Lamotrigine is an antiepileptic drug widely used to treat epileptic seizures. Using whole-cell voltage clamp recordings in combination with a fast drug application approach, we investigated the effects of lamotrigine on 5-hydroxytryptamine (5-HT)₃ receptors in NCB-20 neuroblastoma cells. Co-application of lamotrigine (1~300 µM) resulted in a concentration-dependent reduction in peak amplitude of currents induced by 3 µM of 5-HT for an IC₅₀ value of 28.2±3.6 µM with a Hill coefficient of 1.2±0.1. These peak amplitude decreases were accompanied by the rise slope reduction. In addition, 5-HT₃-mediated currents evoked by 1 mM dopamine, a partial 5-HT₃ receptor agonist, were inhibited by lamotrigine co-application. The EC₅₀ of 5-HT for 5-HT₃ receptor currents were shifted to the right by co-application of lamotrigine without a significant change of maximal effect. Currents activated by 5-HT and lamotrigine co-application in the presence of 1 min pretreatment of lamotrigine were similar to those activated by 5-HT and lamotrigine co-application alone. Moreover, subsequent application of lamotrigine in the presence of 5-HT and 5-hydroxyindole, known to attenuate 5-HT₃ receptor desensitization, inhibited 5-HT₃ receptor currents in a concentration-dependent manner. The deactivation of 5-HT₃ receptor was delayed by washing with an external solution containing lamotrigine. Lamotrigine accelerated the desensitization process of 5-HT₃ receptors. There was no voltage-dependency in the inhibitory effects of lamotrigine on the 5-HT3 receptor currents. These results indicate that lamotrigine inhibits 5-HT₃-activated currents in a competitive manner by binding to the open state of the channels and blocking channel activation or accelerating receptor desensitization.
Dopamine ; Epilepsy ; Neuroblastoma* ; Receptors, Serotonin, 5-HT3 ; Serotonin

5-Hydroxytryptamine (5-HT) type 3 receptor (5-HT₃R) is the only type of ligand-gated ion channel in the 5-HT receptor family. Through the high permeability of Na⁺, K⁺, and Ca²⁺ and activation of subsequent voltage-gated calcium channels (VGCCs), 5-HT₃R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system (CNS). 5-HT₃Rs are widely expressed in the medial prefrontal cortex (mPFC), amygdala (AMYG), hippocampus (HIP), periaqueductal gray (PAG), and other brain regions closely associated with anxiety reactions. They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions. 5-HT₃Rs mediate the activation of the cholecystokinin (CCK) system in the AMYG, and the γ‍-aminobutyric acid (GABA) "disinhibition" mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons (IINs). In contrast, a 5-HT₃R-induced GABA "disinhibition" mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects. 5-HT₂R-mediated regulation of anxiety reactions are also activated by 5-HT₃R-activated 5-HT release in the HIP and PAG. This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT₃Rs. However, given the circuit specific modulation of 5-HT₃Rs on emotion, systemic use of 5-HT₃R agonism or antagonism alone seems unlikely to remedy anxiety, which deeply hinders the current clinical application of 5-HT₃R drugs. Therefore, the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.
Serotonin ; Receptors, Serotonin, 5-HT3 ; Anxiety ; Neurons ; gamma-Aminobutyric Acid

BACKGROUND: Granisetron, a new 5-HT3 receptor antagonist, was reported as a highly effective antiemetics, especially in combination with dexamethasone, in the prevention of acute emesis induced by cisplatin. But there is lack of data about effectiveness in the prevention of delayed emesis. In this study, the efficacy of granisetron plus dexamethasone in the prevention of delayed emesis induced by cisplatin was evaluated. MATERIALS AND METHODS: Sixty-four patients who were to receive high-dose cisplatin containing chemotherapy regimen were enrolled in this study. They were received 20 mg of dexamethasone and 3 mg of granisetron at 30 min and 10 minutes prior to cisplatin infusion, respectively. They were monitored for 5 days, first 24 hours for acute nausea/ vomiting and the subsequent 4 days for delayed nausea/vomiting. Antiemetic effect of granisetron was evaluated according to the criteria of Italian Group of Antiemetic Research. RESULTS: Control of delayed nausea and vomiting was achieved in 58% and 84%, respectively. Eastern Cooperative Oncology Group performance status was a statistically significant prognostic factor for control of acute vomiting and delayed nausea/vomiting. There were no stastically significant differences between control of delayed nausea/ vomiting and other prognostic factors, including sex, age, and prior history of cisplatin therapy. The antiemetic effect was greater in the patients who had controled acute nausea/ vomiting than those who had not. CONCLUSION: Granisetron plus dexamethasone is an excellent regimen in the control of not only acute emesis but also delayed emesis induced by high-dose cisplatin chemotherapy.
Antiemetics ; Cisplatin ; Dexamethasone* ; Drug Therapy ; Granisetron* ; Humans ; Nausea* ; Receptors, Serotonin, 5-HT3 ; Serotonin ; Vomiting*

BACKGROUND: Propofol is a good induction agent, but it has the disadvantage of causing pain on intravenous injection. The incidence of propofol-induced pain is approximately 70%. Palonosetron is a novel second-generation 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist. We presumed that palonosetron would be effective in reducing the occurrence of propofol-induced pain based on similar mechanisms to other 5-HT3 receptor antagonists. METHODS: Eighty patients were randomized to either Group N (0.9% sodium chloride [normal saline] 2 ml, n = 40) or Group P (palonosetron 0.075 mg, 2 ml, n = 40). Patients were intravenously given a 2 ml pretreatment solution, containing either palonosetron 0.075 mg or normal saline. Following pretreatment with 2 ml of palonosetron 0.075 mg or normal saline, we manually occluded venous drainage midarm with the help of an assistant. One minute later, we released the occlusion of venous drainage. This was followed by a 5-second propofol injection at 25% of the total calculated doses. Patients were then interviewed about whether or not they experienced propofol-induced pain. RESULTS: Overall, the incidence of propofol-induced pain was 60% in the normal saline group and 27.5% in the palonosetron group. No patients in the palonosetron group experienced severe pain. The incidence of propofol-induced pain was significantly lower in the palonosetron group compared to the normal saline group (P < 0.01). CONCLUSIONS: Following pretreatment with palonosetron, 72.5% of patients experienced a decrease in the occurrence of propofol-induced pain.
Drainage ; Humans ; Incidence ; Injections, Intravenous ; Propofol* ; Receptors, Serotonin, 5-HT3 ; Serotonin ; Sodium Chloride

Cortical GABAergic inhibitory neurons are composed of three major classes, each expressing parvalbumin (PV), somatostatin (SOM) and 5-hydroxytryptamine receptor 3A (Htr3a), respectively. Htr3a
Animals ; Interneurons/metabolism* ; Mice ; Neurons/metabolism* ; Parvalbumins/metabolism* ; Receptors, Serotonin, 5-HT3/genetics* ; Serotonin ; Somatostatin/metabolism*

A number of studies have demonstrated that 5-hydroxytryptamine (5-HT) can induce muscle contraction or relaxation response and enhance secretion in the gastrointestinal tract via a multiplicity of 5-HT receptor subtypes. In the present study, we investigated the pharmacological characterization of the 5-HT-induced contractile response in longitudinal smooth muscle isolated from the feline ileum. Addition of 5-HT into muscle chambers enhanced the basal tone and spontaneous activity in a concentration-dependent manner. The neurotoxin tetrodotoxin did not alter the 5-HT-induced contraction of the longitudinal muscles. Neither atropine nor guanethidine affected the contraction. The 5-HT agonists, 5-methylserotonin hydrochloride and mosapride, also evoked concentration-dependent contractions. The 5-HT-induced contraction was enhanced by the 5HT2 receptor antagonist ketanserin and the 5-HT3 receptor antagonist ondansetron but was inhibited by the 5-HT1 receptor antagonist methysergide and 5-HT4 receptor antagonist GR113808. These results indicate that 5-HT1 and 5-HT4 receptors may mediate the contraction of the 5-HT-induced response and 5-HT2 and 5-HT3 receptors may mediate 5-HT-induced relaxation in feline ileal longitudinal smooth muscles.
Atropine ; Benzamides ; Contracts ; Gastrointestinal Tract ; Guanethidine ; Ileum ; Indoles ; Ketanserin ; Methysergide ; Morpholines ; Muscle Contraction ; Muscle, Smooth ; Muscles ; Ondansetron ; Receptors, Serotonin ; Receptors, Serotonin, 5-HT1 ; Receptors, Serotonin, 5-HT3 ; Receptors, Serotonin, 5-HT4 ; Relaxation ; Serotonin ; Serotonin Receptor Agonists ; Sulfonamides ; Tetrodotoxin

PURPOSE: This study reported patient outcomes of chemotherapy-induced nausea and vomiting (CINV) prophylaxis for highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) regimens and evaluated its adherence to acute-phase CINV prophylaxis in the Korean population subset of the Pan Australasian Chemotherapy Induced Emesis burden of illness (PrACTICE) study. MATERIALS AND METHODS: This subgroup analysis evaluated 158 Korean patients receiving HEC or MEC and compared the data (wherever possible) with that of 648 patients from the Asia-Pacific (AP) region. Study endpoints included evaluation of primary CINV prophylaxis and adherence to acute-phase CINV prophylaxis in cycle 1 (American Society of Clinical Oncology [ASCO] Quality Oncology Practice Initiative [QOPI]). RESULTS: In South Korea and the AP, a 5-hydroxytryptamine-3 receptor antagonist (5HT₃-RA) prophylaxis for the acute phase was administered to 79/80 patients (98.8%) for HEC and 70/71 patients (98.6%) for MEC regimens (QOPI-1). Triple regimen (corticosteroid–5HT₃-RA–neurokinin 1-RA) was initiated in 46/80 patients (57.5%) for prophylaxis of acute CINV in cycle 1 of HEC (QOPI-3). Double regimen (corticosteroid–5HT₃-RA, with or within NK₁-RA) was initiated in 61/71 patients (83.1%) for control of acute CINV in cycle 1 of MEC a(QOPI-2). CONCLUSION: Active management of CINV is necessary in cycle 1 of HEC in South Korea, despite higher rates than the AP region. Adherence to the international guidelines for CINV prophylaxis requires attention in the acute phase in cycle 1 of the HEC regimen.
Antiemetics ; Cost of Illness* ; Drug Therapy* ; Humans ; Korea* ; Medical Oncology ; Nausea* ; Receptors, Serotonin, 5-HT3 ; Vomiting*

PURPOSE: Granisetron is a potent, the most selective 5-HT3 receptor antagonist and is reported to be effective in treatment of radiation-induced emesis. The antiemetic efficacy and safety of oral granisteron was evaluated in patients with receiving highly emetogenic treatment by conventional fractionated irradiation. MATERIAL AND METHODS: Patients with various cancers who were being treated with irradiation were accrued into the present study. The intensity of nausea was evaluated on first 24 hours and on day-7 by patients according to the degree of interference with normal daily life as followings; a) none; b) present but no interference with normal daily life (mild); c) interference with normal daily life (moderate); and d) bedridden because of nausea (severe). Non or mild state was considered to indicate successful treatment. The efficacy of antiemetic treatment was graded as follows; a) complete response; no vomiting, no worse than mild nausea and receive no rescue antiemetic therapy over the 24h period, b) major response; either one episode of vomiting or moderate/severe nausea or had received rescue medication over 24h period, or any combination of these, c) minor response; two to four episodes of vomiting over the 24h period, regardless of nausea and rescue medication, d) failure; more than four medication. The score of the most sympto m was recorded and the total score over 24 hours was summarized. The complete or major response was considered to indicate successful treatment. RESULTS: A total of 10 patients were enrolled into this study, and all were assessable for efficacy analysis. Total nausea control was achieved in 90% (9/10:none=60% plus mild=30%) of total patients after 7 days. The cotrol of vomiting by granisteron was noted in seven patients (70%) of complete response and three (30%) of major response with a hundred-percent successful treatment over 7 days. The minor response or treatment failure were not observed. No significant adverse events or toxicities from granisetron were recorded in patient receiving granisetron. CONCLUSION: We concluded that granisetron is a highly effective antiemetic agent in controlling radiotherapy-induced nausea or vomiting with a minimal toxicity profile.
Granisetron* ; Humans ; Nausea* ; Radiotherapy ; Receptors, Serotonin, 5-HT3 ; Treatment Failure ; Vomiting*

Current treatment strategies for levodopa-induced psychosis in advanced Parkinson's disease have had limited success. Reduction or discontinuation of levodopa and coadministration with dopamine-blocking neuroleptics may attenuate the psychotic symptoms, but these strategies are associated with worsening of parkinsonian symptoms. Administration of 5-HT3 receptor antagonist ; ondansetron, a newer strategy to attenuate psychosis of Parkinson' disease without motor deterioration was introduced. A 41-year-old young-onset male, who was diagnosed as Parkinson's disease 7 years ago, was treated with levodopa therapy, and had levodopa-induced psychosis(delusion, hallucination, paranoid, insomnia). After trial of ondansetron, he showed improvement in the Brief Psychiatric Rating Scale(from 21 points to 9 points) in spite of increasing the dosage of levodopa. With ondansetron, we could increase the dosage of levodopa without psychotic complications(esp, hallucination), and he showed improvement in the motor fluctuation.
Adult ; Antipsychotic Agents ; Hallucinations ; Humans ; Levodopa ; Male ; Ondansetron ; Parkinson Disease ; Psychotic Disorders* ; Receptors, Serotonin, 5-HT3

BACKGROUND: Nausea and vomiting associated with chemotherapy are common side effects which remain difficult to control. Acute phase nausea and vomiting (0-24 hours after induction of chemotherapy) parallels plasma serotonin release, which explains the effectiveness of 5-HT3 receptor antagonists. Serotonin released from gastrointestinal enterochromaffin cells may mediate chemotherapy-induced emesis. In this study, we analyzed urinary excretion of 5-HIAA, the main metabolite of serotonin. METHODS: Eight men and four women were studied in their cisplatin chemotherapy cycle. Urinary 5-hydroxyindoleacetic aicd (HIAA) levels were determined before and during a 24-hour period under ondansetron prophylaxis. RESULTS: Urinary 5-HIAA excretion for a 24-hour period was increased in all patients after induction of cisplatin (P=0.002). CONCLUSION: Cisplatin chemotherapy is associated with serotonin release in the acute phase. Our finding provides evidence for a relationship between emesis and serotonin following cisplatin chemotherapy.
Cisplatin* ; Drug Therapy* ; Enterochromaffin Cells ; Female ; Humans ; Hydroxyindoleacetic Acid ; Male ; Nausea ; Ondansetron ; Plasma ; Receptors, Serotonin, 5-HT3 ; Serotonin ; Vomiting