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)

Until now, the only well documented, fast excitatory neurotransmitter in the brain has been glutamate. Although there is evidence for adenosine 5'-triphosphate (ATP) acting as a transmitter in the peripheral nervous system, suggestions for such a role in the central nervous system have so far not been supported by any direct evidence. Here we report the recording of evoked and miniature synaptic currents in the rat medial habenula. The fast rise time of the currents showed that they were mediated by a ligand-activated ion channel rather than a second messenger system, thus limiting the known transmitter candidates. Evidence was found for the presence on the cells of glutamate, gamma-aminobutyric acid, acetylcholine and ATP receptors, but not for 5-hydroxytryptamine (5HT3) or glycine receptors. The evoked currents were unaffected by blockers of glutamate, gamma-aminobutyric acid or acetylcholine receptors but were blocked by the ATP receptor-blocker, suramin and the desensitizing ATP receptor-agonist alpha,beta-methylene-ATP. Our evidence identifies for the first time synaptic currents in the brain, mediated directly by ATP receptors.
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PMID:ATP receptor-mediated synaptic currents in the central nervous system. 135 56

The 5-hydroxytryptamine (5-HT)3 receptor blocking properties of YM060, [(R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H- benzimidazole hydrochloride], were examined by electrophysiological and radioligand binding studies. Results were compared with those for ondansetron, granisetron and the enantiomer (S-form) of YM060. 5-HT and 2-methyl-5-HT, a selective 5-HT3 receptor agonist, induced dose-dependent depolarizations of rabbit nodose ganglion with ED50 values of 24.0 (19.9-29.1) and 40.1 (30.9-52.1) nmol, respectively (geometric mean, 95% CL). YM060, ondansetron, granisetron and the S-form dose-dependently inhibited 5-HT-induced depolarizations with IC50 values of 3.85 (2.47-5.98), 1.55 (1.26-1.91), 1.45 (1.18-1.79) and 13.5 (11.2-16.2) nM, respectively. Methysergide, a 5-HT1-like and 5-HT2 receptor antagonist, at a concentration of 10(-5) M had no effect on responses to 5-HT. YM060 up to 10(-5) M produced no significant depression of depolarizing responses to 1,1-dimethyl-4-phenylpiperazinium iodide and gamma-aminobutyric acid. YM060, ondansetron, granisetron and the S-form displaced specific binding of [3H]GR65630 to N1E-115 neuroblastoma cell membranes with Ki values of 0.091 (0.086-0.097), 7.03 (5.96-8.01), 2.02 (1.74-2.30) and 10.3 (9.96-10.6) nM, respectively. These results show that YM060, compared with ondansetron and granisetron, has considerably higher affinity for 5-HT3 receptors in N1E-115 cells and slightly less potent 5-HT3 receptor antagonistic activity in rabbit nodose ganglion. Moreover, the isomeric activity ratio (R-form/S-form) was approximately 112 in N1E-115 cells and no greater than 4 in the ganglion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of YM060, a potent and selective 5-hydroxytryptamine3 receptor antagonist, in rabbit nodose ganglion and N1E-115 neuroblastoma cells. 146 24

1. Tritiated derivatives of the potent and selective 5-HT3 receptor antagonists GR65630 and LY278584 were used to identify 5-HT3 recognition sites in the rat gastrointestinal tract. 2. Binding studies were carried out in homogenates of the rat oesophagus, the cardia, fundus, body and antrum of the stomach, regions of the small intestine, caecum and large intestine. The specific binding of a single concentration of GR65630 (0.5 nM) defined by granisetron (10 microM) in these areas indicated that the density of 5-HT3 recognition sites varied from 2.4 +/- 1.0 to 10.1 +/- 1.0 fmol mg-1 protein. 3. Saturable binding of [3H]-GR65630 could only be demonstrated in the terminal regions of the small intestine (Bmax in the range of 13.83 +/- 4.54-21.19 +/- 0.89 fmol mg-1 protein; mean +/- s.e. mean) and of high affinity (Kd in the range of 0.42 +/- 0.18-0.79 +/- 0.24 nM). Use of [3H]-LY278584 revealed a similar binding density (Bmax 19.54 +/- 0.26 fmol mg-1 protein) and affinity (Kd 1.04 +/- 0.07 nM) in the terminal small intestine. 4. Binding of [3H]-GR65630 and [3H]-LY278584 to the terminal region of the small intestine was inhibited by 5-HT3 receptor ligands ondansetron and S-zacopride (and 5-hydroxytryptamine), but not by 5-HT1, 5-HT2, catecholamine, gamma-aminobutyric acid and opioid receptor ligands. 5. These data demonstrate that there are regional variations in the density of 5-HT3 recognition sites within the rat gastrointestinal tract. Such data are relevant to the potential use of 5-HT3 receptor ligands to modify secretory and contraction responses in the gastrointestinal system.
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PMID:Identification and distribution of 5-HT3 recognition sites in the rat gastrointestinal tract. 150 52

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

The effects of 5-hydroxytryptamine (5-HT) on the release of gamma-aminobutyric acid (GABA) were examined in the longitudinal muscle-myenteric plexus (LM-MP) preparation of guinea-pig ileum. 5-HT increased the spontaneous release and inhibited the electrically-evoked release of [3H]-GABA. The 5-HT-evoked release was Ca2+-dependent and tetrodotoxin-sensitive, and was antagonized by (3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester (ICS 205-930), but not by methysergide and ketanserin. The inhibitory effect of 5-HT was antagonized by methysergide, but not by ketanserin and ICS 205-930. 8-Hydroxy-2-(di-n-propylamino)tetralin mimicked the inhibitory effect of 5-HT. Thus, 5-HT may exert an excitatory effect on the enteric GABAergic neurone via the 5-HT3 receptor and an inhibitory effect via the 5-HT1A receptor.
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PMID:Dual effects of 5-hydroxytryptamine on the release of gamma-aminobutyric acid from myenteric neurones of the guinea-pig ileum. 281 20

In this microiontophoretic study delta 2,1,2,4-triazolin-5-one [1,3-(4-m-chlorophenyl-1-piperazinyl) propyl]-3,4-diethyl hydrochloride (etoperidone, ET, Staff) was applied on rat brainstem (medullary-pontine) reticular neurones to verify its effects on the spontaneous firing and neuronal responses to administrations of 5-hydroxytryptamine (5HT), noradrenaline (norepinephrine, NA), acetylcholine (ACh) and gamma-aminobutyric acid (GABA). ET was able to depress the spontaneous firing by a dose-dependent (for a current intensity range of 40-70 nA) local anaesthetic-like mechanism. At 75 nA a reduction in the amplitude of the action potentials occurred, partially due to a non-specific effect of ET. Repeated administrations of ET caused a progressive neuronal desensitization to the inhibition (tachyphylaxis). All the excitatory neuronal responses to ACh, 5HT and NA (interpreted respectively as nicotinic cholinergic, alpha-noradrenergic, 5HT3-serotonergic) were blocked by ET, while the inhibitory responses to 5HT, NA and GABA were not affected. The analysis of the results leads to postulate for ET a postsynaptic mechanism of action.
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PMID:Inhibitory effects of etoperidone on the spontaneous activity of brainstem neurones and their excitatory responses to some putative transmitters. 288 58

In this study, we examined the response of spontaneously active as well as quiescent cells (L-glutamate-activated) in the rat medial prefrontal cortex (mPFc) to the iontophoresis of 2-methylserotonin (2-Me-5-HT, 5-HT3 receptor agonist), (+/-)-2,5-dimethoxy-(4-iodo-phenyl)-2-aminopropane (DOI, 5-HT2A,2C receptor agonist), 8-hydroxy-N,N-di-propylamino tetralin (8-OH-DPAT, 5-HT1A receptor agonist) and gamma-aminobutyric acid (GABA, a non-selective GABA receptor agonist) after the intracerebral administration of pertussis toxin, an inactivator of the Gi/o protein. This was accomplished using the techniques of extracellular single cell recording and iontophoresis. The administration of pertussis toxin (0.5 microgram, 24 hours before the experiment) into the mPFc did not alter the response of mPFc cells to the iontophoresis of DOI, 2-Me-5HT or GABA compared to saline treated controls. However, the response of mPFc cells to the iontophoresis of 8-OH-DPAT was significantly attenuated in the animals pretreated with pertussis toxin compared to controls. These results suggest that the 5-HT1A but not 5-HT2A,2C or 5-HT3 receptor is coupled to the Gi/o protein.
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PMID:Effect of pertussis toxin on the response of rat medial prefrontal cortex cells to the iontophoresis of serotonin receptor agonists. 786 72

This paper describes pharmacological treatments that can reverse the anxiogenic response detected in animal tests when rats are withdrawn from chronic treatment with diazepam. Concurrent treatment with the calcium channel antagonist verapamil prevented this withdrawal response and the benzodiazepine-receptor antagonist flumazenil reversed the anxiogenic response and restored the system to a drug-naive state. Other treatments that reversed the anxiogenic response were the GABAB agonist baclofen, the 5-HT1A receptor agonist buspirone, and the 5-HT3 receptor antagonist (R,S)-zacopride (GABA = gamma-aminobutyric acid; 5-HT = 5-hydroxytryptamine). Both the enantiomers of zacopride contributed to this reversal. These behavioural reversals are interpreted in the light of biochemical studies showing increased 45Ca2+ flux and [3H]5-HT release from the hippocampus, during benzodiazepine withdrawal (Fig. 1).
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PMID:Benzodiazepine withdrawal: behavioural pharmacology and neurochemical changes. 791 Jul 43

Intra- and extracellular recordings from the in vitro rat hippocampal slice preparation have been used to investigate the influence of serotoninergic, adrenergic and cholinergic receptor antagonists on the excitability of CA1 pyramidal neurones. The serotonin receptor antagonist 4-amino-N-(1-azabicyclo[2.2.2]oct-3yl)-5-chloro-2- methoxybenzamide(E)-2-butenedioate (zacopride, 100 microM) produced multiple population spikes on the orthodromically evoked field potential, in contrast to the lack of effect of another serotonin antagonist 1 alpha H,3 alpha,5 alpha H-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222, 30 microM), as well as the cholinergic antagonists atropine (10 microM) and hexamethonium (100 microM) and the noradrenergic antagonist atenolol (10 microM). Monosynaptic inhibitory postsynaptic potentials (IPSPs) recorded in the presence of the glutamatergic antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) and ketamine (50 microM) were recorded from CA1 pyramidal neurones. Zacopride (100 microM) and MDL 72222 (30 microM) both reduced the isolated IPSP to 54 +/- 9% (n = 8) and 78 +/- 4% (n = 3), respectively. Neither of the cholinergic antagonists had any effect, while atenolol reduced the IPSP to 87 +/- 3% (n = 7) of the control IPSP. We propose that the difference in action of zacopride and MDL 72222 on the field potentials is due to zacopride activating postsynaptic 5HT4 receptors on the pyramidal neurone, thereby reducing a Ca(2+)-activated K(+)-conductance. This, in combination with a 5HT3 receptor-mediated reduction in gamma-aminobutyric acid (GABA)-ergic inhibition, leads to an increase in pyramidal cell excitability evident as epileptic field potentials.
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PMID:Serotoninergic modulation of excitability in area CA1 of the in vitro rat hippocampus. 857

The aim of the study was to further characterize the pharmacological properties of 5-hydroxytryptamine (5-HT)3-like receptors in the rat medial prefrontal cortex (mPFC) using combinations of biochemical and electrophysiological approaches. Phenylbiguanide (PBG) and three chlorinated derivatives, ortho-chloro-PBG (oCPBG), meta-chloro-PBG (mCPBG) and para-chloro-PBG (pCPBG), dose-dependently stimulated phosphoionositide (PI) turnover in fronto-cingulate cortical slices. All three chloro-isomers of PBG were equipotent in stimulating PI turnover. SR 57227A ((4-amino)-(6-chloro-2-pyridyl) L-piperidine hydrochloride, a novel compound with high affinity and selectivity for peripheral and central 5-HT3 receptors) dose-dependently stimulated PI turnover in fronto-cingulate cortical slices. The rank order of potency of all the 5-HT3 receptor agonists tested in the PI assay as compared to 5-HT was: 5-HT > 2-Me-5-HT > SR57227A > PBG = mCPBG = oCPBG = mCPBG. 5-HT and 5-HT receptor agonists depressed the firing rate of both spontaneously active and glutamate-activated quiescent mPFC cells in a current (dose)-dependent fashion. The rank order of effectiveness of these compounds was: 5-HT > SR57227A = 2-Me-5-HT = mCPBG = oCPBG = pCPBG = PBG. Unlike its action on the 5-HT3 receptors in the periphery or cultured cell lines, D-tubocurarine chloride appears to be non-specific in blocking the depressant action of 2-Me-5-HT, gamma-aminobutyric acid and dopamine. Our results combined support the view that the pharmacological properties of 5-HT3-like receptors in the mPFC are not identical to those located in peripheral tissues and in cultured cell lines.
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PMID:5-HT3-like receptors in the rat medial prefrontal cortex: further pharmacological characterization. 889 Dec 44


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