serotonin 5-HT3 receptors


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(Updated 3rd or 4th quarter 2002)

Morales, Marisela, Wang, Shwun-De
Differential Composition of 5-Hydroxytryptamine3 Receptors Synthesized in the Rat CNS and Peripheral Nervous System
J. Neurosci. 2002 22: 6732-6741
"The type 3 serotonin (5-HT3) receptor is the only ligand-gated ion channel receptor for serotonin in vertebrates. Two 5-HT3 receptor subunits have been cloned, subunit A (5-HT3A) and subunit B (5-HT3B). We used in situ hybridization histochemistry and reverse transcriptase-PCR amplification to demonstrate that 5-HT3A subunit transcripts are expressed in central and peripheral neurons. In contrast, 5-HT3B subunit transcripts are restricted to peripheral neurons. Thus, the prevalent form of 5-HT3 receptor synthesized within the CNS lacks the 5-HT3B subunit. Because coexpression of 5-HT3A and 5-HT3B subunits produces heteromeric 5-HT3A/3B receptors with properties that differ from those of 5-HT3A homomeric receptors, we investigated possible coexpression of both subunits at the cellular level. We found that near to 90% of all 5-HT3B expressing neurons coexpress the 5-HT3A subunit in superior cervical and nodose ganglia (NG). In addition, there is a cellular population that expresses only the 5-HT3A subunit. Therefore, peripheral neurons have the capacity to synthesize two different 5-HT3 receptors, 5-HT3A+/3B and 5-HT3A+/3B+ receptors. We also determined that neurons of NG projecting to the nucleus tractus solitarium and those of dorsal root ganglia projecting to superficial layers of the spinal cord express 5-HT3A or 5-HT3A/3B subunits. Thus, presynaptic 5-HT3 receptors containing the 5-HT3B subunit might be present in these target brain areas. The compartmentalized structural composition of the 5-HT3 receptor may be the basis of functional diversity within this receptor. This raises the possibility that 5-HT3 receptors participating in sympathetic, parasympathetic and sensory functions may be functionally different from those involved in cognition and emotional behavior." [Abstract]

Kelley SP, Bratt AM, Hodge CW.
Targeted gene deletion of the 5-HT(3A) receptor subunit produces an anxiolytic phenotype in mice.
Eur J Pharmacol 2003 Feb 7;461(1):19-25
"Anxiety disorders are the most common psychiatric disorders. Typical medications used to treat patients are benzodiazepines or antidepressants that target serotonin (5-HT) activity. The ionotropic 5-HT(3) receptor has emerged as a potential therapeutic target because selective antagonist compounds reduce anxiety in rodents, primates, and humans. 5-HT binds to the extracellular N-terminus of the 5-HT(3A) receptor subunit, but receptor activation is also enhanced by distinct allosteric sites. It is not known if specific molecular subunits of the 5-HT(3) receptor modulate anxiety. To address this issue, we characterized anxiety-like behavior of mice with a targeted deletion of the 5-HT(3A) receptor subunit gene in the light/dark box, elevated plus maze, and novelty interaction animal models of anxiety. 5-HT(3A) null mice exhibited an anxiolytic behavioral phenotype that was highly correlated across behavioral measures. This evidence indicates that the 5-HT(3A) molecular subunit influences anxiety-like behavior. Pharmacotherapy that targets specifically the 5-HT(3A) receptor subunit may provide a novel treatment for anxiety disorders." [Abstract]

Morales, Marisela, Bloom, Floyd E.
The 5-HT3 Receptor Is Present in Different Subpopulations of GABAergic Neurons in the Rat Telencephalon
J. Neurosci. 1997 17: 3157-3167
""To analyze further the role of the 5-HT3R in the CNS, we used in situ hybridization and immunocytochemistry to determine that 5-HT3R-expressing neurons are mainly GABA-containing cells in the rat telencephalon. We determined that 5-HT3R/GABA-containing neurons do not exhibit somatostatin immunoreactivity but often contain cholecystokinin (CCK) immunoreactivity. 5-HT3R-expressing cells with CCK immunoreactivity were observed in the neocortex, olfactory cortex, hippocampus, and amygdala. The 5-HT3R/CCK interneurons represent between 35 and 66% of the total population of CCK-containing cells in the neocortex." [Full Text]

Paudice, P, Raiteri, M
Cholecystokinin release mediated by 5-HT3 receptors in rat cerebral cortex and nucleus accumbens
Br. J. Pharmacol. 1991 103: 1790-1794
"It is concluded that 5-HT can act as a potent releaser of CCK-LI in rat cerebrocortex and nucleus accumbens through the activation of receptors of the 5-HT3 type situated on the CCK-releasing terminals. This interaction may provide a rationale for the clinical development of both 5-HT3 and CCK receptor antagonists as novel anxiolytic drugs." [Article]

Koyama, Susumu, Matsumoto, Nozomu, Kubo, Chiharu, Akaike, Norio
Presynaptic 5-HT3 receptor-mediated modulation of synaptic GABA release in the mechanically dissociated rat amygdala neurons
J Physiol (Lond) 2000 529: 373-383
"Our results suggest that a 5-HT3-specific agonist acts on presynaptic nerve terminals facilitating synaptic GABA release without postsynaptic effects. The facilitation requires calcium influx through presynaptic 5-HT3 receptors. PKA modulates the recovery process from desensitization of presynaptic 5-HT3 receptor-mediated regulation of synaptic GABA release." [Full Text]

Hasegawa M, Sasaki T, Sadakane K, Tabuchi M, Takeda Y, Kimura M, Fujii Y.
Studies for the emetic mechanisms of ipecac syrup (TJN-119) and its active components in ferrets: involvement of 5-hydroxytryptamine receptors.
Jpn J Pharmacol 2002 Jun;89(2):113-9
"Ipecac syrup, prepared from a galentical ipecac, contains the nauseant alkaloids cephaeline and emetine. The involvement of receptors and serotonin- and dopamine-metabolizing enzymes in the emesis induced by ipecac syrup and these components was investigated. 1) In ferrets, the selective 5-HT3-receptor antagonist ondansetron (0.5 mg/kg, p.o.) prevented each emesis induced by TJN-119 (0.5 mL/kg, p.o.), cephaeline (0.5 mg/kg, p.o.) and emetine (5.0 mg/kg, p.o.), but the intraperitoneal administration of the selective dopamine D2-receptor antagonist sulpiride failed to significantly suppress the TJN-119, cephaeline and emetine-induced emesis at a dose of 0.1 mg/kg that blocked apomorphine-induced emesis. 2) In the receptor binding assays, cephaeline and emetine had a distinct affinity to 5-HT4 receptor, but no or weak affinity to 5-HT1A, 5-HT3, nicotine, M3, beta1, NK1, and D2 receptors. 3) Cephaeline and emetine did not affect activities of metabolic enzymes of 5-HT and dopamine (MAO-A, MAO-B, tryptophan 5-hydroxylase and tyrosine hydroxylase) in vitro. These results suggest that 5-HT3 receptor plays an important role in the emetic action of TJN-119, cephaeline and emetine, and the 5-HT4 receptor may be involved in their mechanisms." [Abstract]

Bedford, Fiona K., Julius, David, Ingraham, Holly A.
Neuronal Expression of the 5HT3 Serotonin Receptor Gene Requires Nuclear Factor 1 Complexes
J. Neurosci. 1998 18: 6186-6194
"We report here that the proximal TATA-less promoter of the serotonin-gated ion channel is sufficient for neuronal-specific expression in cultured cell lines. Moreover, an element within this 219 bp fragment matching the known consensus binding site for the NF1 family serves as an essential cis-regulatory element for this restricted transcriptional activity."
[Full Text]

Peter Linz, and Roland Veelken
Serotonin 5-HT3 receptors on mechanosensitive neurons with cardiac afferents
Am J Physiol Heart Circ Physiol 282: H1828-H1835, May 2002. [Abstract]

Adrienne E. Dubin, Rene Huvar, Michael R. D'Andrea, Jayashree Pyati, Jessica Y. Zhu, K. C. Joy, Sandy J. Wilson, Jose E. Galindo, Charles A. Glass, Lin Luo, Michael R. Jackson, Timothy W. Lovenberg, and Mark G. Erlander
The Pharmacological and Functional Characteristics of the Serotonin 5-HT3A Receptor Are Specifically Modified by a 5-HT3B Receptor Subunit
J. Biol. Chem. 274: 30799-30810, October 1999.
"We report the cloning of a subunit 5-HT3B with ~44% amino acid identity to 5-HT3A that specifically modified 5-HT3A receptor kinetics, voltage dependence, and pharmacology. Co-expression of 5-HT3B with 5-HT3A modified the duration of 5-HT3 receptor agonist-induced responses, linearized the current-voltage relationship, increased agonist and antagonist affinity, and reduced cooperativity between subunits. Reverse transcriptase-polymerase chain reaction in situ hybridization revealed co-localization of both 5-HT3B and 5-HT3A in a population of neurons in the amygdala, telencephalon, and entorhinal cortex. Furthermore, 5-HT3A and 5-HT3B mRNAs were expressed in spleen and intestine. Our data suggest that 5-HT3B might contribute to tissue-specific functional changes in 5-HT3-mediated signaling and/or modulation." [Full Text]

Gunthorpe, Martin J., Peters, John A., Gill, Catherine H., Lambert, Jeremy J., Lummis, Sarah C. R.
The 4'lysine in the putative channel lining domain affects desensitization but not the single-channel conductance of recombinant homomeric 5-HT3A receptors
J Physiol (Lond) 2000 522: 187-198
"The 5-HT3 receptor is a transmitter-gated ion channel of the Cys-loop superfamily. Uniquely, 5-HT3 receptor subunits (5-HT3A and 5-HT3B) possess a positively charged lysine residue within the putative channel lining M2 domain (4' position). Using whole cell recording techniques, we examined the role of this residue in receptor function using wild-type (WT) and mutant 5-HT3A receptor subunits of murine origin transiently expressed in human embryonic kidney (HEK 293) cells." [Full Text]

Brown, A. M., Hope, A. G., Lambert, J. J., Peters, J. A.
Ion permeation and conduction in a human recombinant 5-HT3 receptor subunit (h5-HT3A)
J Physiol (Lond) 1998 507: 653-665
"The data indicate that homo-oligomeric receptors composed of h5-HT3A subunits form inwardly rectifying cation-selective ion channels of low conductance that are permeable to Ca2+ and Mg2+." [Full Text]

David C. Reeves, Eric N. Goren, Myles H. Akabas, and Sarah C. R. Lummis
Structural and Electrostatic Properties of the 5-HT3 Receptor Pore Revealed by Substituted Cysteine Accessibility Mutagenesis
J. Biol. Chem. 276: 42035-42042.
"The 5-HT31 receptor is a member of the Cys loop family of ligand-gated ion channels, which includes nicotinic acetylcholine (nACh), GABAA and glycine receptors. These receptors are pentamers, usually formed by the co-assembly of one to four different subunits each with a large extracellular N-terminal region and four putative transmembrane domains (M1-M4)." [Full Text]

Tim Green, Kathrin A. Stauffer, and Sarah C. R. Lummis
Expression of Recombinant Homo-oligomeric 5-Hydroxytryptamine Receptors Provides New Insights into Their Maturation and Structure
J. Biol. Chem. 270: 6056-6061, March 1995. [Full Text]

Martin J. Gunthorpe, and Sarah C. R. Lummis
Conversion of the Ion Selectivity of the 5-HT3A Receptor from Cationic to Anionic Reveals a Conserved Feature of the Ligand-gated Ion Channel Superfamily
J. Biol. Chem. 276: 10977-10983, April 2001.
"The results presented here show that the introduction of three point mutations in or near the M2 domain are sufficient to convert the ion selectivity of homomeric 5-HT3A receptors from cationic to anionic. Substitution of V13'T in M2 together with the neutralization of a ring of glutamate residues (E1'A) and the adjacent insertion of the "extra" amino acid (proline) found in the anionic channels (referred to here as P1") in the M1-M2 loop (Fig. 1) lead to the formation of an anion-selective 5-HT3A receptor."
[Full Text]

Lobitz, Nicole, Gisselmann, Gunter, Hatt, Hanns, Wetzel, Christian H.
A Single Amino-Acid in the TM1 Domain Is an Important Determinant of the Desensitization Kinetics of Recombinant Human and Guinea Pig {alpha}-Homomeric 5-Hydroxytryptamine Type 3 Receptors
Mol Pharmacol 2001 59: 844-851 [Full Text]

Dong Yan, Marvin K. Schulte, Karen E. Bloom, and Michael M. White
Structural Features of the Ligand-binding Domain of the Serotonin 5HT3 Receptor
J. Biol. Chem. 274: 5537-5541, February 1999.
"The data presented here are consistent with the notion that there is a significant amount of structural and functional homology between the AChR and 5HT3R (and by inference, the other members of the ligand-gated ion channel family)." [Full Text]

Coultrap, Steven J., Sun, Hongwei, Tenner, Thomas E., Jr., Machu, Tina K.
Competitive Antagonism of the Mouse 5-Hydroxytryptamine3 Receptor by Bisindolylmaleimide I, a "Selective" Protein Kinase C Inhibitor
J Pharmacol Exp Ther 1999 290: 76-82 [Full Text]

Machu, Tina K., Hamilton, Margaret E., Frye, Tonia F., Shanklin, Christopher L., Harris, Michael C., Sun, Hongwei, Tenner, Thomas E., Jr., Soti, Ferenc S., Kem, William R.
Benzylidene Analogs of Anabaseine Display Partial Agonist and Antagonist Properties at the Mouse 5-Hydroxytryptamine3A Receptor
J Pharmacol Exp Ther 2001 299: 1112-1119 [Abstract]

Khan, Naim Akhtar, Hichami, Aziz
Ionotrophic 5-hydroxytryptamine type 3 receptor activates the protein kinase C-dependent phospholipase D pathway in human T-cells.
BIOCHEMICAL JOURNAL , 344(1):199-204 1999 [Abstract]

Wang, Yun, Ramage, Andrew G., Jordan, David
Presynaptic 5-HT3 receptors evoke an excitatory response in dorsal vagal preganglionic neurones in anaesthetized rats
J Physiol (Lond) 1998 509: 683-694 [Full Text]

Moore, Kimberly A., Taylor, Glen E., Weinreich, Daniel
Serotonin unmasks functional NK-2 receptors in vagal sensory neurones of the guinea-pig
J Physiol (Lond) 1999 514: 111-124
"In sum, these results suggest that stimulation of 5-HT3 receptors activates an intracellular signalling cascade that couples calcium-calmodulin and NO activation to NK-2 receptor unmasking in sensory neurones." [Full Text]

Fu, Liang-Wu, Longhurst, John C.
Role of 5-HT3 receptors in activation of abdominal sympathetic C fibre afferents during ischaemia in cats
J Physiol (Lond) 1998 509: 729-740
"Data from the present study strongly suggest that 5-HT produced during ischaemia contributes to activation of ischaemically sensitive abdominal sympathetic C fibre afferents through stimulation of 5-HT3 receptors."
[Full Text]

De Deurwaerdere, Philippe, Stinus, Luis, Spampinato, Umberto
Opposite Change of In Vivo Dopamine Release in the Rat Nucleus Accumbens and Striatum That Follows Electrical Stimulation of Dorsal Raphe Nucleus: Role of 5-HT3 Receptors
J. Neurosci. 1998 18: 6528-6538 [Full Text]

Herges, Sonja, Taylor, David A.
Involvement of 5-HT3 receptors in the nucleus accumbens in the potentiation of cocaine-induced behaviours in the rat
Br. J. Pharmacol. 2000 131: 1294-1302 [Abstract]

Roerig, Birgit, Nelson, Darin A., Katz, Lawrence C.
Fast Synaptic Signaling by Nicotinic Acetylcholine and Serotonin 5-HT3 Receptors in Developing Visual Cortex
J. Neurosci. 1997 17: 8353-8362
"Thus, both acetylcholine and serotonin can mediate fast synaptic transmission in the visual cortex; the early onset of these mechanisms suggests a role during initial stages of circuit formation and during subsequent experience-dependent remodeling of cortical connections."
[Full Text]

Roerig, Birgit, Katz, Lawrence C.
Modulation of Intrinsic Circuits by Serotonin 5-HT3 Receptors in Developing Ferret Visual Cortex
J. Neurosci. 1997 17: 8324-8338 [Full Text]

Johannes A. van Hooft, Avron D. Spier, Jerrel L. Yakel, Sarah C. R. Lummis, and Henk P. M. Vijverberg
Promiscuous coassembly of serotonin 5-HT3 and nicotinic (alpha)4 receptor subunits into Ca2+-permeable ion channels
PNAS 95: 11456-11461, September 1998
"The results demonstrate that 5-HT3R and nAChR (alpha)4 subunits coassemble into a novel type of heteromeric 5-HT3 receptor channel with enhanced Ca2+ permeability and reduced sensitivity to the antagonist d-tubocurarine as compared with the homomeric 5-HT3 receptor-gated ion channel. These findings have significant implications, both for 5-HT3R pharmacology and function and for ligand-gated ion channels in general."
[Full Text]

Steve Kriegler, Sterling Sudweeks, and Jerrel L. Yakel
The Nicotinic (alpha)4 Receptor Subunit Contributes to the Lining of the Ion Channel Pore When Expressed with the 5-HT3 Receptor Subunit
J. Biol. Chem. 274: 3934-3936, February 1999.
"Our demonstration that the nicotinic (alpha)4 subunit lines the pore of the channel is consistent with the idea that it could modify the single channel conductance and calcium permeability of the 5-HT3R. This may be a general strategy used in neurons to produce the wide range of properties reported." [Full Text]

Zhai, Jin, Gershon, Michael D., Walsh, John H., Wong, Helen C., Kirchgessner, Annette L.
Inward Currents in Neurons from Newborn Guinea Pig Intestine: Mediation by 5-Hydroxytryptamine Type 3 Receptors
J Pharmacol Exp Ther 1999 291: 374-382 [Full Text]

X. W. Fu, D. Wang, J. Pan, S. M. Farragher, V. Wong, and E. Cutz
Neuroepithelial bodies in mammalian lung express functional serotonin type 3 receptor
Am J Physiol Lung Cell Mol Physiol 281: L931-L940, October 2001.
"Our studies suggest that 5-HT3-R in NEB cells may function as an autoreceptor and may potentially be involved in modulation of hypoxia signaling." [Abstract]

Zeitz, Karla P., Guy, Nicolas, Malmberg, Annika B., Dirajlal, Sahera, Martin, William J., Sun, Linda, Bonhaus, Douglas W., Stucky, Cheryl L., Julius, David, Basbaum, Allan I.
The 5-HT3 Subtype of Serotonin Receptor Contributes to Nociceptive Processing via a Novel Subset of Myelinated and Unmyelinated Nociceptors
J. Neurosci. 2002 22: 1010-1019
"Serotonin is a major component of the inflammatory chemical milieu and contributes to the pain of tissue injury via an action on multiple receptor subtypes. Here we studied mice after genetic or pharmacological disruption of the 5-HT3 receptor, an excitatory serotonin-gated ion channel. We demonstrate that tissue injury-induced persistent, but not acute, nociception is significantly reduced after functional elimination of this receptor subtype. Specifically, in the setting of tissue injury, the 5-HT3 receptor mediates activation of nociceptors but does not contribute to injury-associated edema. This result is explained by the localization of 5-HT3 receptor transcripts to a previously uncharacterized subset of myelinated and unmyelinated afferents, few of which express the proinflammatory neuropeptide substance P. Finally, we provide evidence that central serotonergic circuits modulate nociceptive transmission via a facilitatory action at spinal 5-HT3 receptors. We conclude that activation of both peripheral and central 5-HT3 receptors is pronociceptive and that the contribution of peripheral 5-HT3 receptors involves a novel complement of primary afferent nociceptors."

Ferezou, Isabelle, Cauli, Bruno, Hill, Elisa L., Rossier, Jean, Hamel, Edith, Lambolez, Bertrand
5-HT3 Receptors Mediate Serotonergic Fast Synaptic Excitation of Neocortical Vasoactive Intestinal Peptide/Cholecystokinin Interneurons
J. Neurosci. 2002 22: 7389-7397 [Abstract]

Wolf H.
Preclinical and clinical pharmacology of the 5-HT3 receptor antagonists.
Scand J Rheumatol Suppl 2000;113:37-45
"5-HT3-receptor antagonists are potent and highly selective competitive inhibitors of the 5-HT3-receptor with negligible affinity for other receptors. They are rapidly absorbed and penetrate the blood-brain barrier easily. 5-HT3-receptor antagonists are metabolized by diverse subtypes of the cytochrome P450-system, metabolites are excreted mainly in urine. Half-lifes in healthy subjects vary from 3-4 hours (ondansetron, granisetron) to 7-10 hours (tropisetron, hydrodolasetron). 5-HT3-receptor antagonists do not modify any aspect of normal behaviour in animals or induce remarkable changes of physiological functions in healthy subjects. They are well tolerated over wide dose ranges, most common side effects in clinical use are headache and obstipation. Clinical efficacy was first established in chemotherapy-induced emesis. In this indication, 5-HT3-receptor antagonists set a new standard regarding efficacy and tolerability. Further established indications are radiotherapy-induced and post-operative emesis. Antiemetic efficacy results from a simultaneous action at peripheral and central 5-HT3-receptors. Other peripheral actions include reduction of secretion and diarrhea caused by increased intestinal serotonin content (e.g. in carcinoid syndrome), a limited antiarrhythmic activity and a reduction of experimentally induced pain. CNS effects comprise anxiolysis, attenuation of age-associated memory impairment, reduction of alcohol consumption in moderate alcohol abuse and an antipsychotic effect in patients with parkinson psychosis. In migraine, 5-HT3-receptor antagonists show moderate efficacy, as well. Repeatedly demonstrated efficacy of 5-HT3-receptor antagonists in patients suffering from fibromyalgia raises the question for the mechanism of action involved. Ligand binding at the 5-HT3-receptor causes manifold effects on other neurotransmitter and neuropeptide systems. In particular, 5-HT3-receptor antagonists diminish serotonin-induced release of substance P from C-fibers and prevent unmasking of NK2-receptors in the presence of serotonin. These observations possibly provide an approach for the causal explanation of favourable treatment results with 5-HT3-receptor antagonists in fibromyalgia." [Abstract]

Stratz T, Muller W.
The use of 5-HT3 receptor antagonists in various rheumatic diseases--a clue to the mechanism of action of these agents in fibromyalgia?
Scand J Rheumatol Suppl 2000;113:66-71
"With intra-articular injection of tropisetron, an improvement in inflammation and pain was obtained in inflammatory rheumatic diseases and activated osteoarthrosis. Also, the majority of patients with localized soft-tissue rheumatic diseases (periarthritis) demonstrated an obvious decrease in their pain following local infiltration of tropisetron. Chronic low back pain and cervical pain responded somewhat to i.v. treatment with tropisetron." [Abstract]

Sirota, Pinkhas, Mosheva, Tanya, Shabtay, Hertzel, Giladi, Nir, Korczyn, Amos D.
Use of the Selective Serotonin 3 Receptor Antagonist Ondansetron in the Treatment of Neuroleptic-Induced Tardive Dyskinesia
Am J Psychiatry 2000 157: 287-289 [Abstract]

Christian H. R. Wetzel, Bettina Hermann, Christian Behl, Elmar Pestel, Gerhard Rammes, Walter Zieglgänsberger, Florian Holsboer, and Rainer Rupprecht
Functional Antagonism of Gonadal Steroids at the 5-Hydroxytryptamine Type 3 Receptor
Mol. Endocrinol. 12: 1441-1451, 1998.
"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." [Full Text]

Stratz T, Schochat T, Hrycaj P, Lacki J, Mennet P, Farber L, Schweiger C, Muller W.
[Therapy of generalized tendomyopathy (fibromyalgia) caused by blocking 5-HT3 receptors]
Z Rheumatol 1994 Nov-Dec;53(6):335-8
"In more than 40% of patients with fibromyalgia a marked influence on the pain in the skeletal system with a decrease of the tenderness at "tenderpoints" can be achieved by blocking the 5-HT3-receptors with ondansetron or tropisetron-hydrochloride. Physical complaints and vegetative signs also improve. It is discussed if patients not responding to therapy with ondansetron or tropisetron-hydrochloride have to be discriminated as a subgroup of fibromyalgia." [Abstract]

Farber L, Stratz TH, Bruckle W, Spath M, Pongratz D, Lautenschlager J, Kotter I, Zoller B, Peter HH, Neeck G, Welzel D, Muller W
Short-term treatment of primary fibromyalgia with the 5-HT3-receptor antagonist tropisetron. Results of a randomized, double-blind, placebo-controlled multicenter trial in 418 patients.
Int J Clin Pharmacol Res 2001;21(1):1-13
"Short-term treatment of fibromyalgia patients with 5 mg tropisetron for 10 days proved to be efficacious and well tolerated. In this study a bell-shaped dose-response curve was seen." [Abstract]

Samborski W, Stratz T, Lacki JK, Klama K, Mennet P, Muller W.
The 5-HT3 blockers in the treatment of the primary fibromyalgia syndrome: a 10-day open study with Tropisetron at a low dose.
Mater Med Pol 1996 Jan-Mar;28(1):17-9
"The efficacy of Tropisetron in a dose of 5 mg daily was comparable with the results obtained in a previously reported trial with a dose of 10 or 15 mg per day, but the frequency of gastric troubles decreased (21% vs. 60%)." [Abstract]

Muller W, Stratz T.
Results of the intravenous administration of tropisetron in fibromyalgia patients.
Scand J Rheumatol Suppl 2000;113:59-62
"The observed effects on the symptoms of fibromyalgia of daily oral administration of 5 mg of the 5-HT3 receptor antagonist, tropisetron, for 10 days, could be maintained or exceeded with intravenous administration of only 2 mg of the formulation. Following a single i.v. injection of 2 mg tropisetron, a more rapid and profound reduction in pain was achieved than with 5 mg oral tropisetron per day. In individual cases, patients who had previously experienced no reduction in pain from 10 days of 5 mg oral tropisetron daily responded to i.v. therapy. A more favourable and persistent effect on pain, combined with a simultaneous significant improvement in various vegetative and functional symptoms was achieved with five days treatment with 2 mg tropisetron i.v. per day." [Abstract]

Haus U, Varga B, Stratz T, Spath M, Muller W.
Oral treatment of fibromyalgia with tropisetron given over 28 days: influence on functional and vegetative symptoms, psychometric parameters and pain.
Scand J Rheumatol Suppl 2000;113:55-8
"In conclusion, 28 days treatment of fibromyalgia patients with 5 mg tropisetron resulted in significant pain reduction, which was most pronounced after 10 days with a further reduction up to day 28. Psychometric tests showed significant improvements in depression and anxiety state scores, while functional symptoms improved with extended tropisetron treatment." [Abstract]

Rodd-Henricks ZA, McKinzie DL, Melendez RI, Berry N, Murphy JM, McBride WJ.
Effects of serotonin-3 receptor antagonists on the intracranial self-administration of ethanol within the ventral tegmental area of Wistar rats.
Psychopharmacology (Berl) 2002 Nov 23
"RATIONALE. Previous work from our laboratory indicated that Wistar rats will self-administer ethanol (EtOH) directly into the posterior ventral tegmental area (VTA) and that 5-HT(3) antagonists will inhibit EtOH-stimulated somatodendritic release of dopamine within the VTA.OBJECTIVES. The objective of this study was to use the intracranial self-administration procedure to determine the involvement of 5-HT(3)receptors in mediating the reinforcing effects of EtOH within the VTA, and to increase our understanding of central nervous system mechanisms involved in the rewarding effects of EtOH.METHODS. Adult female Wistar rats were stereotaxically implanted with guide cannulae aimed at the posterior VTA. After 1 week, rats were placed into standard two-lever experimental chambers for a total of seven sessions (4-h sessions separated by 48 h) and allowed to self-administer vehicle alone, a 5-HT(3) antagonist alone, 200 mg% EtOH alone, or combinations of 200 mg% EtOH with different concentrations of a 5-HT(3) antagonist ( n=6-9 per group).RESULTS. Throughout all seven sessions, Wistar rats self-infused more 200 mg% ETOH (25+/-5 infusions) than vehicle (5+/-4 infusions) or 5-HT(3) antagonist (6+/-4 infusions) ( P<0.05), and responded significantly more ( P<0.05) on the active than inactive lever (e.g., 50+/-12 vs 12+/-8 responses in session 1). Co-administration of 50 micro M or 100 micro M ICS 205,930 with 200 mg% EtOH completely prevented the acquisition and maintenance of EtOH self-infusion into the posterior VTA. Similarly, co-administration of either 25-100 micro M LY-278-584 or 10-100 micro M zacopride with 200 mg% EtOH completely blocked EtOH-maintained intracranial self-administration behavior.CONCLUSIONS. The results of this study suggest that the reinforcing effects of EtOH within the posterior VTA of Wistar rats require activation of local 5-HT(3) receptors." [Abstract]

Panicker, Sandip, Cruz, Hans, Arrabit, Christine, Slesinger, Paul A.
Evidence for a Centrally Located Gate in the Pore of a Serotonin-Gated Ion Channel
J. Neurosci. 2002 22: 1629-1639 [Abstract]

Mott, David D., Erreger, Kevin, Banke, Tue G., Traynelis, Stephen F.
Open probability of homomeric murine 5-HT3A serotonin receptors depends on subunit occupancy
J Physiol (Lond) 2001 535: 427-443 [Full Text]

Hanna, Michael C., Davies, Paul A., Hales, Tim G., Kirkness, Ewen F.
Evidence for Expression of Heteromeric Serotonin 5-HT3 Receptors in Rodents.
J Neurochem 2000 75: 240-247 [Abstract]

Steward, Lucinda J., Boess, Frank G., Steele, Joy A., Liu, Dan, Wong, Norris, Martin, Ian L.
Importance of Phenylalanine 107 in Agonist Recognition by the 5-Hydroxytryptamine3A Receptor
Mol Pharmacol 2000 57: 1249-1255 [Full Text]

Hope, Anthony G., Belelli, Delia, Mair, Ian D., Lambert, Jeremy J., Peters, John A.
Molecular Determinants of (+)-Tubocurarine Binding at Recombinant 5-Hydroxytryptamine3A Receptor Subunits
Mol Pharmacol 1999 55: 1037-1043
"Interestingly, several of the residues exerting a subtle effect upon the apparent affinity of ACh are homologous to amino acids within mouse and human 5-HT3A subunits that contribute to the differential potency of (+)-Tc." [Full Text]

Lankiewicz, Silke, Lobitz, Nicole, Wetzel, Christian H. R., Rupprecht, Rainer, Gisselmann, Gunter, Hatt, Hanns
Molecular Cloning, Functional Expression, and Pharmacological Characterization of 5-Hydroxytryptamine3 Receptor cDNA and Its Splice Variants from Guinea Pig
Mol Pharmacol 1998 53: 202-212 [Full Text]

Zhou, Xiaoping, Galligan, James J.
Synaptic Activation and Properties of 5-Hydroxytryptamine3 Receptors in Myenteric Neurons of Guinea Pig Intestine
J Pharmacol Exp Ther 1999 290: 803-810 [Full Text]

Steward, Lucinda J., Boess, Frank G., Steele, Joy A., Liu, Dan, Wong, Norris, Martin, Ian L.
Importance of Phenylalanine 107 in Agonist Recognition by the 5-Hydroxytryptamine3A Receptor
Mol Pharmacol 2000 57: 1249-1255 [Full Text]

The 5-HT3B subunit is a major determinant of serotonin-receptor function
Nature 397, 359 - 363 (1999)
"In addition to providing a new target for therapeutic agents, the 5-HT3B subunit will be a valuable resource for defining the molecular mechanisms of ion-channel function."

Avron D. Spier, and Sarah C. R. Lummis
The Role of Tryptophan Residues in the 5-Hydroxytryptamine3 Receptor Ligand Binding Domain
J. Biol. Chem. 275: 5620-5625, February 2000. [Full Text]

Kawa, K.
Distribution and functional properties of 5-HT3 receptors in the rat hippocampal dentate gyrus: a patch-clamp study
J Neurophysiol 1994 71: 1935-1947 [Abstract/Full Text]

Dang, Hong, England, Pamela M., Farivar, S. Sarah, Dougherty, Dennis A., Lester, Henry A.
Probing the Role of a Conserved M1 Proline Residue in 5-Hydroxytryptamine3 Receptor Gating
Mol Pharmacol 2000 57: 1114-1122 [Full Text]

Charlotte M. Deane, and Sarah C. R. Lummis
The Role and Predicted Propensity of Conserved Proline Residues in the 5-HT3 Receptor
J. Biol. Chem. 276: 37962-37966, October 2001. [Full Text]

Sun, Hongwei, McCardy, Elizabeth A., Machu, Tina K., Blanton, Michael P.
Characterization of Interaction of 3,4,5-Trimethoxybenzoic Acid 8-(Diethylamino)octyl Ester with Torpedo californica Nicotinic Acetylcholine Receptor and 5-Hydroxytryptamine3 Receptor
J Pharmacol Exp Ther 1999 290: 129-135 [Full Text]

Ye, Jiang Hong, Schaefer, Rebecca, Wu, Wen-Hsien, Liu, Philip L., Zbuzek, Vlasta K., Mcardle, Joseph J.
Inhibitory Effect of Ondansetron on Glycine Response of Dissociated Rat Hippocampal Neurons
J Pharmacol Exp Ther 1999 290: 104-111
"When examined under current clamp conditions, glycine induced depolarization and hyperpolarization in neonatal and mature neurons, respectively; ondansetron also suppressed these responses to glycine. The data suggest that ondansetron competitively inhibits the glycine receptor." [Full Text]

McMahon, Lori L., Kauer, Julie A.
Hippocampal Interneurons Are Excited Via Serotonin-Gated Ion Channels
J Neurophysiol 1997 78: 2493-2502
"We have demonstrated that CA1 SR interneurons are excited by 5-HT via direct activation of postsynaptic 5-HT3 receptors. The 5-HT responses persist during blockade of fast glutamatergic and GABAergic synaptic transmission, indicating that 5-HT receptors are present on interneurons themselves. The responses are independent of G-protein activation and are effectively blocked by three distinct 5-HT3 receptor antagonists." [Full Text]

Harris LC, Awe SO, Opere CA, LeDay AM, Ohia SE, Sharif NA.
Pharmacology of serotonin receptors modulating electrically-induced [3h]-norepinephrine release from isolated mammalian iris-ciliary bodies.
J Ocul Pharmacol Ther 2002 Aug;18(4):339-48
"We conclude that the excitatory prejunctional 5-HT heteroreceptors present in bovine iris-ciliary bodies belong to the 5-HT3 receptor subtype." [Abstract]

Rosenberg, Madelaine, Pie, Brigitte, Cooper, Ellis
Developing Neonatal Rat Sympathetic and Sensory Neurons Differ in Their Regulation of 5-HT3 Receptor Expression
J. Neurosci. 1997 17: 6629-6638 [Full Text]

Smith, George M., Berry, Richard L., Yang, Jay, Tanelian, Darrell
Electrophysiological Analysis of Dorsal Root Ganglion Neurons Pre- and Post-Coexpression of Green Fluorescent Protein and Functional 5-HT3 Receptor
J Neurophysiol 1997 77: 3115-3121 [Full Text]


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Recent 5-HT3 Research

1) da Silva Lopes L, Marques RB, Fernandes HB, da Silva Pereira S, Ayres MC, Chaves MH, Almeida FR
Mechanisms of the antinociceptive action of (-) Epicatechin obtained from the hydroalcoholic fraction of Combretum leprosum Mart & Eic in rodents.
J Biomed Sci. 2012 Jul 25;19(1):68.
ABSTRACT: BACKGROUND: The mechanisms of the antinociceptive activity of () epicatechin (EPI), a compound isolated from the hydroalcoholic fraction of Combreum leprosum Mart & Eicher. METHODS: were assessed in the model of chemical nociception induced by glutamate (20 mumol/paw). To evaluate the mechanisms involved, the animals , male Swiss mice (25-30 g), received EPI (50 mg/kg p.o.) after pretreatment with naloxone (2 mg/kg s.c. opioid antagonist), glibenclamide (2 mg/kg s.c. antagonist K + channels sensitive to ATP), ketanserin (0.3 mg/kg s.c. antagonist of receptor 5-HT2A), yoimbine (0.15 mg/kg s.c. alpha2 adrenergic receptor antagonist), pindolol (1 mg/kg s.c. 5-HT1a/1b receptor antagonist), atropine (0.1 mg/kg s.c. muscarinic antagonist) and caffeine (3 mg/kg s.c. adenosine receptor antagonist), ondansetron (0.5 mg/kg s.c. for 5-HT3 receptor) and L-arginine (600 mg/kg i.p.). RESULTS: The antinociceptive effect of EPI was reversed by pretreatment with naloxone and glibenclamide, ketanserin, yoimbine, atropine and pindolol, which demonstrates the involvement of opioid receptors and potassium channels sensitive to ATP, the serotoninergic (receptor 5HT1A and 5HT2A), adrenergic (receptor alpha 2) and cholinergic (muscarinic receptor) systems in the activities that were observed. The effects of EPI, however, were not reversed by pretreatment with caffeine, L-arginine or ondansetron, which shows that there is no involvement of 5HT3 receptors or the purinergic and nitrergic systems in the antinociceptive effect of EPI. In the Open Field and Rotarod test, EPI had no significant effect, which shows that there was no central nervous system depressant or muscle relaxant effect on the results. CONCLUSIONS: This study demonstrates that the antinociceptive activity of EPI in the glutamate model involves the participation of the opioid system, serotonin, adrenergic and cholinergic. [PubMed Citation] [Order full text from Infotrieve]

2) Celio L, Agustoni F, Testa I, Dotti K, De Braud F
Palonosetron: an evidence-based choice in prevention of nausea and vomiting induced by moderately emetogenic chemotherapy.
Tumori. 2012 May;98(3):279-86.
Aims and background. In 2003, the second-generation, 5-HT3 receptor antagonist (5-HT3 RA) palonosetron was approved by the FDA for the prevention of nausea and vomiting associated with highly and moderately emetogenic chemotherapy. We reviewed the current knowledge on the role of palonosetron against acute and delayed emesis in patients with solid tumors undergoing single-day moderately emetogenic chemotherapy regimens. Methods. A literature review in PubMed was performed to update currently available preclinical and clinical evidence on palonosetron, prioritizing randomized clinical trials. Results. The distinct pharmacology of palonosetron provides a rationale behind the improved efficacy observed with the drug in prevention of delayed symptoms. This may be explained by allosteric binding properties and by palonosetron-triggered receptor internalization, which result in prolonged inhibition of the 5-HT3 receptor function. Very recent pharmacology experiments have also suggested that palonosetron would be able to differentially inhibit 5-HT3/neurokinin 1 (NK-1) receptor signaling cross-talk. In two recent meta-analyses, palonosetron was shown to be more effective than other available 5-HT3 RAs in preventing acute and delayed nausea and vomiting for both HEC and MEC. Recent findings also suggest that a single-day regimen of palonosetron plus dexamethasone (both drugs administered intravenously) may provide a reasonable therapeutic alternative to reduce the total dexamethasone dose administered in patients undergoing moderately emetogenic chemotherapy. Conclusions. On the basis of accumulating data, the evidence-based international guidelines devised from the major organizations have been recently updated to recommend the use of palonosetron plus 3-day dexamethasone for the optimal prevention of nausea and vomiting due to moderately emetogenic chemotherapy. There is still a need to investigate the efficacy of palonosetron in combination with an NK-1 receptor antagonist and dexamethasone in well-designed randomized trials. [PubMed Citation] [Order full text from Infotrieve]

3) Lin SJ, Hatoum HT, Buchner D, Cox D, Balu S
Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study.
BMC Health Serv Res. 2012 Jul 23;12(1):215.
ABSTRACT: BACKGROUND: 1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5- HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED). METHODS: Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics' (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. RESULTS: Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LCcisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p < 0.05). The BC and LC-carboplatin palonosetron groups experienced 50% and 30% fewer CINV days than the generic 5-HT3 RA group (p < 0.05). CONCLUSIONS: Patients with breast or lung cancer initiated and maintained on palonosetron were at significantly lower risk for potentially costly CINV versus those on older 5-HT3 RAs. Further studies on impact of step therapy policy are warranted in order to minimize the clinical and economic burden of CINV. [PubMed Citation] [Order full text from Infotrieve]

4) Liu FC, Liou JT, Liao HR, Mao CC, Yang P, Day YJ
The anti-aggregation effects of ondansetron on platelets involve IP3 signaling and MAP kinase pathway, but not 5-HT3-dependent pathway.
Thromb Res. 2012 Jul 17;
Ondansetron is a 5-HT3 receptor antagonist with potent antiemetic, analgesic, and antiphlogistic effects. Literature concerning 5-HT3 antagonists on platelets is limited. In this report we examined the pharmacological effects of ondansetron on human washed platelets. Platelet aggregation induced by thrombin (0.1U/mL), collagen (2?g/mL), arachidonic acid (0.5mM), ADP (10?M), or U46619 (2?M) was observed. The effects of ondansetron on platelet aggregation and ATP release were investigated at different concentrations. Cytosolic Ca(2+) influx concentration, TXB2, IP3, and the levels of cAMP and cGMP were monitored, and flow cytometric analysis and immunoblotting were performed to investigate downstream signaling components. Our results showed that ondansetron, in a concentration-dependent manner, inhibited agonist-induced platelet aggregation. At 75?M, ondansetron significantly attenuated intracellular Ca(2+) mobilization, thromboxane B2 formation, and ATP release by human washed platelets activated by thrombin, collagen, or U46619, whereas it only partially attenuated arachidonic acid-driven platelet activation. Administration of ondansetron resulted in attenuated IP3 production in the washed platelets stimulated by thrombin, as determined by reduced IP1 levels, as well as diminished p38 and ERK2 phosphorylation in response to thrombin. No effect of ondansetron on the levels of either cAMP or cGMP in washed platelets was observed. Furthermore, ondansetron-mediated inhibition of platelet aggregation was not impacted by SR 57227A, the 5-HT3 agonist. Thus, rather than involving the 5-HT3-dependent pathway, the negative effect of ondansetron on platelet aggregation is instead manifested through the attenuation of agonist-induced IP3 production and MAPK (p38 and ERK2) phosphorylation that results in suppressed intracellular Ca(2+) mobilization, TXB2 formation, and ATP release. [PubMed Citation] [Order full text from Infotrieve]

5) Agudelo M, Yoo C, Nair MP
Alcohol-induced serotonergic modulation: The role of histone deacetylases.
Alcohol. 2012 Jul 11;
Previous studies have demonstrated that alcohol use disorders (AUDs) are regulated by multiple mechanisms such as neurotransmitters and enzymes. The neurotransmitter, serotonin (5-hydroxytryptamine, 5-HT) may contribute to alcohol effects and serotonin receptors, including 5-HT3, play an important role in AUDs. Recent studies have also implicated histone deacetylases (HDACs) and acetyltransferases (HATS) in regulation of drug addiction, and HDAC inhibitors (HDACi) have been reported as transcriptional modulators of monoaminergic neurotransmission. Therefore, we hypothesize that HDACs may play a role in ethanol-induced serotonergic modulation. The effects of ethanol on serotonin and 5-HT3, and the role HDACs, HDAC activity and the HDACi, trichostatin A (TSA), play in alcohol-induced serotonergic effects were studied. Human SK-N-MC and neurons, were treated with ethanol (0.05, 0.1 and 0.2%), and/or TSA (50 nM), and 5-HT3 levels were assessed at 24-72 h. Gene expression was evaluated by qRT-PCR and protein by western blot and flow cytometry. Serotonin release was assessed by ELISA and HDAC activity by fluorometric assay. Our results show an increase in 5-HT3 gene after ethanol treatment. Further, ethanol significantly increased HDACs 1 and 3 genes accompanied by an increased in HDAC activity while TSA significantly inhibited HDACs. Studies with TSA show a significant upregulation of ethanol effects on 5-HT3, while surprisingly TSA inhibited ethanol-induced serotonin production. These results suggest that ethanol affects 5-HT3 and serotonin through mechanisms involving HDACs and HATs. In summary, our studies demonstrate some of the novel properties of HDAC inhibitors and contribute to the understanding of the mechanisms involve in alcohol-serotonergic modulation in the CNS. [PubMed Citation] [Order full text from Infotrieve]

6) Liu Z, Li H, Liu N, Wu C, Jiang J, Yue J, Jing Y, Dai Q
Diversity and evolution of conotoxins in Conus virgo, Conus eburneus, Conus imperialis and Conus marmoreus from the South China Sea.
Toxicon. 2012 Jul 7;
The venom peptides of cone snails are encoded by a large gene family, and can selectively bind to voltage-gated ion channels (Na(+), K(+) and Ca(2+) channels) and to membrane receptors (nAChR, 5-HT3R, NMDAR). To identify novel conotoxin genes and analyze the evolution of typical conotoxin superfamily genes from different Conus species, we have constructed cDNA libraries derived from the venom ducts of Conusvirgo, Conuseburneus, C. imperialis and Conusmarmoreus, which were collected from the South China Sea. 1312 transcripts from four Conus venom duct cDNA libraries were analyzed and 38.7-49.6% of the transcripts encoded conotoxin sequences. In addition to known conotoxins, 34 novel conotoxins have been identified and can be classified into eleven superfamilies, some of which showed unique patterns of cysteines or different signal peptide sequences. The evolutionary trees of T- and A-superfamily conotoxins were analyzed. Likelihood approaches revealed that T-superfamily conotoxins from the four Conus species undergo positive selection, mostly located in the mature toxin region. These findings contribute to a better understanding of the diversity and evolution of conotoxins from the South China Sea, and some novel conotoxins are valuable for further functional investigations. [PubMed Citation] [Order full text from Infotrieve]

7) Hayashida K, Kimura M, Yoshizumi M, Hobo S, Obata H, Eisenach JC
Ondansetron Reverses Antihypersensitivity from Clonidine in Rats after Peripheral Nerve Injury: Role of γ-Aminobutyric Acid in α2-Adrenoceptor and 5-HT3 Serotonin Receptor Analgesia.
Anesthesiology. 2012 Aug;117(2):389-98.
[PubMed Citation] [Order full text from Infotrieve]

8) Kato S, Matsuda N, Matsumoto K, Wada M, Onimaru N, Yasuda M, Amagase K, Horie S, Takeuchi K
Dual role of serotonin in the pathogenesis of indomethacin-induced small intestinal ulceration: Pro-ulcerogenic action via 5-HT3 receptors and anti-ulcerogenic action via 5-HT4 receptors.
Pharmacol Res. 2012 Sep;66(3):226-34.
Serotonin (5-HT) exerts multiple physiological functions not only in the central and peripheral nervous systems but also in the gastrointestinal tract, and these multiple functions are accounted for by a variety of 5-HT receptor subtypes. We investigated the role of 5-HT in the pathogenesis of indomethacin-induced intestinal lesions in mice, in relation to 5-HT receptor subtypes. A single oral administration of indomethacin (10mg/kg) provoked damage in the small intestine of mice 24h later, and this response was prevented by pretreatment with p-chlorophenylalanine (a 5-HT synthesis inhibitor). The administration of 5-HT3 receptor antagonists, such as ondansetron and ramosetron, dose-dependently reduced the severity of the intestinal lesions, whereas a high dose of GR113808 (a 5-HT4 receptor antagonist) significantly aggravated these lesions. In contrast, NAN-190 (a 5-HT1 receptor antagonist), ketanserin (a 5-HT2 receptor antagonist), and SB269970 (a 5-HT7 receptor antagonist) had no effect on these lesions. Mosapride (a 5-HT4 receptor agonist) significantly reduced the severity of indomethacin-induced intestinal lesions, and this protective effect was totally prevented by either GR113808 or methyllycaconitine (an ?7-nicotinic acetylcholine receptor antagonist). Indomethacin increased the activity of myeloperoxidase and the expression of inducible nitric oxide synthase, inflammatory cytokines, and chemokines in the small intestine; these responses were significantly attenuated by ondansetron and mosapride. These findings suggest that endogenous 5-HT exerts a dual role in the pathogenesis of indomethacin-induced intestinal lesions: pro-ulcerogenic action via 5-HT3 receptors and anti-ulcerogenic action via 5-HT4 receptors, and the latter effect via 5-HT4 receptors may be mediated by activation of ?7-nicotinic acetylcholine receptors. [PubMed Citation] [Order full text from Infotrieve]

9) Dogan U, Yavas G, Tekinalp M, Yavas C, Ata OY, Ozdemir K
Evaluation of the acute effect of palonosetron on transmural dispersion of myocardial repolarization.
Eur Rev Med Pharmacol Sci. 2012 Apr;16(4):462-8.
[PubMed Citation] [Order full text from Infotrieve]

10) van der Velden L, van Hooft JA, Chameau P
Altered dendritic complexity affects firing properties of cortical layer 2/3 pyramidal neurons in mice lacking the 5-HT3A receptor.
J Neurophysiol. 2012 Jun 13;
We have previously shown that the serotonergic input on Cajal-Retzius cells, mediated by 5-HT3 receptors, plays an important role in the early postnatal maturation of the apical dendritic trees of layer 2/3 pyramidal neurons. We reported that knockout mice lacking the 5-HT(3A) receptor showed exuberant apical dendrites of these cortical pyramidal neurons. Since model studies have shown the role of dendritic morphology on neuronal firing pattern, we used the 5-HT(3A) knockout mouse to explore the impact of dendritic hypercomplexity on the electrophysiological properties of this specific class of neurons. Our experimental results show that hypercomplexity of the apical dendritic tuft of layer 2/3 pyramidal neurons affects neuronal excitability by reducing the amount of spike frequency adaptation. This difference in firing pattern, related to a higher dendritic complexity, was accompanied by an altered development of the afterhyperpolarization slope with successive action potentials. Our abstract and realistic neuronal models, which allowed manipulation of the dendritic complexity, showed similar effects on neuronal excitability and confirmed the impact of apical dendritic complexity. Alterations of dendritic complexity, as observed in several pathological conditions such as neurodegenerative diseases or neurodevelopmental disorders, may thus not only affect the input to layer 2/3 pyramidal neurons, but also shape their firing pattern and consequently alter the information processing in the cortex. [PubMed Citation] [Order full text from Infotrieve]

11) Mir O, Durand JP, Boudou-Rouquette P, Giroux J, Coriat R, Cessot A, Ropert S, Goldwasser F, Gaillard R
Interaction between serotonin reuptake inhibitors, 5-HT3 antagonists, and NK1 antagonists in cancer patients receiving highly emetogenic chemotherapy: a case-control study.
Support Care Cancer. 2012 May 30;
BACKGROUND: Previous reports suggested that selective serotonin reuptake inhibitors (SSRI) could decrease the activity of 5-hydroxytryptamine type 3 (5-HT3) antagonists against acute chemotherapy-induced nausea and vomiting (CINV), possibly through serotonin accumulation for 5-HT3 receptors. PATIENTS AND METHODS: Chemonaive cancer patients receiving SSRI and antiemetic agents, including the 5-HT3 antagonist ondansetron and the neurokinin 1 (NK1) antagonist aprepitant for highly emetogenic chemotherapy (etoposide-platinum), were matched to control patients for the following variables: age, gender, primary tumor, past history of gestational emesis, chronic intake of benzodiazepines and/or corticosteroids, chronic alcohol intake, and aprepitant use. The primary evaluation criterion was the occurrence of acute vomiting during the first two cycles of treatment. RESULTS: Forty-four patients were eligible for this analysis. The proportion of patients, who experienced at least one episode of grade ? 1 acute vomiting in patients receiving SSRI, compared to patients who did not, was significantly higher (59.1 vs. 22.7 %, respectively, p?=?0.03, odds ratio 4.72, 95 % confidence interval 1.13-22.88). Grade ? 2 acute vomiting was also significantly more frequent in patients receiving SSRI, even after the implementation of aprepitant to antiemetic prophylaxis (41.2 vs. 5.9 %, p?=?0.04). CONCLUSIONS: Our findings reinforce the hypothesis that SSRI decrease the antiemetic activity of the 5-HT3 serotonin antagonist ondansetron, resulting in higher rates of acute vomiting in cancer patients despite adequate antiemetic prophylaxis. Adding the NK1 antagonist aprepitant do not counterbalance the deleterious effect of SSRI, probably due to the synergistic effects of SSRI and NK1 antagonists on serotonin transmission. [PubMed Citation] [Order full text from Infotrieve]

12) Zhang Y, Zhang RX, Zhang M, Shen XY, Li A, Xin J, Ren K, Berman BM, Tan M, Lao L
Electroacupuncture inhibition of hyperalgesia in an inflammatory pain rat model: involvement of distinct spinal serotonin and norepinephrine receptor subtypes.
Br J Anaesth. 2012 Aug;109(2):245-52.
[PubMed Citation] [Order full text from Infotrieve]

13) Leite GD, Fernandes CN, Alencar de Menezes IR, da Costa JG, Campos AR
Attenuation of visceral nociception by alpha-bisabolol in mice: investigation of mechanisms.
Org Med Chem Lett. 2012 May 21;2(1):18.
ABSTRACT: BACKGROUND: We previously described the visceral antinociceptive property of alpha-bisabolol (BISA) in mouse models of visceral nociception induced by cyclophosphamide and mustard oil (MO). This study examined the effect of BISA in mouse models of visceral nociception induced by acetic acid, capsaicin, formalin, and the contribution of the nitric oxide system, alpha2, KATP+, 5-HT3, and TRPV1 receptors to the effect of BISA on MO-evoked nociceptive behaviors. Mice were pretreated orally with BISA (50, 100, 200 mg/kg) or vehicle, and the pain-related behavioral responses to intraperitoneal administration of acetic acid or intracolonic injection of MO was analyzed. RESULTS: BISA significantly suppressed the nociceptive behaviors in a dose-unrelated manner. The antinociceptive effect of BISA (50 mg/kg) was show to be glibenclamide resistant, but it was not blocked by pretreatment with the other antagonists tested. In the open-field test that detects sedative or motor abnormality, mice received 50 mg/kg BISA did not show any per se influence in ambulation frequency. CONCLUSIONS: However, their precise antinociceptive mechanisms of action have not been determined. [PubMed Citation] [Order full text from Infotrieve]

14) Trattnig SM, Harpsøe K, Thygesen SB, Rahr LM, Ahring PK, Balle T, Jensen AA
J Biol Chem. 2012 Jul 20;287(30):25241-54.
The ligand-gated ion channels in the Cys-loop receptor superfamily mediate the effects of neurotransmitters acetylcholine, serotonin, GABA, and glycine. Cys-loop receptor signaling is susceptible to modulation by ligands acting through numerous allosteric sites. Here we report the discovery of a novel class of negative allosteric modulators of the 5-HT(3) receptors (5-HT(3)Rs). PU02 (6-[(1-naphthylmethyl)thio]-9H-purine) is a potent and selective antagonist displaying IC(50) values of ?1 ?m at 5-HT(3)Rs and substantially lower activities at other Cys-loop receptors. In an elaborate mutagenesis study of the 5-HT(3)A receptor guided by a homology model, PU02 is demonstrated to act through a transmembrane intersubunit site situated in the upper three helical turns of TM2 and TM3 in the (+)-subunit and TM1 and TM2 in the (-)-subunit. The Ser(248), Leu(288), Ile(290), Thr(294), and Gly(306) residues are identified as important molecular determinants of PU02 activity with minor contributions from Ser(292) and Val(310), and we propose that the naphthalene group of PU02 docks into the hydrophobic cavity formed by these. Interestingly, specific mutations of Ser(248), Thr(294), and Gly(306) convert PU02 into a complex modulator, potentiating and inhibiting 5-HT-evoked signaling through these mutants at low and high concentrations, respectively. The PU02 binding site in the 5-HT(3)R corresponds to allosteric sites in anionic Cys-loop receptors, which emphasizes the uniform nature of the molecular events underlying signaling through the receptors. Moreover, the dramatic changes in the functional properties of PU02 induced by subtle changes in its binding site bear witness to the delicate structural discrimination between allosteric inhibition and potentiation of Cys-loop receptors. [PubMed Citation] [Order full text from Infotrieve]

15) Chopra A, Tipps ME, Iyer SV, John Mihic S
Trifluoroacetate is an allosteric modulator with selective actions at the glycine receptor.
Neuropharmacology. 2004;63(3):368-73.
Serotonin (5-hydroxytryptamine; 5-HT), a derivative of the tryptophan amino acid, is a low molecular weight neurotransmitter that plays an important role in the functioning of different physiological, cognitive, and emotional processes. Impairment of the serotonergic system is associated with psychiatric disorders, such as anxiety and depression, and neurological afflictions, such as Parkinson?s disease, Alzheimer?s disease, and epilepsy (1). The 5-HT mediates its biological activity through a group of seven receptors (5-HT1-7R) that are further classified into 14 distinct subtypes on the basis of their structure and pharmacological activity. Except for the 5-HT3R, which is a ligand-gated ion channel, all other 5-HTRs belong to the family of G-protein?coupled seven-transmembrane receptors (2). Radiolabeled tracers have been developed for use with positron emission tomography (PET) to study the different 5-HTR subtypes, and much information is available regarding only the 5-HT1AR, 5-HT1BR, 5-HT2AR, and 5-HT4R subtypes (3). Compared to the discovery of the other 5-HTR subtypes, the identification of 5-HT6R is fairly recent, and this receptor is located mostly in the limbic and cortical regions of the mammalian central nervous system (4). Although the exact mechanism of action of the 5-HT6R is not clear, there are indications that antagonists of this receptor reverse amnesia and improve cognitive and memory functions in individuals suffering from schizophrenia, Parkinson's disease, or Alzheimer?s disease (5). Therefore, it was imperative to develop a ligand that could be used to study the biological characteristics of this receptor. Radioiodinated SB-258585 ([125I]-SB258585), a selective antagonist of the 5-HT6R, has been shown to have a high affinity for this receptor in membranes derived from rat or pig striatum and human caudate putamen (6). Autoradiography of rat brain sections exposed to [125I]-SB258585 revealed that the 5-HT6R was located primarily in the striatum, followed by the cerebral cortex; accumulation was lowest in the cerebellum of these animals. From this observation, the investigators concluded that the receptor was probably involved in cognition, memory, and locomotor control functions in the animals (7). In another study, [N-methyl]3-[(3-fluorophenyl)sulfonyl]-8-(4-methyl-1-piperazinyl)quinoline (GSK215083) was reported to have a 5-fold and >55-fold higher subnanomolar concentration affinity for the 5-HT6R compared to the concentrations required for the 5-HT2AR and the other 5-HTRs, respectively (3). In addition, the lipophilicity of GSK215083 was determined to be suitable for crossing the blood?brain barrier and penetration into the brain. On the basis of these observations, [11C]-GSK215083 was evaluated in vivo as a 5-HT6R ligand in pigs, non-human primates, and humans (3). [PubMed Citation] [Order full text from Infotrieve]

16) Tatara A, Shimizu S, Shin N, Sato M, Sugiuchi T, Imaki J, Ohno Y
Modulation of antipsychotic-induced extrapyramidal side effects by medications for mood disorders.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Sep;38(2):252-9.
Antipsychotic drugs are widely used not only for schizophrenia, but also for mood disorders such as bipolar disorder and depression. To evaluate the interactions between antipsychotics and drugs for mood disorders in modulating extrapyramidal side effects (EPS), we examined the effects of antidepressants and mood-stabilizing drugs on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. The selective serotonin reuptake inhibitors (SSRIs), fluoxetine and paroxetine, and the tricyclic antidepressant (TCA) clomipramine, which showed no EPS by themselves, significantly potentiated HAL-induced bradykinesia and catalepsy in a dose-dependent manner. In contrast, the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine failed to augment, but rather attenuated HAL-induced bradykinesia and catalepsy. Mianserin also tended to reduce the EPS induction. In addition, neither treatment with lithium, sodium valproate nor carbamazepine potentiated HAL-induced EPS. Furthermore, treatment of animals with ritanserin (5-HT2A/2C antagonist), ondansetron (5-HT3 antagonist), and SB-258585 (5-HT6 antagonist) significantly antagonized the EPS augmentation by fluoxetine. Intrastriatal injection of ritanserin or SB-258585, but not ondansetron, also attenuated the EPS induction. The present study suggests that NaSSAs are superior to SSRIs or TCAs in combined therapy for mood disorders with antipsychotics in terms of EPS induction. In addition, 5-HT2A/2C, 5-HT3 and 5-HT6 receptors seem to be responsible for the augmentation of antipsychotic-induced EPS by serotonin reuptake inhibitors. [PubMed Citation] [Order full text from Infotrieve]

17) Kim SH, Park YS, Kim JM, Park HJ, Lee MH, Park HK, Kim YJ, Cho SH, Shaw LM, Kang JS
Pharmacokinetic and bioavailability studies of 5 mg mosapride tablets in healthy Korean volunteers.
Int J Clin Pharmacol Ther. 2012 Aug 7;Volume 50(July):524-531.
Aim: Mosapride is a gastroprokinetic agent, a 5-HT4 receptor agonist and 5-HT3 receptor antagonist exhibiting no activity at dopamine D2, 5-HT1 and 5-HT2 receptors. This study was performed to compare basic pharmacokinetic (PK) characteristics of mosapride for Korean young adults and to evaluate the bioequivalence (BE) of two formulations of drugs mosapride. Volunteers and methods: For pharmacokinetic and bioavailability of 5 mg mosapride tablets in healthy Korean adults, a randomized, twoway, crossover bioequivalence study in 23 healthy Korean volunteers (M : F = 16 : 7) was conducted to compare bioavailability of two formulation of 5 mg mosapride citrate tablets, Moprid® (Chung Kun Dang Pharm Co., Ltd., Korea) as a test and Gasmotin® (Daewoong Pharm Co., Ltd., Korea) as a reference drug. Subjects were administered single dosage of 3 tablets of each formulation with 240 ml water after 10 h overnight fasting on 2 treatment days separated by 1-week washout period. Before and after dosing, blood sample were collected at 0, 0.25, 0.5, 0.8, 1.0, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 h and analyzed by validated liquid chromatography- tandem mass spectrometry (LC-MS/ MS) in the range 1.28 - 192 ng/ml with the lowest limit of quantification of 1.28 ng/ml. Results: Several PK characteristics were determined from the plasma samples, and data from reference and test fomulations in the plasma were represented such as AUC0- t (184.4 vs. 179.6 ng×h/ml), AUC0-? (192.8 vs. 186.6 ng×h/ml), Cmax (98.9 vs. 84.4 ng/ ml), tmax (0.8 vs. 0.7 h), half-life (2.4 vs. 2.3 h), Ke (0.289 vs. 0.301), respectively. AUC0- t and Cmax were tested for bioequivalence after log-transformation of plasma data. PK characteristics with 90% confidence interval (CI) of test/reference ratio based on ANOVA analysis were 0.842 - 1.163 for AUC0-t and 0.753 - 1.088 for Cmax. PK characteristics with 90% CI were within the bioequivalence range of 80 - 125% of FDA statistical limit. Cmax with 90% CI were not within the bioequivalence range of 80 - 125% of FDA statistical limit. However, this result was assessed to bioequivalence in accordance with the "Bioequivalence Test Guidelines" outlined in No. 2005-31 of the KFDA. Conclusion: Therefore, both mosapride formulations were bioequivalent during fasting state in healthy Korean adults. [PubMed Citation] [Order full text from Infotrieve]

18) Haniadka R, Rajeev AG, Palatty PL, Arora R, Baliga MS
Zingiber officinale (ginger) as an anti-emetic in cancer chemotherapy: a review.
J Altern Complement Med. 2012 Jun 19;18(5):440-4.
Despite significant advances and development of novel anti-emetics, nausea and vomiting (emesis) is a major side-effect of cancer chemotherapy. At times, severe nausea and vomiting may also lead to reduction in adherence to the treatment regimen, and this will concomitantly affect the patient's survival. The rhizome of Zingiber officinale, commonly known as ginger, is globally an important spice. It has been used for centuries in the Indian, Chinese, Arabic, Tibetan, Unani, and Siddha systems of traditional medicine to treat nausea and vomiting induced by different stimuli. Preclinical studies with experimental animals (dogs and rats) have shown that the various extracts of ginger and the ginger juice possess anti-emetic effects against chemotherapy-induced nausea and vomiting. Gingerol, the active principle, is also shown to possess anti-emetic effects in minks. However, with regard to humans, while most studies have been supportive of the preclinical observations, a few have been contradictory. The exact mechanism responsible for the anti-emetic effects of ginger is unknown; however, the ginger phytochemicals, especially 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol, may function as a 5-hydroxytryptamine (5-HT3) antagonist, NK1 antagonist, antihistaminic, and possess prokinetic effects. The present review for the first time attempts to address the anti-emetic observations and the variability in response of the anti-emetic effects of ginger in cancer chemotherapy. An attempt is also made to address the lacunae in the published studies and emphasize aspects that need further investigations for ginger to be of use in clinics as an anti-emetic agent in the future. [PubMed Citation] [Order full text from Infotrieve]

19) McKinnon NK, Bali M, Akabas MH
Length and amino acid sequence of peptides substituted for the 5-HT3A receptor M3M4 loop may affect channel expression and desensitization.
PLoS One. 2012 May;7(4):e35563.
5-HT3A receptors are pentameric neurotransmitter-gated ion channels in the Cys-loop receptor family. Each subunit contains an extracellular domain, four transmembrane segments (M1, M2, M3, M4) and a 115 residue intracellular loop between M3 and M4. In contrast, the M3M4 loop in prokaryotic homologues is <15 residues. To investigate the limits of M3M4 loop length and composition on channel function we replaced the 5-HT3A M3M4 loop with two to seven alanine residues (5-HT3A-A(n = 2-7)). Mutants were expressed in Xenopus laevis oocytes and characterized using two electrode voltage clamp recording. All mutants were functional. The 5-HT EC(50)'s were at most 5-fold greater than wild-type (WT). The desensitization rate differed significantly among the mutants. Desensitization rates for 5-HT3A-A(2), 5-HT3A-A(4), 5-HT3A-A(6), and 5-HT3A-A(7) were similar to WT. In contrast, 5-HT3A-A(3) and 5-HT3A-A(5) had desensitization rates at least an order of magnitude faster than WT. The one Ala loop construct, 5-HT3A-A(1), entered a non-functional state from which it did not recover after the first 5-HT application. These results suggest that the large M3M4 loop of eukaryotic Cys-loop channels is not required for receptor assembly or function. However, loop length and amino acid composition can effect channel expression and desensitization. We infer that the cytoplasmic ends of the M3 and M4 segments may undergo conformational changes during channel gating and desensitization and/or the loop may influence the position and mobility of these segments as they undergo gating-induced conformational changes. Altering structure or conformational mobility of the cytoplasmic ends of M3 and M4 may be the basis by which phosphorylation or protein binding to the cytoplasmic loop alters channel function. [PubMed Citation] [Order full text from Infotrieve]