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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 5-HT3 receptor antagonists on ethanol intake were examined in the selectively bred alcohol-preferring P line of rats under continuous and limited access to 10% (v/v) ethanol with food and water ad lib. Single daily injections of either MDL 72222 (MDL) or ICS 205-930 (ICS) (0.01-3.0 mg/kg, SC) given 60 min before a 4-h scheduled access period for 4 consecutive days failed at all doses to alter the intake of a 10% (v/v) ethanol solution by P rats. However, multiple daily injections of either MDL (1-3 mg/kg, SC) or ICS (3.0 and 5.0 mg/kg, SC), given three times daily at 4-h intervals, significantly reduced ethanol intake under 24-h free-choice conditions on the first treatment day. Additionally, a single administration of 1.0 mg/kg MDL reduced 24-h free-choice ethanol intake by approximately 50% of control values and had no effect on 24-h saccharin intake. The effects of MDL were further examined in a 2-h schedule access paradigm in which rats received the access period at the same time every day (Fixed) or randomly during the dark cycle (Variable). Although 1.0 mg/kg MDL had little effect on ethanol drinking in the Fixed group, ethanol intake was reduced by 55% of control levels in the Variable group. Overall, the data indicate that drinking conditions influence the effectiveness of 5-HT3 antagonists to reduce ethanol consumption. Furthermore, the results suggest that conditions, associated with limited access ethanol drinking, markedly reduce the actions of 5-HT3 antagonists on ethanol intake.
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PMID:Serotonin3 receptor antagonism of alcohol intake: effects of drinking conditions. 959 May 13

18F Labelled MR18445 (4-[4-(4-[18F]fluorobenzyl)piperazino]-7-methoxypyrrolo++ +[1,2-alpha] quinoxaline), a selective 5-HT3 receptor partial agonist with nanomolar affinity, was synthesized and examined as a potential radioligand for PET imaging of brain 5HT3 receptors. Radiotracer was prepared by N-alkylation of the MR18491 precursor with 4-[18F]fluorobenzyl iodide. This latter was synthesized in a three-step procedure from 4-[18F]fluorobenzaldehyde obtained by 18F-nucleophilic displacement of 4-nitrobenzaldehyde, subsequently reduced to 4-[18F]fluorobenzyl alcohol and converted into reactive 4-[18F]fluorobenzyl iodide. The reduction step was performed on a column filled with NaBH4/Al2O3 and 4-[18F]fluorobenzyl alcohol was obtained with high reproducible yield (82-93% from 4-[18F]fluorobenzaldehyde) if there were traces of water in the system. The radiosynthesis of [18F]MR18445 required approximately 120 min. Semi-preparative HPLC purification followed by formulation gave injectable solutions of [18F]MR18445 with a radiochemical purity > 99%. The overall yield of the synthesis was mainly dependent upon the first step efficiency of aromatic incorporation of 18F- and varied from 12% to 29%. All the synthetic procedure was realized on a ZYMARK robotic system. Biological in vivo studies in rats showed that uptake of [18F]MR18445 in brain was rapid and high. No evidence of radiolabeled metabolites could be observed in the brain as late as 40 min after injection, despite the rapid appearance of metabolites in the plasma. However, neither phosphorimaging autoradiographic studies in rats nor PET experiments in baboons revealed specific binding of the radiotracer in brain, suggesting [18F]MR18445 is not suitable for 5-HT3 receptors PET studies.
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PMID:Synthesis and biological investigations of [18F]MR18445, a 5-HT3 receptor partial agonist. 968 Nov 44

The effect of a naturally occurring plant phenolic constituent (the acylphloroglucinol derivative, jensenone, derived from Eucalyptus jensenii) on the food intake of two folivorous marsupials, the common ringtail (Pseudocheirus peregrinus) and the common brushtail possum (Trichosurus vulpecula) was studied. When fed diets containing varying concentrations of jensenone, both species regulated their intake of jensenone so as not to exceed a ceiling intake. This ceiling was about twice as high for common ringtails as for common brushtails from northern Australia. Southern populations of common ringtails showed greatly reduced capacities to tolerate jensenone. When common brushtails were injected (0.5 mg.kg-0.75 body mass) with ondansetron (a selective antagonist of serotonin 5HT3 receptors), they ate significantly more jensenone than animals injected with physiological saline. The same pattern was observed when common ringtails were fed diets containing both jensenone and ondansetron (0.0035 mg.g-1 wet mass of diet). Ondansetron injection had no effect on food intake when the food did not contain jensenone while the addition of higher doses of ondansetron to diets of common ringtails very slightly reduced food intakes of a non-jensenone diet. When common brushtails were given 50 mg of jensenone by gastric lavage, their average subsequent intake of dietary jensenone matched the difference between the daily threshold and the dose given, although the response of individuals was highly variable. Lavage with water alone had no effect on subsequent jensenone intake compared with the pre-dose period. We interpret these results as evidence that the antifeedant effects of jensenone and related compounds are partly mediated by serotonin action on 5HT3 receptors most likely via "nausea" to condition a food aversion.
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PMID:Administration of a 5HT3 receptor antagonist increases the intake of diets containing Eucalyptus secondary metabolites by marsupials. 987 45

1. The involvement of pulmonary oedema produced by scorpion venom in augmenting a phenyldiguanide (PDG)-induced reflex response was evaluated in urethane-anaesthetized rats. 2. PDG-induced bradycardiac, hypotensive and apnoeic responses, expressed as time-response area, exhibited similarities before or after venom treatment. Hence, the time-response area of bradycardia was taken as a reflex parameter. Pulmonary oedema was determined by physical evaporation and histological methods. 3. Exposure to Indian red scorpion (Buthus tamulus, BT; i.v.) venom for 30 min increased the pulmonary water content (P < 0.05; Student's t test) and augmented the PDG-induced bradycardiac reflex response by more than 2 times (P < 0.001). The increase of pulmonary water content was maximal with 100 microg kg-1 of venom and the augmentation was maximal with 10 microg kg-1. In a separate series of experiments, the venom (100 microg kg-1)-induced pulmonary oedema was confirmed by histological and physical methods. In this group also, the venom augmented the reflex to the same magnitude. 4. Pulmonary oedema (physical and histological) and augmentation of the bradycardiac reflex response after BT venom (100 microg kg-1; i.v.) were absent in animals pretreated with aprotinin, a kallikrein-kinin inhibitor (6000 KIU; i. v.). 5. Ondansetron (10 microg kg-1; i.v.), a 5-HT3 receptor antagonist, failed to block the venom-induced pulmonary oedema (physical and histological) but blocked the venom-induced augmentation of the reflex. 6. The results of this study indicate that the venom-induced augmentation of the PDG reflex is associated with pulmonary oedema involving kinins utilizing 5-HT3 receptors.
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PMID:Pulmonary oedema produced by scorpion venom augments a phenyldiguanide-induced reflex response in anaesthetized rats. 1058 22

The effects of the receptor antagonists MDL 72222 (MDL, 5-HT3) and naltrindole (delta-opioid) on ethanol reward and its discrimination were examined in ethanol-preferring C57BL/6 (C57) mice. MDL attenuated lever responding for 12% ethanol delivered on a fixed-ratio 8 reinforcement schedule at a dose that did not influence responding for water reward, thus confirming a previous report that ICS 205-930 reduced ethanol reward for Long-Evans rats. Our study in combination with the reduced ethanol consumption reported for C57 mice injected with odansetron indicates that 5-HT3 receptor systems are involved in mediating behavior directed toward obtaining ethanol as well as its consumption. By attenuating the rewarding effects of ethanol or of ethanol conditioned cues (e.g., the operant environment), 5-HT3 antagonists may be useful in the treatment of alcohol abuse. The 5-HT3 antagonist effects in this study are comparable with the effects of naltrexone on ethanol reward in C57 mice, although higher doses were required to reduce operant responding for ethanol reward. In contrast to the 5-HT3 antagonist and naltrexone effects, naltrindole, an antagonist with greater specificity for the delta-opioid receptor, was without effect on ethanol reward. This result and recent reports for rats and monkeys suggests that the general antagonists might be more efficacious in attenuating ethanol reward. Both MDL and naltrindole produced only slight reductions in the ethanol discriminative cue, suggesting that the rewarding and discriminative effects of ethanol are not likely mediated by identical neural mechanisms as previously suggested.
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PMID:Delta-opioid and 5-HT3 receptor antagonist effects on ethanol reward and discrimination in C57BL/6 mice. 1063 48

The anti-emetic profile of the novel brain penetrant tachykinin NK1 receptor antagonist MK-0869 (L-754,030) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluor o)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine and its water soluble prodrug, L-758,298, has been examined against emesis induced by cisplatin in ferrets. In a 4 h observation period, MK-0869 and L-758,298 (3 mg/kg i.v. or p.o.) inhibited the emetic response to cisplatin (10 mg/kg i.v.). The anti-emetic protection afforded by MK-0869 (0.1 mg/kg i.v.) was enhanced by combined treatment with either dexamethasone (20 mg/kg i.v.) or the 5-HT3 receptor antagonist ondansetron (0.1 mg/kg i.v.). In a model of acute and delayed emesis, ferrets were dosed with cisplatin (5 mg/kg i.p.) and the retching and vomiting response recorded for 72 h. Pretreatment with MK-0869 (4-16 mg/kg p.o.) dose-dependently inhibited the emetic response to cisplatin. Once daily treatment with MK-0869 (2 and 4 mg/kg p.o.) completely prevented retching and vomiting in all ferrets tested. Further when daily dosing began at 24 h after cisplatin injection, when the acute phase of emesis had already become established, MK-0869 (4 mg/kg p.o. at 24 and 48 h after cisplatin) prevented retching and vomiting in three out of four ferrets. These data show that MK-0869 and its prodrug, L-758,298, have good activity against cisplatin-induced emesis in ferrets and provided a basis for the clinical testing of these agents for the treatment of emesis associated with cancer chemotherapy.
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PMID:The novel NK1 receptor antagonist MK-0869 (L-754,030) and its water soluble phosphoryl prodrug, L-758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets. 1072 86

5-hydroxytryptamine (5-HT ) is thought to be involved in a wide range of behavioral functions. Based on binding evidence, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), 1-(2,5-dimethoxy-4-indophenyl)-2-aminopropane (DOI), and m-chloro-phenyl-biguanide (m-CPBG) are selective 5-HT1a, 5-HT2, and 5-HT3 receptor agonists, respectively. The present study examined the effects of these 5-HT receptor agonists on operant behavior maintained on the differential reinforcement for low rate response 10-second (DRL 10-s) and 30-second (DRL 30-s) schedules of reinforcement. Water-deprived rats were trained to press a lever in response to DRL 10-s and DRL 30-s schedules. After a stable baseline was set, each subject was then repeatedly challenged using one drug with different doses through peripheral administration. The dose ranges were 0.025, 0.05, and 0.1 mg/kg (SC) for 8-OH-DPAT; 0.5, 1, and 2 mg/kg (SC) for DOI; and 1.3 and 9 mg/kg (IP) for m-CPBG. The overall results of the present work indicate that distinct profiles of operant response on DRL 10-s and DRL 30-s schedules were produced by 8-OH-DPAT, DOI, and, m-CPBG, based on quantitative and qualitative data analyses. All three 5-HT receptor agonists caused the number of responses to the DRL 10-s schedule to decrease significantly in a dose-related fashion. The operant performance on the DRL 10-s schedule was more sensitive to drug treatment than was that on the DRL 30-s schedule. Analyses of inter-response time (IRT) distributions revealed that different time bins were shifted by each of these three agents. The current data indicate that 8-OH-DPAT, DOI and m-CPBG can significantly alter operant response maintained on a DRL schedule. The distinct operant performance for each drug is believed to be derived from drug activation of its own specific 5-HT subtype receptors.
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PMID:Different effects of 5-HT receptor agonists on operant response in rats under DRL 10-s and DRL 30-s schedules. 1169 70

Nicotinic acetylcholine receptors are prototypes for the pharmaceutically important family of pentameric ligand-gated ion channels. Here we present atomic resolution structures of nicotine and carbamylcholine binding to AChBP, a water-soluble homolog of the ligand binding domain of nicotinic receptors and their family members, GABAA, GABAC, 5HT3 serotonin, and glycine receptors. Ligand binding is driven by enthalpy and is accompanied by conformational changes in the ligand binding site. Residues in the binding site contract around the ligand, with the largest movement in the C loop. As expected, the binding is characterized by substantial aromatic and hydrophobic contributions, but additionally there are close contacts between protein oxygens and positively charged groups in the ligands. The higher affinity of nicotine is due to a main chain hydrogen bond with the B loop and a closer packing of the aromatic groups. These structures will be useful tools for the development of new drugs involving nicotinic acetylcholine receptor-associated diseases.
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PMID:Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. 1504 15

Serotonin is known to inhibit food and water intake. However, the effect of its injection into nucleus caudatus on food and water intake is not known. In the present study, serotonin hydrochloride, buspirone (the serotonin 5-HT1A agonist) and ondensetron (the 5HT3 antagonist) were injected into nucleus caudatus through stereotaxically implanted cannulae in three different dosages (1, 2 and 5 microg) and their effects on 24 h food and water intake, and body weight were recorded. The injection of serotonin hydrochloride resulted in a dose- dependent decrease in food intake attaining maximum of 27.3% at 5 microg dose, whereas water intake and body weight were decreased 12% and 4.3% respectively only at the highest does. Buspirone elicited a dose dependent inhibition of food and water intake and body weight (22.3%, 19.8% and 5.1% respectively), whereas ondensetron elicited an increase in food and water intake (37.8% and 36.3% respectively) without significantly altering bodyweight. It was concluded that serotonin hydrochloride injected into nucleus caudatus inhibits food and water intake significantly. These effects are mediated via 5-HT1A and 5HT3 receptors. The effect of injections of 5-HT1A receptor agonist is more pronounced on water intake. The effect of injections of 5HT3 receptor antagonist is also more pronounced on water intake.
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PMID:Effects of injection of serotonin into nucleus caudatus on food and water intake and body weight in albino rats. 1590 52

The use of a recently proposed hydrophobic similarity index for the alignment of molecules and the prediction of their differences in biological activity is described. The hydrophobic similarity index exploits atomic contributions to the octanol/water transfer free energy, which are evaluated by means of the fractional partitioning scheme developed within the framework of the Miertus-Scrocco-Tomasi continuum model. Those contributions are used to define global and local measures of hydrophobic similarity. The suitability of this computational strategy is examined for two series of compounds (ACAT inhibitors and 5-HT3 receptor agonists), which are aligned to maximize the global hydrophobic similarity using a Monte Carlo-simulated protocol. Indeed, the concept of local hydrophobic similarity is used to explore structure-activity relationships in a series of COX-2 inhibitors. Inspection of the 3D distribution of hydrophobic/hydrophilic contributions in the aligned molecules is valuable to identify regions of very similar hydrophobicity, which can define pharmacophoric recognition patterns. Moreover, low similar regions permit to identify structural elements that modulate the differences in activity between molecules. Finally, the quantitative relationships found between the pharmacological activity and the hydrophobic similarity index points out that not only the global hydrophobicity, but its 3D distribution, is important to gain insight into the activity of molecules.
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PMID:Hydrophobic molecular similarity from MST fractional contributions to the octanol/water partition coefficient. 1623 Dec


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