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)

Using the curve-shift method, we studied the effects of four doses (0.003, 0.03, 0.3 and 3 mg/kg, s.c.) of granisetron (endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1H-indazole-3- carboxamide hydrochloride), a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist, on the potentiation of brain stimulation reward by microinjection of 2.5 micrograms/0.25 microliters of morphine sulphate (7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol sulphate) into the ventral tegmental area. As previously reported, morphine produced a significant reduction in reward threshold without altering maximal rates of responding. Granisetron attenuated the potentiating effect of morphine at the highest dose and failed to alter reward threshold or maximal rates of responding when given alone, except at the lowest dose where a small and statistically significant increase in threshold was found. These results provide additional evidence that 5-HT3 receptor antagonists may reduce the rewarding effect of opiates and do not impair the ability to produce operant responses. The weak attenuation observed with granisetron alone suggests that 5-HT3 receptors are unlikely to constitute an important influence on the directly stimulated reward-relevant pathway(s).
Eur J Pharmacol 1995 Dec 20
PMID:Effects of granisetron, a 5-HT3 receptor antagonist, on morphine-induced potentiation of brain stimulation reward. 899

Autoradiographic binding studies using the 5-HT3 (5-hydroxytryptamine3) receptor radioligand, [3H]-(S)-zacopride (0.5 nM), identified a heterogeneous distribution of specific binding sites (defined by granisetron, 1 microM) throughout the human brain. Highest radiolabelled 5-HT3 receptor densities were detected in discrete nuclei within the brainstem (nucleus tractus solitarius, area postrema, spinal trigeminal nerve nucleus; 50-200 fmol/mg tissue equivalent) with more modest levels of expression in the forebrain (e.g. hippocampus, nucleus accumbens, putamen, caudate; 4-17 fmol/mg tissue equivalent). Within the hippocampal formation, radiolabelled 5-HT3 receptors were differentially distributed with highest levels in the granule cell layer of the dentate gyrus. Saturation studies with [3H]-(S)-zacopride (0.05-16 nM; non-specific binding defined by granisetron, 10 microM) binding to homogenates of human putamen indicated that [3H]-(S)-zacopride (0.05-16 nM; non-specific binding defined by granisetron, 10 microM) binding to homogenates of human putamen indicated that [3H]-(S)-zacopride labelled an apparently homogenous population of binding sites (Bmax = 72 + 7 fmol mg-1 protein, pKd = 8.69 +/- 0.09, Hill coefficient = 0.99 +/- 0.06, mean +/- SEM, n = 4). The pharmacological profile of [3H]-(S)-zacopride binding to homogenates of putamen indicated the selective labelling of the human variant of the 5-HT3 receptor. The marked differences, however, in the pharmacology (e.g. low affinity for D-tubocurarine) and relative distribution (e.g. presence of 5-HT3 receptors in the human extrapyramidal system) of 5-HT3 receptors in the human forebrain when compared with other species further necessitates caution in predicting clinical responses based on data generated in animal models of disease.
J Neurol Sci 1996 Dec
PMID:Autoradiographic distribution of [3H]-(S)-zacopride-labelled 5-HT3 receptors in human brain. 899 13

Volume-sensitive and chemosensitive cardiopulmonary reflexes modulate volume homeostasis via renal sympathetic nerve activity (RSNA). Blunting of volume-sensitive cardiopulmonary reflexes is associated with volume retention, e.g., in hypertension, whereas the role of chemosensitive cardiopulmonary reflexes is largely unknown. To elucidate the possible role of chemosensitive cardiopulmonary reflexes in control of volume homeostasis, we investigated whether subthreshold stimulation of 5-HT3 receptors modulates the control of RSNA by volume-sensitive cardiopulmonary reflexes or the arterial baroreceptor reflex in rats. Phenyl biguanide (PBG) was infused intravenously to stimulate 5-HT3 receptors. Higher doses of PBG lowered RSNA, but a dose of 6 micrograms/min, given as a background infusion throughout the experiment, did not change arterial pressure, heart rate (HR), or RSNA. Ten minutes after beginning the 6 micrograms/min PBG infusion, a 15-min volume expansion (0.9% saline, 5 or 10% body weight) was started to stimulate volume-sensitive cardiopulmonary reflexes. In separate experiments, 5-min ramp infusions of methoxamine and nitroglycerin to stimulate the arterial baroreceptor reflex (evaluated by a 4-parameter logistic regression) were performed 15 min after beginning the PBG background infusion (6 micrograms/min). During PBG infusion, the RSNA responses to volume expansions were significantly impaired (5% body weight: PBG -6 +/- 6%, n = 7 vs. control -39 +/- 9%, n = 6, P < 0.001; 10% body weight: PBG -33 +/- 6%, n = 8 vs. control -52 +/- 5%, n = 7, P < 0.05). The 5-HT3 receptor antagonist odansetron (GR-38032F) abolished these effects of PBG. The maximum HR gain of the arterial baroreceptor reflex was impaired but the arterial baroreceptor control of RSNA was unaffected by PBG background infusion. We conclude that 5-HT3-serotonergic cardiopulmonary chemoreceptors blunt the RSNA decrease to volume loading. This mechanism may facilitate volume retention when cardiac serotonin is increased.
Am J Physiol 1996 Dec
PMID:Subthreshold stimulation of a serotonin 5-HT3 reflex attenuates cardiovascular reflexes. 899 45

We investigated the participation of cholinergic and tachykininergic mechanisms in 5-hydroxytryptamine (5-HT)-induced contraction via 5-HT3 receptors in longitudinal and circular muscle of guinea-pig isolated distal colon. 5-HT produced concentration-dependent contractile responses in longitudinal and circular muscle. The 5-HT3 receptor antagonists ramosetron (YM060) ((R)-5-[(1-methyl-3-indolyl) carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride), YM114 (KAE-393) ((R)-5-[(2,3-dihydro-1-indolyl)carbonyl]-4,5,6,7-tetrahydro-1 H-benzimidazole hydrochloride), ondansetron and granisetron produced a concentration-dependent shift to the right of the 5-HT concentration-response curves in both muscle. However, methysergide and GR113808 had no effect on 5-HT-induced contraction. In the longitudinal muscle, atropine concentration-dependently inhibited 5-HT-induced contraction, and tetrodotoxin abolished it. (+/-)-CP96,345 attenuated the contractile response to 5-HT, but (+/-)-SR48,968 had no effect on it. In the presence of atropine, (+/-)-CP96,345 completely blocked 5-HT-induced contraction. In the circular muscle, atropine had no effect on the contractile response to 5-HT, whereas tetrodotoxin completely suppressed it. The contractile response elicited by 5-HT in the circular muscle was not inhibited by either (+/-)-CP96,345, (+/-)-SR48,968, devazepide, L-365,260 or indomethacin. It is suggested that 5-HT acts via 5-HT3 receptors to release acetylcholine and substance P, which in turn are responsible for contraction of the longitudinal muscle. In the circular muscle, as in the longitudinal muscle, 5-HT-induced contraction is mediated by the 5-HT3 receptor. Unlike the case in longitudinal muscle, however, this contraction involves neither cholinergic nor tachykininergic transmission. It is also suggested that neither cholecystokinin (CCK) nor prostaglandins participate in 5-HT3 receptor-mediated contraction in circular muscle.
Eur J Pharmacol 1996 Dec 19
PMID:Investigation of 5-HT3 receptor-mediated contraction in guinea-pig distal colon. 899 21

Subcutaneous administration of granisetron (BRL 43694, endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl-1 H-indazole-3-carboxamide) and zacopride (4-amino-N-(1-azabicyclo[2.2.2.]oct-3-yl)-5-chloro-2-methoxybenzamide), two 5-HT3 receptor antagonists, at doses ranging from 3 to 1000 micrograms/kg, inhibited abdominal contractions induced by distension (30 mmHg, 10 min) of irritated colon (0.6% acetic acid) in conscious rats with a bell-shaped dose-response curve. The ED50 of granisetron and zacopride were 17.6 and 8.2 micrograms/kg, respectively. In contrast, both tropisetron (ICS 205-930, (3-a-tropanyl)t-indole-3-carboxylic ester) and ondansetron (GR38032F, 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1 H-imidazol-1-yl)methyl]-4 H-carbazol-4-one hydrocloride dihydrate) were inactive in this model. These data further support the concept of a heterogeneity in the potency of 5-HT3 receptor antagonists in modulating visceral hypersensitivity in conscious rats. This finding is in agreement with a reported efficacy of granisetron but not of ondansetron in patients with irritable bowel syndrome.
Eur J Pharmacol 1996 Dec 27
PMID:Response heterogeneity of 5-HT3 receptor antagonists in a rat visceral hypersensitivity model. 900 25

The effects of whole-body gamma-radiation (10 Gy) on intestinal motor activity was examined in the small and large intestine of the guinea pig 18 hr post irradiation. Neurally mediated relaxations of isolated gut bath preparations were generally unaffected. However, the contractile responses to direct smooth muscle stimulation with the cholinergic muscarinic agonist carbachol or ganglionic stimulation of intrinsic cholinergic motor neurones were significantly increased in the duodenum and colon but not the jejunum. This increased sensitivity to cholinergic stimulation was reflected in an increased contractility and a shift in the concentration-response curves for carbachol. The specificity of radiation actions for cholinergic mediated contractions was further supported by the observation that histamine-evoked contractions were unaffected. In a second series of experiments we examined the effects of gamma-radiation on the rate of pellet expulsion from freshly excised colons. Both colons from irradiated animals and nonirradiated colons exposed to carbachol showed significantly faster rates of pellet expulsion, indicative of increased propulsive motility. Pretreatment of animals with 0.5 mg/kg sc of the 5HT3 receptor antagonist Granisetron prevented the effect of radiation and reduced the pellet expulsion rate to below normal. These results indicate that gastrointestinal motility disturbances seen in organ-bath preparations of the intestine from rats exposed to whole-body gamma-radiation may be related to an increased sensitivity of the cholinergic muscarinic system.
Dig Dis Sci 1996 Dec
PMID:The effects of gamma-radiation on intestinal motor activity and faecal pellet expulsion in the guinea pig. 901 34

Substantial evidence indicates that serotonin receptors are involved in the regulation of acetylcholine release in CNS regions important to mnemonic processes, and may thus be exploited pharmacologically as targets for memory improvement. In the present study, the (R) and (S) isomers of a potent serotonin (5-HT3) receptor ligand, RS-56812 were evaluated for potential memory effects in five macaques trained to perform a delayed matching-to-sample (DMTS) task. While both isomers enhanced certain aspects of task performance, the (R) isomer produced more systematic improvements. This differential sensitivity to the isomers in regard to DMTS performance appears to parallel the higher 5-HT3 receptor affinity of the R enanantiomer. The results are consistent with a potential therapeutic role for RS-56812 in disorders involving cognitive decline.
Neuroreport 1996 Dec 20
PMID:The 5-HT3 receptor antagonist, RS-56812, enhances delayed matching performance in monkeys. 905 51

Chemotherapy-induced nausea and vomiting, two of the most distressing side-effects of cancer chemotherapy, have been the subject of a number of fundamental and clinical investigations. These have led to the development of a novel class of antiemetic agents, the 5-HT3 receptor antagonists. The pathophysiology of the emetic reflex and the clinical management of emesis are very complicated. Two experimental preclinical animal models are available (ferret and dog) and are particularly used to assess monochemotherapy as a single dose. Results are fairly good for acute nausea and vomiting. However, no optional animal model is available for the assessment of delayed and anticipated emesis. The clinical settings are so complex and variable that they preclude the development of an adequate model in all cases. It is also impossible to carry out clinical studies to assess each issue. Management of nausea and vomiting depends on the analysis by the physician of individual and drug-related parameters and on his own expertise. Scores can be assigned to each parameter and a decision tree can be elaborated to help the decision and improve the management of patients. The first goal is to obtain an optimal control of emesis from the very first cycle of chemotherapy in order to ensure good control during subsequent cycles.
Bull Cancer 1996 Dec
PMID:[Chemotherapy-induced nausea and vomiting: from experimentation to experience]. 911 65

The effects of ondansetron, a highly potent and selective 5-HT3 receptor antagonist, in the prevention of tolerance to and dependence on morphine were studied in mice using a 9-day schedule. Chronic administration of morphine (10 mg/kg i.p. twice daily for 9 days) produced tolerance to the analgesic effects and animals showed withdrawal jumps on day 10 when challenged with naloxone (2 mg/kg). Chronic treatment with ondansetron (0.01 and 0.1 mg/kg) followed by saline on days 1-9 failed to produce any significant change in tail-flick latency in the saline-pretreated group. Repeated administration of ondansetron (0.01 and 0.1 mg/kg) for 9 days, however, attenuated the development of tolerance to the analgesic effect of morphine (10 mg/kg). The higher dose of ondansetron (0.1 mg/kg) also suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg)-precipitated withdrawal on day 10 of testing.
Methods Find Exp Clin Pharmacol 1996 Dec
PMID:Prevention of morphine discontinuation phenomenon in mice by ondansetron, a selective 5-HT3 antagonist. 912 Dec 24

Pentagastrin, a cholecystokinin (CCK) agonist, produces anxiety and panic in patients with panic disorder and social phobia. Preclinical data suggests that pentagastrin-induced anxiogenesis may be mediated via 5-HT3 receptors. In the present study, 14 patients with panic disorder or social phobia underwent pharmacological challenge in three conditions: (1) pretreatment with saline followed by pentagastrin infusion; (2) pretreatment with ondansetron followed by pentagastrin infusion; and (3) pretreatment with saline followed by saline infusion. As expected, pentagastrin administration led to increased anxiety, physical symptoms of panic attacks, pulse, plasma adrenocorticotropic hormone (ACTH), and cortisol. Pentagastrin's behavioral effects were not blocked by ondansetron, and in fact, tended to be exaggerated. Ondansetron pretreatment did not alter the pentagastrin-induced cortisol increase but significantly prolonged the pentagastrin-induced increase in ACTH. These findings suggest that pentagastrin's behavioral effects are not mediated by 5HT3 receptors. Mechanisms by which peripherally administered CCK agonists lead to anxiety remain to be elucidated.
Neuropsychopharmacology 1997 Dec
PMID:Effects of the 5-HT3 antagonist, ondansetron, on the behavioral and physiological effects of pentagastrin in patients with panic disorder and social phobia. 939 24


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