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Several fungi belonging to the genus Psilocybe , also called "magic mushrooms", contain the hallucinogenic drugs psilocybin and psilocin. They are chemically related to serotonin (5-HT). In addition to being abused as drugs, they are now also being discussed or used as a treatment option for depression. Here, we hypothesized that psilocybin and psilocin may act also on cardiac serotonin receptors and studied them in vitro in atrial preparations of our transgenic mouse model with cardiac myocytes-specific overexpression of the human 5-HT 4 receptor (5-HT 4 -TG) as well as in human atrial preparations. Both psilocybin and psilocin enhanced the force of contraction in isolated left atrial preparations from 5-HT 4 -TG, increased the beating rate in isolated spontaneously beating right atrial preparations from 5-HT 4 -TG and augmented the force of contraction in the human atrial preparations. The inotropic and chronotropic effects of psilocybin and psilocin at 10 µM were smaller than that of 1 µM 5-HT on the left and right atria from 5-HT 4 -TG, respectively. Psilocybin and psilocin were inactive in WT. In the human atrial preparations, inhibition of the phosphodiesterase III by cilostamide was necessary to unmask the positive inotropic effects of psilocybin or psilocin. The effects of 10 µM psilocybin and psilocin were abrogated by 10 µM tropisetron or by 1 µM GR125487, a more selective 5-HT 4 receptor antagonist. In summary, we demonstrated that psilocin and psilocybin act as agonists on cardiac 5-HT 4 receptors. • The hallucinogens psilocybin or psilocin are used as new treatment for depression. • In the human brain, they act mainly via 5-HT 2A serotonin receptors. • Hypothetically, that they may act also on cardiac 5-HT 4 serotonin receptors. • Here, we demonstrated that they act as agonists on human cardiac 5-HT 4 receptors. • Possibly, psilocybin or psilocin may have cardiac side effects. [ABSTRACT FROM AUTHOR]

In recent years, particular attention has been paid to the serotonin 4 receptor, which is well expressed in the brain, but also peripherally in various organs. The cerebral distribution of this receptor is well conserved across species, with high densities in the basal ganglia, where they are expressed by GABAergic neurons. The 5-HT4 receptor is also present in the cerebral cortex, hippocampus, and amygdala, where they are carried by glutamatergic or cholinergic neurons. Outside the central nervous system, the 5-HT4 receptor is notably expressed in the gastrointestinal tract. The wide distribution of the 5-HT4 receptor undoubtedly contributes to its involvement in a plethora of functions. In addition, the modulation of this receptor influences the release of serotonin, but also the release of other neurotransmitters such as acetylcholine and dopamine. This is a considerable asset, as the modulation of the 5-HT4 receptor can therefore play a direct or indirect beneficial role in various disorders. One of the main advantages of this receptor is that it mediates a much faster antidepressant and anxiolytic action than classical selective serotonin reuptake inhibitors. Another major benefit of the 5-HT4 receptor is that its activation enhances cognitive performance, probably via the release of acetylcholine. The expression of the 5-HT4 receptor is also altered in various eating disorders, and its activation by the 5-HT4 agonist negatively regulates food intake. Additionally, although the cerebral expression of this receptor is modified in certain movement-related disorders, it is still yet to be determined whether this receptor plays a key role in their pathophysiology. Finally, there is no longer any need to demonstrate the value of 5-HT4 receptor agonists in the pharmacological management of gastrointestinal disorders. [ABSTRACT FROM AUTHOR]

Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson's disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson's disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA's pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.

One common event that is the most detrimental in neurodegenerative disorders, even though they have a complex pathogenesis, is the increased rate of neuronal death. Endogenous neurotrophins consist of the major neuroprotective factors, while brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor TrkB are described in a number of studies for their important neuronal effects. Normal function of this receptor is crucial for neuronal survival, differentiation, and synaptic function. However, studies have shown that besides direct activation, the TrkB receptor can be transactivated via GPCRs. It has been proven that activation of the 5-HT4 receptor and transactivation of the TrkB receptor have a positive influence on neuronal differentiation (total dendritic length, number of primary dendrites, and branching index). Because of that and based on the main structural characteristics of LM22A-4, a known activator of the TrkB receptor, and RS67333, a partial 5-HT4 receptor agonist, we have designed and synthesized a small data set of novel compounds with potential dual activities in order to not only prevent neuronal death, but also to induce neuronal differentiation in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Serotonergic dysfunction is related to both motor and nonmotor symptoms in Parkinson's disease (PD). As a 5-HT receptor, 5-HT4 receptor (5-HT4R) is well-studied and already-used in clinical therapy of constipation, which is a typical non-motor symptom in PD. In this study, we investigated the role of 5-HT4R as a regulator of gut function in MPTP-induced acute PD mice model. Daily intraperitoneal injection of GR 125487 (5-HT4R antagonist) was administered 3 days before MPTP treatment until sacrifice. Seven days post-MPTP treatment, feces were collected and gastrointestinal transit time (GITT) was measured, 8 days post-MPTP treatment, behavioral tests were performed, and then animals were sacrificed for the further analysis. We found GR 125487 pretreatment not only increased GITT, but also aggravated MPTP-induced motor bradykinesia. In addition, GR 125487 pretreatment exacerbated the loss of dopaminergic neurons probably by suppressing JAK2/PKA/CREB signaling pathway and increased reactive glia and neuroinflammation in the striatum. 16 S rRNA sequencing of fecal microbiota showed that GR 125487 pretreatment altered the composition of gut microbiota, in which the abundance of Akkermansia muciniphila and Clostridium clostridioforme was increased, whereas that of Parabacteroides distasonis and Bacteroides fragilis was decreased, which are closely associated with inflammation condition. Taken together, we demonstrated that GR 125487 pretreatment exacerbates MPTP-induced striatal neurodegenerative processes possibly via the JAK2/PKA/CREB pathway and neuroinflammation by altering gut microbiota composition. In the microbiota-gut-brain axis of PD, 5-HT4R should be further explored and might serve as a target for PD diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: 5‐hydroxytryptamine 4 receptors (5‐HT4Rs) are expressed in the colonic epithelium, and previous studies have demonstrated that luminal administration of agonists enhances motility, suppresses nociception, and is protective in models of inflammation. We investigated whether stimulation with a luminally acting 5‐HT4R agonist is comparable to previously tested absorbable compounds. Methods: The dextran sodium sulfate (DSS), trinitrobenzene sulfonic acid (TNBS), and interleukin 10 knockout (IL‐10KO) models of colitis were used to test the protective effects of the luminally acting 5‐HT4R agonist, 5HT4‐LA1, in the absence and presence of a 5‐HT4R antagonist. The compounds were delivered by enema to mice either before (prevention) or after (recovery) the onset of active colitis. Outcome measure included disease activity index (DAI) and histological evaluation of colon tissue, and effects on wound healing and fecal water content were also assessed. Key Results: Daily enema of 5HT4‐LA1 attenuated the development of, and accelerated recovery from, active colitis. Enema administration of 5HT4‐LA1 did not attenuate the development of colitis in 5‐HT4R knockout mice. Stimulation of 5‐HT4Rs with 5HT4‐LA1 increased Caco‐2 cell migration (accelerated wound healing). Daily administration of 5HT4‐LA1 did not increase fecal water content in active colitis. Conclusions and Inferences: Luminally restricted 5‐HT4R agonists are comparable to absorbable compounds in attenuating and accelerating recovery from active colitis. Luminally acting 5‐HT4R agonists may be useful as an adjuvant to current inflammatory bowel disease (IBD) treatments to enhance epithelial healing. [ABSTRACT FROM AUTHOR]

In the present study, we investigated the regulatory mechanisms underlying sperm hyperactivation enhanced by 5-hydroxytryptamine (5-HT) in hamsters. First, we examined the types of 5-HT receptors that regulate hyperactivation. Hyperactivation was significantly enhanced by 5-HT2A and 5-HT4 receptor agonists. Moreover, the results of the motility assay revealed that 5-HT2A, 5-HT3, and 5-HT4 receptor agonists significantly decreased the velocity and/or amplitude of sperm. Under 5-HT2 receptor stimulation, hyperactivation was associated with phospholipase C (PLC), inositol 1,4,5-trisphosphate (IP3) receptor, soluble adenylate cyclase (sAC), and protein kinase A (PKA). In contrast, under 5-HT4 receptor stimulation, hyperactivation was associated with transmembrane adenylate cyclase (tmAC), sAC, PKA, and CatSper channels. Accordingly, under the condition that sperm are hyperactivated, 5-HT likely stimulates PLC/IP3 receptor signals via the 5-HT2A receptor and tmAC/PKA/CatSper channel signals via the 5-HT4 receptor. After sAC and PKA are activated by these stimulations, sperm hyperactivation is enhanced.

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Background: 5‐HT4 receptor (5‐HT4R) agonists exert prokinetic actions in the GI tract, but non‐selective actions and potential for stimulation of non‐target 5‐HT4Rs have limited their use. Since 5‐HT4Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5‐HT4R agonists promote intestinal motility. Methods: Non‐absorbed 5‐HT4R agonists, based on prucalopride and naronapride, were assessed for potency at the 5‐HT4R in vitro, and for tissue and serum distribution in vivo in mice. In vivo assessment of prokinetic potential included whole gut transit, colonic motility, fecal output, and fecal water content. Colonic motility was also studied ex vivo in mice treated in vivo. Immunofluorescence was used to evaluate receptor distribution in human intestinal mucosa. Key Results: Pharmacological screening demonstrated selectivity and potency of test agonists for 5‐HT4R. Bioavailability studies showed negligible serum detection. Gavage of agonists caused faster whole gut transit and colonic motility, increased fecal output, and elevated fecal water content. Prokinetic actions were blocked by a 5‐HT4R antagonist and were not detected in 5‐HT4R knockout mice. Agonist administration promoted motility in models of constipation. Evaluation of motility patterns ex vivo revealed enhanced contractility in the middle and distal colon. Immunoreactivity for 5‐HT4R is present in the epithelial layer of the human small and large intestines. Conclusions and Inferences: These findings demonstrated that stimulation of epithelial 5‐HT4Rs can potentiate propulsive motility and support the concept that mucosal 5‐HT4Rs could represent a safe and effective therapeutic target for the treatment of constipation. [ABSTRACT FROM AUTHOR]

Background: 5-HT4 receptor stimulation has pro-cognitive and antidepressant-like effects in animal experimental studies; however, this pharmacological approach has not yet been tested in humans. Here we used the 5-HT4 receptor partial agonist prucalopride to assess the translatability of these effects and characterise, for the first time, the consequences of 5-HT4 receptor activation on human cognition and emotion. Methods: Forty one healthy volunteers were randomised, double-blind, to a single dose of prucalopride (1 mg) or placebo in a parallel group design. They completed a battery of cognitive tests measuring learning and memory, emotional processing and reward sensitivity. Results: Prucalopride increased recall of words in a verbal learning task, increased the accuracy of recall and recognition of words in an incidental emotional memory task and increased the probability of choosing a symbol associated with a high likelihood of reward or absence of loss in a probabilistic instrumental learning task. Thus acute prucalopride produced pro-cognitive effects in healthy volunteers across three separate tasks. Conclusions: These findings are a translation of the memory enhancing effects of 5-HT4 receptor agonism seen in animal studies, and lend weight to the idea that the 5-HT4 receptor could be an innovative target for the treatment of cognitive deficits associated with depression and other neuropsychiatric disorders. Contrary to the effects reported in animal models, prucalopride did not reveal an antidepressant profile in human measures of emotional processing. [ABSTRACT FROM AUTHOR]

Serotonin affects many functions in the body, both in the central nervous system (CNS) and the periphery. However, its effect on the blood–brain barrier (BBB) in separating these two worlds has been scarcely investigated. The aim of this work was to characterize the serotonin receptor 5-HT4 in the hCMEC/D3 cell line, in the rat and the human BBB. We also examined the effect of prucalopride, a 5-HT4 receptor agonist, on the permeability of the hCMEC/D3 in an in vitro model of BBB. We then confirmed our observations by in vivo experiments. In this work, we show that the 5-HT4 receptor is expressed by hCMEC/D3 cells and in the capillaries of rat and human brains. Prucalopride increases the BBB permeability by downregulating the expression of the tight junction protein, occludin. This effect is prevented by GR113808, a 5-HT4 receptor antagonist, and is mediated by the Src/ERK1/2 signaling pathway. The canonical G-protein-dependent pathway does not appear to be involved in this phenomenon. Finally, the administration of prucalopride increases the diffusion of Evans blue in the rat brain parenchyma, which is synonymous with BBB permeabilization. All these data indicate that the 5-HT4 receptor contributes to the regulation of BBB permeability.

We developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was informed by published preclinical and clinical data. Our simulations provide clinically relevant readouts of bowel movement frequency and stool consistency. The model recapitulates healthy and slow transit constipation phenotypes, and the effect of a 5-HT4 receptor agonist in healthy volunteers. Using the calibrated model, we predicted the agonist dose to normalize defecation frequency in slow transit constipation while avoiding the onset of diarrhea. Model sensitivity analysis predicted that changes in HAPC frequency and liquid secretion have the greatest impact on colonic motility. However, exclusively increasing the liquid secretion can lead to diarrhea. In contrast, increasing HAPC frequency alone can enhance bowel frequency without leading to diarrhea. The quantitative systems pharmacology approach used here demonstrates how mechanistic modeling of disease pathophysiology expands our understanding of biology and supports judicious hypothesis generation for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxy-tryptamine, 5-HT) exerted concentration-dependent positive inotropic effects or positive chronotropic effects in transgenic (TG) mice which overexpress the human 5-HT4a receptor in the heart but not in littermate wild-type (WT) mice. These positive inotropic effects and positive chronotropic effects are thought to be mediated by cyclic adenosine 3′,5′-monophosphate (cAMP) in TG cardiomyocytes. To determine whether these effects are antagonized by endogenous phosphodiesterases (PDEs), the inotropic and chronotropic effects of 5-HT were tested in the additional presence of the PDE inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA) (1 μM, a PDE2 inhibitor) or cilostamide (1 μM, a PDE3 inhibitor), rolipram (0.1 μM and 1 μM, a PDE4 inhibitor), and their combinations. For comparison, 3-isobutyl-1-methylxanthine (IBMX), an unspecific PDE inhibitor, was investigated. The use of 10 μM IBMX, the combination of rolipram (1 μM) and EHNA (1 μM), and the combination of rolipram (0.1 μM) and cilostamide (1 μM) each increased the potency of 5-HT to elevate the force of contraction in TG mice, but not the potency of 5-HT to increase the beating rate in TG mice. This indicates that PDE4 and PDE2 regulate the inotropic but not the chronotropic effects of 5-HT in TG mice. In contrast, cilostamide (1 μM) alone, EHNA (1 μM) alone, or in combination decreased the potency of 5-HT to increase force of contraction in TG mice. In summary, our present data suggest that the positive chronotropic effect of 5-HT in TG mice does not involve PDE activities, whereas the positive inotropic effect of 5-HT and the basal force in TG mice are diminished by endogenous activity of PDE4. Phosphorylation of PDE4, when PDE2 or PDE3 is inhibited, might enhance the activity of PDE4. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study was to investigate the effects and mechanism of 6-hydroxydopamine (6-OHDA) lesions and serotonin 4 (5-HT4) receptors in the lateral habenula (LHb) on Parkinson's disease (PD) related working memory. Methods: The working memory was measured by the T-maze rewarded alternation test in sham rats and rats with unilateral 6-OHDA lesions of substantia nigra pars compacta (SNc). The concentrations of dopamine (DA), noradrenaline (NA) and 5-HT in the related brain regions were measured by neurochemistry.Results: The results showed that 6-OHDA lesions of the SNc induced working memory impairment. Intra-LHb injection of 5-HT4 receptor agonist BIMU-8 (2, 4 or 8 μg) and antagonist GR113808 (1, 3.3 or 10 μg) improved the working memory only in the lesioned rats. Intra-LHb injection of BIMU-8 (8 μg) significantly increased DA levels in the medial prefrontal cortex, dorsal hippocampus and amygdala in the lesioned rats but not in sham rats. BIMU-8 did not change NA and 5-HT levels in the related brain regions in both sham and lesioned rats. Intra-LHb injection of GR113808 (10 μg) changed DA, NA and 5-HT levels in related brain regions in both sham and the lesioned rats. In addition, the 5-HT4 receptor-positive neurons in the LHb increased significantly in the lesioned rats.Conclusion: These findings suggested that unilateral lesions of the SNc induced working memory impairment and up-regulation of 5-HT4 receptors in the LHb. Activation and blockade of LHb 5-HT4 receptors improved working memory, that were related to the change of monoamines levels. Abbreviation: 6-OHDA: 6-hydroxydopamine; serotonin:5-HT; LHb: lateral habenula; PD: Parkinson's disease; SNc: substantia nigra pars compacta; DA: dopamine; NA: noradrenaline [ABSTRACT FROM AUTHOR]

Background: Enteric serotonin may function as a mucosal growth factor. Previous work demonstrated increased crypt cell proliferation and intestinal mucosal surface area with potentiation of serotonin. While an indirect mechanism was postulated to explain these effects, the presence of 5-HT4 receptors on enterocytes raises the possibility of a direct action of serotonin. We hypothesized that a 5-HT4 specific agonist, prucalopride, would stimulate intestinal mucosal growth and enhance absorptive function in the murine small intestine.Methods: Adult wild-type mice were treated parenterally with prucalopride for 14 days via surgically implanted osmotic pumps. In vivo D-xylose absorption was assessed by oral gavage and serum D-xylose measurements. On day 14, glucose absorption was assessed by instilling a glucose solution into isolated segments of small intestine. The bowel was harvested and examined for morphologic parameters and crypt cell proliferation.Results: Villus height, crypt depth, and crypt proliferation were significantly increased in the distal small bowel of prucalopride-treated mice compared with control animals. Crypt depth was also increased in the proximal and middle small intestine in treated mice. There was no difference in D-xylose absorption throughout the study period; however, glucose absorption was significantly increased in the distal small intestine of prucalopride-treated mice.Conclusion: Parenteral administration of the 5-HT4 receptor specific agonist, prucalopride, results in morphologic and functional changes in the murine small intestine that are most prominent in the distal small bowel. While further studies are necessary to delineate the mechanism, it is plausible that the effects are mediated by 5-HT4 receptors on enterocytes. [ABSTRACT FROM AUTHOR]

Background: As the signal transduction of 5-HT4 receptors on cholinergic neurons innervating smooth muscle is controlled by phosphodiesterase (PDE) 4 in porcine stomach and colon, and human large intestine, the in vivo gastroprokinetic effects of a 5-HT4 receptor agonist might be enhanced by combination with a selective PDE4 inhibitor. The presence of 5-HT4 receptors on cholinergic neurons towards murine gastrointestinal circular muscle was recently shown. If the control of this receptor pathway by PDE4 is also present in mice, this might be a good model for in vivo testing of the combination therapy. Therefore this study investigates the role of cAMP catalyzing PDEs in smooth muscle cell activity and in the intraneuronal signal transduction of the 5-HT4 receptors in the gastrointestinal tract of C57Bl/6J mice.Methods: In circular smooth muscle strips from murine fundus, jejunum, and colon, submaximal cholinergic contractions were induced by either electrical field stimulation (EFS) or by carbachol (muscarinic receptor agonist). The influence of the PDE inhibitors IBMX (non-selective), vinpocetine (PDE1), EHNA (PDE2), cilostamide (PDE3), and rolipram (PDE4) was tested on these contractions and on the facilitating effect of a submaximal concentration of prucalopride (5-HT4 receptor agonist) on EFS-induced contractions.Results: In the three gastrointestinal regions, IBMX and cilostamide concentration-dependently decreased carbachol- as well as EFS-induced contractions. Some inhibitory effect was also observed with rolipram. In the fundus a non-significant trend for an enhancement of the facilitating effect of prucalopride on EFS-induced contractions was observed with IBMX, but none of the selective PDE inhibitors enhanced the facilitating effect of prucalopride in fundus, jejunum or colon.Conclusion: In analogy with the porcine gastrointestinal tract, in murine fundus, jejunum, and colon circular smooth muscle PDE3 is the main regulator of the cAMP turnover, with some contribution of PDE4. In contrast to the porcine gastrointestinal tract, the in vitro facilitation of electrically induced cholinergic contractions by 5-HT4 receptor stimulation could not be enhanced by specific PDE inhibition. The C57Bl/6J murine model is thus not suitable for in vivo testing of a 5-HT4 receptor agonist combined with a selective PDE4 inhibitor.

Chronic constipation is a common gastrointestinal disease severely affecting the patient׳s quality of life. The traditional treatment of constipation is the use of laxatives. Recently, several new drugs including lubiprostone, linaclotide and prucalopride have been approved for treatment of chronic constipation. However, a significant unmet medical need still remains, particularly among those patients achieving poor results by current therapies. The 5-HT4 receptor modulators velusetrag and naronapride, the guanylate cyclase C agonist plecanatide and the ileal bile acid transporter inhibitor elobixibat are recognized as the most promising drugs under investigation. Herein, we give a comprehensive review on the pharmacological therapeutics for the treatment of chronic constipation, with the purpose of reflecting the drug development trends in this field.

Cisapride and prucalopride act as 5-HT4 receptor agonists. As a part of our ongoing effort to study the utility of a transgenic (TG) mouse model overexpressing cardiac 5-HT4 receptors, we assessed the extent to which we could recapitulate cisapride and prucalopride agonists. Contractile studies were performed using isolated left and right atrial preparations of TG mice showing cardiac-specific human 5-HT4a receptor expression and those of their wild-type (WT) littermates. 5-Hydroxytryptamine (5-HT), cisapride, and prucalopride exerted concentration-dependent positive inotropic effects in the left atrial preparations of TG mice. Moreover, 5-HT induced concentration-dependent arrhythmias in the right atrial preparations of TG mice starting from 10-nM concentration. However, cisapride induced arrhythmias not only in the right atrial preparations of TG mice but also in the right atrial preparations of WT mice. For instance, 10 μM cisapride induced arrhythmias in the right atrial preparations of TG and WT mice to the same extent. Prucalopride did not exert concentration-dependent proarrhythmic effects in the isolated atrial preparations (left or right, WT or TG). Furthermore, cisapride and prucalopride increased the contractility and beating rate in vivo in TG mice, as assessed by performing echocardiography and surface electrocardiography. In summary, our results indicate that cisapride and prucalopride increase contractility and beating rate in the isolated atrial preparations of TG mice or in intact TG mice. Moreover, 5-HT induced arrhythmias in the isolated right atrial preparations of TG mice in a concentration-dependent manner. Furthermore, cisapride induced arrhythmias in the isolated right atrial preparations of both TG and WT mice. In contrast, prucalopride did not induce arrhythmias in the atrial preparations (left or right) of both WT and TG mice. We suggest that the present TG mouse model might be useful to predict at least some important cardiac effects of 5-HT4 receptor agonists in the human heart. [ABSTRACT FROM AUTHOR]

Background: As the signal transduction of 5-HT4 receptors on cholinergic neurons innervating smooth muscle is controlled by phosphodiesterase (PDE) 4 in porcine stomach and colon, and human large intestine, the in vivo gastroprokinetic effects of a 5-HT4 receptor agonist might be enhanced by combination with a selective PDE4 inhibitor. The presence of 5-HT4 receptors on cholinergic neurons towards murine gastrointestinal circular muscle was recently shown. If the control of this receptor pathway by PDE4 is also present in mice, this might be a good model for in vivo testing of the combination therapy. Therefore this study investigates the role of cAMP catalyzing PDEs in smooth muscle cell activity and in the intraneuronal signal transduction of the 5-HT4 receptors in the gastrointestinal tract of C57Bl/6J mice. Methods: In circular smooth muscle strips from murine fundus, jejunum, and colon, submaximal cholinergic contractions were induced by either electrical field stimulation (EFS) or by carbachol (muscarinic receptor agonist). The influence of the PDE inhibitors IBMX (non-selective), vinpocetine (PDE1), EHNA (PDE2), cilostamide (PDE3), and rolipram (PDE4) was tested on these contractions and on the facilitating effect of a submaximal concentration of prucalopride (5-HT4 receptor agonist) on EFS-induced contractions. Results: In the three gastrointestinal regions, IBMX and cilostamide concentrationdependently decreased carbachol-as well as EFS-induced contractions. Some inhibitory effect was also observed with rolipram. In the fundus a non-significant trend for an enhancement of the facilitating effect of prucalopride on EFS-induced contractions was observed with IBMX, but none of the selective PDE inhibitors enhanced the facilitating effect of prucalopride in fundus, jejunum or colon. Conclusion: In analogy with the porcine gastrointestinal tract, in murine fundus, jejunum, and colon circular smooth muscle PDE3 is the main regulator of the cAMP turnover, with some contribution of PDE4. In contrast to the porcine gastrointestinal tract, the in vitro facilitation of electrically induced cholinergic contractions by 5-HT4 receptor stimulation could not be enhanced by specific PDE inhibition. The C57Bl/6J murine model is thus not suitable for in vivo testing of a 5-HT4 receptor agonist combined with a selective PDE4 inhibitor. [ABSTRACT FROM AUTHOR]

Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) specifically increase serotonin (5-HT) levels in the synaptic cleft and are widely used to treat mood and anxiety disorders. There are 14 established subtypes of 5-HT receptors in rodents, each of which has regionally different expression patterns. Many preclinical studies have suggested that the hippocampus, which contains abundant 5-HT1A and 5-HT4 receptor subtypes in the dentate gyrus (DG), is critically involved in the mechanisms of action of antidepressants. This review article will analyze studies demonstrating regulation of hippocampal functions and hippocampus-dependent behaviors by SSRIs and similar serotonergic agents. Multiple studies indicate that 5-HT1A and 5-HT4 receptor signaling in the DG contributes to SSRI-mediated promotion of neurogenesis and increased neurotrophic factors expression. Chronic SSRI treatment causes functions and phenotypes of mature granule cells (GCs) to revert to immature-like phenotypes defined as a “dematured” state in the DG, and to increase monoamine reactivity at the dentate-to-CA3 synapses, via 5-HT4 receptor signaling. Behavioral studies demonstrate that the 5-HT1A receptors on mature GCs are critical for expression of antidepressant effects in the forced swim test and in novelty suppressed feeding; such studies also note that 5-HT4 receptors mediate neurogenesis-dependent antidepressant activity in, for example, novelty-suppressed feeding. Despite their limitations, the collective results of these studies describe a potential new mechanism of action, in which 5-HT1A and 5-HT4 receptor signaling, either independently or cooperatively, modulates the function of the hippocampal DG at multiple levels, any of which could play a critical role in the antidepressant actions of 5-HT-enhancing drugs.

Abstract: Background: Gastroprokinetic properties of 5‐HT4 receptor agonists, such as prucalopride, are attributed to activation of 5‐HT4 receptors on cholinergic nerves innervating smooth muscle in the gastrointestinal smooth muscle layer, increasing acetylcholine release and muscle contraction. In porcine stomach and colon, phosphodiesterase (PDE) 4 has been shown to control the signaling pathway of these 5‐HT4 receptors. The aim of this study was to investigate the PDE‐mediated control of these 5‐HT4 receptors in human large intestine. Methods: Circular smooth muscle strips were prepared from human large intestine; after incubation with [³H]‐choline, electrically induced tritium outflow was determined as a measure for acetylcholine release. The influence of PDE inhibition on the facilitating effect of prucalopride on electrically induced acetylcholine release was studied. Key Results: The non‐selective PDE inhibitor IBMX enhanced the facilitating effect of prucalopride on electrically induced acetylcholine release. The selective inhibitors vinpocetine (PDE1), EHNA (PDE2) and cilostamide (PDE3) did not influence, while rolipram and roflumilast (PDE4) enhanced the prucalopride‐induced facilitation to the same extent as IBMX. Conclusions & Inferences: In human large intestinal circular muscle, the intracellular pathway of 5‐HT4 receptors facilitating cholinergic neurotransmission to large intestinal circular smooth muscle is controlled by PDE4. If the synergy between 5‐HT4 receptor agonism and PDE4 inhibition is confirmed in a functional assay with electrically induced cholinergic contractions of human large intestinal circular smooth muscle strips, combination of a selective 5‐HT4 receptor agonist with a selective PDE4 inhibitor might enhance the in vivo prokinetic effect of the 5‐HT4 receptor agonist in the large intestine. [ABSTRACT FROM AUTHOR]

Background In the gastrointestinal tract of several species, facilitating 5- HT4 receptors were proposed on myenteric cholinergic neurons innervating smooth muscle by in vitro study of the effect of the selective 5- HT4 receptor agonist prucalopride on submaximal cholinergic contractions. This was not yet established in the murine gastrointestinal tract. Methods In circular smooth muscle strips from murine fundus, jejunum and colon, contractions were induced by electrical field stimulation in the presence of guanethidine, L- NAME and for colon also MRS 2500. Submaximal contractions were induced to study the influence of prucalopride. Key Results Electrical field stimulation at reduced voltage induced reproducible submaximal neurogenic and cholinergic contractions as the contractions were abolished by tetrodotoxin and atropine. Hexamethonium had no systematic inhibitory effect but mecamylamine reduced the responses, suggesting that part of the cholinergic response is due to activation of preganglionic neurons. Prucalopride concentration-dependently increased the submaximal cholinergic contractions in the three tissue types, reaching maximum from 0.03 μmol/L onwards. The facilitation in the different series with 0.03 μmol/L prucalopride ranged from 41% to 104%, 30% to 76% and 24% to 74% in fundus, jejunum, and colon, respectively. The effect of 0.03 μmol/L prucalopride was concentration-dependently inhibited by GR 113808. Conclusions & Inferences In the murine gastrointestinal tract, activation of 5- HT4 receptors with prucalopride enhances cholinergic contractions, illustrating facilitation of myenteric cholinergic neurotransmission. The degree of enhancement with prucalopride is of similar magnitude as previously reported in other species, but the effective concentrations are lower than those needed in the gastrointestinal tract of other species. [ABSTRACT FROM AUTHOR]

Background We have previously identified an inverse relationship between cerebral serotonin 4 receptor (5- HT4R) binding and nonaffective episodic memory in healthy individuals. Here, we investigate in a novel sample if the association is related to affective components of memory, by examining the association between cerebral 5- HT4R binding and affective verbal memory recall. Methods Twenty-four healthy volunteers were scanned with the 5- HT4R radioligand [11C] SB207145 and positron emission tomography, and were tested with the Verbal Affective Memory Test-24. The association between 5- HT4R binding and affective verbal memory was evaluated using a linear latent variable structural equation model. Results We observed a significant inverse association across all regions between 5- HT4R binding and affective verbal memory performances for positive ( p = 5.5 × 10−4) and neutral ( p = .004) word recall, and an inverse but nonsignificant association for negative ( p = .07) word recall. Differences in the associations with 5- HT4R binding between word categories (i.e., positive, negative, and neutral) did not reach statistical significance. Conclusion Our findings replicate our previous observation of a negative association between 5- HT4R binding and memory performance in an independent cohort and provide novel evidence linking 5- HT4R binding, as a biomarker for synaptic 5- HT levels, to the mnestic processing of positive and neutral word stimuli in healthy humans. [ABSTRACT FROM AUTHOR]

The involvement of serotonin (5-HT) and/or noradrenaline in acute pruriceptive processing in the central nervous system (CNS) has been reported using antidepressants, such as milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant; however, the roles of 5-HT receptor family in acute pruriceptive processing have not been fully elucidated in the CNS. In the present study, scratching behavior induced by chloroquine (CQ) was ameliorated by milnacipran or mirtazapine, and these effects were reversed by SB207266, a 5-HT 4 antagonist, or SB258585, a 5-HT 6 antagonist, but not by SB258585, a 5-HT 5 antagonist. Moreover, CQ-induced scratches were mitigated by intrathecal injection of 5-HT 4 agonists, such as BIMU8 and ML10302, and the 5-HT 6 agonist, WAY208466. Conversely, histamine-induced scratches were not affected by the 5-HT 4 agonists or a 5-HT 6 agonist. Similarly, the amelioration of histamine-induced scratches by these antidepressants was not reversed by the 5-HT 4 , 5-HT 5 , or 5-HT 6 receptor antagonist. Therefore, 5-HT is involved in the amelioration of CQ-induced scratches by milnacipran and mirtazapine, and 5-HT 4 , 5-HT 5 , and 5-HT 6 receptors play differential roles in acute pruriceptive processing after administration of CQ or histamine.

Background This study compared prucalopride, a selective, prokinetic, 5- HT4 receptor agonist, with polyethylene glycol 3350 + electrolytes ( PEG3350), an osmotic laxative, on colonic motility parameters, primarily high-amplitude propagating contractions ( HAPCs) in patients with chronic constipation. Methods This randomized, cross-over, reader-blinded study was conducted at a single site in the USA. The study was open to men and women aged 18-75 years who met study inclusion criteria. Colonic manometry catheters were inserted the day before investigation. On the investigation days, patients received oral 2 mg prucalopride or 2 × 13.8 g PEG3350 in solution. The primary endpoint was HAPC count (threshold: mean amplitude ≥100 mmHg, propagation ≥20 cm [ HAPC1]) in the 12 h after treatment administration. Analyses were also conducted at two co-primary thresholds: mean amplitude ≥75 mmHg, propagation ≥20 cm ( HAPC2); and mean amplitude ≥75 mmHg, propagation ≥10 cm ( HAPC3). Secondary endpoints included HAPC area under the curve ( AUC), contraction force, amplitude, duration, and propagation velocity. Key Results Thirteen women were enrolled, with 12 completing the study. Significantly more HAPC1 (8.7 ± 2.06 vs 2.9 ± 2.06; p = 0.012) and HAPC2 (9.0 ± 2.11 vs 3.3 ± 2.11; p = 0.017) were observed in the 12-h periods with prucalopride than with PEG3350. Prucalopride significantly increased mean propagation distance and velocity ( HAPC2) and mean AUC, force, and amplitude ( HAPC3) compared with PEG3350. Adverse events were mild or moderate. Conclusions & Inferences Prucalopride was superior to PEG3350 in inducing HAPCs in patients with chronic constipation. number NCT01707667. [ABSTRACT FROM AUTHOR]

Background Gastroparesis is a chronic gastric disorder characterized by delayed gastric emptying without mechanical obstruction, and clinical symptoms as postprandial fullness, early satiety, bloating, nausea, vomiting, and abdominal pain. Prokinetic agents are used for the treatment of gastroparesis. Revexepride, a 5-hydroxytryptamine (serotonin) receptor (5- HT4R) agonist, could be a good candidate drug for the gastroparesis treatment. Aim: In the current phase II, exploratory, double-blind, randomized, stratified, placebo-controlled, repeated dose trial (Eudra CT number 2007-004997-23), the efficacy on gastrointestinal symptoms and gastric emptying rate, safety, and pharmacokinetic profile of three oral doses of revexepride (0.02, 0.1, and 0.5 mg administered orally t.i.d. for 4 weeks) was evaluated in trial participants (diabetic and non-diabetic) with upper gastrointestinal tract symptoms suggestive for gastroparesis. Methods Eighty participants, enrolled in four parallel treatment groups, were asked to score their symptom diary data, gastroparesis cardinal symptom index ( GCSI), patient assessment of upper gastrointestinal disorders-symptom severity index (PAGI-SYM), quality of life questionnaires, and meal-related symptom score. Gastric emptying rate was evaluated by 13C-octanoic acid breath test. Key Results The severity of the symptoms assessed by means of GCSI and PAGI- SYM decreased at Week 2 and decreased further at Week 4 in all treatment groups including placebo, with similar trends in all treatment groups. Quality of life improved in all treatment groups after 4 weeks of treatment. No differences on gastric emptying rate were shown between any of the active treatment groups and placebo. Revexepride was generally safe and well-tolerated. Conclusions & Inferences Four weeks of revexepride treatment did not improve symptoms or gastric emptying over placebo in patients with symptoms suggestive of gastroparesis. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors are the mostly widely used treatment for major depressive disorders and also are prescribed for several anxiety disorders. However, similar to most antidepressants, selective serotonin reuptake inhibitors suffer from two major problems: They only show beneficial effects after 2 to 4 weeks and only about 33% of patients show remission to first-line treatment. Thus, there is a considerable need for development of more effective antidepressants. There is a growing body of evidence supporting critical roles of 5-HT1A and 5-HT4 receptor subtypes in mediating successful depression treatments. In addition, appropriate activation of these receptors may be associated with a faster onset of the therapeutic response. This review will examine the known roles of 5-HT1A and 5-HT4 receptors in mediating both the pathophysiology of depression and anxiety and the treatment of these mood disorders. At the end of the review, the role of these receptors in the regulation of adult hippocampal neurogenesis will also be discussed. Ultimately, we propose that novel antidepressant drugs that selectively target these serotonin receptors could be developed to yield improvements over current treatments for major depressive disorders. [ABSTRACT FROM AUTHOR]

Background: Chronic treatment with selective serotonin (5-HT) reuptake inhibitors (SSRIs) facilitates adult neurogenesis and reverses the state of maturation in mature granule cells (GCs) in the dentate gyrus (DG) of the hippocampus. Recent studies have suggested that the 5-HT4 receptor is involved in both effects. However, it is largely unknown how the 5-HT4 receptor mediates neurogenic effects in the DG and, how the neurogenic and dematuration effects of SSRIs interact with each other. Results: We addressed these issues using 5-HT4 receptor knockout (5-HT4R KO) mice. Expression of the 5-HT4 receptor was detected in mature GCs but not in neuronal progenitors of the DG. We found that chronic treatment with the SSRI fluoxetine significantly increased cell proliferation and the number of doublecortin-positive cells in the DG of wild-type mice, but not in 5-HT4R KO mice. We then examined the correlation between the increased neurogenesis and the dematuration of GCs. As reported previously, reduced expression of calbindin in the DG, as an index of dematuration, by chronic fluoxetine treatment was observed in wild-type mice but not in 5-HT4R KO mice. The proliferative effect of fluoxetine was inversely correlated with the expression level of calbindin in the DG. The expression of neurogenic factors in the DG, such as brain derived neurotrophic factor (Bdnf), was also associated with the progression of dematuration. These results indicate that the neurogenic effects of fluoxetine in the DG are closely associated with the progression of dematuration of GCs. In contrast, the DG in which neurogenesis was impaired by irradiation still showed significant reduction of calbindin expression by chronic fluoxetine treatment, suggesting that dematuration of GCs by fluoxetine does not require adult neurogenesis in the DG. Conclusions: We demonstrated that the 5-HT4 receptor plays an important role in fluoxetine-induced adult neurogenesis in the DG in addition to GC dematuration, and that these phenomena are closely associated. Our results suggest that 5-HT4 receptor-mediated phenotypic changes, including dematuration in mature GCs, underlie the neurogenic effect of SSRIs in the DG, providing new insight into the cellular mechanisms of the neurogenic actions of SSRIs in the hippocampus. [ABSTRACT FROM AUTHOR]

In this study, the effects of 5-HT4 receptors of the CA1 on MK801-induced amnesia and hyperlocomotion were examined. One-trial step-down method was used to assess memory retention and then, the hole-board method to assess exploratory behaviors. The results showed that post-training intra-CA1 administration of RS67333 (62.5 and 625 ng/mouse) and RS23597 (1 and 10 ng/mouse) decreased memory consolidation, but it did not alter head-dip counts, head-dip latency and locomotor activity. Similarly, MK801 (0.5 and 1 μg/mouse) decreased memory consolidation, but had no effect on head-dip counts and head-dip latency. Interestingly, it increased locomotor activity. The results also showed that post-training intra-CA1 injection of a sub-threshold dose of RS67333 (6.25 ng/mouse) or RS23597 (0.1 ng/mouse) could heighten MK801 induced amnesia and decrease locomotor activity, but it did not alter head-dip counts and head-dip latency. In conclusion, our findings suggest that the CA1 5-HT4 receptors are involved in MK801-induced amnesia and hyperlocomotion. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) has been implicated in multiple aspects of brain function including regulation of serotonin signaling. The BDNF val66met polymorphism (rs6265) has been linked to aspects of serotonin signaling in humans but its effects are not well understood. To address this, we evaluated whether BDNF val66met was predictive of a putative marker of brain serotonin levels, serotonin 4 receptor (5-HT4) binding assessed with [11C]SB207145 positron emission tomography, which has also been associated with the serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphism. We applied a linear latent variable model (LVM) using regional 5-HT4 binding values (neocortex, amygdala, caudate, hippocampus, and putamen) from 68 healthy humans, allowing us to explicitly model brain-wide and region-specific genotype effects on 5-HT4 binding. Our data supported an LVM wherein BDNF val66met significantly predicted a LV reflecting [11C]SB207145 binding across regions ( P = 0.005). BDNF val66met met-carriers showed 2-9% higher binding relative to val/val homozygotes. In contrast, 5-HTTLPR did not predict the LV but S-carriers showed 7% lower neocortical binding relative to LL homozygotes ( P = 7.3 × 10−6). We observed no evidence for genetic interaction. Our findings indicate that BDNF val66met significantly predicts a common regulator of brain [11C]SB207145 binding, which we hypothesize reflects brain serotonin levels. In contrast, our data indicate that 5-HTTLPR specifically affects 5-HT4 binding in the neocortex. These findings implicate serotonin signaling as an important molecular mediator underlying the effects of BDNF val66met and 5-HTTLPR on behavior and related risk for neuropsychiatric illness in humans. Hum Brain Mapp, 36:313-323, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of G s , G i, or G q proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT 4 , 5-HT 6 , and 5-HT 7 with G s , and 5-HT 4 with G i1. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for G s and G i , respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with G s or G i. Together, these results present a common mechanism of G s versus G i protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors. [Display omitted] • Cryo-EM structures of serotonin receptor 5-HT 4 , 5-HT 6 , and 5-HT 7 complexed with Gα s • Cryo-EM structure of serotonin receptor 5-HT 4 complexed with Gα i • The conserved binding mode of serotonin and the selective binding mode of 5-CT • The TM5-TM6 switches are key to G s and G i selectivity for class A GPCRs Huang et al. report four structures of the serotonin receptors 5-HT 4 , 5-HT 6 , and 5-HT 7 with G s , and 5-HT 4 with G i1. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for G s and G i , respectively. [ABSTRACT FROM AUTHOR]

Abstract: 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-HT4) 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-HT4 receptor binding assessed with [11C]SB207145 positron emission tomography (PET). We observed a significant association within the neocortex where [11C]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 [11C]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. [Copyright &y& Elsevier]

Abstract: The influence of the selective 5-HT4 receptor agonist prucalopride on acetylcholine release from cholinergic nerve endings innervating pig gastric circular muscle and the possible regulation of this effect by phosphodiesterases (PDEs) was investigated, as PDEs have been shown to control the response to 5-HT4 receptor activation in pig left atrium. Circular muscle strips were prepared from pig proximal stomach and either submaximal cholinergic contractions or tritium outflow after incubation with [3H]-choline, induced by electrical field stimulation, were studied. Prucalopride concentration-dependently increased the amplitude of submaximal cholinergic contractions and of acetylcholine release induced by electrical field stimulation. The effect of the highest concentration tested (0.3 μM) on cholinergic contractions was antagonized by the selective 5-HT4 receptor antagonist GR113808 but not by granisetron or methysergide; the antagonism of prucalopride by GR113808 was confirmed in the release assay. The non-selective PDE-inhibitor 3-isobutyl-methyl-xanthine (IBMX) concentration-dependently reduced the amplitude of the cholinergic contractions; 3 μM IBMX reduced the cholinergic contractions maximally by 16% but it enhanced the facilitating effect of prucalopride from 51 to 83%. IBMX (10 μM) induced and enhanced the facilitating effect of prucalopride on electrically induced acetylcholine release. The selective inhibitors vinpocetine (PDE1), EHNA (PDE2) and cilostamide (PDE3) did not influence the effect of prucalopride on acetylcholine release but the PDE4-inhibitor rolipram (1 μM) enhanced the facilitating effect of prucalopride to the same extent as IBMX. These results demonstrate that 5-HT4 receptors are present on the cholinergic nerves towards the pig gastric circular muscle, facilitating acetylcholine release; the intracellular transduction pathway of this facilitation is regulated by PDE4. Combination of a 5-HT4 receptor agonist with selective inhibition of the PDE involved in this regulation of transmitter release might enhance the prokinetic effect of the 5-HT4 receptor agonist. [Copyright &y& Elsevier]

Background: Clinical studies show that disturbed colonic motility induced by extrinsic nerves damage is restored over time. We studied whether 5-HT3 and 5HT4 receptors are involved in mediating the adaptive mechanisms following parasympathetic denervation. Methods: Parasympathetic denervation of the entire colon was achieved by bilateral pelvic nerve transection and truncal vagotomy in rats. Colonic transit was measured by calculating the geometric center (GC) of 51Cr distribution. Expression of 5-HT3 and 5HT4 receptor mRNA was determined by real time RT-PCR. Results: Parasympathetic denervation caused a significant delay in colonic transit (GC = 4.36) at postoperative day (POD) 1, compared with sham operation (GC = 6.31). Delayed transit was gradually restored by POD 7 (GC = 5.99) after the denervation. Restored colonic transit was antagonized by the administration of 5-HT3 and 5HT4 receptors antagonists at POD 7. 5-HT3 and 5HT4 receptors mRNA expression were significantly increased in the mucosal/submucosal layer at POD 3 or POD 7, whereas no significant difference was observed in the longitudinal muscle layers adherent with the myenteric plexus (LMMP). Conclusions: It is suggested that up-regulation of 5-HT3 and 5-HT4 receptors expression in the mucosal/submucosal layer is involved to restore the delayed transit after the parasympathetic denervation in rats. [ABSTRACT FROM AUTHOR]