Involvement Of 5-HT2 Receptors Research Articles

5-HT2-Receptors and 5-HIAA – Therapeutic Targets for Evaluation of Severity, Progression and Effectiveness of Treatment in Immature Male Rats in a Monocrotalin Model of Pulmonary Hypertension

Suppression of the proliferation of vascular endothelial cells and the interaction of endothelial with smooth muscle cells in pulmonary hypertension (PH) are impaired. Participation of the 5-HT2a-receptor in the mitogenic effect on endothelial, and 5-HT2b-receptor – on vascular smooth muscle cells was revealed. The main organ that metabolizes serotonin is the lung. In the endothelial cells of the vessels of the lungs under the action of the enzyme monoamine oxidase And serotonin is converted to 5-hydroxyindoleacetic acid (5-HIAA), which is subsequently excreted in the urine. Currently, the role of 5-HT2-receptors is not taken into account in the treatment of children with pulmonary hypertension. We have modified the monocrotaline model of pulmonary hypertension for immature rats. A scheme for the administration of a 5-HT2-receptor blocker for the prevention and treatment of pulmonary hypertension in immature rats was developed and tested. A positive correlation was found between the concentration of 5-HIAA in urine and the degree of pulmonary hypertension, which can become a potential marker of pulmonary hypertension. The data obtained indicate the development of pulmonary hypertension in immature rats after a single injection of monocrotaline in the form of replacement of lung tissue with fibrous tissue, the development of pneumosclerosis and bronchiectasis. Also, in animals in this model, changes in the structure of the heart muscle and vascular wall are formed with the development of fibrous tissue, which may indicate the involvement of 5HT2-receptors in the activation of fibroblasts and, accordingly, in the pathogenesis of pulmonary hypertension.

Antidepressant-like Effects of Intra-cerebroventricular Microinjection of Kaempferol in Male Rats: Involvement of 5-HT2 Receptors

Background and Objective: Kaempferol (KM) is a flavonoid found in plant-derived foods and medicinal plants. Recently, it has been well established that KM plays a protective role against the development of Alzheimer's disease. This study evaluated the effect of intracerebroventricular microinjection of KM on depression and identified the potentially related serotonergic mechanisms in rats. Materials and Methods: Male rats were assigned to control, vehicle (dimethyl sulfoxide), KM, fluoxetine, cyproheptadine, KM (20 mg/rat) + cyproheptadine (1 mg/rat), and KM (20 mg/rat) + cyproheptadine (4 mg/rat) groups. All the groups received their respective treatments for 30 days. Depression was evaluated by both forced swimming and tail suspension tests. Monoamine oxidase-A (MAO-A), as a neurochemical parameter, was also evaluated in the liver and brain of animals. Results: Treatment with KM significantly decreased immobility time in both forced swimming and tail suspension tests, compared to the vehicle. In the forced swimming test, remarkable effects in immobility time were induced by KM + cyproheptadine after a single dose during weeks 2, 3, and 4 of treatment, compared to the cyproheptadine group. In the tail suspension test, both fluoxetine and KM indicated remarkable effects in the immobility time during weeks 3 and 4. In addition, in both the brain and liver, MAO-A activity was decreased after treatment with KM. Conclusions: These results indicated the antidepressant-like effects of KM through the involvement of 5HT2 receptors in male rats.

The effect of 5-HT4 serotonin receptors in the CA3 hippocampal region on D-AP5-induced anxiolytic-like effects: Isobolographic analyses

Increasing evidence shows the close relationship between hippocampal glutamatergic and serotonergic systems through the modulation of behavioral responses. This study aimed to investigate the possible involvement of 5-HT4 receptors in the CA3 hippocampal region in anxiolytic-like effects induced by D-AP5 (a competitive antagonist of the glutamate NMDA [N-Methyl-D-aspartate] receptor). Male Wistar rats were placed in the elevated plus maze (EPM) apparatus that is used to assess anxiety-related behaviors, and the percentages of open arm time (%OAT) and open arm entries (%OAE) which are associated with anxiety-related behaviors were measured. The close arm entries (CAE) which is correlated with locomotor activity was also evaluated. The results showed that, intra-CA3 injection of D-AP5 (0.4 μg/rat), RS67333 (1.2 μg/rat; a 5-HT4 receptor agonist), and RS23597-190 (1.2 μg/rat; a 5-HT4 receptor antagonist) increased %OAT and %OAE, indicating the anxiolytic-like effect of these drugs. Also, only RS23597-190 (1.2 μg/rat) decreased CAE. Intra-CA3 injection of sub-threshold dose of RS67333 (0.012 μg/rat) or RS23597-190 (0.012 μg/rat), 5 min before the injection of D-AP5 (0.2 μg/rat) increased %OAT, indicating potentiating the anxiolytic-like effect of D-AP5. The isobolographic analyses also showed the additive or synergistic anxiolytic-like effect of intra-CA3 co-administration of D-AP5 with RS67333 or RS23597-190, respectively. In conclusion, CA3 5-HT4 receptors are involved in D-AP5-induced anxiolytic-like behaviors in rats.

Contractile effects of 3,4-methylenedioxymethamphetamine on the human internal mammary artery

Since the late 1980s numerous reports have detailed adverse reactions to the use of 3,4-methylenedioxymethamphetamine (MDMA) associated with cardiovascular collapse and sudden death, following ventricular tachycardia and hypertension. For a better understanding of the effects of MDMA on the cardiovascular system, it is critical to determine their effects at the vasculature level, including the transporter or neurotransmitter systems that are most affected at the whole range of drug doses. With this purpose in mind, the aim of our study was to evaluate the contractile effect of MDMA in the human internal mammary artery, the contribution of SERT for this effect and the responsiveness of this artery to 5-HT in the presence of MDMA. We have also studied the possible involvement of 5-HT2 receptors on the MDMA contractile effect in this human blood vessel using ketanserin. Our results showed that MDMA contracted the studied human's internal mammary artery in a SERT-independent form, through activation of 5-HT2A receptors. Considering the high plasma concentrations achieved in heavy users or in situations of acute exposure to drugs, this effect is probably involved in the cardiovascular risk profile of this psychostimulant, especially in subjects with pre-existing cardiovascular disease.

5-HT2 receptors mediate functional modulation of GABAa receptors and inhibitory synaptic transmissions in human iPS-derived neurons

Neural progenitors differentiated from induced pluripotent stem cells (iPS) hold potentials for treating neurological diseases. Serotonin has potent effects on neuronal functions through multiple receptors, underlying a variety of neural disorders. Glutamate and GABA receptors have been proven functional in neurons differentiated from iPS, however, little is known about 5-HT receptor-mediated modulation in such neuronal networks. In the present study, human iPS were differentiated into cells possessing featured physiological properties of cortical neurons. Whole-cell patch-clamp recording was used to examine the involvement of 5-HT2 receptors in functional modulation of GABAergic synaptic transmission. We found that serotonin and DOI (a selective agonist of 5-HT2A/C receptor) reversibly reduced GABA-activated currents, and this 5-HT2A/C receptor mediated inhibition required G protein, PLC, PKC, and Ca2+ signaling. Serotonin increased the frequency of miniature inhibitory postsynaptic currents (mIPSCs), which could be mimicked by α-methylserotonin, a 5-HT2 receptor agonist. In contrast, DOI reduced both frequency and amplitude of mIPSCs. These findings suggested that in iPS-derived human neurons serotonin postsynaptically reduced GABAa receptor function through 5-HT2A/C receptors, but presynaptically other 5-HT2 receptors counteracted the action of 5-HT2A/C receptors. Functional expression of serotonin receptors in human iPS-derived neurons provides a pre-requisite for their normal behaviors after grafting.

The role of serotonergic system in cardiovascular diseases development in children

The role of the serotonin system as a link in the pathogenesis of atherosclerosis and arterial hypertension is widely discussed during the recent decades. Serotonin and histamine are part of humoral system of physiological processes regulators and modulators which under pathological conditions are transformed into factors contributing to the disease development. The membrane serotonin transporter has been identified on neurons, platelets, myocardium and smooth muscle cells. The higher is the activity of membrane transporter, the higher is the platelet serotonin concentration, its release into the blood plasma increases thus implementing its negative effects on platelets and wall of the vessels. 5-HT1A, 5-HT2 and 5-HT3 receptor subtypes play a key role in the central mechanisms of regulation of cardiovascular activities while peripheral effects of serotonin on the vascular system are mediated by 5-HT1, 5-HT2, 5-HT3, 5-HT4 and 5-HT7 receptor subtypes. Activation of 5-HT1A receptors causes inhibition of central sympathetic influences and further bradycardia, while 5-HT2 receptors activation - arousal of the sympathetic division, blood pressure elevation, and tachycardia. With the development of anaerobic processes serotonin via 5-HT2 receptors triggers apoptosis of cardiomyocytes leading to the development and progression of heart failure. Participation of 5HT2B receptors in the regulation of heart development during embryogenesis was shown on the mutant mice: cardiomyopathy with ventricular mass loss due to reduction of cardiomyocytes number and size was revealed. The involvement of 5-HT4 receptors in the development of sinus tachycardia and atrial fibrillation; in turn, the use of 5-HT4 receptor antagonists proved to be effective in the treatment of this kind of arrhythmias. Therefore, the study of the serotonergic system role in the development of cardiovascular diseases will allow to open new links in the pathogenesis of arterial hypertension in childhood.

Involvement of 5-HT2 receptors in the expression of withdrawal diarrhea in morphine-dependent mice

The withdrawal syndrome after the cessation of μ-opioid receptor agonists remains an obstacle in the clinical treatment of pain. We recently showed that peripheral opioid receptors play a significant role in the withdrawal signs in morphine-dependent mice. Therefore, the present study was designed to investigate the underlying mechanism of morphine-induced withdrawal symptoms, especially the peripheral oriented body-weight loss that accompanied diarrhea, in mice. Withdrawal signs were precipitated by the injection of naloxone 1 day after the slow-release emulsion administration of morphine. Withdrawal body-weight loss and diarrhea precipitated by naloxone in morphine-dependent mice were significantly suppressed by ritanserin (a 5-HT2 receptor antagonist), olanzapine (5-HT2/D2 receptor antagonist) and fullerene (a free radical scavenger), whereas neither ondansetron (a 5-HT3 receptor antagonist) nor atropine (a muscarine receptor antagonist) significantly suppressed naloxone-precipitated diarrhea. 5-HT3-receptors (but not 5-HT2-receptors) are known to play a significant role in 5-HT-induced diarrhea. Therefore, we also examined the effects of ritanserin and fullerene on 5-HT-induced diarrhea in morphine-dependent mice. Ritaserin significantly suppressed 5-HT-induced diarrhea in morphine-dependent mice, but not saline-treated mice. These results suggest that peripheral 5-HT2-receptor function could be altered in morphine-dependent mice, and the blockade of 5-HT2 receptor or free radical scavengers may be useful for the treatment of opioid-withdrawal diarrhea.

Effects of acute systemic administration of serotonin2A/C receptor ligands in a delay-based decision-making task in rats

Serotonin (5-hydoxytryptamine; 5-HT) has been implicated in the regulation of impulsivity, and high levels of impulsive behavior are associated with certain neuropsychiatric disorders. An important aspect of impulsive behavior is the inability to tolerate delays in reward. This study investigated the effects of the 5-HT(2A/C) receptor agonist DOI [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropan hydrochloride] and the 5-HT(2A) receptor antagonist ketanserin on impulsive behavior measured in a delay-based decision-making task. Male Wistar rats were trained in a T-maze to choose a large but 10-s delayed food reward instead of a small immediate reward. After stable baseline performance (70% choice of large reward), the effects of acute systemic administration of 5-HT(2A/C) receptor ligands on waiting capacity were tested. Systemic administration of DOI (0.1, 0.3, and 0.5 mg/kg) impaired waiting capacity in a dose-dependent manner, whereas ketanserin had no effect. When combined with ketanserin, DOI did not impair waiting capacity. The data indicate that DOI-induced impairment of the ability to discount a delay in reward in a T-maze is probably regulated by 5-HT(2A) receptors. Furthermore, this study extends the existing findings of 5-HT2 receptor involvement in different tasks of delay aversion in rodents.

Quantitative mRNA analysis of serotonin 5-HT4 receptor isoforms, calcium handling proteins and ion channels in human atrial fibrillation

Serotonin 5-HT4 receptors are present in human atrial myocytes and have been proposed to contribute to the generation of atrial fibrillation (AF). Here, we quantified 5-HT4 receptors as well as other key genes involved in cardiac rhythm and contraction in right atrial appendages of patients with chronic AF (CAF) and acute AF (AAF). Right atrial appendages were obtained from eleven patients in sinus rhythm (SR), five with AAF and six with CAF (>12 months). TaqMan real time quantitative RT-PCR was performed on total RNA. Results were normalised to the average of three housekeeping genes, cyclophilin, GADPH and RL-19. The rank order of expression of h5-HT4 receptors variants was (b)>(a)>(g)>(c) in the group of patients in SR. In AAF, we found a strong decrease in h5-HT4(b), h5-HT4(c), and h5-HT4(g) transcripts. In CAF patients, the mRNA expression level of the h5-HT4(b) isoform significantly increased two fold versus SR. A similar increase was reported for β1-adrenergic receptor, connexin 43 and the L-type Ca2+ channel CaCNA1C subunit. Interestingly, CAF was associated with a strong increase in the expression of Na+/Ca2+ exchanger and the voltage-dependent Na+ channel SCN5A subunit. Our results indicate that h5-HT4(b) is the dominant cardiac isoform of human 5-HT4 receptors and its expression is increased in CAF. These data support the involvement of 5-HT4 receptors in atrial arrhythmia.

New Insights into Serotonin 5-HT4 Receptors : A Novel Therapeutic Target for Alzheimers Disease?

The serotonin 5-HT4 receptor mediates many physiological effects in the central nervous system. The recent molecular identification of 5-HT4 receptors and the development of selective 5-HT4 receptor ligands have led to many important new insights into the signalling pathways and the physiological roles of these G protein-coupled-receptors in neurones. With respect to neurodegenerative disorders, it is suggested that 5-HT4 agonists may represent a new avenue for the treatment of Alzheimer's disease. This mini-review will focus on recent in vitro and in vivo pharmacological and biochemical studies showing the involvement of 5-HT4 receptors in cognitive processes and the amyloid precursor protein processing. The potential use of 5-HT4 agonists for the treatment of AD will be discussed.

S.25.01 Psychotropic drugs in the prevention of suicide

Superfusion of hemisected lumbar spinal cord of the neonatal rat with solutions containing 10−6 to 10−3 M 5-hydroxytryptamine (5-HT) elicited depolarizations of graded amplitude which were recorded from motorneurones through a ventral root. Maximum responses (amplitude 1.0 ± 0.1 mV, mean ± SEM, n = 30) were evoked by 10−4 M 5-HT. Repeated concentration-response curves could be determined from the same preparation.There was no involvement of 5-HT2 receptors in the depolarizing response to 5-HT, since neither ritanserin nor ICI 169, 369 showed any antagonist action.Amongst agents with activity at 5-HT1A sites, the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), neither mimicked the action of 5-HT nor antagonised it, while spiperone (10−8-10−7 M) antagonised responses to 5-HT in a concentration-related manner. Responses to 10−4 M noradrenaline, used as a control depolarizing agent, were unaffected by spiperone. The onset of blockade by spiperone was slow, 1 hr being required for equilibration of the tissue with antagonist. The blockade was surmountable by larger concentrations of 5-HT. Concentration-response curves to 5-HT were shifted to the right in an approximately parallel manner by spiperone. The dose ratios measured from these curves at the EC50 level, yielded an apparent pA2 of 8.24 ±0.14 (mean ± SEM, n = 15), although the Schild plot of the data had a slope less than unity.The lack of activity of the selective 5-HT1B receptor agonist, RU 24969, and the 5-HT1B receptor antagonists, (±) cyanopindolol and quipazine, indicated that 5-HT1B receptors were not involved in the 5-HT response of motorneurones to 5-HT.Mesulergine, metergoline and cyproheptadine also antagonised responses of motorneurones to 5-HT, producing a surmountable blockade. Mesulergine (10−8, 3 × 10−8 and 10−7 M) caused a progressive rightward shift of the concentration-response curves, but 10−7 M depressed the maximum response to 5-HT. Responses to noradrenaline were not affected by these concentrations of mesulergine. The apparent pA2 for blockade of 5-HT responses by mesulergine, calculated from experiments in which there was a parallel displacement of the concentration-response curves, was 8.75 ± 0.11 (mean ± SEM, n = 10). Metergoline (10−7 M) produced a modest degree of antagonism, the apparent pA2 being 7.2 ± 0.2(mean ± SEM, n = 6). Cyproheptadine (10−9 and 10−8 M) induced rightward, parallel shifts of the concentration-response curves to 5-HT and the apparent pA2 was 8.88 ± 0.24 (mean ± SEM, n = 10). Responses to noradrenaline were unaffected by these concentrations of cyproheptadine.The pharmacological profile of the 5-HT receptor of the motorneurone from this and previous results (Connell and Wallis, 1988) is, thus: (a) 5-HT, α-Me-5-HT, 5-carboxamidotryptamine (5-CT) and 5-methoxytryptamine (5-MeOT) were full agonists, the order of agonist potency being 5-HT > α-Me-5-HT > 5-CT > 5-MeOT ⪢ tryptamine. The compounds 8-OH-DPAT, RU 24969 and 2-Me-5-HT were inactive as agonists, (b) Methysergide, spiperone, mesulergine, cyproheptadine and metergoline were antagonists active at nM concentrations. Ketanserin was a weak antagonist, while ritanserin, methiothepin, (±) cyanopindolol, MDL 72222, ICS 205-930, quipazine, ICI 169, 369, yohimbine, 8-OH-DPAT and RU 24969 were without antagonist activity.This profile cannot be equated with the CNS 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D or 5-HT2 binding sites, nor with 5-HT3 receptors. It is also distinguishable from a number of other functional 5-HT, -like receptors which do not conform to an identified 5-HT binding site.

560 Differential activation of natriuretic peptides in human heart failure and relationship to cardiac function: evidence for peptide deficiency

Contraction-relaxation cycle characteristics and sensitivity to cholinergic stimulation suggest involvement of the Gs-adenylyl cyclase-pathway. The concentration response curves to 5-HT were shifted to higher concentrations by 0.5 nM of the 5-HT4 selective antagonist GR113808, with pEC50-values of 7.62 ± 0.06 (SEM, n = 6) and 7.32 ± 0.06 (SEM, n = 6, p < 0.005), respectively, and the derived pKb value of 9.5 for GR113808 documents involvement of 5-HT4 receptors. Quantitative RT-PCR revealed a 4-fold increase of 5-HT4(b) mRNA expression in ventricles from CHF rat hearts compared to SHAM rat hearts.

The involvement of 5-HT3 and 5-HT4 receptors in anticancer drug-induced emesis

—Emesis caused by cytotoxic drugs is associated with an increase in the concentration of serotonin (5-hydroxytryptamine: 5-HT) in the intestine and the brainstem. 5-HT receptors in the central nervous system (CNS) and the gut participate in the induction of emesis. 5-HT1 receptors are negatively coupled to adenylate cyclase, but the 5-HT2C subtype is linked to phospholipase (PL) C activation. The 5-HT4 receptor, by contrast, is positively coupled to adenylate cyclase. 5-HT1A and 5-HT2A /5-HT2C agonists exhibit antiemetic properties. The 5-HT1D agonist reduces the emesis accompanying migraine headaches. Through use of 5-HT3 receptor antagonists, which selectively antagonize 5-HT3 receptors on the abdominal vagal afferent fibers, as much as 60% of the initial emetic response can be prevented. Inhibition of acute emesis also appears to be attained by blocking the initiation of the emetic reflex induced via 5-HT3 receptors by 5-HT released from enterochromaffin (EC) cells in the small intestine. Although 5-HT4 receptor antagonists have an antiemetic activity in some experimental models, the precise role of 5-HT4 receptors has not been fully elucidated. The present review aims to compare the involvement of 5-HT4 receptors with that of the 5-HT3 receptors in anticancer drug-induced emesis.

Serotonin type-4 receptors modulate the sensitivity of intramural mechanoreceptive afferents of the cat rectum.

It has been suggested that serotonin (5-hydroxytryptamine) type-4 (5-HT4) receptors modulate the sensitivity of intrinsic afferents of the intestinal mucosa. We studied the involvement of 5-HT4receptors in the modulation of extrinsic afferent sensitivity of the intestinal wall. During distension ramps, mechanoreceptive rectal afferents in sacral dorsal roots were examined in decerebrate anaesthesia-free cats using the selective 5-HT4receptor partial agonist, tegaserod (HTF 919), and the 5-HT4receptor antagonist, SB 203186. The static discharge rate of the afferents evoked by rectal distension decreased after intravenous (i.v.) administration of tegaserod at intraluminal pressures above 30 mmHg, with the most effective reduction occurring at 50 mmHg. The effect was dose-dependent, with maximal reduction occurring at 1.2 mg kg-1 bodyweight, and could be partly reversed by i.v. administration of SB 203186. Tegaserod did not alter the pressure-volume relationship (compliance) of the rectum. It is tentatively concluded that 5-HT4receptor activation has an inhibitory effect on intramural mechanoreceptors in the cat's rectum. Our results are in line with the observation that tegaserod relieves the sensory symptoms of patients suffering from irritable bowel syndrome.

Role of Central 5-HT2 Receptors in Fluoxetine-Induced Decreases in T Lymphocyte Activity

Previous studies have demonstrated that fluoxetine administration decreases mitogen-induced T lymphocyte proliferation. The present studies were carried out to determine which receptor subtype(s) was involved and whether these effects on lymphocyte responses were centrally or peripherally mediated. Two hours following administration of the 5-HT1A agonist 8-OH-DPAT (1 mg/kg), there was no change in lymphocyte proliferation responses, whereas the 5-HT2 agonist DOI (2.5 mg/kg) significantly decreased (80%) proliferation. Similarly, pretreatment with the 5-HT2 antagonists ritanserin (5 mg/kg, 30 min) or ketanserin (5 mg/kg, 1 h) was found to completely antagonize the effects of fluoxetine on lymphocyte proliferation. Consistent with central 5-HT2 receptor involvement, microinjection of DOI (50 μg) resulted in a decrease in lymphocyte proliferation similar to that observed following systemic administration. Furthermore, central administration of ketanserin (20 μg) prevented the suppressive effects of systemic fluoxetine. Collectively, these results suggest that decreases in mitogen-induced lymphocyte proliferation following acute fluoxetine administration was due to indirect effects of fluoxetine following the activation of central 5-HT2 receptors.

Possible Involvement of 5-HT4 Receptors, in Addition to 5-HT3 Receptors, in the Emesis Induced by High-Dose Cisplatin in Suncus murinus

To clarify the mechanism for the severe emesis concomitant with intensive chemotherapy, we investigated the effects of 5-HT3- and 5-HT4-receptor antagonists on the emesis induced by the high-dose of cisplatin in Suncus murinus. The emesis induced by 50 mg /kg of cisplatin was reduced by the oral pretreat-ment with tropisetron, which is known as a 5-HT3- and 5-HT4-receptor dual antagonist in vitro, with the ID50 value of 0.52 mg /kg. On the contrary, granisetron, a selective 5-HT3-receptor antagonist, did not markedly inhibit the emesis at up to 30 mg /kg. Moreover, GR125487, a selective 5-HT4-receptor antagonist, did not inhibit the emesis. However, co-administration of GR125487 and granisetron significantly reduced the number of emetic episodes. The study of the co-administration of GR125487 with tropisetron showed that GR125487 did not further enhance the inhibitory effect of tropisetron alone, suggesting that the anti-emetic effect of tropisetron is mediated via the blockade of both 5-HT3 and 5-HT4 receptors. These results suggest that both the 5-HT3 and 5-HT4 receptors are involved in the emesis induced by the high-dose of cisplatin in Suncus murinus.

Prucalopride stimulates 5-HT4 receptors on cholinergic nerves of human colonic longitudinal muscle resulting in contraction

Introduction: The mechanisms underlying the colokinetic actions of the selective 5HT4 receptor agonist prucalopride (R093877) are not fully known. Although in vitro studies demonstrated relaxatory smooth muscle 5-HT4 receptors on the circular muscle, involvement of 5HT4 receptors on the longitudinal muscle (LM) has not yet been demonstrated. We aimed to characterise the effects of prucalopride on electrically stimulated human colon LM in vitro. Methods: Human colonic longitudinal muscle strips (mucosa and mesentery removed) were placed in an organ bath set-up (at 37°C, bubbled with carbogen and filled with LNNA (O.lmM)-enriched Krebs-Henseleit solution) for isotonic measurement (2 g). After stabilisation (30min), electrical field stimulation (EFS; lOs pulse trains at Ims width each 3 min at 12Hz and submaximal voltage) was applied, resulting in contractions. After obtaining reproducible contractions upon EFS for 15min (i.e 5 pulses), solvent, GR1l3808 (O.I/LM), atropine (11J-M) or tetrodotoxin (O.3/LM) was added followed by a 15-min incubation period. Then, prucalopride (O.3/LM) was added and the EFS-induced contractions were followed for another 15 min. Results were expressed as percentage of the average EFS-induced contraction before addition of antagonist. Results: Atropine (l/LM) and tetrodotoxin (O.3/LM) almost completely inhibited the EFS-induced response, but GR113808 (O.l/LM) left them unaffected. Prucalopride (O.3/LM) enhanced the EFS-induced contractions by 33 ~ 5.7% (P < 0.05, Student s t-test), but did not affect them after atropine-, tetrodotoxinor GR1l3808-pre-treatment. Conclusions: On the cholinergic nerves of human colon LM, prucalopride stimulates 5HT4 receptors facilitating release of acetylcholine, resulting in contraction. This suggests that 5HT4 receptor-mediated propulsion is due to circular muscle relaxation (previous studies) and longitudinal muscle contraction (present study).

P-8 - Involvement of 5-HT2 receptors in hyperglycemic effects of imipramine

P-8 - Involvement of 5-HT2 receptors in hyperglycemic effects of imipramine

P–347 - Involvement of 5-HT4 receptors in regulation of defecation.

P–347 - Involvement of 5-HT4 receptors in regulation of defecation.

BIMU1 Increases Associative Memory in Rats by Activating 5-HT4 Receptors

Olfactory association learning was used to investigate the involvement of 5-HT4 receptors in learning and long-term memory. The behavioral role of the 5-HT4 receptors was studied by using BIMU1 (3-ethyl-2,3-dihydro-N-[endo-8-methyl-8-azabicyclo(3.2.1)oct-3-yl]-2-oxo-1H-benzimidazole-1-carboxamide, hydrochloride (Boehringer Ingelheim, Italy); a mixed 5-HT4 agonist/5-HT3 antagonist, and GR125487 (1-[2-[methyl sulphonyl)-amino]ethyl]-4-piperidinyl-methyl 5-fluoro-2-methoxy-1H-indole-3-carboxylate; Glaxo Group Research, Hertfordshire, U.K.), a specific 5-HT4 antagonist. The intraperitoneal injections of BIMU1 at 1, 5, and 10 mg/kg were followed by an substantial improvement (>15% in percentage of correct responses at the dose of 10 mg/kg) in associative memory. Difficulty rapidly reversing behavioral responses to previously learned association, 1 month later indicated that the BIMU1 effect at 10 mg/kg was not transient, but correlated to long-term memory. The effects of BIMU1 are most likely to be mediated by 5-HT4 receptors since they were blocked by GR125487 at 10 mg/kg. These data suggest that activation of 5-HT4 receptors may modulate cognitive processes like learning and memory. © 1997 Elsevier Science Ltd.