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

Whereas serotonin and substance P stimulate in-vivo and in-vitro myoelectric activity in the small intestine, their effects on transit are unclear. We used a validated in-vivo transit model in the chloral hydrate-anaesthetized rat to study the effects of serotonin, substance P and motilin, three putative mediators of carcinoid diarrhoea, on transit through the upper digestive tract. Intra-arterial serotonin accelerated gastric emptying of a radiolabelled liquid, while motilin accelerated overall upper gastrointestinal transit. Substance P slowed overall upper gastrointestinal transit without altering gastric emptying. The antagonists to serotonin receptor subtypes, R-zacopride (5-HT3) and ketanserin (5-HT2), also accelerated rat gastric emptying of liquids; in contrast, a 5-HT4 agonist, SC53116, resulted in a less pronounced effect on gastric emptying at the dose tested. We conclude that circulating substance P is unlikely to be an important accelerator of transit through the upper digestive tract; in contrast, hyperserotoninaemia significantly accelerates transit through the stomach, and 5-HT2 and 5-HT3 receptor subtypes may play a role in the motor effects of serotonin in the stomach.
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PMID:Effect of putative carcinoid mediators on gastric and small bowel transit in rats and the role of 5-HT receptors. 767 34

Molecular cloning efforts have provided primary amino acid sequence and signal transduction data for a large collection of serotonin receptor subtypes. These include five 5-HT1-like receptors, three 5-HT2 receptors, one 5-HT3 receptor, two 5-HT5 receptors, one 5-HT6 receptor and one 5-HT7 receptor. Molecular biological information on the 5-HT4 receptor is notably absent from this list. We now report the cloning of the pharmacologically defined 5-HT4 receptor. Using degenerate oligonucleotide primers, we identified a rat brain PCR fragment which encoded a '5-HT receptor-like' amino acid sequence. The corresponding full length cDNA was isolated from a rat brain cDNA library. Transiently expressed in COS-7 cells, this receptor stimulates adenylyl cyclase activity and is sensitive to the benzamide derivative cisapride. The response is also blocked by ICS-205930. Interestingly, we isolated two splice variants of the receptor, 5-HT4L and 5-HT4S, differing in the length and sequence of their C-termini. In rat brain, the 5-HT4S transcripts are restricted to the striatum, but the 5-HT4L transcripts are expressed throughout the brain, except in the cerebellum where it was barely detectable. In peripheral tissues, differential expression was also observed in the atrium of the heart where only the 5-HT4S isoform was detectable.
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PMID:The 5-HT4 receptor: molecular cloning and pharmacological characterization of two splice variants. 779 7

Several lines of evidence have suggested a link between serotonergic and dopaminergic systems in the brain. The interpretation of much of these early data needs careful reevaluation in light of the recent understanding of the plethora of serotonin receptor subtypes, their distribution in the brain and the new findings with more selective serotonin antagonists. Electrophysiological, biochemical and behavioral evidence obtained using highly selective antagonists of the 5-HT2 or 5-HT3 receptor subtypes, MDL 100,907 or MDL 73,147EF, respectively, supports the thesis that serotonin modulates the dopaminergic system. This modulation is most evident when the dopaminergic system has been activated.
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PMID:Electrophysiological, biochemical and behavioral evidence for 5-HT2 and 5-HT3 mediated control of dopaminergic function. 783 42

We investigated the potential of cross-over to the serotonin receptor (5HT3) antagonist ondansetron after protection failure with tropisetron. Several cases of complete protection were observed. These limited data suggest that there is an indication for retreatment with a different 5HT3 antagonist after an initial failure to another and also stress the need and relevance for comparative studies between 5HT3 antagonists.
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PMID:Possible lack of full cross-resistance of 5HT3 antagonists; a pilot study. 788 75

Considerable progress has been made in the development of means to limit nausea and vomiting arising from cancer chemotherapy. A number of key conceptual advances in the last decade have been critically important. these include recognition of the value of combination antiemetic therapy, identification of important patient- and treatment-related factors predictive of emesis, and appreciation of the importance of serotonin (5-HT) in the pathophysiology of emesis and the value of selective antagonists of the type-3 serotonin receptor. Comparative trials of the 5-HT3 receptor antagonists and classic antiemetic agents have helped define optimal antiemetic approaches in a number of settings. A combination of a 5-HT3 antagonist and dexamethasone is the treatment of choice for patients receiving single- and multiple-day cisplatin. The 5-HT3 antagonists are also effective agents with noncisplatin chemotherapy. Clear-cut superiority to classic antiemetics such as dexamethasone has not been consistently demonstrated, however. Results with the 5-HT3 antagonists in cisplatin-induced delayed emesis have been disappointing to date. The results of ongoing prospective trials should define their role more clearly. At present a combination of metoclopramide and dexamethasone is the treatment of choice in this setting. Results of trials comparing 5-HT3 antagonists are beginning to emerge. Available information suggests no clinically relevant differences in antiemetic efficacy between these agents. Many questions regarding the optimal use of the 5-HT3 antagonists and their integration into clinical practice remain unanswered and are the appropriate focus for additional study.
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PMID:Treatment of chemotherapy-induced emesis in the 1990s: impact of the 5-HT3 receptor antagonists. 800 Jul 24

Biochemical and electrophysiological approaches were used to assess the possible changes in 5-hydroxytryptamine (serotonin) 5-HT1A receptors in the rat brain after a long-term treatment with cericlamine [2-(3,4-dichlorobenzyl)-2-dimethylamino-1-propanol], a novel serotonin reuptake inhibitor with antidepressant properties. Possible changes in other serotonin receptor binding sites (5-HT2A, 5-HT2C and 5-HT3) were also investigated after this treatment. Cericlamine was injected for 2 weeks at a dose (16 mg/kg i.p., twice daily) that ensured complete prevention of 4-methyl-alpha-ethyl-meta-tyramine-induced depletion of brain serotonin. In vitro binding and quantitative autoradiographic studies showed that neither 5-HT1A, 5-HT2A, 5-HT2C nor 5-HT3 receptor binding sites in various brain areas were affected by the 14-day treatment with cericlamine. Although forskolin-stimulated adenylate cyclase activity was significantly increased in hippocampal homogenates from cericlamine-treated rats, the reduction in this enzymatic activity due to 5-HT1A receptor stimulation by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was unchanged in these animals as compared with controls. In contrast, in vitro and in vivo electrophysiological recordings of serotoninergic neurons in the dorsal raphe nucleus revealed a clearcut functional desensitization of somatodendritic 5-HT1A autoreceptors. Thus the potency of 8-OH-DPAT and ipsapirone to depress the firing rate of these neurons in brain stem slices was significantly reduced after the 2-week treatment with cericlamine. In vivo, the potency of an injection of cericlamine to inhibit the discharge of serotoninergic neurons was also markedly less in rats that had been pretreated for 2 weeks with this drug as compared with controls. However, the inhibitory effects of systemically injected 8-OH-DPAT and ipsapirone on the electrical activity of serotoninergic neurons were as pronounced in cericlamine-treated rats as in controls. In addition, the reduction in serotonin synthesis due to an acute treatment with 8-OH-DPAT (0.1 or 0.3 mg/kg s.c.) was not significantly different in both groups of rats. These data support the idea that postsynaptic (in the hippocampus) and somatodendritic (in the dorsal raphe nucleus) 5-HT1A receptors are differently regulated in the rat brain, because only the latter receptors desensitized after a long-term blockade of serotonin reuptake by cericlamine. They also suggest that the inhibitory influence of systemically administered direct 5-HT1A agonists such as 8-OH-DPAT and ipsapirone on the electrical and metabolic activity of serotoninergic neurons does not result solely from the stimulation of somatodendritic 5-HT1A autoreceptors.
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PMID:Central pre- and postsynaptic 5-HT1A receptors in rats treated chronically with a novel antidepressant, cericlamine. 813 56

Typical neuroleptics (e.g. haloperidol) can induce catalepsy in rodents. Selective 5-hydroxytryptamine1A (5-HT1A) receptor antagonists reduce neuroleptic-induced catalepsy (NIC), suggesting that this subtype of serotonin receptor plays a role in the modulation of nigrostriatal dopaminergic transmission. The present study was designed to evaluate the participation of other 5-HT receptor subtypes in NIC. Adult albino mice (both sexes, 26-35 g) were used. Catalepsy was induced with haloperidol (H; 1.5 mg/kg, ip) and measured at 30-min intervals by means of a bar test. Cyanopindolol (a 5-HT1B receptor antagonist), ICI 169,369 (a 5-HT1C/2 receptor antagonist) and granisetron (a 5-HT3 receptor antagonist) were used. Buspirone, a 5-HT1A partial antagonist, cisapride, a 5-HT3/5-HT4 ligand and clomipramine, a 5-HT neuronal uptake blocker, were also employed. These drugs were injected ip, 20 min before H, with each animal (9-10 per group) used only once. Cyanopindolol (0.3 mg/kg) or ICI 169,369 (5 mg/kg) did not significantly affect NIC (375 +/- 39 and 378 +/- 34 s vs 372 +/- 44 s for controls, at 2 h after H). Buspirone (1 mg/kg) reduced, while pretreatments with either granisetron (0.5 mg/kg), cisapride (5 mg/kg) or clomipramine (5 mg/kg) potentiated the cataleptic effect of H (107 +/- 19, 576 +/- 52, 815 +/- 76 and 800 +/- 97 s vs 374 +/- 40 s in the control group, at 2 h after H).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of the 5-HT receptor antagonists cyanopindolol, ICI 169,369, cisapride and granisetron on neuroleptic-induced catalepsy in mice. 829 21

Recent studies have shown that serotonin (5-hydroxytryptamine; 5-HT) is required for the induction of interstitial collagenase in cultured rat and human myometrial smooth muscle cells. The present study was performed to determine which serotonin receptor subtype mediates the induction of collagenase in these cells. [125I]DOI ((+/- )-1-(2,5-dimethoxy-4-[125I]iodophenyl)-2-aminopropane), a 5-HT2 receptor agonist radioligand, bound specifically to sites in myometrial cell membranes, and exhibited binding characteristics essentially identical to those observed with brain 5-HT2 receptors. Radioligands selective for other serotonin receptor subtypes (5-HT1 and 5-HT3) failed to yield detectable binding. Northern blot analysis demonstrated the presence of 5-HT2 mRNA in the uterine smooth muscle cell cultures, whereas transcripts for 5-HT1A and 5-HT1C receptors were not detectable. Moreover, RT-PCR indicated that 5-HT2 receptor mRNA is present in freshly isolated uterine tissue as well. Selective antagonists of the 5-HT2 receptor, ketanserin and spiperone, displayed concentration-dependent inhibition of serotonin-mediated collagenase induction in the myometrial cultures. These antagonists yielded IC50 values of 4.7 nM and 2.7 nM respectively, characteristic of values expected from a 5-HT2 receptor-mediated response. In addition, a number of selective 5-HT2 receptor agonists (quipazine, alpha-methyl-serotonin, DOI) mimicked the ability of serotonin to induce collagenase production, whereas compounds selective for 5-HT1 and 5-HT3 receptor subtypes had little effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serotonin-dependent collagenase induction in rat myometrial smooth muscle cells: mediation by the 5-HT2 receptor. 847 55

The field of high-dose chemotherapy with stem cell transplantation has been expanded recently as a treatment for solid tumors and hematological malignancies. Severe emesis remains one of the main extramedullary side-effects of high-dose regimens during the first week of treatment. Traditional antiemetics such as chlorpromazine, diazepam, and phenothiazines are extensively used but are unable to control emesis. The new antiemetic ondansetron, a serotonin receptor (5HT3) antagonist appears to be superior to these drugs for cisplatin-induced emesis. The study we present here is an attempt to control emesis following high-dose regimens, during bone marrow or peripheral stem cell transplantation, with ondansetron. To our knowledge no other paper has reported the efficacy of this antiemetic in such group of patients. A total of 29 patients who received highly emetogenic polychemotherapy as conditioning regimens for bone marrow transplantation were treated with ondansetron, which was given as an 8-mg i.v. short infusion prior the initiation of treatment and every 6 h thereafter for 3 days, and an 8-mg dose every 8 h for 5 additional days. All the patients had previously been treated with chemotherapy and were evaluable for response and toxicity. Complete and major protection of vomiting on day 1 was achieved by 76% of the patients, 58% on day 2 and 52% on day 3. Nausea was absent or mild in 79% of patients on day 1, 45% on day 2 and 41% on day 3.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A phase II study of ondansetron as antiemetic prophylaxis in patients receiving high-dose polychemotherapy and stem cell transplantation. 852 Aug 76

Vomiting may be induced by a variety of agents such as drugs, oncolytics, and provocative motion, as well as being conditioned to occur to environmental stimuli. Such emesis has recently been shown to be blocked by agonists at the 5-HT1A subtype of serotonin receptor. The antiemetic effects of LY228729 [(-)-4-(dipropylamine)-1,3,4,5-tetrahydrobenz-(c,d)indole-6- carboxamide], a 5-HT1A receptor agonist, were tested and compared to the antiemetic effects of the 5-HT3 receptor antagonists ondansetron, tropisetron, and MDL 72222 (3-tropanyl-3,5-dichlorobenzoate). The emetic stimuli tested are known to be blocked by 5-HT3 antagonists in species other than the pigeon. In the pigeon, LY228729 totally abolished vomiting induced by fully emetic doses of cisplatin (10 mg/kg), ipecac (3 ml/kg), emetine (10 mg/kg), and a 5-HT3 agonist, m-(chlorophenyl)-biguanide (1.25 mg/kg). MDL 72222 blocked ipecac-induced vomiting in a dose-related manner and was partially effective in attenuating cisplatin-induced emesis. Ondansetron and tropisetron were partially effective in blocking emetine- and mCPBG-induced vomiting. Ondansetron exhibited an intrinsic emetic response that could not be blocked by MDL 7222, but which was eliminated by LY228729. It was concluded that 5-HT1A agonists are more effective in the pigeon than are 5-HT3 antagonists against these types of emetic stimuli. These results broaden the range of emetic stimuli that are blocked by 5-HT1A agonists in the pigeon.
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PMID:Comparison of the antiemetic effects of a 5-HT1A agonist, LY228729, and 5-HT3 antagonists in the pigeon. 854 76


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