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Filippo Drago - One of the best experts on this subject based on the ideXlab platform.
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Antidepressant properties of the 5-HT4 Receptor partial agonist, SL65.0155: Behavioral and neurochemical studies in rats
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2009Co-Authors: Alessandra Tamburella, Andrea Navarria, Vincenzo Micale, Filippo DragoAbstract:This study was undertaken to investigate the potential antidepressant-like properties of SL65.0155, a serotonin 5-HT4 Receptor partial agonist, in male rats of the Wistar strain tested in the forced swim test (FST), an experimental model widely used to assess antidepressant-like activity. The expression of hippocampal neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF), the phosphorilated cAMP response element-binding protein (p-CREB), the B cell lymphoma-2 (Bcl-2), the Bax and the vascular endothelium growth factor (VEGF) were also evaluated by Western Blot analysis. Different groups of rats received intraperitoneally (i.p.) injections of SL65.0155 (0.1, 0.5 and 1??mg/kg), clomipramine (50??mg/kg), citalopram (15??mg/kg) or vehicle, respectively, 24, 5 and 1??h prior to the FST. Compared to the control group, SL65.0155 (0.5 and 1??mg/kg), clomipramine or citalopram injected animals showed an increased swimming and climbing behavior and reduced immobility time in the FST. Interestingly, this effect was not due to changes in the locomotor activity since all treated groups failed to show any change in motor ability as assessed in the open field test. Western blot analysis of hippocampal homogenates showed an enhancement of p-CREB, BDNF Bcl-2 and VEGF protein levels in SL65.0155 treated groups, but not in citalopram or clomipramine treated groups, used here as positive control. No change was found in Bax expression in any treated group. These findings give further support to the hypothesis that the stimulation of serotonin 5-HT4 Receptors may be a therapeutic target for depression. ?? 2009 Elsevier Inc. All rights reserved.
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Cognitive effects of SL65.0155, a serotonin 5-HT4 Receptor partial agonist, in animal models of amnesia
Brain Research, 2006Co-Authors: Vincenzo Micale, Carmen Mazzola, Gian Marco Leggio, Filippo DragoAbstract:Given that several data suggest the involvement of serotonergic (5-HT) system, particularly the serotonin 5-HT4 Receptors, in memory processes; this study was undertaken to investigate the role of serotonin 5-HT4 Receptors in different experimental models of amnesia in male Swiss mice or in male Sprague-Dawley rats, tested in learning and memory tasks. Amnesia was induced in mice by intracerebroventricular (i.c.v.) injection of ??-amyloid 1-42 fragment (BAP 1-42; 400 pmol/mouse) or of galanin (GAL) 1-29 (3????g/mouse). Another group of animals was exposed to carbon monoxide (CO). Treatments were made 14??days, 15??min or 8??days prior to the learning trial of a step-through passive avoidance paradigm, respectively. Latency to re-enter the dark box appeared to be reduced in all treatment groups. Intraperitoneal (i.p.) administration of SL65.0155 (5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenylethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one-monohydrochloride), a serotonin 5-HT4 Receptor partial agonist (1??mg/kg/day), for 7??days prior to the learning trial, inhibited the amnesic effect of both peptides increasing the latency to re-enter the dark box also in mice exposed to CO. In rats with ibotenate-induced lesions of the nucleus basalis magnocellularis (NBM) or prenatally exposed to methylazoxymethanol (MAM), SL65.0155 (1??mg/kg/day, i.p.) administered for 7??days, improved the learning and memory capacity in animals tested in shuttle-box active avoidance and radial maze tests. These findings give further support to the hypothesis of SL65.0155 cognition-enhancing activity across a range of tasks. ?? 2006 Elsevier B.V. All rights reserved.
Alberto J. Kaumann - One of the best experts on this subject based on the ideXlab platform.
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Appearance of a ventricular 5-HT4 Receptor-mediated inotropic response to serotonin in heart failure
Cardiovascular Research, 2005Co-Authors: Eirik Qvigstad, Alberto J. Kaumann, Trond Brattelid, Ivar Sjaastad, Kjetil Wessel Andressen, Kurt A. Krobert, Jon Arne Kro Birkeland, Ole M. Sejersted, Tor Skomedal, Jan-bjørn OsnesAbstract:Background : Current pharmacological treatment of congestive heart failure (CHF) addresses changes in neurohumoral stimulation or cardiac responsiveness to such stimulation. Yet, undiscovered neurohumoral changes, adaptive or maladaptive, may occur in CHF and suggest novel pharmacological treatment. Serotonin [5-hydroxytryptamine (5-HT)] enhances contractility and causes arrhythmias through 5-HT4 Receptors in human atrium and ventricle but not through rat ventricular 5-HT4 Receptors. Objective : We investigated whether CHF could induce ventricular responsiveness to serotonin. Methods : Postinfarction CHF was induced in male Wistar rats by coronary artery ligation. Contractility was measured in left ventricular papillary muscles 6 weeks after infarction. Messenger RNA was quantified by RT-PCR and cAMP by RIA. Results : Serotonin caused positive inotropic (−logEC50=7.5) and lusitropic effects in CHF but not Sham papillary muscles. The inotropic effect of 10 μM serotonin in CHF (31.3 ± 2.2%) was of similar size as the effect of 10 μM isoproterenol (34.0 ± 1.7%). The effects of serotonin were antagonised by GR113808 (0.5–5 nM), consistent with mediation through 5-HT4 Receptors. This was further supported by positive inotropic effects of the 5-HT4-selective partial agonist RS67506. Carbachol blunted the serotonin responses and serotonin increased ventricular and cardiomyocyte cAMP, consistent with coupling to Gs and adenylyl cyclase. Quantitative RT-PCR revealed fourfold increased 5-HT4(b) mRNA expression in CHF vs. Sham ventricles. Conclusion : Functional ventricular 5-HT4 Receptors are induced by myocardial infarction and CHF of the rat heart. We propose that they are a model for ventricular 5-HT4 Receptors of human failing heart and may play a pathophysiological role in heart failure.
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Comparison of the densities of 5-HT4 Receptors, beta 1- and beta 2-adrenoceptors in human atrium: functional implications.
Naunyn-schmiedebergs Archives of Pharmacology, 1996Co-Authors: Alberto J. Kaumann, James A. Lynham, Anthony M. BrownAbstract:We measured in human atrium the density of 5-HT4 Receptors, labelled with [125I]-SB 207710 (1-butyl-4-piperidinyl) methyl 8-amino-7-iodo-1, (4-benzodioxan-5-carboxylate), and compared it with the density of β1- and β2-adrenoceptors, labelled with (−)-[125I]-cyanopindolol. [125I]-SB 207710 (5–1200 pmol/l) labelled a small population of saturable binding sites (Bmax ≈ 4 fmol/mg protein) with a pKD of 9.7 and with 5-HT4 Receptor characteristics, as assessed with competing ligands. The density of atrial binding sites with 5-HT4 Receptor characteristics was 10 and 5 times lower, respectively, than the density of β1- and β2-adrenoceptors. We suggest that the small 5-HT4 Receptor population may in part explain why the positive inotropic effects of 5-HT are smaller than those of catecholamines mediated through β1- and β2-adrenoceptors.
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Labelling with [125I]‐SB 207710 of a small 5‐HT4 Receptor population in piglet right atrium: functional relevance
British Journal of Pharmacology, 1995Co-Authors: Alberto J. Kaumann, James A. Lynham, Anthony M. BrownAbstract:Abstract 1. We investigated the affinity of SB 207710 for sinoatrial 5-HT4 Receptors and the density of right atrial 5-HT4 Receptors with [125I]-SB 207710 in right atria of new-born piglets. 2. SB 207710 (1-100 nM) antagonized the 5-HT-evoked tachycardia surmountably with a pKB of 9.8. 3. [125I]-SB 207710 (5-1500 pM) labelled a small population of saturable binding sites with a pKD of 10.1 and with 5-HT4 Receptor characteristics. The density of atrial binding sites with 5-HT4 Receptor characteristics was 174 and 22 times lower respectively than those of atrial beta 1- and beta 2-adrenoceptors, labelled with (-)-[125I]-cyanopindolol. 4. We suggest that the small 5-HT4 Receptor population may in part explain why the maximal tachycardia caused by 5-HT is smaller than that caused by catecholamines.
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Blockade of human atrial 5-HT4 Receptors by SB 207710, a selective and high affinity 5-HT4 Receptor antagonist
Naunyn-schmiedebergs Archives of Pharmacology, 1994Co-Authors: Alberto J. Kaumann, Frank King, Laramie Mary Gaster, Anthony M. BrownAbstract:The mode of antagonism of 5-hydroxytryptamine-induced positive inotropic effects by the highly selective 5-HT4 Receptor antagonist SB 207710 (1-butyl4-piperidinyl) methyl 8-amino-7-iodo-1,4-benzodioxan-5-carboxylate was investigated on isolated preparations of human right atrial appendage. SB 207 710 caused concentration-dependent (0.1–10 nmol/l) surmountable antagonism of the effects of 5-hydroxytryptamine with a pKB (mol/l) of 10.1. Due to its high selectivity and affinity, SB 207710 could be a powerful tool for the comparison of human atrial 5-HT4 Receptors with 5-HT4 Receptors of other organs of man and other species.
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Blockade of human atrial 5‐HT4 Receptors by GR 113808
British Journal of Pharmacology, 1993Co-Authors: Alberto J. KaumannAbstract:Abstract 1. The mode of antagonism of 5-hydroxytryptamine (5-HT)-induced positive inotropic effects by the highly selective 5-HT4 Receptor antagonist GR 113808 ([1-[2-methylsulphonylamino ethyl]-4-piperidinyl]methyl 1-methyl-1H-indole-3-carboxylate) was investigated on isolated preparations of human right atrium. 2. GR 113808 caused concentration-dependent (2-100 nM) surmountable antagonism of the effects of 5-HT with a pKB (M) of 8.8. 3. The affinity of GR 113808 for human atrial 5-HT4 Receptors, together with its high selectivity for 5-HT4 Receptors comprise useful properties for investigating the question of 5-HT4 Receptor subtypes.
Vincenzo Micale - One of the best experts on this subject based on the ideXlab platform.
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Antidepressant properties of the 5-HT4 Receptor partial agonist, SL65.0155: Behavioral and neurochemical studies in rats
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2009Co-Authors: Alessandra Tamburella, Andrea Navarria, Vincenzo Micale, Filippo DragoAbstract:This study was undertaken to investigate the potential antidepressant-like properties of SL65.0155, a serotonin 5-HT4 Receptor partial agonist, in male rats of the Wistar strain tested in the forced swim test (FST), an experimental model widely used to assess antidepressant-like activity. The expression of hippocampal neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF), the phosphorilated cAMP response element-binding protein (p-CREB), the B cell lymphoma-2 (Bcl-2), the Bax and the vascular endothelium growth factor (VEGF) were also evaluated by Western Blot analysis. Different groups of rats received intraperitoneally (i.p.) injections of SL65.0155 (0.1, 0.5 and 1??mg/kg), clomipramine (50??mg/kg), citalopram (15??mg/kg) or vehicle, respectively, 24, 5 and 1??h prior to the FST. Compared to the control group, SL65.0155 (0.5 and 1??mg/kg), clomipramine or citalopram injected animals showed an increased swimming and climbing behavior and reduced immobility time in the FST. Interestingly, this effect was not due to changes in the locomotor activity since all treated groups failed to show any change in motor ability as assessed in the open field test. Western blot analysis of hippocampal homogenates showed an enhancement of p-CREB, BDNF Bcl-2 and VEGF protein levels in SL65.0155 treated groups, but not in citalopram or clomipramine treated groups, used here as positive control. No change was found in Bax expression in any treated group. These findings give further support to the hypothesis that the stimulation of serotonin 5-HT4 Receptors may be a therapeutic target for depression. ?? 2009 Elsevier Inc. All rights reserved.
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Cognitive effects of SL65.0155, a serotonin 5-HT4 Receptor partial agonist, in animal models of amnesia
Brain Research, 2006Co-Authors: Vincenzo Micale, Carmen Mazzola, Gian Marco Leggio, Filippo DragoAbstract:Given that several data suggest the involvement of serotonergic (5-HT) system, particularly the serotonin 5-HT4 Receptors, in memory processes; this study was undertaken to investigate the role of serotonin 5-HT4 Receptors in different experimental models of amnesia in male Swiss mice or in male Sprague-Dawley rats, tested in learning and memory tasks. Amnesia was induced in mice by intracerebroventricular (i.c.v.) injection of ??-amyloid 1-42 fragment (BAP 1-42; 400 pmol/mouse) or of galanin (GAL) 1-29 (3????g/mouse). Another group of animals was exposed to carbon monoxide (CO). Treatments were made 14??days, 15??min or 8??days prior to the learning trial of a step-through passive avoidance paradigm, respectively. Latency to re-enter the dark box appeared to be reduced in all treatment groups. Intraperitoneal (i.p.) administration of SL65.0155 (5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenylethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one-monohydrochloride), a serotonin 5-HT4 Receptor partial agonist (1??mg/kg/day), for 7??days prior to the learning trial, inhibited the amnesic effect of both peptides increasing the latency to re-enter the dark box also in mice exposed to CO. In rats with ibotenate-induced lesions of the nucleus basalis magnocellularis (NBM) or prenatally exposed to methylazoxymethanol (MAM), SL65.0155 (1??mg/kg/day, i.p.) administered for 7??days, improved the learning and memory capacity in animals tested in shuttle-box active avoidance and radial maze tests. These findings give further support to the hypothesis of SL65.0155 cognition-enhancing activity across a range of tasks. ?? 2006 Elsevier B.V. All rights reserved.
Jan A.j. Schuurkes - One of the best experts on this subject based on the ideXlab platform.
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Chronic 5-HT4 Receptor activation decreases Aβ production and deposition in hAPP/PS1 mice.
Neurobiology of Aging, 2013Co-Authors: Ina Tesseur, Jan A.j. Schuurkes, Anna A. Pimenova, Adrian C. Lo, Marta Ciesielska, Stefan F. Lichtenthaler, Joris H. De Maeyer, Rudi D'hooge, Bart De StrooperAbstract:Lowering the production and accumulation of Aβ has been explored as treatment for Alzheimer's disease (AD), because Aβ is postulated to play an important role in the pathogenesis of AD. 5-HT4 Receptors are an interesting drug target in this regard, as their activation might stimulate α-secretase processing, which increases sAPPα and reduces Aβ, at least according to the central dogma in APP processing. Here we describe a novel high-affinity 5-HT4 Receptor agonist SSP-002392 that, in cultured human neuroblastoma cells, potently increases the levels of cAMP and sAPPα at 100-fold lower concentrations than the effective concentrations of prucalopride, a known selective 5-HT4 Receptor agonist. Chronic administration of this compound in a hAPP/PS1 mouse model of Alzheimer's disease decreased soluble and insoluble Aβ in hippocampus, but the potential mechanisms underlying these observations seem to be complex. We found no evidence for direct α-secretase stimulation in the brain in vivo, but observed decreased APP and BACE-1 expression and elevated astroglia and microglia responses. Taken together these results provide support for a potential disease-modifying aspect when stimulating central 5-HT4 Receptors; however, the complexity of the phenomena warrants further research.
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5‐HT4 Receptor agonists: similar but not the same
Neurogastroenterology and Motility, 2008Co-Authors: J. De Maeyer, Romain Lefebvre, Jan A.j. SchuurkesAbstract:Abstract 5-Hydroxytryptamine4 (5-HT4) Receptors are an interesting target for the management of patients in need of gastrointestinal (GI) promotility treatment. They have proven therapeutic potential to treat patients with GI motility disorders. Lack of selectivity for the 5-HT4 Receptor has limited the clinical success of the agonists used until now. For instance, next to their affinity for 5-HT4 Receptors, both cisapride and tegaserod have appreciable affinity for other Receptors, channels or transporters [e.g. cisapride: human ether-a-go-go-related gene (hERG) is K+ channel and tegaserod: 5-HT1 and 5-HT2 Receptors]. Adverse cardiovascular events observed with these compounds are not 5-HT4 Receptor-related. Recent efforts have led to the discovery of a series of selective 5-HT4 Receptor ligands, with prucalopride being the most advanced in clinical development. The selectivity of these new compounds clearly differentiates them from the older generation compounds by minimizing the potential of target-unrelated side effects. The availability of selective agonists enables the focus to shift to the exploration of 5-HT4 Receptor-related differences between agonists. Based on drug- and tissue-related properties (e.g. differences in Receptor binding, Receptor density, effectors, coupling efficiency), 5-HT4 Receptor agonists are able to express tissue selectivity, i.e. behave as a partial agonist in some and as a full agonist in other tissues. Furthermore, the concept of ligand-directed signalling offers great opportunities for future drug development by enlarging the scientific basis for the generation of agonist-specific effects in different cell types, tissues or organs. Selective 5-HT4 Receptor agonists might thus prove to be innovative drugs with an attractive safety profile for better treatment of patients suffering from hypomotility disorders.
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5-HT4 Receptors located on cholinergic nerves in human colon circular muscle.
Neurogastroenterology and Motility, 2005Co-Authors: P. G. Leclere, N H Prins, Jan A.j. Schuurkes, Romain LefebvreAbstract:Abstract 5-Hydroxytryptamine 4 (5-HT4) Receptor agonists promote colonic propulsion. The alteration of circular muscle (CM) motility underlying this involves inhibition of contractility via smooth muscle 5-HT4 Receptors and proximal colonic motility stimulation, the mechanism of the latter not having been characterized. Our aim was to identify and characterize a 5-HT4 Receptor-mediated stimulation of human colon CM contractile activity. 5-HT4 Receptor ligands were tested on electrical field stimulation (EFS)-induced contractions of human colonic muscle strips cut in the circular direction (called ‘whole tissue’ strips). Additionally, after incubation of tissues with [3H]-choline these compounds were tested on EFS-induced release of tritium in whole tissue strips and in ‘isolated’ CM strips, obtained by superficial cutting in the CM layer. Tetrodotoxin and atropine blocked EFS-induced contractions of whole tissue CM strips. Prucalopride (0.3 μmol L−1) evoked a heterogenous response on EFS-induced contraction, ranging from inhibition (most frequently observed) to enhancement. In the release experiments, EFS-induced tritium efflux was blocked by tetrodotoxin. Prucalopride increased EFS-induced tritium and [3H]-acetylcholine efflux in whole tissue and in isolated CM strips. All effects of prucalopride were antagonized by the selective 5-HT4 Receptor antagonist GR113808. The results obtained indicate the presence of excitatory 5-HT4 Receptors on cholinergic nerves within the CM of human colon.
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5‐HT4 Receptors mediating enhancement of contractility in canine stomach; an in vitro and in vivo study
British Journal of Pharmacology, 2001Co-Authors: N H Prins, Romain Lefebvre, L M A Akkermans, A Van Der Grijn, Jan A.j. SchuurkesAbstract:We aimed to study 5-HT4 Receptors in canine stomach contractility both in vivo and in vitro. In anaesthetized Beagle dogs, the selective 5-HT4 Receptor agonist prucalopride (i.v.) induced dose-dependent tonic stomach contractions under isobaric conditions, an effect that was antagonized by the selective 5-HT4 Receptor antagonist GR 125487 (10 μg kg−1, i.v.). Electrical field stimulation (EFS) of corpus longitudinal muscle strips resulted in atropine- and tetrodotoxin-sensitive contractions (L-NOARG (0.1 mM) present in all organ bath solutions). Prucalopride increased these contractions (maximal response after single-dose addition (0.3 μM): 165% of initial value, or after cumulative addition: 188%). In the presence of methysergide (3 μM), 5-HT also increased EFS-contractions (after single-dose addition (0.3 μM): increase to 192%, after cumulative addition: 148%). The selective 5-HT4 Receptor antagonists GR 113808 (0.1 μM) or GR 125487 (10 nM) antagonized the prucalopride (0.3 μM)-induced contraction increments. When EFS-induced contractions were blocked by atropine or tetrodotoxin, prucalopride was ineffective. In the presence of methysergide (3 μM), the contraction increases to 5-HT (0.3 μM) were prevented by GR 113808 (0.1 μM). The prucalopride curve (pEC50 7.9) was shifted in parallel to the right by GR 113808 3 nM (pA2 9.4). In the presence of methysergide (3 μM), the curve to 5-HT (pEC50 8.1) was competitively antagonized by GR 113808, yielding a Schild slope of 0.8±0.2 (pKB of 9.1 with unit Schild slope). In corpus circular muscle strips, the prucalopride (0.3 μM)-induced augmentation of EFS-contractions (258%) was also prevented by GR 113808 (0.1 μM) (124%). In conclusion, the effects of 5-HT4 Receptor agonists on proximal stomach motor activity in vivo can be explained by an effect on 5-HT4 Receptors on cholinergic nerves within the gastric muscle wall. British Journal of Pharmacology (2001) 132, 1941–1947; doi:10.1038/sj.bjp.0703985
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5-HT4 Receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle
British Journal of Pharmacology, 2000Co-Authors: N H Prins, Romain Lefebvre, L M A Akkermans, Jan A.j. SchuurkesAbstract:5-HT4 Receptors mediate circular muscle relaxation in both human and canine large intestine, but this phenomenon alone can not explain the improvement in colonic motility induced by selective 5-HT4 Receptor agonists in vivo. We set out to characterize 5-HT4 Receptor-mediated effects in longitudinal muscle strips of canine and human large intestine. Electrical field stimulation (EFS) was applied providing submaximal isotonic contractions. L-NOARG (0.1 mM) was continuously present in the organ bath to preclude nitric oxide-induced relaxation to EFS. The selective 5-HT4 Receptor agonist prucalopride (0.3 μM) enhanced EFS-evoked contractions, that were antagonized in both preparations by the selective 5-HT4 Receptor antagonist GR 113808 (0.1 μM). The prucalopride-induced increase was present in canine ascending and descending colon, but absent in rectum. Regional differences in response to prucalopride were not observed in human ascending and sigmoid colon and rectum. Incubation with atropine (1 μM) or tetrodotoxin (0.3 μM) inhibited EFS-induced contractions, which were then unaffected by prucalopride (0.3 μM) in both tissues. In the presence of methysergide (3 μM; both tissues) and granisetron (0.3 μM; only human tissues), 5-HT (0.3 μM) enhanced EFS-induced contractions, an effect that was antagonized by GR 113808 (0.1 μM). In the presence of atropine or tetrodotoxin, EFS-induced contractions were inhibited, leaving 5-HT (0.3 μM) ineffective in both preparations. This study demonstrates for the first time that in human and canine large intestine, 5-HT4 Receptors are located on cholinergic neurones, presumably mediating facilitating release of acetylcholine, resulting in enhanced longitudinal muscle contractility. This study and previous circular muscle strip studies suggest that 5-HT4 Receptor agonism facilitates colonic propulsion via a coordinated combination of inhibition of circumferential resistance and enhancement of longitudinal muscle contractility. British Journal of Pharmacology (2000) 131, 927–932; doi:10.1038/sj.bjp.0703615
Aline Dumuis - One of the best experts on this subject based on the ideXlab platform.
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5-HT4 Receptors, a place in the sun: act two
Current Opinion in Pharmacology, 2011Co-Authors: Joël Bockaert, Valérie Compan, Sylvie Claeysen, Aline DumuisAbstract:5-HT4 Receptors control brain physiological functions such as learning and memory, feeding and mood behaviour as well as gastro-intestinal transit. 5-HT4 Receptors are one of the 5-HT Receptors for which the available drugs and signalling knowledge are the most advanced. Several therapeutic 5-HT4 Receptor drugs have been commercialized. Therefore, the hope that 5-HT4 Receptors could also be the target for brain diseases is reasonable. Several major devastating illnesses could benefit from 5-HT4 Receptors-directed therapy such as Alzheimer's disease, feeding-associated diseases such as anorexia and major depressive disorders.
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5-HT4 Receptors: History, molecular pharmacology and brain functions
Neuropharmacology, 2008Co-Authors: Joël Bockaert, Valérie Compan, Sylvie Claeysen, Aline DumuisAbstract:Abstract Twenty years ago, we started the characterization of a 5-HT Receptor coupled to cAMP production in neurons. This Receptor obviously had a different pharmacology to the other 5-HT Receptors described at that time, i.e. the 5-HT1, 5-HT2, 5-HT3 Receptors. We proposed to name it the 5-HT4 Receptor. Nowadays, 5-HT4 Receptors are one of the most studied GPCRs belonging to the “rhodopsin” family. Thanks to the existence of a great variety of ligands with inverse agonist, partial agonist, agonist and antagonist profiles, the pharmacological and physiological properties of this Receptor are beginning to emerge. Although some 5-HT4 partial agonists have been on the market for gastro-intestinal pathologies, 5-HT4 Receptor drugs have still to be commercialized for brain disorders. However, since 5-HT4 Receptors have recognized effects on memory, depression and feeding in animal models, there is still hope for a therapeutic destiny of this interesting target in brain disorders.
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5-HT4 Receptors
Current Drug Targets - Cns & Neurological Disorders, 2004Co-Authors: Joël Bockaert, Michèle Sebben, Hervé Ansanay, Christian Waeber, Laurent Fagni, Aline DumuisAbstract:Serotonin 5-HT4 Receptors were first described in mouse colliculi neurons. They are positively coupled to adenylyl cyclase, and possess unique pharmacological properties. Indeed, they are not blocked by classical 5-HT1, 5-HT2 or 5-HT3 antagonists. Several classes of specific 5-HT4 Receptor agonists (benzarnides and benzimidazoles) and antagonists have now been described. The most specific and potent 5-HT4 antagonist is an indole derivative, GR-113808, which has been used to prepare a radioligand for 5-HT4 Receptors.
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Attenuated Response to Stress and Novelty and Hypersensitivity to Seizures in 5-HT4 Receptor Knock-Out Mice
The Journal of Neuroscience, 2004Co-Authors: Valérie Compan, Aline Dumuis, Mingming Zhou, Régis Grailhe, Russell A. Gazzara, Renee S. Martin, Jay A. Gingrich, Daniela Brunner, Joël BockaertAbstract: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.
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Differential modulation of the 5-HT4 Receptor agonists and antagonist on rat learning and memory
Neuropharmacology, 2000Co-Authors: Evelyne Marchetti, Joël Bockaert, Aline Dumuis, Bernard Soumireu-mourat, Francois RomanAbstract:Abstract Recent data suggest that activation of 5-HT4 Receptors may modulate cognitive processes such as learning and memory. In the present study, the effects of two potent and selective 5-HT4 agonists, RS 17017 [1-(4-amino-5-chloro-2-methoxyphenyl)-5-(piperidin-1-yl)-1-pentanone hydrochloride] and RS 67333 [1(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone], were studied in an olfactory associative discrimination task. The implication of 5-HT4 Receptors in the associative discriminative task was suggested by the following observation. Injection of a selective 5-HT4 Receptor antagonist RS 67532 [1-(4-amino-5-chloro-2-(3,5-dimethoxybenzyloxyphenyl)-5-(1-piperidinyl)-1-pentanone; 1 mg/kg: i.p.] before the third training session induced a consistent deficit in associative memory during the following training sessions. This deficit was absent when the antagonist was injected together with either a specific hydrophilic 5-HT4 (RS 17017, 1 mg/kg) or a specific hydrophobic (RS 67333, 1 mg/kg) 5-HT4 Receptor agonist. RS 67333 was more potent than RS 17017. This difference in potency certainly reflects a difference in their capacity to enter into the brain. This is also likely to be the reason why, injected alone, the hydrophobic 5-HT4 agonist (RS 67333) but not the hydrophilic 5-HT4 agonist (RS 17017) improved learning and memory performance.