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)

Sixteen known 5-HT3 receptor blockers, including clozapine, fully or partially reverse the inhibitory effect of 1 microM GABA on [35S]TBPS binding, indicating that they are also GABA(A) antagonists, some of them selective for subsets of GABA(A) receptors. The 5-HT3 receptor blocker, ondansetron, has been reported to produce some antipsychotic and anxiolytic effects. However, no antipsychotic effects have been reported for a large number of highly potent 5-HT3 receptor blockers. Like clozapine, ondansetron partially reverses the inhibitory effect of GABA on [35S]TBPS binding. Additivity experiments suggest that ten 5-HT3 receptor blockers tested at low concentrations preferentially block subtypes of GABA(A) receptors that are among those blocked by clozapine. Wiley and Porter (29) reported that MDL-72222, the most potent GABA(A) antagonist described here, partially generalizes (71%) with clozapine in rats trained to discriminate an interoceptive clozapine stimulus, but only at a dose that severely decreases responding. Tropisetron (ICS-205,930) exhibits both GABA-positive and GABA-negative effects. R-(+)-zacopride is 6-fold more potent than S-(-)-zacopride as a GABA(A) antagonist. We conclude that the observed antipsychotic and, possibly, anxiolytic effects of some 5-HT3 receptor blockers are due to selective antagonism of certain GABA(A) receptors, and not to blockade of 5-HT3 receptors. We speculate that the anxiolytic and sedative effects of clozapine and several other antipsychotic drugs may be due to selective blockade of alpha1beta2gamma2 GABA(A) receptors which are preferentially located on certain types of GABAergic interneurons (probably parvalbumin positive). Blockade of these receptors will increase the inhibitory output of these interneurons. So far, no highly potent GABA(A) antagonists with clozapine-like selectivity have been identified. Such compounds may exhibit improved clozapine-like antipsychotic activity.
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PMID:Clozapine's antipsychotic effects do not depend on blockade of 5-HT3 receptors. 1034 95

1. The in vitro hemisected spinal cord from young rat was used to investigate the mechanism of serotoninergic modulation of primary afferent-mediated synaptic transmission in the dorsal horn through activation of the 5-HT3 receptor. 2. Dorsal root-evoked excitatory post-synaptic potentials (DR-EPSPs) were recorded intracellularly from dorsal horn neurones. Extracellular recordings of the population primary afferent depolarization (PAD) and the dorsal root-evoked dorsal root reflex (DR-DRR) were made from segmental dorsal roots. 3. 5-Hydroxytryptamine (5-HT) and the selective 5-HT3 receptor agonist 1-(m-chloro-phenyl)-biguanide hydrochloride (m-ChPB) (10 and 50 microM) induced statistically significant reductions of the DR-EPSP amplitude (P<0.001) and duration (P<0.001) in the majority of dorsal horn neurones. The 5-HT3 receptor selective antagonists 3-Tropanyl-indole-3-carboxylate hydrochloride (Tropisetron, 10 microM) and N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazine-8-carboxamide (Y-25130, 10 microM) abolished m-ChPB-induced DR-EPSP attenuation and partially blocked the 5-HT effect. 4. m-ChPB (50 microM)-induced DR-EPSP amplitude and duration attenuation was retained in the presence of the GABA(A) receptor antagonist bicuculline (30 microM), the GABA(B) receptor antagonist saclofen (50 microM) and the opioid receptor antagonist naloxone (50 microM). 5. Both 5-HT and m-ChPB (10 and 50 microM) induced a PAD but the mean peak amplitude of 5-HT-induced PAD was significantly greater than PAD to m-ChPB (98.6+/-12 microV compared to 51.8+/-10 V for 50 microM of agonist, respectively). Tropisetron partially reduced 5-HT-induced PAD and abolished m-ChPB-induced PAD. 5-HT, but not m-ChPB, significantly (P<0.001) reduced the peak amplitude of the DR-DRR and this action of 5-HT was unaffected by Tropisetron or Y-25130. 6. These data provide experimental evidence for a putative cellular mechanism at the level of the dorsal horn for anti-nociceptive effects of 5-HT3 receptor activation. This 5-HT3-mediated modulation of sensory afferent transmission was evidently independent of inhibitory GABA- or opioid-dependent interneuronal pathways. The extent to which the 5-HT3 receptor could be involved in the operation of endogenous analgesia and sensory modulation by descending monoamine bulbo-spinal pathways is discussed.
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PMID:Modulation of afferent-evoked neurotransmission by 5-HT3 receptors in young rat dorsal horn neurones in vitro: a putative mechanism of 5-HT3 induced anti-nociception. 1043 90

Patient-controlled analgesia (PCA) is associated with a high incidence of vomiting which is distressing and interferes with postoperative recovery. Tropisetron, a long-acting selective 5-HT3 receptor antagonist, has been shown to be effective in preventing nausea and vomiting associated with PCA use in adults and chemotherapy in children. We assessed the efficacy of prophylactic intraoperative administration of tropisetron on the incidence of vomiting in children using morphine PCA. We studied 58 patients, allocated randomly to receive tropisetron 0.1 mg kg-1 to a maximum of 5 mg, or normal saline. Children who received tropisetron had an incidence of vomiting during the first 24 h after operation of 22% compared with 66% in the control group (P = 0.001). In addition, the severity of vomiting was less in the tropisetron group with only one child (4%) vomiting more than twice compared with nine (31%) in the control group (P = 0.01). We conclude that tropisetron is efficacious in reducing the incidence and severity of postoperative vomiting in children using PCA.
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PMID:Effect of tropisetron on vomiting during patient-controlled analgesia in children. 1067 78

Nystatin-perforated patch recordings were made from mechanically dissociated basolateral amygdala neurons with preserved intact native presynaptic nerve terminals to study the mechanism of 5-HT3 receptor-mediated serotonergic modulation of GABAergic inhibition. The specific 5-HT3 agonist mCPBG (1 microM) rapidly facilitated the frequency of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) and this facilitation desensitized within 1 min. Tropisetron (30 nM), a specific 5-HT3 antagonist, blocked the mCPBG effect. mCPBG augmented mIPSC amplitude. However, no direct postsynaptic serotonergic currents were evoked by mCPBG. Neither GABA-evoked current amplitude nor the kinetics of individual GABAergic mIPSCs were affected by mCPBG. Therefore, the augmentation is unlikely to be due to postsynaptic effects evoked by mCPBG. At higher concentrations mCPBG produced shorter-duration facilitation of miniature events. While mCPBG increased the mIPSC frequency in calcium-containing solution with Cd2+, this increase was absent in Ca2+-free external solution. It appears that the Ca2+ influx through voltage-dependent calcium channels was not as crucial as that through 5-HT3 receptors for synaptic GABA release. When two pulses of mCPBG (each 1 microM, 1 min) were given, the response to the second pulse elicited full recovery when the interval between pulses was at least 9 min. Protein kinase A (PKA) activation by 8-Br-cAMP (300 microM) shortened and PKA inhibition by Rp-cAMP (100 microM) prolonged the recovery time. PKA activity did not affect the time course of fast desensitization. Our results suggest that a 5-HT3-specific agonist acts on presynaptic nerve terminals facilitating synaptic GABA release without postsynaptic effects. The facilitation requires calcium influx through presynaptic 5-HT3 receptors. PKA modulates the recovery process from desensitization of presynaptic 5-HT3 receptor-mediated regulation of synaptic GABA release.
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PMID:Presynaptic 5-HT3 receptor-mediated modulation of synaptic GABA release in the mechanically dissociated rat amygdala neurons. 1110 47

The 5-hydroxytryptamine (5-HT) receptors mediating contraction in human isolated mesenteric arteries were characterized. Endothelium-denuded human isolated mesenteric arteries were used. 5-HT induced concentration-dependent contractions in mesenteric arteries (Emax, 127.37 +/- 7.61% of 80 mM KCl maximal contraction; pD2, 6.73 +/- 0.09 [-logEC50]). Sumatriptan, a selective 5-HT1B/1D receptor agonist, induced concentration-dependent contractions in some of the arteries (Emax, 61.82 +/- 10.04%; pD2, 6.56 +/- 0.21, n = 9) but not in the others (Emax < 5%, n = 13), suggesting that functional 5-HT1B/1D receptors exist in some but not in all mesenteric arteries. GR127935 (a selective 5-HT1B/1D receptor antagonist, 3 nM) inhibited sumatriptan-induced contractions in arteries in which sumatriptan responses were strong in an insurmountable manner. GR127935 (10 nM) also inhibited 5-HT responses and shifted the concentration-response curve of 5-HT to the right significantly (p < 0.05; pD2s were 6.54 +/- 0.18 and 5.93 +/- 0.11 in the presence of vehicle and GR127935, respectively). Ketanserin (0.01-1 microM) competitively antagonized 5-HT responses in human mesenteric arteries: pA2 value was 8.40 +/- 0.25 (slope of Schild regression, 1.43 +/- 0.18; r2, 0.98). Tropisetron (5-HT3 receptor antagonist) and prazosin (alpha1-adrenoceptor antagonist) did not affect the contractions induced by 5-HT. These results suggest that 5-HT2A and 5-HT1B/1D receptors, but not 5-HT3 and alpha1-adrenoceptors, are involved in the 5-HT-induced contractions in human isolated mesenteric arteries. Sumatriptan-induced and 5-HT1B/1D receptor-mediated responses vary greatly among patients.
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PMID:Pharmacologic characterization of contractile serotonergic receptors in human isolated mesenteric artery. 1254 93

Modern management of fibromyalgia (FM) requires a holistic approach, which includes nonpharmacologic strategies (both exercise and behavioral strategies) and pharmacologic treatment. Despite only partial effects in some patients, tricyclic antidepressants, selective serotonin reuptake inhibitors, nonsteroidal antiinflammatory drugs, analgesics and opioids are in use. The use of antiepileptic drugs and antispasticity agents is mainly supported by anecdotal data. Three other classes of agents are currently thought to have useful potentials. N-methyl-D-aspartate-(NMDA-)mediated neurotransmission may play an important role in mediating wind-up and related phenomena in pain pathways. Recent studies have demonstrated that NMDA receptor antagonists improve pain symptoms in FM. But a poor side effect profile represents a significant problem. Cerebrospinal fluid substance P concentrations are significantly elevated in FM patients, but the analgesic potential of neurokinin-1 (NK1) receptor antagonists did not meet early expectations. Tropisetron, a 5-HT3 receptor antagonist, was tested in a multicenter, double-blind, randomized, placebo-controlled trial including 403 patients. In those receiving 5 mg tropisetron, 39.2% fulfilled the response criterion (pain reduction 35%) as compared to 26.2% in the placebo group (p=0.033). On 10 and 15 mg, the responder rates were smaller and statistically not significant. A total of 78 responders to therapy were followed up for 12 months. After the end of treatment, pain intensity rose within one month in all 4 groups. Patients having received 5 or 10 mg showed a less pronounced increase in pain. In addition, even 12 months after stopping treatment, pain was still markedly below baseline levels in the 5 and 10 mg groups.
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PMID:[What's new in the therapy of fibromyalgia?]. 1464 17

Current research suggests an involvement of 5-HT3 receptors in peripheral and central perception and processing of pain as well as in inflammation. Tropisetron and other selective 5-HT3 receptor antagonists have been used successfully for pain reduction and treatment of related symptoms in patients diagnosed with fibromyalgia. This article proposes a concept of the underlying pathophysiology and mechanisms of action of 5-HT3 receptor antagonists in the context of the relevant clinical data on their application in patients with rheumatic disease.
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PMID:Analgesic effects of 5-HT3 receptor antagonists. 1551 7

The alpha7 nicotinic acetylcholine receptor (nAChR)-selective partial agonist tropisetron is a conjugate of an indole and a tropane group. We tested compounds structurally related to either the indole or tropane domains of tropisetron on oocytes expressing human alpha7. alpha4beta2, or alpha3beta4 nAChR or rat 5HT(3A) receptors. The simple compounds tropane and tropinone had alpha7-selective agonist activity comparable to that of tropisetron. Tropinone was more efficacious than tropisetron but 100-fold less potent. Some tropane compounds had antagonist activity on alpha3beta4 nAChR but no effect on alpha4beta2 nAChR. Some tropanes also affected the responses of 5HT3 receptors to serotonin. Tropisetron was more potent at inhibiting alpha3beta4 receptors (IC(50)=1.8+/-0.6) than was tropane or tropinone, suggesting that the presence of the indole group has a large impact on the potency of tropisetron, both as an alpha7 agonist and as an alpha3beta4 antagonist. The further reduced structures of dimethyl piperidinium and 1-methylpyrrolidine also had agonist activity on alpha7 receptors, suggesting that the minimal activating pharmacophore of these compounds, as with tetramethylammonium, may simply be the charged nitrogen, while additional structure elements impact subtype selectivity, potency, and efficacy. It has previously been reported that 5-hydroxyindole (5HI) can potentiate alpha7 receptor responses to acetylcholine (ACh). However, the site where 5HI binds to the receptor is not known. We tested the hypothesis that the tropisetron binding site might overlap the 5HI site and thereby produce a block of 5HI potentiation. Our results indicate that the indole portion of tropisetron is not likely to be binding to the same site where 5HI binds to potentiate alpha7 receptor responses since 5HI can greatly potentiate responses of tropisetron, tropinone, and other partial agonists such as 4OH-GTS-21.
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PMID:Molecular dissection of tropisetron, an alpha7 nicotinic acetylcholine receptor-selective partial agonist. 1578 Nov 47

Offensive aggression in golden hamsters is inhibited by 5-hydroxytryptamine (5-HT)1A receptors and facilitated by 5-HT3 receptor activation. As such, we sought to determine whether these receptors function similarly between animals expressing an impulsive-aggressive phenotype, as compared to normal animals. Animals were screened for aggressive and impulsive choice behaviors and categorized into Low-Aggression (L-Agg) and High-Aggression (H-Agg) groups, and then tested for behavior under effective doses of 5-HT1A receptor agonist 8-hydroxy-N, N-dipropyl-2-aminotetralin (DPAT; 0.1 mg/kg and 0.3 mg/kg) or 5-HT3 receptor antagonist tropisetron (0.3 mg/kg) treatment. Low-dose DPAT treatment inhibited both behaviors in H-Agg animals, however yielding more modest effects in L-Agg animals; while high-dose DPAT effects were confounded by side effects on locomotion. Tropisetron, on the other hand, had differential effects between groups, as aggression and impulsive choice were both inhibited in H-Agg animals, while enhanced in L-Agg individuals. In addition, while the effects of the 5-HT1A receptor were limited, the broad effects of 5-HT3 receptor included repetitive and impulsive elements of behavior, pointing to the importance of the receptor's role in the modulation of these particular aspects within the phenotype.
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PMID:Differential responses to serotonin receptor ligands in an impulsive-aggressive phenotype. 2069 45

Tropisetron, a selective 5-HT3 receptor (5-HT3R) antagonist, has been widely used to counteract chemotherapy-induced emesis. New investigations described the immunomodulatory properties of tropisetron which may not be 5HT3R mediated. In the present study, we assessed the potential effects of tropisetron on an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). EAE was induced in C57BL/6 mice by myelin oligodendrocyte glycoprotein peptide (MOG35-55) immunization. Animals were treated with tropisetron (5 mg/kg/day); m-chlorophenylbiguanide (mCPBG), a selective 5-HT3R agonist (10 mg/kg/day); tropisetron (5 mg/kg/day) plus mCPBG (10 mg/kg/day), and granisetron (5 mg/kg/day) intraperitoneally on days 3-35 post-immunization. Treatment with tropisetron and granisetron markedly suppressed the clinical symptoms of EAE (p<0.001) and reduced leukocyte infiltration as well as demyelination in the spinal cord (p<0.05). In addition, in vivo tropisetron, granisetron or tropisetron plus mCPBG therapy greatly reduced in vitro MOG35-55-stimulated proliferation of mononuclear cells from spleens, and MOG35-55-induced IL-2, IL-6 and IL-17 production by splenocytes isolated from EAE-induced mice (p<0.05). Concurrent administration of tropisetron and mCPBG did not significantly alter the histological damage in the spinal cord. mCPBG had no effect on the mentioned parameters. Taken together, these findings indicate that tropisetron has considerable immunoregulatory functions in EAE and may be promising for the treatment of MS or other autoimmune and inflammatory diseases of the CNS. Furthermore, beneficial effects of tropisetron in this setting seem to be both receptor dependent and receptor independent in the early phase of the disease.
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PMID:Tropisetron diminishes demyelination and disease severity in an animal model of multiple sclerosis. 2377 31


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