Receptor Antagonist Ondansetron Research Articles

Nephrotoxicity Evaluation on Cisplatin Combined with 5-HT3 Receptor Antagonists: A Retrospective Study

Objective 5-HT3 receptor antagonist (ondansetron) has been reported to have nephrotoxic effect when combined with cisplatin in mice; however, little evidence exists in explaining its nephrotoxic effects on patients. The aim of this present study was to investigate whether 5-HT3 receptor antagonist could enhance or aggravate the incidence of cisplatin-induced nephrotoxicity in patients. Methods We retrospectively reviewed 600 tumor patients which were treated with cisplatin (⩾60 mg/m2) as a first-time chemotherapy and combined with 5-HT3 receptor antagonist (i.e., ondansetron, tropisetron, or ramosetron, each kind of 5-HT3 receptor antagonist contains 200 cases) between January 2010 and December 2015. Cisplatin dosing, the baseline creatinine clearance, and other independent risk factors such as patient's age, sex, PS score, and weight associated with nephrotoxicity were evaluated in a multivariable model. Results The incidence of Grade ⩾ 2 serum creatinine elevation in cisplatin + ondansetron group was significantly higher than cisplatin + tropisetron group (P = 0.04), but no significant difference was found between cisplatin + ondansetron group and cisplatin + ramosetron group (P = 0.3). It was also found that cisplatin dosage and tumor type were independent risk factors in the development of nephrotoxicity. Conclusion Higher cisplatin dosage and regular use of ondansetron combined with cisplatin are more likely to increase the incidence of nephrotoxicity; tropisetron showed the relatively mild effect on kidney function, suggesting that tropisetron is a preferable alternative in the process of cisplatin chemotherapy.

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca2+-activated K+ channels.

Apamin-sensitive small-conductance Ca2+-activated K+ (SK) current ( IKAS) is encoded by Ca2+-activated K+ channel subfamily N ( KCNN) genes. IKAS importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that IKAS inhibition contributes to drug-induced long QT syndrome (diLQTS), we screened for KCNN variants among patients with diLQTS, determined the properties of heterologously expressed wild-type (WT) and variant KCNN channels, and determined if the 5-HT3 receptor antagonist ondansetron blocks IKAS. We searched 2,306,335 records in the Indiana Network for Patient Care and found 11 patients with diLQTS who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-yr-old woman presenting with corrected QT interval prolongation at baseline (473 ms) and further corrected QT interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNE1 and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 variant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca2+ sensitivity, increasing IKAS density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of WT KCNN2 protein. Ondansetron at nanomolar concentrations inhibited WT and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced IKAS inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F503L KCNN2 variant increases Ca2+ sensitivity and IKAS density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent IKAS blocker. NEW & NOTEWORTHY We showed that ondansetron, a 5-HT3 receptor antagonist, blocks small-conductance Ca2+-activated K+ (SK) current. Ondansetron may be useful in controlling arrhythmias in which increased SK current is a likely contributor. However, its SK-blocking effects may also facilitate the development of drug-induced long QT syndrome.

Vortioxetine Treatment Reverses Subchronic PCP Treatment-Induced Cognitive Impairments: A Potential Role for Serotonin Receptor-Mediated Regulation of GABA Neurotransmission.

Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine’s effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected vortioxetine’s cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating vortioxetine’s effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT3 receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABAB receptor expression in a manner that was insensitive to vortioxetine treatment, and subchronic vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA’s affinity for the GABAA receptor. These data suggest that vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that vortioxetine’s GABAergic and glutamatergic effects are relevant for cognitive function.

The multimodal antidepressant vortioxetine may facilitate pyramidal cell firing by inhibition of 5-HT3 receptor expressing interneurons: An in vitro study in rat hippocampus slices

The multimodal antidepressant vortioxetine is thought to mediate its pharmacological effects via 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, 5-HT1D, 5-HT3, 5-HT7 receptor antagonism and 5-HT transporter inhibition. Here we studied vortioxetine’s functional effects across species (canine, mouse, rat, guinea pig and human) in cellular assays with heterologous expression of 5-HT3A receptors (in Xenopus oocytes and HEK-293 cells) and in mouse neuroblastoma N1E-115 cells with endogenous expression of 5-HT3A receptors. Furthermore, we studied the effects of vortioxetine on activity of CA1 Stratum Radiatum interneurons in rat hippocampus slices using current- and voltage-clamping methods. The patched neurons were subsequently filled with biocytin for confirmation of 5-HT3 receptor mRNA expression by in situ hybridization. Whereas, both vortioxetine and the 5-HT3 receptor antagonist ondansetron potently antagonized 5-HT-induced currents in the cellular assays, vortioxetine had a slower off-rate than ondansetron in oocytes expressing 5-HT3A receptors. Furthermore, vortioxetine’s but not ondansetron’s 5-HT3 receptor antagonistic potency varied considerably across species. Vortioxetine had the highest potency at rat and the lowest potency at guinea pig 5-HT3A receptors. Finally, in 5-HT3 receptor-expressing GABAergic interneurons from the CA1 stratum radiatum, vortioxetine and ondansetron blocked depolarizations induced by superfusion of either 5-HT or the 5-HT3 receptor agonist mCPBG. Taken together, these data add to a growing literature supporting the idea that vortioxetine may inhibit GABAergic neurotransmission in some brain regions via a 5-HT3 receptor antagonism-dependent mechanism and thereby disinhibit pyramidal neurons and enhance glutamatergic signaling.

Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: a blinded crossover study

BackgroundNausea is a subjective sensation which is difficult to measure in non-verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18 mg/m2 cisplatin intravenously, followed 45 min later by a 15 min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5 mg/kg; 5-HT3 antagonist), maropitant (1 mg/kg; NK1 antagonist) or metoclopramide (0.5 mg/kg; D2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15 min for 8 h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations.ResultsThe placebo treated group vomited an average number of 7 times (range 2–13). None of the dogs in either the ondansetron or maropitant treated groups vomited during the observation period. The onset of nausea-like behaviour in the placebo-treated group occurred at t3.5h and peaked at t4.75h with nausea behaviour score of 58.5 ± 4.6 mm. Ondansetron and maropitant reduced overall the area under the curve of nausea behaviour score by 90% and 25%, respectively. Metoclopramide had no effect on either vomiting or nausea.Cisplatin-induced nausea and vomiting caused concomitant increases in AVP and cortisol. In the placebo-treated group, AVP and cortisol increased from t2.5h, peaked at t5h (11.3 ± 2.9 pmol L−1 and 334.0 ± 46.7 nmol/L, respectively) and returned to baseline by t8h. AVP and cortisol increases were completely prevented by ondansetron and only partially by maropitant, while metoclopramide had no effect. The terminal half-lives (harmonic mean ± pseudo SD) for ondansetron, maropitant and metoclopramide were 1.21 ± 0.51, 5.62 ± 0.77 and 0.87 ± 0.17 h respectively.Conclusions5-HT3 receptor antagonist ondansetron demonstrates the greatest anti-emetic and anti-nausea efficacy of the three drugs. AVP and cortisol appear to be selective biomarkers of nausea rather than emesis, providing a means of objectively measuring of nausea in the dog.

The 5-HT3 Receptor Antagonist Ondansetron Attenuates Pancreatic Injury in Cerulein-Induced Acute Pancreatitis Model.

The 5-hydroxytryptamine-3 receptor (5-HT3R) antagonist ondansetron has been clinically approved as an anti-emetic agent. Recent findings indicate that ondansetron has anti-inflammatory properties. The aim of the present study was to assess the therapeutic action of ondansetron in cerulein-induced acute pancreatitis model. Male-BALB/c mice were used in the present study. Acute pancreatitis was induced by an hourly injection of cerulein. Ondansetron was administered subcutaneously at a dose of 3mg/kg. The messenger RNA (mRNA) expression of 5-HT3 R in pancreatic tissue was assessed with RT-PCR. Plasma amylase, lipase, and interleukin (IL)-6 levels were evaluated. Pancreatic injury was histopathologically graded, and myeloperoxidase (MPO)-positive cells were counted. 5-HT3R mRNA was expressed in the pancreas. In acute pancreatitis model mice, amylase, lipase, and IL-6 levels were significantly increased in the blood. With ondansetron treatment, these levels were significantly decreased. Histopathological evaluation revealed that ondansetron attenuated the inflammatory damage in acute pancreatitis. The number of infiltrated neutrophils stained by MPO was decreased by ondansetron treatment. In summary, the 5-HT3R antagonist ondansetron attenuated pancreatic injury through its anti-inflammatory action. These findings suggest that ondansetron may potentially be of use for therapy of acute pancreatitis.

5-HT secretion by enterochromaffin cells is a very touching story.

Gastrointestinal (GI) function is controlled by sympathetic, parasympathetic, sensory and enteric nerves. In addition, the gut mucosa contains enteroendocrine cells which release hormones and paracrine signalling molecules in response to chemical and mechanical stimulation by GI luminal content. Enterochromaffin (EC) cells are an enteroendocrine cell type in the gut mucosa. EC cells release 5-hydroxytryptamine (5-HT) in response to mechanical and chemical stimuli. 5-HT released from EC cells stimulates intestinal motor and secretomotor reflexes by activating 5-HT receptors on terminals of intrinsic primary afferent neurons (IPANS) whose cell bodies are located in the enteric nerve plexuses. IPANS synapse with interneurons which excite other enteric neurons to initiate reflex responses. EC cell-derived 5-HT also acts at 5-HT receptors on extrinsic sensory nerve terminals to convey nociceptive signals to the CNS (via spinal afferents) or to initiate GI reflexes via vagal afferents. TRPA1 channels are chemosensitive ion channels expressed by EC cells and TRPA1 stimulants cause 5-HT release from EC cells (Nowaza et al. 2009). EC cells are also activated by mechanical stimulation and EC cells express unidentified mechanosensitive proteins. The paper by Wang et al. (2017) in this issue of The Journal of Physiology provides exciting new data indicating that Piezo2 is a mechanosensitive ion channel expressed by EC cells. Piezo2 is one of two Piezo ion channels (Piezo1 and Piezo2) expressed by proprioceptive cells (Woo et al. 2015). Piezo2 was also shown to be important for mechanosensation by Aβ nerve fibres that together with Merkel cells (Merkel-cell–neurite complexes) are involved in light touch sensation (Ranade et al. 2014). Piezo channels are large proteins (∼2600 amino acids) and the murine Piezo1 channel has 14 transmembrane spanning domains (Ge et al. 2015). Human Piezo2 has a single channel conductance of ∼26 pS and the channel inactivates during continuous mechanical stimulation of the cell. Piezo2 is a non-selective cation channel (Irev = ∼0 mV) with a rank order permeability of Ca2+ > Na+ > K+. The high Ca2+ permeability may be particularly important for EC cell 5-HT release. Wang and co-workers provide immunohistochemical data showing Piezo2 co-localized with 5-HT in EC cells in the human jejunum. Piezo2 was also co-expressed in EC cells in the small intestine of transgenic mice where cyano-fluorescent protein (CFP) expression was driven by the tryptophan hydroxylase-1 (TpH-1) promoter. TpH-1 is the rate limiting enzyme in the 5-HT biosynthetic pathway in EC cells. Piezo2 also co-localized with TpH-1 cells in the mucosa of the mouse jejunum. Wang and colleagues (2017) used QGP-1 cells (an EC cell line) to study mechanically activated inward currents. Mechanical stimulation of QGP-1 cells produced a stimulus intensity-related and rapidly inactivating (≤10 ms) inward current that had a reversal potential near 0 mV. These data suggest that Piezo2 in EC cells is a non-selective cation channel. Mechanically activated currents and 5-HT release from QGP-1 cells were inhibited by Piezo2 siRNA knockdown and by the Piezo2 blockers, Gd3+ and Ruthenium Red and by D-GsMTx4, a mechanosensitive ion channel blocker. The contribution of Piezo2 to intestinal function was assessed using Ussing chambers to measure short circuit currents (ISC) across full thickness preparations of mouse jejunum. Pressure applied to the mucosa evoked an increase in ISC and 5-HT release. These responses were inhibited by mucosally applied Gd3+, Ruthenium Red and GsMTX4, suggesting that Piezo2 blockers act directly on EC cells. Previous ultrastructural studies in the mouse duodenum revealed close appositions between the basolateral surface of EC cells and nerve fibres (Wade & Westfall, 1985) These subepithelial nerve fibres could be targets for 5-HT released from EC cells. Wang et al. (2017) found that the 5-HT3 and 5-HT4 receptor antagonists ondansetron and GR 113808 blocked pressure-evoked ISC when the drugs were applied to the basolateral (serosal) but not mucosal surface of the tissue. It is possible that 5-HT diffuses (at least in ex vivo preparations) to the nerve plexuses to activate secretomotor circuits. However, these data do not yet rule out the possibility of direct subepithelial nerve fibre activation by EC cell 5-HT. 5-HT released from EC cells participates in several physiological (gut secretion, for example) and pathophysiological (GI pain) responses in the gut. The irritable bowel syndrome (IBS) is a gastrointestinal motility/sensation disorder in which EC cell 5-HT release is a key player. Intestinal Piezo2 might be a target for new drugs that could treat IBS or other disorders associated with excessive 5-HT release from EC cells. The author has no conflicts to disclose.

Modern Management of Irritable Bowel Syndrome: More Than Motility

In the treatment of irritable bowel syndrome (IBS), loperamide seems efficacious for diarrhea and ispaghula for constipation, while musculotropic spasmolytics may relieve abdominal pain. Antidepressants were found to be efficacious for abdominal pain, but their tolerance may be problematic and the therapeutic effect varied largely between trials. While meta-analyses suggest efficacy of probiotics as a group, the quality of the trials is often suboptimal and there is large variability. Lubiprostone, a chloride channel activator, and linaclotide, a guanylyl cyclase-C agonist, showed favorable effects on multiple symptoms in IBS with constipation. For IBS with diarrhea (IBS-D), the 5-HT₃ receptor antagonist ramosetron showed efficacy in men and women, but is currently only approved in Japan. A multicenter study with the anti-emetic 5-HT₃ receptor antagonist ondansetron showed efficacy on stool pattern in IBS-D. The poorly absorbable antibiotic rifaximin and eluxadoline, a mu opioid receptor agonist and delta antagonist, both showed efficacy in phase III trials in IBS-D and were approved by the FDA. Eluxadoline was associated with increased occurrence of sphincter of Oddi spasm and biliary pancreatitis. The non-pharmacological treatment of IBS, with dietary interventions (mainly gluten elimination and low FODMAP (fructose, oligo-, di-, monosaccharides and polyols)) has received a lot of attention lately. While responder rates vary across studies, perhaps based on regional variations in dietary intake of FODMAPs, the dietary approach seems to have acquired recognition as a valid therapeutic alternative. Long-term studies and comparative studies with pharmacotherapy, as well as elucidation of the underlying mechanisms of action, are needed.

Evaluation of the Efficacy and Safety of Ramosetron versus Ondansetron for prevention of postoperative nausea and vomiting in gynaecological surgery

Context: Postoperative Nausea and Vomiting (PONV) is a frequent and distressing complication after anaesthesia and surgery with a reported incidence of 20-30% and up to 80% in high-risk cases. It results in increased morbidity, prolonged hospital stay and increased healthcare costs. The multifactorial aetiology of PONV necessitates a combination of prophylactic antiemetic agents to prevent it. Aims: In our study, we compared the efficacy of a combination of dexamethasone and 5HT3 receptor antagonist (Ondansetron or Ramosetron) in preventing PONV in patients undergoing gynaecological surgeries under subarachnoid block. Settings and Design: Prospective, randomised, double blind controlled clinical study. Methods and Material:60 patients between the ages of 20 and 60 years with ASA physical status class I and II, undergoing elective total abdominal hysterectomy under subarachnoid block were selected and divided randomly into two groups of 30 members each. Group OD received Inj. Ondansetron 4 mg IV and Group RD received Inj. Ramosetron 0.3 mg IV, 20 minutes before completion of surgery. Inj. Dexamethasone 8 mg IV was given to patients in both groups immediately before spinal anaesthesia. PONV was assessed using a 4-point scoring system for 0-6, 6-12, 12-18 and 18-24 hours observational periods postoperatively. Incidence of nausea, vomiting, retching and other adverse effects were recorded. Statistical analysis used: analysis of variance, x2 test, two-tailed Fisher’s exact probability test, or the Mann-Whitney U-test, as appropriate. Results: Both groups of patients had significantly low incidence of PONV across all four observation periods with no statistically significant difference between groups OD and RD. In the overall 24 hour postoperative period, 84% of subjects in group OD and 94% in group RD showed a complete response to the prophylactic combination antiemetic therapy with no n

Comparative study of granisetron versus pethidine for the prevention of perioperative shivering under spinal Anesthesia

Aims: Shivering, the big little problem, has an incidence of 19-33% following spinal anesthesia. Recently, studies showed the involvement of serotonergic system in the control of postanesthetic shivering. Pharmacological management includes opioids (pethidine) and nonopioids like 5-HT3 receptor antagonists (ondansetron and granisetron). Pethidine which is considered as a time-tested drug for control of shivering can have adverse effects such as respiratory depression, nausea, and vomiting. This study was performed to compare the effect of prophylactic granisetron versus pethidine in prevention of perioperative shivering in patients under spinal anesthesia. Settings and Design: A prospective randomized, double blinded study was conducted on 60 patients of ASA I and II physical status aged between 20-50 years scheduled for elective lower abdominal surgeries under spinal anesthesia. Subjects and Methods: After obtaining ethical committee clearance and patient consent, sixty American Statistical Association Grade I and II patients, aged 20-50 years scheduled for elective lower abdominal surgeries under spinal anesthesia were recruited for a randomized double-blinded study divided into Group G and Group P and received intravenous (IV) granisetron 40 mcg/kg and pethidine 0.4 mg/kg, respectively. Perioperatively, vitals and core temperature were monitored and shivering was assessed using 5-item scale once in every 15 min up to 6 h. Statistical Analysis: The results were analysed using Statistical Package for Social Science software. Results: Of the sixty patients we studied, the demographic profile between the two groups was comparable. Six patients had shivering in each group. The mean temperature at which patient developed shivering was 36.31°C in Group G and 35.85°C in Group P. The mean time of onset for shivering to occur in Group G was 95 min and in Group P was 65 min. None of the patients received rescue drug. Patients in both the groups were hemodynamically stable. Conclusions: Prophylactic granisetron 40 μg/kg IV is as effective as pethidine 0.4 mg/kg IV in preventing perioperative shivering following spinal anesthesia and also reduces the need of antiemetics.

The role of the AMPA receptor and 5-HT3 receptor on aggressive behavior and depressive-like symptoms in chronic social isolation-reared mice

Chronic social isolation (SI)-reared mice exhibit aggressive and depressive-like behaviors. However, the pathophysiological changes caused by chronic SI remain unclear. The hypothalamus and amygdala have been suggested to be associated with the stress of SI. In addition to serotonin 3 (5-HT3) receptors, AMPA receptors have also been suggested to be involved in aggressive behavior and depressive-like symptoms in animals. Therefore, we examined whether chronic SI affects AMPA and 5-HT3 receptor expression levels in these regions. A Western blot analysis revealed that after four weeks of SI, mice exhibited up-regulated AMPA receptor subunit (GluR1, GluR2) protein levels in the amygdala and down-regulated hypothalamic 5-HT3 receptor protein levels. The AMPA/kainate receptor antagonist NBQX (10mg/kg; i.p.) attenuated SI-induced depressive-like symptoms but not aggressive behavior. Intra-amygdalar infusions of the selective AMPA receptor agonist (S)-AMPA (10μM) induced despair-like behavior, but not sucrose preference or aggressive behavior, in mice not reared in SI (naïve mice). Alternatively, treatment with the 5-HT3 receptor agonist SR57227A (3.0mg/kg; i.p.) decreased aggression levels. In addition, intra-hypothalamic infusions of the 5-HT3 receptor antagonist ondansetron (3μM) did not trigger aggressive behavior in naïve mice; however, the administration of ondansetron (0.3mg/kg; i.p.) increased aggression levels in two-week SI mice, which rarely exhibited the aggressive behavior. Moreover, ondansetron did not affect the depressive-like symptoms of the SI mice. These results suggest that SI-induced up-regulation of GluR1 and GluR2 subunits protein levels in the amygdalar region and down-regulation of 5-HT3 receptor proteins level in the hypothalamic region are associated with the effect of AMPA receptor agonist and 5-HT3 receptor antagonist -induced aggressive behavior and depressive-like symptoms.

Nitric oxide regulation of migrating motor complex: randomized trial of N(G)-monomethyl-L-arginine effects in relation to muscarinic and serotonergic receptor blockade.

The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using N(G)-monomethyl-L-arginine (L-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron. Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor L-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using L-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry. L-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. L-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated by L-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells. Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3 -ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3 -ergic mechanisms.

Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism.

Antidepressants often disrupt sleep. Vortioxetine, a multimodal antidepressant acting through serotonin (5-HT) transporter (SERT) inhibition, 5-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism, and 5-HT1A receptor agonism, had fewer incidences of sleep-related adverse events reported in depressed patients. In the accompanying paper a polysomnographic electroencephalography (sleep-EEG) study of vortioxetine and paroxetine in healthy subjects indicated that at low/intermediate levels of SERT occupancy, vortioxetine affected rapid eye movement (REM) sleep differently than paroxetine. Here we investigated clinically meaningful doses (80–90% SERT occupancy) of vortioxetine and paroxetine on sleep-EEG in rats to further elucidate the serotoninergic receptor mechanisms mediating this difference. Cortical EEG, electromyography (EMG), and locomotion were recorded telemetrically for 10 days, following an acute dose, from rats receiving vortioxetine-infused chow or paroxetine-infused water and respective controls. Sleep stages were manually scored into active wake, quiet wake, and non-REM or REM sleep. Acute paroxetine or vortioxetine delayed REM onset latency (ROL) and decreased REM episodes. After repeated administration, vortioxetine yielded normal sleep-wake rhythms while paroxetine continued to suppress REM. Paroxetine, unlike vortioxetine, increased transitions from non-REM to wake, suggesting fragmented sleep. Next, we investigated the role of 5-HT3 receptors in eliciting these differences. The 5-HT3 receptor antagonist ondansetron significantly reduced paroxetine’s acute effects on ROL, while the 5-HT3 receptor agonist SR57227A significantly increased vortioxetine’s acute effect on ROL. Overall, our data are consistent with the clinical findings that vortioxetine impacts REM sleep differently than paroxetine, and suggests a role for 5-HT3 receptor antagonism in mitigating these differences.

Sleep Deprivation-Induced Blood-Brain Barrier Breakdown and Brain Dysfunction are Exacerbated by Size-Related Exposure to Ag and Cu Nanoparticles. Neuroprotective Effects of a 5-HT3 Receptor Antagonist Ondansetron.

Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB disruption and brain pathology, (ii) nanoparticles exacerbate SD-induced brain damage, and (iii) serotonin 5-HT3 receptor antagonist ondansetron is neuroprotective in SD that is further potentiated byTiO2-nanowired delivery, not reported earlier.

5‐HT 3 Receptor Signaling in a Rat Model of Sex Specific Visceral Hypersensitivity

Background Irritable bowel syndrome (IBS) is a functional gastrointestinal motor and visceral sensation disorder that is more prominent in women compared to men. 5-Hydroxytryptamine (5-HT, serotonin) signaling is disrupted in some IBS patients possibly due to polymorphic variations in the gene encoding the serotonin transporter (SERT) which result in increased extracellular 5-HT availability. Female SERT knockout (KO) rats exhibit visceral hypersensitivity to colonic distention that mimics colonic hypersensitivity known to occur in female IBS patients. Objective. We tested the hypothesis that 5-HT action at 5-HT3 receptors contributes to visceral hypersensitivity. Methods. We examined the effects of acute administration of morphine and the 5-HT3 receptor antagonists alosetron, granisetron, and ondansetron on visceral sensitivity in SERT KO and wild type (WT) rats. We measured the visceromotor response (VMR) to colorectal distension (CRD). Results. Ondansetron (0.1 mg/kg, s.c) did not affect visceral sensitivity, while alosetron (0.1 mg/kg, s.c.) increased the VMR to CRD in SERT KO female rats and WT male rats. Granisetron (0.1 mg/kg, s.c.) increased VMR to CRD in SERT KO female rats only. Morphine (3 mg/kg s.c.) suppressed the VMR to CRD in all rats. Conclusions The results suggest that acute peripheral administration of some 5-HT3 receptor antagonists causes a paradoxical increase in the VMR to CRD. 5-HT3 receptor antagonists may interact with ascending pain pathways and descending pain inhibitory pathways. Supported by: 5R21NS075841

Role of 5-HT3 receptor on food intake in fed and fasted mice.

BackgroundMany studies have shown that 5-hydroxytryptamine (5-HT) receptor subtypes are involved in the regulation of feeding behavior. However, the relative contribution of 5-HT3 receptor remains unclear. The present study was aimed to investigate the role of 5-HT3 receptor in control of feeding behavior in fed and fasted mice.Methodology/Principal FindingsFood intake and expression of c-Fos, tyrosine hydroxylase (TH), proopiomelanocortin (POMC) and 5-HT in the brain were examined after acute treatment with 5-HT3 receptor agonist SR-57227 alone or in combination with 5-HT3 receptor antagonist ondansetron. Food intake was significantly inhibited within 3 h after acute treatment with SR 57227 in fasted mice but not fed mice, and this inhibition was blocked by ondansetron. Immunohistochemical study revealed that fasting-induced c-Fos expression was further enhanced by SR 57227 in the brainstem and the hypothalamus, and this enhancement was also blocked by ondansetron. Furthermore, the fasting-induced downregulation of POMC expression in the hypothalamus and the TH expression in the brain stem was blocked by SR 57227 in the fasted mice, and this effect of SR 57227 was also antagonized by ondansetron.Conclusion/SignificanceTaken together, our findings suggest that the effect of SR 57227 on the control of feeding behavior in fasted mice may be, at least partially, related to the c-Fos expression in hypothalamus and brain stem, as well as POMC system in the hypothalamus and the TH system in the brain stem.

A 5-HT3 receptor antagonist potentiates the behavioral, neurochemical and electrophysiological actions of an SSRI antidepressant

More effective treatments for major depression are needed. We studied if the selective 5-HT3 receptor antagonist ondansetron can potentiate the antidepressant potential of the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine using behavioral, neurochemical and electrophysiological methods. Flinders Sensitive Line (FSL) rats, treated with ondansetron, and/or a sub-effective dose of paroxetine, were assessed in the forced swim test. The effects of an acute intravenous administration of each compound alone and in combination were evaluated with respect to 5-HT neuronal firing rate in the dorsal raphe nucleus (DRN). Effects of s.c. administration of the compounds alone and in combination on extracellular levels of 5-HT were assessed in the ventral hippocampus of freely moving rats by microdialysis. The results showed that ondansetron enhanced the antidepressant activity of paroxetine in the forced swim test. It partially prevented the suppressant effect of paroxetine on DRN 5-HT neuronal firing and enhanced the paroxetine-induced increase of hippocampal extracellular 5-HT release. These findings indicate that 5-HT3 receptor blockade potentiates the antidepressant effects of SSRIs. Since both paroxetine and ondansetron are used clinically, it might be possible to validate this augmentation strategy in depressed patients.

The effects of varenicline on sensory gating and exploratory behavior with pretreatment with nicotinic or 5-HT3A receptor antagonists.

Individuals with schizophrenia smoke at high frequency relative to the general population. Despite the harmful effects of cigarette smoking, smoking among schizophrenic patients improves cognitive impairments not addressed or worsened by common neuroleptics. Varenicline, a nonselective neuronal nicotinic receptor (NNR) agonist and full agonist of 5-HT3A receptors, helps reduce smoking among schizophrenic patients. To determine whether varenicline also improves a cognitive symptom of schizophrenia, namely, impaired sensory gating, a transgenic mouse with schizophrenia, th-fgfr1(tk-), was used. Varenicline dose-dependently increased prepulse inhibition (PPI) of the startle response, a measure of sensory gating, in th-fgfr1(tk-) mice and normalized PPI deficits relative to nontransgenic controls. With the highest dose (10 mg/kg), however, there was a robust elevation of PPI and startle response, as well as reduced exploratory behavior in the open field and elevated plus maze. Pretreatment with the nonspecific NNR antagonist mecamylamine attenuated the exaggerated PPI response and, similar to the 5-HT3A receptor antagonist ondansetron, it prevented the reduction in exploratory behavior. Collectively, these results indicate that varenicline at low-to-moderate doses may be beneficial against impaired sensory gating in schizophrenia; however, higher doses may induce anxiogenic effects, which can be prevented with antagonists of NNRs or 5-HT3A receptors.

Nanoparticles exacerbate sleep deprivation induced brain pathology and functional disturbances. Neuroprotective effects of TiO2 nanowired delivery of 5-HT3 receptor antagonist ondansetron

Nanoparticles exacerbate sleep deprivation induced brain pathology and functional disturbances. Neuroprotective effects of TiO2 nanowired delivery of 5-HT3 receptor antagonist ondansetron

Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression.

To investigate the antidepressant-like effects of a novel 5-HT3 receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression. 5-HT3 receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.5-2 mg/kg, ip). In chronic depression model, mice were exposed to a 4-week chronic unpredictable stress (CUS) protocol, and treated with 6z (0.5-2 mg·kg(-1)·d(-1), po) or a positive drug fluoxetine (10 mg·kg(-1)·d(-1), po) in the last 2 weeks, followed by behavioral and biochemical assessments. The 5-HT3 receptor antagonism of 6z (pA2=7.4) in guinea pig ileum was more potent than that of a standard 5-HT3 receptor antagonist ondansetron (pA2=6.9). In acute depression model, 6z administration significantly decreased the immobility duration. In chronic depression model, 6z administration reversed CUS-induced depressive-like behavior, as evidenced by increased immobility duration in the forced swim test and sucrose preference in the sucrose preference test. Furthermore, chronic administration of 6z prevented CUS-induced brain oxidative stress, with significant reduction of pro-oxidant markers and elevation of antioxidant enzyme activity. Moreover, chronic administration of 6z attenuated CUS-induced hypothalamic-pituitary-adrenal axis hyperactivity, as shown by reduced plasma corticosterone levels. Similar results were observed in the fluoxetine-treated group. 6z is a novel 5-HT3 receptor antagonist with potential antidepressant-like activities, which may be related to modulating hypothalamic-pituitary-adrenal axis and attenuating brain oxidative damage.