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)

The effects of the 5-HT3 receptor antagonists, zacopride, ondansetron and ICS 205-930, were investigated in an animal model of depression, the learned helplessness test. Rats previously subjected to a session of 60 inescapable foot-shocks exhibited a deficit of escape performance in three subsequent shuttle-box sessions. The 5-HT3 receptor antagonists administered i.p. twice daily on a chronic schedule (zacopride 0.03-2 mg/kg per day; ondansetron and ICS 205-930: 0.125-2 mg/kg per day) reduced the number of escape failures at low to moderate daily doses. This effect was not observed with the highest dose(s) of zacopride, ondansetron and ICS 205-930 tested. These results indicate that 5-HT3 antagonists may have effects like those of conventional antidepressants in rats.
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PMID:5-HT3 receptor antagonists reverse helpless behaviour in rats. 153 55

5-Hydroxytryptamine (5-HT) mechanisms may play a role in opioid-mediated antinociception. Since opioid mechanisms have been implicated in nitrous oxide antinociception, this study was conducted to determine the possible role of 5-HT receptors in nitrous oxide antinociception. Male Swiss Webster mice were pretreated with one of two 5-HT receptor blockers and then tested in the acetic acid abdominal constriction test for their antinociceptive response to nitrous oxide, the kappa-opioid agonist U-50,488H, or the mu-opioid agonist sufentanil. Results indicate that the 5-HT3 receptor blocker ICS-205,930 antagonized both nitrous oxide and U-50,488H effects but not that of sufentanil. Mianserin, a 5-HT1c/5-HT2 receptor blocker, effects but not that of sufentanil. Mianserin, a 5-HT1c/5-HT2 receptor blocker, potentiated effects of both nitrous oxide and U-50,488H but not that of sufentanil. These findings show similarities in nitrous oxide and U-50,488H antinociception and further support our hypothesis that nitrous oxide works through central kappa-opioid mechanisms in mice. The results also suggest different roles for 5-HT receptor subtypes in mediating or modulating the antinociceptive effect of nitrous oxide.
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PMID:Contrasting influences of 5-hydroxytryptamine receptors in nitrous oxide antinociception in mice. 153 64

The discriminative stimulus induced in rats by amphetamine has previously been shown to be due to raised mesolimbic dopamine levels. As 5-HT3 receptor antagonists have been shown to inhibit hyperactivity resulting from raised mesolimbic dopamine levels, the present study examined their effects against the amphetamine discriminative stimulus. None of the 5-HT3 receptor antagonists tested (MDL 72,222EF, 0.3-10 mg/kg s.c.; MDL 73,147EF, 0.3-10 mg/kg s.c.; ICS 205-930, 0.01-10.0 mg/kg s.c.; ondansetron, 0.1-1000 micrograms/kg s.c.) antagonised the effects of amphetamine in this test. This suggests that 5-HT3 receptors cannot modulate the effects of raised mesolimbic dopamine in pathways involved in the interoceptive effects of amphetamine.
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PMID:The effect of 5-HT3 receptor antagonists on the discriminative stimulus effects of amphetamine. 153 68

In the present study, we investigated the effects of various serotonin (5-HT) antagonists on 5-HT's action on medial prefrontal cortical cells (mPFc) using the techniques of single cell recording and microiontophoresis. The microiontophoretic application of 5-HT (10-80 nA) produced a current-dependent suppression of mPFc cell firing and this effect was blocked by the selective 5-HT3 receptor antagonists (+/-)-zacopride, ICS 205930 and granisetron at currents of 5-20 nA. Furthermore, the intravenous (i.v.) administration of (+/-)-zacopride (5-50 micrograms/kg) markedly attenuates the suppressive action of 5-HT on mPFc cell firing. In contrast, the microiontophoresis of 5-HT1 and 5-HT2 receptor antagonists such as (+/-)-pindolol, spiperone, metergoline, and ritanserin (10-20 nA) failed to block 5-HT's effect. In fact, in some cells, spiperone and ritanserin potentiated 5-HT's action and prolonged neuronal recovery. In addition, the intravenous administration of either ritanserin (5-2,000 micrograms/kg) or metergoline (4-2,400 micrograms/kg) failed to alter 5-HT's action. The electrical stimulation of the caudal linear raphe nucleus (CLi) suppressed the spontaneous activity of 83% of the mPFc cells tested by 45 +/- 2%. This suppression was significantly attenuated by the iontophoresis of granisetron (2.5-5 nA) but not by the 5-HT2 and 5-HT1C receptor antagonist ritanserin or the relatively selective 5-HT2 receptor antagonist (+)-MDL 11,939 (10-40 nA). However, the i.v. administration of ritanserin (0.5-1.5 mg/kg) or S-zacopride (0.1 mg/kg) significantly blocked the suppression of mPFc cell firing produced by CLi stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Action of serotonin in the medial prefrontal cortex: mediation by serotonin3-like receptors. 153 32

Two new classes of potent 5-HT3 agents have been developed and examined as inhibitors of cytotoxic drug induced emesis in the ferret and dog. The absolute configuration of the most active molecules 10 and 18 have been determined by X-ray crystallography. These two compounds are more potent than known 5-HT3 receptor antagonists both in vivo and in vitro in blocking 5-HT3 receptor activation and preventing chemotherapeutic induced emesis. Compared with 5-HT3 antagonists, such as GR 38032F, zacopride, BRL 43694, and ICS 205-930, compound 10 was more potent in (1) inhibiting binding to 5-HT3 receptor binding sites in rat cortex (Ki = 0.17 nM), (2) blocking the von Bezold-Jarisch effect in the rat (lowest effective dose, 1 microgram/kg iv), and (3) inhibiting 5-HT-induced contraction of guinea pig ileum (lowest effective concentration, 10(-9) M). This novel agent was as effective given po as when given iv in reducing cisplatin-induced emetic episodes in the ferret (ED50 = 4 micrograms/kg iv or po). A 1 mg/kg po dose of 10 virtually abolished cisplatin-induced emesis for 10 h in the ferret. However, it was inactive against apomorphine or copper sulfate-induced vomiting. These data, coupled with receptor binding studies of ligands for D2-dopamine, a1, a2, 5-HT1, 5-HT2, and muscarinic receptors demonstrate that 10 is a highly selective 5-HT3 receptor antagonist with remarkable potency in vivo.
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PMID:Development of high-affinity 5-HT3 receptor antagonists. 2. Two novel tricyclic benzamides. 154 79

The influence of three azabicycloalkyl benzimidazolone derivatives, DAU 6236, BIMU 1 and BIMU 8, which act as agonists at central 5-hydroxytryptamine (5-HT)4 receptors, has been investigated on cholinergic neuromuscular transmission and peristalsis in the guinea pig small intestine. In the longitudinal muscle myenteric plexus preparations, these compounds caused a concentration-dependent (range 1-300 nM) enhancement of the amplitude of nerve-mediated cholinergic submaximal contractions to electrical stimulation. In comparison to the potentiating effect of 5-methoxytryptamine (a reference 5-HT4 receptor agonist), the rank order of agonist potency was BIMU 8 = BIMU 1 greater than DAU 6236 = 5-methoxytryptamine. In whole ileal segments, DAU 6236, BIMU 1 and BIMU 8 increased markedly (maximum increase, 200%) the frequency of peristalsis within the range of 0.1 to 3 microM. Micromolar concentrations of ICS 205-930, which is a low affinity antagonist of 5-HT4 receptors, were required to antagonize the facilitatory effect on cholinergic transmission caused by benzimidazolone derivatives and 5-methoxytryptamine (pA2 values, 6.5 in average) and to reverse the increase in the frequency of peristalsis induced by DAU 6236, BIMU 1 and BIMU 8. By contrast, the potent and selective 5-HT3 receptor antagonist ondansetron (1 microM) was ineffective. Our findings indicate that benzimidazolone derivatives act as agonists in the guinea pig ileum causing enhancement of acetylcholine release and peristaltic activity. The neural receptor site involved in the action of benzimidazolone derivatives and which showed low affinity for ICS 205-930 is probably identical to the putative 5-HT4 receptor subtype agonized by indoleamines and substituted benzamide derivative prokinetic agents.
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PMID:Benzimidazolone derivatives: a new class of 5-hydroxytryptamine4 receptor agonists with prokinetic and acetylcholine releasing properties in the guinea pig ileum. 157 56

We examined ethanol's interactions with serotonin (5-HT) receptor-mediated [3H]5-HT high-affinity uptake by adult rat forebrain synaptosomes. The serotonergic transport mechanism was chosen because ethanol consumption patterns can be manipulated by serotonin receptors and uptake blockers. We report that a dose of ethanol which causes general anesthesia in humans (54 mM) applied in vitro enhanced rat synaptosomal [3H]5-HT uptake after 5 min at 37 degrees C. Similar levels of stimulation by 54 mM ethanol were seen in hippocampal, cerebral cortex and brainstem synaptosomes. Significant inhibition of uptake was not detected until concentrations of ethanol reached 2.1 M, which is lethal in vivo. Ryanodine and the 5-HT2 agonist, DOI, are believed to cause an increase in intracellular Ca2+ levels. We observed that they also caused an elevation of [3H]5-HT uptake, and this stimulation was less than additive with the ethanol-induced increase. Inhibition of the 5-HT3, receptor-mediated Na+ channel with the antagonist ICS 205930, partially reversed ethanol's stimulatory effects on [3H]5-HT uptake. Blockade of voltage-dependent Na+ flux with tetrodotoxin and lidocaine, however, had no effect on the stimulation by ethanol. But tetraethylammonium, which blocks voltage-dependent K+ channels, partially counteracted ethanol's action on [3H]5-HT uptake. These compounds had no effect on uptake by themselves. These results indicate that ethanol's stimulation of [3H]5-HT uptake involves a rise in [Ca2+]i which is sensitive to voltage-dependent K+ flux and 5-HT3 receptor-mediated Na+ flux, and would decrease the availability of synaptic 5-HT.
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PMID:Ethanol stimulates [3H]5-HT high-affinity uptake by rat forebrain synaptosomes: role of 5-HT receptors and voltage channel blockers. 164 10

The effect of endogenous serotonin on the release of [3H]gamma-aminobutyric acid ([3H]GABA) from slices of rat caudate-putamen was studied. p-Chloroamphetamine was used to release endogenous serotonin. p-Chloroamphetamine (100 nM) enhanced the release of [3H]GABA induced by 20 mM K+, while 1000 nM p-chloroamphetamine decreased it. The 5-HT3 receptor antagonists ICS 205-930 (50 nM) and MDL 72222 (100 nM) prevented this facilitation caused by 100 nM p-chloroamphetamine. ICS 205-903 (50 nM), when used alone, reduced the release of [3H]GABA caused by 23 mM K+. This finding confirmed the hypothesis that endogenous serotonin can enhance the release of [3H]GABA via 5-HT3 receptors. In contrast, an effect of 5-HT1 and 5-HT2 receptors could not be clearly established. It is likely that the release of endogenous GABA from striatonigral GABA neurons may also be affected by serotonin via 5-HT3 receptors.
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PMID:Effects of p-chloroamphetamine on release of [3H]gamma-aminobutyric acid from slices of rat caudate-putamen. 165 73

1. We describe the effects of pretreatment with 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on neurogenically-mediated plasma protein extravasation ([125I]-albumin) in rat dura mater and in extracranial tissues (temporalis muscle fascia, conjunctiva, eyelid and lip) induced by electrical stimulation of the right trigeminal ganglion. 2. Leakage of [125I]-bovine serum albumin from blood vessels in dura mater following high intensity stimulation (1.2 mA, 5 ms, 5 Hz for 5 min) was significantly reduced by the intravenous administration of drugs active at 5-HT receptors with some selectivity for the 5-HT1 receptor subtypes: 5-carboxamidotryptamine (5-CT) (threshold dose, 1 ng kg-1); 5-benzyloxytryptamine (5-BT) (10, 30 or 100 micrograms kg-1); 8-hydroxydipropylaminotetralin (8-OH-DPAT) (300 micrograms kg-1); and as previously reported, sumatriptan (100 micrograms kg-1), dihydroergotamine (DHE) (50 micrograms kg-1); ergotamine tartrate (100 micrograms kg-1) and chronically administered methysergide (1 mg kg-1). 3. The putative 5-HT receptor antagonist, metergoline 100 micrograms kg-1, inhibited partially the effect of sumatriptan in dura mater providing additional evidence for a 5-HT1 receptor subtype-mediated mechanism, although it was not effective against 5-CT (1 ng kg-1). Methiothepin (300 micrograms kg-1) did not affect the response to sumatriptan. When administered at high concentrations (1 mg kg-1) methiothepin and metergoline decreased plasma protein extravasation in rat dura mater. 4. Pretreatment with the 5-HT2 receptor antagonists pizotifen, 300pugkg 1, or ketanserin, 300,ugkg ', or the 5-HT3 receptor antagonists MDL 72222, 300,ugkg-1, or ICS 205-930, 300pgkg-1, did not affect plasma protein leakage following electrical trigeminal stimulation. Blockade by sumatriptan of plasma protein extravasation was not inhibited by pizotifen (300,ug kg-1) or MDL 72222 (300pg kg- '). 5. The 5-HT receptor(s) mediating this response were present only on intracranial tissues innervated by the trigeminal nerve; plasma protein extravasation in extracranial tissues was not blocked by pretreatment with the equivalent or higher concentrations of the above drugs following low intensity trigeminal stimulation (0.1 mA, 5 ms, 5 Hz). 6. The putative 5-HT receptor(s) mediating this response were not present on sympathetic fibres innervating dura mater since unilateral removal of the superior cervical ganglion did not prevent the development of plasma protein extravasation nor did it affect the blockade by sumatriptan IOOpug kg- '. 7. The above pharmacological data suggest that intracranial vessels possess 5-HT receptor(s) which are coupled to inhibition of neurogenically-mediated plasma protein extravasation. These receptors cannot be detected on extracranial cephalic blood vessels innervated by the trigeminal nerve, although available evidence strongly suggests that the 5-HT receptors reside on perivascular trigeminal nerve fibres. The rank order of effective doses (threshold concentrations; 5-CT < 5-BT < DHE < sumatriptan < 8-OHDPAT) is most consistent with a 5-HTlB- or 5-HTlD-mediated response, among the known 5-HT1 family of receptors. However, the lack of effect of methiothepin against the actions of sumatriptan, or metergoline against the effects of 5-CT suggest important differences and the possibility that a previously unrecognized 5-HT receptor(s) is involved in this response.
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PMID:Further characterization of the putative 5-HT receptor which mediates blockade of neurogenic plasma extravasation in rat dura mater. 165 72

The feeding responses to essential dietary amino acid (AA) disproportion have been useful in nutritional studies. These responses involve first: recognition of the imbalance and second: rejection of the diet, likely via development of a learned aversion. In the rat, we have studied the role of the limiting AA and protein synthesis in the recognition phase by replacement of the limiting AA into a brain area essential for the initial depressed feeding response. We have also reported a reciprocal relationship between serotonin (5HT) activity and intake of imbalanced diets. High doses of the 5HT3 receptor antagonist, ICS 205-930 (ICS; 9 mg/kg IP), restored food intake to 85% or more of control intake. In the present experiments, similar treatment with ICS blocked the classical conditioned taste aversion to a saccharin solution paired with lithium chloride. These results suggest that the increased intake of AA imbalanced diets after ICS may be due to 5HT-mediated blockade of a learned aversion.
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PMID:Amino acid imbalance, a nutritional model: serotonin3 mediation of aversive responses. 165 37


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