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)

Imidazoline binding sites are now generally accepted as being receptors. Despite this acceptance, the molecular structure and signal transduction mechanisms of these receptors are still poorly understood. The I1-imidazoline binding site (I1-receptor) is localized to the plasma membrane, but it is not clear if this represents a conventional receptor. It is also not clear if there are multiple forms of the I1-receptor. The signal transduction mechanisms of I1-receptors are similarly unclear, but much progress has been made. Evidence clearly indicates that ligands with high affinity for I1-receptors stimulate a novel signal transduction pathway, phosphatidylcholine-selective phospholipase C, in the rat adrenal medullary tumor cell line PC-12. However, this may not be the case in all cell types as microphysiometry, a novel technique for determining cellular activation, could not detect receptor activation in cultured bovine adrenal medullary cells exposed to a number of imidazolines considered to be agonists at the I1-receptor. This suggests that there is no I1-receptor-mediated stimulation of phosphatidylcholine-specific phospholipase C in these cells. By contrast, nicotine-stimulated increases in ion entry were blocked by clonidine. Ion channels have been suggested as another possible I1-imidazoline "receptor" family and may represent the low affinity I1-receptor. I1-Receptor ligands can be shown to bind to, or block, the following members of the ligand-gated ion channel super family, the 5HT3, K+ATP, NMDA, and nicotinic acetylcholine receptors. The site of action appears to be the phencyclidine binding site in these channels, but other possibilities cannot be excluded. Molecular modeling suggests that I1-receptor-selective ligands share a common three-dimensional structure with phencyclidine, providing a basis for these actions. This suggests that a phencyclidine-binding site motif may represent a novel site of action for I1-receptor ligands and that searches for receptors based on this motif may reveal novel imidazoline "receptors."
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PMID:Novel targets and techniques in imidazoline receptor research. 1041 31

The possible participation of glutamate and NO/cGMP in the pressor response to 5-HT3 receptor activation in the nucleus tractus solitarii (NTS) was investigated using selective antagonists in urethane-anaesthetized rats. Intra-NTS administration of NMDA and non-NMDA receptor antagonists, but not metabotropic glutamate receptor antagonists, markedly reduced (70%) the increase in blood pressure caused by local application of the potent 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide. The 5-HT3 receptor-mediated pressor response was also significantly attenuated by the local blockade of nitric oxide synthase and soluble guanylyl cyclase. These data suggest that ionotropic glutamate receptors and the associated NO/cGMP transduction mechanism contribute downstream to the pressor effect elicited by 5-HT3 receptor stimulation in the NTS.
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PMID:Glutamate and NO mediation of the pressor response to 5-HT3 receptor stimulation in the nucleus tractus solitarii. 1199 97

Whole-cell voltage-clamp recordings were performed to investigate the serotonergic modulation of neurotransmitter release onto rat area postrema neurons in vitro. The bath application of serotonin (5-HT; 50 microM) or phenylbiguanide (PBA; 50 microM), a potent 5-HT3 receptor agonist, increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) or miniature EPSCs (mEPSCs) in 35 of 83 neurons (42%). These increases occurred in all electrophysiological cell classes. No cells exhibited a decrease in EPSC frequency. The majority of responding cells showed no inward currents during the application of serotonergic agonists (n = 34/35). However, the amplitude of mEPSCs was increased in 11/11 cells with 5-HT or 3/11 cells with PBA. ICS-205,930, a potent 5-HT3 receptor antagonist, markedly suppressed the 5-HT-induced facilitation of sEPSCs (n = 5) or mEPSCs (n = 5). An increase in the frequency of mEPSCs after PBA exposure was found, even with media containing Cd2+ (50 microM) or zero Ca2+. mEPSCs and evoked EPSCs were completely blocked in media containing the non-NMDA ionotropic receptor antagonist, CNQX (10 microM), indicating that EPSCs were glutamate events. These results suggest that glutamate release is increased in the area postrema by presynaptic 5-HT3 receptor activation. Furthermore, we present evidence that 5-HT3 receptor activation may be able to directly release glutamate from terminals, bypassing a requirement for voltage-dependent calcium entry into terminals. Such a mechanism may contribute to the chemosensitive function of area postrema neurons.
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PMID:Activation of presynaptic 5-HT3 receptors facilitates glutamatergic synaptic inputs to area postrema neurons in rat brain slices. 1560 21

Brainstem 5-hydroxytryptamine (5-HT, serotonin)-containing neurones modulate cardiovascular reflex responses but the differing roles of the many 5-HT receptors have not been thoroughly investigated. The present experiments on anaesthetized rats investigated the role of 5-HT3 receptors in modulating vagal afferent evoked activity of nucleus tractus solitarius (NTS) neurones. Recordings were made from 301 NTS neurones receiving an input at long (> 20 ms) minimum onset latency from stimulation of the vagus nerve. These included 140 neurones excited by activating non-myelinated cardiopulmonary afferents by right atrial injection of phenylbiguanide (PBG). Ionophoretic application of PBG, a highly selective 5-HT3 receptor agonist, significantly increased activity (from 2.4 +/- 0.4 to 5.5 +/- 0.8 spikes s(-1)) in 96 of 106 neurones tested and in all 17 neurones tested the increase in activity (3.4 +/- 1.1 to 7.0 +/- 1.9 spikes s(-1)) was significantly attenuated (3.0 +/- 0.9 to 3.8 +/- 1.1 spikes s(-1)) by the selective 5-HT3 receptor antagonist granisetron. Ionophoretic application of PBG potentiated responses to vagus nerve and cardiopulmonary afferent stimulation, and granisetron significantly attenuated this cardiopulmonary input (20.2 +/- 5.7 to 10.6 +/- 4.1 spikes burst(-1)) in 9 of 10 neurones tested. Ionophoretic application of AMPA and NMDA also excited NTS neurones and these excitations could be selectively antagonized by the non-NMDA and NMDA receptor antagonists DNQX and AP-5, respectively. At these selective currents, DNQX and AP-5 also attenuated PBG- and cardiopulmonary input-evoked increases in NTS activity. These data are consistent with the hypothesis that vagal inputs, including non-myelinated cardiopulmonary inputs to the NTS, utilize a 5-HT-containing pathway which activates 5-HT3 receptors. This excitatory response to 5-HT3 receptor activation may be partly a direct postsynaptic action but part may also be due to facilitation of the release of glutamate which in turn acts on either non-NMDA or NMDA receptors to evoke excitation.
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PMID:The role of central 5-HT3 receptors in vagal reflex inputs to neurones in the nucleus tractus solitarius of anaesthetized rats. 1590 16

Recent literature and our previous observations indicated the presence of both NMDA and serotonin type 3 receptors in human platelets with very similar ionic currents to that of cultured mammalian neuronal receptors. Baseline electrophysiological data shows similar profile for platelets from both normal and schizophrenic subjects, whereas serotonin receptor studies exhibited the presence of 5-hydroxytryptamine type-3 (5-HT3) currents in both normal and schizophrenic platelets significantly different from each other. The two major differences observed were: first, 5-HT3 receptors present in the platelets of schizophrenic patients were four times more sensitive to serotonin than those present in the platelets of normal subjects and, second, that D: -serine in micro molar concentrations dampens this effect in platelets from schizophrenic patients but increases the sensitivity of serotonin for platelet 5-HT3 receptors of normal subjects. Patch clamp technique was used to measure the whole cell currents passing through serotonin receptors in these two types of human platelets. The currents were found to be 5-HT3 receptor currents as they were abolished by 10 microM D-tubocurarine. Similarly, micromolar concentrations of D: -serine increased the sensitivity of 5HT3 receptor currents in the normal human platelets but decreased it in the platelets of the schizophrenic patients. This effect was reversed when D-amino acid oxidase (0.3 microM) was co applied with 100 microM of D-serine, raising the possibility that D-serine by itself may act as a modulator for platelet 5-HT3 receptor channel currents. These observations raised exciting new questions about the role of platelet serotonin receptors and their regulation by D-serine.
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PMID:Effect of D-serine on the serotonin receptors of human platelets. 1668 Apr 25

Cocaine abusers remain vulnerable to drug craving and relapse for many years after abstinence is achieved. We have recently shown that ondansetron (a 5-HT3 receptor antagonist) given 3.5 h after each daily cocaine injection reverses previously established behavioral sensitization. The purpose of the present investigation was two-fold. First, as cocaine cannot be used as therapy, we examined whether pergolide (a D1/D2 receptor agonist with reduced abuse potential) and ondansetron could reverse behavioral sensitization. Second, we investigated whether these behavioral changes were associated with parallel alterations in expression levels and/or phosphorylation changes in the NR2B and GluR1 subunits of the respective NMDA and AMPA receptors. Rats were injected for 5 consecutive days with cocaine or saline followed by 9 days of withdrawal. Starting on withdrawal day 10, animals were given vehicle, pergolide/saline, or pergolide/ondansetron for 5 consecutive days. Following a second 9-day period of withdrawal, all animals were challenged with cocaine for assessment of behavioral sensitization and tissues were collected on the following day for Western blot. Sensitization was associated with increased NR2B expression in the accumbens (NAc) shell and decreased Tyr1472 phosphorylation in the NAc core, as well as increased Ser845 phosphorylation of the GluR1 subunit in prefrontal cortex, NAc core, and shell. Pergolide/ondansetron treatment, but not pergolide alone, consistently reversed both the behavioral sensitization and the associated changes in the NMDA and AMPA receptor subunits. To the extent that sensitization plays a role in chronic cocaine abuse, a combination of these clinically available drugs may be useful in treatment of the disorder.
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PMID:Reversal of cocaine-induced behavioral sensitization and associated phosphorylation of the NR2B and GluR1 subunits of the NMDA and AMPA receptors. 1679 74

We have previously found the 5-HT3 receptor antagonist ondansetron to be useful in reducing cocaine self-administration and cocaine induced sensitization in rats when given during cocaine withdrawal. More recently we have found the combination of the dopamine agonist pergolide plus ondansetron, 3.5 h later, to reverse cocaine sensitization and associated changes in NMDA and AMPA receptors. Here we tested this drug combination in 1) a methamphetamine sensitization model and 2) a reinstatement model after intravenous methamphetamine self-administration using a nose-poke task. We found pergolide plus ondansetron given from days 3-7 of methamphetamine withdrawal to reverse methamphetamine induced sensitization and attenuate reinstatement. We hypothesize that pergolide may evoke a methamphetamine associated memory and that ondansetron can disrupt its reconsolidation. These data suggest that pergolide plus ondansetron treatment may be useful as a therapy to reduce relapse in methamphetamine abusers.
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PMID:Reduction in methamphetamine induced sensitization and reinstatement after combined pergolide plus ondansetron treatment during withdrawal. 1740 14

Lucifer Yellow CH (LY), a fluorescent membrane-impermeable cell-marker dye, has been routinely loaded into cells through recording electrodes to visualize these cells after electrophysiological investigation. Recently we showed that LY produced superoxide when LY was exposed to light at ordinary intensities for microscopy, and that the resultant superoxide retarded the inactivation of voltage-gated Na+ channels even in the dark. Here, we show that superoxide produced by exposure to light prolongs the duration of action potentials, and increases the magnitude of outward rectifier K+ currents and inward rectifier K+ currents in cultured mouse hippocampal neurons. Superoxide also increases the current response of AMPA receptors, but has no effect on that of kainate and NMDA receptors, GABA(A) receptors, high-voltage activated Ca2+ channels of the hippocampal neurons, nor on 5HT3 receptors of N1E-115 cells. These superoxide effects are irreversible. The addition of superoxide dismutase, an enzyme that selectively decomposes superoxide, to LY-loaded recording electrodes reverses the superoxide effects, but addition of heat-inactivated superoxide dismutase fails to reverse the effects. The application of dithiothreitol, a free radical scavenger, to a bathing solution also reverses the superoxide effects. This shows that superoxide rather selectively modifies ion channels. The effects of exogenous and endogenous superoxide on the superoxide-susceptible channels are discussed.
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PMID:Superoxide modifies AMPA receptors and voltage-gated K+ channels of mouse hippocampal neurons. 1875 63

Ecstasy, 3,4-methylenedioxymetamphetamine (MDMA), is a recreational drug used among adolescents, including young pregnant women. MDMA passes the placental barrier and may therefore influence fetal development. The aim was to investigate the direct effect of MDMA on cortical cells using dissociated CNS cortex of rat embryos, E17. The primary culture was exposed to a single dose of MDMA and collected 5 days later. MDMA caused a dramatic, dose-dependent (100 and 400 microM) decrease in nestin-positive stem cell density, as well as a significant reduction (400 microM) in NeuN-positive cells. By qPCR, MDMA (200 microM) caused a significant decrease in mRNA expression of the 5HT3 receptor, dopamine D(1) receptor, and glutamate transporter EAAT2-1, as well as an increase in mRNA levels of the NMDA NR1 receptor subunit and the 5HT(1A) receptor. In conclusion, MDMA caused a marked reduction in stem cells and neurons in embryonic cortical primary cell cultures, which was accompanied by changes in mRNA expression of specific receptors and transporters for glutamatergic and monoaminergic neurotransmitters.
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PMID:MDMA (Ecstasy) decreases the number of neurons and stem cells in embryonic cortical cultures. 1954 26

Systemic inhibition of complex I by rotenone in rats represents a model of Parkinson's disease (PD). The aim of this study was to elucidate whether neramexane (NMDA, nicotinic alpha9/alpha10 and 5-HT3 receptor antagonist), idazoxan (alpha2-adrenoceptor antagonist) or 2-methyl-6-(phenyl-ethyl)-pyrimidine (MPEP, metabotropic glutamate receptor 5 antagonist) prevents rotenone-induced parkinsonian-like behaviours and neurochemical changes in rats. Rotenone (2.5 mg/kg i.p. daily) was administered over 60 days together with saline, neramexane (5 mg/kg i.p., b.i.d.), idazoxan (2.5 mg/kg i.p., b.i.d.) or MPEP (2.5 mg/kg i.p., b.i.d.). The same doses of neramexane, idazoxan and MPEP were administered to rats treated with vehicle instead of rotenone. Treatment-related effects on parkinsonian-like behaviours, such as hypokinesia/rigidity and locomotor activity, were evaluated. Moreover, concentrations of dopamine, serotonin and their metabolites were measured in rats from each experimental group. Over the 60-day treatment period, the rotenone+saline treated animals developed hypokinesia, expressed as an increase in the bar and grid descent latencies in the catalepsy test, and a decrease in locomotor activity. Neramexane and idazoxan partially prevented the development of catalepsy in rotenone-treated rats. Co-administration of MPEP with rotenone resulted only in a decrease in descent latency in the grid test on day 60. Chronic rotenone treatment reduced concentrations of dopamine and serotonin in the anterior striatum, which was blocked by co-treatment with neramexane or idazoxan but not with MPEP. Only neramexane treatment blocked the rotenone-induced decrease in dopamine levels in the substantia nigra pars compacta. In conclusion, neramexane and idazoxan counteracted to some extent the development of parkinsonian symptoms and neurochemical alterations in the rotenone model of Parkinson's disease.
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PMID:Effects of glutamate and alpha2-noradrenergic receptor antagonists on the development of neurotoxicity produced by chronic rotenone in rats. 1961 71


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