5-HT3 Receptor Research -- Neurotransmitter.net

(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."
[Abstract]
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]

PAUL A. DAVIES, MARCO PISTIS†, MICHAEL C. HANNA, JOHN A. PETERS, JEREMY J. LAMBERT, TIM G. HALES & EWEN F. KIRKNESS
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." [Abstract]
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) Brugnatelli S, Gattoni E, Grasso D, Rossetti F, Perrone T, Danova M
Single-dose palonosetron and dexamethasone in preventing nausea and vomiting induced by moderately emetogenic chemotherapy in breast and colorectal cancer patients.
Tumori. 2011 May-Jun;97(3):362-6.
Aims and background. Palonosetron, a unique second-generation 5-HT3 receptor antagonist, has been demonstrated to control emesis related to chemotherapy-induced nausea and vomiting (CINV). The aim of this study was to evaluate the efficacy and tolerability of palonosetron followed by a single dose of dexamethasone in patients with breast cancer (BC) or colorectal cancer (CRC) receiving moderate emetogenic chemotherapy (MEC). Methods and study design. Chemotherapy-naive BC and CRC patients were given MEC as adjuvant or first-line treatment. Palonosetron (0.25 mg IV) and dexamethasone (8 mg IV) were administered before chemotherapy on day 1. The primary endpoint was complete response (CR; no vomiting and no use of rescue medication) during the overall study period (days 1-5). The antiemetic response was evaluated during the acute (day 1) and delayed (days 2-5) phases. Results. Sixty-eight patients were enrolled (median age 61 years, 56 females; BC = 40, CRC = 28). CR was observed in 46 of 68 patients (67.6%), while CR during the acute and delayed phases was 75.0% in each cancer group. The antiemetic regimen was well tolerated. Conclusions. A single administration of palonosetron and dexamethasone on day 1 in BC and CRC patients adequately controls CINV during the entire period of emetic risk. [PubMed Citation] [Order full text from Infotrieve]

2) Lummis SC, Thompson AJ, Bencherif M, Lester HA
Varenicline is a potent agonist of the human 5-HT3 Receptor.
J Pharmacol Exp Ther. 2011 Jul 20;
Varenicline, a widely used and successful smoking cessation agent, acts as a partial agonist at nicotinic acetylcholine receptors. Here we explore the effects of varenicline at human and mouse 5-HT(3) receptors. Application of varenicline to human 5-HT(3) receptors expressed in Xenopus oocytes reveal it is almost a full agonist (Rmax ~80%) with an EC50 (5.9 �M) ~ 3 fold higher than 5-HT. At mouse 5-HT(3) receptors varenicline is a partial agonist (Rmax ~35%) with an EC50 (18 �M) ~20 fold higher than 5-HT. Displacement of the competitive 5-HT(3) receptor antagonist [3H]granisetron reveals similar IC50s for varenicline at mouse and human receptors expressed in HEK293 cells, although studies in these cells using a membrane potential sensitive dye show that again varenicline is a ~3 fold or ~20 fold less potent agonist than 5-HT in human and mouse receptors respectively. Thus the data suggest that the efficacy, but not the affinity, of varenicline is greater at human 5-HT(3) receptors when compared to mouse. Docking studies provide an explanation for this difference as they suggest distinct orientations of the ligand in the mouse vs human 5-HT(3) agonist binding sites. Additional binding selectivity studies in a broad panel of recombinant receptors and enzymes confirmed an interaction with 5-HT(3) receptors but revealed no additional interactions of varenicline. Therefore, activation of human 5-HT(3) receptors may be responsible for some of the side effects that preclude use of higher doses during varenicline treatment. [PubMed Citation] [Order full text from Infotrieve]

3) Ogawa E, Sakakibara R, Kishi M, Tateno F
Constipation triggered the malignant syndrome in Parkinson's disease.
Neurol Sci. 2011 Jul 20;
A 69-year-old, chronically constipated patient with Parkinson's disease developed fecal impaction and the malignant syndrome simultaneously, even while the patient was taking anti-parkinsonian drugs as prescribed. Administration of intravenous levodopa and oral Dai-kenchu-tou, an herbal medicine with serotonergic 5-HT3 receptor agonistic property successfully ameliorated his clinical symptoms. Constipation may trigger worsening of Parkinson's disease and occurrence of the malignant syndrome by affecting levodopa absorption. Further, improved bowel motility may prevent worsening of Parkinson's disease and occurrence of the malignant syndrome. [PubMed Citation] [Order full text from Infotrieve]

4) Alvarez E, Perez V, Dragheim M, Loft H, Artigas F
A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder.
Int J Neuropsychopharmacol. 2011 Jul 18;:1-12.
The efficacy, safety, and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in patients with DSM-IV-TR major depressive disorder (MDD) were evaluated. Lu AA21004 is a novel antidepressant that is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines. In this 6-wk, multi-site study, 429 patients were randomly assigned (1:1:1:1) to 5 or 10 mg Lu AA21004, placebo or 225 mg venlafaxine XR. All patients had a baseline Montgomery-�sberg Depression Rating Scale (MADRS) total score ?30. The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity using a hierarchical testing procedure starting with the highest dose vs. placebo. Lu AA21004 was statistically significantly superior to placebo (n=105) in mean change from baseline in MADRS total score at week 6 (p<0.0001, last observation carried forward), with a mean treatment difference vs. placebo of 5.9 (5 mg, n=108), and 5.7 (10 mg, n=100) points. Venlafaxine XR (n=112) was also significantly superior to placebo at week 6 (p<0.0001). In total, 30 patients withdrew due to adverse events (AEs) - placebo: four (4%); 5 mg Lu AA21004: three (3%); 10 mg Lu AA21004: seven (7%); and venlafaxine: 16 (14%). The most common AEs were nausea, headache, hyperhidrosis, and dry mouth. No clinically relevant changes over time were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD. [PubMed Citation] [Order full text from Infotrieve]

5) Baptista-Hon DT, Deeb TZ, Othman NA, Sharp D, Hales TG
The 5-HT3B subunit affects high potency 5-HT(3) receptor inhibition by morphine.
Br J Pharmacol. 2011 Jul 8;
Background and purpose:? Morphine is an antagonist at 5-HT(3) A receptors. 5-HT(3) and opioid receptors are expressed in many of the same neuronal pathways where they modulate gut motility, pain and reinforcement. There is increasing interest in the 5-HT3B subunit which confers altered pharmacology to 5-HT(3) receptors. We investigated the mechanisms of inhibition by morphine of 5-HT(3) receptors and the influence of the 5-HT3B subunit. Experimental approach:? 5-HT-evoked currents were recorded from voltage clamped HEK293 cells expressing human 5-HT3A subunits alone or in combination with 5-HT3B subunits. The affinity of morphine for the orthosteric site of 5-HT(3) A or 5-HT(3) AB, receptors was assessed using radioligand binding with the antagonist [(3) H]GR65630. Key results:? When pre-applied morphine potently inhibited 5-HT-evoked currents mediated by 5-HT(3) A receptors. The 5-HT3B subunit reduced the potency of morphine four-fold and increased the rates of inhibition and recovery. The inhibition by pre-applied morphine was insurmountable by 5-HT, was voltage-independent and occurred through a site outside the second membrane-spanning domain. When applied simultaneously with 5-HT, morphine caused a lower potency and surmountable inhibition of 5-HT(3) A and 5-HT(3) AB receptors. Morphine also fully displaced [(3) H]GR65630 from 5-HT(3) A and 5-HT(3) AB receptors with similar potency. Conclusions and implications:? These findings suggest that morphine has two sites of action, a low affinity, competitive site and a high affinity, non-competitive site that is not available when the channel is activated. The affinity of morphine for the latter is reduced by the 5-HT3B subunit. Our results reveal that morphine causes a high affinity insurmountable subunit-dependent inhibition of human 5-HT(3) receptors. [PubMed Citation] [Order full text from Infotrieve]

6) Thompson AJ, Price KL, Lummis SC
Cysteine modification reveals which subunits form the ligand binding site in human heteromeric 5-HT3AB receptors.
J Physiol. 2011 Jun 27;
The ligand binding site of Cys-loop receptors is formed by residues on the principal (+) and complementary (-) faces of adjacent subunits, but the subunits that constitute the binding pocket in many heteromeric receptors is not yet clear. To probe the subunits involved in ligand binding in heteromeric human 5-HT3AB receptors, we made cysteine substitutions to the + and - faces of A and B subunits, and measured their functional consequences in receptors expressed in Xenopus oocytes. All A subunit mutations altered or eliminated function. The same pattern of changes were seen at homomeric and heteromeric receptors containing cysteine substitutions at AR92 (- face), AL126(+), AN128(+), AI139(-), AQ151(-) and AT181(+), and these receptors displayed further changes when the sulphydryl modifying reagent methanethiosulfonate-ethylammonium (MTSEA) was applied. Modifications of AR92C(-) and AT181C(+)-containing receptors were protected by the presence of agonist (5-HT) or antagonist (d-TC). In contrast modifications of the equivalent B subunit residues did not alter heteromeric receptor function. In addition a double mutant, AS206C(-)/E229C(+), only responded to 5-HT following DTT treatment in both homomeric and heteromeric receptors, indicating receptor function was inhibited by a disulphide bond between an A+ and an A- interface in both receptor types. Our results are consistent with binding to an A+A- interface at both homomeric and heteromeric human 5-HT3 receptors, and explain why the competitive pharmacologies of these two receptors are identical. [PubMed Citation] [Order full text from Infotrieve]

7) Takeuchi K, Tanaka A, Nukui K, Kojo A, Gyenge M, Amagase K
Aggravation by Paroxetine, A Selective Serotonin Re-Uptake Inhibitor, of Antral Lesions Generated by Nonsteroidal Anti-inflammatory Drugs in Rats.
J Pharmacol Exp Ther. 2011 Jun 24;
Recent clinical studies have suggested a risk of adverse gastric reactions from the concomitant use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with nonsteroidal anti-inflammatory drugs (NSAIDs). We examined the adverse effects of SSRIs on antral lesions produced by indomethacin in rats. Rats fasted for 24 h were refed for 1 h, then administered indomethacin (30 mg/kg) s.c. 1 h after the refeeding, and killed 6 h later. Paroxetine (1~10 mg/kg) was given p.o. 30 min before indomethacin. Indomethacin caused antral lesions in re-fed rats. Paroxetine dose-dependently aggravated these lesions, despite provoking no damage by itself. Similar results were obtained when other NSAIDs such as diclofenac, flurbiprofen, and loxoprofen were co-administered with paroxetine or when indomethacin was co-administered with other antidepressants such as fluvoxamine and milnacipran, but not imipramine or maprotiline. Exogenous 5-HT also worsened the indomethacin-induced antral damage, while the aggravating effect of paroxetine was attenuated by ondansetron, a selective 5-HT3 antagonist, but not antagonists for other 5-HT receptor subtypes. Indomethacin plus paroxetine had no effect on gastric secretion but significantly decreased mucosal superoxide dismutase (SOD) activity as well as glutathione content. The antral damage induced by indomethacin plus paroxetine was significantly prevented by antisecretory (acid or pepsin) agents and mucosal protective agents as well as SOD and allopurinol. These results suggest that SSRIs aggravate NSAID-induced antral lesions, probably via the activation of 5HT3 receptors, and the mechanism of aggravation may involve the corrosive action of acid/pepsin as well as an impaired anti-oxidative system. [PubMed Citation] [Order full text from Infotrieve]

8) Hashimoto K
[Development of new therapeutic drugs based on the pathophysiology of schizophrenia].
Seishin Shinkeigaku Zasshi. 2011;113(4):368-73.
Cognitive deficits in schizophrenia are the core symptoms of this disorder, and are strongly correlated with decreased QOL in patients. Antipsychotic drugs have been used therapeutically for positive symptoms, including hallucinations and delusions. However, many patients treated with antipsychotic drugs fail to recover from cognitive deficits. Therefore, a number of new therapeutic drugs for cognitive deficits in schizophrenia are currently being developed around the world. A number of studies suggest that nicotine, a major component of cigarettes, could improve cognitive deficits in patients with schizophrenia. Accumulating evidence suggests that the alpha7 subtype of nicotinic receptors (alpha7 nAchRs) play a role in the pathophysiology of schizophrenia, as well as deficits in auditory evoked potential P50 in patients with schizophrenia. We have reported that the antiemetic drug tropisetron (alpha7 nAchR agonist and 5-HT3 receptor antagonist) improved auditory P20-N40 deficits in DBA/2 mice, and cognitive deficits after administration of the NMDA receptor antagonist phencyclidine. Furthermore, a single administration of tropisetron was associated with improved auditory P50 deficits in non-smoking patients with schizophrenia. Moreover, a randomized, double-blind, placebo-controlled study demonstrated that tropisetron significantly improved auditory P50 deficits and attention deficits in patients with schizophrenia. In this paper, the author will discuss the therapeutic potential of alpha7 nAChR agonists for cognitive deficits in patients with schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

9) Crisafulli C, Fabbri C, Porcelli S, Drago A, Spina E, De Ronchi D, Serretti A
Pharmacogenetics of antidepressants.
Front Pharmacol. 2011;2:6.
Up to 60% of depressed patients do not respond completely to antidepressants (ADs) and up to 30% do not respond at all. Genetic factors contribute for about 50% of the AD response. During the recent years the possible influence of a set of candidate genes as genetic predictors of AD response efficacy was investigated by us and others. They include the cytochrome P450 superfamily, the P-glycoprotein (ABCB1), the tryptophan hydroxylase, the catechol-O-methyltransferase, the monoamine oxidase A, the serotonin transporter (5-HTTLPR), the norepinephrine transporter, the dopamine transporter, variants in the 5-hydroxytryptamine receptors (5-HT1A, 5-HT2A, 5-HT3A, 5-HT3B, and 5-HT6), adrenoreceptor beta-1 and alpha-2, the dopamine receptors (D2), the G protein beta 3 subunit, the corticotropin releasing hormone receptors (CRHR1 and CRHR2), the glucocorticoid receptors, the c-AMP response-element binding, and the brain-derived neurotrophic factor. Marginal associations were reported for angiotensin I converting enzyme, circadian locomotor output cycles kaput protein, glutamatergic system, nitric oxide synthase, and interleukin 1-beta gene. In conclusion, gene variants seem to influence human behavior, liability to disorders and treatment response. Nonetheless, gene?�?environment interactions have been hypothesized to modulate several of these effects. [PubMed Citation] [Order full text from Infotrieve]

10) Lee TH, Kim KH, Lee SO, Lee KR, Son M, Jin M
Tetrahydroberberine, an Isoquinoline Alkaloid Isolated from Corydalis Tuber, Enhances Gastrointestinal Motor Function.
J Pharmacol Exp Ther. 2011 Jun 9;
As delayed gastric emptying and impaired gastric accommodation are regarded as the pathophysiological mechanisms underlying functional dyspepsia (FD), prokinetic and fundic relaxants have been suggested as a new treatment for FD. We isolated tetrahydroberberine (THB), an isoquinoline alkaloid, (5,8,13,13 a-Tetrahydro-9,10-dimethoxy-6H-benzo[g]-1,3-benzodioxolo[5,6-a]quinolizine) from Corydalis Tuber, and found that it has micromolar affinity for dopamine D2 (pKi 6.08) and 5-HT1A (pKi 5.38) receptors, but moderate to no affinity for other relevant serotonin receptors [i.e., 5-HT1B, 5-HT1D, 5-HT3, and 5-HT4: pKi < 5.00]. Oral administration of THB not only significantly accelerated gastric emptying of normal rats in a bell-shaped relationship with a maximal efficacy at the dose of 30 ?g/kg, but also restored the delayed gastric emptying caused by apomorphine, which might be mediated by an anti-dopaminergic effect. Data from electromyography indicated that THB enhanced gastro motor function of the upper GI tract by strengthening contractility and shortening the contraction interval. Furthermore, in rats stressed by repeated restraint, a significantly higher shift in pressure-volume curve by THB (10 ?g/kg, P<0.05), which was inhibited by WAY100635, a 5- HT1A antagonist and L-NAME, a NOS inhibitor, but not VIP antagonist, was observed. Oral administration of THB resulted in a drastic increase of gastric accommodation in Beagle dogs. Area under the volume versus time curve was significantly increased by THB (30 ?g/kg, p<0.01), comparable to that of sumatriptan (3 mg/kg), a potent fundic relaxant. Taken together, our data suggested that THB, with D2 antagonist and 5-HT1A agonist properties, has great potential as a therapeutic for treatment of FD. [PubMed Citation] [Order full text from Infotrieve]

11) Chen JS, Chen YY, Huang JS, Yeh KY, Chen PT, Shen WC, Hsu HC, Lin YC, Wang HM
A multiple-center phase II study of weekly docetaxel and oxaliplatin as first-line treatment in patients with advanced gastric cancer.
Gastric Cancer. 2011 Jun 8;
BACKGROUND: Docetaxel and oxaliplatin are active agents for advanced gastric cancer (GC). The combination of these two drugs in a triweekly schedule is an active and attractive regimen for gastric cancer but with significant hematological toxicities. A multicenter phase II study was designed to establish an active regimen with good tolerability by using a weekly docetaxel-oxaliplatin (DO) combination in GC patients. METHODS: Eligible patients had histologically confirmed stage IV gastric cancer without previous palliative chemotherapy; age ?18 years; Eastern Cooperative Oncology Group (ECOG) performance status ?2; at least one measurable lesion; and adequate hematological, renal, and liver functions. All patients received premedications with dexamethasone and 5-HT3 antagonist before the chemotherapy. Docetaxel (Taxotere(�); Sanofi-Aventis) 30�mg/m(2) followed by oxaliplatin (Eloxatin(�); Sanofi-Aventis) 65�mg/m(2) were administered on days 1 and 8 of each 21-day cycle. Treatment continued until disease progression, intolerable toxicity, or consent withdrawal. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0. Tumor responses were evaluated every 2 cycles by the Response Evaluation Criteria in Solid Tumors Guidelines. RESULTS: From May 2007 to December 2008, a total of 47 patients were enrolled. There were 8 females and 39 males with a median age of 57�years (range 26-76). Forty-three patients were evaluable for response. Two patients obtained a complete response (4.7%) and 12 patients had a partial response (27.9%), with an overall response rate of 32.6% (95% confidence interval [CI] 19.1-48.5); 20 patients experienced stable disease (46.5%), and the disease progressed in 9 patients (20.9%). Median time to disease progression was 4.2�months and median overall survival was 8.3�months. All 47 patients were assessable for toxicity. Major grade 3/4 hematological toxicities were anemia (5 patients, 10.6%), neutropenia (2 patients, 4.3%), and leukopenia (1 patient, 2.1%). The most common grade 3/4 non-hematological toxicities were fatigue (3 patients, 6.4%) and aspartate aminotransferase (AST) elevation in 3 patients (6.4%). CONCLUSIONS: The combination of weekly DO demonstrated a well-tolerated profile with moderate activity in the treatment of advanced gastric cancer. Further studies of the combination together with a fluoropyrimidine are warranted. [PubMed Citation] [Order full text from Infotrieve]

12) Li TC, Shiah IS, Sun CJ, Tzang RF, Huang KC, Lee WK
Mirtazapine relieves post-electroconvulsive therapy headaches and nausea: a case series and review of the literature.
J ECT. 2011 Jun;27(2):165-7.
Headaches and nausea are the 2 most common adverse effects of electroconvulsive therapy (ECT). These adverse effects have been frequently reported in the postictal period and make it difficult for the patient to continue with the following ECTs. Mirtazapine is an antidepressant with a mechanism that involves activating serotonin (5-HT1) receptors. This mechanism has been hypothesized to be the underlying therapeutic effects for depression and anxiety. In addition, mirtazapine possesses antagonistic effects on the postsynaptic serotonin 5-HT2 and 5-HT3 receptors. The pharmacological actions are hypothesized to be related to its treatment effects of headaches and nausea. Here, we report a case series of patients developing post-ECT headaches and nausea, and the concomitant administration of mirtazapine successfully relieved the ECT-associated adverse effects. This case series suggest that mirtazapine may be an optional treatment for ECT-induced headaches and nausea. [PubMed Citation] [Order full text from Infotrieve]

13) Blitz JD, Haile M, Kline R, Franco L, Didehvar S, Pachter HL, Newman E, Bekker A
A Randomized Double Blind Study to Evaluate Efficacy of Palonosetron With Dexamethasone Versus Palonosetron Alone for Prevention of Postoperative and Postdischarge Nausea and Vomiting in Subjects Undergoing Laparoscopic Surgeries with High Emetogenic Risk.
Am J Ther. 2011 Apr 23;
Postoperative nausea and vomiting (PONV) and postdischarge nausea and vomiting (PDNV) are common occurrences (50%-80%) after laparoscopic surgery. Palonosetron (Pal), the newest 5-HT3 antagonist, is an effective antiemetic that has advantages in treating PDNV due to its prolonged duration of action. We hypothesized that a combination of Pal and dexamethazone (Dex) could further improve the efficacy of the treatment in comparison to Pal alone in patients at high risk for PONV. Patients scheduled to undergo laparoscopic surgeries under general anesthesia were randomized to receive 8-mg dexamethasone + 0.075-mg palonosetron (Pal + Dex) or an equivalent volume of saline + 0.075 mg palonosetron (Pal). Data was collected at defined postoperative times (2, 6, 12, 24, and 72 hours). All patients also completed an 18-question QOL-Functional Living Index-Emesis instrument at 96 hours. We enrolled 118 patients, ASA 1-2, with at least 3 PONV risk factors, who were undergoing outpatient surgery. Both groups had a low incidence of vomiting in the PACU (Pal + Dex, 1.7%; Pal, 6.8%) and at 72 hours (0.0% both groups). Complete response (no vomiting, no rescue medication) was not different between treatment groups for any time intervals. Cumulative success rates over the entire 72 hours were 60.4% (Pal + Dex) versus 60.0% (Pal). The Pal + Dex group showed a trend toward greater satisfaction on the QOL- Functional Living Index-Emesis scores with the greatest differences in the "nausea domain". The combination therapy of palonosetron + dexamethasone did not reduce the incidence of PONV or PDNV when compared with palonosetron alone. There was no change in comparative efficacy over 72 hours, most likely due to the low incidence of PDNV in both groups. [PubMed Citation] [Order full text from Infotrieve]

14) Hassan BA, Yusoff ZB
Genetic polymorphisms in the three malaysian races effect granisetron clinical antiemetic actions in breast cancer patients receiving chemotherapy.
Asian Pac J Cancer Prev. 2011;12(1):185-91.
Introduction: Nausea and vomiting are recognized as two separate and distinct conditions with a wide spectrum of etiologies either directly associated with cancer itself or its treatment. According to the new ranking of chemotherapy side effects, nausea is the number one or the most disturbing side effects while vomiting is the third and sometimes the fifth. The introduction of 5-HT3-recptor antagonists in the early of 1990s has revolutionized the treatment of nausea and vomiting, these agents remaining the mainstay of antiemetic therapy today. Ethnic variation (due to genetic polymorphisms) may lead to diversity in antiemetic treatment pharmacokinetic and pharmacodynamic properties, in terms of distribution, elimination, disposition and clinical effects. The aim of the present study was to clarify genetic polymorphism effects in the three main races in Malaysia i.e., Malay, Chinese and Indian, on the clinical antiemetic effects of granisetron. Methods: In this longitudinal prospective observational study, 158 breast cancer patients treated with chemotherapy were monitored for nausea and vomiting in the first 24 hours after chemotherapy administration. The patients were then followed up again after 3 to 5 days of chemotherapy. Results: Genetic polymorphisms in the three races in Malaysia have significant effect on granisetron clinical antiemetic action because each is characterized by variant CYP3A4 enzymatic action. Conclusion: According to the result, different type of 5-HT3 receptor antagonists, such as tropisetron and dolasetron which are predominantly metabolized by CYP2D6, should be used especially for Chinese breast cancer patients. [PubMed Citation] [Order full text from Infotrieve]

15) Song Z, Meyerson BA, Linderoth B
Spinal 5-HT receptors that contribute to the pain-relieving effects of spinal cord stimulation in a rat model of neuropathy.
Pain. 2011 Jul;152(7):1666-73.
Spinal cord stimulation (SCS) is extensively employed in the management of neuropathic pain, but the underlying mechanisms are only partially understood. Recently, we demonstrated that the pain-relieving effect of SCS appears to involve the spinal serotonin system, and the present study aimed at identifying the types of the spinal serotonin receptors involved. Experiments were performed on rats with neuropathy produced by partial ligation of the sciatic nerve. Tactile sensitivity was assessed using von Frey filaments, and cold and heat sensitivity with cold spray and radiant heat, respectively. Selective 5-HT receptor antagonists, methiothepin (5-HT(1),(6),(7)), ketanserin tartrate (5-HT(2A)), TICM (5-HT(3)), SDZ-205,557 (5-HT(4)), as well as receptor agonists, ?-m-5-HT (5-HT(2)), m-CPBG (5-HT(3)) in per se ineffective doses, or vehicle, were administrated intrathecally 5minutes prior to the application of SCS. Ketanserin and SDZ-205,557 significantly attenuated the suppressive effect of SCS on tactile hypersensitivity, while methiothepin and TICM were ineffective. The suppressive effect on cold hypersensitivity of SCS was counteracted by ketanserin only. None of the 5-HT receptor antagonists attenuated the suppressive effect on heat hyperalgesia of SCS. Subeffective doses of ?-m-5-HT and m-CPBG enhanced the suppressive effect of SCS on tactile hypersensitivity. The enhancing effect of m-CPBG was abolished by a ?-aminobutyric acid (GABA)(A) or GABA(B) antagonist intrathecally. These results suggest that the activation of 5-HT(2A), 5-HT(3), and 5-HT(4) receptors plays an important role in SCS-induced relief of neuropathic pain. The activation of 5-HT(3) receptors appears to operate via spinal GABAergic interneurons. The activation of 5-HT2A, 5-HT3, and 5-HT4 receptors plays an important role in spinal cord stimulation-induced relief of neuropathic pain. [PubMed Citation] [Order full text from Infotrieve]

16) Thompson AJ, Duke RK, Lummis SC
Binding Sites for Bilobalide, Diltiazem, Ginkgolide, and Picrotoxinin at the 5-HT3 Receptor.
Mol Pharmacol. 2011 Jul;80(1):183-90.
Bilobalide (BB), ginkgolide B (GB), diltiazem (DTZ), and picrotoxinin (PXN) are 5-hydroxytryptamine type 3 (5-HT(3)) receptor antagonists in which the principal sites of action are in the channel. To probe their exact binding locations, 5-HT(3) receptors with substitutions in their pore lining residues were constructed (N-4'Q, E-1'D, S2'A, T6'S, L7'T, L9'V, S12'A, I16'V, D20'E), expressed in Xenopus laevis oocytes, and the effects of the compounds on 5-HT-induced currents were examined. EC(50) values at mutant receptors were less than 6-fold different from those of wild type, indicating that the mutations were well tolerated. BB, GB, DTZ, and PXN had pIC(50) values of 3.33, 3.14, 4.67, and 4.97, respectively. Inhibition by BB and GB was abolished in mutant receptors containing T6'S and S12'A substitutions, but their potencies were enhanced (42- and 125-fold, respectively) in S2'A mutant receptors. S2'A substitution also caused GB ligand trap. PXN potency was modestly enhanced (5-fold) in S2'A, abolished in T6'S, and reduced in L9'V (40-fold) and S12'A (7-fold) receptors. DTZ potency was reduced in L7'T and S12'A receptors (5-fold), and DTZ also displaced [(3)H]granisetron binding, indicating mixed competitive/noncompetitive inhibition. We conclude that regions close to the hydrophobic gate of M2 are important for the inhibitory effects of BB, GB, DTZ, and PXN at the 5-HT(3) receptor; for BB, GB, and PXN, the data show that the 6' channel lining residue is their major site of action, with minor roles for 2', 9', and 12' residues, whereas for DTZ, the 7' and 12' sites are important. [PubMed Citation] [Order full text from Infotrieve]

17) Nishi K, Kurokawa K, Hara J, Demura Y, Fujikawa N, Nikko Y, Yoshizaki S, Yamada C
[The current status of nausea, vomiting and food intake in outpatients with cancer chemotherapy].
Gan To Kagaku Ryoho. 2011 Apr;38(4):607-11.
A survey on chemotherapy-induced nausea, vomiting and food intake was conducted on 126 outpatients receiving chemotherapy during a days from February 1 to February 12, 2010 in our hospital. Responses were obtained from 66 outpatients. In the acute phase, 11%of the patients developed nausea. In the late phase, 35%patients developed nausea. The development of nausea was significantly increased in the late phase, compared to the acute phase(p=0. 0008). Though nobody developed vomiting in the acute phase, 3% of the patients developed vomiting in the late phase. For food intake, in the acute phase, nobody showed a"reduced amount of diet", and 12% showed"not eating". In the late phase, 26% of the patients showed"reduced amount of food", and 8%"not eating". Food intake was significantly decreased in the late phase, compared in acute phase(p=0. 0001). Currently, in our hospital, steroids and/or 5-HT3 antagonists are given for antiemetic therapy, but the effect is not enough. We should add other antiemetics, which act in the late phase. [PubMed Citation] [Order full text from Infotrieve]

18) Livesey MR, Cooper MA, Lambert JJ, Peters JA
Rings of charge within the extracellular vestibule influence ion permeation of the 5-HT3A receptor.
J Biol Chem. 2011 May 6;286(18):16008-17.
The determinants of single channel conductance (?) and ion selectivity within eukaryotic pentameric ligand-gated ion channels have traditionally been ascribed to amino acid residues within the second transmembrane domain and flanking sequences of their component subunits. However, recent evidence suggests that ? is additionally controlled by residues within the intracellular and extracellular domains. We examined the influence of two anionic residues (Asp(113) and Asp(127)) within the extracellular vestibule of a high conductance human mutant 5-hydroxytryptamine type-3A (5-HT(3)A) receptor (5-HT(3)A(QDA)) upon ?, modulation of the latter by extracellular Ca(2+), and the permeability of Ca(2+) with respect to Cs(+) (P(Ca)/P(Cs)). Mutations neutralizing (Asp ? Asn), or reversing (Asp ? Lys), charge at the 113 locus decreased inward ? by 46 and 58%, respectively, but outward currents were unaffected. The D127N mutation decreased inward ? by 82% and also suppressed outward currents, whereas the D127K mutation caused loss of observable single channel currents. The forgoing mutations, except for D127K, which could not be evaluated, ameliorated suppression of inwardly directed single channel currents by extracellular Ca(2+). The P(Ca)/P(Cs) of 3.8 previously reported for the 5-HT(3)A(QDA) construct was reduced to 0.13 and 0.06 by the D127N and D127K mutations, respectively, with lesser, but clearly significant, effects caused by the D113N (1.04) and D113K (0.60) substitutions. Charge selectivity between monovalent cations and anions (P(Na)/P(Cl)) was unaffected by any of the mutations examined. The data identify two key residues in the extracellular vestibule of the 5-HT(3)A receptor that markedly influence ?, P(Ca)/P(Cs), and additionally the suppression of ? by Ca(2+). [PubMed Citation] [Order full text from Infotrieve]

19) Kilpatrick LA, Labus JS, Coveleskie K, Hammer C, Rappold G, Tillisch K, Bueller JA, Suyenobu B, Jarcho JM, McRoberts JA, Niesler B, Mayer EA
The HTR3A polymorphism c. -42C>T is associated with amygdala responsiveness in patients with irritable bowel syndrome.
Gastroenterology. 2011 Jun;140(7):1943-51.
[PubMed Citation] [Order full text from Infotrieve]

20) Khropycheva R, Andreeva J, Uneyama H, Torii K, Zolotarev V
Dietary glutamate signal evokes gastric juice excretion in dogs.
Digestion. 2011;83 Suppl 1:7-12.
[PubMed Citation] [Order full text from Infotrieve]