Role Of 5-HT3 Receptors Research Articles

The effects of 5-HT receptor blockade and stimulation, during six hours of atrial fibrillation

Stimulation of atrial 5-HT4 receptors is associated with arrhythmias. Their blockade prolongs atrial effective refractory period (ERP), following short runs of atrial fibrillation (AF). The role of 5-HT4 receptors during longer periods of AF is unknown. In this study, we investigated the effects of the selective 5-HT4 receptor stimulation and blockade on porcine atria, during 6 h of AF. Atrial ERP, monophasic action potential (MAP) duration, time to sinus rhythm restoration (TSRR) and ERP/MAP ratio were assessed in 27 pigs, at baseline and every hour, during 6 h of AF, induced by rapid atrial pacing. Ten animals were used as controls, 10 were administered the selective 5-HT4 antagonist SB203186 and seven were administered the selective 5-HT4 agonist RS67333. During the first few hours of fibrillation, ERP, MAP and TSRR were preserved in SB203186-treated pigs, while they were shortened in controls and RS67333-treated animals. After 6 h of arrhythmia, ERP and MAP were shortened in all three groups, but the decrease was less in SB203186-treated pigs. ERP/MAP ratio increased in controls and RS67333-treated animals, while it remained unchanged in SB203186-treated pigs. Towards the end of the AF period, four of the SB203186-treated pigs developed sustained atrial tachycardia. Following short periods of AF, 5-HT4 receptors' blockade protects the porcine atria against ERP and MAP shortening, while their stimulation has the opposite result. This beneficial effect, though, is gradually diminished following longer periods of AF and atrial tachycardia may develop.

Activation of 5-HT2 receptors enhances the release of acetylcholine in the prefrontal cortex and hippocampus of the rat.

The role of 5-HT2 receptors in the regulation of acetylcholine (ACh) release was examined in the medial prefrontal cortex and dorsal hippocampus using in vivo microdialysis. The 5-HT(2A/2C) agonist +/-1-(2,5-dimethoxy-4-iodophenyl) -2- aminopropane hydrochloride (DOI) (1 and 2 mg/kg, i.p.) significantly increased the extracellular concentration of ACh in both brain regions, and this response was attenuated in rats treated with the 5-HT(2A/2B/2C) antagonist LY-53,857 (3 mg/kg, i.p.). Treatment with LY-53,857 alone did not significantly alter ACh release in either brain region The 5-HT(2C) agonist 6-chloro-2-(1-piperazinyl)-pyrazine) (MK-212) (5 mg/kg, i.p.) significantly enhanced the release of ACh in both the prefrontal cortex and hippocampus, whereas the 5-HT2 agonist mescaline (10 mg/kg, i.p.) produced a 2-fold increase in ACh release only in the prefrontal cortex. Intracortical, but not intrahippocampal, infusion of DOI (100 microM) significantly enhanced the release of ACh, and intracortical infusion of LY-53,857 (100 microM) significantly attenuated this response. These results suggest that the release of ACh in the prefrontal cortex and hippocampus is influenced by 5-HT2 receptor mechanisms. The increase in release of ACh induced by DOI in the prefrontal cortex, but not in the hippocampus, appears to be due to 5-HT2 receptor mechanisms localized within this brain region. Furthermore, it appears that the prefrontal cortex is more sensitive than the dorsal hippocampus to the stimulatory effect of 5-HT2 agonists on ACh release.

Gastric distension-induced release of 5-HT stimulates c-fos expression in specific brain nuclei via 5-HT3 receptors in conscious rats.

We examined c-fos expression in specific brain nuclei in response to gastric distension and investigated whether 5-HT released from enterochromaffin (EC) cells was involved in this response. The role of 5-HT3 receptors in this mechanism was also addressed. Release of 5-HT was examined in an ex vivo-perfused stomach model, whereas c-fos expression in brain nuclei induced by gastric distension was examined in a freely moving conscious rat model. Physiological levels of gastric distension stimulated the vascular release of 5-HT more than luminal release of 5-HT, and induced c-fos expression in the nucleus of the solitary tract (NTS), area postrema (AP), paraventricular nucleus (PVN), and supraoptic nucleus (SON). The c-fos expression in all these brain nuclei was blocked by truncal vagotomy as well as by perivagal capsaicin treatment, suggesting that vagal afferent pathways may mediate this response. Intravenous injection of 5-HT3 receptor antagonist granisetron blocked c-fos expression in all brain nuclei examined, although intracerebroventricular injection of granisetron had no effect, suggesting that 5-HT released from the stomach may activate 5-HT3 receptors located in the peripheral vagal afferent nerve terminals and then induce brain c-fos expression. c-fos Positive cells in the NTS were labeled with retrograde tracer fluorogold injected in the PVN, suggesting that neurons in the NTS activated by gastric distension project axons to the PVN. The present results suggest that gastric distension stimulates 5-HT release from the EC cells and the released 5-HT may activate 5-HT3 receptors located on the vagal afferent nerve terminals in the gastric wall leading to neuron activation in the NTS and AP and subsequent activation of neurons in the PVN and SON.

Role of 5-HT3 receptors in the mechanisms of central pain syndrome.

Electrophysiological and behavioral studies showed that spinal 5-HT3 receptors are involved in the regulation of pain sensitivity in rats. Intrathecal administration of the 5-HT3 receptor antagonist tropine (200 microg) produced allodynia, reduced the threshold, decreased the latency, and increased the number of spikes in the late component of the nociceptive flexion reflex. Intrathecal administration of 5-HT3 receptor agonist quipazine (200 mg) abolished nociceptive flexion reflex and alleviated spinal pain syndrome produced by impairment of GABAergic inhibition in the lumbar spinal segments. Our results indicate that spinal 5-HT3 receptors are involved in the modulation of pain sensitivity: activation of these receptors inhibits nociceptive reactions, while blockade of 5-HT3 receptors potentiates the nociceptive response via modulation of excitability of GABAergic interneurons.

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.

Role of 5-HT6 receptors in memory formation.

Mice lacking the 5-HT(6) receptor presented neither gross anatomical or behavioral abnormalities nor obvious changes in microscopic brain morphology, and their performance in rotarod, open field and novel object testing paradigms revealed no differences compared with wild-type animals. Nevertheless, an association between the 5-HT(6) receptor polymorphism C267T and Alzheimer's disease has been reported. Interestingly, the 5-HT(6) antisense oligonucleotide decreased 5-HT(6) gene expression and enhanced spatial learning acquisition in the water maze. Similarly, injection of the 5-HT(6) receptor antagonist Ro-04-6790 improved learning consolidation in an autoshaping task, while mCPP, scopolamine and dizocilpine decreased performance. The effect induced by scopolamine or dizocilpine, but not that induced by mCPP, was completely or partially reversed by Ro-04-6790. Ro-04-6790 did not modify the 8-OH-DPAT facilitatory effects on learning consolidation. Since Ro-04-6790 facilitatory effect was unaffected by 5-HT(1A), 5-HT(2A/2B/2C), 5-HT(3), 5-HT(4) or 5-HT(7) receptor blockade, the facilitatory effect induced by Ro-04-6790 involved specifically 5-HT6 receptors. Similarly, the 5-HT(6) receptor antagonist SB-271046 improved retention in the water maze and produced a significant performance improvement in aged rats in an operant-delayed alternation task. A series of Ro-04-6790 analogues that penetrate the brain and specifically bind to 5-HT(6) receptors reversed scopolamine-induced retention deficit in a passive avoidance learning test. Collectively, these data provide further support to the notion that 5-HT systems, via 5-HT(6) receptors, also play a significant role in memory formation under normal and dysfunctional memory conditions.

Psychological and Physiological Effects of MDMA (“Ecstasy”) after Pretreatment with the 5-HT2 Antagonist Ketanserin in Healthy Humans

MDMA (3,4-methylenedioxymethamphetamine, “Ecstasy”) mainly releases serotonin and dopamine. In animals, pretreatment with 5-HT2 antagonists has been shown to attenuate neurochemical and behavioral effects of MDMA. In humans, the role of 5-HT2 receptors in the action of MDMA has not been studied. We investigated the effect of pretreatment with the 5-HT2A/C antagonist ketanserin (50 mg p.o.) on subjective responses to MDMA (1.5 mg/kg p.o.) in 14 healthy volunteers using a double-blind placebo-controlled within-subject design. Subjective effects were rated by psychometric rating scales. Physiological effects measured were blood pressure, heart rate, and body temperature. Adverse effects were assessed during the sessions, and after one and three days. Ketanserin attenuated MDMA-induced perceptual changes, emotional excitation, and acute adverse responses but had little effect on MDMA-induced positive mood, well-being, extroversion, and short-term sequelae. Body temperature was lower under MDMA plus ketanserin compared to MDMA alone. The results suggest a contributing role for 5-HT2 receptors in the action of MDMA in humans.

The role of 5-HT 2 receptors in experimentally induced anxiety

The role of 5-HT 2 receptors in experimentally induced anxiety

Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study.

Widespread disturbances of serotonin (5-HT) are implicated in the pathophysiology of depression. Of 5-HT receptor abnormalities reported, the most replicated finding is increased 5-HT2 receptor binding in the postmortem prefrontal cortex of depressed suicide victims. The extent to which these findings exist in depressed persons without recent suicide attempts is uncertain. The objective of this study was to evaluate 5-HT2 receptors in depressed patients who were medication-free and who had not made recent suicide attempts. With the use of [18F]setoperone and positron emission tomography (PET), 5-HT2 receptor binding potential was assessed in 14 depressed and 19 healthy subjects. Exclusion criteria for depressed patients included use of antidepressant medication within the past 6 months, a history of suicide attempts within the past 5 years, other current axis I disorders including bipolar disorder, and the presence of psychotic symptoms. The 5-HT2 (setoperone) binding potential in the two groups of subjects was compared by analysis of covariance with age as the covariate. Age had a significant effect on 5-HT2 binding potential, but depression did not. The interaction of age and depression was not significant. The 5-HT2 binding potential is not increased in untreated depressed subjects who have not made recent suicide attempts. This negative finding does not rule out the possibility that there is a role for 5-HT2 receptors in treatment or that 5-HT2 receptors are increased in highly suicidal states.

5-HT3 receptor over-expression enhances ethanol sensitivity in mice.

Ethanol sensitivity may play a role in the risk of developing alcoholism. The role of 5-HT3 receptors in sensitivity to ethanol was assessed in mice over-expressing the 5-HT3 receptor in the forebrain. Sleep time and ED50 for loss of righting reflex (LRR) were used to assess the effect of a high dose of ethanol in transgenic versus non-transgenic mice. The ED50 for ethanol-induced increase in open field activity was used to measure differences in sensitivity to low dose ethanol. The ED50 for ethanol-induced increase in activity was 41% lower in the 5-HT3 receptor over-expressing transgenic mice compared to non-transgenic mice. However, 5-HT3 receptor over-expressing mice did not differ from control mice in ethanol metabolism, ED50 for LRR, and ethanol sleep time. Over-expression of 5-HT3 receptors in mouse forebrain results in an enhanced sensitivity to the stimulating effects of a low dose of ethanol without altering ethanol sedating effects or ethanol metabolism. These data suggest that 5-HT3 receptors modulate low dose ethanol sensitivity and may explain why, in previous studies, these mice consume less ethanol.

Age-dependent effect of ketanserin on the sleep-waking phases in rats

The age-dependent effect of the specific 5-HT2 receptor antagonist ketanserin at two doses (1 mg/kg and 6 rag/kg) on six sleep-waking phases was electroencephalographically (EEG) examined in young, middle-aged, and old male Wistar rats. Because 5-HT2 receptor binding sites decrease with aging, the question of whether ketanserin can produce any effect on sleep-wake in advanced age was Addressed. Ketanserin enhanced deep slow wave sleep in the three age groups. However, in the old rats this effect was much less pronounced and did not depend on the dose. Only in the young and middle-aged animals, ketanserin reduced wakefulness in a dose-dependent manner. The suppression of paradoxical sleep with ketanserin did not depend on the age. The results suggest that the model of aging may be useful to study the functional role of 5-HT2 receptors in sleep-waking regulation.

Differential effects of ondansetron and α-flupenthixol on responding for conditioned reward

Previous experiments have suggested that 5-HT3 antagonists such as ondansetron may alter reward-related behaviour that is dependent in part upon raised mesolimbic dopamine activity. However, the evidence for this is far from conclusive. One major behavioural role of dopamine is in the control of behaviour elicited by conditioned rewarding stimuli. To date, the effects of 5-HT3 antagonists on this function of mesolimbic dopamine have not been examined. Two experimental procedures were employed to examine the effects of ondansetron (10 and 100 micrograms/kg) on the acquisition of responding for conditioned reward, and on the response potentiating effect of intra-accumbens d-amphetamine (10 micrograms). These effects were compared to those elicited by the dopamine antagonist alpha-flupenthixol (0.1 mg/kg). In the first procedure, rats were trained to associate food pellet delivery with a conditioned stimulus (CS). Rats subsequently allowed to respond on a lever delivering this CS, and on an inactive lever, showed a greater preference for the lever delivering the CS, indicating that this CS functioned as a conditioned reward (CR). Ondansetron administered during the conditioning phase did not alter subsequent responding for the CR, but alpha-flupenthixol induced a small but significant reduction in responding on the CR lever. These results suggest that blockade of dopamine receptors, but not 5-HT3 receptors interfere with the learning of stimulus reward relationships. In the second procedure, d-amphetamine injected into the nucleus accumbens markedly potentiated responding for CR. Ondansetron at 10 micrograms/kg induced a small attenuation of this effect, without altering responding in its own right. However, at a higher dose (100 micrograms/kg) ondansetron plus amphetamine treatment significantly enhanced responding on the inactive lever. At both doses, the net effect of ondansetron was to produce a subtle impairment in the allocation of responses such that the differential responding on the CR versus NCR lever was diminished. In contrast to these effects alpha-flupenthixol significantly attenuated d-amphetamine's selective enhancement of responding for conditioned reward, as well as impairing the ability of the conditioned reward to elicit and maintain behaviour. These results confirm the role of dopamine in responding for conditioned reward, and suggest a possible modulators role for 5-HT3 receptors in this process. However, the effects of ondansetron on the acquisition of, and responding for, conditioned reward are clearly different from those induced by blockade of dopamine receptors.

Cardiovascular effects of microinjection of low doses of serotonin into the NTS of unanesthetized rats

In the present study, we analyzed in conscious rats the effects of microinjections of serotonin (5-HT; pmol range) into the nucleus of the solitary tract (NTS) on basal mean arterial pressure (MAP) and heart rate (HR) and also on the reflex bradycardia induced by the activation of the baro- and chemoreflex evaluated 1 min after 5-HT microinjection into the NTS. The data show that unilateral microinjection of 5-HT in the picomolar range into the NTS of unanesthetized rats produced a dose-dependent decrease in MAP and HR, which was blocked by previous microinjection of ketanserin (250 pmol/50 nl) into the NTS. The changes in MAP and HR induced by 5-HT were of very short duration, with a return to baseline values a few seconds later. The cardiovascular responses to baro- or chemoreflex activation 1 min after 5-HT microinjection into the NTS did not differ from the control, indicating that low doses of 5-HT produced no effect on the cardiovascular reflexes tested at that time. The present data show that, as also observed in anesthetized rats, the microinjection of picomolar doses of 5-HT into the NTS elicits the typical cardiovascular responses to baroreceptor activation. These effects, hypotension and bradycardia, seem to be mediated by 5-HT2 receptors because both were blocked by a selective 5-HT2 receptor antagonist. However, since microinjection of 5-HT (1 pmol) into the NTS produced no changes in the cardiovascular responses to the baro- and chemoreflex activated 1 min later, the role of 5-HT2 receptors in the processing of the cardiovascular afferent messages in the NTS remains to be elucidated.

5-HT4 receptors are not involved in the control of small intestinal transit in the fasted conscious rat.

Cisapride and metoclopramide are used clinically in the treatment of gastro-oesophageal reflux disease and also in a variety of motility disorders of the gastrointestinal tract. Their prokinetic effect is thought to be due to the augmentation of acetylcholine release from the myenteric plexus, an effect likely to be mediated through the stimulation of 5-HT4 receptors. The role of 5-HT4 receptors in the control of intestinal motility in man and animals is not clear, therefore we have investigated their role in the control of small intestinal transit in the rat. Radioactive microspheres were administered into the proximal duodenum of fasted conscious rats through an indwelling cannula. The extent of small intestinal transit was examined by determining the distribution of the microspheres within the intestine. Following i.p. injection small intestinal transit was inhibited (78%) by atropine (3 mg/kg), suggesting the presence of a basal cholinergic influence. Furthermore, in the presence of p-amino clonidine intestinal transit was stimulated (126%) by bethanechol (3 mg/kg). The 5-HT4 receptor agonists cisapride (1.0 mg/kg) and zacopride (1.0 mg/kg) failed to increase small intestinal transit. The 5-HT4 receptor selective antagonist GR125487 (1 mg/kg) was also without effect. These data suggest that 5-HT4 receptors are not involved in the control of small intestinal transit in the fasted conscious rat.

P-646 - The role of 5HT2 receptor In endothelium-dependent vasorelaxation

P-646 - The role of 5HT2 receptor In endothelium-dependent vasorelaxation

Temperature, food intake, and locomotor activity effects of a 5-HT3 receptor agonist and two 5-HT3 receptor antagonists in rats.

This study investigated three physiologic functions known to be modulated by serotonin-temperature, food intake and locomotor activity - using the 5-HT3 receptor agonist, m-chlorophenylbiguanide (m-CPBG), and two 5-HT3 antagonists, MDL-72222 and ondansetron. m-CPBG produced dose-dependent elevations in rectal temperature. MDL-72222, which had no effects on temperature when given alone, significantly attenuated m-CPBG-induced hyperthermia. Food intake in food-deprived rats was reduced during the first hour by the highest dose of m-CPBG. Food intake was also dose-dependently reduced by MDL-72222; m-CPBG plus MDL-72222 led to greater reductions in food intake. Food intake in freely fed rats was unaffected by m-CPBG or MDL-72222. Locomotor activity was unaffected by m-CPBG, but was dose-dependently reduced by MDL-72222, an effect which may have contributed to its hypophagic effects. Ondansetron, used in ten-fold lower doses than MDL-72222, was inactive in all of these paradigms. These data: (1) provide some evidence for 5-HT3 receptor-mediated changes in temperature; (2) are in agreement with two prior studies which reported locomotor activity reductions following 5-HT3 antagonists; but (3) do not support an important role for 5-HT3 receptors in the regulation of food intake in rats.

Embryonic Expression of the 5-HT3 Receptor Subunit, 5-HT3R-A, in the Rat: An in Situ Hybridization Study

The role of serotonin as a neurotransmitter in the vertebrate central and peripheral nervous systems has been extensively studied. In addition to its well-defined role in neurotransmission, serotonin has also been implicated in development. We have used in situ hybridization to localize 5-HT3 receptor mRNA in embryonic rat sections from Embryonic Day 10 (E10) to E18. Expression was first detected in the cranial sensory ganglia starting on E10. Expression was later detected in many regions within the developing CNS. In addition to the cranial sensory ganglia, expression was detected in many regions of the peripheral nervous system including dorsal root, sympathetic, and parasympathetic ganglia, and in the myenteric plexus of the enteric nervous system. Expression was also detected in many nonneuronal cell populations including the choroid plexus, co-chlear duct, and olfactory epithelium. Expression in regions of active epithelial-mesenchymal interaction such as the tooth bud, lung, and submandibular gland may indicate a role for 5-HT3 receptors in the process of secondary induction.

Role of 5-HT4 receptors in motility and secretion

Role of 5-HT4 receptors in motility and secretion

Mode of action of atypical neuroleptics in relation to the phencyclidine model of schizophrenia: role of 5-HT2 receptor and alpha 1-adrenoceptor antagonism [corrected

In experiments in rats, by the use of single-cell recordings from midbrain dopamine (DA) neurons of the ventral tegmental area (VTA), the systemic administration of the schizophrenomimetic N-methyl-D-aspartate receptor antagonists phencyclidine (PCP) or dizocilpine (MK-801) caused an increased firing rate but reduced the variability of firing in VTA DA neurons. Burst firing was increased in cells predominantly located in the paranigral nucleus, a subdivision of the VTA largely projecting to the nucleus accumbens and other limbic regions, but reduced in DA cells predominantly located in the parabrachial pigmented nucleus, another subdivision of the VTA that projects largely to the prefrontal cortex (PFC). Thus, a severely impaired signal-to-noise ratio within the PFC DA projection was obtained, concomitant with an overactive mesolimbic DA system. The administration of high doses of ritanserin or atypical neuroleptics with prominent serotonin (5-hydroxytrypyamine) 5-HT2 receptor antagonist action, such as clozapine or amperozide, produced preferential activation of the PFC DA projection. In contrast, the selective D2 receptor antagonist raclopride caused a greater activation of the subcortical than cortical DA projections, as assessed by microdialysis experiments in vivo from our laboratory. Adding ritanserin treatment to raclopride markedly enhanced the raclopride-induced increase in DA levels in the medial PFC, an effect probably mediated by augmentation of the raclopride-induced increase in the burst firing of meso-cortical DA neurons, but failed to affect the action of raclopride on striatal DA levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of 5-HT3 receptors and afferent fibers in the effects of mast cell degranulation on colonic motility in rats

Background/Aims: Mediators released by mast cell degranulation contribute to digestive motility disturbances. According to the role of serotonin and the close proximity of mast cells to nerves, the aim of this study was to assess the role of 5-hydroxytryptamine 3 (5-HT3) receptors, capsaicin-sensitive afferent fibers, and some of their neuropeptides (substance P and calcitonin gene-related peptide) in colonic motor alterations induced by degranulation of mast cells by the compound BrX-537A. Methods: The effects of BrX-537A (2 mg/kg intraperitoneally) were determined by electromyography in conscious rats implanted with electrodes in the cecocolonic wall. Results: BrX-537A inhibited cecocolonic myoelectric activity for 7–8 hours. A primary and dramatic reduction of spike burst frequency, lasting 30 minutes, was affected by none of the pretreatments tested. The following inhibition was fully antagonized by ketotifen (mast cell stabilizer), granisetron and ondansetron (5-HT3 antagonists), RP-67,580 (NK1 antagonist), and perivagal capsaicin pretreatment. A temporary blockade was observed after administration of CP-96,345 (NK1 antagonist) and in rats systemically treated by capsaicin. The calcitonin generelated peptide antagonist, hCGRP(8–37) did not modify the BrX-537A-induced inhibition. Conclusions: 5-HT3 receptors, sensory afferent fibers reaching the vagus nerves, and substance P are major components of the colonic motor inhibition induced by mast cell degranulation.