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Cancer Treatment and Research... 2021The significant physical and emotional effects of chemotherapy-induced nausea and vomiting (CINV) are experienced by cancer patients. Severe symptoms decrease the... (Review)
Review
The significant physical and emotional effects of chemotherapy-induced nausea and vomiting (CINV) are experienced by cancer patients. Severe symptoms decrease the patient's quality of life and potentially deters further treatment. The five main forms of CINV (i.e., acute, delayed, anticipatory, breakthrough, and refractory) require different treatment regimens, which often include 5-HT3 receptor antagonists, NK1 receptor antagonists, and corticosteroids. Despite a significant amount of research and development of antiemetic agents, management of CINV remains a great challenge with many needs waiting to be adequately addressed, such as controlling non-acute CINV, developing appropriate CINV treatment protocols for multiple-day chemotherapy patients, and providing options for those prone to CINV despite treatment. Further research is required to optimize CINV management for these patients.
Topics: Antiemetics; Antineoplastic Agents; Glucocorticoids; Humans; Medication Adherence; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Quality of Life; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 33360668
DOI: 10.1016/j.ctarc.2020.100278 -
International Journal of Molecular... Jan 2021Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine produced from the essential amino acid tryptophan. Serotonin's role as a neurotransmitter in the central... (Review)
Review
Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine produced from the essential amino acid tryptophan. Serotonin's role as a neurotransmitter in the central nervous system and a motility mediator in the gastrointestinal tract has been well defined, and its function in tumorigenesis in various cancers (gliomas, carcinoids, and carcinomas) is being studied. Many studies have shown a potential stimulatory effect of serotonin on cancer cell proliferation, invasion, dissemination, and tumor angiogenesis. Although the underlying mechanism is complex, it is proposed that serotonin levels in the tumor and its interaction with specific receptor subtypes are associated with disease progression. This review article describes serotonin's role in cancer pathogenesis and the utility of the serotonin pathway as a potential therapeutic target in cancer treatment. Octreotide, an inhibitor of serotonin release, is used in well-differentiated neuroendocrine cancers, and the tryptophan hydroxylase (TPH) inhibitor, telotristat, is currently being investigated in clinical trials to treat patients with metastatic neuroendocrine tumors and advanced cholangiocarcinoma. Several in vitro studies have shown the anticancer effect of 5-HT receptor antagonists in various cancers such as prostate cancer, breast cancer, urinary bladder, colorectal cancer, carcinoid, and small-cell lung cancer. More in vivo studies are needed to assess serotonin's role in cancer and its potential use as an anticancer therapeutic target. Serotonin is also being evaluated for its immunoregulatory properties, and studies have shown its potential anti-inflammatory effect. Therefore, it would be of interest to explore the combination of serotonin antagonists with immunotherapy in the future.
Topics: Antineoplastic Agents, Hormonal; Carcinoma, Neuroendocrine; Cell Movement; Cell Proliferation; Cholangiocarcinoma; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Neovascularization, Pathologic; Octreotide; Phenylalanine; Pyrimidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Signal Transduction; Tryptophan Hydroxylase; Tumor Cells, Cultured
PubMed: 33525332
DOI: 10.3390/ijms22031268 -
Biochemical Pharmacology Jun 2022Blockade of the serotonin 5-HT G protein-coupled receptor (5-HTR) is a fundamental pharmacological characteristic of numerous antipsychotic medications, which are... (Review)
Review
Blockade of the serotonin 5-HT G protein-coupled receptor (5-HTR) is a fundamental pharmacological characteristic of numerous antipsychotic medications, which are FDA-approved to treat schizophrenia, bipolar disorder, and as adjunctive therapies in major depressive disorder. Meanwhile, activation of the 5-HTR by serotonergic psychedelics may be useful in treating neuropsychiatric indications, including major depressive and substance use disorders. Serotonergic psychedelics and other 5-HTR agonists, however, often bind other receptors, and standard 5-HTR antagonists lack sufficient selectivity to make well-founded mechanistic conclusions about the 5-HTR-dependent effects of these compounds and the general neurobiological function of 5-HTRs. This review discusses the limitations and strengths of currently available "selective" 5-HTR antagonists, the molecular determinants of antagonist selectivity at 5-HTRs, and the utility of molecular pharmacology and computational methods in guiding the discovery of novel unambiguously selective 5-HTR antagonists.
Topics: Depressive Disorder, Major; Hallucinogens; Humans; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin 5-HT2 Receptor Agonists
PubMed: 35381208
DOI: 10.1016/j.bcp.2022.115028 -
International Journal of Molecular... Feb 2021In the 21st century and especially during a pandemic, the diagnosis and treatment of depression is an essential part of the daily practice of many family doctors. It... (Review)
Review
In the 21st century and especially during a pandemic, the diagnosis and treatment of depression is an essential part of the daily practice of many family doctors. It mainly affects patients in the age category 15-44 years, regardless of gender. Anxiety disorders are often diagnosed in children and adolescents. Social phobias can account for up to 13% of these diagnoses. Social anxiety manifests itself in fear of negative social assessment and humiliation, which disrupts the quality of social functioning. Treatment of the above-mentioned disorders is based on psychotherapy and pharmacotherapy. Serious side effects or mortality from antidepressant drug overdose are currently rare. Recent studies indicate that paroxetine (ATC code: N06AB), belonging to the selective serotonin reuptake inhibitors, has promising therapeutic effects and is used off-label in children and adolescents. The purpose of this review is to describe the interaction of paroxetine with several molecular targets in various points of view including the basic chemical and pharmaceutical properties. The central point of the review is focused on the pharmacodynamic analysis based on the molecular mechanism of binding paroxetine to various therapeutic targets.
Topics: Animals; Antidepressive Agents, Second-Generation; Depressive Disorder; Humans; Paroxetine; Serotonin Antagonists
PubMed: 33562229
DOI: 10.3390/ijms22041662 -
Comprehensive Psychiatry Jan 2023Serotonin reuptake inhibitor (SRI) medications are well established as first-line pharmacotherapeutic treatment for Obsessive-Compulsive Disorder (OCD). However, despite... (Review)
Review
Serotonin reuptake inhibitor (SRI) medications are well established as first-line pharmacotherapeutic treatment for Obsessive-Compulsive Disorder (OCD). However, despite the excellent safety profile and demonstrated efficacy of these medications, a substantial proportion of individuals with OCD fail to attain sufficient benefit from SRIs. In this narrative review, we discuss clinical features of OCD that have been associated with poorer response to SRIs, and we present pharmacotherapeutic interventions that have been explored as augmenting or alternative treatments for treatment-resistant OCD. We additionally highlight non-SRI interventions for OCD that are currently under investigation. Pharmacotherapeutic interventions were identified via expert consensus. To assess the evidence base for individual pharmacotherapies, targeted searches for relevant English-language publications were performed on standard biomedical research databases, including MEDLINE. Information relevant to ongoing registered clinical trials in OCD was obtained by search of ClinicalTrials.gov. Pharmacotherapies are grouped for review in accordance with the general principles of Neuroscience-based Nomenclature (NbN). Clinical features of OCD that may suggest poorer response to SRI treatment include early age of onset, severity of illness, duration of untreated illness, and the presence of symmetry/ordering or hoarding-related symptoms. Based on evolving pathophysiologic models of OCD, diverse agents engaging serotonin, dopamine, norepinephrine, glutamate, and anti-inflammatory pathways have been explored as alternative or adjunctive therapies for treatment-resistant OCD and have at least preliminary evidence of efficacy. Medications with dopamine antagonist activity remain the most robustly evidence-based of augmenting interventions, yet dopamine antagonists benefit only a minority of those who try them and carry elevated risks of adverse effects. Interventions targeting glutamatergic and anti-inflammatory pathways are less well evidenced, but may offer more favorable benefit to risk profiles. Ongoing research should explore whether specific interventions may benefit individuals with particular features of treatment-resistant OCD.
Topics: Humans; Obsessive-Compulsive Disorder; Anti-Inflammatory Agents
PubMed: 36368186
DOI: 10.1016/j.comppsych.2022.152352 -
Gastroenterology Jun 2022Increased colonic serotonin (5-HT) level and decreased serotonin reuptake transporter (SERT) expression in irritable bowel syndrome (IBS) may contribute to diarrhea and...
BACKGROUND & AIMS
Increased colonic serotonin (5-HT) level and decreased serotonin reuptake transporter (SERT) expression in irritable bowel syndrome (IBS) may contribute to diarrhea and visceral hypersensitivity. We investigated whether mucosal SERT is modulated by gut microbiota via a mast cell-prostaglandin E2 (PGE2) pathway.
METHODS
C57Bl/6 mice received intracolonic infusion of fecal supernatant (FS) from healthy controls or patients with diarrhea-predominant irritable bowel syndrome (IBS-D). The role of mast cells was studied in mast cell-deficient mice. Colonic organoids and/or mast cells were used for in vitro experiments. SERT expression was measured by quantitative polymerase chain reaction and Western blot. Visceromotor responses to colorectal distension and colonic transit were assessed.
RESULTS
Intracolonic infusion of IBS-D FS in mice caused an increase in mucosal 5-HT compared with healthy control FS, accompanied by ∼50% reduction in SERT expression. Mast cell stabilizers, cyclooxygenase-2 inhibitors, and PGE2 receptor antagonist prevented SERT downregulation. Intracolonic infusion of IBS-D FS failed to reduce SERT expression in mast cell-deficient (W/Wv) mice. This response was restored by mast cell reconstitution. The downregulation of SERT expression evoked by IBS FS was prevented by lipopolysaccharide (LPS) antagonist LPS from Rhodobacter sphaeroides and a bacterial trypsin inhibitor. In vitro LPS treatment caused increased cyclooxygenase-2 expression and PGE2 release from cultured mouse mast cells. Intracolonic infusion of IBS-D FS in mice reduced colonic transit, increased fecal water content, and increased visceromotor responses to colorectal distension. Ondansetron prevented these changes.
CONCLUSIONS
Fecal LPS acting in concert with trypsin in patients with IBS-D stimulates mucosal mast cells to release PGE2, which downregulates mucosal SERT, resulting in increased mucosal 5-HT. This may contribute to diarrhea and abdominal pain common in IBS.
Topics: Animals; Colorectal Neoplasms; Diarrhea; Dinoprostone; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Irritable Bowel Syndrome; Lipopolysaccharides; Mast Cells; Mice; Serotonin; Serotonin Plasma Membrane Transport Proteins
PubMed: 35167867
DOI: 10.1053/j.gastro.2022.02.016 -
Proceedings of the National Academy of... Apr 2021Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the...
Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however. We therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-HT2AR activation. Using chronically stressed male mice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. The antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus-a characteristic of traditional and fast-acting antidepressants. Neither behavioral nor electrophysiological responses to psilocybin were prevented by pretreatment with the 5-HT2A/2C antagonist ketanserin, despite positive evidence of ketanserin's efficacy. We conclude that psilocybin's mechanism of antidepressant action can be studied in animal models and suggest that altered perception may not be required for its antidepressant effects. We further suggest that a 5-HT2AR-independent restoration of synaptic strength in cortico-mesolimbic reward circuits may contribute to its antidepressant action. The possibility of combining psychedelic compounds and a 5-HT2AR antagonist offers a potential means to increase their acceptance and clinical utility and should be studied in human depression.
Topics: Animals; Depression; Drug Evaluation, Preclinical; Hallucinogens; Hippocampus; Ketanserin; Male; Mice, Inbred C57BL; Psilocybin; Receptors, Serotonin, 5-HT2; Serotonin 5-HT2 Receptor Agonists; Stress, Psychological; Mice
PubMed: 33850049
DOI: 10.1073/pnas.2022489118 -
Neuron Aug 2019The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting...
The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents. VIDEO ABSTRACT.
Topics: Animals; Arousal; Buspirone; Circadian Rhythm; Fenclonine; Homeostasis; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Optogenetics; Quipazine; Raphe Nuclei; Serotonergic Neurons; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sleep; Sleep Deprivation; Tryptophan Hydroxylase; Wakefulness; Zebrafish; Zebrafish Proteins
PubMed: 31248729
DOI: 10.1016/j.neuron.2019.05.038