serotonin 5-HT4 receptors


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(Updated 8/9/04)

Bockaert J, Claeysen S, Compan V, Dumuis A.
5-HT4 receptors.
Curr Drug Targets CNS Neurol Disord. 2004 Feb;3(1):39-51.
"Serotonin 4 receptors (5-HT(4)Rs) were discovered 15 years ago. They are coded by a very complex gene (700Kb, 38 exons) which generates eight carboxy-terminal variants (a, b, c, d, e, f, g, n). Their sequences differ after position L(358). Another variant is characterized by a 14 residue insertion within the extracellular loop 2. Highly selective potent 5-HT(4) receptor antagonists and partial agonists which cross the blood-brain barrier have been synthesized, but a specific full agonist for brain studies is still missing. Based on physiological and behavioral experiments, 5-HT(4)Rs may be targets to treat cognitive deficits, abdominal pain and feeding disorders. One 5-HT(4)R-directed drug (SL65.0155) is already in phase II to treat patients suffering from memory deficits or dementia."

Varnas K, Halldin C, Pike VW, Hall H.
Distribution of 5-HT4 receptors in the postmortem human brain--an autoradiographic study using [125I]SB 207710.
Eur Neuropsychopharmacol. 2003 Aug;13(4):228-34.
"The autoradiographic distribution of the 5-HT4 receptor was described using human postmortem brain sections and the selective radioligand [125I]SB 207710 [(1-n-butyl-4-piperidinyl)methyl-8-amino-7-[125I]iodo-1,4-benzodioxane-5-carboxylate]. The specific binding was highest in regions of the basal ganglia (caudate nucleus, putamen, nucleus accumbens, globus pallidus and substantia nigra) and the hippocampal formation (CA1 and subiculum). In the neocortex, the binding showed a distinct lamination pattern with high levels in superficial layers and a band displaying lower levels in deep cortical layers. The results confirm previous studies on the distribution of 5-HT4 receptors in the human brain in vitro and provide high-resolution correlates for in vivo imaging studies using the radioligand recently developed for single photon emission tomography (SPET), [123I]SB 207710." [Abstract]

Pike VW, Halldin C, Nobuhara K, Hiltunen J, Mulligan RS, Swahn CG, Karlsson P, Olsson H, Hume SP, Hirani E, Whalley J, Pilowsky LS, Larsson S, Schnell PO, Ell PJ, Farde L.
Radioiodinated SB 207710 as a radioligand in vivo: imaging of brain 5-HT4 receptors with SPET.
Eur J Nucl Med Mol Imaging. 2003 Nov;30(11):1520-8. Epub 2003 Sep 23. [Abstract]

Moser, Paul C., Bergis, Olivier E., Jegham, Samir, Lochead, Alistair, Duconseille, Elee, Terranova, Jean-Paul, Caille, Dominique, Berque-Bestel, Isabelle, Lezoualc'h, Frank, Fischmeister, Rodolphe, Dumuis, Aline, Bockaert, Joel, George, Pascal, Soubrie, Philippe, Scatton, Bernard
SL65.0155, A Novel 5-Hydroxytryptamine4 Receptor Partial Agonist with Potent Cognition-Enhancing Properties
J Pharmacol Exp Ther 2002 302: 731-741
"Furthermore, the combined administration of an inactive dose of SL65.0155 with the cholinesterase inhibitor rivastigmine resulted in a significant promnesic effect, suggesting a synergistic interaction. SL65.0155 was devoid of unwanted cardiovascular, gastrointestinal, or central nervous system effects with doses up to more than 100-fold higher than those active in the cognitive tests. These results characterize SL65.0155 as a novel promnesic agent acting via 5-HT4 receptors, with an excellent preclinical profile. Its broad range of activity in cognitive tests and synergism with cholinesterase inhibitors suggest that SL65.0155 represents a promising new agent for the treatment of dementia."

Kemp A, Manahan-Vaughan D.
Hippocampal long-term depression and long-term potentiation encode different aspects of novelty acquisition.
Proc Natl Acad Sci U S A. 2004 May 25;101(21):8192-7. Epub 2004 May 18.
"The hippocampus is required for encoding spatial information. Little is known however, about how different attributes of learning are related to different types of synaptic plasticity. Here, we investigated the association between long-term depression (LTD) and long-term potentiation, both cellular models for learning, and novelty exploration. We found that exploration of a new environment containing unfamiliar objects and/or familiar objects in new locations facilitated LTD, whereas exploration of the new environment itself, in the absence of objects, impaired LTD. Furthermore, we found this phenomenon to be modulated by 5-hydroxytryptamine 4 receptor activation. In contrast, long-term potentiation was facilitated by exploration of an empty novel environment, but simultaneous object exploration caused depotentiation. We also found that no further LTD could be induced. These findings support a decisive role for LTD in the acquisition of object-place configuration and consolidate its candidacy as a learning mechanism." [Abstract]

Lamirault L, Guillou C, Thal C, Simon H.
Combined treatment with galanthaminium bromide, a new cholinesterase inhibitor, and RS 67333, a partial agonist of 5-HT4 receptors, enhances place and object recognition in young adult and old rats.
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Feb;27(1):185-95. [Abstract]

Galeotti, Nicoletta, Ghelardini, Carla, Bartolini, Alessandro
Role of 5-HT4 Receptors in the Mouse Passive Avoidance Test
J Pharmacol Exp Ther 1998 286: 1115-1121
"These results suggest that the modulation of 5-HT4 receptors plays an important role in the regulation of memory processes. On these bases, the 5-HT4 receptor agonists could be useful in the treatment of cognitive deficits although 5-HT4 receptor antagonists may represent pharmacological tools for investigation of new potential antiamnesic drugs."

Fontana DJ, Daniels SE, Wong EH, Clark RD, Eglen RM.
The effects of novel, selective 5-hydroxytryptamine (5-HT)4 receptor ligands in rat spatial navigation.
Neuropharmacology 1997 Apr-May;36(4-5):689-96
"These data suggest that RS 67333 reversed the cognitive deficit induced by atropine and support a role of 5-HT4 receptors in rat spatial learning and memory." [Abstract]

Orsetti M, Dellarole A, Ferri S, Ghi P.
Acquisition, retention, and recall of memory after injection of RS67333, a 5-HT(4) receptor agonist, into the nucleus basalis magnocellularis of the rat.
Learn Mem. 2003 Sep-Oct;10(5):420-6.
"The serotonin 5-HT4 subtype receptor is predominantly localized into anatomical structures linked to memory and cognition. A few experimental studies report that the acute systemic administration of selective 5-HT4 agonists has ameliorative effects on memory performance, and that these effects are reversed by contemporary administration of 5-HT4 receptor antagonists. To verify whether this procognitive action occurs via the activation of the cholinergic nucleus basalis magnocellularis (NBM)-cortical pathways, we examined the effects of RS67333, a selective partial agonist of the 5-HT4 receptor, on rat performance in a place recognition task upon local administration of the drug into the NBM area. The intra-NBM administration of RS67333 enhances the acquisition (200-500 ng/0.5 microL) and the consolidation (40-200 ng/0.5 microL) of the place recognition memory. These effects are reversed by pretreatment with the selective 5-HT4 receptor antagonist RS39604 (300 ng/0.5 microL). Conversely, the recall of memory is not affected by the 5-HT4 agonist. Our results indicate that 5-HT4 receptors located within the NBM may play a role in spatial memory and that the procognitive effect of RS67333 is due, at least in part, to the potentiation of the activity of cholinergic NBM-cortical pathways." [Abstract]

Marchetti-Gauthier E, Roman FS, Dumuis A, Bockaert J, Soumireu-Mourat B.
BIMU1 increases associative memory in rats by activating 5-HT4 receptors.
Neuropharmacology 1997 Apr-May;36(4-5):697-706 [Abstract]

Lezoualc'h F, Robert SJ.
The serotonin 5-HT4 receptor and the amyloid precursor protein processing.
Exp Gerontol. 2003 Jan-Feb;38(1-2):159-66.
"A large body of evidence supports a major role for the serotonin 5-HT(4) receptor in learning and memory and it is suggested that 5-HT(4) agonists may be beneficial for memory disorders such as Alzheimer's disease (AD). The 5-HT(4) receptors are members of the G protein-coupled receptor superfamily and are positively coupled to adenylyl cyclase. In this communication we show that a neuronal isoform of the human 5-HT(4) receptor, h5-HT(4(g)) regulates the metabolism of the amyloid precursor protein (APP695). This process is observed in Chinese hamster ovary (CHO) cells stably coexpressing the neuronal h5-HT(4(g)) receptor isoform as well as the human APP695. The 5-HT(4) agonists strongly stimulate the release of the non-amyloidogenic soluble amyloid precursor protein sAPPalpha as detected by immunoblot. Prucalopride was more potent than serotonin (5-HT) with regard to enhanced of sAPPalpha secretion. This process was blocked by a selective 5-HT(4) antagonist, GR113808. Furthermore, 5-HT(4) ligands enhance sAPPalpha secretion via cAMP-dependent and PKA-independent signalling pathways indicating there are alternative pathways by which the h5-HT(4) receptor via cAMP regulates APP metabolism. Because the alpha-cleavage event may preclude the formation of amyloidogenic peptides, and secreted sAPPalpha has putative neuroprotective and enhancing-memory properties, our present data suggest the 5-HT(4) receptor as a novel target for the treatment of AD." [Abstract]

Sylvain J. Robert, José L. Zugaza, Rodolphe Fischmeister, Alain M. Gardier, and Frank Lezoualc'h
The Human Serotonin 5-HT4 Receptor Regulates Secretion of Non-amyloidogenic Precursor Protein
J. Biol. Chem. 276: 44881-44888, November 30, 2001. [Full Text]

E Marchetti, A Dumuis, J Bockaert, B Soumireu-Mourat, and FS Roman
Differential modulation of the 5-HT(4) receptor agonists and antagonist on rat learning and memory.
Neuropharmacology, Aug 2000; 39(11): 2017-27. [Abstract]

Blondel, O, Gastineau, M, Dahmoune, Y, Langlois, M, Fischmeister, R
Cloning, expression, and pharmacology of four human 5-hydroxytryptamine 4 receptor isoforms produced by alternative splicing in the carboxyl terminus
J Neurochem 1998 70: 2252-2261
"We report here the molecular cloning of three new splice variants of the human serotonin 5-hydroxytryptamine4 (h5-HT4) receptor, which we named h5-HT4(b), h5-HT4(c), and h5-HT4(d)." [Abstract]

Brattelid T, Kvingedal AM, Krobert KA, Andressen KW, Bach T, Hystad ME, Kaumann AJ, Levy FO.
Cloning, pharmacological characterisation and tissue distribution of a novel 5-HT4 receptor splice variant, 5-HT4(i).
Naunyn Schmiedebergs Arch Pharmacol. 2004 Jun;369(6):616-28. Epub 2004 Apr 30.
"5-HT4 receptor pre-mRNA is alternatively spliced in human (h) tissue to produce several splice variants, called 5-HT4(a) to 5-HT4(h) and 5-HT4(n). Polymerase chain reaction (PCR) with primers designed to amplify both 5-HT4(a) and 5-HT4(b) amplified three additional bands in different tissues, two representing different mRNA species both encoding 5-HT4(g) and one representing mRNA for a novel splice variant named 5-HT4(i), cloned from testis and pancreas respectively. Primary and nested PCR detected both 5-HT4(g) and 5-HT4(i) in multiple tissues. Whereas 5-HT4(i), was found in all cardiovascular tissues analysed, 5-HT4(g) was mainly present in atria. However, quantitative RT-PCR indicated 5-HT4(g) expression also in cardiac ventricle. The pharmacological profiles and ability to activate adenylyl cyclase (AC) were compared between four recombinant h5-HT4 splice variants (a, b, g and i) expressed transiently and stably in HEK293 cells. Displacement of [(3)H]GR113808 with ten ligands revealed identical pharmacological profiles (affinity rank order: GR125487, SB207710, GR113808>SB203186>serotonin, cisapride, tropisetron>renzapride, 5-MeOT>5-CT). In transiently transfected HEK293 cells cisapride was a partial agonist compared to serotonin at 5-HT4(b), 5-HT4(g) and 5-HT4(i) receptors. In membranes from HEK293 cells stably expressing 5-HT4(g) (3,000 fmol/mg protein) or 5-HT4(i) (500 fmol/mg protein), serotonin and 5-MeOT were full agonists while cisapride was full agonist at 5-HT4(g) and partial agonist at 5-HT4(i), probably due to different receptor expression levels. At both 5-HT4(g) and 5-HT4(i), the behaviour of 5-HT4 receptor antagonists was dependent on receptor level. At high receptor levels, tropisetron and SB207710 and to a variable extent SB203186 and GR113808 displayed some partial agonist activity, whereas GR125487 and SB207266 reduced the AC activity below basal, indicating both receptors to be constitutively active. We conclude that the novel 5-HT4(i) receptor splice variant is pharmacologically indistinguishable from other 5-HT4 splice variants and that the 5-HT4(i) C-terminal tail does not influence coupling to AC." [Abstract]

Gerald C, Adham N, Kao HT, Olsen MA, Laz TM, Schechter LE, Bard JA, Vaysse PJ, Hartig PR, Branchek TA, et al.
The 5-HT4 receptor: molecular cloning and pharmacological characterization of two splice variants.
EMBO J 1995 Jun 15;14(12):2806-15
"Interestingly, we isolated two splice variants of the receptor, 5-HT4L and 5-HT4S, differing in the length and sequence of their C-termini. In rat brain, the 5-HT4S transcripts are restricted to the striatum, but the 5-HT4L transcripts are expressed throughout the brain, except in the cerebellum where it was barely detectable. In peripheral tissues, differential expression was also observed in the atrium of the heart where only the 5-HT4S isoform was detectable." [Abstract]

Claeysen S, Faye P, Sebben M, Lemaire S, Bockaert J, Dumuis A.
Cloning and expression of human 5-HT4S receptors. Effect of receptor density on their coupling to adenylyl cyclase.
Neuroreport 1997 Oct 20;8(15):3189-96 [Abstract]

Claeysen S, Sebben M, Journot L, Bockaert J, Dumuis A.
Cloning, expression and pharmacology of the mouse 5-HT(4L) receptor.
FEBS Lett 1996 Nov 25;398(1):19-25
"In contrast to the previously described distribution, we found that mRNA encoding for both the short (5-HT(4S))and the long form (5-HT(4L)) of 5-HT4 receptors are expressed in all mouse and rat brain areas." [Abstract]

Bender, Eckhard, Pindon, Armelle, van Oers, Irma, Zhang, Yu-Bin, Gommeren, Walter, Verhasselt, Peter, Jurzak, Mirek, Leysen, Josee, Luyten, Walter
Structure of the Human Serotonin 5-HT4 Receptor Gene and Cloning of a Novel 5-HT4 Splice Variant

J Neurochem 2000 74: 478-489 [Abstract]

Van den Wyngaert, I, Gommeren, W, Verhasselt, P, Jurzak, M, Leysen, J, Luyten, W, Bender, E
Cloning and expression of a human serotonin 5-HT4 receptor cDNA
J Neurochem 1997 69: 1810-1819 [Abstract]

Guillaume Lucas and Guy Debonnel
5-HT4 receptors exert a frequency-related facilitatory control on dorsal raphé nucleus 5-HT neuronal activity
European Journal of Neuroscience 16 (5), 817-822.
doi: 10.1046/j.1460-9568.2002.02150.x
"We investigated, using single-unit recordings in chloral hydrate-anaesthetized rats, the role of serotonin4 (5-HT4) receptors in the control of dorsal raphé nucleus (DRN) 5-HT neuron activity. About one-half (36) of the 76 neurons recorded were affected by either the preferential 5-HT4 agonist cisapride (500 and 1000 µg/kg, i.v.) or the selective 5-HT4 antagonist, GR 125487 (200- 2000 µg/kg, i.v.). Responding neurons displayed a significantly higher mean basal firing rate (1.93 ± 0.1 Hz) than non-responders (1.31 ± 0.1 Hz). The firing rate of responding 5-HT neurons was enhanced dose-dependently by cisapride (+47 and +94% at 500 and 1000 µg/kg, respectively), an effect abolished by GR 125487 (500 µg/kg) and reduced by the 5-HT4 antagonist, SDZ 205557 (500 µg/kg, i.v). Conversely, GR 125487 induced a dose-dependent inhibition of responders activity, which was almost completely suppressed at the dose of 2000 µg/kg. In a separate set of experiments, the selective 5-HT4 agonist, prucalopride (500 µg/kg, i.v), increased the firing activity (+35%) of 5-HT neurons displaying a high basal firing rate; subsequent injection of GR 125487 (500 µg/kg, i.v.) suppressed this effect. These results indicate that 5-HT4 receptors exert both a tonic and a phasic, positive, frequency-related control on DRN 5-HT neuronal activity. The existence of such a control might open new avenues for therapeutic research in the antidepressant field." [Abstract]

Wagstaff AJ, Frampton JE, Croom KF.
Tegaserod: a review of its use in the management of irritable bowel syndrome with constipation in women.
Drugs. 2003;63(11):1101-20.
"The treatment of irritable bowel syndrome with constipation (IBS-C) has historically been based on the severity of symptoms, with education, reassurance, dietary advice, bulking agents and laxative therapy offered as appropriate. Tegaserod (Zelnorm, Zelmac) is the first selective serotonin 5-HT(4) receptor partial agonist to be approved for the treatment of this syndrome. Tegaserod is active against multiple irritable bowel syndrome (IBS) symptoms; it stimulates gut motility and reduces visceral sensitivity and pain. The drug does not cure IBS and was not designed to treat the diarrhoea-predominant version. Its efficacy in men has not been established. Three large well designed clinical trials of tegaserod 6 mg twice daily for 12 weeks in patients (mainly women) with IBS-C have demonstrated superiority versus placebo in global relief from symptoms. Global relief response rates were 38.4-46.8% with tegaserod 6 mg twice daily and 28.3-38.8% with placebo (p < 0.05-0.0001 vs placebo). The relative increases in response rates with tegaserod 6 mg twice daily over the already high responses in the placebo groups ranged from 12-65% after 4-12 weeks of treatment. A response was seen within the first week. The proportion of patients with satisfactory relief from symptoms fell over the 4-week period following withdrawal of tegaserod and placebo, but did not reach baseline levels during this time. Diarrhoea has been associated with tegaserod in clinical trials (an incidence of about 10% versus 5% with placebo, usually occurring in the first week of treatment), but the drug is otherwise well tolerated. There were no apparent changes in the tolerability profile with extended tegaserod treatment (</=12 months). In conclusion, oral tegaserod 6 mg twice daily for 12 weeks is effective and well tolerated in the treatment of IBS-C in women. Data on long term and comparative efficacy, cost-effectiveness and quality-of-life effects would be beneficial; however, in light of the fact that very few alternatives for the treatment of IBS-C have proven efficacy, tegaserod appears to be a promising option in women not responding to increased dietary fibre or osmotic laxative therapy." [Abstract]

Hasler WL, Schoenfeld P.
Safety Profile of Tegaserod, a 5-HT(4) Receptor Agonist, for the Treatment of Irritable Bowel Syndrome.
Drug Saf. 2004;27(9):619-31.
"This article reviews the safety and tolerability profile of tegaserod, a novel selective partial agonist of the serotonin 5-HT(4) receptor. Tegaserod was recently approved for the treatment of women with irritable bowel syndrome (IBS) with constipation.Tegaserod exhibits rapid absorption from the small intestine, and is excreted unchanged in the faeces and as metabolites in the urine. Meal ingestion decreases its bioavailability. There is little effect of age or gender on pharmacokinetics, although plasma levels may be slightly higher in the elderly. Tegaserod has no effect on plasma levels of other drugs metabolised by cytochrome P450 enzyme systems.Gastrointestinal symptoms are the most common adverse effects of tegaserod therapy. In data pooled from phase III randomised controlled trials (RCTs) in IBS with constipation patients, diarrhoea was reported by 8.8% of patients treated with tegaserod 6mg twice daily versus 3.8% of patients receiving placebo. Similar rates have been observed in international post-US marketing RCTs. In most patients, tegaserod-induced diarrhoea was mild and transient. In RCTs, it did not elicit fluid or electrolyte disturbances, and fewer than 3% of IBS patients discontinued tegaserod due to diarrhoea. Since its release, rare cases of more severe diarrhoea and ischaemic colitis have been reported. The incidence of other gastrointestinal symptoms (e.g. abdominal pain, nausea, and flatulence) has been similar among tegaserod-treated patients and placebo-treated patients. Pooled analysis of phase III RCTs and post-US marketing RCTs have not demonstrated significant differences between tegaserod-treated patients and placebo-treated patients in the incidence of abdominal-pelvic surgery. There is no convincing evidence that rebound gastrointestinal symptoms occur upon termination of tegaserod therapy.Pooled analysis of phase III RCTs demonstrated an increase in the incidence of headaches among tegaserod-treated patients (6mg twice daily) compared with placebo-treated patients (15% vs 12.3%, respectively, p < 0.05), although post-US marketing RCTs have not observed this increase. Other extra-gastrointestinal adverse events occur with similar frequency among tegaserod-treated patients and placebo-treated patients. Tegaserod-treated patients in RCTs have not demonstrated significant prolongation of the QTc interval or cardiac arrhythmias compared with placebo-treated patients. Supra-therapeutic doses in healthy volunteers did not effect electrocardiographic parameters. Laboratory parameters are mostly unaffected by tegaserod, although several individuals have exhibited increased eosinophil counts.In summary, tegaserod exhibits a favourable safety and tolerability profile in IBS patients based on data from clinical trials. Diarrhoea is the most common adverse event associated with tegaserod use. Continued post-US marketing surveillance will further define the safety and tolerability profile of tegaserod." [Abstract]

Emma Edwards, and Julian F. R. Paton
5-HT4 receptors in nucleus tractus solitarii attenuate cardiopulmonary reflex in anesthetized rats
Am J Physiol Heart Circ Physiol 277: H1914-H1923, November 1999. [Full Text]

Pindon, Armelle, van Hecke, Geert, van Gompel, Paul, Lesage, Anne S., Leysen, Josee E., Jurzak, Mirek

Differences in Signal Transduction of Two 5-HT4 Receptor Splice Variants: Compound Specificity and Dual Coupling with Galpha s- and Galpha i/o-Proteins
Mol Pharmacol 2002 61: 85-96 [Abstract]

Mialet, Jeanne, Berque-Bestel, Isabelle, Eftekhari, Pierre, Gastineau, Monique, Giner, Mireille, Dahmoune, Yamina, Donzeau-Gouge, Patrick, Hoebeke, Johan, Langlois, Michel, Sicsic, Sames, Fischmeister, Rodolphe, Lezoualc'h, Frank
Isolation of the serotoninergic 5-HT4(e) receptor from human heart and comparative analysis of its pharmacological profile in C6-glial and CHO cell lines
Br. J. Pharmacol. 2000 129: 771-781 [Abstract]

Mialet, Jeanne, Berque-Bestel, Isabelle, Sicsic, Sames, Langlois, Michel, Fischmeister, Rodolphe, Lezoualc'h, Frank
Pharmacological characterization of the human 5-HT4(d) receptor splice variant stably expressed in Chinese hamster ovary cells
Br. J. Pharmacol. 2000 131: 827-835 [Abstract]

Mialet J, Fischmeister R, Lezoualc'h F.
Characterization of human 5-HT4(d) receptor desensitization in CHO cells.
Br J Pharmacol. 2003 Feb;138(3):445-52. [Abstract]

Norum JH, Hart K, Levy FO.
Ras-dependent ERK activation by the human G(s)-coupled serotonin receptors 5-HT4(b) and 5-HT7(a).
J Biol Chem. 2003 Jan 31;278(5):3098-104. Epub 2002 Nov 21. [Full Text]

Mialet, Jeanne, Dahmoune, Yamina, Lezoualc'h, Frank, Berque-Bestel, Isabelle, Eftekhari, Pierre, Hoebeke, Johan, Sicsic, Sames, Langlois, Michel, Fischmeister, Rodolphe
Exploration of the ligand binding site of the human 5-HT4 receptor by site-directed mutagenesis and molecular modeling
Br. J. Pharmacol. 2000 130: 527-538 [Abstract]

Yamaguchi T, Suzuki M, Yamamoto M.
Facilitation of acetylcholine release in rat frontal cortex by indeloxazine hydrochloride: involvement of endogenous serotonin and 5-HT4 receptors.
Naunyn Schmiedebergs Arch Pharmacol 1997 Dec;356(6):712-20 [Abstract]

Prins, N. H., Akkermans, L. M.A., Lefebvre, R. A., Schuurkes, J. A.J.
5-HT4 receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle
Br. J. Pharmacol. 2000 131: 927-932 [Abstract]

Leclere, Pascal G., Lefebvre, Romain A.
Presynaptic modulation of cholinergic neurotransmission in the human proximal stomach
Br. J. Pharmacol. 2002 135: 135-142 [Abstract]

SS Hegde, and RM Eglen
Peripheral 5-HT4 receptors
FASEB J. 10: 1398-1407 [Abstract]

Bourdon, D. M., Camden, J. M., Landon, L. A., Levy, F. O., Turner, J. T.
Identification of the adenylyl cyclase-activating 5-hydroxytryptamine receptor subtypes expressed in the rat submandibular gland
Br. J. Pharmacol. 2000 130: 104-108
"These findings indicate the presence in rat SMG of both 5-HT4(b) and 5-HT7(a) receptors positively coupled to AC." [Abstract]

Nagakura, Yasunori, Kontoh, Akiko, Tokita, Kenichi, Tomoi, Masaaki, Shimomura, Kyoichi, Kadowaki, Makoto
Combined Blockade of 5-HT3- and 5-HT4-Serotonin Receptors Inhibits Colonic Functions in Conscious Rats and Mice
J Pharmacol Exp Ther 1997 281: 284-290 [Full Text]

5-HT4 Receptors: Gene, Transduction and Effects on Olfactory Memory
Ann NY Acad Sci 1998 861: 1-15 [Abstract]

Contesse V, Hamel C, Delarue C, Lefebvre H, Vaudry H.
Effect of a series of 5-HT4 receptor agonists and antagonists on steroid secretion by the adrenal gland in vitro.
Eur J Pharmacol 1994 Nov 14;265(1-2):27-33
"We have previously shown that serotonin (5-hydroxytryptamine, 5-HT) stimulate corticosterone and aldosterone secretion from perifused frog adrenal gland in vitro through activation of 5-HT4 receptors. In the present study, we have used this model to investigate the effect of newly discovered 5-HT4 receptor agonists and antagonists on corticosteroid secretion." [Abstract]

Manzke T, Guenther U, Ponimaskin EG, Haller M, Dutschmann M, Schwarzacher S, Richter DW.
5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia.
Science. 2003 Jul 11;301(5630):226-9.
"Opiates are widely used analgesics in anesthesiology, but they have serious adverse effects such as depression of breathing. This is caused by direct inhibition of rhythm-generating respiratory neurons in the Pre-Boetzinger complex (PBC) of the brainstem. We report that serotonin 4(a) [5-HT4(a)] receptors are strongly expressed in respiratory PBC neurons and that their selective activation protects spontaneous respiratory activity. Treatment of rats with a 5-HT4 receptor-specific agonist overcame fentanyl-induced respiratory depression and reestablished stable respiratory rhythm without loss of fentanyl's analgesic effect. These findings imply the prospect of a fine-tuned recovery from opioid-induced respiratory depression, through adjustment of intracellular adenosine 3',5'-monophosphate levels through the convergent signaling pathways in neurons." [Full Text]

Matsumoto, Machiko, Togashi, Hiroko, Mori, Kiyoshi, Ueno, Ken-ichi, Ohashi, Satoshi, Kojima, Taku, Yoshioka, Mitsuhiro
Evidence for Involvement of Central 5-HT4 Receptors in Cholinergic Function Associated with Cognitive Processes: Behavioral, Electrophysiological, and Neurochemical Studies
J Pharmacol Exp Ther 2001 296: 676-682
"The 5-HT4 receptor agonists, therefore, could be useful in the treatment of cognitive deficits by enhancement of cholinergic neurotransmission."
[Full Text]

Lelong V, Lhonneur L, Dauphin F, Boulouard M.
BIMU 1 and RS 67333, two 5-HT4 receptor agonists, modulate spontaneous alternation deficits induced by scopolamine in the mouse.
Naunyn Schmiedebergs Arch Pharmacol. 2003 Jun;367(6):621-8. Epub 2003 May 08.
"The present study was conducted to determine the effects of two potent 5-HT4 receptor agonists, BIMU 1 (1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo (3.2.1)-oct-3-yl]-2-oxo-1H) benzimidazole-1-carboxamide hydrochloride; 1, 3, 10 mg/kg, i.p.) and RS 67333 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone; 0.25, 0.5, 1 mg/kg, i.p.) on the learning impairment induced by the muscarinic acetylcholine receptor antagonist, scopolamine (1 mg/kg) in mice. Working memory was examined by observing spontaneous alternation behavior in the Y-maze test. Both BIMU 1 (10 mg/kg) and RS 67333 (1 mg/kg) prevented the scopolamine-induced alternation deficits, whereas no effect could be evidenced on locomotor or emotional indices. The reversal actions of BIMU 1 and RS 67333 on this cognitive dysfunction were abolished by the selective 5-HT4 receptor antagonist GR 125487 (1-[2-[(methyl sulfonyl)-amino]-ethyl]-4-piperidinyl-methyl-5-fluoro-2-methoxy-1H-indole-3-carboxylate; 10 mg/kg, i.p.). When given alone at the same doses, none of the three serotonergic agents had any measurable effect. These results demonstrate the ability of 5-HT4 receptor agonists to reverse spontaneous working memory deficits and further confirm the therapeutic potential of such ligands in the treatment of cognitive alterations that associate short-term working memory disorders and cholinergic hypofunction." [Abstract]

Compan V, Zhou M, Grailhe R, Gazzara RA, Martin R, Gingrich J, Dumuis A, Brunner D, Bockaert J, Hen R.
Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knock-out mice.
J Neurosci. 2004 Jan 14;24(2):412-9.
"To study the functions of 5-HT4 receptors, a null mutation was engineered in the corresponding gene. 5-HT4 receptor knock-out mice displayed normal feeding and motor behaviors in baseline conditions but abnormal feeding and locomotor behavior in response to stress and novelty. Specifically, stress-induced hypophagia and novelty-induced exploratory activity were attenuated in the knock-out mice. In addition, pentylenetetrazol-induced convulsive responses were enhanced in the knock-out mice, suggesting an increase in neuronal network excitability. These results provide the first example of a genetic deficit that disrupts the ability of stress to reduce feeding and body weight and suggest that 5-HT4 receptors may be involved in stress-induced anorexia and seizure susceptibility." [Abstract]

Compan V, Charnay Y, Dusticier N, Daszuta A, Hen R, Bockaert J.
[Feeding disorders in 5-HT4 receptor knockout mice]
J Soc Biol. 2004;198(1):37-49.
"To study the functional contributions of the 5-HT4 receptor subtype of serotonin (5-HT), we have generated knockout mice lacking the 5-HT4 receptor gene. The male mutant mice exhibit a hyposensitivity to anorexic stress. Our recent data indicate that the pharmacological inactivation, using a systemic injection of the 5-HT4 receptor antagonist RS39604 (0.5 mg/kg), suppressed restraint stress-induced anorexia in wild-type female mice. In parallel, the same treatment reduced the 3,4-N-methylenedioxymethamphetamine (" ecstasy", 10 mg/kg)-induced anorexia in male wild-type mice. Our neurochemical analyses suggest that the mechanisms underlying feeding disorders in 5-HT4 receptor knockout mice are related to a lesser efficacy of 5-HT (hypothalamus, nucleus accumbens), leptin and the cocaine-amphetamine related transcript to reduce food intake following stress." [Abstract]

Rosel P, Arranz B, Urretavizcaya M, Oros M, San L, Navarro MA.
Altered 5-HT2A and 5-HT4 postsynaptic receptors and their intracellular signalling systems IP3 and cAMP in brains from depressed violent suicide victims.
Neuropsychobiology. 2004;49(4):189-95.
"Serotonin 5-HT2A and 5-HT4 binding parameters and their second messengers 1,4,5-inositol triphosphate (IP3) and cyclic adenosyl monophosphate (cAMP) were studied in the frontal cortex, hippocampus, caudate nucleus and amygdala of 19 control subjects and 19 antidepressant-free, violent suicide victims. A significantly higher number of 5-HT4 receptors and higher second messenger cAMP concentrations were found in the frontal cortex and caudate nucleus of the depressed suicide victims as compared with the control group. Furthermore, significantly increased 5-HT2A binding sites and IP3 concentrations were noted in the caudate nucleus of the suicide victims, together with a significantly reduced number of 5-HT2A binding sites, higher binding affinity and increased IP3 concentrations in the hippocampus. No significant alterations in 5-HT4 and cAMP or in 5-HT2A and IP3 concentrations were observed in the amygdala. The caudate nucleus of depressed suicide victims seems to be the brain region with the highest alteration of the serotonergic system, and hence with the most diagnostic sensitivity. Further studies on suicidality and depression should focus on the functionality of the caudate nucleus." [Abstract]

Miro Smriga, and Kunio Torii
L-Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats
PNAS 100: 15370-15375. 2003.
"The purpose of this investigation was to determine whether a nutritionally essential amino acid, L-lysine, acts like a serotonin receptor 4 (5-HT4) antagonist, and if L-lysine is beneficial in animal models of serotonin (5-HT)-induced anxiety, diarrhea, ileum contractions, and tachycardia and in stress-induced fecal excretion. The radioligand-binding assay was used to test the binding of L-lysine to various 5-HT receptors. The effects of L-lysine on 5-HT-induced contractions of isolated guinea pig ileum were studied in vitro. The effects of oral administration of L-lysine on diarrhea, stress-induced fecal excretion, and 5-HT-induced corticosterone release, tachycardia, and anxiety (an elevated plus maze paradigm) were studied in rats in vivo. L-Lysine (0.8 mmol/dl) inhibited (9.17%) binding of 5-HT to the 5-HT4 receptor, without any effect on 5-HT1A,2A,2B,2C,3 binding. L-Lysine (0.07 and 0.7 mmol/dl) blocked 5-HT-induced contractions of an isolated guinea pig ileum in vitro (P < 0.05 and P < 0.01). Orally applied L-lysine (1 g/kg of body weight) inhibited (P < 0.12) diarrhea triggered by coadministration of restraint stress and 5-hydroxytryptophane (10 mg/kg of body weight), and significantly blocked anxiety induced by the 5-HT4 receptor agonist (3.0 mmol/liter) in rats in vivo. No effects of L-lysine or the 5-HT4 receptor agonist on plasma corticosterone and heart rate were recorded. L-Lysine may be a partial 5-HT4 receptor antagonist and suppresses 5-HT4 receptor-mediated intestinal pathologies and anxiety in rats. An increase in nutritional load of L-lysine might be a useful tool in treating stress-induced anxiety and 5-HT-related diarrhea-type intestinal dysfunctions." [Full Text]

Porras G, Di Matteo V, De Deurwaerdere P, Esposito E, Spampinato U.
Central serotonin4 receptors selectively regulate the impulse-dependent exocytosis of dopamine in the rat striatum: in vivo studies with morphine, amphetamine and cocaine.
Neuropharmacology. 2002 Dec;43(7):1099-109.
"In vivo microdialysis and single-cell extracellular recordings were used to assess the involvement of serotonin(4) (5-HT(4)) receptors in the effects induced by morphine, amphetamine and cocaine on nigrostriatal and mesoaccumbal dopaminergic (DA) pathway activity.The increase in striatal DA release induced by morphine (2.5 mg/kg, s.c.) was significantly reduced by the selective 5-HT(4) antagonists GR 125487 (0.1 and 1 mg/kg, i.p.) or SB 204070 (1 mg/kg, i.p.), and potentiated by the 5-HT(4) agonist prucalopride (5 mg/kg, i.p.). Neither of these compounds affected morphine-stimulated DA release in the nucleus accumbens. In both regions, amphetamine (2 mg/kg, i.p.) and cocaine (15 mg/kg, i.p.) induced DA release was affected neither by GR 125487 nor by prucalopride. None of the 5-HT agents used modified basal DA release in either brain region. Finally, GR 125487 (445 microg/kg, i.v.), whilst not affecting basal firing of DA neurons within either the substantia nigra pars compacta nor the ventral tegmental area, significantly reduced morphine (0.1-10 mg/kg, i.v.) stimulated firing of nigrostriatal DA neurons only.These results confirm that 5-HT(4) receptors exert a state-dependent facilitatory control restricted to the nigrostriatal DA pathway, and indicate that 5-HT(4) receptors selectively modulate DA exocytosis associated with increased DA neuron firing rate." [Abstract]

Paolucci E, Berretta N, Tozzi A, Bernardi G, Mercuri NB.
Depression of mGluR-mediated IPSCs by 5-HT in dopamine neurons of the rat substantia nigra pars compacta.
Eur J Neurosci. 2003 Nov;18(10):2743-50.
"Dopamine neurons of the substantia nigra pars compacta receive a prominent serotonin (5-HT) projection from the dorsal raphe nucleus and important functional interactions between the serotonergic and the dopaminergic system have been postulated. In the present report we examined the role of 5-HT in the modulation of the metabotropic glutamate receptor-mediated inhibitory postsynaptic current (mGluR-IPSC) in midbrain dopamine neurons, and we found a reversible depression of this synaptic response at concentrations of 5-HT ranging from 100 nm to 30 microm (EC50 1.06 microm). This resulted in a shift towards excitation of the overall dopamine neuron response to glutamatergic synaptic input. This effect was not because of a direct modulation of the Ca2+-sensitive K+ conductances underlying the mGluR-IPSC, but was associated with a decrease in the intracellular calcium signal triggered by mGluR stimulation. Similar results were obtained with alpha-methyl-5-hydroxytryptamine and 5-methoxytryptamine, but not with 5-carboxamidotryptamine or 1-(3-chlorophenyl) piperazine. No significant depression of the mGluR-IPSC by 5-HT was observed in the presence of the 5-HT2 antagonist cinanserin or the 5-HT4 receptor antagonist RS 23597-190, whereas the 5-HT2C antagonist RS 102221 was ineffective. Our results demonstrate a powerful inhibition of the mGluR-IPSC by 5-HT in midbrain dopamine neurons, most probably through stimulation of 5-HT2A and 5-HT4 receptors." [Abstract]

Beique JC, Chapin-Penick EM, Mladenovic L, Andrade R.
Serotonergic facilitation of synaptic activity in the developing rat prefrontal cortex.
J Physiol. 2004 May 1;556(Pt 3):739-54. Epub 2004 Jan 23.
"Previous studies have outlined an important role for serotonin (5-HT) in the development of synaptic connectivity and function in the cerebral cortex. In this study, we have examined the effects of 5-HT on synaptic function in prefrontal cortex at a time of intense synapse formation and remodelling. Whole-cell recordings in slices derived from animals aged postnatal (P) days 16-20 showed that administration of 5-HT induced a robust increase in synaptic activity that was blocked by CNQX but not by bicuculline. This 5-HT-induced increase in glutamate-mediated synaptic activity was pharmacologically heterogeneous as it was differentially inhibited by the receptor subtype-selective antagonists SB-269970, MDL 100907 and GR 113808 and thus involved 5-HT(7), 5-HT(2A) and 5-HT(4) receptors. These results, obtained in juvenile cortex, contrast with those seen in adults where the increase in spontaneous excitatory postsynaptic currents (sEPSCs) was mediated solely by 5-HT(2A) receptors. In developing cortex, activation of 5-HT(7), but not 5-HT(2A) or 5-HT(4) receptors, elicited a robust inward current. However, the facilitation of synaptic activity mediated by all three of these receptors involved increases in both the amplitude and frequency of sEPSCs and was blocked by TTX. These results are best interpreted as indicating that all three receptor subtypes increase synaptic activity by exciting neuronal elements within the slice. No evidence was found for a postsynaptic facilitation of synaptic currents by 5-HT. Together, these results show that the repertoire of electrophysiologically active 5-HT receptors in prefrontal cortex is developmentally regulated, and that 5-HT(7) and 5-HT(4) receptors play a previously unsuspected role in regulating synaptic activity in this region." [Abstract]

Evgeni G. Ponimaskin, Jasmina Profirovic, Rita Vaiskunaite, Diethelm W. Richter, and Tatyana A. Voyno-Yasenetskaya
5-Hydroxytryptamine 4(a) Receptor Is Coupled to the G alpha Subunit of Heterotrimeric G13 Protein
J. Biol. Chem. 277: 20812-20819, March 2002. [Abstract]

Evgeni G. Ponimaskin, Martin Heine, Lara Joubert, Michèle Sebben, Ulf Bickmeyer, Diethelm W. Richter, and Aline Dumuis
The 5-Hydroxytryptamine(4a) Receptor Is Palmitoylated at Two Different Sites, and Acylation Is Critically Involved in Regulation of Receptor Constitutive Activity
J. Biol. Chem. 277: 2534-2546.
"The most distinctive finding of the present study was the ability of palmitoylation to modulate the agonist-independent constitutive 5-HT4(a) receptor activity." [Abstract]

Kulla, Alexander, Manahan-Vaughan, Denise
Modulation by Serotonin 5-HT4 Receptors of Long-term Potentiation and Depotentiation in the Dentate Gyrus of Freely Moving Rats
Cereb. Cortex 2002 12: 150-162
"These results strongly support a role for 5-HT4 receptors in hippocampal synaptic plasticity and provide an important link to findings with regard to the involvement of 5-HT in processes related to learning and memory." [Abstract]

Andrade, R, Chaput, Y
5-Hydroxytryptamine4-like receptors mediate the slow excitatory response to serotonin in the rat hippocampus
J Pharmacol Exp Ther 1991 257: 930-937 [Abstract]

Torres, GE, Chaput, Y, Andrade, R
Cyclic AMP and protein kinase A mediate 5-hydroxytryptamine type 4 receptor regulation of calcium-activated potassium current in adult hippocampal neurons
Mol Pharmacol 1995 47: 191-197 [Abstract]

Cai, Xiang, Flores-Hernandez, Jorge, Feng, Jian, Yan, Zhen
Activity-dependent bidirectional regulation of GABAA receptor channels by the 5-HT4 receptor-mediated signalling in rat prefrontal cortical pyramidal neurons
J Physiol (Lond) 2002 540: 743-759 [Abstract]

Bianchi C, Rodi D, Marino S, Beani L, Siniscalchi A.
Dual effects of 5-HT4 receptor activation on GABA release from guinea pig hippocampal slices.
Neuroreport. 2002 Dec 3;13(17):2177-80.
"The effects of BIMU-8, a 5-HT4 receptor agonist, were studied on GABA release in guinea pig hippocampal slices. BIMU-8 did not modify GABA outflow at rest but did display a complex action in electrically stimulated slices: at low concentrations it increased, and at higher concentrations inhibited, GABA release. These responses were competitively counteracted by GR 125487, a selective 5-HT4 receptor antagonist. The dual effects of BIMU-8 are consistent with its indirect cholinergic action since the M1 and M3 antagonist, 4-DAMP, prevented BIMU-8-elicited GABA facilitation, whereas the M2 antagonist AFDX-116 cancelled GABA inhibition. These results provide evidence that serotonin exerts a complex modulation on the GABAergic system, via 5-HT4 receptors, and suggest that the amine releases acetylcholine which, in turn, bidirectionally modulates GABA release." [Abstract]

Cardenas, Carla G., Del Mar, Lucinda P., Cooper, Brian Y., Scroggs, Reese S.
5HT4 Receptors Couple Positively to Tetrodotoxin-Insensitive Sodium Channels in a Subpopulation of Capsaicin-Sensitive Rat Sensory Neurons
J. Neurosci. 1997 17: 7181-7189 [Full Text]

Lara Joubert, Sylvie Claeysen, Michèle Sebben, Anne-Sophie Bessis, Robin D. Clark, Renee S. Martin, Joël Bockaert, and Aline Dumuis
A 5-HT4 Receptor Transmembrane Network Implicated in the Activity of Inverse Agonists but Not Agonists
J. Biol. Chem. 277: 25502-25511, July 2002. [Abstract]

Vilaro MT, Cortes R, Gerald C, Branchek TA, Palacios JM, Mengod G.
Localization of 5-HT4 receptor mRNA in rat brain by in situ hybridization histochemistry.
Brain Res Mol Brain Res 1996 Dec 31;43(1-2):356-60
"Comparison of mRNA distribution with receptor distribution as visualized with [125I]SB 207710 indicates that 5-HT4 receptors are localized both somatodendritically in e.g. caudate putamen and on axon terminals in e.g. substantia nigra and globus pallidus." [Abstract]

Prins, N. H., Shankley, N. P., Welsh, N. J., Briejer, M. R., Lefebvre, R. A., Akkermans, L. M.A., Schuurkes, J. A.J.
An improved in vitro bioassay for the study of 5-HT4 receptors in the human isolated large intestinal circular muscle
Br. J. Pharmacol. 2000 129: 1601-1608 [Abstract]

Mine, Yukiko, Yoshikawa, Takashi, Oku, Seiko, Nagai, Ryuji, Yoshida, Naoyuki, Hosoki, Kanoo
Comparison of Effect of Mosapride Citrate and Existing 5-HT4 Receptor Agonists on Gastrointestinal Motility In Vivo and In Vitro
J Pharmacol Exp Ther 1997 283: 1000-1008 [Full Text]

Claeysen, Sylvie, Sebben, Michele, Becamel, Carine, Bockaert, Joel, Dumuis, Aline
Novel Brain-Specific 5-HT4 Receptor Splice Variants Show Marked Constitutive Activity: Role of the C-Terminal Intracellular Domain
Mol Pharmacol 1999 55: 910-920 [Full Text]

Lefebvre H, Contesse V, Delarue C, Feuilloley M, Hery F, Grise P, Raynaud G, Verhofstad AA, Wolf LM, Vaudry H.
Serotonin-induced stimulation of cortisol secretion from human adrenocortical tissue is mediated through activation of a serotonin4 receptor subtype.
Neuroscience 1992;47(4):999-1007
"The benzamide derivative zacopride, considered as a serotonin4 agonist, induced a robust stimulation of cortisol secretion. In addition, the corticotropic effects of serotonin (10(-7) M) and zacopride (10(-6) M) were not additive. Incubation of adrenocortical fragments with zacopride (10(-6) M) or serotonin (10(-6) M) caused a significant increase in cAMP formation. Taken together, these data suggest that serotonin, locally released by intra-adrenal mast-like cells, may act as a paracrine factor to stimulate cortisol secretion in man. Our results also indicate that serotonin-induced corticosteroid production is mediated through activation of a serotonin4 receptor subtype positively coupled to adenylate cyclase." [Abstract]

Herve Lefebvre, Dorthe Cartier, Celine Duparc, Isabelle Lihrmann, Vincent Contesse, Catherine Delarue, Michel Godin, Rodolphe Fischmeister, Hubert Vaudry, and Jean-Marc Kuhn
Characterization of Serotonin4 Receptors in Adrenocortical Aldosterone-Producing Adenomas: In Vivo and in Vitro Studies
J. Clin. Endocrinol. Metab. 87: 1211-1216, 2002.
"We have previously shown that serotonin (5-HT) stimulates aldosterone secretion from the human adrenal gland through activation of 5-HT4 receptors. The aim of the present study was to investigate in vivo and in vitro the presence of 5-HT4 receptors in aldosterone-producing adenomas (aldosteronomas)." [Abstract]

Claeysen, Sylvie, Sebben, Michele, Becamel, Carine, Eglen, Richard M., Clark, Robin D., Bockaert, Joel, Dumuis, Aline
Pharmacological Properties of 5-Hydroxytryptamine4 Receptor Antagonists on Constitutively Active Wild-Type and Mutated Receptors
Mol Pharmacol 2000 58: 136-144 [Full Text]

Silvestre JS, Fernandez AG, Palacios JM.
Effects of 5-HT4 receptor antagonists on rat behaviour in the elevated plus-maze test.
Eur J Pharmacol 1996 Aug 15;309(3):219-22 [Abstract]

Blondel O, Vandecasteele G, Gastineau M, Leclerc S, Dahmoune Y, Langlois M, Fischmeister R.
Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium.
FEBS Lett 1997 Aug 4;412(3):465-74 [Abstract]

Candura, SM, Messori, E, Franceschetti, GP, D'Agostino, G, Vicini, D, Tagliani, M, Tonini, M
Neural 5-HT4 receptors in the human isolated detrusor muscle: effects of indole, benzimidazolone and substituted benzamide agonists and antagonists
Br. J. Pharmacol. 1996 118: 1965-1970 [Abstract]

Prins, N. H., van der Grijn, A., Lefebvre, R. A., Akkermans, L. M.A., Schuurkes, J. A.J.
5-HT4 receptors mediating enhancement of contractility in canine stomach; an in vitro and in vivo study
Br. J. Pharmacol. 2001 132: 1941-1947 [Abstract]

Jin, J.-G., Foxx-Orenstein, A. E., Grider, J. R.
Propulsion in Guinea Pig Colon Induced by 5-Hydroxytryptamine (HT) via 5-HT4 and 5-HT3 Receptors
J Pharmacol Exp Ther 1999 288: 93-97 [Full Text]

Prins, N. H., Van Haselen, J. F.W.R., Lefebvre, R. A., Briejer, M. R., Akkermans, L. M.A., Schuurkes, J. A.J.
Pharmacological characterization of 5-HT4 receptors mediating relaxation of canine isolated rectum circular smooth muscle
Br. J. Pharmacol. 1999 127: 1431-1437 [Abstract]

Bharucha AE, Camilleri M, Haydock S, Ferber I, Burton D, Cooper S, Tompson D, Fitzpatrick K, Higgins R, Zinsmeister AR.
Effects of a serotonin 5-HT4 receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans
Gut ; 47: 667-674. [Abstract]

McLean, PG, Coupar, IM, Molenaar, P
A comparative study of functional 5-HT4 receptors in human colon, rat oesophagus and rat ileum
Br. J. Pharmacol. 1995 115: 47-56 [Abstract]

Prins, N. H., Shankley, N. P., Welsh, N. J., Briejer, M. R., Lefebvre, R. A., Akkermans, L. M.A., Schuurkes, J. A.J.
An improved in vitro bioassay for the study of 5-HT4 receptors in the human isolated large intestinal circular muscle
Br. J. Pharmacol. 2000 129: 1601-1608 [Abstract]

Leclere, Pascal G., Lefebvre, Romain A.
Presynaptic modulation of cholinergic neurotransmission in the human proximal stomach
Br. J. Pharmacol. 2002 135: 135-142
"These results suggest that the release of acetylcholine from the cholinergic neurones, innervating the circular muscle in the human proximal stomach, can be inhibited via presynaptic muscarinic auto-receptors and {alpha}2-adrenoceptors, and stimulated via presynaptic 5-HT4-receptors. No evidence for modulation by NO or VIP was obtained." [Abstract]







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Recent 5-HT4 Receptor Research

1) Polsinelli G, Zai CC, Strauss J, Kennedy JL, De Luca V
Association and CpG SNP analysis of HTR4 polymorphisms with suicidal behavior in subjects with schizophrenia.
J Neural Transm. 2012 Jul 29;
Suicide is a major contributor to the morbidity and mortality rates in schizophrenia. Genetic and epigenetic factors have been reported to modulate the risk for suicide although the precise mechanism and magnitude of these contributions is unknown. Previous research indicates that suicide attempters present abnormalities in the serotonergic system. The present study aimed to identify genetic and epigenetic risk variants of the serotonin 5-HT(4) receptor gene (HTR4) for suicidal behavior. We included 234 subjects diagnosed with schizophrenia. For this purpose, we analyzed 11 markers across HTR4 and performed genotype, haplotype and potential methylation analyses, correcting for clinical covariates and ethnic stratification. Three blocks were revealed from the LD analysis. Haplotypes in Block 3 were significantly associated with suicide attempt. The potential methylation analysis was not significant. Our results suggest that HTR4 polymorphisms may not play a major role in the susceptibility for suicidal behavior in subjects with schizophrenia. Moreover, although not significant, the CpG SNP potential methylation analysis would be informative for future methylation analysis on this gene. [PubMed Citation] [Order full text from Infotrieve]

2) Takahashi T
Mechanism of interdigestive migrating motor complex.
J Neurogastroenterol Motil. 2012 Jul;18(3):246-57.
Migrating motor complex (MMC) is well characterized by the appearance of gastrointestinal contractions in the interdigestive state. This review article discussed the mechanism of gastrointestinal MMC. Luminal administration of 5-hydroxytryptamine (5-HT) initiates duodenal phase II followed by gastrointestinal phase III with a concomitant increase of plasma motilin release in conscious dogs. Duodenal 5-HT concentration is increased during gastric phase II and phase III. Intravenous infusion of motilin increases luminal 5-HT content and induces gastrointestinal phase III. 5-HT(4) antagonists significantly inhibits both of gastric and intestinal phase III, while 5-HT(3) antagonists inhibited only gastric phase III. These suggest that gastrointestinal MMC cycle is mediated via the interaction between motilin and 5-HT by the positive feedback mechanism. Gastric MMC is regulated via vagus, 5-HT(3/4) receptors and motilin, while intestinal MMC is regulated via intrinsic primary afferent neurons and 5-HT(4) receptors. Stress is highly associated with the pathogenesis of functional dyspepsia. Acoustic stress attenuates gastric phase III without affecting intestinal phase III in conscious dogs, via reduced vagal activity and increased sympathetic activity. It has been shown that subset of functional dyspepsia patients show reduced vagal activity and impaired gastric phase III. The physiological importance of gastric MMC is a mechanical and chemical cleansing of the empty stomach in preparation for the next meal. The impaired gastric MMC may aggravate dyspeptic symptoms following a food ingestion. Thus, maintaining gastric MMC in the interdigestive state is an important factor to prevent the postprandial dyspeptic symptoms. [PubMed Citation] [Order full text from Infotrieve]

3) Yan C, Xin-Guang L, Hua-Hong W, Jun-Xia L, Yi-Xuan L
Effect of the 5-HT4 receptor and serotonin transporter on visceral hypersensitivity in rats.
Braz J Med Biol Res. 2012 Jul 26;
[PubMed Citation] [Order full text from Infotrieve]

4) Hashimoto G, Sakurai M, Teich AF, Saeed F, Aziz F, Arancio O
5-HT4 Receptor Stimulation Leads to Soluble AβPPα Production through MMP-9 Upregulation.
J Alzheimers Dis. 2012 Jul 17;
Serotonin 4 (5-HT4) receptor signaling does not only have the physiological function of improving cognition, but might also be helpful in the therapy of Alzheimer's disease (AD) through regulation of the production of soluble amyloid-? protein precursor alpha (sA?PP?). To analyze the relationship between 5-HT4 receptor signaling and sA?PP? production, we stably transfected H4 cells with A?PP and 5-HT4 receptor (H4/A?PP/5-HT4 cells). We found that 24-h incubation with the 5-HT4 receptor agonist RS-67333 upregulates matrix metalloproteinase-9 (MMP-9). Furthermore, MMP-9 overexpression enhanced sA?PP? levels, whereas knockdown with MMP-9 siRNA decreased sA?PP? levels. When RS-67333 was injected for 10 days in Tg2576 mice, a model of amyloid-? peptide (A?) deposition, there was an increase in hippocampal levels of sA?PP?, C-terminal fragment ?, and MMP-9, as well as a decrease in hippocampal senile plaque number and levels of the 40 amino acid peptide, A?40. Taken all together, these experiments demonstrate that 5-HT4 receptor stimulation induces expression of MMP-9 which cleaves A?PP through ?-secretase-like activity, leading to an increase of sA?PP? levels and a reduction of A? load. [PubMed Citation] [Order full text from Infotrieve]

5) Godínez-Chaparro B, López-Santillán FJ, Orduña P, Granados-Soto V
Secondary mechanical allodynia and hyperalgesia depend on descending facilitation mediated by spinal 5-HT(4), 5-HT(6) and 5-HT(7) receptors.
Neuroscience. 2012 Jul 13;
In the present study we determined the role of spinal 5-hydroxytriptamine (5-HT) and 5-HT(4/6/7) receptors in the long-term secondary mechanical allodynia and hyperalgesia induced by formalin in the rat. Formalin produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term secondary mechanical allodynia and hyperalgesia in both paws. In addition, formalin increased the tissue content of 5-HT in the ipsilateral, but not contralateral, dorsal part of the spinal cord compared to control animals. Intrathecal (i.t.) administration of 5,7-dihydroxytriptamine (5,7-DHT), a serotonergic neurotoxin, diminished tissue 5-HT content in the ipsilateral and contralateral dorsal parts of the spinal cord. Accordingly, i.t. 5,7-DHT prevented formalin-induced secondary allodynia and hyperalgesia in both paws. I.t. pre-treatment (-10min) with ML-10302 (5-HT(4) agonist), EMD-386088 (5-HT(6) agonist) and LP-12 (5-HT(7) agonist) significantly increased secondary mechanical allodynia and hyperalgesia in both paws. In contrast, i.t. pre-treatment (-20min) with GR-125487 (5-HT(4) antagonist), SB-258585 (5-HT(6) antagonist) and SB-269970 (5-HT(7) antagonist) significantly prevented formalin-induced long-term effects in both paws. In addition, these antagonists prevented the pro-nociceptive effect of ML-10302, EMD-386088 and LP-12, respectively. The i.t. post-treatment (6days after formalin injection) with GR-125487, SB-258585 and SB-269970 reversed formalin-induced secondary allodynia and hyperalgesia in both paws. These results suggest that spinal 5-HT, released from the serotonergic projections in response to formalin injection, activates pre- or post-synaptic 5-HT(4/6/7) receptors at the dorsal root ganglion/spinal cord promoting the development and maintenance of secondary allodynia and hyperalgesia. [PubMed Citation] [Order full text from Infotrieve]

6) Morais TC, Lopes SC, Carvalho KM, Arruda BR, de Souza FT, Trevisan MT, Rao VS, Santos FA
Mangiferin, a natural xanthone, accelerates gastrointestinal transit in mice involving cholinergic mechanism.
World J Gastroenterol. 2012 Jul 7;18(25):3207-14.
[PubMed Citation] [Order full text from Infotrieve]

7) Coupar IM, Irving HR, Manallack DT, Tan YY, Ayad F, Iulio JD, Tochon-Danguy N, Iskander MN
Assessment of the pharmacological properties of 5-methoxyindole derivatives at 5-HT(4) receptors.
J Pharm Pharmacol. 2012 Aug;64(8):1099-106.
Objectives? The aim was to examine the biological activity of 5-methoxytryptamine derivatives at the 5-hydroxytryptamine (5-HT)(4) receptor to explore the effect of substitution on the aliphatic amine of the 5-methoxyamine scaffold. Methods? Three compounds were tested for affinity at the 5-HT(4) receptor by radioligand binding and functional activity using guinea-pig ileum and human colon circular muscle preparations and also in the mouse whole gut transit test. Key findings? The three compounds all had agonist properties at the 5-HT(4) receptor but their efficacy differed in the different functional tests. Compound 3 had the highest affinity for the 5-HT(4) receptor and was a full agonist at relaxing human colon circular muscle with efficacy closest to 5-HT. Compounds 1 and 2 were partial agonists in this assay with lower efficacies; compound 2 was a full agonist in the guinea-pig ileum assay whereas compound 3 was a partial agonist. Compounds 1 and 2 also showed activity in the mouse gut transit assay while compound 3 had no activity. Conclusions? Of the compounds tested, compound 3 was the most promising 5-HT(4) receptor agonist and the results highlight the value of using human tissue in functional tests when assessing compounds for potential activity. [PubMed Citation] [Order full text from Infotrieve]

8) Del Tredici K, Jost WH
[Gastrointestinal dysfunction in idiopathic Parkinson's disease.]
Nervenarzt. 2012 Jun 30;
Gastrointestinal dysfunction is frequent during all stages of Parkinson's disease. The entire gastrointestinal tract becomes involved and symptoms include sialorrhea, dysphagia (difficulties swallowing), delayed gastric emptying, absorption problems and constipation. These non-motor symptoms can be manifested even prior to the initial Parkinson diagnosis, i.e. during the so-called premotor phase of the disorder and may serve as prodromal markers of the early non-motor disease phase. In addition to causing patients major discomfort and a reduced quality of life, such gastrointestinal complaints can also negatively influence the therapy with antiparkinsonian medications. Thus, delayed gastric emptying is an important cause of unforeseen motor fluctuations.Gastrointestinal dysfunction is attributable in part to the presence of synucleinopathy (Lewy pathology) both in the dorsal motor nucleus of the vagus nerve, which supplies the parasympathetic innervation of the gut from the distal esophagus to the left colonic flexure, as well as in the intramural Meissner and Auerbach plexuses of the enteric nervous system (ENS). In all probability the development of the lesions in the lower brainstem and in the ENS precedes neurodegeneration of the dopaminergic nigrostriatal system. From a diagnostic standpoint, neurologists need not only a carefully taken patient history and the clinical findings but also esophagography (barium study), gastric scintigraphy and assessment of the colonic transit time. The therapeutic options for impaired upper gastrointestinal tract motility are still limited. Sialorrhea can be reduced by prescribing anticholinergics or injections of botulinum toxin and the peristalsis can be modulated by domperidone. In the lower gastrointestinal tract, constipation can be conservatively treated by using macrogol (polyethylene glycol) and, in the future, perhaps by serotonine (5-HT4) agonists. [PubMed Citation] [Order full text from Infotrieve]

9) Haahr ME, Fisher P, Holst K, Madsen K, Jensen CG, Marner L, Lehel S, Baaré W, Knudsen G, Hasselbalch S
The 5-HT(4) receptor levels in hippocampus correlates inversely with memory test performance in humans.
Hum Brain Mapp. 2012 Jun 26;
The cerebral serotonin (5-HT) system is involved in cognitive functions such as memory and learning and animal studies have repeatedly shown that stimulation of the 5-HT type 4 receptor (5-HT(4) R) facilitates memory and learning and further that the 5-HT(4) R modulates cellular memory processes in hippocampus. However, any associations between memory functions and the expression of the 5-HT(4) R in the human hippocampus have not been investigated. Using positron emission tomography with the tracer [(11) C]SB207145 and Reys Auditory Verbal Learning Test we aimed to examine the individual variation of the 5-HT4R binding in hippocampus in relation to memory acquisition and consolidation in healthy young volunteers. We found significant, negative associations between the immediate recall scores and left and right hippocampal BP(ND) , (p = 0.009 and p = 0.010 respectively) and between the right hippocampal BP(ND) and delayed recall (p = 0.014). These findings provide evidence that the 5-HT(4) R is associated with memory functions in the human hippocampus and potentially pharmacological stimulation of the receptor may improve episodic memory. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc. [PubMed Citation] [Order full text from Infotrieve]

10) Haahr ME, Rasmussen PM, Madsen K, Marner L, Ratner C, Gillings N, Baaré WF, Knudsen GM
Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry.
Neuroimage. 2012 Mar 27;61(4):884-888.
The neurobiology underlying obesity is not fully understood. The neurotransmitter serotonin (5-HT) is established as a satiety-generating signal, but its rewarding role in feeding is less well elucidated. From animal experiments there is now evidence that the 5-HT(4) receptor (5-HT(4)R) is involved in food intake, and that pharmacological or genetic manipulation of the receptor in reward-related brain areas alters food intake. Here, we used positron emission tomography in humans to examine the association between cerebral 5-HT(4)Rs and common obesity. We found in humans a strong positive association between body mass index and the 5-HT(4)R density bilaterally in the two reward 'hot spots' nucleus accumbens and ventral pallidum, and additionally in the left hippocampal region and orbitofrontal cortex. These findings suggest that the 5-HT(4)R is critically involved in reward circuits that regulate people's food intake. They also suggest that pharmacological stimulation of the cerebral 5-HT(4)R may reduce reward-related overeating in humans. [PubMed Citation] [Order full text from Infotrieve]

11) 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]

12) Hejazi RA, McCallum RW, Sarosiek I
Prokinetics in diabetic gastroparesis.
Curr Gastroenterol Rep. 2012 Aug;14(4):297-305.
Within the last 50 years, diabetic gastroparesis has become a well recognized complication of type 1 and type 2 diabetes. It is a syndrome characterized by abnormal gastric function, resulting in delayed emptying of the stomach in the absence of any evident mechanical obstruction, predominantly manifested by early satiety, postprandial fullness, nausea, vomiting, and weight loss. The past five years have shown significant advances in its pathophysiology and in new diagnostic tests. Prokinetic medications remain the therapeutic focus for improving clinical symptoms of gastroparesis through enhanced gastric emptying. This article summarizes the present knowledge of prokinetics, with emphasis on medications currently available, as well as drugs under clinical investigation, including some agents in advanced clinical trials that are likely to be used in the treatment of diabetic gastroparesis in the future. These include the ghrelin agonists and newer 5-HT4 agonists devoid of cardiac side effects. [PubMed Citation] [Order full text from Infotrieve]

13) Parkman HP, Mishra A, Jacobs M, Pathikonda M, Sachdeva P, Gaughan J, Krynetskiy E
Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters.
J Clin Gastroenterol. 2012 Jul;46(6):494-503.
[PubMed Citation] [Order full text from Infotrieve]

14) Long DD, Armstrong SR, Beattie DT, Choi SK, Fatheree PR, Gendron RA, Goldblum AA, Humphrey PP, Marquess DG, Shaw JP, Smith JA, Derek Turner S, Vickery RG
Discovery, oral pharmacokinetics and in vivo efficacy of a highly selective 5-HT(4) receptor agonist: Clinical compound TD-2749.
Bioorg Med Chem Lett. 2012 Jul 15;22(14):4849-53.
Further application of our multivalent approach to drug discovery directed to 5-HT(4) receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identification of clinical compound TD-2749. [PubMed Citation] [Order full text from Infotrieve]

15) Mitchelson FJ
The pharmacology of McN-A-343.
Pharmacol Ther. 2012 Aug;135(2):216-45.
The unusual pharmacology of McN-A-343 was first described by Roszowski in 1961. The agonist appeared to be a selective stimulant of muscarinic receptors in sympathetic ganglia, now known to be the muscarinic M(1) receptor subtype. However, subsequent research demonstrated that McN-A-343 is a partial agonist with similar affinity at all five muscarinic acetylcholine receptor subtypes and its relative selectivity depends on a higher efficacy at the M(1) (and M(4)) subtypes. Being a partial agonist its action is also dependent on factors, such as receptor density and coupling efficacy between receptor activation and tissue response. Nevertheless, the relatively high efficacy at M(1) receptors led to its widespread use as an aid to distinguish responses mediated through M(1) receptors from those utilizing M(2) or M(3) muscarinic receptor subtypes, especially in the CNS. There is also evidence that it has an allosteric action at some receptor subtypes. Recently, it was demonstrated that McN-A-343 can bind to an allosteric site on the M(2) receptor as well as to the orthosteric site and has thus been termed a "bitopic agonist". This allosteric site differs from that occupied by allosteric modulators, such as gallamine. Comparison of comparable mutagenic changes in M(2) and M(4) receptors also suggests that McN-A-343 utilizes different regions of the two receptors for ERK1/2 activation. McN-A-343 has a number of non-muscarinic actions. These include activation of some types of nicotinic acetylcholine receptors, antagonism of serotonin 5-HT(3) and 5-HT(4) receptor subtypes, inhibition of the uptake(1) mechanism and a local anesthetic action. [PubMed Citation] [Order full text from Infotrieve]

16) Fisher PM, Holst KK, Mc Mahon B, Haahr ME, Madsen K, Gillings N, Baaré WF, Jensen PS, Knudsen GM
5-HTTLPR status predictive of neocortical 5-HT(4) binding assessed with [(11)C]SB207145 PET in humans.
Neuroimage. 2012 Aug 1;62(1):130-6.
Serotonin (5-HT) is a neuromodulator affecting myriad aspects of personality and behavior and has been implicated in the pathophysiology of affective disorders including depression and anxiety. The 5-HTTLPR is a common genetic polymorphism within the promoter region of the gene coding for the serotonin transporter such that the S allele is associated with reduced transcriptional efficacy compared to the L allele, potentially contributing to increased serotonin levels. In humans, this genetic variant has been linked to inter-individual variability in risk for affective disorders, related aspects of personality and brain function including response to threat. However, its effects on aspects of serotonin signaling in humans are not fully understood. Studies in animals suggest that the 5-HT 4 receptor (5-HT(4)) shows a monotonic inverse association with long-term changes in serotonin levels indicating that it may be a useful measure for identifying differences in serotonergic neurotransmission. In 47 healthy adults we evaluated the association between 5-HTTLPR status and in vivo 5-HT(4) receptor binding assessed with [(11)C]SB207145 positron emission tomography (PET). We observed a significant association within the neocortex where [(11)C]SB207145 binding was 9% lower in S carriers compared to LL homozygotes. We did not find evidence for an effect of season or a season-by-5-HTTLPR interaction effect on regional [(11)C]SB207145 binding. Our findings are consistent with a model wherein the 5-HTTLPR S allele is associated with relatively increased serotonin levels. These findings provide novel evidence supporting an effect of 5-HTTLPR status on serotonergic neurotransmission in adult humans. There were no indications of seasonal effects on serotonergic neurotransmission. [PubMed Citation] [Order full text from Infotrieve]

17) Nima S, Kasiwong S, Ridtitid W, Thaenmanee N, Mahattanadul S
Gastrokinetic activity of Morinda citrifolia aqueous fruit extract and its possible mechanism of action in human and rat models.
J Ethnopharmacol. 2012 Jul 13;142(2):354-61.
[PubMed Citation] [Order full text from Infotrieve]

18) Chen A, Kelley LD, Janušonis S
Effects of prenatal stress and monoaminergic perturbations on the expression of serotonin 5-HT₄ and adrenergic β₂ receptors in the embryonic mouse telencephalon.
Brain Res. 2012 Jun 12;1459:27-34.
The serotonin 5-HT(4) receptor (5-HT(4)R) is coded by a complex gene that produces four mRNA splice variants in mice (5-HT(4(a))R, 5-HT(4(b))R, 5-HT(4(e))R, 5-HT(4(f))R). This receptor has highly dynamic expression in brain development and its splice variants differ in their developmental trajectories. Since 5-HT(4)Rs are important in forebrain function (including forebrain control of serotonergic activity in the brainstem), we investigated the susceptibility of 5-HT(4)R expression in the mouse embryonic telencephalon to prenatal maternal stress and altered serotonin (5-hydroxytryptamine, 5-HT) levels. Because the gene coding the adrenergic ?(2) receptor (?(2)AR) is embedded in the 5-HT(4)R gene, we also investigated whether 5-HT(4)R mRNA levels were modulated by selective ?(2)AR agents. Timed-pregnant C57BL/6 mice were treated beginning at embryonic day (E) 14 and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to assess the mRNA levels of all 5-HT(4)R splice variants and ?(2)AR in the embryonic telencephalon at E17. Maternal prenatal stress and 5-HT depletion with pCPA, a tryptophan hydroxylase inhibitor, reduced the levels of the 5-HT(4(b))R splice variant. Terbutaline (a selective ?(2)AR agonist) and ICI 118,551 (a selective ?(2)AR antagonist) had no effect on ?(2)AR and 5-HT(4)R mRNA levels. These results show that prenatal stress and reduced 5-HT levels can alter 5-HT(4)R expression in the developing forebrain and that some 5-HT(4)R splice variants may be more susceptible than others. [PubMed Citation] [Order full text from Infotrieve]

19) Gómez-Lázaro E, Garmendia L, Beitia G, Perez-Tejada J, Azpiroz A, Arregi A
Effects of a putative antidepressant with a rapid onset of action in defeated mice with different coping strategies.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Aug 7;38(2):317-27.
There is evidence suggesting that stressful social events may result in depressive-like disorders, but the development of these disorders depend on the way in which people cope with stress. Although antidepressants are useful their drawback is a delay in the therapeutic effects, moreover not all the patients show an adequate response to this treatment. The aim of this study was to analyse the effect of RS 67333, which is a 5-HT(4) receptor partial agonist and a putative antidepressant which exhibits a rapid onset of action and to determine whether this drug reverses the behavioural and physiological effects that are generated by chronic defeat in subjects who manifest a more vulnerable profile in their response to stress. Male mice were exposed to defeat for 21 consecutive days using a sensorial contact model. After 18days of defeat, 2 groups of subjects were established, active and passive, in accordance with the behaviour that was manifested during social confrontation, and drug treatment was initiated for 5days. Finally, the animals were subjected to a forced swimming test (FST). The results revealed higher corticosterone levels in passive mice after the last defeat. Additionally, 3days after the last defeat, they showed lower corticosterone levels and higher splenic IL-6 and TNF-? levels and hypothalamic GR mRNA levels when compared to their active and manipulated control counterparts. Passive mice had higher 5-HT(1A) receptor mRNA levels than the manipulated controls and a lower MR/GR ratio than active mice. Similar to stress, the drug increased hypothalamic GR mRNA levels, but it did not affect other measured physiological variables or social behaviour, which suggested that the mechanism of this drug is not the most adequate for reversing stress-induced effects in this model. Nevertheless, the treatment increased swimming and decreased immobility in the FST, suggesting an antidepressant potential for this drug. [PubMed Citation] [Order full text from Infotrieve]

20) 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 Jun 19;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]