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Depression astonishingly can be stopped instantly by electrotherapies or through some psychedelics like psilocybin. In explaining this, the traditional approaches to their antidepressant effects via "reset" models and orthosteric serotonin receptors has neglected the only serotonin channel 5HT3, which e.g. has emerged as being helpful for the neurotrophic translation for all anti-depressants and final synaptic effects. Psychedelics here are confronted with a panorama of also anti-depressant 5HT3-channels and a search for their part e.g. in the "3 pillars" reigning depression. Of these M1) mitochondria, parasitic organelles from a fusion between some proto-bacteria and archae, founding eukaryotes, also through 5HT3 in depression determine much of its somatic crises. Two further pillars, "pushback" and "shame-link", are clarified by the parasympathetic (PS-) conspiciously 5HT3-rich "nasal" pterygo-palatine ganglion (PPG): PPG-1.) Intramural "pushbacks" intoxicating brain's tissues, show up on MRI e.g. along branches of the peri-/subcallosal artery. The brain-draining circular chambers, by CIMURAF, are plausibly driven by the PPG (and other PS-ganglia) through their dense nitrergic grid, causing loose wrung areas creating hyperboloid stenoses where they delimit contracted sliding segments PPG-2.) Existential conflicts trigger last-resort attacks, whereby the subduing are stopped into submissive shame. This plausibly occurs via the antidromic "Suzuki-link" from preparatory attack-biting (V3) via the trigeminal ggl. V3-V2-crosstalk onto the PPG, which, blushing via PACAP, maybe via MCs opens the BBB causing foggy confusion. Mushrooms may have acquired psilocybin to similarly stop feeding moves of worms (C. elegans) via the >100 5HT3-like ion channels. While on MOD-1 serotonin elicits "dwelling", collective feeding on just one fungus, psilocin could on promote audacious "roaming" (protecting fungi) - channel LGC-50 learning from this. The biphasic and pervasive H 2 S, being a dipole, might be flushed by ECT and on the 5HT3-receptors might get worms (and us) to move.

Pain in Parkinson's disease (PD) is increasingly recognized as a major factor associated with poor life quality of PD patients. However, classic therapeutic drugs supplying dopamine have limited therapeutic effects on PD-related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-hydroxytryptamine; 5-HT) in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been confirmed to be associated with nociception in the spinal cord, such as 5-HT1A receptor, 5-HT1B receptor, 5-HT2 receptor, 5-HT3 receptor, and 5-HT7 receptor. Most research has shown that 5-HT1A receptor and 5-HT3 receptor play a key role in pain transmission in the spinal cord. We hypothesized that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons, and functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA lesioned rats and decrease cell excitability of SDH neurons. To test this hypothesis, we used whole-cell patch-clamp and pharmacological methods to evaluate the effect of 5-HT3 receptor and 5-HT1A receptor on the hyperalgesia of 6-OHDA rats. The results suggested that increased excitability in SDH neurons could be reversed by 5-HT3 receptor antagonist ondansetron (20 μmol/L) and palosetron (10 μmol/L), but not 5-HT3 receptor agonist m-CPBG (30 μmol/L) and SR 57,727 (10 μmol/L), 5-HT1A receptor agonist 8-OH DPAT (10 μmol/L) and eptapirone (10 μmol/L) and 5-HT1A receptor antagonist WAY-100635 (10 μmol/L) and p-MPPI (10 μmol/L). Intrathecal injection of ondansetron (0.1 mg/kg) but not m-CPBG (0.1 mg/kg), 8-OH DPAT (0.1 mg/kg), and WAY-100635 (0.1 mg/kg) significantly attenuated the mechanical hyperalgesia and thermal hyperalgesia in 6-OHDA lesioned rats. In conclusion, the present study suggests that inhibition of spinal 5-HT3 receptor and SDH neuronal excitability alleviates hyperalgesia in PD rats. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The cochlear efferent feedback system plays important roles in auditory processing, including regulation of the dynamic range of hearing, and provides protection against acoustic trauma. These functions are performed through medial olivocochlear (MOC) neurons. However, the underlying cellular and molecular mechanisms are not fully understood. The serotonin type 3A (5-HT3A) receptor is widely expressed throughout the nervous system, which suggests important roles in various neural functions. However, involvement of the 5-HT3A receptor in the MOC system remains unclear. We used mice in this study and found that the 5-HT3A receptor was expressed in MOC neurons that innervated outer hair cells in the cochlea and was involved in the activation of MOC neurons by noise exposure. 5-HT3A receptor knockout impaired MOC functions, potentiated noise-induced hearing loss, and increased loss of ribbon synapses following noise exposure. Furthermore, 5-HT3 receptor agonist treatment alleviated the noise-induced hearing loss and loss of ribbon synapses, which enhanced cochlear protection provided by the MOC system. Our findings demonstrate that the 5-HT3A receptor plays fundamental roles in the MOC system and critically contributes to protection from noise-induced hearing impairment., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Fadolmidine is an α 2 -adrenoceptor full agonist developed for spinal analgesia with a local mode of action. The purpose of this study was to demonstrate the safety of fadolmidine on known α 2 -adrenoceptor-related effects: kidney function, urodynamics and cardiovascular variables. Furthermore, the binding affinity of fadolmidine for the 5-HT 3 receptor prompted functional studies on 5-HT 3 . According to the binding affinity data, fadolmidine demonstrated partial agonism on the 5-HT 3 receptor in transfected cells and in guinea pig ileum preparation. However, intravenous (IV) fadolmidine did not produce any 5-HT 3 -related hemodynamic effects in anaesthetised rats. In urodynamic studies, intrathecal (IT) fadolmidine interrupted volume-evoked voiding cycles and induced overflow incontinence at high concentrations in anaesthetised rats; however, at the analgesic dose range, the effects were mild. The effects of fadolmidine on kidney function were studied in conscious rats after IV and IT dosing. While IT fadolmidine increased dose-dependent urine output, sodium ion concentration, IV doses increased only sodium ion concentration The effects of IT fadolmidine on heart rate (HR), mean arterial pressure (MAP) and sedation were evaluated in the home cage and in the open field using a telemetry system. In resting conditions, fadolmidine decreased HR dose-dependently and increased initial MAP, whereas in actively moving rats, there were no effects at analgesic doses. The results suggest that at anticipated analgesic clinical doses, IT fadolmidine provides analgesia without significant adverse effects on sedation, MAP or HR and with only modest effects on kidney function and urodynamics., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Serotonin (5-HT) is implicated in the underlying mechanisms which mediate cell death following ionizing radiation exposure, however, effects appear to be cell type-dependent. We sought to further characterize the role of 5-HT and 5-HT receptors (5-HTRs) in the exacerbation of cell death following ionizing radiation exposure in human colon carcinoma cells. Materials and methods: We examined the clonogenic survival of colon carcinoma HCT116 cells treated with 5-HT and the selective 5-HTR antagonists ketanserin (5-HT 2A ) and ondansetron (5-HT 3 ), following exposure to direct ionizing radiation and irradiated cell-conditioned medium (ICCM). The relative expression of these target receptors was measured using western blotting. Results: Western blotting results revealed that relative protein levels of the 5-HT 2A and 5-HT 3 receptors were similar. 5-HT concentration-dependent increases in cell death that occurred following direct ionizing radiation exposure were abolished by both 5-HTR antagonists. Death of nonirradiated cells recipient of ICCM was increased in a concentration-dependent manner by 5-HT when present during donor cell irradiation. Both 5-HTR antagonists completely abolished the increases in bystander-induced cell death generated by 5-HT. Finally, we show that exposure of cells to 5-HT prior to receipt of ICCM can also dictate the degree of bystander-induced cell death. Conclusions: Our findings demonstrate a definitive role for 5-HT in the exacerbation of cell death following ionizing radiation exposure in colon carcinoma cells and highlight 5-HTRs as potential markers for predicting cellular radiosensitivity.

Male Syrian hamsters (Mesocricetus auratus) administered anabolic/androgenic steroids during adolescent development display increased aggression and decreased anxious behavior during the adolescent exposure period. Upon withdrawal from anabolic/androgenic steroids, this neurobehavioral relationship shifts and hamsters exhibit decreased aggression and increased anxious behavior. This study investigated the hypothesis that alterations in anterior hypothalamic signaling through serotonin type-3 receptors modulate the behavioral shift between adolescent anabolic/androgenic steroid-induced aggressive and anxious behaviors during the withdrawal period. To test this, hamsters were administered anabolic/androgenic steroids during adolescence then withdrawn from drug exposure for 21 days and tested for aggressive and anxious behaviors following direct pharmacological manipulation of serotonin type-3 receptor signaling within the latero-anterior hypothalamus. Blockade of latero-anterior hypothalamic serotonin type-3 receptors both increased aggression and decreased anxious behavior in steroid-treated hamsters, effectively reversing the pattern of behavioral responding normally observed during anabolic/androgenic steroid withdrawal. These findings suggest that the state of serotonin neural signaling within the latero-anterior hypothalamus plays an important role in behavioral shifting between aggressive and anxious behaviors following adolescent exposure to anabolic/androgenic steroids., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Previous reports suggest flavonoids as potent analgesic compounds. Based on these observations, the present study investigated the antinociceptive action of flavonol, 3', 4'-dimethoxy flavonol, 6, 3'-dimethoxy flavonol, 7, 2'-dimethoxy flavonol, and 7, 3'-dimethoxy flavonol and the possible mechanisms involved in these effects. The antinociceptive effect of the investigated compounds in doses of 25, 50, 100, and 200 mg/kg was evaluated in male Swiss albino mice using the acetic acid test, formalin-induced nociception, and hot water tail immersion test. The role of opioid, tryptaminergic, adrenergic, dopaminergic, GABAergic, and K + ATP channels in producing the antinociceptive effect was also studied using appropriate interacting agents. Treatment with flavonol and dimethoxy flavonols resulted in a significant reduction in the number of abdominal constrictions in the acetic acid test, a significant inhibition of the paw-licking/biting response time in both the phases of formalin nociception and also a significant increase in mean reaction time in the hot water tail immersion test. These observations revealed the antinociceptive effect of dimethoxy flavonols. The role of opioid, serotonergic (5HT 3 ), and dopaminergic system was identified in the antinociceptive effect of flavonol and all dimethoxy derivatives investigated. In addition, the role of GABAergic, K + ATP channel, and α-2 adrenergic mechanisms were also observed in the antinociceptive action of some of the investigated compounds. The present study identified the antinociceptive effect of flavonol and dimethoxy flavonols in mice acting through different neuronal pathways.

Prenatal nicotinic exposure (PNE) reportedly sensitizes bronchopulmonary C-fibers (PCFs) and prolongs PCF-mediated apnea in rat pups, contributing to the pathogenesis of sudden infant death syndrome. Serotonin, or 5-hydroxytryptamine (5-HT), induces apnea via acting on 5-HT receptor 3 (5-HT 3 R) in PCFs, and among the 5-HT 3 R subunits, 5-HT 3B is responsible for shortening the decay time of 5-HT 3 R-mediated currents. We examined whether PNE would promote pulmonary 5-HT secretion and prolong the apnea mediated by 5-HT 3 Rs in PCFs via affecting the 5-HT 3B subunit. To this end, the following variables were compared between the control and PNE rat pups: 1 ) the 5-HT content in bronchoalveolar lavage fluid, 2 ) the apneic response to the right atrial bolus injection of phenylbiguanide (a 5-HT 3 R agonist) before and after PCF inactivation, 3 ) 5-HT 3 R currents and the stimulus threshold of the action currents of vagal pulmonary C-neurons, and 4 ) the immunoreactivity (IR) and mRNA expression of 5-HT 3A and 5-HT 3B in these neurons. Our results showed that PNE up-regulated the pulmonary 5-HT concentration and strengthened the PCF 5-HT 3 R-mediated apnea. PNE significantly facilitated neural excitability by shortening the decay time of 5-HT 3 R currents, lowering the stimulus threshold, and increasing 5-HT 3B IR. In summary, PNE prolongs the apnea mediated by 5-HT 3 Rs in PCFs, likely by increasing 5-HT 3B subunits to enhance the excitability of 5-HT 3 channels.-Zhao, L., Gao, X., Zhuang, J., Wallen, M., Leng, S., Xu, F. Prolongation of bronchopulmonary C-fiber-mediated apnea by prenatal nicotinic exposure in rat pups: role of 5-HT 3 receptors.

Background: We previously reported that intrathecal injection of noradrenaline or dopamine causes enhancement of colorectal motility. As these monoamines are neurotransmitters of descending pain inhibitory pathways in the spinal cord, we hypothesized that serotonin, which is one of the neurotransmitters involved in descending pain inhibition, also influences the lumbosacral defecation center. Therefore, we examined whether serotonin acting on the spinal defecation center enhances colorectal motility., Methods: Colorectal intraluminal pressure and propelled liquid volume were recorded in vivo in anesthetized rats., Key Results: Intrathecal injection of serotonin into the L6-S1 spinal cord elicited periodic increases in colorectal intraluminal pressure, being associated with increases in liquid output. Pharmacological experiments revealed that the effect of serotonin is mediated by both 5-HT 2 and 5-HT 3 receptors. The serotonin-induced enhancement of colorectal motility was unaffected even after disconnection of the defecation center from supraspinal regions by cutting the T8 spinal cord, while transection of the parasympathetic pelvic nerves prevented the colokinetic effect of serotonin. Finally, we investigated interactions among serotonin, noradrenaline and dopamine. Simultaneous administration of sub-effective doses of these monoamine neurotransmitters into the spinal cord caused propulsive colorectal motility slightly but substantially., Conclusions and Inferences: These results demonstrate that exogenous serotonin acts on 5-HT 2 and 5-HT 3 receptors in the lumbosacral defecation center and activates the parasympathetic nervous system to enhance colorectal motility in cooperation with noradrenaline and dopamine., (© 2017 John Wiley & Sons Ltd.)

Background: Serotonin receptors such as 5-HT3 plays critical role in regulation of sleep, wake cycle and cognitive process. Thus, we investigated the role of CA1 5HT3 serotonin receptors in memory acquisition deficit induced by total sleep deprivation (TSD; for 24 hour) and REM sleep deprivation (RSD; for 24 hour). Pain perception and locomotor activity were also assessed as factors that may affect the memory process., Methods: Modified water box and multi-platform apparatus were used to induce TSD or RSD, respectively. Passive avoidance, hot plate and open field devices were used for assessment of memory acquisition, pain and locomotor activity, respectively., Results: Totally, 152 male Wistar rats were used in the study. Pre-training, intra-CA1 injection of 5-HT3 receptor agonist Chlorophenylbiguanide (Mchl; 0.01 and 0.001 µg/rat; P < 0.001) and antagonist Y-25130 (0.1 µg/rat; P < 0.001) reduced memory acquisition and did not alter pain response, while higher dose of both drugs increased locomotor activity in normal rats. Both TSD and RSD reduced memory acquisition (P < 0.001) and did not alter locomotor activity, while TSD (P < 0.001) but not RSD induced analgesia effect. The amnesia induced by TSD was restored by subthreshold dose of Y25130 (0.001 µg/rat; P < 0.001) but not Mchl (0.0001 µg/rat), while both drugs reversed TSD-induced analgesia effect (P < 0.01 for Mchl and P < 0.05 for Y25130), and Y25130 increased locomotor activity in TSD rats (P < 0.05). In RSD rats, subthreshold dose of both drugs did not alter memory acquisition deficit and increased locomotor activity (P < 0.001 for Mchl and P < 0.01 for Y25130), while the Y25130 (P < 0.001), but not Mchl induced analgesia in the RSD rats., Conclusion: Based on the above data, CA1 5HT3 receptors seem to play a critical role in cognitive and non-cognitive behaviors induced by TSD and RSD.

Although serotonin (5-HT) signaling is known to regulate food intake and energy homeostasis, the roles of the 5-HT 3 receptor in feeding processes have been elusive. 5-HT 3 receptors are found throughout mesolimbic circuitry that promote feeding not only in response to hunger, but also to the palatable and rewarding properties of food. These experiments examined if stimulation or blockade of the 5-HT 3 receptor of the nucleus accumbens (NAcc) or ventral tegmentum affected food intake in the rat in response to hunger or the presence of a palatable diet. Rats (N=6-9/group) received bilateral injections of the 5-HT 3 agonist m-chlorophenylbiguanide hydrochloride (mCPBG; at 0.0, 10.0, or 20.0μg/0.5μl/side) or the 5-HT 3 antagonist ondansetron hydrochloride (at 0.0, 1.0, 2.0, or 5.0μg/0.5μl/side) into either the NAcc or the ventral tegmentum. NAcc 5-HT 3 receptor stimulation significantly increased 2-h food intake in food-deprived animals offered rat chow and in a separate group of unrestricted rats offered a sweetened fat diet. In contrast to the feeding increase seen with NAcc treatments, stimulation of 5-HT 3 receptors of the ventral tegmentum significantly reduced food and water intake in food-restricted animals; reductions of intake in non-restricted rats offered the palatable diet did not approach significance. Blockade of the 5-HT 3 receptor had no effect on feeding in either brain region. These data support a functional role for serotonergic signaling in the mesolimbic pathway on motivated behavior, and demonstrate that 5-HT 3 receptors differentially modulate food consumption in a region-dependent manner., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this meta-analysis was to evaluate the preventive efficacy and safety of 5-HT 3 receptor antagonists (5-HT 3 RAs) on perioperative shivering. Relevant databases were searched to identify eligible randomized, controlled trials through January 2016. Primary outcome was the incidence of perioperative shivering, and secondary outcomes were the incidence of safety-related outcomes including postoperative nausea and vomiting (PONV), bradycardia, and hypotension. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data. Trial sequential analysis was performed to assess the risk of random errors and calculate the required information size. Sixteen studies with a total of 1126 patients were included in the meta-analysis. Compared with the control group, 5-HT 3 RAs administered intravenously could statistically significantly reduce the incidence of perioperative shivering (RR, 0.44; 95%CI, 0.35 to 0.56; P < .00001; heterogeneity: I 2 = 30%) as well as PONV (RR, 0.52; 95%CI, 0.28 to 0.97; P = .04; heterogeneity: I 2 = 0%). However, they did not show superiority in lowering the rate of bradycardia (RR, 0.75; 95%CI, 0.38 to 1.49; P = 0.42; heterogeneity: I 2 = 0%) or hypotension (RR, 0.79; 95%CI, 0.44 to 1.43; P = .44; heterogeneity: I 2 = 24%). Trial sequential analysis of primary outcome showed that the required information size was 2634 patients and that the trial sequential monitoring boundary was crossed. Thus, more high-quality randomized, controlled trials with larger sample sizes are still required to draw a definite conclusion about the preventive efficacy of 5-HT 3 RAs on perioperative shivering prevention in the future., (© 2016, The American College of Clinical Pharmacology.)

Background: Several preclinical studies have shown that serotonergic 5-HT3 receptor antagonists play an important role in the management of neuropsychiatric disorders, such as depression and anxiety. In the present study the compound "6n" (N-n-propyl-3-ethoxyquinoxaline-2-carboxamide), a novel 5-HT3 receptor antagonist with an optimal log P (2.52) and pA2 (7.6) value was screened for its neuro-pharmacological potential in chronic rodent models of depression and anxiety named traumatic brain injury (TBI)., Methods: In this model, a 1 cm midline scalp incision was made, and the muscles were retracted to expose the skull. A stainless steel disc (10 mm in diameter and 3 mm in depth) was placed centrally between the lambda and bregma regions. The injury was induced using the impact acceleration model of TBI. Specifically, a 400 g metal weight was dropped from a height of 1 m guided by a straight pipe, onto the metal disc placed over the rat's skull., Results: The behavioral anomalies of the TBI rats were attenuated by the chronic treatment of compound 6n (1 and 2 mg/kg, p.o.; 14 days) as observed by the modified open field test (ambulation, rearing, and fecal pellet), sucrose consumption test (% sucrose consumption), elevated plus maze [% open arm entries [OAE] and % time spent in open arm (TSOA)], and marble burying test (numbers). In addition, 6n also increased the levels of neurotransmitters (norepinephrine and serotonin) and brain derived neurotrophic factor (BDNF) in TBI rats., Conclusions: The result suggests that compound 6n exhibited antidepressant- and anxiolytic-like effects in rodent models of depression and anxiety.

Background: 5-HT3 receptor antagonists play a key role in the management of psychiatric disorders such as, depression and anxiety. They may act through modulation of serotonergic transmission. In the present study, a novel and potential 5-HT3 receptor antagonist, 6g (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone, which exhibited good log P (3.08) and pA2 (7.5) values was screened for its anxiolytic property in lipopolysaccharide (LPS) induced anxiety models., Methods: LPS, an endotoxin, present in the cell wall of Gram negative bacteria was injected 0.83 mg/kg, i.p. as a single dose to induce anxiety-like symptoms in mice. Compound 6g (1 and 2 mg/kg, p.o.) and standard fluoxetine (FLX) (20 mg/kg, p.o.) were injected to treatment groups for 7 days and evaluated in various behavioral paradigms such as elevated plus maze (EPM), light and dark (L/D) test, and open field test (OFT). Their effects on serotonin levels in mice brain were also examined., Results: The results showed that LPS induced anxiety-like symptoms in mice, as indicated by a significantly decreased percentage open arm entries and percentage time spent in open arms in EPM; decreased time spent in light area and number of transition between chambers in L/D test; decreased ambulation and rearing scores in OFT. Compound 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) reversed the LPS-induced behavioral changes and significantly affected all the behavioral parameters mentioned above. In addition 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) increased the levels of serotonin in mice brain., Conclusions: Compound 6g produced anxiolytic-like effects in various anxiety paradigms in LPS-treated mice as well as restored the decreased serotonin levels in mice brain.

Experiences and environments have a variety of effects on brain plasticity at levels ranging from the molecular and cellular to the behavioral. Brain plasticity is one of the most important characteristics of animal survival. In particular, environmental enrichment and exercise induce many structural and functional changes in the brain, and it is noteworthy that these changes result in further beneficial effects at behavioral levels, such as improved learning behavior and antidepressant effects. The effects of enrichment and exercise, and the mechanisms involved in both, provide crucial evidence for the prevention and treatment of brain disorders. However, the enriched environment- and exercise-induced mechanisms underlying the structural and behavioral effects in the brain remain poorly understood. In this review I discuss the molecular mechanisms of environment- and experience-dependent brain plasticity based on the results of studies carried out by our research group at the Department of Neuroscience and Cell Biology, Osaka University. This review consists of three parts: first, a description of a role for the motor protein KIF1A in enhanced synaptogenesis and memory function induced by environmental enrichment; second, a discussion of the function of the 5-HT 3 receptor in hippocampal neurogenesis and behavioral changes induced by exercise; third, a discussion of the role of the 5-HT 3 receptor in fear extinction.

Background: Serotonin (5-HT) is known to play an important role in regulating uterine contractions. However, the specific receptors involved have not been well characterized. We evaluated whether 5-HT3 receptors exist in human myometrium, and their effects on myometrial contractility when stimulated by a 5-HT3 agonist., Methods: Four tissue samples taken from patients undergoing hysterectomy (n=2) and elective cesarean delivery (n=2) were used to detect expression of 5-HT3 receptors on the myometrium using western blotting. For isometric tension measurement, another 12 myometrial strips obtained from patients undergoing elective cesarean delivery were randomly divided into a control group (Group CON) and an RS56812 group (Group RG). In increasing doses from 10 -7 M to 10 -4 M, RS56812, a 5-HT3 receptor agonist, was used to investigate the contractile effects after bonding to the 5-HT3 receptor, following which the effects of granisetron were assessed. Amplitude, interval and duration of myometrial contractions were recorded., Results: Proteins with a molecular mass of 55kDa, consistent with 5-HT3 receptors, were detected both on non-pregnant and late-pregnant human uteri. RS56812 increased the contractile amplitude at concentrations of 10 -6 M, 10 -5 M and 10 -4 M, achieving maximum effect at 10 -5 M. A prolonged contractile interval was detected at the concentration of 10 -4 M. However, RS56812 showed no significant effect on contraction duration. Granisetron did not reverse the contractile effects induced by RS56812., Conclusion: 5-HT3 receptors are expressed on non-pregnant and pregnant uteri. RS56812 enhanced myometrial contractions, but this was not affected by granisetron, the mechanism of which requires further investigation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Hypotension remains a frequent complication of spinal anesthesia, increasing the risk of nausea and vomiting, altered mental status, and aspiration. The aim of this systematic review and meta-analysis was to determine whether 5-hydroxytryptamine3 (5-HT3) receptor antagonists, administered before the initiation of spinal anesthesia, mitigate hypotension., Methods: After a systematic literature search in various databases, randomized placebo-controlled double-blind trials studying the preventive effect of 5-HT3 receptor antagonists were included. A random-effects model was applied, risk ratio (RR, binary variables) or weighted mean difference (continuous variables) with 95% confidence intervals (CIs) were calculated. The primary outcome was the incidence of hypotension., Results: Seventeen trials (8 obstetric, 9 non-obstetric) reporting on 1604 patients were identified. Ondansetron in doses from 2 to 12 mg was studied in 12 trials. Prophylactic 5-HT3 administration significantly reduced the risk of hypotension in the combined analysis of 17 trials, RR 0.54 (95% CI 0.36-0.81, I = 79%). In obstetric trials, the RR was 0.52, 95% CI 0.30-0.88, I = 87% (number needed to treat 4). In non-obstetric studies, the 95% CIs were wide and included a clinically relevant reduction in the risk of hypotension (RR 0.50, 95% CI 0.22-1.16; I = 66%). Contour-enhanced funnel plots confirmed publication bias. Meta-regression showed a significant ondansetron dose response in non-obstetric patients (β = -0.355, P = .04). In the combined and in the obstetric-only analysis, the risk of bradycardia was significantly reduced as was the use of phenylephrine equivalents., Conclusions: 5-HT3 antagonists are effective in reducing the incidence of hypotension and bradycardia; the effects are moderate and are only significant in the subgroup of patients undergoing cesarean delivery. The effects in the non-obstetric population are not significant.

Key Points: Cholera causes more than 100,000 deaths each year as a result of severe diarrhoea, vomiting and dehydration due to the actions of cholera toxin; more females than males are affected. Cholera toxin induces hypersecretion via release of mucosal serotonin and over-activation of enteric neurons, but its effects on gastrointestinal motility are not well characterized. We found that cholera toxin rapidly and reversibly reduces colonic motility in female mice in oestrus, but not in males or females in prooestrus, an effect mediated by 5-HT in the colonic mucosa and by 5-HT3 receptors. We show that the number of mucosal enterochromaffin cells containing 5-HT changes with the oestrous cycle in mice. These findings indicate that cholera toxin's effects on motility are rapid and depend on the oestrous cycle and therefore can help us better understand differences in responses in males and female patients., Abstract: Extensive studies of the mechanisms responsible for the hypersecretion produced by cholera toxin (CT) have shown that this toxin produces a massive over-activation of enteric neural secretomotor circuits. The effects of CT on gastrointestinal motility, however, have not been adequately characterized. We investigated effects of luminal CT on neurally mediated motor activity in ex vivo male and female mouse full length colon preparations. We used video recording and spatiotemporal maps of contractile activity to quantify colonic migrating motor complexes (CMMCs) and resting colonic diameter. We compared effects of CT in female colon from wild-type and mice lacking tryptophan hydroxylase (TPH1KO). We also compared CMMCs in colons of female mice in oestrus with those in prooestrus. In female (but not male) colon, CT rapidly, reversibly and concentration-dependently inhibits CMMC frequency and induces a tonic constriction. These effects were blocked by granisetron (5-HT3 antagonist) and were absent from TPH1KO females. CT effects were prominent at oestrus but absent at prooestrus. The number of EC cells containing immunohistochemically demonstrable serotonin (5-HT) was 30% greater in female mice during oestrus than during prooestrus or in males. We conclude that CT inhibits CMMCs via release of mucosal 5-HT, which activates an inhibitory pathway involving 5-HT3 receptors. This effect is sex- and oestrous cycle-dependent and is probably due to an oestrous cycle-dependent change in the number of 5-HT-containing EC cells in the colonic mucosa., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

The lateral habenula (LHb) is bilaterally connected with serotoninergic raphe nuclei, and expresses high density of serotonin receptors. However, actions of serotonin on the excitatory synaptic transmission to LHb neurons have not been thoroughly investigated. The LHb contains two anatomically and functionally distinct regions: lateral (LHbl) and medial (LHbm) divisions. We compared serotonin's effects on glutamatergic transmission across the LHb in rat brains. Serotonin bi-directionally and differentially modulated glutamatergic transmission. Serotonin inhibited glutamatergic transmission in higher percentage of LHbl neurons but potentiated in higher percentage of LHbm neurons. Magnitude of potentiation was greater in LHbm than in LHbl. Type 2 and 3 serotonin receptor antagonists attenuated serotonin's potentiation. The serotonin reuptake blocker, and the type 2 and 3 receptor agonists facilitated glutamatergic transmission in both LHbl and LHbm neurons. Thus, serotonin via activating its type 2, 3 receptors, increased glutamate release at nerve terminals in some LHb neurons. Our data demonstrated that serotonin affects both LHbm and LHbl. Serotonin might play an important role in processing information between the LHb and its downstream-targeted structures during decision-making. It may also contribute to a homeostatic balance underlying the neural circuitry between the LHb and raphe nuclei.

Chronic social isolation (SI)-reared mice exhibit aggressive and depressive-like behaviors. However, the pathophysiological changes caused by chronic SI remain unclear. The hypothalamus and amygdala have been suggested to be associated with the stress of SI. In addition to serotonin 3 (5-HT3) receptors, AMPA receptors have also been suggested to be involved in aggressive behavior and depressive-like symptoms in animals. Therefore, we examined whether chronic SI affects AMPA and 5-HT3 receptor expression levels in these regions. A Western blot analysis revealed that after four weeks of SI, mice exhibited up-regulated AMPA receptor subunit (GluR1, GluR2) protein levels in the amygdala and down-regulated hypothalamic 5-HT3 receptor protein levels. The AMPA/kainate receptor antagonist NBQX (10 mg/kg; i.p.) attenuated SI-induced depressive-like symptoms but not aggressive behavior. Intra-amygdalar infusions of the selective AMPA receptor agonist (S)-AMPA (10 μM) induced despair-like behavior, but not sucrose preference or aggressive behavior, in mice not reared in SI (naïve mice). Alternatively, treatment with the 5-HT3 receptor agonist SR57227A (3.0 mg/kg; i.p.) decreased aggression levels. In addition, intra-hypothalamic infusions of the 5-HT3 receptor antagonist ondansetron (3 μM) did not trigger aggressive behavior in naïve mice; however, the administration of ondansetron (0.3 mg/kg; i.p.) increased aggression levels in two-week SI mice, which rarely exhibited the aggressive behavior. Moreover, ondansetron did not affect the depressive-like symptoms of the SI mice. These results suggest that SI-induced up-regulation of GluR1 and GluR2 subunits protein levels in the amygdalar region and down-regulation of 5-HT3 receptor proteins level in the hypothalamic region are associated with the effect of AMPA receptor agonist and 5-HT3 receptor antagonist -induced aggressive behavior and depressive-like symptoms., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Purpose: The 5-HT3 receptor is a member of the pentameric ligand-gated ion channel family and is pharmacologically targeted to treat irritable bowel syndrome and nausea/emesis. Furthermore, many antidepressants elevate extracellular concentrations of 5-HT. This study investigates the functional consequences of exposure of recombinant 5-HT3 A receptors to agonists and antagonists., Experimental Approach: We used HEK cells stably expressing recombinant 5-HT3 A receptors and the ND7/23 (mouse neuroblastoma/dorsal root ganglion hybrid) cell line, which expresses endogenous 5-HT3 receptors. Surface expression of recombinant 5-HT3 A receptors, modified to contain the bungarotoxin (BTX) binding sequence, was quantified using fluorescence microscopy to image BTX-conjugated fluorophores. Whole cell voltage-clamp electrophysiology was used to measure the density of current mediated by 5-HT3 A receptors., Key Results: 5-HT3 A receptors were up-regulated by the prolonged presence of agonists (5-HT and m-chlorophenylbiguanide) and antagonists (MDL-72222 and morphine). The up-regulation of 5-HT3 A receptors by 5-HT and MDL-72222 was time- and concentration-dependent but was independent of newly translated receptors. The phenomenon was observed for recombinant rodent and human 5-HT3 A receptors and for endogenous 5-HT3 receptors in neuronal ND7/23 cells., Conclusions and Implications: Up-regulation of 5-HT3 A receptors, following exposure to either agonists or antagonists suggests that this phenomenon may occur in response to different therapeutic agents. Medications that elevate 5-HT levels, such as the antidepressant inhibitors of 5-HT reuptake and antiemetic inhibitors of 5-HT3 receptor function, may both raise receptor expression. However, this will require further investigation in vivo., (© 2015 The British Pharmacological Society.)

Repeated forced swim (FS) conditioning enhances nociceptive responses to temporomandibular joint (TMJ) stimulation in female rats. The basis for FS-induced TMJ hyperalgesia remains unclear. To test the hypothesis that serotonin 3 receptor (5HT3R) mechanisms contribute to enhanced TMJ nociception after FS, ovariectomized female rats were treated with estradiol and subjected to FS for three days. On day 4, rats were anesthetized with isoflurane and TMJ-responsive neurons were recorded from superficial and deep laminae at the trigeminal subnucleus caudalis/upper cervical (Vc/C1-2) region and electromyographic (EMG) activity was recorded from the masseter muscle. Only Vc/C1-2 neurons activated by intra-TMJ injections of ATP were included for further analysis. Although neurons in both superficial and deep laminae were activated by ATP, only neurons in deep laminae displayed enhanced responses after FS. Local application of the 5HT3R antagonist, ondansetron (OND), at the Vc/C1-2 region reduced the ATP-evoked responses of neurons in superficial and deep laminae and reduced the EMG response in both sham and FS rats. OND also decreased the spontaneous firing rate of neurons in deep laminae and reduced the high-threshold convergent cutaneous receptive field area of neurons in superficial and deep laminae in both sham and FS rats. These results revealed that central application of a 5HT3R antagonist, had widespread effects on the properties of TMJ-responsive neurons at the Vc/C1-2 region and on jaw muscle reflexes under sham and FS conditions. It is concluded that 5HT3R does not play a unique role in mediating stress-induced hyperalgesia related to TMJ nociception., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

This is part of a continuing patch-clamp study exploring molecular actions of anesthetics and systematically varied related substances on 5-HT3A receptors as prototypes of ligand-gated ion channels. Specifically, n-alkanols, related to but simpler in structure than propofol, were studied to explore the complex actions of this leading intravenous anesthetic. Outside-out patches excised from HEK 293 cells heterologously expressing human 5-HT3A receptors were superfused with even-numbered n-alkanols (ethanol through n-tetradecanol) of different concentrations. Fast solution exchange for varying durations allowed separation of drug actions by their kinetics. Compared with propofol the electrophysiological responses to n-alkanols were not much simpler. n-Alkanols produced fast and slow inhibition or potentiation of current amplitudes, and acceleration of current rise and decay time constants, depending on exposure time, concentration, and chain-length of the drug. Inhibition dominated, characterized by fast and slow processes with time constants separated by two orders of magnitude which were similar for different n-alkanols and for propofol. Absolute interaction energies for ethanol to n-dodecanol (relative to xenon) ranged from -10.8 to -37.3kJmol(-1). No two n-alkanols act completely alike. Potency increases with chain length (until cutoff) mainly because of methylene groups interacting with protein sites rather than because of their tendency to escape from the aqueous phase. Similar wash-in time constants for n-alkanols and propofol suggest similar mechanisms, dominated by the kinetics of conformational state changes rather than by binding reactions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Previously, we have shown that anabolic androgenic steroid (AAS) exposure throughout adolescence stimulates offensive aggression while also reducing anxious behaviors during the exposure period. Interestingly, AAS exposure through development correlates with alterations to the serotonin system in regions known to contain 5HT3 receptors that influence the control of both aggression and anxiety. Despite these effects, little is known about whether these separate developmental AAS-induced behavioral alterations occur as a function of a common neuroanatomical locus. To begin to address this question, we localized 5HT3 receptors in regions that have been implicated in aggression and anxiety. To examine the impact these receptors may have on AAS alterations to behavior, we microinjected the 5HT3 agonist mCPBG directly into a region know for its influence over aggressive behavior, the lateral division of the anterior hypothalamus, and recorded alterations to anxious behaviors using the elevated plus maze. AAS exposure primarily reduced the presence of 5HT3 receptors in aggression/anxiety regions. Accordingly, mCPBG blocked the anxiolytic effects of adolescent AAS exposure. These data suggest that the 5HT3 receptor plays a critical role in the circuit modulating developmental AAS-induced changes to both aggressive and anxious behaviors, and further implicates the lateral division of the anterior hypothalamus as an important center for the negative behavioral effects of developmental AAS-exposure., (Copyright © 2015. Published by Elsevier Inc.)

Aversive experiences in early life are thought to dispose to psychopathologies such as mood or anxiety disorders. In a two-hit stress model, we assessed the effects of juvenile and/or adult stress on the 5-HT-mediated modulation of synaptic inhibition of ventral dentate gyrus granule cells. Combined but not single stress exposure led to a significant reduction in activity and increased anxiety-like behavior. Similarly, the 5-HT1A receptor-mediated inhibition of evoked inhibitory postsynaptic currents (IPSCs) of granule cells was only reduced in single stress exposed animals. This was also true for the number of granule cells responding with a 5-HT3 receptor-dependent burst of miniature IPSCs. 5-HT3 receptors are expressed on cholecystokinin (CCK)+ basket cells in the hippocampus. In fact, we observed a reduction of steady-state mRNA levels of CCK+ basket cell markers after single juvenile or adult stress and partial recovery after combined stress, thus matching the electrophysiological findings. Adaptive changes in 5-HT-mediated modulation of synaptic inhibition and CCK+ basket cells in the DG may help to maintain normal levels of anxiety after single juvenile or adult stress exposure, as indicated by the increased anxiety that accompanies the loss of this regulation upon combined stress., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Irritable bowel syndrome (IBS) is one of the most widespread functional gastrointestinal disorders characterized by abdominal pain. A key pathophysiological mechanism of abdominal pain is associated with disturbances of serotonergic transmission in feedback control loops of endogenous pain modulation in which the ventrolateral medulla (VLM) plays an important role. The receptors to serotonin (5-HT), and particularly the serotonin 3 (5-HT3) receptors have been extensively used as a potential target for abdominal pain treatment of IBS patients due to antinociceptive features of the 5-HT3 receptor antagonists. The precise mechanisms underlying the antinociceptive action of these antagonists remain unclear. The main objective of our study was to evaluate the involvement of the 5-HT3 receptors in abdominal pain transmission within the VLM. Experiments were carried out on urethane-anaesthetized rats using the animal model of abdominal pain. Noxious colorectal distension (CRD) with a pressure of 80mmHg induced a significant increase in VLM neuron-evoked activity and depressor reactions (171.1±12.7% and 64±1.8% to baseline, accordingly). Selective blockade of the 5-HT3 receptors with granisetron at doses of 1.0 or 2.0mg/kg (i.v) resulted in long-lasting (90min) dose-dependent inhibition of VLM neuron-evoked activity and depressor reactions. When brainstem dorsal surface applications of granisetron (10 or 20µM) were used, the changes were more pronounced. These results suggest involvement of the 5-HT3 receptors in abdominal pain transmission within the VLM, which will be discussed in relation to the central antinociceptive effect of granisetron., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background and Purpose: A ligand is believed to produce either positive or negative responses, or to block both of them. However, an indole compound was found to promote both positive and negative effects at the 5-HT3 AB receptor, which displays a low level of spontaneous activity. The present study attempted to delineate the mechanisms underlying this phenomenon., Experimental Approach: The spontaneously active V291S 5-HT3 A receptor was used to explore the properties of 5-hydroxyindole (5-HoI) and 5-methoxyindole (5-MoI), structural analogues of 5-HT, either alone or in combination with orthosteric probes., Key Results: Two types of efficacy switching were initiated by altering ligand structure and concentration. At lower concentrations, a subtle structural change at position 5 of the indole molecule resulted in opposite effects. 5-HoI apparently elicited partial allosteric inverse agonism, whereas 5-MoI induced allosteric agonism. Interestingly, at a higher concentration, these indoles produced distinct auto-inhibition, manifested as a switch from positive to negative effects. 5-HoI induced a transition from orthosteric agonism to allosteric inverse agonism, whereas 5-MoI produced a shift from allosteric agonism to orthosteric inverse agonism. The auto-inhibition appears to involve communication between orthosteric and allosteric sites of the active receptor conformation and/or between inactive and active conformations. An additive effect of orthosteric and allosteric inverse agonism and insensitivity of allosteric agonism to orthosteric antagonism were also demonstrated., Conclusions and Implications: Together, the results suggest that the moiety at position 5 of the indole structure is a critical determinant of a ligand's properties at the 5-HT3 A receptor, providing new insights into understanding ligand-receptor interactions., (© 2014 The British Pharmacological Society.)

5-Hydroxytrytamine (serotonin) type 3A receptors (5-HT3ARs), as the only ligand-gated ion channels in the serotonin receptor family, are known to regulate neuronal excitation and release of GABA in hippocampal interneurons. However, their physiological role in glutamatergic synaptic plasticity remains unclear. Here, we show that deletion of the 5-HT3AR gene in transgenic mice abolished N-methyl-d-aspartate (NMDA) receptor (NMDAR)-dependent long-term depression (LTD) induced by low-frequency stimulation (LFS) in hippocampal CA1 synapses in slices, whereas the metabotropic glutamate receptor (mGluR)-dependent LTD did not change in the 5-HT3AR knockout mice. In addition, 5-HT3ARs disruption inhibited α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) internalization, without altering basal surface levels of AMPARs. However, the deletion of 5-HT3ARs did not lead to loss of synapses and structural alteration of dendritic spines. Furthermore, the concentrations of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus were not affected by the deletion of 5-HT3ARs. These observations revealed an important role of 5-HT3ARs in NMDAR-dependent long-term depression, which is critical for learning behaviors., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

Stimulation of 5-HT3 receptors (5-HT3Rs) by 2-methylserotonin (2-Me-5-HT), a selective 5-HT3 receptor agonist, can induce vomiting. However, downstream signaling pathways for the induced emesis remain unknown. The 5-HT3R channel has high permeability to extracellular calcium (Ca(2+)) and upon stimulation allows increased Ca(2+) influx. We examined the contribution of Ca(2+)/calmodulin-dependent protein kinase IIα (Ca(2+)/CaMKIIα), interaction of 5-HT3R with calmodulin, and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling to 2-Me-5-HT-induced emesis in the least shrew. Using fluo-4 AM dye, we found that 2-Me-5-HT augments intracellular Ca(2+) levels in brainstem slices and that the selective 5-HT3R antagonist palonosetron, can abolish the induced Ca(2+) signaling. Pre-treatment of shrews with either: i) amlodipine, an antagonist of L-type Ca(2+) channels present on the cell membrane; ii) dantrolene, an inhibitor of ryanodine receptors (RyRs) Ca2+-release channels located on the endoplasmic reticulum (ER); iii) a combination of their less-effective doses; or iv) inhibitors of CaMKII (KN93) and ERK1/2 (PD98059); dose-dependently suppressed emesis caused by 2-Me-5-HT. Administration of 2-Me-5-HT also significantly: i) enhanced the interaction of 5-HT3R with calmodulin in the brainstem as revealed by immunoprecipitation, as well as their colocalization in the area postrema (brainstem) and small intestine by immunohistochemistry; and ii) activated CaMKIIα in brainstem and in isolated enterochromaffin cells of the small intestine as shown by Western blot and immunocytochemistry. These effects were suppressed by palonosetron. 2-Me-5-HT also activated ERK1/2 in brainstem, which was abrogated by palonosetron, KN93, PD98059, amlodipine, dantrolene, or a combination of amlodipine plus dantrolene. However, blockade of ER inositol-1, 4, 5-triphosphate receptors by 2-APB, had no significant effect on the discussed behavioral and biochemical parameters. This study demonstrates that Ca(2+) mobilization via extracellular Ca(2+) influx through 5-HT3Rs/L-type Ca(2+) channels, and intracellular Ca(2+) release via RyRs on ER, initiate Ca(2+)-dependent sequential activation of CaMKIIα and ERK1/2, which contribute to the 5-HT3R-mediated, 2-Me-5-HT-evoked emesis.

Background: Spinal serotonin (5-HT) receptors 3 (5-HT3R) and 7 (5-HT7R) are differentially involved in facilitatory or inhibitory descending modulation, respectively. Electrophysiological studies of the spinal cord have demonstrated that 5-HT3R is involved in nociception induced by intraplantar injection of formalin, but not carrageenan. In addition, depletion of spinal serotonin has been shown to attenuate pain behaviour in the formalin test, but there have been no such reports regarding the carrageenan model. This study compared the role of 5-HT7R and the influence of descending serotonergic modulation between formalin- and carrageenan-induced inflammatory pain., Methods: Effects of intrathecal (i.t.) AS-19 (5-HT7R agonist) and SB-269970 (5-HT3R antagonist) on flinching response in the formalin test and mechanical allodynia in the carrageenan model were evaluated in male Sprague-Dawley rats. The effect of serotonin depletion by i.t. 5,7-dihydroxytryptamine was also examined in the two models., Results: Intrathecal AS-19 significantly reduced the flinching responses in the formalin test (P<0.01), which was reversed by i.t. SB269970. However, neither AS-19 nor SB269970 produced a significant change in mechanical allodynia in the carrageenan model. Depletion of spinal serotonin attenuated the flinching response in phase 2 of the formalin test (P<0.01), but increased mechanical allodynia in the carrageenan model compared with controls (P<0.01)., Conclusions: Spinal 5-HT7R plays a significant inhibitory role in descending serotonergic modulation in pain induced by formalin but not carrageenan. Descending serotonergic modulation is differentially involved in inflammatory pain induced by formalin and carrageenan, with facilitatory and inhibitory effects, respectively., (© The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Double-blinded, randomized, placebo-control trials of selective serotonin 3 receptor antagonists (5-HT3R-ANTs) for schizophrenia have differed in outcome. This meta-analysis tests the hypothesis that 5-HT3R-ANTs are effective for the treatment for schizophrenia. We searched PubMed, the Cochrane Library database, and PsycINFO up to June 15, 2013. We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing 5-HT3R-ANTs add-on therapy with placebo. The risk ratio (RR), 95 % confidence intervals (CI), and standardized mean difference (SMD) were calculated. A random-effects model was used. Six studies (total n = 311) were identified. These included one granisetron plus risperidone study, one ondansetron plus risperidone study, one ondansetron plus haloperidol, and three tropisetron plus risperidone studies. The statistically significant effects of 5-HT3R-ANTs add-on therapy on Positive and Negative Syndrome Scale (PANSS) total scores were SMD = -1.03, CI = -1.70 to -0.36, p = 0.003 (I (2) = 82 %, 5 studies, n = 261); on negative scores were SMD = -1.10, CI = -1.82 to -0.39, p = 0.002 (I (2) = 84 %, 5 studies, n = 261); and on PANSS general scores were SMD = -0.70, CI = -1.23 to -0.17, p = 0.01 (I (2) = 73 %, 5 studies, n = 261). However, 5-HT3R-ANTs add-on therapy was not superior to placebo in PANSS positive scores (SMD = -0.12, p = 0.33). Dropout due to all cause (RR = 0.80, p = 0.50), inefficacy (RR = 0.76, p = 0.65), or adverse events (RR = 0.84, p = 0.75) was similar in both groups. Constipation occurred significantly more often with 5-HT3R-ANTs than placebo (RR = 2.05, CI = 1.07-3.91, p = 0.03, NNH = 11, p = 0.02). 5-HT3R-ANTs add-on therapy is more beneficial on the psychopathology (especially negative symptoms) than controls in patients with schizophrenia, and 5-HT3R-ANTs seem to be well-tolerated treatments.

5-hydroxytryptamine 3 (5HT3) receptors are important modulators of mesostriatal dopaminergic transmission and have been implicated in the pathophysiology of cocaine reward, withdrawal and self-administration. In addition, the 5HT3 antagonist ondansetron is effective in treating early-onset, but not late-onset, alcohol-dependent subjects. To explore the role of 5HT3 receptor systems in cocaine addiction using functioning imaging, we administered ondansetron to 23 abstinent, treatment-seeking cocaine-addicted and 22 sex-, age- and race-matched healthy control participants. Differences between early- (first use before 20 years, n = 10) and late-onset (first use after 20 years, n = 10) cocaine-addicted subjects were also assessed. On two separate days, subjects were administered ondansetron (0.15 mg/kg intravenously over 15 minutes) or saline. Regional cerebral blood flow (rCBF) was measured following each infusion with single photon emission computed tomography. No significant rCBF differences between the cocaine-addicted and control participants were observed following ondansetron relative to saline. Early-onset subjects, however, showed increased (P < 0.001) right posterior parahippocampal rCBF following ondansetron. In contrast, late-onset subjects showed decreased rCBF following ondansetron in an overlapping region of the right parahippocampal/hippocampal gyrus. Early-onset subjects also displayed increased rCBF in the left anterior insula and subthalamic nucleus following ondansetron; late-onset subjects showed decreased rCBF in the right anterior insula. These findings suggest that the age of drug use onset is associated with serotonergic biosignatures in cocaine-addicted subjects. Further clarification of these alterations may guide targeted treatment with serotonergic medications similar to those successfully used in alcohol-dependent patients., (Published 2012. This article is a U.S. Government work and is in the public domain in the USA.)

Several lines of evidence suggest that 5-HT receptors play a critical role in the expression of clock genes in the suprachiasmatic nucleus, the main circadian oscillator in hamsters. The contributions of 5-HT-receptor subtypes in the intestine, where they are expressed at high concentrations, are however not yet clarified. The 5-HT synthesis inhibitor, p-chlorophenylalanine, attenuated the daily rhythm of Per1 and Per2 gene expression in the intestine. Injection of 5-HT and agonists of the 5-HT3 and 5-HT4 receptors increased Per1/Per2 expression and decreased Bmal1 expression in a dose-dependent manner. Although treatment with antagonists of 5-HT3 and 5-HT4 alone did not affect clock gene expression, co-injection of these antagonists with 5-HT blocked the 5-HT-induced changes in clock gene expression. Increased tissue levels of 5-HT due to treatment with the antidepressants clomipramine and fluvoxamine did not affect clock gene expression. The present results suggest that the 5-HT system in the small intestine may play a critical role in regulating circadian rhythms through 5-HT3/5-HT4-receptor activation.

The 5-HT3 receptor, the only ionotropic 5-HT receptor, is expressed in limbic regions, including the hippocampus, amygdala, and cortex. However, it is not known whether it has a role in fear memory processes. Analysis of 5-HT3A receptor knockout mice in fear conditioning paradigms revealed that the 5-HT3A receptor is not required for the acquisition or retention of fear memory but is essential for the extinction of contextual and tone-cued fear. Our data suggest that the 5-HT3A receptor could be a key molecule regulating fear memory processes and a potential therapeutic target for fear disorders.

Although there is general agreement that mucosal 5-hydroxytryptamine (5-HT) can initiate peristaltic reflexes in the colon, recent studies have differed as to whether or not the role of mucosal 5-HT is critical. We therefore tested the hypothesis that the secretion of 5-HT from mucosal enterochromaffin (EC) cells is essential for the manifestation of murine colonic peristaltic reflexes. To do so, we analysed the mechanisms underlying faecal pellet propulsion in isolated colons of mice lacking tryptophan hydroxylase 1 (Tph1(-/-) mice), which is the rate-limiting enzyme in the biosynthesis of mucosal but not neuronal 5-HT. We used video analysis of faecal pellet propulsion, tension transducers to record colonic migrating motor complexes (CMMCs) and intracellular microelectrodes to record circular muscle activity occurring spontaneously or following intraluminal distension. When compared with control (Tph1(+/+)) mice, Tph1(-/-) animals exhibited: (1) an elongated colon; (2) larger faecal pellets; (3) orthograde propulsion followed by retropulsion (not observed in Tph1(+/+) colon); (4) slower in vitro propulsion of larger faecal pellets (28% of Tph1(+/+)); (5) CMMCs that infrequently propagated in an oral to anal direction because of impaired descending inhibition; (6) reduced CMMCs and inhibitory responses to intraluminal balloon distension; (7) an absence of reflex activity in response to mucosal stimulation. In addition, (8) thin pellets that propagated along the control colon failed to do so in Tph1(-/-) colon; and (9) the 5-HT3 receptor antagonist ondansetron, which reduced CMMCs and blocked their propagation in Tph1(+/+) mice, failed to alter CMMCs in Tph1(-/-) animals. Our observations suggest that mucosal 5-HT is essential for reflexes driven by mucosal stimulation and is also important for normal propagation of CMMCs and propulsion of pellets in the isolated colon.

Objective: Disturbances of the enteric serotonergic system have been implicated in several intestinal motility disorders. Patients with diverticular disease (DD) have been reported to exhibit abnormal intestinal motility and innervation patterns. Gene expression profiles of the serotonergic system and distribution of the serotonin type 4 receptor (5HT-4R) were thus studied in patients with DD., Design: Colonic specimens from patients with DD and controls were subjected to quantitative PCR for serotonin receptors 2B, 3A, 4, serotonin transporter and synthesising enzyme tryptophan hydroxylase. Localisation of 5HT-4R was determined by dual-label immunocytochemistry using smooth muscle actin (α-SMA) and pan-neuronal markers (PGP 9.5) and quantitative analysis was carried out. Site-specific gene expression analysis of 5HT-4R was assessed within myenteric ganglia and muscle layers. Correlation of 5HT-4R with muscarinic receptors 2 and 3 (M2R, M3R) messenger RNA expression was determined., Results: 5HT-4R mRNA expression was downregulated in the tunica muscularis and upregulated in the mucosa of patients with DD, whereas the other components of the serotonergic system remained unchanged. 5HT-4R was detected in ganglia and muscle layers, but was decreased in the circular muscle layer and myenteric ganglia of patients with DD. 5HT-4R mRNA expression correlated with M2R/M3R mRNA expression in controls, but not in patients with DD., Conclusions: The serotonergic system is compromised in DD. Altered expression of 5HT-4R at mRNA and protein levels may contribute to intestinal motor disturbances reported in patients with DD. The findings support the hypothesis that DD is associated and possibly promoted by an enteric neuromuscular pathology.

It has been described that endogenous ATP via activation of P2X3 and P2X2/3 receptors contributes to inflammatory nociception in different models, including the formalin injected in subcutaneous tissue of the rat's hind paw. In this study, we have evaluated whether TRPA1, 5-HT3 and 5-HT1A receptors, whose activation is essential to formalin-induced inflammatory nociception, are involved in the nociception induced by activation of P2X3 receptors on subcutaneous tissue of the rat's hind paw. We have also evaluated whether the activation of P2X3 receptors increases the susceptibility of primary afferent neurons to formalin action modulated by activation of TRPA1, 5-HT3 or 5-HT1A receptors. Nociceptive response intensity was measured by observing the rat's behavior and considering the number of times the animal reflexively raised its hind paw (flinches) in 60min. Local subcutaneous administration of the selective TRPA1, 5-HT3 or 5-HT1A receptor antagonists HC 030031, tropisetron and WAY 100,135, respectively, prevented the nociceptive responses induced by the administration in the same site of the non-selective P2X3 receptor agonist αβmeATP. Administration of the selective P2X3 and P2X2/3 receptor antagonist A-317491 or pretreatment with oligonucleotides antisense against P2X3 receptor prevented the formalin-induced behavioral nociceptive responses during the first and second phases. Also, the co-administration of a subthreshold dose of αβmeATP with a subthreshold dose of formalin induced nociceptive behavior, which was prevented by local administration of tropisetron, HC 030031 or WAY 100, 135. These findings have demonstrated that the activation of P2X3 receptors induces inflammatory nociception modulated by TRPA1, 5-HT3 and 5-HT1A receptors. Also, they suggest that inflammatory nociception is modulated by the release of endogenous ATP and P2X3 receptor activation, which in turn, increases primary afferent nociceptor susceptibility to the action of inflammatory mediators via interaction with TRPA1, 5-HT3 and 5-HT1A receptors in the peripheral tissue., (© 2013.)

Background: Monoaminergic pathways, impinging an adrenergic and 5-HT3 serotonin receptors, modulate nociceptive transmission, but their mechanisms and interactions has not been clarified yet., Objectives: The study was designed to investigate the influence of the neonatal noradrenergic system lesion on the antinociceptive effect of 5-HT3 receptor ligands assessed in adult animals., Material and Methods: Intact male rats were contrasted with rats in which noradrenergic nerve terminals were largely destroyed shortly after birth with neurotoxin DSP-4 [(N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine; 50 mg/kg × 2 subcutaneously (sc)], on the 1st and 3rd days of postnatal life. Control animals were injected with saline (1.0 mL/kg sc). When the rats attained 10 weeks of age, painful reactions were assessed by means of writhing and formalin tests after intraperitoneal (ip) administration of 1-phenylbiguanid (FBG; 7.5 mg/kg) or ondansetrone (1.0 mg/kg) with FBG (7.5 mg/kg). Morphine was used as a model analgesic drug., Results: Injections of morphine (7.5 mg/kg sc) evoked similar antinociception in the visceral pain model (writhing test) in both tested groups (control and DSP-4). In control rats, a 5-HT₃ receptor agonist FBG (7.5 mg/kg) elicited analgesia similar to that of morphine but the effect was significantly lower in DSP-4 treated animals. A 5-HT₃ receptor antagonist ondansetrone (1.0 mg/kg) injected before FBG did not modify the effect in the control but suppressed it in the DSP-4 group. In the formalin test, morphine produced higher analgesia in control rats in comparison with the DSP-4 group (pain intensity score of 1 point vs. 2-3 points, respectively). Ondansetrone injected before FBG alleviated the observed effect., Conclusions: Based on the obtained results, we concluded that the neonatal DSP-4 treatment alters the antinociceptive effects of morphine and serotoninergic 5-HT₃ receptor ligands. The above may explain altered (diminished) reactions of analgesics applied to patients with noradrenergic system dysfunction (e.g. depression and/or anxiety disorders).

In the present study, the role of 5-HT3 receptors in pudendal neuromodulation of bladder activity and its interaction with opioid receptors were investigated in anesthetized cats. The bladder was distended with either saline to induce normal bladder activity or with 0.25% acetic acid (AA) to induce bladder overactivity. Pudendal afferent nerves were activated by 5-Hz stimulation at multiples of the threshold (T) intensity for the induction of anal twitching. AA irritation significantly reduced bladder capacity to 16.5 ± 3.3% of saline control capacity, whereas pudendal nerve stimulation (PNS) at 1.5-2 and 3-4 T restored the capacity to 82.0 ± 12% (P = 0.0001) and 98.6 ± 15% (P < 0.0001), respectively. Cumulative doses (1-3 mg/kg iv) of ondansetron, a 5-HT3 receptor antagonist, eliminated low-intensity (1.5-2 T) PNS inhibition and reduced high-intensity (3-4 T) PNS inhibition of bladder overactivity. During saline distention, PNS at 1.5-2 and 3-4 T significantly increased bladder capacity to 173.2 ± 26.4% (P = 0.036) and 193.2 ± 22.5% (P = 0.008), respectively, of saline control capacity, but ondansetron (0.003-3 mg/kg iv) did not alter PNS inhibition. Ondansetron (0.1-3 mg/kg) also significantly (P < 0.05) increased control bladder capacity (50-200%) during either AA irritation or saline distention. In both conditions, the effects of low- and high-intensity PNS were not significantly different. After ondansetron (3 mg/kg) treatment, naloxone (1 mg/kg iv) significantly (P < 0.05) decreased control bladder capacity (40-70%) during either AA irritation or saline distention but failed to affect PNS inhibition. This study revealed that activation of 5-HT3 receptors has a role in PNS inhibition of bladder overactivity. It also indicated that 5-HT3 receptor antagonists might be useful for the treatment of overactive bladder symptoms.

The 5-HT3A receptor homology model, based on the partial structure of the nicotinic acetylcholine receptor from Torpedo marmorata, reveals an asymmetric ion channel with five portals framed by adjacent helical amphipathic (HA) stretches within the 114-residue loop between the M3 and M4 membrane-spanning domains. The positive charge of Arg-436, located within the HA stretch, is a rate-limiting determinant of single channel conductance (γ). Further analysis reveals that positive charge and volume of residue 436 are determinants of 5-HT3A receptor inward rectification, exposing an additional role for portals. A structurally unresolved stretch of 85 residues constitutes the bulk of the M3-M4 loop, leaving a >45-Å gap in the model between M3 and the HA stretch. There are no additional structural data for this loop, which is vestigial in bacterial pentameric ligand-gated ion channels and was largely removed for crystallization of the Caenorhabditis elegans glutamate-activated pentameric ligand-gated ion channels. We created 5-HT3A subunit loop truncation mutants, in which sequences framing the putative portals were retained, to determine the minimum number of residues required to maintain their functional integrity. Truncation to between 90 and 75 amino acids produced 5-HT3A receptors with unaltered rectification. Truncation to 70 residues abolished rectification and increased γ. These findings reveal a critical M3-M4 loop length required for functions attributable to cytoplasmic portals. Examination of all 44 subunits of the human neurotransmitter-activated Cys-loop receptors reveals that, despite considerable variability in their sequences and lengths, all M3-M4 loops exceed 70 residues, suggesting a fundamental requirement for portal integrity.

Anxiety disorders in humans reduce both the heart rate variability (HRV) and the sensitivity of the cardiac baroreflex (BRS). Both may contribute to sudden death. To elucidate the mechanisms underlying these alterations, male rats were subjected to social defeat sessions on four consecutive days. Five days later, the rats were found to be in an anxiety-like state. At this time point, we analysed HRV and BRS in the defeated rats, with or without treatment with the anxiolytic chlordiazepoxide (CDZ). HRV was reduced after social defeat, due to changes in the autonomic balance favouring the sympathetic over the parasympathetic component. Spontaneous and pharmacological baroreflex gains were also reduced. CDZ abolished anxiety-like symptoms as well as HRV and BRS alterations. Inhibition of the dorsomedial hypothalamus (DMH) with muscimol reversed all cardiovascular alterations, whereas blockade of the nucleus tractus solitarii (NTS) 5-HT3 receptor by the local or systemic administration of granisetron restored only baroreflex gains and the parasympathetic component of HRV. In conclusion, repeated social defeat in the rat lead to an anxiety-like state that was associated with lasting reduction in HRV and baroreflex gains. The DMH and the NTS were responsible for these chronic cardiovascular alterations. These regions may therefore constitute new therapeutic targets for reducing cardiac dysfunction and fibrillation in anxiety disorders.

The 5-hydroxytryptamine (serotonin, 5-HT) type 3 (5-HT3) receptor belongs to the superfamily of Cys-loop ligand-gated ion channels, and can be either homopentameric (5-HT3A) or heteropentameric (5-HT3AB) receptor. Several modulators are known, which either inhibit or potentiate this channel, but few have any appreciable selectivity between the two subtypes or can modulate one receptor differently to the other. In this study, we show that the anticancer drug, topotecan, bidirectionally modulates the 5-HT3 receptor using a two-electrode voltage clamp technique. Topotecan inhibited 5-HT-gated current through homomeric 5-HT3A receptors. Interestingly, however, additional expression of the 5-HT3B subunit changed the response to topotecan dramatically from an inhibitory to a potentiatory one. This effect was dependent on the level of 5-HT3B subunit expression. Moreover, the effect was reduced in the receptors containing the 5-HT3B(Y129S) polymorphic variant. These finding could explain individual differences in the sensitivity to topotecan-induced nausea and vomiting., (© 2013 The Authors Journal of Neurochemistry © 2013 International Society for Neurochemistry.)

Functional serotonin 3 (5-HT3) receptors are transiently expressed by cerebellar granule cells during early postnatal development, where they modulate short-term synaptic plasticity at the parallel fibre-Purkinje cell synapse. Here, we show that serotonin controls maturation of Purkinje cells in the mouse cerebellum. The 5-HT3 receptors regulate morphological maturation of Purkinje cells during early postnatal development, and this effect is mediated by the glycoprotein reelin. Using whole-cell patch-clamp recordings we also investigated physiological development of Purkinje cells in 5-HT3A receptor knockout mice during early postnatal development, and found abnormal physiological maturation, characterized by a more depolarized resting membrane potential, an increased input resistance and the ability to fire action potentials upon injection of a depolarizing current at an earlier age. Furthermore, short-term synaptic plasticity was impaired at both the parallel fibre-Purkinje cell and the climbing fibre-Purkinje cell synapses, and both the amplitude and the frequency of spontaneous miniature events recorded from Purkinje cells were increased. The expedited morphological and physiological maturation affects the whole cerebellar cortical network, as indicated by delayed climbing fibre elimination in 5-HT3A receptor knockout mice. There was no difference between wild-type and 5-HT3A receptor knockout mice in any of the morphological or physiological properties described above at later ages, indicating a specific time window during which serotonin regulates postnatal development of the cerebellum via 5-HT3 receptors expressed by granule cells.

The orofacial region is a major focus of chronic neuropathic pain conditions characterized by primary hyperalgesia at the site of injury and secondary hyperalgesia outside the injured zone. We have used a rat model of injury to the maxillary branch (V2) of the trigeminal nerve to produce constant and long-lasting primary hyperalgesia in the V2 territory and secondary hyperalgesia in territories innervated by the mandibular branch (V3). Our findings indicate that the induction of primary and secondary hyperalgesia depended on peripheral input from the injured nerve. In contrast, the maintenance of secondary hyperalgesia depended on central mechanisms. The centralization of the secondary hyperalgesia involved descending 5-HT drive from the rostral ventromedial medulla and the contribution of 5-HT3 receptors in the trigeminal nucleus caudalis (Vc), the homolog of the spinal dorsal horn. Electrophysiological studies further indicate that after nerve injury spontaneous responses and enhanced poststimulus discharges in Vc nociresponsive neurons were time-dependent on descending 5-HT drive and peripheral input. The induction phase of secondary hyperalgesia involved central sensitization mechanisms in Vc neurons that were dependent on peripheral input, whereas the maintenance phase of secondary hyperalgesia involved central sensitization in Vc neurons conducted by a delayed descending 5-HT drive and a persistence of peripheral inputs. Our results are the first to show that the maintenance of secondary hyperalgesia and underlying central sensitization associated with persistent pain depend on a transition to supraspinal mechanisms involving the serotonin system in rostral ventromedial medulla-dorsal horn circuits.

Background: 5-Hydroxytryptamine type 3 (5-HT(3)) receptors are excitatory ion channels belonging to the cys-loop family of ligand-gated ion channels. They are involved in nausea and vomiting and their antagonists are used clinically as antiemetic drugs. We previously reported the development of a novel pyrrole analog of etomidate, (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), which retains etomidate's desirable anesthetic and hemodynamic properties, but lacks its potent inhibitory effect on adrenocorticotropic hormone-stimulated steroid synthesis. Also in contrast to etomidate, carboetomidate potently inhibits nicotinic acetylcholine receptors. Because nicotinic acetylcholine and 5-HT(3) receptors are highly homologous, we hypothesized that carboetomidate might also potently inhibit 5-HT(3) receptors with potentially important implications for the drug's emetogenic activity. In the current studies, we investigated and compared modulation of 5-HT(3A) receptors by carboetomidate and etomidate., Methods: 5-HT(3) receptors were heterologously expressed in human embryonic kidney cells. Drugs were applied with a multichannel superfusion pipette coupled to piezoelectric elements, and currents were recorded from cells in either the whole-cell or excised outside-out patch configuration of patch-clamp recordings., Results: Carboetomidate and etomidate inhibited integrated 5-HT(3A) receptor-mediated currents with respective half-inhibitory concentrations of 1.9 μM (95% confidence interval [CI] = 1.4-2.7 μM) and 25 μM (95% CI = 17-37 μM). These values may be compared with respective hypnotic concentrations of 5.4 and 2.3 µM. This inhibition reflected hypnotic effects on peak current amplitudes and desensitization rates. Half-inhibitory concentrations for reducing peak current amplitudes were 34 μM (95% CI = 24-48 µM) for carboetomidate and 171 μM (95% CI = 128-228 µM) for etomidate. Half-inhibitory concentrations for reducing the desensitization time constant were 3.5 μM (95% CI = 2.4-5.1 µM) for carboetomidate and 36 μM (95% CI = 21-59 µM) for etomidate., Conclusions: In contrast to etomidate, carboetomidate inhibits 5-HT(3A) receptor-mediated currents at hypnotic concentrations. This inhibition is primarily the result of enhancing the rate of desensitization. Because carboetomidate potently inhibits 5-HT(3A) receptors, it may be less emetogenic than etomidate.

Serotonin (5-HT) released from descending fibers plays important roles in spinal functions such as locomotion and nociception. 5-HT2A and 5-HT3 receptors are suggested to contribute to spinal antinociception, although their activation also contributes to neuronal excitation. In the neonatal spinal cord, DL-p-chloroamphetamine (pCA), a 5-HT releaser, inhibited both A fiber-evoked monosynaptic reflex potential (MSR) and C fiber-evoked slow ventral root potential (sVRP). The pCA-mediated inhibition was reversed by ketanserin (a 5-HT2A receptor antagonist) and tropisetron (a 5-HT3 receptor antagonist). Bath-applied 5-HT also inhibited MSR and sVRP; in this case, the actions of 5-HT were antagonized by ketanserin, but not by tropisetron. The pCA-evoked inhibition of sVRP was reduced by bicuculline (a GABAA receptor antagonist) and strychnine (a glycine receptor antagonist). Furthermore, ketanserin inhibited the pCA-evoked release of gamma-aminobutyric acid (GABA) and glycine, while tropisetron inhibited the pCA-evoked release of 5-HT. These results suggest that 5-HT released by pCA activates 5-HT2A receptors, which in turn stimulates the release of GABA/glycine and thereby blocks the spinal nociceptive pathway. 5-HT3 receptors may be involved in the facilitation of 5-HT release via a positive feedback process., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain, discomfort, and altered bowel habits, which have a significant impact on quality of life for approximately 10-20% of the population. IBS can be divided into three main types IBS-D (diarrhea predominant), IBS-C (constipation predominant), and mixed or alternating IBS. 5-HT(3) receptor antagonism has proved to be an efficacious treatment option for IBS-D. For example, alosetron displays efficacy in the treatment of multiple symptoms, including abdominal pain, discomfort, urgency, stool frequency and consistency. However, significant constipation occurred in approximately 25% of patients, leading to withdrawal of up to 10% of patients in clinical trials. Targeting compounds with partial agonist activity at the 5-HT(3) receptor represents a mechanistic departure from the classic 5-HT(3) receptor antagonist approach and should result in agents that are applicable to a broader array of IBS patient populations. Attenuation of the activity of the ion channel without completely abolishing its function may control or normalize bowel function without leading to a total block associated with severe constipation. We have identified a new class of selective, orally active 5-HT(3) receptor ligands with high 5-HT(3) receptor affinity and low partial agonist activity currently in preclinical development that should offer a significant advantage over existing therapies.

Migrating motor complex (MMC) is well characterized by the appearance of gastrointestinal (GI) contractions in the interdigestive state. The physiological importance of gastric MMC is a mechanical and chemical cleansing of the empty stomach in preparation for the next meal. MMC cycle is mediated via the interaction between motilin and 5-hydroxytryptamine (5-HT) by the positive feedback mechanism in conscious dogs. Luminal administration of 5-HT initiates duodenal phase II and phase III with a concomitant increase of plasma motilin release. Duodenal 5-HT concentration is increased during gastric phase II and phase III. Intravenous infusion of motilin increases luminal 5-HT content and induces phase III. 5-HT4 antagonists significantly inhibit both of gastric and intestinal phase III, while 5-HT3 antagonists inhibit only gastric phase III. These suggest that gastric MMC is regulated via vagus, 5-HT3/4 receptors and motilin, while intestinal MMC is regulated via intrinsic primary afferent neurons (IPAN) and 5-HT4 receptors. We propose the possibility that maximally released motilin by a positive feedback depletes 5-HT granules in the duodenal EC cells, resulting in no more contractions. Stress is highly associated with the pathogenesis of functional dyspepsia (FD). Acoustic stress attenuates gastric phase III without affecting intestinal phase III in conscious dogs, via reduced vagal activity. Subset of FD patients shows reduced vagal activity and impaired gastric phase III. The impaired gastric MMC may aggravate dyspeptic symptoms following a food ingestion. Maintaining MMC cycle in the interdigestive state is an important factor to prevent the postprandial dyspeptic symptoms.

Background and Purpose: Disturbed cortical gamma band oscillations (30-80 Hz) have been observed in schizophrenia: positive symptoms of the disease correlate with an increase in gamma oscillation power, whereas negative symptoms are associated with a decrease., Experimental Approach: Here we investigated the effects of first and second generation antipsychotics (FGAs and SGAs, respectively) on gamma oscillations. The FGAs haloperidol, flupenthixol, chlorpromazine, chlorprothixene and the SGAs clozapine, risperidone, ziprasidone, amisulpride were applied on gamma oscillations induced by acetylcholine and physostigmine in the CA3 region of rat hippocampal slices., Key Results: Antipsychotics inhibited the power of gamma oscillations and increased the bandwidth of the gamma band. Haloperidol and clozapine had the highest inhibitory effects. To determine which receptor is responsible for the alterations in gamma oscillations, the effects of the antipsychotics were plotted against their pK(i) values for 19 receptors and analysed for correlation. Our results indicated that 5-HT(3) receptors have an enhancing effect on gamma oscillations whereas dopamine D(3) receptors inhibit them. To test this prediction, m-chlorophenylbiguanide, PD 128907 and CP 809101, selective agonists at 5-HT(3) , D(3) and 5-HT(2C) receptors were applied and revealed that 5-HT(3) receptors indeed enhanced the gamma power whereas D(3) receptors reduced it. As predicted, 5-HT(2C) receptors had no effects on gamma oscillations., Conclusion and Implications: Our data suggest that antipsychotics alter hippocampal gamma oscillations by interacting with 5-HT(3) and dopamine D(3) receptors. Moreover, a correlation of receptor affinities with the biological effects can be used to predict targets for the pharmacological effects of multi-target drugs., (© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

The serotonin type 3A (5-HT(3)A) receptor is a Cys-loop (pentameric) neurotransmitter-gated ion channel found in the central and peripheral nervous systems and implicated in numerous diseases. In previous studies with the endogenous agonist serotonin, we identified two interactions critical for receptor function: a cation-π interaction with W183 in loop B (TrpB) and a hydrogen bond to E129 in loop A. Here we employ mutant cycle analyses utilizing conventional and unnatural amino acid mutagenesis to demonstrate that a third residue, D124 of loop A, forms two functionally important hydrogen bonds to the backbone of loop B. We also show that these three interactions, the cation-π interaction, the backbone hydrogen bonds, and the E129 hydrogen bond, are tightly coupled to each other, suggesting they function as a single unit. We also identify key functional differences between serotonin and the competitive partial agonist m-chlorophenyl biguanide (mCPBG) at these residues. mCPBG displays no cation-π at TrpB and extreme sensitivity to the positioning of E129, on which it is reliant for initiation of channel gating.