5-HT2 Agonist Research Articles

Episodic respiratory motor output is decreased by 5‐HT3 receptor agonists and increased by 5‐HT3 receptor antagonists in isolated adult turtle brainstems

Episodic breathing is a respiratory pattern marked by episodes of several consecutive breaths that are separated by non‐ventilatory pauses. Episodic breathing occurs naturally in some ectothermic vertebrates, but the underlying mechanisms are not known. Approximately 56% of isolated turtle brainstems produce single bursts of respiratory motor output on hypoglossal nerves (bursts/episode < 1.25), while 25% of isolated turtle brainstems produce episodic respiratory bursts (bursts/episode > 1.75; n=171; Johnson & Creighton, Am J Physiol Regul Integr Comp Physiol, 2005). Bath‐application of 5‐HT3 agonists, such as phenylbiguanide (PBG; 20 µM; n=8) or 1‐(m‐Chlorophenyl)biguanide hydrochloride (mCPBG; 50 µM; n=6), onto isolated turtle brainstems switched episodic respiratory bursts (2.04 ± 0.06 bursts/episode) into singlet bursts (1.31 ± 0.09 bursts/episode) after 1.0 h (P<0.001). Bath‐application of 5‐HT3 antagonists, such as tropisetron (50 µM; n=5) and MDL‐72222 (50 µM; n=3) tended to switch singlet respiratory bursts (1.05 ± 0.03 bursts/episode) into episodic bursts (1.52 ± 0.06 bursts/episode) after 2.0 h (P>0.05). These data suggest that 5‐HT3 receptors in the brainstem are involved in regulating episodic breathing in turtles.

5-HT-induced depression of the spinal monosynaptic reflex potential utilizes different types of 5-HT receptors depending on Mg2+ availability

Receptor subtypes involved in the 5-hydroxytryptamine (5-HT)-induced depression of synaptic transmission in neonatal rat spinal cords in vitro were evaluated in the absence or presence of Mg2+ in the medium. Stimulation of a dorsal root evoked monosynaptic reflex potential (MSP) and polysynaptic reflex potential (PSP) in the segmental ventral root in Mg2+-free medium where the voltage-dependent blockade of NMDAreceptors is absent. The 5-HT (0.3–50μM) in the Mg2+-free medium depressed the MSPand PSP in a concentration-dependent manner. At 30μM of 5-HT, the depression was 57% and 95% for MSP and PSP, respectively, and no further depression was seen at 50μM. The 5-HT-induced depression of the reflexes in the Mg2+-free medium was blocked by ondansetron (5-HT3 receptor antagonist), but not by spiperone (5-HT2A/2C antagonist). In the Mg2+-free medium, phenylbiguanide (5-HT3 agonist) also depressed the MSPand PSP in a concentration-dependent manner and was blocked by ondansetron. Addition of Mg2+ (1.3mM) to the medium abolished the PSP and decreased the MSPby 30%. In the presence of Mg2+, 5-HT (1–50μM) also depressed the MSP in a concentration-dependent manner. At 10μM of 5-HT, there was approximately 20% depression and at 50μM the depression was 100%. The 5-HT-induced depression of MSP in the Mg2+-containing medium was antagonized by spiperone (p<0.05, two-way ANOVA), but not by ondansetron. The results indicate that the 5-HT-induced depression of MSPinvolves 5-HT3 receptors in the Mg2+-free medium and 5-HT2A/2C in the presence of Mg2+ when NMDA receptors are in the closed state.

Serotonin in the gastrointestinal tract

To assess the role of serotonin and its control in the manifestations and treatment of lower functional gastrointestinal disorders. Recent literature has explored several novel concepts in the association of serotonin and symptoms, alterations in tissue levels of serotonin and its reuptake protein, aspects of the genetic determinants of serotonergic function (particularly 5-HTTLPR) and its relationship to gastrointestinal motor and sensory functions, and novel serotonergic agents used in therapy of lower functional gastrointestinal disorders. The most consistent findings are the increase in plasma 5-hydroxytryptamine (5-HT) in diarrheal diseases and reduction in constipation. The serotonin transporter in platelets has an impact on the circulating level of 5-HT. Meta-analysis shows that 5-HTTLPR genotype is not significantly associated with irritable bowel syndrome in Whites or Asians. New 5-HT3 antagonists and 5-HT4 agonists are efficacious and promise to provide relief for patients if they can pass regulatory hurdles. Although the most relevant implication for clinical practice remains the evidence that serotonergic agents are efficacious in the treatment of chronic constipation, chronic diarrhea and irritable bowel syndrome, the role of genetic control of 5-HT and its receptors is the subject of ongoing research, and is likely to enhance understanding of the mechanisms and treatment of these diseases.

Normal memory recovery by activation of 5-HT4 receptors in hippocampal lesioned and normal aged rats

Event Abstract Back to Event Normal memory recovery by activation of 5-HT4 receptors in hippocampal lesioned and normal aged rats Evelyne Marchetti1*, Marlyse Jacquet1, Helene Jeltsh2, Martine Migliorati1, Emmanuel Nivet1, Jean-Christophe Cassel2 and Francois S. Roman1 1 Universite de Provence, Laboratoire de Neurobiologie des Processus Mnesiques, France 2 Universite Louis Pasteur, Laboratoire d-Imagerie et de Neurosciences Cognitives, France Colchicine lesions induced a substantial loss of granule cells and damage to the overlying pyramidal cell layer in region CA1 in adult male Long-Evans rats. All rats with such lesions showed a significant associative learning deficit in an olfactory discrimination task, while being unimpaired in the procedural component of this task. Injection of a partial selective 5-HT4 agonist (SL65.0155 ; 0.01 mg/kg, i.p.,vs.saline) before the third of six training sessions enabled complete recovery of associative learning performance in the lesioned rats. In the same way this specific agonist improved memory performance in the same task in aged rats. Activation of 5-HT4 receptors by a selective agonist such as SL65.0155 might therefore provide an opportunity to reduce learning and memory deficits associated with temporal lobe damage, and could be useful for the symptomatic treatment of memory dysfunctions related to normal an pathological aging such as Alzheimer's disease. Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Marchetti E, Jacquet M, Jeltsh H, Migliorati M, Nivet E, Cassel J and Roman FS (2009). Normal memory recovery by activation of 5-HT4 receptors in hippocampal lesioned and normal aged rats. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.223 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Jun 2009; Published Online: 11 Jun 2009. * Correspondence: Evelyne Marchetti, Universite de Provence, Laboratoire de Neurobiologie des Processus Mnesiques, 13331 Marseille, France, evelyne.marchetti-gauthier@univ-provence.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Evelyne Marchetti Marlyse Jacquet Helene Jeltsh Martine Migliorati Emmanuel Nivet Jean-Christophe Cassel Francois S Roman Google Evelyne Marchetti Marlyse Jacquet Helene Jeltsh Martine Migliorati Emmanuel Nivet Jean-Christophe Cassel Francois S Roman Google Scholar Evelyne Marchetti Marlyse Jacquet Helene Jeltsh Martine Migliorati Emmanuel Nivet Jean-Christophe Cassel Francois S Roman PubMed Evelyne Marchetti Marlyse Jacquet Helene Jeltsh Martine Migliorati Emmanuel Nivet Jean-Christophe Cassel Francois S Roman Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Prucalopride for chronic constipation

Chronic constipation is a frequently reported medical disorder that reduces patients' quality of life and imposes a significant economic burden on the health care system. Symptoms of constipation are diverse and include infrequent bowel movements, hard stool, straining at stool, sensations of anorectal obstruction and feelings of incomplete evacuation. Patients with chronic constipation can be categorized into one of three main groups based on their underlying pathophysiology: normal transit constipation; colonic inertia; and pelvic floor dyssynergia. Specialized tests (i.e., anorectal manometry, radio-opaque marker study) may be required in some patients to help distinguish the different subtypes of constipation and to guide appropriate therapy. Although the underlying mechanism of constipation differs among patients, serotonin (5-hydroxytryptamine (5-HT)) appears to have an important role in colonic motility in some patients. Previous research has demonstrated that stimulation of 5-HT4 receptors improves symptoms of chronic constipation in some patients. Prucalopride, a selective 5-HT4 agonist, relieved symptoms of constipation in phase II and phase III clinical trials. In this monograph, we review the pharmacology, mechanism of action, efficacy and safety of the selective 5-HT4 agonist prucalopride in patients with chronic constipation.

An Evidence-Based Systematic Review on the Management of Irritable Bowel Syndrome

An Evidence-Based Systematic Review on the Management of Irritable Bowel Syndrome

Serotoninergic modulation of cortical and respiratory responses to episodic hypoxia.

Biphasic respiratory response to hypoxia in anesthetized animals is accompanied by changes in the EEG mostly in the low EEG frequency bands. Serotonin is a potent modulator of cortical and respiratory activity through 5-HT2 receptors. Present study investigated whether 5-HT2 receptors might be involved in the EEG and respiratory relationship during normoxic and hypoxic respiration assessed from integrated phrenic (Phr) and hypoglossal (HG) nerve activities. EEG signal recorded from the frontal cortex was subjected to power spectral analysis in delta, theta, alpha, and beta frequency bands. Systemic administration of 5-HT2 agonist DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) enhanced tonic and lowered peak phasic respiratory activity, and increased frequency of bursts of Phr and HG activity. At the same time, EEG activity became desynchronized and arterial blood pressure (ABP) increased. Following DOI pretreatment, 11% hypoxia induced an augmented respiratory response in comparison with the response in the baseline condition. ABP fell less then in the control hypoxia. EEG pattern changed less than in the baseline state. Subsequent administration of ketanserin, a 5-HT2 antagonist increased respiratory activity, elicited a synchronization of EEG activity and hypotension. The respiratory response to hypoxia was attenuated and cortical response was more potent in comparison with that after DOI injection. Arterial blood pressure decreased more then during baseline hypoxic response. The results suggest that modulation of cortical synchronization and desynchronization through 5-HT2 receptor active agents may impact to hypoxic respiratory response.

P03-33 An investigation of 5-HT2 involvement in the acute behavioural effects of fluoxetine and mCPP in an animal model of OCD

Background:We reported that the non-specific 5HT agonist m-chlorophenylpiperazine (mCPP) and the SSRI fluoxetine (FLX) both cause acute persistence increases in the rewarded alternation (RA) model of OCD. Chronic pretreatment with either substance or their combined subclinical doses protects from this ‘pathogenic’ effect, so mCPP and fluoxetine exhibit cross-tolerance and synergy.Aims:Using specific 5HT2A and 5HT2C receptor antagonists we investigated whether these receptors participate in a common mechanism of action mediating the acute mCPP/fluoxetine effect in our model.Methods:Naïve, male Wistars were used. Drugs used (intraperitoneally): FLX (10mg/kg), mCPP (2.5mg/kg), M100907 (5HT2A antagonist, 0.03mg/kg), SB242084 (5HT2C antagonist, 0.5mg/kg), vehicle. Experiments included a drug-free training/baseline phase in T-maze RA (group-matching for spontaneous persistence: SP).Experiment 1: Effects of M100907, SB242084, vehicle were assessed on 3 matched low SP and 3 high SP groups.Experiment 2: the acute effect of FLX, mCPP and saline were examined on RA in 3 SP-matched groups.Experiment 3: Effects of Vehicle+FLX, M100900+FLX, SB242084+FLX and Vehicle were examined on RA, in 4 SP-matched groups.Experiment 4: Correspondingly for mCPP.Results:Experiment 1: Neither M100907 nor SB242084 affected high or low SP.Experiment 2 replicated the pathogenic effects of FLX/mCPP.Experiment 3: Neither M100907 nor SB242084 affected the pathogenic effect of FLX.Experiment 4: in contrast, SB242084 (but not M100907) significantly reduced the pathogenic mCPP effect.Conclusions:The acute pathogenic action of mCPP, but not of FLX, involves 5HT2C but not 5HT2A receptors. the similar acute action of mCPP and FLX on persistence cannot be attributed to 5HT2 mediation.

Responses to 5-HT in morphologically identified neurons in the rat substantia gelatinosa in vitro

Bath application of 5-HT (1-1000 μM) induced a tetrodotoxin (TTX)-resistant outward current at the holding membrane potential (VH) of −50 mV in 104/162 (64.2%) of substantia gelatinosa (SG) neurons from the rat spinal cord in vitro. The 5-HT-induced outward current was suppressed by an external solution containing Ba2+, or a pipette solution containing Cs2SO4 and tetraethylammonium. It was reversed near the equilibrium potential of the K+ channel. The response to 5-HT was abolished 30 min after patch formation with a pipette solution containing guanosine-5-O-(2-thiodiphosphate)-S. The 5-HT-induced outward current was mimicked by a 5-HT1A agonist, (±)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide, and suppressed by a 5-HT1A antagonist, WAY100635, suggesting the 5HT1A receptor-mediated activation of K+ channels in the outward current. In 11/162 (6.8%) SG neurons, 5-HT produced an inward current, which was mimicked by a 5-HT3 agonist, 1-(m-chlorophenyl)-biguanide (mCPBG). The 5-HT-induced outward currents were observed in vertical cells (21/34) and small islet cells (11/34), while inward currents were induced in islet cells (1/5) and small islet (4/5) cells, but not in vertical cells. It is known that most vertical cells and islet cells in the SG are excitatory (glutamatergic) and inhibitory interneurons, respectively, while small islet cells consist of both excitatory and inhibitory neurons. Bath application of 5-HT or mCPBG increased the amplitude and the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), but no neurons showed a decrease in sIPSC. Furthermore, frequency, but not amplitude, of miniature IPSCs increased with perfusion with 5-HT in the presence of TTX. These findings, taken together, suggest that 5-HT induces outward currents through 5-HT1A receptors in excitatory SG neurons. These findings also suggest that the inward currents are post- and presynaptically evoked through 5-HT3 receptors, probably in inhibitory neurons.

Prucalopride: the evidence for its use in the treatment of chronic constipation

Prucalopride: the evidence for its use in the treatment of chronic constipation Georges CoremansDivision of Gastroenterology, University Hospital Gasthuisberg, University of Leuven, Leuven, BelgiumIntroduction: Chronic constipation is a common condition that is difficult to treat. Existing options for the treatment of patients with different subgroups of constipation are limited. A new efficacious and safe drug is needed to limit the frequently observed adverse effects induced by laxatives, to improve general wellbeing and quality of life, and to provide an alternative for enemas or even resectional surgery in patients in whom stimulant laxatives cause disabling adverse effects or fail to increase bowel movement frequency. Aims: The purpose of this article is to assess the current evidence supporting the use of the selective and high affinity serotonin-4 (5-HT4) receptor agonist prucalopride in the management of chronic constipation.Evidence review: There are now convincing data from phase II and multicenter phase III randomized, double-blind, placebo-controlled trials that prucalopride treatment results in a clinically meaningful increase in the number of spontaneous complete bowel movements, a reduction of perceived severity of symptoms and improved disease-related quality of life in a significant proportion of patients. There is a rapid onset of the effect and the improvement is maintained for at least 12 weeks. Prucalopride in a dose of up to 4 mg per day appeared generally well tolerated and devoid of serious cardiac events. Adverse events, most frequently headache and nausea, are usually mild or moderate and occur mainly during the first days of treatment. Prucalopride should be used with prudence and with careful assessment of the benefit-risk ratio until more clinical and electrophysiologic data become available, because relatively few patients have been exposed to the drug for long periods of time.Place in therapy: Prucalopride 1–2 mg once daily may be given to patients suffering from chronic constipation for whom laxatives do not provide adequate relief of their symptoms. Patients with severe constipation and slow transit, who frequently develop tolerance to stimulant laxatives, are also eligible for prucalopride treatment.Key words: prucalopride, 5-HT4 agonist, chronic constipation, laxatives, bowel movements, safety, tolerance, gastric emptying, small bowel transit, colonic transit

Cabergoline: Pharmacology, ocular hypotensive studies in multiple species, and aqueous humor dynamic modulation in the Cynomolgus monkey eyes

The aims of the current studies were to determine the in vitro and in vivo ocular and non-ocular pharmacological properties of cabergoline using well documented receptor binding, cell-based functional assays, and in vivo models. Cabergoline bound to native and/or human cloned serotonin-2A/B/C (5HT2A/B/C), 5HT1A, 5HT7, α2B, and dopamine-2/3 (D2/3) receptor subtypes with nanomolar affinity. Cabergoline was an agonist at human recombinant 5HT2, 5HT1A and D2/3 receptors but an antagonist at 5HT7 and α2 receptors. In primary human ciliary muscle (h-CM) and trabecular meshwork (h-TM) cells, cabergoline stimulated phosphoinositide (PI) hydrolysis (EC50=19±7nM in TM; 76nM in h-CM) and intracellular Ca2+ ([Ca2+]i) mobilization (EC50=570±83nM in h-TM; EC50=900±320nM in h-CM). Cabergoline-induced [Ca2+]i mobilization in h-TM and h-CM cells was potently antagonized by a 5HT2A-selective antagonist (M-100907, Ki=0.29–0.53nM). Cabergoline also stimulated [Ca2+]i mobilization more potently via human cloned 5HT2A (EC50=63.4±10.3nM) than via 5HT2B and 5HT2C receptors. In h-CM cells, cabergoline (1μM) stimulated production of pro-matrix metalloproteinases-1 and -3 and synergized with forskolin to enhance cAMP production. Cabergoline (1μM) perfused through anterior segments of porcine eyes caused a significant (27%) increase in outflow facility. Topically administered cabergoline (300–500μg) in Dutch-belted rabbit eyes yielded 4.5μM and 1.97μM levels in the aqueous humor 30min and 90min post-dose but failed to modulate intraocular pressure (IOP). However, cabergoline was an efficacious IOP-lowering agent in normotensive Brown Norway rats (25% IOP decrease with 6μg at 4h post-dose) and in conscious ocular hypertensive cynomolgus monkeys (peak reduction of 30.6±3.6% with 50μg at 3h post-dose; 30.4±4.5% with 500μg at 7h post-dose). In ketamine-sedated monkeys, IOP was significantly lowered at 2.5h after the second topical ocular dose (300μg) of cabergoline by 23% (p<0.02) and 35% (p<0.004) in normotensive and ocular hypertensive eyes, respectively. In normotensive eyes, cabergoline increased uveoscleral outflow (0.69±0.7μL/min–1.61±0.97μL/min, n=13; p<0.01). However, only seven of the eleven ocular hypertensive monkeys showed significantly increased uveoscleral outflow. These data indicate that cabergoline's most prominent agonist activity involves activation of 5HT2, 5HT1A, and D2/3 receptors. Since 5HT1A agonists, 5HT7 antagonists, and α2 antagonists do not lower IOP in conscious ocular hypertensive monkeys, the 5HT2 and dopaminergic agonist activities of cabergoline probably mediated the IOP reduction observed with this compound in this species.

Renzapride: a new drug for the treatment of constipation in the irritable bowel syndrome

Renzapride is a novel drug currently under clinical evaluation for the treatment of irritable bowel syndrome (IBS). Renzapride is a mixed 5-hydroxytryptamine type 4 (5-HT4) agonist and 5-HT3 receptor antagonist that has a stimulatory effect on gastrointestinal motility and transit, as established by in vivo and in vitro studies. Its therapeutic efficacy, tolerability and safety have been evaluated in diabetic gastroparesis in a single study, as well as in IBS in a few other studies. Phase II studies indicated potential beneficial effects on symptoms and bowel habits in patients with constipation-predominant IBS and mixed-type IBS. The outcome of Phase III studies is currently under evaluation.

5-HT4 receptor agonism in the five-choice serial reaction time task

5-HT4 agonists are currently being developed for the treatment of Alzheimer’s disease and have previously been demonstrated to improve cognitive performance in a variety of tests but none that specifically test attention. Here we characterise the 5-HT4 partial agonist SL65.0155 compared to the reference drug, nicotine, in a test that is used to measure attention in rats, the five-choice serial reaction time task (5CSRTT). SL65.0155 (0.1 or 1 mg/kg s.c) and nicotine (0.2 mg/kg s.c.) were tested in protocols using fixed or variable stimulus durations. SL65.0155 improved performance by virtue of reducing incorrect responses and increasing % correct trials. Perseverative responses were reduced by SL65.0155, and latency during incorrect trials was increased following treatment with 0.1 mg/kg SL65.0155. Nicotine, as previously reported, improved performance in several parameters in the 5CSRTT, including response latencies, errors of omission and correct responses in both the baseline and variable stimulus protocol. These data suggest 5-HT4 agonists may have beneficial effects on attention and thereby may be useful for the treatment of cognitive deficits.

Anticonvulsant serotonergic and deep brain stimulation in anterior thalamus

Anterior thalamus (AN) has been shown to mediate seizures in both focal and generalized models. Specific regional increase in AN serotonergic activity was observed following AN-DBS in our pentylenetetrazol (PTZ) rodent model of acute seizures, and this increase may inhibit seizures and contribute to the mechanism of anticonvulsant DBS. Anesthetized rats with AN-directed dialysis cannula with scalp/depth EEG were infused with PTZ at 5.5mg/(kg min) until an EEG seizure occurred. Eight experimental groups of AN-dialysis infusion were evaluated: controls (dialysate-only), 10 and 100 microM serotonin 5-HT(7) agonist 5-carboxamidotryptamine (5-CT), 1, 10 and 100 microM serotonin antagonist methysergide (METH), AN-DBS, and 100 microM METH+AN-DBS. Latency for seizures in control animals was 3,120+/-770 s (S.D.); AN-DBS delayed onset to 5018+/-1100 (p<0.01). AN-directed 5-CT increased latency in dose-dependent fashion: 3890+/-430 and 4247+/-528 (p<0.05). Methysergide had an unexpected protective effect at low-dose (3908+/-550, p<0.05) but not at 100 microM (2687+/-1079). The anticonvulsant action of AN-DBS was blocked by prior dialysis using 100 microM METH. Surface EEG burst count and nonlinear analysis (H-Statistic) noted significant (p<0.05) increased pre-ictal epileptiform bursts in 5-CT, methysergide, but not DBS group compared to control. Increased serotonergic activity in AN raised PTZ seizure threshold, similar to DBS, but without preventing cortical bursting. 5-Carboxamidotryptamine, a 5-HT(7) agonist, demonstrated dose-dependent seizure inhibition. Methysergide proved to have an inverse, dose-dependent agonist property, antagonizing the action of AN-DBS at the highest dose. Anticonvulsant AN-DBS may in part act to selectively alter serotonin neurotransmission to raise seizure threshold.

Tegaserod in patients with mechanical sensitivity and overlapping symptoms of functional heartburn and functional dyspepsia

ABSTRACTBackground: While functional heartburn (FH) and functional dyspepsia (FD) are recognized clinical entities, symptoms often overlap across both disorders. Despite their frequency, little is known of the underlying pathophysiology of overlapping symptoms. This study evaluated the effect of the 5-HT4 agonist, tegaserod, on visceral sensitivity and symptom improvement in patients with overlapping symptoms of FH and FD.Research design and methods: Patients with overlapping symptoms of FH and FD (ROME II) and mechanical hypersensitivity (Barostat examination) were randomized to tegaserod 6 mg bid or placebo for 2 weeks with treatment crossover after a 2-week washout period. Esophageal and gastric Barostat sensory tests were performed and patients rated their overall symptoms at study end. When carry-over was detected, data were presented for period 1 only. Safety was also assessed.Results: Sixty patients were screened of whom 30 were randomized and 25 completed. Mechanical hypersensitivity was reported by 83% of 47 patients completing esophageal and gastric baseline Barostat examinations. Tegaserod did not significantly alter balloon volume to pain (primary variable); however, pressure to gastric pain increased (p = 0.044 vs. placebo). The severity of heartburn, regurgitation, early fullness, and bloating was significantly lower following tegaserod vs. placebo treatment (p = 0.026, p = 0.021, p = 0.016, and p = 0.030). Overall symptom improvement was reported by 52% tegaserod vs. 32% placebo patients (p = 0.275), and treatment was well tolerated.Conclusions: Results suggest that tegaserod may increase the gastric pain threshold and decrease the severity of individual symptoms in patients with overlapping FH and FD. However, these findings must be considered within the context of the study limitations, including the small number of subjects, potential for and presence of a carry-over effect, along with the impact of Barostat balloon use on the assessment of gastric function.

Activation of 5-HT2A/C Receptors Counteracts 5-HT1A Regulation of N-Methyl-D-aspartate Receptor Channels in Pyramidal Neurons of Prefrontal Cortex

Abnormal serotonin-glutamate interaction in prefrontal cortex (PFC) is implicated in the pathophysiology of many mental disorders, including schizophrenia and depression. However, the mechanisms by which this interaction occurs remain unclear. Our previous study has shown that activation of 5-HT1A receptors inhibits N-methyl-d-aspartate (NMDA) receptor (NMDAR) currents in PFC pyramidal neurons by disrupting microtubule-based transport of NMDARs. Here we found that activation of 5-HT2A/C receptors significantly attenuated the effect of 5-HT1A on NMDAR currents and microtubule depolymerization. The counteractive effect of 5-HT2A/C on 5-HT1A regulation of synaptic NMDAR response was also observed in PFC pyramidal neurons from intact animals treated with various 5-HT-related drugs. Moreover, 5-HT2A/C stimulation triggered the activation of extracellular signal-regulated kinase (ERK) in dendritic processes. Inhibition of the β-arrestin/Src/dynamin signaling blocked 5-HT2A/C activation of ERK and the counteractive effect of 5-HT2A/C on 5-HT1A regulation of NMDAR currents. Immunocytochemical studies showed that 5-HT2A/C treatment blocked the inhibitory effect of 5-HT1A on surface NR2B clusters on dendrites, which was prevented by cellular knockdown of β-arrestins. Taken together, our study suggests that serotonin, via 5-HT1A and 5-HT2A/C receptor activation, regulates NMDAR functions in PFC neurons in a counteractive manner. 5-HT2A/C, by activating ERK via the β-arrestin-dependent pathway, opposes the 5-HT1A disruption of microtubule stability and NMDAR transport. These findings provide a framework for understanding the complex interactions between serotonin and NMDARs in PFC, which could be important for cognitive and emotional control in which both systems are highly involved.

Emotional distress prior to chemotherapy and delayed nausea in breast cancer patients

9527 Background: Delayed nausea following cancer chemotherapy (occurring more than 24 hours post-treatment) is not well controlled by antiemetic medication and remains a widespread problem in clinical practice. Possible modifiable risk factors for delayed nausea are thus an important area for research. Two recent small scale studies with heterogeneous patient samples have raised the possibility that heightened levels of pretreatment emotional distress may be one such risk factor. The present study analyzed a preexisting dataset to test the hypothesis that patients’ levels of emotional distress on the morning of their first chemotherapy infusion would predict the severity of delayed nausea assessed daily following treatment. Methods: Data from women (n=118) with breast cancer (mean age = 52.2 years) treated as outpatients with doxorubicin and standard antiemetics (e.g., 5HT3 agonists) were included in this study. Patients were asked to rate their emotional distress (independent variable) for the morning of...

Complete recovery of olfactory associative learning by activation of 5-HT4 receptors after dentate granule cell damage in rats

Bilateral intradentate injections of 3.0μg of colchicine induced a substantial loss of granule cells and damage to the overlying pyramidal cell layer in region CA1 in adult male Long-Evans rats. All rats with such lesions showed a significant associative learning deficit in an olfactory discrimination task, while being unimpaired in the procedural component of this task. Injection of a partial selective 5-HT4 agonist (SL65.0155; 0.01mg/kg, i.p., vs. saline) before the third of six training sessions enabled complete recovery of associative learning performance in the lesioned rats. Activation of 5-HT4 receptors by a selective agonist such as SL65.0155 might therefore provide an opportunity to reduce learning and memory deficits associated with temporal lobe damage, and could be useful for the symptomatic treatment of memory dysfunctions related to pathological aging such as Alzheimer’s disease.

The efficacy of combined estrogen and buspirone treatment in olivopontocerebellar atrophy

Olivopontocerebellar atrophy (OPCA) is a chronic neurodegenerative disease with symptoms of cerebellar ataxia, parkinsonism, autonomic disturbances and ophthalmoplegia. Buspirone, a 5-HT1(A) agonist could constitute a symptomatic improvement in cerebellar dysfunction whereas estrogen has been investigated for neuroprotection. We conducted an open-labeled pilot trial to assess the efficacy of estrogen with buspirone treatment. Eighteen patients (7 male and 11 female) with OPCA were randomized into the buspirone (15 mg/day, n=9), or the combined treatment group (estrogen, 0.625 mg/d plus buspirone, n=9). For the clinical rating, International Cooperative Ataxia Rating Scale (ICARS) was used and dysarthria, gaze evoked nystagmus, finger to nose, pronation-supination alternating movement, knee-tibia test, and gait speed were evaluated for 12 months. Buspirone-treated group showed improvements in finger to nose and pronation-supination alternating movement test (p=0.046 and p=0.025, respectively). The combination group (Estrogen+buspirone), however, showed no improvement in cerebellar sub-scales compared to the baseline. Buspirone treatment showed feasible efficacies for OPCA, while the combined treatment of estrogen and buspirone failed to improve, suggesting estrogen may not have further benefit in cerebellar dysfunction.

T1399 In Patients with Chronic Constipation, TD-5108, a Selective 5-HT4 Agonist with High Intrinsic Activity, Relieves Straining and Bloating, Normalizes Stool Consistency and Reduces Laxative Use

T1399 In Patients with Chronic Constipation, TD-5108, a Selective 5-HT4 Agonist with High Intrinsic Activity, Relieves Straining and Bloating, Normalizes Stool Consistency and Reduces Laxative Use