5-HT3 Receptor Research Articles

5-Hydroxytryptamine: a potential therapeutic target in amyotrophic lateral sclerosis.

Previous studies have indicated that the pathogenesis of amyotrophic lateral sclerosis (ALS) is closely linked to 5-hydroxytryptamine (5-HT). To investigate this further, we administered 5-HT receptor antagonists to SOD1*G93A transgenic (ALS mouse model) and wide-type mice. This involved intraperitoneal injections of either granisetron, piboserod, or ritanserin, which inhibit the 5-HT3, 5-HT4, and 5-HT2 receptors, respectively. The transgenic mice were found to have fewer 5-HT-positive cells in the spinal cord compared with wide-type mice. We found that the administration of granisetron reduced the body weight of the transgenic mice, while piboserod and ritanserin worsened the motor functioning, as assessed using a hanging wire test. However, none of the 5-HT receptor antagonists affected the disease progression. We analyzed the distribution and/or expression of TAR DNA binding protein 43 (TDP-43) and superoxide dismutase 1 G93A (SOD1-G93A), which form abnormal aggregates in ALS. We found that the expression of these proteins increased following the administration of all three 5-HT receptor antagonists. In addition, the disease-related mislocalization of TDP-43 to the cytoplasm increased markedly for all three drugs. In certain anatomical regions, the 5-HT receptor antagonists also led to a marked increase in the number of astrocytes and microglia and a decrease in the number of neurons. These results indicate that 5-HT deficiency may play a role in the pathogenesis of amyotrophic lateral sclerosis by inducing the abnormal expression and/or distribution of TDP-43 and SOD1-G93A and by activating glial cells. 5-HT could therefore be a potential therapeutic target for amyotrophic lateral sclerosis.

Olanzapine for The Prevention of Nausea and Vomiting Caused by Chemoradiotherapy with High-Dose Cisplatin for Head and Neck Cancer.

Chemotherapy-induced nausea and vomiting (CINV) are the most common and distressing adverse events in patients receiving anticancer therapy. Radiotherapy also induces nausea and vomiting, so concurrent chemoradiotherapy-induced nausea and vomiting (CRINV) are significant problems for patients undergoing chemoradiotherapy. Conventionally, three-drug combination therapy with dexamethasone, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, and neurokinin-1 (NK1) receptor antagonist has been used to prevent CRINV induced by concurrent chemoradiotherapy with cisplatin for patients with head and neck cancer (HNC). Nonetheless, CRINV still remains a problem. The effectiveness of adding olanzapine to prevent CINV has been reported, suggesting the efficacy of four-drug combination therapy for CRINV. However, its effectiveness has hardly been reported in patient receiving chemoradiotherapy for HNC. A total of 109 patients with HNC who received concurrent chemoradiotherapy with cisplatin from April 2014 to March 2021 were included and divided into the following two groups according to antiemetic treatment regimen: the conventional group (Con group; n = 78) who received three-drug combination therapy and the olanzapine group (Olz group; Olz group, n = 31) who received four-drug combination therapy with olanzapine. Acute (0 to 24 h from cisplatin) and delayed (25 to 120 h from cisplatin) CRINV were then compared using the Common Terminology Criteria for Adverse Events. No significant difference in acute CRINV were observed between both groups (P = 0.5761, Fisher's exact test). However, the Olz group had a significantly lower incidence rate of delayed CRINV over Grade 3 compared to the Con group (P = 0.0318, Fisher's exact test). Four-drug combination therapy with olanzapine was effective in suppressing delayed CRINV due to chemoradiotherapy with cisplatin for HNC.

Stress induced exacerbation of Alzheimer's disease brain pathology is thwarted by co-administration of nanowired cerebrolysin and monoclonal amyloid beta peptide antibodies with serotonin 5-HT6 receptor antagonist SB-399885.

Alzheimer's disease is one of the devastating neurodegenerative diseases affecting mankind worldwide with advancing age mainly above 65 years and above causing great misery of life. About more than 7 millions are affected with Alzheimer's disease in America in 2023 resulting in huge burden on health care system and care givers and support for the family. However, no suitable therapeutic measures are available at the moment to enhance quality of life to these patients. Development of Alzheimer's disease may reflect the stress burden of whole life inculcating the disease processes of these neurodegenerative disorders of the central nervous system. Thus, new strategies using nanodelivery of suitable drug therapy including antibodies are needed in exploring neuroprotection in Alzheimer's disease brain pathology. In this chapter role of stress in exacerbating Alzheimer's disease brain pathology is explored and treatment strategies are examined using nanotechnology based on our own investigation. Our observations clearly show that restraint stress significantly exacerbate Alzheimer's disease brain pathology and nanodelivery of a multimodal drug cerebrolysin together with monoclonal antibodies (mAb) to amyloid beta peptide (AβP) together with a serotonin 5-HT6 receptor antagonist SB399885 significantly thwarted Alzheimer's disease brain pathology exacerbated by restraint stress, not reported earlier. The possible mechanisms and future clinical significance is discussed.

Comparative Efficacy of Different Classes of Antiemetic Medications for the Prevention of Nausea and Vomiting in Cesarean Section: A Network Meta-Analysis.

Antiemetic medications have been associated with the prevention of nausea and vomiting in cesarean section, although less is known about the comparative efficacy of different medication classes. We conducted a systematic review with network meta-analyses to compare and rank antiemetic medication classes (5-HT3 receptor antagonists, dopamine receptor antagonists, corticosteroids, antihistamines, anticholinergic agents, sedatives, and opioid antagonists or partial agonists) in terms of preventing intra- and postoperative nausea and vomiting among patients undergoing cesarean section. We included all randomized controlled trials (RCTs) that evaluated any antiemetic medication classes' treatment for target outcomes. Network meta-analysis was conducted with a frequentist approach using the R netmeta package. A total of 58 trials were included (6,665 women undergoing cesarean section; mean age, 28.1 years). Results: Compared with placebo, all interventions reduced the odds of intraoperative nausea (except antihistamines), intraoperative vomiting (except antihistamines), postoperative nausea (except anticholinergic agents and opioid antagonists), and postoperative vomiting (except opioid antagonists). In terms of intraoperative nausea and both intra- and postoperative vomiting, sedatives ranked first among other medication classes. The relative effect sizes for various classes of antiemetic medication in preventing nausea and vomiting in the cesarean section were modeled using the principles of network meta-analysis which may facilitate informed clinical decision-making.

Quipazine: Classical hallucinogen? Novel psychedelic?

Quipazine, first identified in the 1960s, has been the topic of >1000 published papers. On the basis of available 5-HT2 serotonin receptor radioligand binding data and various preclinical studies, it might be thought that quipazine bears the hallmarks of a classical hallucinogen or psychedelic agent – agents currently being examined for their potential use in treating certain neuropsychiatric disorders. Nevertheless, by definition, such agents require the availability of human data, which, in the case of quipazine, are lacking. Because quipazine is also a 5-HT3 receptor agonist, future human studies with this agent might prove problematic because 5-HT3 agonists are known to produce emesis. Nevertheless, continued investigation of novel quipazine analogs with modified pharmacological profiles might prove worthwhile.

Association between ondansetron use and mortality of patients on mechanical ventilation in the intensive care unit: a retrospective cohort study.

Basic studies show that selective 5-hydroxytryptamine type 3 (5-HT3) serotonin-receptor antagonists can protect organs from inflammatory injury and have shown lung protection. Whether 5-HT3 receptor antagonists ondansetron benefits patients with mechanical ventilation is unclear in the intensive care unit (ICU). The Medical Information Mart for Intensive Care-IV (MIMIC-IV) database was reviewed to identify patients on mechanical ventilation (aged >16 years) in the ICU, which was divided into two groups according to whether ondansetron is used. Demographic characteristics, medical history data, clinical parameters, diagnosis and treatment measures were included as covariates. Ondansetron use was defined as any kind of ondansetron administration regardless of the dose before the induction of mechanical ventilation. The primary outcome was in-hospital death. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated by multivariable Cox regression. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to further adjust for confounding factors. Kaplan-Meier (KM) curves with log-rank test were also performed. A total of 18,566 patients on mechanical ventilation were included (5,735 with ondansetron use). The overall in-hospital mortality rate of patients on mechanical ventilation was 18.9% (3,512/18,566). Approximately 13.0% (746/5,735) and 21.6% (2,766/12,831) in-hospital mortality rates occurred in the ondansetron and non-ondansetron use groups, respectively. Multivariable regression indicated that ondansetron usage was associated with a 33% and 32% lower risk of in-hospital and 60-day death (HR =0.77, 95% CI: 0.70-0.85, P<0.001; HR =0.68, 95% CI: 0.62-0.75, P<0.001) in the whole sample. Multivariable regression post-PSM indicated that ondansetron usage was associated with a 38% and 31% lower risk of in-hospital and 60-day death (HR =0.62, 95% CI: 0.56-0.68, P<0.001; HR =0.69, 95% CI: 0.62-0.77, P<0.001). Log-rank test for the KM curve of ondansetron and 60-day death was statistically significant (P<0.001). The duration of ventilator use pre- and post-PSM was statistically different (P<0.001 and P=0.007) in the two groups. Ondansetron usage was significantly associated with a lower mortality risk of ventilated patients in the ICU. The 5-HT3 receptor antagonist use is may be new potential adjunctive therapeutic strategy for patients on mechanical ventilation in the ICU.

Nicotine neurotoxicity exacerbation following engineered Ag and Cu (50-60nm) 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 (50-60nm) 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.

Effect of Palonosetron in the Prevention of Spinal Anaesthesia-induced Hypotension and Bradycardia: A Randomised Controlled Trial

Introduction: Spinal Anaesthesia (SA) is frequently associated with hypotension, which is due to sympathectomy causing vasodilation, leading to relative hypovolemia. This decrease in venous return to the heart causes a decrease in left ventricular filling pressure, leading to the activation of the Bezold-Jarisch Reflex (BJR), which causes bradycardia. This response is mediated by mechanoreceptors and chemoreceptors present on the heart walls. These chemoreceptors are mediated through serotonin (5-HT). Therefore, the activation of 5-HT3 receptors at sensory vagal nerve endings in the heart causes hypotension and bradycardia. Aim: To assess the efficacy of Palonosetron in attenuating spinal anaesthesia-induced hypotension and bradycardia. Materials and Methods: The trial was a parallel-design, randomised, double-blind controlled trial conducted over two years, from February 2021 to August 2022 in the Department of Anaesthesiology, Kalinga Institution of Medical Sciences (KIMS), Bhubaneswar, Odisha, India, among patients undergoing spinal anaesthesia for various surgeries. The patients were divided into two groups based on the type of medication received: Group APalonosetron group and Group B- the saline group. Computergenerated random number generator software was used for randomisation. At a 1:1 ratio, 150 patients were chosen (75 in each group). Baseline assessment of haemodynamic parameters was performed, followed by continuous monitoring. The drug was administered 10 minutes prior to spinal anaesthesia, and the haemodynamic parameters (Heart Rate [HR], Systolic Blood Pressure [SBP], Diastolic Blood Pressure [DBP], and Mean Arterial Pressure [MAP]) were monitored. Continuous variables are expressed as mean±Standard Deviation (SD). The Student’s t-test was used to compare the difference between the two groups, and categorical variables are expressed as frequency and percentage, with comparisons done using the Chi-square test. A p-value of &lt;0.05 was considered statistically significant. Results: The mean age of Group A and Group B was 40.88 and 42.14, respectively. Significant haemodynamic changes (hypotension) were observed following induction in Group B (28 [37.3%]) compared to Group A (9 [12%]). Consumption of vasopressors and intravenous (i.v.) fluids was significantly higher in Group B compared to Group A. The incidence of bradycardia in Group A and Group B was 15 (20%) and 18 (24%), respectively. Postoperative Nausea and Vomiting (PONV) in Group A and Group B were 3 (4%) and 8 (10.7%), respectively. Conclusion: Based on the present study, the prophylactic administration of 0.075 mg Palonosetron 10 minutes before subarachnoid block is effective in attenuating the incidence of spinal anaesthesia-induced hypotension and bradycardia. There is also decreased consumption of vasopressors and a lower incidence of PONV..

Association between ondansetron use and mortality of patients on mechanical ventilation in the intensive care unit: a retrospective cohort study

Background: Basic studies show that selective 5-hydroxytryptamine type 3 (5-HT3) serotonin-receptor antagonists can protect organs from inflammatory injury and have shown lung protection. Whether 5-HT3 receptor antagonists ondansetron benefits patients with mechanical ventilation is unclear in the intensive care unit (ICU).

Identification and Pharmacological Characterization of Two Serotonin Type 7 Receptor Isoforms from Mythimna separata

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 5-HT7 receptors from oriental armyworm Mythimna separata (Walker) (Lepidoptera: Noctuidae), an important migratory and polyphagous pest species. We found that the 5-HT7 receptor gene encodes two molecularly distinct transcripts, Msep5-HT7L and Msep5-HT7S, by the mechanism of alternative splicing in M. separata. 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 M. separata adults, as determined by qPCR assay. This study is the first comprehensive characterization of two splicing isoforms of 5-HT7 receptors in M. separata, 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.

Ondansetron: A selective 5HT3 receptor antagonist and it advances in drug delivery system

Ondansetron is a serotonin (5HT3) receptor antagonist used for the prevention and treatment of postoperative nausea and vomiting. It is available in many dosage forms in the market. Various analytical methods used for the determination of Ondansetron have been studied in this review article such as UV spectroscopy, mass spectroscopy, high-performance liquid chromatography, high-performance thin layer chromatography, a new electrospray ionization mass spectrometry etc. Ondansetron in human plasma can be estimated using this method. With time many advances have been made in the formulation aspects of Ondansetron, such as now a days it is available in floating drug delivery, transdermal as well as gastroretentive and orodispersible drug delivery system. New novel technologies are also mentioned in this review article related to 3D printing, nanofibers etc

Ondansetron: A selective 5HT3 receptor antagonist and it advances in drug delivery system

Ondansetron: A selective 5HT3 receptor antagonist and it advances in drug delivery system

Hybrid molecules combining GABA-A and serotonin 5-HT6 receptors activity designed to tackle neuroinflammation associated with depression

There is clear evidence that the presence of inflammatory factors and impaired GABA-ergic neurotransmission in depressed patients is associated with poor clinical outcome. We designed hybrid molecules, bearing the GABA molecule assembled with chemical fragments that interact with the serotonin 5-HT6 receptor. Such a combination aimed to curb neuroinflammation, remodel GABA-ergic signaling, and provide antidepressant-like activity. The most promising hybrid 3B exerted nanomolar affinity for 5-HT6 receptors and exerted agonistic properties on GABA-A receptors. Developability studies conferred that 3B exerted favorable drug-like properties and optimal brain penetration. In in vivo studies, 3B exerted robust antidepressant-like activity and proved to be highly effective in reducing levels of oxidative stress markers and the pro-inflammatory cytokine IL-6. The inetersting pharmacological profile of 3B makes it a promising candidate for further development for depression associated with neuroinflammation.

Comparison of the Effectiveness of Palonosetron and Ramosetron in Preventing Postoperative Nausea and Vomiting: Updated Systematic Review and Meta-Analysis with Trial Sequential Analysis.

This updated systematic review and meta-analysis with trial sequential analysis aimed to compare the efficacy of the perioperative administration of palonosetron with that of ramosetron in preventing postoperative nausea and vomiting (PONV). A total of 17 randomized controlled trials comparing the efficacy of the perioperative administration of palonosetron to that of ramosetron for preventing PONV were included. The primary outcomes were the incidences of postoperative nausea (PON), postoperative vomiting (POV), and PONV, which were measured in early, late, and overall phases. Subgroup analysis was performed on the basis of the administration time of the 5-HT3 receptor antagonist and divided into two phases: early phase and the end of surgery. A total of 17 studies with 1823 patients were included in the final analysis. The incidence of retching (relative risk [RR] = 0.525; 95% confidence interval [CI] = 0.390 to 0.707) and late POV (RR = 0.604; 95% CI = 0.404 to 0.903) was significantly lower in the palonosetron group than in the ramosetron group. No significant differences were demonstrated in the incidence of PON, PONV, complete response, use of antiemetics, and adverse effects. Subgroup analysis showed that palonosetron was superior to ramosetron in terms of early PON, late PON, overall POV, and use of rescue antiemetics when they were administered early; in terms of retching, regardless of the timing of administration. Ramosetron was superior to palonosetron in terms of early PON when they were administered late. The prophylactic administration of palonosetron was more effective than that of ramosetron in preventing the development of retching and late POV. In this meta-analysis, no significant differences in PONV prevention between the two drugs were demonstrated. Further studies are required to validate the outcomes of our study.

Serotonin distinctly controls behavioral states in restrained and freely moving Drosophila

When trapped in a physical restraint, animals must select an escape strategy to increase their chances of survival. After falling into an inescapable trap, they react with stereotypical behaviors that differ from those displayed in escapable situations. Such behaviors involve either a wriggling response to unlock the trap or feigning death to fend off a predator attack. The neural mechanisms that regulate animal behaviors have been well characterized for escapable situations but not for inescapable traps. We report that restrained vinegar flies exhibit alternating flailing and immobility to free themselves from the trap. We used optogenetics and intersectional genetic approaches to show that, while broader serotonin activation promotes immobility, serotonergic cells in the ventral nerve cord (VNC) regulate immobility states majorly via 5-HT7 receptors. Restrained and freely moving locomotor states are controlled by distinct mechanisms. Taken together, our study has identified serotonergic switches of the VNC that promote environment-specific adaptive behaviors.

Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D3-Selective Antagonists.

Previous studies have confirmed that the binding of D3 receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D3 receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D3 receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D3 receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D3 receptor affinities (Ki = 0.8-13.2 nM) with subtype selectivity to the D2 receptor ranging from 22- to 180-fold. The β-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC50 = 1.3 nM). Computational studies demonstrated that the high potency of 21c and its analogs was the result of interactions with the secondary binding site of the D3 receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT3 receptors and TSPO. The results of this study revealed that a new class of selective D3 receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.

Efficacy and safety of low doses of olanzapine for the prevention of nausea and vomiting in children and adolescents receiving highly emetogenic chemotherapy. The interim results of a randomized trial

International studies and the analysis of our own data demonstrate that the standard three-drug (5-HT3 receptor antagonist, aprepitant and dexamethasone) regimen used for the prevention of chemotherapy-induced nausea and vomiting (CINV) gives the possibility to achieve complete CINV control in less than 50% of children receiving highly emetogenic chemotherapy. According to the results of randomized trials in adult patients, the addition of low doses of olanzapine increases the efficacy of CINV prophylaxis. There is no data on the efficacy and safety of low-dose olanzapine used for the prevention of CINV in children. The aim of this study is to assess the efficacy and safety of adding low doses (0.07 mg/kg, maximum 5 mg) of olanzapine to the standard regimen used for CINV prophylaxis after highly emetogenic chemotherapy in children. The study includes patients receiving highly emetogenic chemotherapy at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation, in case of which there are no other (except for chemotherapy) obvious reasons for nausea and vomiting and no contraindications for the use of olanzapine. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation, and registered in the US National Library of Medicine clinical trials registry (http://clinicaltrials.gov), the identification number is NCT05346731. Patients were randomized in a 1:1 ratio and stratified (previously received highly emetogenic therapy or not; regimens with high doses of cisplatin/carboplatin and without it) to receive the first cycle of highly emetogenic chemotherapy with standard three-drug prophylaxis with the addition of low doses of olanzapine or without it. Then, the patients underwent a second similar cycle of highly emetogenic chemotherapy with a change in the antiemetic prophylaxis option (crossover). For the assessment of CINV, we used the Pediatric Nausea Assessment Tool (PeNAT). Adverse events were assessed using CTCAE v.5.0. This is an interim analysis and it was carried out in order to assess whether it was reasonable to continue the study. From March to August 2022, 31 patients were included in the study, the median age was 14 (5–18) years, the ratio of boys:girls was 15:16; all patients suffered from extracranial solid tumors. Considering crossover, 31 patients included in the study received 62 cycles of chemotherapy (31 cycles with olanzapine and 31 cycles without it). Out of 31 cycles of chemotherapy with standard three-drug prophylaxis, complete CINV control was achieved in 16 (52%) cases, out of 31 cycles with prophylaxis, which included low doses of olanzapine – in 24 (77%) cases (p = 0.027). Adverse events associated with olanzapine were quite common (sedation - 97%, weight gain -76%), but mild (&lt; Grade III). According to the patient survey results, 30/31 (97%) patients preferred the regimen with olanzapine, and only 1 patient preferred neither of the regimens. The interim analysis of the study results shows that the addition of low doses of olanzapine significantly increases the efficacy of CINV prophylaxis in pediatric patients receiving highly emetogenic chemotherapy, is well tolerated, safe and preferred by the vast majority of patients. It is necessary to continue the study until the planned number of patients for the final analysis is included.

Impact of specific serotonin receptor modulation on restricted repetitive behaviors.

Restricted, repetitive behaviors (RRBs) are commonly divided into two behavioral categories, lower-order and higher-order RRBs. Individuals displaying lower-order motoric RRBs may express repetitive hand flapping behaviors, body rocking back and forth movements, and continuous body spinning. Higher-order RRBs most commonly cover the behavior inflexibility and cognitive rigidity commonly found in disorders such as autism spectrum disorder and obsessive-compulsive disorder. Various neuropsychiatric disorders are plagued by RRBs yet no FDA-approved treatments have been identified. In rodents, lower-order RRBs are commonly measured through various tasks, such as repetitive self-grooming, marble burying, and stereotypic motor behaviors. This review focuses on the effects that modulation of specific serotonin receptors have on lower-order RRBs. Although there is research examining how changes in 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor modulation, more research has focused on the 5-HT1A, 5-HT2A, and 5-HT2C receptors. The accumulating data suggest that increasing 5-HT1A activation decreases RRBs while blocking 5-HT1A activation has no effect on RRBs. While there are mixed findings regarding the impact of 5-HT2A modulation on RRBs, the general trend shows mixed effects of 5-HT2A receptor activation RRB expression, whereas blockade generally decreases RRBs. 5-HT2C receptor activation can modulate RRBs in either direction depending on the 5-HT2C drug used, blocking 5-HT2C activation only seems to show therapeutic properties when 5-HT2C activation is already elevated. The other 5-HT receptors have been explored far less but show promise as potential targets for regulating RRBs. Although it is less clear due to the involvement of 5-HT1D, 5-HT1A activation increases RRBs, and blocking 5-HT1A tends to decrease RRBs. 5-HT2B activation could reduce RRBs, while inhibiting 5-HT2B does not impact RRBs. Increasing 5-HT3 has not been shown to affect RRBs. Yet, increases in RRBs have been observed in Htr3a KO mice. 5-HT6 receptor activation can increase RRBs, while blocking 5-HT6 activity tends to decrease RRBs. Lastly, neither increasing or blocking 5-HT7 activity can reduce RRBs. In sum, there is no uniform pattern in whether all specific 5-HT receptors affect RRBs in either direction, instead, there is evidence suggesting that different 5-HT receptors can modulate RRBs in different directions. Further researching the less explored receptors and aiming to understand why these receptors can differently modulate RRBs, may play a key role in developing therapeutics that treat RRBs.

Fluoxetine increased adult neurogenesis is mediated by 5-HT3 receptor

Adult neurogenesis is an aspect of structural plasticity that remains active during adulthood in some brain regions. One of them is the subgranular zone (SGZ) of the dentate gyrus of the hippocampus. Adult neurogenesis is reduced by different factors and in disorders of the CNS, including major depression. Antidepressant treatments, such as chronic fluoxetine administration, recover the normal level of adult neurogenesis. Fluoxetine treatment increases the free concentration of the neurotransmitter serotonin and this monoamine is implicated in the regulation of the neurogenic process; however, the target of the action of this neurotransmitter has not been fully elucidated. In this study, we have tried to determine the relevance of the serotonin receptor 3 (5-HT3) in the hippocampal neurogenesis of adult rats. We have used fluorescent immunohistochemistry to study the expression of the 5-HT3 receptor in different neurogenesis stages in the SGZ, identifying its expression in stem cells, amplifying neural progenitors and immature neurons. Moreover, we have studied the impact of a 5-HT3 antagonist (ondansetron) in the fluoxetine-induced adult neurogenesis. We observed that fluoxetine alone increases the number of both proliferating cells (ki67 positive) and immature neurons (DCX positive) in the SGZ. By contrast, co-treatment with ondansetron blocked the increase in proliferation and neurogenesis. This study demonstrates that the activation of 5-HT3 receptors is necessary for the increase of adult neurogenesis induced by fluoxetine.

Pharmacokinetic and Pharmacologic Characterization of the Dihydrotetrabenazine Isomers of Deutetrabenazine and Valbenazine.

Valbenazine and deutetrabenazine are vesicular monoamine transporter 2 (VMAT2) inhibitors approved for tardive dyskinesia. The clinical activity of valbenazine is primarily attributed to its only dihydrotetrabenazine (HTBZ) metabolite, [+]-α-HTBZ. Deutetrabenazine is a deuterated form of tetrabenazine and is metabolized to four deuterated HTBZ metabolites: [+]-α-deuHTBZ, [+]-β-deuHTBZ, [-]-α-deuHTBZ, and [-]-β-deuHTBZ. An open-label, crossover study characterized the pharmacokinetic profiles of the individual deuHBTZ metabolites, which have not been previously reported. VMAT2 inhibition and off-target interactions of the deuHTBZ metabolites were evaluated using radioligand binding. The only valbenazine HTBZ metabolite, [+]-α-HTBZ, was a potent VMAT2 inhibitor, with negligible affinity for off-target dopamine, serotonin, and adrenergic receptors. Following deutetrabenazine administration, [-]-α-deuHTBZ represented 66% of circulating deuHTBZ metabolites and was a relatively weak VMAT2 inhibitor with appreciable affinity for dopamine (D2S , D3 ) and serotonin (5-HT1A , 5-HT2B , 5-HT7 ) receptors. [+]-β-deuHTBZ was the most abundant deuHTBZ metabolite that potently inhibited VMAT2, but it represented only 29% of total circulating deuHTBZ metabolites. The mean half-life of [+]-α-HTBZ (22.2hours) was ∼3× longer than that of [+]-β-deuHTBZ (7.7hours). These findings are similar to studies with tetrabenazine, in that deutetrabenazine is metabolized to four deuHTBZ stereoisomers, the most abundant of which has negligible interaction with VMAT2 in vitro and appreciable affinity for several off-target receptors. In contrast, valbenazine's single HTBZ metabolite is a potent VMAT2 inhibitor in vitro with no discernible off-target activity. Determination of the effects of intrinsic/extrinsic variables on deutetrabenazine's safety/efficacy profile should incorporate assessment of the effects on all deuHTBZ metabolites.