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)

Within the ventromedial nucleus of the hypothalamus (VMN), serotonin exerts a dual role in the control of female rat lordosis behavior. Most emphasis has been placed on 5-HT1A and 5-HT2 receptors, which inhibit and facilitate the behavior, respectively. In the current experiment, a potential role for VMN 5-HT3 receptors in the control of lordosis behavior was examined. Ovariectomized rats, hormonally primed with 25 microg estradiol benzoate and 500 microg progesterone, received bilateral VMN infusions with 100 ng, 250 ng or 500 ng of the 5-HT3 receptor antagonist, tropisetron. In these rats, there was a dose-dependent decline in both the lordosis to mount (L/M) ratio and in the quality of the lordosis reflex with 500 ng tropisetron producing the most consistent change in lordosis behavior. Relative to hormone-primed, ovariectomized rats, lordosis behavior of proestrous females was less affected by VMN infusions with the 5-HT3 receptor antagonist. The 5-HT3 receptor agonist, m-chlorophenylbiguanide (mCPBG), attenuated the effect of tropisetron; of the three mCPBG doses (500 ng, 1000 ng, 1500 ng) examined, 1000 ng was the most effective, perhaps because, alone, 1500 ng mCPBG slightly reduced lordosis behavior. These observations emphasize the potential role for VMN 5-HT3 receptors in the control of lordosis behavior.
Brain Res 1997 Sep 19
PMID:5-HT3 receptors in the ventromedial nucleus of the hypothalamus and female sexual behavior. 937 68

1. We investigated 5-hydroxytryptamine3 (5-HT3) receptor-mediating contractions and relaxations in the guinea-pig isolated distal colon using various 5-HT3 receptor agonists and antagonists, including GK-128 (2-[(2-methylimidazol-1-yl) methyl] benzo[f] thiochromen-1-one monohydrochloride hemihydrate). 2. Selective 5-HT3 receptor agonists, 2-methyl-5-HT and m-chlorophenylbiguanide, produced spantide-insensitive contraction and atropine-insensitive contraction and the relaxation. These agonists showed a small, but significant, difference of potency between contraction and relaxation. 3. GK-128 competitively blocked both 2-methyl-5-HT- and m-chlorophenylbiguanide-induced responses with similar potency. The affinities of GK-128 for spantide-insensitive contraction and atropine-insensitive contraction were ten-fold higher than for relaxation. 4. Other selective 5-HT3 receptor antagonists, azasetron and tropisetron, also exhibited higher affinity in contraction than in relaxation, but the extent of their affinity differences was smaller than that observed in GK-128. In contrast, granisetron, ramosetron and ondansetron exhibited no significant differences in their affinity values among the three responses. 5. These results suggest that the 5-HT3 receptors which mediate contraction and relaxation in the guinea-pig distal colon may not be the same, and that GK-128 is a 5-HT3 receptor antagonist with a stronger potency for contraction.
Gen Pharmacol 1997 Sep
PMID:Effect of a novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist, GK-128, on 5-HT3 receptors mediating contractions and relaxations in guinea-pig distal colon. 937 39

Dopamine (DA) has been shown to be required for the induction of striatal gene expression by psychostimulants. However, direct DA agonists or selective inhibitors of DA reuptake are relatively weak inducers of striatal gene expression compared with cocaine or amphetamine. So although necessary, DA alone is not sufficient to mediate the full gene induction response to psychostimulants. In addition to its actions on the DA transporter, amphetamine also enhances serotonin (5-HT) release in the striatum. In this study, we investigated the mechanism by which 5-HT contributes to the regulation of striatal gene expression by amphetamine. We found that selective lesions of serotonergic terminals in the rat forebrain using 5,7-dihydroxytryptamine prevented the full induction of striatal c-Fos by 4 mg/kg amphetamine. Furthermore, amphetamine-induced striatal c-Fos was completely inhibited by administration of the 5-HT3 receptor antagonist, MDL-72222, but not by the 5-HT2A/2C receptor antagonist, ritanserin. Consistent with this finding, the induction of c-Fos by 5-HT in primary cultures of E18 striatal neurons devoid of DA input was blocked by the 5-HT3 receptor antagonists, MDL-72222 and ICS 205-930, but not by 5-HT2A/2C antagonism. Additionally, blockade of 5-HT3 receptors by MDL-72222 inhibited the phosphorylation of activating transcription factor-1 (ATF-1) at Ser63 by amphetamine, but not the phosphorylation of cAMP response element binding protein (CREB) at Ser133. These results suggest that 5-HT3 receptor activation may be required for amphetamine-induced expression of ATF-1-regulated target genes in the striatum, which may include c-Fos.
Synapse 1998 Sep
PMID:5-HT3 receptor activation is required for induction of striatal c-Fos and phosphorylation of ATF-1 by amphetamine. 970 83

Steroid hormone action involves binding to cognate intracellular receptors that, in turn, bind to respective response elements and thus modulate gene expression. The present study shows that the gonadal steroids, 17beta-estradiol and progesterone, may also act as functional antagonists at the 5-hydroxytryptamine type 3 (5-HT3) receptor in whole-cell voltage-clamp recordings of HEK 293 cells stably expressing the 5-HT3 receptor. Functional antagonistic properties at this ligand-gated ion channel could also be shown for 17alpha-estradiol, 17alpha-ethinyl-17beta-estradiol, mestranol, R 5020, testosterone, and allopregnanolone but not for pregnenolone sulfate and cholesterol. An antagonism at the 5-HT3 receptor could further be observed with the aromatic alcohol 4-dodecylphenol but not with phenol or ethanol. Thus, the modulation of 5-HT3 receptor function by steroids or alcohols is dependent on their respective molecule structure. The antagonistic action of steroids at the 5-HT3 receptor is not mediated via the serotonin binding site because the steroids did not alter the binding affinity of [3H]GR65630 to the 5-HT3 receptor, and kinetic experiments revealed a quite different response pattern to 17beta-estradiol when compared with the competitive antagonist metoclopramide. BSA-conjugated gonadal steroids labeled with fluorescein isothiocyanate bound to membranes of HEK 293 cells expressing the 5-HT3 receptor in contrast to native HEK 293 cells. However, there was no dose-dependent displacement of the binding of gonadal steroids to membranes of cells expressing the 5-HT3 receptor in binding experiments or fluorescence studies. Thus, gonadal steroids probably interact allosterically with the 5-HT3 receptor at the receptor-membrane interface. The functional antagonism of gonadal steroids at the 5-HT3 receptor may play a role for the development and course of nausea during pregnancy and of psychiatric disorders.
Mol Endocrinol 1998 Sep
PMID:Functional antagonism of gonadal steroids at the 5-hydroxytryptamine type 3 receptor. 973 11

Dolasetron mesilate is a selective 5-HT3 receptor antagonist that prevents chemotherapy-induced and postoperative nausea and vomiting. For the majority of patients in intravenous dolasetron trials for chemotherapy-induced nausea and vomiting, dosing has been based on body weight (mg/kg). The approved weight-based dose is 1.8 mg/kg based on results of controlled clinical trials. However, trials of dolasetron evaluating oral doses for prevention of chemotherapy-induced emesis, and intravenous doses for prevention and treatment of postoperative emesis have used a fixed milligram dose. To identify an appropriate intravenous fixed milligram dose for the prevention of chemotherapy-induced nausea and vomiting, this analysis was performed to derive efficacy results for fixed milligram doses from pooled results obtained with dosing based on body weight. Intravenous dolasetron doses for 1,598 patients treated on a mg/kg basis (0.3, 0.6, 1.2, 1.8, 2.4, 3.0 and 5.0 mg/kg) in 14 clinical trials were converted to fixed milligram doses based on weight. Fixed-dose groups were established at doses of 50, 75, 100, 125, 150, and 200 mg. Doses less than or equal to the midpoint between two dose groups were included in the lower dose group. Pooled results showed that the 100 mg intravenous dolasetron dose group (who received actual doses of 88-112 mg) produced the highest rate (53%) of complete response (0 emetic episodes and no rescue medication in the 24-h period following initiation of chemotherapy).
Support Care Cancer 1998 Sep
PMID:Rationale for the use of a single fixed intravenous dolasetron dose for the prevention of cisplatin-induced nausea and vomiting. Pooled analysis of 14 clinical trials. 977 66

Thresholds for detection of both pressure and thermal pain are elevated in patients with bulimia nervosa. The present study was aimed at determining (1) if pressure pain detection thresholds (PDT) varied dynamically with the primary disease symptoms of binge eating and vomiting and (2) if the elevation in PDT was effected by treatment with ondansetron (ONDAN), a 5-HT3 receptor antagonist. PDT was defined as the mean of the minimal amount of pressure (measured in g) perceived as painful when exerted by a 1 mm2 blunted point onto the center of the ventral surface of the ungual phalanx of digits 2-5 of the non-dominant hand. Fourteen female patients with severe bulimia nervosa (currently >seven binge/vomit episodes per week; > 2 years illness duration) served as participants. PDT were evaluated at weekly intervals during the course of ongoing treatment studies (double-blind and 'open' label) investigating the therapeutic effects of ONDAN. Data were analyzed by random regression analyses, allowing for the repeated-measures and non-orthogonal design. Data collected from 14 patients under the no-drug condition indicated that PDT increased over the interval between binge/vomit episodes, with significant elevations occurring at times when patients had naturally exceeded their average inter-binge interval. Eleven of these 14 patients underwent 4 weeks of ONDAN treatment. Under this drug condition, the time since the last binge/vomit episode was no longer a significant predictor of PDT. These patients also experienced a significant reduction in the frequency of bulimic behaviors, a finding reported in detail elsewhere. The above finding from untreated patients support the involvement of a common underlying mechanism driving both the increase in pain detection thresholds and the occurrence of the next bulimic episode. This possibility is further supported by the findings that ONDAN treatment is associated with a significant moderation of both variables. The effect of ONDAN may be mediated by blockade of afferent vagal neurotransmission, although other mechanisms must be considered.
Pain 1998 Sep
PMID:Effect of ondansetron, a 5-HT3 receptor antagonist, on the dynamic association between bulimic behaviors and pain thresholds. 980 55

1. To extend our knowledge of the site and mechanism of action of L-type Ca2+ channel antagonists on 5-HT3 receptors, whole-cell voltage clamp electrophysiology was used to investigate the action of one of these compounds, diltiazem, on the recombinant receptor expressed in human embryonic kidney (HEK) 293 cells. 2. Application of diltiazem with 5-HT (30 microM) caused an increase in the rate of receptor current decay, but did not significantly affect peak current (Ip), the EC50 or the Hill coefficient, indicating a non-competitive mechanism of action. Pre-application of the antagonist had no effect indicating that diltiazem mediates its effects by binding preferentially to the open state of the 5-HT3 receptor. 3. To examine the effects of diltiazem on the open state of the receptor in more detail we used 10 mM 5-hydroxyindole (5-OHi) to reduce receptor desensitisation. These experiments showed that diltiazem causes a rapid, reversible, block in the presence of agonist but can become trapped in the unliganded state of the receptor by prior washout of agonist. Dose-inhibition data yielded an IC50 of 5.5 microM and a Hill coefficient of 0.96; inhibition was slightly voltage dependent as the degree of blockade at +60 mV was reduced. 4. The Hill coefficient of near unity suggests a single molecule of diltiazem mediates inhibition and, indeed, kinetic analysis verified that the interaction of diltiazem with the 5-HT3 receptor was well described by a bimolecular reaction scheme. The results suggest that diltiazem acts by causing open-channel block of the 5-HT3 receptor.
J Physiol 1999 Sep 15
PMID:Diltiazem causes open channel block of recombinant 5-HT3 receptors. 1045 85

The study was conducted on a human (Jurkat) T cell line, loaded with a Na+ fluorescent probe, SBFI/AM. Serotonin and an agonist of 5-HT3 receptor-channels, 2-methyl-5HT, evoked Na+ influx, whereas the agonists of other serotonergic receptor subtypes, i.e., 5-HT1A and 5-HT1B receptors, failed to induce Na+ influx in these cells. By using 3H-BRL43694, an agonist of 5-HT3 receptor-channels, we characterized 5-HT3 lymphocyte receptors which exhibited a density (Bmax) of 300 +/- 20 fmol/10(6) cells and a Kd of 30 nM in Jurkat T cells. The T-cell 5-HT3 receptor-channel is not regulated either by the protein kinase C or by the free intracellular calcium concentrations as the agents known to activate the PKC and to induce increases in intracellular free calcium concentrations failed to influence the free intracellular Na+ concentrations, [Na+]i, in these cells. Furthermore, an increase in [Na+]i, induced by 2-methyl-5HT, via 5-HT3 receptor-channels seems to stimulate T-cell activation by facilitating the progression of T cells from S to G2/M phase of the cell cycle.
J Neuroimmunol 1999 Sep 01
PMID:5-HT3 receptor-channels coupled with Na+ influx in human T cells: role in T cell activation. 1049 77

Both the phenethylamine hallucinogen (-)-1-2, 5-dimethoxy-4-bromophenyl-2-aminopropane (DOB), a selective serotonin 5-HT2A,2C receptor agonist, and the indoleamine hallucinogen D-lysergic acid diethylamide (LSD, which binds to 5-HT1A, 1B, 1D, 1E, 1F, 2A, 2C, 5, 6, 7, dopamine D1 and D2, and alpha1 and alpha2 adrenergic receptors), but not their non-hallucinogenic congeners, inhibited N-methyl-D-aspartate (NMDA)-induced inward current and NMDA receptor-mediated synaptic responses evoked by electrical stimulation of the forceps minor in pyramidal cells of the prefrontal cortical slices. The inhibitory effect of hallucinogens was mimicked by 5-HT in the presence of selective 5-HT1A and 5-HT3 receptor antagonists. The inhibitory action of DOB, LSD and 5-HT on the NMDA transmission was blocked by the 5-HT2A receptor antagonists R-(+)-alpha-(2, 3-dimethoxyphenil)-1-[4-fluorophenylethyl]-4-piperidineme thanol (M100907) and ketanserin. However, at low concentrations, when both LSD and DOB by themselves only partially depressed the NMDA response, they blocked the inhibitory effect of 5-HT, suggesting a partial agonist action. Whereas N-(4-aminobutyl)-5-chloro-2-naphthalenesulphonamide (W-7, a calmodulin antagonist) and N-[2-[[[3-(4'-chlorophenyl)- 2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4'-methoxy-b enzenesulphonamide phosphate (KN-93, a Ca2+/CaM-KII inhibitor), but not the negative control 2-[N-4'methoxybenzenesulphonyl]amino-N-(4'-chlorophenyl)-2-propeny l-N -methylbenzylamine phosphate (KN-92), blocked the inhibitory action of LSD and DOB, the selective protein kinase C inhibitor chelerythrine was without any effect. We conclude that phenethylamine and indoleamine hallucinogens may exert their hallucinogenic effect by interacting with 5-HT2A receptors via a Ca2+/CaM-KII-dependent signal transduction pathway as partial agonists and modulating the NMDA receptors-mediated sensory, perceptual, affective and cognitive processes.
Eur J Neurosci 1999 Sep
PMID:LSD and DOB: interaction with 5-HT2A receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex. 1051 Jan 70

The analgesic effect of activation of 5-HT3 receptors at the spinal cord is attenuated by the opioid antagonist naloxone. Enkephalin-immunoreactive neurons in the spinal cord superficial dorsal horn are innervated by 5-HT-immunoreactive fibers. This prompted us to examine whether enkephalinergic dorsal horn neurons express 5-HT3 receptors. Using the technique of single-cell RT-PCR adapted for small neurons in the superficial dorsal horn, methionine-enkephalin sequence-specific PCR products were observed in about half of the neurons studied. Furthermore, 5-HT3 receptor mRNA was detected in approximately 25% of enkephalinergic neurons. These observations suggest that at least part of the antinociception elicited by activation of 5-HT3 receptors at the spinal cord may involve enkephalinergic dorsal horn neurons.
Neuroreport 1999 Sep 09
PMID:Enkephalinergic neurons express 5-HT3 receptors in the spinal cord dorsal horn: single cell RT-PCR analysis. 1051 34


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