority of schizophrenia patients, suggesting the need for alternative approaches. The primary focus of this review is to assess the evidence for the role of the serotonin type 2A receptor (5-HTR) in schizophrenia. Topics include an overview of 5-HTR physiology and pathophysiology in schizophrenia, 5-HTR interaction with other neurotransmitter systems, including the glutamatergic system, a review of the 5-HTR/d-lysergic acid diethylamide (LSD) model of schizophrenia, a contrast of the 5-HTR and glutamatergic models of schizophrenia, and finally, a review of Food and Drug Administration (FDA)-approved and investigational 5-HTR-modulating compounds. Recent studies with lumeteperone, pimavanserin, and roluperidone are highlighted.
Topics: Animals; Antipsychotic Agents; Heterocyclic Compounds, 4 or More Rings; Humans; Indoles; Lysergic Acid Diethylamide; Piperidines; Receptor, Serotonin, 5-HT2A; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Urea
PubMed: 32783116
DOI: 10.1007/s40263-020-00752-2 -
Hormones and Behavior Sep 2020Stress is known to modulate behavioral responses and rapid decision-making processes, especially under challenging contexts which often occur in social and cooperative...
Stress is known to modulate behavioral responses and rapid decision-making processes, especially under challenging contexts which often occur in social and cooperative interactions. Here, we evaluated the effects of acute stress on cooperative behavior of the Indo-Pacific cleaner wrasse (Labroides dimidiatus) and the implications of pre-treatment with monoaminergic compounds: the selective serotonin reuptake inhibitor - fluoxetine, the 5-HT receptor antagonist - WAY-100,635, the D receptor agonist - SKF-38393, and the D receptor antagonist - SCH-23390. We demonstrated that stress decreased the predisposal to interact and increased cortisol levels in cleaners, which are alleviated by fluoxetine and the dopaminergic D antagonist. Overall, our findings highlight the crucial influence of stress on cooperative behavior.
Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Behavior, Animal; Benzazepines; Cooperative Behavior; Dopamine; Dopamine Antagonists; Fishes; Fluoxetine; Perciformes; Piperazines; Pyridines; Receptors, Dopamine D1; Serotonin; Stress, Physiological
PubMed: 32619442
DOI: 10.1016/j.yhbeh.2020.104813