Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the present study was to examine the role of serotonin (5HT) in the discriminative stimulus effects of kappa opioids. Pigeons were trained to discriminate 5.6 mg/kg of the kappa opioid, U50,488, from water. During substitution tests, both U50,488 and another kappa opioid, spiradoline, produced > 80% responding on the U50,488-appropriate key. In contrast, the non-opioid compound, phencyclidine and several serotonergic compounds failed to substitute for the U50,488 discriminative stimulus across a wide range of doses. During combination tests, the selective 5HT1A agonist, 8-OH-DPAT (0.001-3.2 mg/kg), dose-dependently attenuated the discriminative stimulus effects of 5.6 mg/kg U50,488 and 3.2 mg/kg spiradoline. This effect was reversed by the 5HT1A antagonist, NAN-190 (0.01-1 mg/kg), in a dose-dependent manner. Buspirone (0.01-10 mg/kg), a 5HT1A partial agonist, also attenuated the discriminative stimulus effects of the training dose of U50,488 but ipsapirone, another 5HT1A partial agonist, did not. Ketanserin, a 5HT2 antagonist, and MDL72222, a 5HT3 antagonist, attenuated the effects of U50,488, whereas the 5HT1B,1C agonist, mCPP, and the 5HT2 agonist, DOI, did not. Depletion of 5HT with p-CPA also attenuated U50,488's discriminative stimulus effects. Taken together, the results suggest that serotonin release is an important component in the discriminative stimulus effects produced by kappa opioids; however, the effects of DOI and mCPP alone suggest that activation of post-synaptic 5HT receptors is not sufficient to produce the full spectrum of kappa opioid discriminative stimulus effects.
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PMID:Serotonin involvement in the discriminative stimulus effects of kappa opioids in pigeons. 787 Sep 36

The emetic effects of five anticancer drugs, cyclophosphamide, nitrogen mustard-N-oxide, actinomycin D, 5-fluorouracil and L-asparaginase, and the effects of bilateral abdominal vagotomy and bilateral greater splanchnic nerve section or a 5-HT3 receptor antagonist on the emesis induced by these drugs were investigated in dogs. Cyclophosphamide (20 mg/kg, i.v.), nitrogen mustard-N-oxide (5 mg/kg, i.v.) and actinomycin D (50 micrograms/kg, i.v.) caused vomiting in dogs with a long latency period. 5-Fluorouracil (5 mg/kg, i.v.) and L-asparaginase (2000 K.U./kg, i.v.) failed to induce vomiting. Bilateral abdominal vagotomy and bilateral greater splanchnic nerve section completely inhibited the vomiting induced by the former three anticancer drugs. Furthermore, the vomiting was inhibited completely by intravenous administration of ICS205930 (2 x 0.1 mg/kg), a 5-HT3 receptor antagonist. These results suggest that activation of visceral afferents through 5-HT3 receptors mediates the vomiting induced by cyclophosphamide, nitrogen mustard-N-oxide and actinomycin D.
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PMID:Emetic effects of anticancer drugs and involvement of visceral afferent fibers and 5-HT3 receptors in dogs. 811 85

Cyclophosphamide-based chemotherapy is often given to patients for the treatment of breast cancer. This chemotherapy can induce severe nausea and vomiting in these patients, which can adversely affect their quality of life, especially as these regimens are often given on an outpatient basis over several courses. This paper reviews 5 randomised, double-blind, multicenter comparative studies which have been carried out in breast cancer patients to evaluate the efficacy and safety profile of the potent and highly selective 5-HT3 receptor antagonist, ondansetron. These studies have shown that ondansetron is superior to placebo in the control of emesis induced by a 14-day CMF schedule and that it is superior to conventional anti-emetics (metoclopramide and alizapride) in the control of acute and delayed emesis induced by regimens containing high-dose cyclophosphamide. Ondansetron was well tolerated in these studies and did not induced any extrapyramidal reactions. The efficacy and tolerability of ondansetron was reflected in a better quality of life for patients given this anti-emetic which was formally assessed in 2 of the studies using the Rotterdam Symptom Checklist or the Functional Living Index-Emesis. In conclusion, ondansetron is an effective and well-tolerated anti-emetic for patients receiving cyclophosphamide-based chemotherapy for the treatment of breast cancer. Ondansetron provides significant benefits for patients' quality of life compared with conventional anti-emetics particularly as these patients are often treated on an outpatient basis and can be treated with oral ondansetron at home.
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PMID:Improved control of emesis and quality of life with ondansetron in breast cancer. 845 89

Chemotherapy-induced emesis is dependent not only on individual parameters but also on treatment parameters (type and dose of the cytotoxic drug, combination with other cytotoxic drugs). Cyclophosphamide-based chemotherapy is potentially emetogenic and the emtogenicity is proportionally dependent on the dose. Therefore, the preventive antiemetic treatment must be adapted to this emetogenic risk. A number of studies have assessed the efficacy of ondansetron, a highly selective 5-HT3 receptor antagonist, for the control of 'non cisplatin' chemotherapy. In mild emetogenic regimens, oral ondansetron is more effective than placebo and its efficacy is similar to the classic antiemetic regimen metoclopramide-dexamethasone. Concerning moderately emetogenic chemotherapies, iv ondansetron is highly effective and its effecicay is superior to that of metoclopramide and alizapride. Delayed nausea and vomiting can be controlled by an oral ondansetron treatment. This allows to maintain the good response obtained by the initial antiemetic regimen. With very high doses of cyclophosphamide, as in conditioning chemotherapy and total body irradiation prior to bone marrow transplantation, no optimal antiemetic treatment has still been defined; but the combination of ondansetron with dexamethasone should be used according to the poor control obtained with ondansetron alone. However, studies combining 5-HT3 receptor antagonists with dexamethasone are warranted in order to define the optimal treatment in this particularly emetogenic treatment setting.
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PMID:[Optimal control by ondansetron of acute and prolonged emesis induced by chemotherapy without cisplatin]. 867 59

Emesis is a common side effect of chemotherapeutic drugs. Cisplatin, nitrogen mustard and dacarbazine induce increases in urinary 5-hydroxyindoleacetic acid (5-HIAA) in parallel with the development of the period of emesis which is sensitive to 5-HT3 receptor antagonists ('acute emesis'). It is suggested that these cytotoxics release serotonin from enterochromaffin cells, which then acts on 5-HT3 receptors to trigger the emetic response. Cyclophosphamide, on the other hand, induces a modest emetic response, partly sensitive to 5-HT3 receptor antagonists, but not associated with increases in urinary 5-HIAA. It is suggested that cyclophosphamide-induced emesis is not mediated by the release of serotonin from enterochromaffin cells. Although after high-dose cisplatin most emesis is sensitive to 5-HT3 receptor antagonists, patients often present a milder, although more prolonged form of emesis which is mostly resistant to 5-HT3 receptor antagonists (also known as 'delayed emesis'). This form of emesis is not associated with increases in urinary 5-HIAA (not due to serotonin released from the enterochromaffin cells). Treatment with p-chlorophenylalanine (a serotonin synthesis inhibitor) inhibited cisplatin-induced emesis and cisplatin-induced increases in urinary 5-HIAA excretion. In summary, these results indicate that in human patients, serotonin plays a fundamental role in chemotherapy-induced emesis. Serotonin released from enterochromaffin cells seems to mediate emesis sensitive to 5-HT3 receptor antagonists induced by cisplatin, dacarbazine and nitrogen mustard. Emesis sensitive to 5-HT3 receptor antagonists associated with cyclophosphamide treatment, is not mediated by the release of serotonin from enterochromaffin cells by the cytotoxic. Therefore, cyclophosphamide could induce serotonin release either from enteric serotonin nerves or from the CNS. Cisplatin-induced emesis resistant to 5-HT3 receptor antagonists ('delayed emesis') is not mediated by serotonin released from enterochromaffin cells.
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PMID:Serotonin mechanisms in chemotherapy-induced emesis in cancer patients. 869 46

The aim of the work was to evaluate the impact of cyclophosphamide and ondansetron on serotonin metabolism measured by urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion. The pattern of urinary 5-HIAA excretion was analysed within 24 h following cyclophosphamide, epirubicin and 5-fluorouracil (FEC) chemotherapy (n = 14), ondansetron as single agent (n = 31), and in a control group (n = 62). 5-HIAA was measured by a fluorescence/polarisation immunoassay. Both FEC and ondansetron alone induced a significantly higher 5-HIAA increase following the first 12 h after drug administration when compared to the control group. The comparison of quantitative variables of 5-HIAA excretion between FEC and ondansetron failed to reveal any statistical differences. Cyclophosphamide-based chemotherapy is associated with only minor increases of 5-HIAA excretion. Analysis of 5-HIAA excretion does not help in the description of the pathophysiology of cyclophosphamide-induced emesis. In contrast to experimental data, serotonin 3 receptor antagonism with ondansetron induces an increase of 5-HIAA excretion in humans.
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PMID:5-Hydroxyindoleacetic acid excretion following combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil plus ondansetron compared to ondansetron alone. 888 33

The effect of serotonergic agents was studied on the adenosine A2 receptor agonist NECA-induced catalepsy in mice. The 5-HT releaser fenfluramine, the 5-HT1A agonist 8-OH-DPAT, the 5-HT(2A/1C) receptor agonist DOI and the 5-HT(2A/1C) receptor antagonists ketanserin and mianserin reversed NECA-induced catalepsy. p-MPPI and ketanserin reversed the anticataleptic actions of 8-OH-DPAT and DOI, respectively. Further, the 5-HT reuptake inhibitor fluoxetine, the 5-HT(1B/1C) receptor agonist TFMPP, the 5-HT synthesis inhibitor p-CPA, the selective 5-HT1A receptor antagonist p-MPPI, the 5-HT(1A/1B) receptor antagonist pindolol and the 5-HT3 receptor antagonist LY 278, 584 had no effect on NECA-induced catalepsy. The anticataleptic action of fenfluramine was not affected by pretreatment with p-CPA. In p-CPA treated rats, ketanserin did not affect the anticataleptic effect of fenfluramine, whereas p-MPPI partially reversed this effect. It is concluded that modulation of serotonergic neurotransmission at 5-HT1A and 5-HT(2A/1C) receptors affects the cataleptic action of experimental antipsychotic agents with adenosine A2 receptor agonistic activity.
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PMID:Effect of serotonergic agents on adenosine A2 receptor mediated catalepsy in mice. 962 97

Cardioinhibitory cardiac vagal neurons (CVNs) do not receive inspiratory-related excitatory inputs under normal conditions. However, excitatory purinergic and serotonergic pathways are recruited during inspiratory activity after episodes of hypoxia and hypercapnia (H/H). Prenatal nicotine (PNN) exposure is known to dramatically change cardiorespiratory responses and decrease the ability to resuscitate from H/H. This study tested whether PNN exposure alters excitatory neurotransmission to CVNs in the nucleus ambiguus during and after H/H. Spontaneous and inspiratory evoked excitatory postsynaptic currents were recorded in CVNs from rats that were exposed to nicotine (6 mg x kg(-1) x d(-1)) throughout the prenatal period. In contrast to unexposed animals, in PNN animals H/H recruited excitatory neurotransmission to CVNs during inspiratory-related activity that was blocked by the alpha3beta4 nicotinic acetylcholine receptor (nAChR) blocker alpha-conotoxin AuIB (alpha-CTX AuIB, 100 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 50 microM) and d(-)-2-amino-5-phosphonopentanoic acid (AP5, 50 microM), selective AMPA/kainate and N-methyl-d-aspartate receptor blockers, respectively. Following H/H, there was a significant increase in inspiratory-related excitatory postsynaptic currents that were unaltered by alpha-CTX AuIB or ondansetron, a 5-HT3 receptor blocker, but were subsequently inhibited by pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic acid (100 microM), a purinergic receptor blocker and CNQX and AP5. The results from this study demonstrate that with PNN exposure, an excitatory neurotransmission to CVNs is recruited during H/H that is glutamatergic and dependent on activation of alpha3beta4-containing nAChRs. Furthermore, exposure to PNN abolishes a serotonergic long-lasting inspiratory-related excitation of CVNs that is replaced by recruitment of a glutamatergic pathway to CVNs post H/H.
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PMID:Abolishment of serotonergic neurotransmission to cardiac vagal neurons during and after hypoxia and hypercapnia with prenatal nicotine exposure. 1909 27