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5-HT1 agonists reduce 5-hydroxytryptamine release in rat hippocampus in vivo as determined by brain microdialysis.  

PubMed Central

1. An intracerebral perfusion method, brain microdialysis, was used to assess changes of 5-hydroxytryptamine (5-HT) release in the ventral hippocampus of the chloral hydrate-anaesthetized rat in response to systemic administration of a variety of 5-HT1 receptor agonists. 2. A stable output of reliably detectable endogenous 5-HT was measured in dialysates collected from ventral hippocampus with the 5-HT reuptake inhibitor, citalopram, present in the perfusion medium. 3. Under these conditions the putative 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) caused a dose-dependent (5-250 micrograms kg-1, s.c.) reduction of 5-HT in hippocampal dialysates. 4. Similarly, the putative 5-HT1A agonists gepirone (5 mg kg-1, s.c.), ipsapirone (5 mg kg-1, s.c.) and buspirone (5 mg kg-1, s.c.) markedly reduced levels of 5-HT in hippocampal perfusates whereas their common metabolite 1-(2-pyrimidinyl) piperazine (5 mg kg-1, s.c.), which does not bind to central 5-HT1A recognition sites, had no effect. 5. 5-Methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969), a drug with reported high affinity for brain 5-HT1B binding sites, also produced a dose-dependent (0.25-5 mg kg-1, s.c.) decrease of hippocampal 5-HT output. 6. These data are direct biochemical evidence that systemically administered putative 5-HT1A and 5-HT1B agonists markedly inhibit 5-HT release in rat ventral hippocampus in vivo. PMID:2466516

Sharp, T.; Bramwell, S. R.; Grahame-Smith, D. G.



5-Hydroxytryptamine (5-HT) Cellular Sequestration during Chronic Exposure Delays 5-HT3 Receptor Resensitization due to Its Subsequent Release.  


The serotonergic synapse is dynamically regulated by serotonin (5-hydroxytryptamine (5-HT)) with elevated levels leading to the down-regulation of the serotonin transporter and a variety of 5-HT receptors, including the 5-HT type-3 (5-HT3) receptors. We report that recombinantly expressed 5-HT3 receptor binding sites are reduced by chronic exposure to 5-HT (IC50 of 154.0 ± 45.7 ?m, t½ = 28.6 min). This is confirmed for 5-HT3 receptor-induced contractions in the guinea pig ileum, which are down-regulated after chronic, but not acute, exposure to 5-HT. The loss of receptor function does not involve endocytosis, and surface receptor levels are unaltered. The rate and extent of down-regulation is potentiated by serotonin transporter function (IC50 of 2.3 ± 1.0 ?m, t½ = 3.4 min). Interestingly, the level of 5-HT uptake correlates with the extent of down-regulation. Using TX-114 extraction, we find that accumulated 5-HT remains soluble and not membrane-bound. This cytoplasmically sequestered 5-HT is readily releasable from both COS-7 cells and the guinea pig ileum. Moreover, the 5-HT level released is sufficient to prevent recovery from receptor desensitization in the guinea pig ileum. Together, these findings suggest the existence of a novel mechanism of down-regulation where the chronic release of sequestered 5-HT prolongs receptor desensitization. PMID:25281748

Hothersall, J Daniel; Alexander, Amy; Samson, Andrew J; Moffat, Christopher; Bollan, Karen A; Connolly, Christopher N



5-Hydroxytryptamine (5-HT) Cellular Sequestration during Chronic Exposure Delays 5-HT3 Receptor Resensitization due to Its Subsequent Release*  

PubMed Central

The serotonergic synapse is dynamically regulated by serotonin (5-hydroxytryptamine (5-HT)) with elevated levels leading to the down-regulation of the serotonin transporter and a variety of 5-HT receptors, including the 5-HT type-3 (5-HT3) receptors. We report that recombinantly expressed 5-HT3 receptor binding sites are reduced by chronic exposure to 5-HT (IC50 of 154.0 ± 45.7 ?m, t½ = 28.6 min). This is confirmed for 5-HT3 receptor-induced contractions in the guinea pig ileum, which are down-regulated after chronic, but not acute, exposure to 5-HT. The loss of receptor function does not involve endocytosis, and surface receptor levels are unaltered. The rate and extent of down-regulation is potentiated by serotonin transporter function (IC50 of 2.3 ± 1.0 ?m, t½ = 3.4 min). Interestingly, the level of 5-HT uptake correlates with the extent of down-regulation. Using TX-114 extraction, we find that accumulated 5-HT remains soluble and not membrane-bound. This cytoplasmically sequestered 5-HT is readily releasable from both COS-7 cells and the guinea pig ileum. Moreover, the 5-HT level released is sufficient to prevent recovery from receptor desensitization in the guinea pig ileum. Together, these findings suggest the existence of a novel mechanism of down-regulation where the chronic release of sequestered 5-HT prolongs receptor desensitization. PMID:25281748

Hothersall, J. Daniel; Alexander, Amy; Samson, Andrew J.; Moffat, Christopher; Bollan, Karen A.; Connolly, Christopher N.



5-HT1-like receptors mediate 5-hydroxytryptamine-induced contraction of human isolated basilar artery.  

PubMed Central

1. The 5-hydroxytryptamine (5-HT) receptor mediating contraction of endothelium denuded human basilar artery has been characterized in vitro. 2. 5-HT and a variety of 5-HT agonists contracted human isolated basilar artery with a rank order of agonist potency, 5-carboxamidotryptamine (5-CT) greater than 5-HT identical to methysergide greater than GR43175 much greater than 8-OHDPAT much greater than 2-methyl-5-HT. The maximum response produced by these agonists differed. 3. None of the agonists relaxed human basilar artery when tone was elevated with prostaglandin F2 alpha, indeed further contraction was seen. 4. The contractile responses of human basilar artery to 5-HT and the selective 5-HT1-like agonist GR43175 were highly reproducible whilst those to 5-CT were not. 5. The contractile response to both 5-HT and GR43175 was resistant to antagonism by ketanserin and GR38032, thus excluding activation of 5-HT2 and 5-HT3 receptors. The contractile action of 5-HT and GR43175 was also not antagonized by (+/-)-cyanopindolol, excluding the activation of receptors similar to 5-HT1A and 5-HT1B recognition sites identified in ligand binding studies. 6. In marked contrast, methiothepin was a potent antagonist of the contractile actions of both 5-HT and GR43175, with a pA2 value of 8.8 against both agonists. Methiothepin (100 nM) had no effect on the contractile response to the thromboxane A2-mimetic U46619. 7. We conclude that 5-HT and GR43175 contract the human isolated basilar artery by activating the same receptor type.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2538194

Parsons, A. A.; Whalley, E. T.; Feniuk, W.; Connor, H. E.; Humphrey, P. P.



Phosphorylation of the 5-hydroxytryptamine3 (5-HT3) receptor expressed in HEK293 cells.  


The 5-hydroxytrptamine3 (5-HT3) receptor is a pentameric complex belonging to the family of ligand-gated ion channels. A variety of studies have suggested that phosphorylation regulates the rate of desensitisation and the size of amplitude of the receptor current. In this study we have examined the phosphorylation of the myc-tagged wild-type 5-HT3A receptor subunits from guinea-pig expressed in HEK293 cells (human embryonic kidney). Stably transfected cells were metabolically labelled with 32P-phosphoric acid. The results of immunoprecipitation and autoradiography demonstrate that both splicc variants of the 5-HT3A receptor subunit are phosphorylated in HEK293 cells. Site-specific mutagenesis revealed that phosphorylation occurs at serine 409, a potential target of protein kinase A. Thus the 5-HT3 receptor might be modulated by intracellular pathways, that allow variable 5-hydroxytryptamine action as responses to different extracellular stimuli. PMID:10800772

Lankiewicz, S; Hüser, M B; Heumann, R; Hatt, H; Gisselmann, G



Potentiation of 5-hydroxytryptamine (5HT) responses by a 5HT uptake inhibitor in pulmonary and systemic vessels: effects of exposing rats to hypoxia  

Microsoft Academic Search

The aim was to determine whether uptake of 5-hydroxytryptamine (5-HT) by the 5-HT transporter (SERT) modulates contractile responses to 5-HT in rat pulmonary arteries and whether this modulation is altered by exposure of rats to chronic hypoxia (10% oxygen; 8 h\\/day; 5 days). The effects of the SERT inhibitor, citalopram (100 nM), on contractions to 5-HT were determined in isolated ring preparations of

Janet C. Wanstall; Steven A. Fiore; Agatha Gambino; Russell Chess-Williams



Fading of 5-HT4 receptor-mediated inotropic responses to 5-hydroxytryptamine is caused by phosphodiesterase activity in porcine atrium.  


Inotropic responses to 5-hydroxytryptamine (5-HT) in human and porcine atrium can fade, suggesting 5-HT(4) receptor desensitization. De Maeyer et al., however, show in this issue that inhibition of phosphodiesterases with isobutyl-methyl-xanthine prevents fading of 5-HT(4) receptor-mediated responses to 5-HT and the partial agonist prucalopride in porcine atrium. PMID:16331292

Kaumann, Alberto J; Levy, Finn Olav



Role of 5-ht7 receptors in the long-lasting hypotensive response induced by 5-hydroxytryptamine in the rat  

PubMed Central

The receptor mediating the long-lasting hypotensive effect of intravenous (i.v.) 5-hydroxytryptamine (5-HT) in the rat was originally classified as 5-HT1-like. Since some pharmacological properties of this receptor are closely similar to those for the cloned 5-ht7 receptor, the present study investigated the effects of several 5-HT receptor agonists and antagonists showing high affinity for the cloned 5-ht7 receptor in pithed rats with artificially raised blood pressure. I.v. bolus administration of 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine, lisuride and sumatriptan to bilaterally vagotomized pithed rats pretreated with ketanserin (0.18??mol?kg?1, i.v.), the diastolic blood pressure of which had been raised by a continuous i.v. infusion of methoxamine (60–80?nmol?kg?1?min?1), produced dose-dependent hypotensive responses; only 5-HT and 5-CT displayed similar maximum effects. In addition to mimicking the hypotensive action of 5-HT with a lower maximum effect, lisuride strongly antagonized the 5-CT-induced hypotensive responses thus suggesting a partial agonist effect. The rank order of hypotensive agonist potency was 5-CT >> 5-HT ? 5-methoxytryptamine ? lisuride >> sumatriptan. In experiments with antagonists, i.v. treatment with metergoline (2.48??mol?kg?1), mesulergine (2.76??mol?kg?1), methysergide (2.13??mol?kg?1), lisuride (0.22??mol?kg?1), methiothepin (0.68??mol?kg?1), mianserin (10.6??mol?kg?1), or the atypical antipsychotic drugs, clozapine (11.0??mol?kg?1) or risperidone (78.0?nmol?kg?1), produced significant rightward displacements of the dose-response curve for 5-CT in methoxamine-infused pithed animals pretreated with ketanserin (0.18??mol?kg?1, i.v.); lisuride, methiothepin and risperidone behaved as non-competitive antagonists as they elicited a significant reduction of the maximum effect to 5-CT. In contrast, blockade of 5-HT1, 5-HT3 and 5-HT4 receptors with i.v. propranolol (3.38??mol?kg?1), MDL-72222 (1.59??mol?kg?1) and GR125487 (1.91??mol?kg?1), respectively, did not alter 5-CT-induced hypotensive responses; ketanserin (0.18??mol?kg?1, i.v.) failed to modify the dose-response curve for 5-CT in saline-pretreated animals. Lastly, inhibition of the prostaglandin-forming cyclo-oxygenase and nitric oxide synthase with indomethacin (14??mol?kg?1, i.v.) and NG-nitro-L-arginine methyl ester (L-NAME, 120??mol?kg?1, i.v.), respectively, had no significant effects on 5-CT-induced hypotensive effects. Taken together, the present pharmacological data suggest that the long-lasting vasodepressor action of 5-HT in the rat involves activation of receptors closely similar to the cloned 5-ht7 subtype. Since no evidence for an indirect mechanism could be obtained, these receptors may be primarily located in the vascular smooth muscle of the systemic resistance vessels. These findings represent further evidence favouring the functional role of the 5-ht7 receptor. PMID:9179401

Terrón, José A



Pharmacological characterisation of the decrease in 5-HT synthesis in the mouse brain evoked by the selective serotonin re-uptake inhibitor citalopram.  


The selective serotonin re-uptake inhibitor (SSRI) citalopram decreases the synthesis of 5-hydroxytryptamine (5-HT) in the mouse brain in vivo. The underlying mechanism was studied by recording the accumulation of 5-hydroxytryptophan (5-HTP) in hypothalamus and hippocampus after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD 1015). Depletion of 5-HT with reserpine markedly reduced the citalopram-induced decrease of 5-HTP but not that evoked by the 5-HT1A receptor agonist 8-OH-DPAT, which indicates that the presence of endogenous 5-HT is necessary for full effect of citalopram. In contrast to the almost complete antagonism of the decrease in 5-HT synthesis induced by 8-OH-DPAT, the 5-HT1A receptor antagonist WAY-100,635 only slightly affected the citalopram-evoked decrease in 5-HT synthesis. Likewise, the 5-HT1B receptor antagonists NAS-181 and GR127935 only slightly antagonised the citalopram effect although they strongly inhibited the decrease in 5-HT synthesis induced by the 5-HT1B receptor agonist anpirtoline. Combined treatment with 5-HT1A and 5-HT1B receptor antagonists did not produce any additive antagonistic effect on the citalopram-induced decrease in 5-HT synthesis. The 5-HT2A/2C receptor antagonist ketanserin, the 5-HT3 receptor antagonist ondansetron and the 5-HT4 receptor antagonist RS-39604 had no effect on the citalopram-induced decrease in 5-HT synthesis. The same was found for several other non-selective 5-HT receptor antagonists, e.g. cyproheptadine, dihydroergotamine, methiothepin, methysergide, metergoline and mianserin. It is concluded that the citalopram-induced decrease in 5-HT synthesis differs in sensitivity from that mediated by 5-HT1A or 5-HT1B receptor agonists and citalopram also seems to require endogenous 5-HT for its full effect. PMID:11218075

Stenfors, C; Yu, H; Ross, S B



Characterization and localization of a peripheral neural 5-hydroxytryptamine receptor subtype (5-HT1P) with a selective agonist, /sup 3/H-5-hydroxyindalpine  

SciTech Connect

Peripheral neural 5-hydroxytryptamine (5-HT) receptors are different from both classes 5-HT1 and 5-HT2, which have been described from studies of 5-HT receptors in the brain. Recently, it has been shown that, as in the CNS, there is more than a single type of neural receptor for 5-HT in the enteric nervous system. One of these, called 5-HT1P, has a high affinity for 3H-5-HT, initiates a long-lasting depolarization of enteric neurons associated with an increase in membrane resistance, and is the physiological receptor through which enteric serotoninergic neurons mediate slow EPSPs. The other receptor, called 5-HT3 (5-HT2P), does not bind /sup 3/H-5-HT with high affinity, and initiates a brief depolarization of enteric neurons with decreased input resistance, but a physiological action of 5-HT mediated by these receptors has not yet been identified. Hydroxylated indalpines have been found to be agonists at 5-HT1P receptors. We have now examined 5-HT1P receptors using 5-hydroxyindalpine (5-OHIP) as a probe. The action of 5-OHIP on enteric neurons was determined electrophysiologically and compared with that of 5-HT; the binding of /sup 3/H-5-OHIP to isolated enteric membranes was studied by rapid filtration, and to frozen sections of tissue by radioautography. /sup 3/H-5-OHIP binding was compared with that of /sup 3/H-5-HT. 5-OHIP, like 5-HT, induced a triphasic response in most enteric neurons: an initial short-lived depolarization, during which input resistance fell, followed by recovery, and then a long-lasting depolarization, during which the input resistance increased. 5-OHIP bound saturably, reversibly, and with high affinity to enteric membranes (Kd = 7.6 +/- 0.7 nM; Bmax = 76 +/- 14 fmol/mg protein).

Branchek, T.A.; Mawe, G.M.; Gershon, M.D.



Prediction of clinical response based on pharmacokinetic/pharmacodynamic models of 5-hydroxytryptamine reuptake inhibitors in mice  

PubMed Central

Background and purpose: Bridging the gap between preclinical research and clinical trials is vital for drug development. Predicting clinically relevant steady-state drug concentrations (Css) in serum from preclinical animal models may facilitate this transition. Here we used a pharmacokinetic/pharmacodynamic (PK/PD) modelling approach to evaluate the predictive validity of 5-hydroxytryptamine (5-HT; serotonin) transporter (SERT) occupancy and 5-hydroxytryptophan (5-HTP)-potentiated behavioral syndrome induced by 5-HT reuptake inhibitor (SRI) antidepressants in mice. Experimental approach: Serum and whole brain drug concentrations, cortical SERT occupancy and 5-HTP-potentiated behavioral syndrome were measured over 6?h after a single subcutaneous injection of escitalopram, paroxetine or sertraline. [3H]2-(2-dimethylaminomethylphenylsulphanyl)-5-methyl-phenylamine ([3H]MADAM) was used to assess SERT occupancy. For PK/PD modelling, an effect-compartment model was applied to collapse the hysteresis and predict the steady-state relationship between drug exposure and PD response. Key results: The predicted Css for escitalopram, paroxetine and sertraline at 80% SERT occupancy in mice are 18?ng?mL?1, 18?ng?mL?1 and 24?ng mL?1, respectively, with corresponding responses in the 5-HTP behavioral model being between 20–40% of the maximum. Conclusions and implications: Therapeutically effective SERT occupancy for SRIs in depressed patients is approximately 80%, and the corresponding plasma Css are 6–21?ng?mL?1, 21-95?ng?mL?1 and 20–48?ng?mL?1 for escitalopram, paroxetine and sertraline, respectively. Thus, PK/PD modelling using SERT occupancy and 5-HTP-potentiated behavioral syndrome as response markers in mice may be a useful tool to predict clinically relevant plasma Css values. PMID:18552871

Kreilgaard, M; Smith, D G; Brennum, L T; Sánchez, C



Pharmacological characterization of a rat 5-hydroxytryptamine type3 receptor subunit (r5-HT3A(b)) expressed in Xenopus laevis oocytes  

PubMed Central

The present study has utilized the two electrode voltage-clamp technique to examine the pharmacological profile of a splice variant of the rat orthologue of the 5-hydroxytryptamine type 3A subunit (5-HT3A(b)) heterologously expressed in Xenopus laevis oocytes. At negative holding potentials, bath applied 5-HT (300?nM–10??M) evoked a transient, concentration-dependent (EC50=1.1±0.1??M), inward current. The response reversed in sign at a holding potential of ?2.1±1.6?mV. The response to 5-HT was mimicked by the 5-HT3 receptor selective agonists 2-methyl-5-HT (EC50=4.1±0.2??M), 1-phenylbiguanide (EC50=3.0±0.1??M), 3-chlorophenylbiguanide (EC50=140± 10?nM), 3,5-dichlorophenylbiguanide (EC50=14.5±0.4?nM) and 2,5-dichlorophenylbiguanide (EC50= 10.2±0.6?nM). With the exception of 2-methyl-5-HT, all of the agonists tested elicited maximal current responses comparable to those produced by a saturating concentration (10??M) of 5-HT. Responses evoked by 5-HT at EC50 were blocked by the 5-HT3 receptor selective antagonist ondansetron (IC50=231±22?pM) and by the less selective agents (+)-tubocurarine (IC50=31.9± 0.01?nM) and cocaine (IC50=2.1±0.2??M). The data are discussed in the context of results previously obtained with the human and mouse orthologues of the 5-HT3A subunit. Overall, the study reinforces the conclusion that species differences detected for native 5-HT3 receptors extend to, and appear largely explained by, differences in the properties of homo-oligomeric receptors formed from 5-HT3A subunit orthologues. PMID:9756382

Mair, Ian D; Lambert, Jeremy J; Yang, Jay; Dempster, John; Peters, John A



Detection of 5-hydroxytryptamine (5-HT) in vitro using a hippocampal neuronal network-based biosensor with extracellular potential analysis of neurons.  


5-hydroxytryptamine (5-HT) is an important neurotransmitter in regulating emotions and related behaviors in mammals. To detect and monitor the 5-HT, effective and convenient methods are demanded in investigation of neuronal network. In this study, hippocampal neuronal networks (HNNs) endogenously expressing 5-HT receptors were employed as sensing elements to build an in vitro neuronal network-based biosensor. The electrophysiological characteristics were analyzed in both neuron and network levels. The firing rates and amplitudes were derived from signal to determine the biosensor response characteristics. The experimental results demonstrate a dose-dependent inhibitory effect of 5-HT on hippocampal neuron activities, indicating the effectiveness of this hybrid biosensor in detecting 5-HT with a response range from 0.01?mol/L to 10?mol/L. In addition, the cross-correlation analysis of HNNs activities suggests 5-HT could weaken HNN connectivity reversibly, providing more specificity of this biosensor in detecting 5-HT. Moreover, 5-HT induced spatiotemporal firing pattern alterations could be monitored in neuron and network levels simultaneously by this hybrid biosensor in a convenient and direct way. With those merits, this neuronal network-based biosensor will be promising to be a valuable and utility platform for the study of neurotransmitter in vitro. PMID:25530536

Hu, Liang; Wang, Qin; Qin, Zhen; Su, Kaiqi; Huang, Liquan; Hu, Ning; Wang, Ping



Mass spectrometric characterization of recombinant rat 5-hydroxytryptamine receptor 1A (5-HT(1A) R) expressed in tsA201 human embryonic kidney cells.  


The 5-hydroxytryptamine 1A receptor (serotonin 1A receptor; 5-HT(1A) R) is involved in a large series of brain functions, and roles in anxiety, depression, and cognition have been reported. So far, published information on mass spectrometrical characterization of 5-HT(1A) R is limited to the presence of two 5-HT(1A) R peptides in rat's whole brain as observed by in-solution digestion followed by LC-MS/MS. Knowledge about the protein sequence and PTMs, however, would have implications for generation of specific antibodies and designing studies on the 5-HT(1A) R at the protein level. A rat recombinant 5-HT(1A) R was extracted from the tsA201 cell line, run using several gel-based principles with subsequent in-gel digestion with several proteases, chymotrypsin, trypsin, AspN, proteinase K, and pepsin followed by nano-LC-ESI-MS/MS analysis on a high capacity ion trap and an LTQ Orbitrap Velos. Using two search engines, Mascot and Modiro™, the recombinant 5-HT(1A) R was identified showing 94.55% sequence coverage. A single phosphorylation at S301 was identified and verified by phosphatase treatment and a series of amino acid substitutions were detected. Characterization of 5-HT(1A) R, a key player of brain functions and neurotransmission, was shown and may enable generation of specific antibodies, design of future, and interpretation of previous studies in the rat at the protein level. PMID:22997067

Heo, Seok; Yang, Jae-Won; Huber, Marie L; Planyavsky, Melanie; Bennett, Keiryn L; Lubec, Gert



5-Hydroxytryptamine and depression  

PubMed Central

1 Theories linking 5-hydroxytryptamine (5-HT) with depression are briefly reviewed. The various experimental strategies adopted to investigate this relationship, examination of autopsy data, CSF metabolite data, 5-HT re-uptake patterns in human blood platelets and imipramine binding studies in human platelets, are discussed. 2 Recent studies of 5-hydroxyindole acetic acid (5-HIAA) levels in cerebrospinal fluid have revealed a linkage between low 5-HIAA levels and suicide, aggression and impulsivity. Decreases in the number of imipramine binding sites have also been found in brains of suicide victims. 3 The available data lead to the conclusion that decreased 5-hydroxytryptaminergic function may be associated with an increased risk of depression, suicide, and some types of aggression. ImagesFigure 2 PMID:6190490

Goodwin, F. K.; Post, R. M.



Antihypertensive effects of chronic 5-hydroxytryptamine (5HT 2 ) receptor blockade with ketanserin in the spontaneously hypertensive rat  

Microsoft Academic Search

The effects of chronic oral treatment with the 5-hydroxytryptamine (serotonin) receptor blocking agent ketanserin (17 mg\\/100 g dry food) on blood pressure, heart weight, peripheral vascular reactivity, baroreceptor sensitivity, central cardiovascular reactivity and central catecholamine turnover were investigated in the spontaneously hypertensive rat. Blood pressure measurements were performed in conscious rats 24 h after insertion of catheters. After 6 weeks

Anders Pettersson; Bengt Persson; Matts Henning; Thomas Hedner



The influence of 5-hydroxytryptamine re-uptake blockade on CCK receptor antagonist effects in the rat elevated zero-maze.  


In this study, the elevated zero-maze model of anxiety was used to investigate CCK receptor antagonist effects on the behaviour of male Lister-hooded rats and to demonstrate, by administering antagonists in the presence or absence of selective 5-hydroxytryptamine (5-HT) re-uptake inhibitors, the involvement of 5-HT in the mediation of these effects. Devazepide, a selective CCKA receptor antagonist, L-365,260 (3R(+)-N-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin- 3-yl-N1- (3-methyl-phenyl)urea) or CI-988 (4-([2-[[3-(1H-indol-3-yl)-2-methyl-1- oxo-2-[[(tricyclo[]-dec-2-yloxy)-carbonyl]-amin o]- propyl]-amino]-1-phenylethyl]-amino)-4-oxo-[R-(R*,R*)]-butanoate- N-methyl-D-glucamine), both selective CCKB receptor antagonists, were administered 30 min prior to testing. Behavioural analysis during testing included measures of risk-assessment behaviours (e.g. stretched-attend posture) in addition to time spent on the open quadrants. Devazepide induced significant anxiolytic effects, whereas CI-988 produced inconsistent results and L-365,260 was ineffective. When administered simultaneously with the 5-HT re-uptake inhibitors zimelidine or Wy 27587 (N-[[[1-[(6- fluoro-2-naphthalenyl)methyl]-4-piperidinyl]amino] carbonyl]-3-pyridine carboxamide methyl sulphonate salt), the significant anxiolytic effect induced by devazepide was dose-dependently and significantly attenuated. Zimelidine and Wy27587 had little effect alone on zero-maze behaviour at the lower of two doses given. These data show that the elevated zero-maze, in conjunction with the analysis of 'risk-assessment' behaviours, is an anxiety model which is sensitive to the anxiolytic effects of CCK receptor antagonism.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7705440

Bickerdike, M J; Marsden, C A; Dourish, C T; Fletcher, A



Molecular cloning of 5-hydroxytryptamine (5HT) type 1 receptor genes from the Japanese puffer fish, Fugu rubripes  

Microsoft Academic Search

To characterize the structure of Fugu G-protein coupled receptor family and its evolutionary divergence, we have cloned and sequenced the Fugu 5-HT type 1 receptor genes by Polymerase Chain Reaction (PCR) with degenerate primers followed by phage library screening. The analysis of the deduced amino acid sequences showed that F1A? and F1A? have the highest homology to the human 5-HT1A

Fuminori Yamaguchi; Sydney Brenner



Investigation of the mechanisms underlying the hypophagic effects of the 5-HT and noradrenaline reuptake inhibitor, sibutramine, in the rat  

PubMed Central

Sibutramine is a novel 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin- noradrenaline reuptake inhibitor, SNRI) which is currently being developed as a treatment for obesity. Sibutramine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine the pharmacological mechanisms underlying sibutramine-induced hypophagia. Individually-housed male Sprague-Dawley rats were maintained on reversed phase lighting with free access to food and water. Drugs were administered at 09?h 00?min and food intake was monitored over the following 8?h dark period. Sibutramine (10?mg?kg?1, p.o.) produced a significant decrease in food intake during the 8?h following drug administration. This hypophagic response was fully antagonized by the ?1-adrenoceptor antagonist, prazosin (0.3 and 1?mg?kg?1, i.p.), and partially antagonized by the ?1-adrenoceptor antagonist, metoprolol (3 and 10?mg?kg?1, i.p.) and the 5-HT receptor antagonists, metergoline (non-selective; 0.3?mg?kg?1, i.p.); ritanserin (5-HT2A/2C; 0.1 and 0.5?mg?kg?1, i.p.) and SB200646 (5-HT2B/2C; 20 and 40?mg?kg?1, p.o.). By contrast, the ?2-adrenoceptor antagonist, RX821002 (0.3 and 1?mg?kg?1, i.p.) and the ?2-adrenoceptor antagonist, ICI 118,551 (3 and 10?mg?kg?1, i.p.) did not reduce the decrease in food intake induced by sibutramine. These results demonstrate that ?1-adrenoceptors, 5-HT2A/2C-receptors and particularly ?1-adrenoceptors, are involved in the effects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypophagia is related to its ability to inhibit the reuptake of both noradrenaline and 5-HT, with the subsequent activation of a variety of noradrenaline and 5-HT receptor systems. PMID:9283694

Jackson, Helen C; Bearham, M Clair; Hutchins, Lisa J; Mazurkiewicz, Sarah E; Needham, Andrew M; Heal, David J



Interactions of metoclopramide and ergotamine with human 5-HT3A receptors and human 5-HT reuptake carriers  

PubMed Central

The actions of metoclopramide and ergotamine, drugs which are used as a combined migraine medication, on human (h)5-HT3A receptors and 5-HT reuptake carriers, stably expressed in HEK-293 cells, were studied with patch-clamp- and ([3H]5-HT)-uptake techniques. At clinical concentrations, metoclopramide inhibited peak and integrated currents through h5-HT3A receptors concentration-dependently (IC50=0.064 and 0.076??M, respectively) when it was applied in equilibrium (60?s before and during 5-HT (30??M) exposure). The onset and offset time constants of metoclopramide action were 1.3 and 2.1?s, respectively. The potency of metoclopramide when exclusively applied during the agonist pulse decreased more than 200-fold (IC50=19.0??M, peak current suppression). Metoclopramide (0.10??M) did not alter the EC50 of 5-HT-induced peak currents. In contrast to the lack of competitive interaction between metoclopramide and 5-HT in this functional assay, metoclopramide inhibited specific [3H]GR65630 binding to human h5-HT3A receptors in a surmountable manner. This seeming discrepancy between functional studies and radioligand binding experiments may be accounted for by (1) the slow kinetics of inhibition of peak currents by metoclopramide compared with the fast onset and offset kinetics of 5-HT-induced currents and (2) the low efficacy of metoclopramide in inhibiting radioligand binding (e.g. only 20% binding inhibition compared to 79% peak current suppression by 200?nM metoclopramide). At low concentrations (1–10?nM), ergotamine had no effect on 5-HT (30??M)-induced peak currents. Above clinical concentrations, ergotamine (>3??M) inhibited them. When both drugs were applied together (0.10??M metoclopramide+0.001 to 0.01??M ergotamine), an inhibition of both, peak and integrated current responses was observed. Neither metoclopramide (?30??M) nor ergotamine (?30??M) had an effect on the 5-HT reuptake carrier as they did not alter the citalopram-sensitive [3H]5-HT uptake. PMID:16041395

Walkembach, Jan; Brüss, Michael; Urban, Bernd W; Barann, Martin



Electrophysiological evidence for rapid 5-HT?A autoreceptor inhibition by vilazodone, a 5-HT?A receptor partial agonist and 5-HT reuptake inhibitor.  


This study examined the effect of vilazodone, a combined serotonin (5-HT) reuptake inhibitor and 5-HT(1A) receptor partial agonist, paroxetine and fluoxetine on the sensitivity of 5-HT(1A) autoreceptors of serotonergic dorsal raphe nucleus neurons in rats. These effects were assessed by determining the intravenous dose of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) required to suppress the basal firing rate of these neurons by 50% (ID??) in anesthetized rats using in vivo electrophysiology. 5-HT uptake inhibition was determined by the ability of the compounds to reverse (±)-p-chloroamphetamine (PCA)-induced rat hypothalamic 5-HT depletion ex vivo. Acute vilazodone administration (0.63 and 2.1 µmol/kg, s.c.), compared with vehicle, significantly increased (2-3-fold) the ID?? of 8-OH-DPAT at 4 h, but not 24h after administration. Subchronic administration (3 days) significantly increased the ID?? value at 4 h (3-4-fold) and at 24 h (~2-fold). In contrast, paroxetine and fluoxetine at doses that were supramaximal for 5-HT uptake inhibition did not significantly alter the ID?? value of 8-OH-DPAT after acute or subchronic administration. Vilazodone antagonized the action of PCA 3.5 h and 5 h after a single dose (ID?? 1.49 and 0.46 µmol/kg, s.c., respectively), but was inactive 18 h post-administration, corroborating the electrophysiological results at 24 h following acute administration. The results are consistent with the concept of rapid and, following repeated treatment, prolonged inhibition of 5-HT(1A) autoreceptors by vilazodone. This effect could occur by either direct interaction with, or desensitization of, these receptors, an effect which cannot be ascribed to vilazodone's 5-HT reuptake inhibiting properties. PMID:23872377

Ashby, Charles R; Kehne, John H; Bartoszyk, Gerd D; Renda, Matthew J; Athanasiou, Maria; Pierz, Kerri A; Seyfried, Christoph A



Characterization of [³H]Lu AE60157 ([³H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) binding to 5-hydroxytryptamine? (5-HT?) receptors in vivo.  


The serotonin6 (5-HT(6)) receptor has received attention for its proposed role in cognitive impairments associated with schizophrenia and Alzheimer's disease. This has lead to a search for selective 5-HT(6) receptor ligands useful for in vivo imaging in animals and humans. The novel 5-HT(6) receptor antagonist Lu AE60157 (8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) displays high affinity for the human (h) 5-HT(6) receptor (K(d) 0.2nM), and broad profiling in 60 additional binding and enzyme assays showed that Lu AE60157 displays 16-fold selectivity to the h5-HT(2A) receptor (K(i) 3.2nM) and >100-fold selectivity to all other evaluated targets. Lu AE60157 was labeled with tritium in the N-methyl group and evaluated as a radioligand in vitro as well as in vivo in rats and mice. Autoradiography experiments showed that [(3)H]Lu AE60157 bound preferentially to rat brain regions with expected high 5-HT(6) receptor density. Furthermore, [(3)H]Lu AE60157 showed good brain penetration after systemic administration and high (about 75%) specific in vivo binding to the striatal 5-HT(6) receptor in rats. The striatal binding of [(3)H]Lu AE60157 was fully displaced by selective 5-HT(6) receptor antagonists (SB-742457; Lu AE58054) and antipsychotics known to inhibit the binding of 5-HT(6) receptors in vitro (clozapine; olanzapine; sertindole), but was not displaced by antipsychotics lacking high 5-HT(6) receptor affinities (risperidone; haloperidol; quetiapine). No specific binding to mouse brain tissue in vivo could be obtained. In conclusion, [(3)H]Lu AE60157 is suitable for measuring in vivo occupancies of 5-HT(6) receptor ligands in rat brain regions in which 5-HT(2A) receptors do not interfere. PMID:22155399

Witten, Louise; Bang-Andersen, Benny; Nielsen, Søren Møller; Miller, Silke; Christoffersen, Claus Tornby; Stensbøl, Tine Bryan; Brennum, Lise Tøttrup; Arnt, Jørn



5-Hydroxytryptamine (5HT, serotonin)-1A receptor in brain areas of alcohol-preferring P and non-preferring NP rats  

SciTech Connect

Binding of {sup 3}H-80HDPAT to 5HT-1A receptor in membranes isolated from cerebral cortex of P and NP rats which had not been exposed to ethanol were equally sensitive to the displacement by nanomolar concentrations of agonists, including 5HT, buspirone and ipsapirone, and of antagonists metergoline and spiperone. Binding with increasing concentrations of {sup 3}H-80HDPAT was saturable in membranes of cerebral cortex from P and NP rats. Scatchard analysis revealed single components of binding sites with dissociation constants of 1.54 and 2.03 nM and maximum density of 177.3 and 129.3 fmol/mg protein, respectively, suggesting higher affinity and density of 5HT-1A receptors in cerebral cortex of P than NP rats. Higher densities are also found in other brain areas, including hypothalamus, striatum and hippocampus, of P than NP rats, but not in brainstem. Thus, an enrichment of 5HT-1A receptors in specific brain areas was developed during selective breeding for alcohol preference, or an upregulation of the receptors resulted from the lower concentrations of 5HT in brain areas of P as compared with NP rats.

Reid, L.R.; Wong, D.T.; Li, T.K.; Lumeng, L. (Lilly Research Labs., Indianapolis, IN (United States) Indiana Univ., Indianapolis (United States))



Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5HT 3) receptor antagonists: effectiveness of ondansetron  

Microsoft Academic Search

The objective of the present study was to determine whether ondansetron, a specific serotonin type 3 receptor antagonist (5-HT3), relieves cholestatic pruritus in patients resistant to conventional antipruritic therapy (antihistamines and cholestyramine).In a placebo-controlled study the acute effect of an intravenous injection of ondansetron (4 mg, 8 mg) or placebo (NaCl solution) was tested in 10 patients (41–66 years of

Harald Schwörer; Heinz Hartmann; Giuliano Ramadori



5-Hydroxytryptamine metabolism in sheep  

PubMed Central

1. 5-Hydroxytryptamine (5-HT) (10 mg) administered intravenously to sheep was mostly excreted in the urine as 5-HT-O-glucuronide (705±162 ?g, mean from six wethers±S.E.M.) and 5-hydroxyindolylacetic acid (5-HIAA) (6,850±1,538 ?g). Oral administration of 5-HT (100 mg) led to the excretion of 590±212 ?g 5-HT-O-glucuronide (mean from five wethers±S.E.M.) and 7,394±2,093 ?g 5-HIAA in the urine. 2. After administration of DL-5-hydroxytryptophan (DL-5-HTP) (20 mg i.v. or 200 mg orally) sheep excreted about 5 mg 5-HT in the urine together with 5-HT-O-glucuronide and 5-HIAA. The excretion of 5-HT suggests that some DL-5-HTP perfused the liver and the lungs before being decarboxylated. 3. Twenty-four hour specimens of control urine contained 335±45 ?g 5-HT, 909±90 ?g 5-HT-O-glucuronide and 3,352±362 ?g 5-HIAA (seven sheep in each instance). Thus endogenous 5-HT seemed to be conjugated with glucuronic acid to a greater extent than administered 5-HT. 4. Although urinary 5-HIAA was reduced after a single dose of isocarboxazid (20 mg/kg daily) the 5-HT-O-glucuronide content of the specimens was not increased until two or three doses of the drug had been given. 5. Carbon tetrachloride (4 ml orally) reduced the urinary excretion of 5-HT-O-glucuronide. Although the conjugation of 5-HT with glucuronic acid was inhibited after administration of carbon tetrachloride the excretion of 5-HT and 5-HIAA was not increased. This observation suggests that carbon tetrachloride impaired the formation or clearance of endogenous 5-HT in sheep. PMID:5314578

Bartlet, A. L.



Blockade of the high-affinity noradrenaline transporter (NET) by the selective 5-HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice  

PubMed Central

BACKGROUND AND PURPOSE Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT]ext). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA]ext). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined. EXPERIMENTAL APPROACH This study examined the effects of escitalopram, on both [5-HT]ext and [NA]ext in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT?/?) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA]ext, either by a direct mechanism involving the inhibition of the low- or high-affinity noradrenaline transporters, or by an indirect mechanism promoted by [5-HT]ext elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT]ext and/or [NA]ext affected the antidepressant-like activity of escitalopram. KEY RESULTS In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT]ext and [NA]ext. As expected, escitalopram failed to increase cortical [5-HT]ext in SERT?/? mice, whereas its neurochemical effects on [NA]ext persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5-HT uptake mediated by low-affinity monoamine transporters. CONCLUSIONS AND IMPLICATIONS These experiments suggest that escitalopram enhances, although moderately, cortical [NA]extin vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET). PMID:22233336

Nguyen, Hai T; Guiard, Bruno P; Bacq, Alexandre; David, Denis J; David, Indira; Quesseveur, Gaël; Gautron, Sophie; Sanchez, Connie; Gardier, Alain M



Antidepressant-Like Activity of YL-0919: A Novel Combined Selective Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist  

PubMed Central

It has been suggested that drugs combining activities of selective serotonin reuptake inhibitor and 5-HT1A receptor agonist may form a novel strategy for higher therapeutic efficacy of antidepressant. The present study aimed to examine the pharmacology of YL-0919, a novel synthetic compound with combined high affinity and selectivity for serotonin transporter and 5-HT1A receptors. We performed in vitro binding and function assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of YL-0919. YL-0919 displayed high affinity in vitro to both 5-HT1A receptor and 5-HT transporter prepared from rat cortical tissue. It exerted an inhibitory effect on forskolin-stimulated cAMP formation and potently inhibited 5-HT uptake in both rat cortical synaptosomes and recombinant cells. After acute p.o. administration, very low doses of YL-0919 reduced the immobility time in tail suspension test and forced swimming test in mice and rats, with no significant effect on locomotor activity in open field test. Furthermore, WAY-100635 (a selective 5-HT1A receptor antagonist, 0.3 mg/kg) significantly blocked the effect of YL-0919 in tail suspension test and forced swimming test. In addition, chronic YL-0919 treatment significantly reversed the depressive-like behaviors in chronically stressed rats. These findings suggest that YL-0919, a novel structure compound, exerts dual effect on the serotonergic system, as both 5-HT1A receptor agonist and 5-HT uptake blocker, showing remarkable antidepressant effects in animal models. Therefore, YL-0919 may be used as a new option for the treatment of major depressive disorder. PMID:24367588

Zhang, Li-ming; Xue, Rui; Xu, Xiao-dan; Zhao, Nan; Qiu, Zhi-kun; Wang, Xian-wang; Zhang, You-zhi; Yang, Ri-fang; Li, Yun-feng



The role of the 5-hydroxytryptamine pathway in reflux-induced esophageal mucosal injury in rats  

PubMed Central

Background Dysfunction of the 5-hydroxytryptamine (5-HT) signaling pathway can lead to gastrointestinal motility and secretion abnormalities and to visceral hypersensitivity. The aim of this study is to investigate the role of 5-HT in reflux-induced esophageal mucosal injury. Methods Fifty 8-week-old male Sprague-Dawley (SD) rats were randomly divided into a gastroesophageal reflux (GER) model group (30 rats) and a sham surgery control group (20 rats). Four weeks after surgery, the esophageal mucosa was collected for histological evaluation, 5-HT concentrations, and 5-HT selective reuptake transporter (SERT) mRNA and 5-HT4 receptor (5-HT4R) protein expressions. Results Twenty-seven rats in the GER model group survived, and three rats died. Histologically, in the GER model group, 20 rats had reflux esophagitis (RE group), and 7 rats had non-erosive reflux disease (NERD group). The 5-HT levels in the esophageal tissue from the RE group were significantly higher than those from the control and NERD groups. Both the RE and NERD groups showed significant increases in SERT mRNA expression of the esophageal mucosa than that of the controls, and the SERT mRNA level in the RE group was significantly higher than that in the NERD group. The 5-HT4R protein level of the esophageal mucosa in the RE group was significantly lower than that in the controls and the NERD group. Conclusions We conclude that a 5-HT signaling pathway disorder could be a major factor in the pathogenesis of GER and RE. PMID:23092450



A 5-hydroxytryptamine receptor in human atrium.  

PubMed Central

1. The effects of 5-hydroxytryptamine (5-HT) were investigated on right atrial appendages obtained from patients treated with beta-adrenoceptor blocking agents who were undergoing open heart surgery. Atrial strips were paced under isometric conditions. 2. 5-HT increased contractile force to approximately one half of the force produced by a saturating concentration of (-)-isoprenaline. Both 5-HT and (-)-isoprenaline accelerated the onset of relaxation, as indicated by an abbreviation of time to peak force. 3. The effects of 5-HT were resistant to blockade by 0.4 microM (+/-)-propranolol, 1 microM (-)-pindolol, 0.4 microM methiothepin, 4 microM yohimbine, 0.4 microM ketanserin, 10 microM phenoxybenzamine, 1 microM methysergide, 2 microM MDL 72222 and 20 microM granisetron. 4. Cocaine 6 microM potentiated the effects of 5-HT, increasing the pEC50 from 6.6 to 7.4. The inotropic potency of 5-HT is five times greater than that of (-)-noradrenaline. 5. ICS 205930 antagonized competitively the effects of 5-HT with a pKB of 6.7. 6. In the presence of 0.4 microM (+/-)-propranolol, 10 microM 5-HT increased both adenosine 3':5' cyclic-monophosphate (cyclic AMP) levels and cyclic AMP-dependent protein kinase activity by approximately one half and two thirds respectively, of the corresponding effects of 200 microM (-)-isoprenaline. 7. Both the increase in cyclic AMP levels and the stimulation of protein kinase activity are consistent with the inotropic effects of 5-HT being mediated by cyclic AMP-dependent phosphorylation of Ca2+ channels and of proteins involved in contraction and relaxation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2169944

Kaumann, A. J.; Sanders, L.; Brown, A. M.; Murray, K. J.; Brown, M. J.



Acute Effects of Sceletium tortuosum (Zembrin), a Dual 5-HT Reuptake and PDE4 Inhibitor, in the Human Amygdala and its Connection to the Hypothalamus  

PubMed Central

The South African endemic plant Sceletium tortuosum has a long history of traditional use as a masticatory and medicine by San and Khoikhoi people and subsequently by European colonial farmers as a psychotropic in tincture form. Over the past decade, the plant has attracted increasing attention for its possible applications in promoting a sense of wellbeing and relieving stress in healthy individuals and for treating clinical anxiety and depression. The pharmacological actions of a standardized extract of the plant (Zembrin) have been reported to be dual PDE4 inhibition and 5-HT reuptake inhibition, a combination that has been argued to offer potential therapeutic advantages. Here we tested the acute effects of Zembrin administration in a pharmaco-fMRI study focused on anxiety-related activity in the amygdala and its connected neurocircuitry. In a double-blind, placebo-controlled, cross-over design, 16 healthy participants were scanned during performance in a perceptual-load and an emotion-matching task. Amygdala reactivity to fearful faces under low perceptual load conditions was attenuated after a single 25?mg dose of Zembrin. Follow-up connectivity analysis on the emotion-matching task showed that amygdala–hypothalamus coupling was also reduced. These results demonstrate, for the first time, the attenuating effects of S. tortuosum on the threat circuitry of the human brain and provide supporting evidence that the dual 5-HT reuptake inhibition and PDE4 inhibition of this extract might have anxiolytic potential by attenuating subcortical threat responsivity. PMID:23903032

Terburg, David; Syal, Supriya; Rosenberger, Lisa A; Heany, Sarah; Phillips, Nicole; Gericke, Nigel; Stein, Dan J; van Honk, Jack



Systemic modulation of serotonergic synapses via reuptake blockade or 5HT1A receptor antagonism does not alter perithreshold taste sensitivity in rats.  


Systemic blockade of serotonin (5HT) reuptake with paroxetine has been shown to increase sensitivity to sucrose and quinine in humans. Here, using a 2-response operant taste detection task, we measured the effect of paroxetine and the 5HT1A receptor antagonist WAY100635 on the ability of rats to discriminate sucrose, NaCl, and citric acid from water. After establishing individual psychometric functions, 5 concentrations of each taste stimulus were chosen to represent the dynamic portion of the concentration-response curve, and the performance of the rats to these stimuli was assessed after vehicle, paroxetine (7mg/kg intraperitoneally), and WAY100635 (0.3mg/kg subcutaneously; 1mg/kg intravenously) administration. Although, at times, overall performance across concentrations dropped, at most, 5% from vehicle to drug conditions, no differences relative to vehicle were seen on the parameters of the psychometric function (asymptote, slope, or EC50) after drug administration. In contrast to findings in humans, our results suggest that modulation of 5HT activity has little impact on sucrose detectability at perithreshold concentrations in rats, at least at the doses used in this task. In the rat model, the purported paracrine/neurocrine action of serotonin in the taste bud may work in a manner that does not impact overt taste detection behavior. PMID:25056731

Mathes, Clare M; Spector, Alan C



The 5-hydroxytryptamine 4 receptor agonist mosapride does not antagonize morphine-induced respiratory depression  

Microsoft Academic Search

Background: On the basis of experiments in rats, serotonin 4 receptor (5-hydroxytryptamine 4 [5-HT4]) agonists have been proposed as a novel therapeutic strategy for the selective treatment of respiratory depression caused by opioids while leaving analgesic effects unaffected. The effects in rats have been seen with the 5-hydroxytryptamine 4a (5-HT4a) agonist BIMU8, which is currently not available for use in

Jörn Lötsch; Carsten Skarke; Andreas Schneider; Thomas Hummel; Gerd Geisslinger




EPA Science Inventory

The intraperitoneal injection of 5-hydroxytryptamine (5-HT) in unrestrained and unanesthetized mice held at 22C causes a hypothermia which is maximal after approximately 15 minutes. When mice injected with 5-HT were held in a controlled environment of 22C and 50% relative humidit...


Antidepressant-Like Behavioral Effects in 5Hydroxytryptamine1A and 5Hydroxytryptamine1B Receptor Mutant Mice  

Microsoft Academic Search

The development of serotonin receptor knockout mice has provided an opportunity to study antidepressant drug effects in animals with targeted genetic deletion of receptors involved in antidepressant responses. In the current study, the effects of two types of antidepressant drugs, the selective serotonin re- uptake inhibitors fluoxetine and paroxetine and the selective norepinephrine reuptake inhibitor desipramine, were examined in 5-hydroxytryptamine



Comparative analysis of two types of 5-hydroxytryptamine receptor mediating vasorelaxation: differential classification using tryptamines  

Microsoft Academic Search

Two receptors mediating relaxant responses to 5-hydroxytryptamine (5-HT) were studied comparatively in rings of rabbit jugular vein contracted with U-46619 (10 nmol\\/l). At low concentrations of 5-HT (0.001–0.1 µmol\\/l) vascular relaxation was mediated indirectly by the endothelial 5-HT receptor previously described by Leff et al. (1987). In preparations denuded of endothelium, higher concentrations of the amine (0.03–30 µmol\\/l) caused relaxation

G. R. Martin; P. Leff; D. Cambridge; V. J. Barrett



Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study  

Microsoft Academic Search

Background—Increased concentrations of 5-hydroxytryptamine (5-HT) can be detected in the systemic circulation after a meal and may be involved in the physiological control of gastrointestinal motility. Abnormalities of 5-HT release after a meal might explain some of the postprandial symptoms associated with the irritable bowel syndrome (IBS).Aim—To investigate the effect of a standard meal on plasma 5-HT and urinary 5-hydroxyindole

C P Bearcroft; D Perrett; M J G Farthing



Recent advances in understanding the role of serotonin in gastrointestinal motility in functional bowel disorders: alterations in 5-HT signalling and metabolism in human disease.  


Serotonin (5-hydroxytryptamine, 5-HT) is present in abundance within the gut, most stored in enterochromaffin cell granules. It is released by a range of stimuli, most potently by mucosal stroking. Released 5-HT stimulates local enteric nervous reflexes to initiate secretion and propulsive motility. It also acts on vagal afferents altering motility and in large amounts induces nausea. Rapid reuptake by a specific transporter (serotonin transporter, SERT) limits its diffusion and actions. Abnormally increased 5-HT is found in a range of gastrointestinal disorders including chemotherapy-induced nausea and vomiting, carcinoid syndrome, coeliac disease, inflammatory bowel disease and irritable bowel syndrome (IBS) with diarrhoea (IBS-D), especially that developing following enteric infection. Impaired SERT has been described in IBS-D and might account for some of the increase in mucosal 5-HT availability. 5-HT(3) receptor antagonists inhibit chemotherapy-induced nausea and diarrhoea associated with both carcinoid syndrome and IBS. While IBS-D is associated with increased 5-HT postprandially, IBS with constipation (IBS-C) is associated with impaired 5-HT response and responds to 5-HT(4) agonists such as Prucalopride and 5-HT(4) partial agonists such as Tegaserod. PMID:17620085

Spiller, R



Mechanism of the AntiEmetic Activity of 5HT3 Receptor Antagonists  

Microsoft Academic Search

Ondansetron, a potent and highly selective 5-HT3 receptor antagonist, prevents emesis following chemotherapy by antagonising the action of 5-hydroxytryptamine (5-HT) at 5-HT3 receptors on vagal afferent neurones that innervate the gastrointestinal tract and 5-HT3 receptors in the central vomiting system. Evidence suggests that chemotherapy induces the release of 5-HT from enterochromaffin cells in the small intestine. This stimulates vagal afferent

M. B. Tyers; A. J. Freeman



5Hydroxytryptamine modifies neuronal responses to glutamate in the red nucleus of the rat  

Microsoft Academic Search

The effects of 5-hydroxytryptamine (5-HT) on the responses of red nucleus (RN) neurones to glutamate (glu) and its agonists\\u000a were studied using a microiontophoretic technique in anaesthetised rats. Extracellular unitary recordings of RN neuronal activity\\u000a showed that 5-HT application induced a significant and reversible depression of glu-evoked excitations in 85% of the RN units\\u000a tested. This effect was independent of

Flora Licata; Guido Li Volsi; Lucia Ciranna; Giuseppe Maugeri; Francesca Santangelo



Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat  

PubMed Central

The effects of the potent 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI), sibutramine, on the cumulative food intake of freely-feeding male Sprague-Dawley rats during an 8?h dark period were investigated and compared to those of the selective 5-HT reuptake inhibitor (selective serotonin reuptake inhibitor, SSRI), fluoxetine; the selective noradrenaline reuptake inhibitor, nisoxetine; the 5-HT and noradrenaline reuptake inhibitors, venlafaxine and duloxetine; and the 5-HT releaser and 5-HT reuptake inhibitor, (+)-fenfluramine. Sibutramine (3 and 10?mg?kg?1, p.o.) and (+)-fenfluramine (1 and 3?mg?kg?1, p.o.) produced a significant, dose-dependent decrease in food intake over the 8?h dark period. These responses became apparent within the first 2?h following drug administration. Fluoxetine (3, 10 and 30?mg?kg?1, p.o.), and nisoxetine (3, 10 and 30?mg?kg?1, p.o.) had no significant effect on food intake during the 8?h dark period. However, a combination of fluoxetine and nisoxetine (30?mg?kg?1, p.o., of each) significantly decreased food intake 2 and 8?h after drug administration. Venlafaxine (100 and 300?mg?kg?1, p.o.) and duloxetine (30?mg?kg?1, p.o.) also significantly decreased food intake in the 2 and 8?h following drug administration. The results of this study demonstrate that inhibition of 5-HT and noradrenaline reuptake by sibutramine, venlafaxine, duloxetine, or by a combination of fluoxetine and nisoxetine, markedly reduces food intake in freely-feeding rats and suggest that this may be a novel approach for the treatment of obesity. PMID:9283714

Jackson, Helen C; Needham, Andrew M; Hutchins, Lisa J; Mazurkiewicz, Sarah E; Heal, David J



Direct Subunit-Dependent Multimodal 5-Hydroxytryptamine3 Receptor Antagonism by Methadone  

PubMed Central

Homomeric 5-hydroxytryptamine (5-HT)3A and heteromeric 5-HT3AB receptors mediate rapid excitatory responses to serotonin in the central and peripheral nervous systems. The alkaloid morphine, in addition to being a ?-opioid receptor agonist, is a potent competitive inhibitor of 5-HT3 receptors. We examined whether methadone, an opioid often used to treat morphine dependence, also exhibited 5-HT3 receptor antagonist properties. Racemic (R/S)-methadone inhibited currents mediated by human homomeric 5-HT3A receptors (IC50 = 14.1 ± 2.5 ?M). Incorporation of the 5-HT3B subunit into heteromeric 5-HT3AB receptors reduced the potency of inhibition by (R/S)-methadone (IC50 = 41.1 ± 0.9 ?M). (R/S)-Methadone also increased apparent desensitization of both 5-HT3 receptor subtypes. The inhibition of the 5-HT3A receptor was competitive; however, incorporation of the 5-HT3B subunit caused the appearance of inhibition that was insurmountable by 5-HT. In the absence of rapid desensitization, when dopamine was used as an agonist of 5-HT3AB receptors, the inhibition by (R/S)-methadone was voltage-dependent. The antagonist and desensitization-enhancing effects of (R/S)-methadone were shared by pure (R)- and (S)-methadone enantiomers, which had similar actions on 5-HT-evoked currents mediated by 5-HT3 receptors. However, (R)-methadone exhibited a larger voltage-dependent inhibition of dopamine-evoked currents mediated by 5-HT3AB receptors than did (S)-methadone. Inhibition of 5-HT3A receptors by (R/S)-methadone was not influenced by voltage. Thus, methadone displays multimodal subunit-dependent antagonism of 5-HT3 receptors. PMID:19131665

Deeb, Tarek Z.; Sharp, Douglas; Hales, Tim G.



Effects of 5-HT2B, 5-HT3 and 5-HT4 receptor antagonists on gastrointestinal motor activity in dogs  

PubMed Central

AIM: To study the effects of 5-hydroxytryptamine (5-HT) receptor antagonists on normal colonic motor activity in conscious dogs. METHODS: Colonic motor activity was recorded using a strain gauge force transducer in 5 dogs before and after 5-HT2B, 5-HT3 and 5-HT4 receptor antagonist administration. The force transducers were implanted on the serosal surfaces of the gastric antrum, terminal ileum, ileocecal sphincter and colon. Test materials or vehicle alone was administered as an intravenous bolus injection during a quiescent period of the whole colon in the interdigestive state. The effects of these receptor antagonists on normal gastrointestinal motor activity were analyzed. RESULTS: 5-HT2B, 5-HT3 and 5-HT4 receptor antagonists had no contractile effect on the fasting canine terminal ileum. The 5-HT3 and 5-HT4 receptor antagonists inhibited phase III of the interdigestive motor complex of the antrum and significantly inhibited colonic motor activity. In the proximal colon, the inhibitory effect was dose dependent. Dose dependency, however, was not observed in the distal colon. The 5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity. CONCLUSION: The 5-HT3 and 5-HT4 receptor antagonists inhibited normal colonic motor activity. The 5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity. PMID:24151388

Morita, Hiroki; Mochiki, Erito; Takahashi, Nobuyuki; Kawamura, Kiyoshi; Watanabe, Akira; Sutou, Toshinaga; Ogawa, Atsushi; Yanai, Mitsuhiro; Ogata, Kyoichi; Fujii, Takaaki; Ohno, Tetsuro; Tsutsumi, Souichi; Asao, Takayuki; Kuwano, Hiroyuki



Alniditan, a new 5-hydroxytryptamine1D agonist and migraine-abortive agent: ligand-binding properties of human 5-hydroxytryptamine1D alpha, human 5-hydroxytryptamine1D beta, and calf 5-hydroxytryptamine1D receptors investigated with [3H]5-hydroxytryptamine and [3H]alniditan.  


Alniditan is a new migraine-abortive agent. It is a benzopyran derivative and therefore structurally unrelated to sumatriptan and other indole-derivatives and to ergoline derivatives. The action of sumatriptan is thought to be mediated by 5-hydroxytryptamine (5-HT)1D-type receptors. We investigated the receptor-binding profile in vitro of alniditan compared with sumatriptan and dihydroergotamine for 28 neurotransmitter receptor subtypes, several receptors for peptides and lipid-derived factors, ion channel-binding sites, and monoamine transporters. Alniditan revealed nanomolar affinity for calf substantia nigra 5-HT1D and for cloned h5-HT1D alpha, h5-HT1D beta and h5-HT1A receptors (Ki = 0.8, 0.4, 1.1, and 3.8 nM, respectively). Alniditan was more potent than sumatriptan at 5-HT1D-type and 5-HT1A receptors. Alniditan showed moderate-to-low or no affinity for other investigated receptors; sumatriptan showed additional binding to 5-HT1F receptors. Dihydroergotamine had a much broader profile with high affinity for several 5-HT, adrenergic and dopaminergic receptors. In signal transduction assays using cells expressing recombinant h5-HT1D alpha, h5-HT1D beta, or h5-HT1A receptors, alniditan (like 5-HT) was a full agonist for inhibition of stimulated adenylyl cyclase (IC50 = 1.1, 1.3, and 74 nM, respectively, for alniditan). Therefore, in functional assays, the potency of alniditan was much higher at 5-HT1D receptors than at 5-HT1A receptors. We further compared the properties of [3H]alniditan, as a new radioligand for 5-HT1D-type receptors, with those of [3H]5-HT in membrane preparations of calf substantia nigra, C6 glioma cells expressing h5-HT1D alpha, and L929 cells expressing h5-HT1D beta receptors. [3H]Alniditan revealed very rapid association and dissociation binding kinetics and showed slightly higher affinity (Kd = 1-2 nM) than [3H]5-HT. We investigated 25 compounds for inhibition of [3H]alniditan and [3H]5-HT binding in the three membrane preparations; Ki values of the radioligands were largely similar, although some subtle differences appeared. Most compounds did not differentiate between 5-HT1D alpha and 5-HT1D beta receptors, except methysergide, ritanserin, ocaperidone, risperidone, and ketanserin, which showed 10-60-fold higher affinity for the 5-HT1D alpha receptor. The Ki values of the compounds obtained with 5-HT1D receptors in calf substantia nigra indicated that these receptors are of the 5-HT1D beta-type. We demonstrated that alniditan is a potent agonist at h5-HT1D alpha and h5-HT1D beta receptors; its properties probably underlie its cranial vasoconstrictive and antimigraine properties. PMID:8967979

Leysen, J E; Gommeren, W; Heylen, L; Luyten, W H; Van de Weyer, I; Vanhoenacker, P; Haegeman, G; Schotte, A; Van Gompel, P; Wouters, R; Lesage, A S



An electrophysiological study of 5-hydroxytryptamine receptors of neurones in the molluscan nervous system  

PubMed Central

1. 5-Hydroxytryptamine (5-HT) has been iontophoretically applied to the membrane of central neurones of Cryptomphallus aspersa; CILDA neurones (cells with inhibition of long duration) (Gerschenfeld & Tauc, 1964) are the only cells sensitive to 5-HT. The responses to 5-HT is always a depolarization. The CILDA cells studied were also depolarized by ACh. 2. From experiments in which pulses of 5-HT and ACh were applied from a double-barrelled micropipette to the CILDA cell soma, it has been calculated that 5-HT and ACh receptors were located at different distances from the injecting micropipette tip. It has also been calculated from the diffusion equation that in the same CILDA cell a 5-HT concentration of 8·2 × 10-9 M and a ACh concentration of 1·3 × 10-8 M caused a similar peak depolarization. 3. CILDA neurones show `anomalous' rectification. 5-HT increases the membrane conductance of CILDA. 4. 5-HT receptors of CILDA neurone are desensitized by repeated application of 5-HT. The desensitization lasts for ca. 40 sec. 5. 5-HT receptors are blocked by lysergic acid diethylamide and its derivatives. Morphine chlorhydrate blocks them non-competitively. 6. Some inhibitors of monoamine oxidase (trancylpromine, isocarboxazide, iproniazide and nialamide) have been tested. They do not prolong the action of 5-HT, but block the 5-HT receptors. 7. No crossed desensitization between 5-HT and ACh has been observed. Atropine blocks both ACh-receptors and 5-HT receptors, 5-HT receptors appear to be blocked to a greater extent. 8. The data presented support the assumption of a excitatory transmitter role of 5-HT to CILDA neurones, but further evidence is necessary to confirm this hypothesis. PMID:5918062

Gerschenfeld, H. M.; Stefani, E.



Radioisotopic studies of the binding, exchange, and distribution of 5-hydroxytryptamine synthesized from its radioactivity precursor  

PubMed Central

1. The synthesis, distribution, storage, and subsequent metabolism of 5-hydroxytryptamine (5-HT) produced in mice from the administration of its radioactive precursor, 5-hydroxytryptophan, has been investigated to form the basis for a similar study to be conducted by radioautography. 2. Intravenous injection of the radioactive material was found to be essential for significant uptake of radioactivity by tissue. The duration of the period during which radioactive material was available for uptake by the tissue was 2 hr. 3. The relative distribution of radioactivity in individual organs was studied and the radioactive compounds present in each were identified and quantitatively assayed. No unrelated routes of metabolism of the labelled material were found and radioautographic results may be interpreted in terms of the metabolic picture which emerged. 4. Radioactive 5-HT was bound in tissues in preference to both its precursor, and metabolite, 5-hydroxytryptamine-O-glucuronide, and the radioactive 5-HT produced in vivo after the injection of labelled 5-hydroxytryptophan probably entered and labelled the endogenous 5-HT pool. 5. Fixatives prepared with buffer solutions made hypertonic by the addition of sucrose could rapidly and effectively halt the movement of radioactive 5-HT out of tissues and prevent its subsequent extraction during histological processing. 6. It is concluded that localization of sites concerned with 5-HT metabolism by means of radioautography is feasible and the 5-HT so localized will probably reflect the physiological compartmentalization of the amine. PMID:5298336

Gershon, M. D.; Ross, L. L.



Release of 3H-5-hydroxytryptamine from isolated rabbit aorta.  


The main aim of the present investigation was to study systematically the passive and stimulation-evoked release of 3H-5-hydroxytryptamine (3H-5-HT) from rabbit isolated aorta. This was accomplished by preloading rings of aorta with 3H-5-HT (10(-6)M) and then monitoring by fractional collection the basal 3H-outflow and stimulation-evoked 3H-overflow. The basal 3H-outflow from aorta preloaded with 10(-6)M of either 3H-5-HT or (-)-3H-noradrenaline (3H-NA) leveled off about 100 min. after the onset of wash-out and remained almost constant thereafter (100-240 min.). The basal 3H-outflow from tissue preloaded with 3H-5-HT was almost 3-fold higher (70-240 min.) than that seen after preloading with 3H-NA. Cocaine (3 x 10(-5)M) did not alter the basal 3H-outflow (15-240 min.) from tissue preloaded with 3H-5-HT, while pargyline (5 x 10(-4)M) decreased it by about 66% (100-240 min.). Electrical-field stimulation (S1-S7, 200 mA, 600 pulses, 0.5 msec., 3 Hz) were applied to the tissue. The initial stimulation-evoked 3H-overflow from aorta preloaded with 3H-5-HT was higher than the subsequent ones (S1-S7; 100, 35, 35, 35, 35, 37, and 40%). Similar results to these were obtained with tissues preloaded with 3H-NA. The stimulation (S1-S7; 200 mA). 600 pulses, 0.5 msec, 3 Hz)-evoked 3H-overflow increased in an apparent linear manner with the amount of current used (50-200 mA).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7617558

Gouliaev, A H; Nedergaard, O A



Dopamine uptake inhibitor-induced rotation in 6-hydroxydopamine-lesioned rats involves both D1 and D2 receptors but is modulated through 5-hydroxytryptamine and noradrenaline receptors.  


Dopamine uptake inhibitors may provide a means of sustaining endogenous and exogenous striatal dopamine levels in Parkinson's disease, but most are not selective and also inhibit the noradrenaline and 5-hydroxytryptamine (5-HT) transporters. To determine the involvement of the individual monoamine transporters in the production of motor activity, the effect of the nonselective monoamine uptake inhibitor BTS 74 398 1-([1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio) ethanone monocitrate) and the selective dopamine, GBR 12909 [1-(2-(bis-(4-fluorphenyl)-methyl)ethyl)-4-(3-phenylpropyl)piperazine) dihydrochloride], noradrenaline (nisoxetine), and 5-HT (fluvoxamine) reuptake inhibitors on circling in the unilateral 6-hydroxydopamine-lesioned rat was investigated. GBR 12909 induced ipsilateral circling, but fluvoxamine and nisoxetine were without effect. However, when administered with GBR 12909, fluvoxamine enhanced rotation, whereas nisoxetine had no effect. The results suggest that 5-HT, but not noradrenaline, reuptake inhibition facilitates dopamine-mediated motor activity. To test this hypothesis, BTS 74 398 was administered in combination with selective dopamine, 5-HT, and noradrenaline receptor antagonists. Both D(1) and D(2) receptor antagonists, SCH 23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] and raclopride, inhibited BTS 74 398-induced circling. In contrast, the 5-HT(1A) 5-HT(1A/B) antagonists, WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexane-carboxamide maleate) and pindolol, and the 5-HT(2A) antagonist, ketanserin, had no effect. The nonspecific 5-HT((1/2)) antagonists, methysergide and metergoline, and the specific 5-HT(2C) antagonist, N-desmethylclozapine, enhanced BTS 74 398-induced circling, as did the alpha(2)-adrenoceptor antagonist idazoxan. Overall, the data suggest that inhibition of the 5-HT and noradrenaline transporters modulate dopamine uptake inhibitor-mediated motor activity. However, the mechanism of this interaction is complex, involving opposing effects of noradrenaline and 5-HT agonism and antagonism. PMID:15542624

Lane, E L; Cheetham, S; Jenner, P



GR 38032F (Ondansetron), a selective 5HT 3 receptor antagonist, slows colonic transit in healthy man  

Microsoft Academic Search

The newly recognized class of 5-hydroxytryptamine receptors (5HT3) may be involved in the induction of nausea, since their pharmacological antagonists are effective against emesis induced by chemotherapy. 5HT3 receptors are present on enteric neurons, and 5HT3 blockers may produce mild constipation; we thus hypothesized that 5HT3 receptors would modulate colonic motility. To determine if GR 38032F, a selective 5HT3 antagonist

N. J. Talley; S. F. Phillips; A. Haddad; L. J. Miller; C. Twomey; A. R. Zinsmeister; R. L. MacCarty; A. Ciociola



Memory formation and memory alterations: 5-HT6 and 5-HT7 receptors, novel alternative.  


Agonists and antagonists of the 5-hydroxytryptamine (serotonin) receptor6 (5-HT6) or receptor7 (5-HT7) might improve memory and/or reverse amnesia, although the mechanisms involved are poorly understood. Hence, the current work summarizes recent reviews and findings involving these receptors. Evidence indicates that diverse 5-HT6 receptor antagonists produce promnesic and/or antiamnesic effect in conditions, such as memory formation, age-related cognitive impairments and memory deficit in preclinical studies, as well as in diseases such as schizophrenia, Parkinson's, and Alzheimer's disease (AD). Memory, aging, and AD modify 5-HT6 receptors and signaling cascades; likewise, the modulation of 5-HT6 drugs on memory seems to be accompanied with neural changes. Moreover, 5-HT7 receptors are localized in brain areas mediating memory, including the cortex, hippocampus (e.g., Zola-Morgan and Squire, 1993) and raphe nuclei; however, the role of these receptors on memory has yet to be fully explored. Hence, findings and reviews are summarized in this work. Evidence suggests that both 5-HT7 receptor agonists and antagonists might have promnesic and anti-amnesic effects. These effects seem to be dependent on the basal level of performance, i.e., normal or impaired. Available evidence suggests that a potential utility of 5-HT6 and 5-HT7 receptor in mild-to-moderate AD patients and other memory dysfunctions as therapeutic targets. PMID:24698823

Meneses, Alfredo



Identification of a novel 5-HT(4) receptor splice variant (r5-HT(4c1)) and preliminary characterisation of specific 5-HT(4a) and 5-HT(4b) receptor antibodies.  


The human 5-hydroxytryptamine (5-HT(4)) receptor is encoded by a highly complex gene which gives rise to at least 10 distinct splice variants. However, the functional relevance of these variants is unknown. In rat, only three such variants have been identified, 5-HT(4a) (r5-HT(4a)), 5-HT(4b) (r5-HT(4b)) and 5-HT(4e) (r5-HT(4e)). In the current study we identify and characterise the pharmacology of a novel rat splice variant (r5-HT(4c1)) and present the first comprehensive analysis of 5-HT(4) splice variant mRNA expression levels throughout the rat gastrointestinal tract. In addition, we describe preliminary characterisation of the first 5-HT(4) splice variant specific antibodies. In transfected cells, r5-HT(4c1) receptor exhibited similar binding properties to r5-HT(4a) and r5-HT(4b). Functional studies showed that 5-HT(4) agonists prucalopride (4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofuran carboxamide monohydrochloride and renzapride (+/-)-endo-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide monohydrochloride) acted as partial agonists at r5-HT(4c1), but full agonists at r5-HT(4a) and r5-HT(4b). Moreover, in contrast to r5-HT(4a) and r5-HT(4b), r5-HT(4c1) was not constitutively active. TaqMan mRNA analysis showed that r5-HT(4a) expression in brain and dorsal root ganglion exceeded that in the gastrointestinal tract, whilst the reverse was true for r5-HT(4b) and r5-HT(4c1). mRNA expression of each variant also increased distally throughout the gastrointestinal tract with the highest levels in the colon. r5-HT(4a) and r5-HT(4b) specific immunoreactivity was abundant on enteric neurons in jejunum, ileum and colon as well as neurons and satellite cells of the dorsal root ganglion. Only r5-HT(4b) immunoreactivity was observed on endocrine cells in the duodenum. These data could have implications in rat models and aid understanding of 5-HT(4) splice variant function. PMID:19100256

Ray, Alison M; Kelsell, Rosemary E; Houp, Jennifer A; Kelly, Fiona M; Medhurst, Andrew D; Cox, Helen M; Calver, Andrew R



Characterization of a novel /sup 3/H-5-hydroxytryptamine binding site subtype in bovine brain membranes  

SciTech Connect

/sup 3/H-5-Hydroxytryptamine (5-HT) binding sites were analyzed in bovine brain membranes. The addition of either the 5-HT1A-selective drug 8-OH-DPAT (100 nM) or the 5-HT1C-selective drug mesulergine (100 nM) to the assay resulted in a 5-10% decrease in specific /sup 3/H-5-HT binding. Scatchard analysis revealed that the simultaneous addition of both drugs decreased the Bmax of /sup 3/H-5-HT binding by 10-15% without affecting the KD value (1.8 +/- 0.3 nM). Competition studies using a series of pharmacologic agents revealed that the sites labeled by /sup 3/H-5-HT in bovine caudate in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine appear to be homogeneous. 5-HT1A selective agents such as 8-OH-DPAT, ipsapirone, and buspirone display micromolar affinities for these sites. RU 24969 and (-)pindolol are approximately 2 orders of magnitude less potent at these sites than at 5-HT1B sites which have been identified in rat brain. Agents displaying nanomolar potencies for 5-HT1C sites such as mianserin and mesulergine are 2-3 orders of magnitude less potent at the /sup 3/H-5-HT binding sites in bovine caudate. In addition, both 5-HT2- and 5-HT3-selective agents are essentially inactive at these binding sites. These /sup 3/H-5-HT sites display nanomolar affinity for 5-carboxyamidotryptamine, 5-methoxytryptamine, metergoline, and 5-HT. Apparent Ki values of 10-100 nM are obtained for d-LSD, RU 24969, methiothepin, tryptamine, methysergide, and yohimbine, whereas I-LSD and corynanthine are significantly less potent. In addition, these /sup 3/H-5-HT labeled sites are regulated by guanine nucleotides and calcium. Regional studies indicate that this class of sites is most dense in the basal ganglia but exists in all regions of bovine brain. These data therefore demonstrate the presence of a homogeneous class of 5-HT1 binding sites in bovine caudate that is pharmacologically distinct from previously defined 5-HT1A, 5-HT1B, 5-HT1C, 5-HT2, and 5-HT3 receptor subtypes. (Abstract Truncated)

Heuring, R.E.; Peroutka, S.J.



Contractile 5-HT1 receptors in human isolated pial arterioles: correlation with 5-HT1D binding sites.  

PubMed Central

1. The 5-hydroxytryptamine (5-HT) receptor responsible for inducing vasoconstriction in human isolated pial arterioles has been pharmacologically characterized. 2. Of several 5-HT agonists tested, 5-carboxamidotryptamine (5-CT) was the most potent and the rank order of agonist potency can be summarized as: 5-CT greater than 5-HT greater than RU 24969 = alpha-methyl-5-HT = methysergide much greater than MDL 72832 = 2-methyl-5-HT much greater than 2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydro-naphthalene (8-OH-DPAT). With few exceptions, the maximal contractile responses of these agonists were comparable to that induced by 5-HT. 3. A correlation analysis performed between the agonists vascular potency (pD2 values) and their affinities (pKD values) published at various subtypes of 5-HT binding sites showed a positive significant correlation with rat cortical 5-HT1B (r = 0.86; P less than 0.01) and human caudate 5-HT1D (r = 0.98; P less than 0.005) subtypes. 4. Selective antagonists at 5-HT2 (ketanserin, mianserin, MDL 11939) and 5-HT3 (MDL 72222) sites were totally devoid of inhibitory activity on the 5-HT-induced contraction, an observation which agreed with the agonist data and further excluded activation of these receptors. In contrast, the 5-HT1-like/5-HT2 antagonist methiothepin and the non-selective 5-HT1D compound metergoline inhibited with high affinity the contraction induced by 5-HT with respective pA2 values of 8.55 +/- 0.16 and 6.88 +/- 0.05. This contractile response was, however, insensitive to 5-HT1B (propranolol) and 5-HT1C (mesulergine, mianserin) antagonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2043924

Hamel, E.; Bouchard, D.



Experimental diabetes induces hyperreactivity of rabbit renal artery to 5-hydroxytryptamine.  


The influence of diabetes on the response of isolated rabbit renal arteries to 5-hydroxytryptamine (5-HT) was examined. 5-HT induced a concentration-related contraction that was higher in arteries from diabetic rabbits than in arteries from control rabbits. Endothelium removal did not significantly modify 5-HT contractions in arteries from control rabbits but enhanced the response to 5-HT in arteries from diabetic rabbits. Incubation with N(G)-nitro-L-arginine (L-NA) enhanced contractions to 5-HT in arteries from control and diabetic rabbits. In arteries with endothelium, this L-NA enhancement was lower in diabetic rabbits than in control rabbits. In arteries without endothelium, incubation with L-NA enhanced the maximal contractions to 5-HT in control rabbits but did not in diabetic rabbits. Indomethacin inhibited 5-HT-induced contraction of arteries from control rabbits and enhanced the maximal contraction to 5-HT of arteries from diabetic rabbits. In summary, diabetes enhances contractile response of rabbit renal artery to 5-HT. In control animals, this response is regulated by both endothelial and non-endothelial (neuronal) nitric oxide (NO) and by a vasoconstrictor prostanoid. Diabetes impairs the release of non-endothelial NO and the vasoconstrictor prostanoid. PMID:11937101

Miranda, Francisco J; Alabadí, José A; Lloréns, Silvia; Ruiz de Apodaca, Rosa F; Centeno, José M; Alborch, Enrique



Serotonin Augments Gut Pacemaker Activity via 5-HT3 Receptors  

PubMed Central

Serotonin (5-hydroxytryptamine: 5-HT) affects numerous functions in the gut, such as secretion, muscle contraction, and enteric nervous activity, and therefore to clarify details of 5-HT's actions leads to good therapeutic strategies for gut functional disorders. The role of interstitial cells of Cajal (ICC), as pacemaker cells, has been recognised relatively recently. We thus investigated 5-HT actions on ICC pacemaker activity. Muscle preparations with myenteric plexus were isolated from the murine ileum. Spatio-temporal measurements of intracellular Ca2+ and electric activities in ICC were performed by employing fluorescent Ca2+ imaging and microelectrode array (MEA) systems, respectively. Dihydropyridine (DHP) Ca2+ antagonists and tetrodotoxin (TTX) were applied to suppress smooth muscle and nerve activities, respectively. 5-HT significantly enhanced spontaneous Ca2+ oscillations that are considered to underlie electric pacemaker activity in ICC. LY-278584, a 5-HT3 receptor antagonist suppressed spontaneous Ca2+ activity in ICC, while 2-methylserotonin (2-Me-5-HT), a 5-HT3 receptor agonist, restored it. GR113808, a selective antagonist for 5-HT4, and O-methyl-5-HT (O-Me-5-HT), a non-selective 5-HT receptor agonist lacking affinity for 5-HT3 receptors, had little effect on ICC Ca2+ activity. In MEA measurements of ICC electric activity, 5-HT and 2-Me-5-HT caused excitatory effects. RT-PCR and immunostaining confirmed expression of 5-HT3 receptors in ICC. The results indicate that 5-HT augments ICC pacemaker activity via 5-HT3 receptors. ICC appear to be a promising target for treatment of functional motility disorders of the gut, for example, irritable bowel syndrome. PMID:21949791

Liu, Hong-Nian; Ohya, Susumu; Nishizawa, Yuji; Sawamura, Kenta; Iino, Satoshi; Syed, Mohsin Md; Goto, Kazunori; Imaizumi, Yuji; Nakayama, Shinsuke



Leukotrienes mediate 5-hydroxytryptamine-induced plasm extravasation in the rat knee joint via CysLT-type receptors  

Microsoft Academic Search

Objective and design:The aim of this study was to investigate whether leukotrienes synthesized by 5-lipoxygenase (5-LO) and acting via leukotriene (LT) receptors contribute to 5-hydroxytryptamine (5-HT)-induced knee joint plasma extravasation (PE). Materials and methods:Knee joints of rats under anesthesia were perfused with 5-HT and synovial vascular Evans Blue dye leakage was measured spectrophotometrically. A series of 5-LO inhibitors and LT

Y. Wang; J. Mitchell; M. Sharma; A. Gabriel; K. Moriyama; P. Pierce Palmer



Upregulation of 5-Hydroxytryptamine Receptor Signaling in Coronary Arteries after Organ Culture  

PubMed Central

Background 5-Hydroxytryptamine (5-HT) is a powerful constrictor of coronary arteries and is considered to be involved in the pathophysiological mechanisms of coronary-artery spasm. However, the mechanism of enhancement of coronary-artery constriction to 5-HT during the development of coronary artery disease remains to be elucidated. Organ culture of intact blood-vessel segments has been suggested as a model for the phenotypic changes of smooth muscle cells in cardiovascular disease. Methodology/Principal Findings We wished to characterize 5-HT receptor-induced vasoconstriction and quantify expression of 5-HT receptor signaling in cultured rat coronary arteries. Cumulative application of 5-HT produced a concentration-dependent vasoconstriction in fresh and 24 h-cultured rat coronary arteries without endothelia. 5-HT induced greater constriction in cultured coronary arteries than in fresh coronary arteries. U46619- and CaCl2-induced constriction in the two groups was comparable. 5-HT stimulates the 5-HT2A receptor and cascade of phospholipase C to induce coronary vasoconstriction. Calcium influx through L-type calcium channels and non-L-type calcium channels contributed to the coronary-artery constrictions induced by 5-HT. The contractions mediated by non-L-type calcium channels were significantly enhanced in cultured coronary arteries compared with fresh coronary arteries. The vasoconstriction induced by thapsigargin was also augmented in cultured coronary arteries. The decrease in Orai1 expression significantly inhibited 5-HT-evoked entry of Ca2+ in coronary artery cells. Expression of the 5-HT2A receptor, Orai1 and STIM1 were augmented in cultured coronary arteries compared with fresh coronary arteries. Conclusions An increased contraction in response to 5-HT was mediated by the upregulation of 5-HT2A receptors and downstream signaling in cultured coronary arteries. PMID:25202989

Rao, Fang; Xue, Yu-Mei; Zhou, Zhi-Ling; Liu, Xiao-Ying; Shan, Zhi-Xin; Li, Xiao-Hong; Lin, Qiu-Xiong; Wu, Shu-Lin; Yu, Xi-Yong



Chronic escitalopram treatment caused dissociative adaptation in serotonin (5-HT) 2C receptor antagonist-induced effects in REM sleep, wake and theta wave activity.  


Several multi-target drugs used in treating psychiatric disorders, such as antidepressants (e.g. agomelatine, trazodone, nefazodone, amitriptyline, mirtazapine, mianserin, fluoxetine) or most atypical antipsychotics, have 5-hydroxytryptamine 2C (5-HT2C) receptor-blocking property. Adaptive changes in 5-HT2C receptor-mediated functions are suggested to contribute to therapeutic effects of selective serotonin reuptake inhibitor (SSRI) antidepressants after weeks of treatment, at least in part. Beyond the mediation of anxiety and other functions, 5-HT2C receptors are involved in sleep regulation. Anxiety-related adaptive changes caused by antidepressants have been studied extensively, although sleep- and electroencephalography (EEG)-related functional studies are still lacking. The aim of this study was to investigate the effects of chronic SSRI treatment on 5-HT2C receptor antagonist-induced functions in different vigilance stages and on quantitative EEG (Q-EEG) spectra. Rats were treated with a single dose of the selective 5-HT2C receptor antagonist SB-242084 (1 mg/kg, i.p.) or vehicle at the beginning of passive phase following a 20-day-long SSRI (escitalopram; 10 mg/kg/day, osmotic minipump) or VEHICLE pretreatment. Fronto-parietal electroencephalogram, electromyogram and motility were recorded during the first 3 h of passive phase. We found that the chronic escitalopram pretreatment attenuated the SB-242084-caused suppression in rapid eye movement sleep (REMS). On the contrary, the 5-HT2C receptor antagonist-induced elevations in passive wake and theta (5-9 Hz) power density during active wake and REMS were not affected by the SSRI. In conclusion, attenuation in certain, but not all vigilance- and Q-EEG-related functions induced by the 5-HT2C receptor antagonist, suggests dissociation in 5-HT2C receptor adaptation. PMID:24395141

Kostyalik, Diána; Kátai, Zita; Vas, Szilvia; Pap, Dorottya; Petschner, Péter; Molnár, Eszter; Gyertyán, István; Kalmár, Lajos; Tóthfalusi, László; Bagdy, Gyorgy



Effect of 8-OH-DPAT on temporal discrimination following central 5-hydroxytryptamine depletion  

Microsoft Academic Search

The 5-hydroxytryptamine (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) alters performance in discrete-trials timing schedules. 5-HT1A receptors occur both presynaptically and postsynaptically, but it is not known which receptor population mediates the effects of 8-OH-DPAT on timing. Rats received intra-raphe injections of 5,7-dihydroxytryptamine (n=16) or sham lesions (n=14). They were trained in a discrete-trials psychophysical procedure in which levers were presented at

S Body; T.-J Chiang; S Mobini; M.-Y Ho; C. M Bradshaw; E Szabadi



Influence of 5-hydroxytryptamine (serotonin) on blood flow in the dog pulp  

SciTech Connect

The effect of intra-arterial injection of 5-hydroxytryptamine (5-HT) on pulpal blood flow of the dog was determined using the 15-micron radioisotope-labeled microsphere injection method. Pulpal blood flow was significantly reduced following the 5-HT injection. This decrease in blood flow appeared to be due to vasoconstriction as determined by an increase in pulpal vascular hindrance. However, our findings do not preclude the possibility that blood flow was reduced as a result of passive compression of venules produced by vasodilation in a low-compliance environment.

Kim, S.; Trowbridge, H.O.; Dorscher-Kim, J.E.



The effect of 5-hydroxytryptamine on the potassium exchange of human platelets  

PubMed Central

1. The concentration of potassium in platelets freshly isolated from nine persons was 74 ± 4·8 ?mole/1011 platelets (mean ± S.E.M.). 2. The influx of potassium into platelets from citrated plasma at 37° C, estimated with the use of 42K, was 18·3 ± 1·6 n-mole/sec. 1011 platelets. 3. When plasma contained 5-hydroxytryptamine (5-HT) at a concentration of about 5 ?g/ml., the influx of potassium into platelets was increased for as long as they took up 5-HT. This effect was absent when the concentration of 5-HT was either lower (2 ?g/ml.) or much higher (50 ?g/ml.). 4. The concentration of 5-HT in the platelets did not affect their potassium flux. PMID:6048996

Born, G. V. R.



Studies of Platelet 5-Hydroxytryptamine (Serotonin) in Storage Pool Disease and Albinism  

PubMed Central

Platelets in patients with storage pool disease are markedly deficient in a nonmetabolic (storage) pool of ADP that is important in platelet aggregation. They are also deficient in ATP, although to a lesser degree. In seven patients with this disorder, including one with albinism, platelet 5-hydroxytryptamine (5-HT) levels were reduced in proportion to the reduction in ATP (r = 0.94). Their platelets show diminished capacity to absorb [14C]5-HT, and the type of defect was similar to that produced in normal platelets by reserpine, a drug known to inhibit the uptake of 5-HT by the platelet dense granules. Storage pool-deficient platelets also converted more [3H]5-HT to [3H]5-hydroxyindoleacetic acid than did normal platelets, and the platelets in one of two patients studied contained increased amounts of 5-HT metabolites. The above findings, together with those reported previously, support the conclusion that the capacity of the dense granules (which may be either diminished or functionally abnormal) for storing 5-HT is decreased in storage pool disease; as a result, the 5-HT that enters the platelet may be more exposed to monoamine oxidases present on mitochondrial membranes. This diminished storage capacity (for 5-HT) may also explain why preincubating platelet-rich plasma with 5-HT for 45 min without stirring inhibits subsequent platelet aggregation by 5-HT to a greater degree in patients with storage pool disease than in normal subjects. The latter finding is also consistent with the theory that the aggregation of platelets by 5-HT is mediated by the same receptors on the plasma membrane that are involved in its uptake. The diminished release of platelet-bound [14C]5-HT by collagen that we found in these patients, as well as findings in previous studies, suggests that the release reaction may also be abnormal in storage pool disease. Images PMID:4847252

Weiss, Harvey J.; Tschopp, Thomas B.; Rogers, John; Brand, Harvey



Brain as an endocrine source of circulating 5-hydroxytryptamine in ontogenesis in rats.  


This study was aimed to test the authors' hypothesis stating that the developing brain before the closure of the blood brain barrier (BBB) operates as an endocrine organ that secretes classical neurotransmitters and neuropeptides into the general circulation. 5-Hydroxytryptamine (5-HT) was selected as a marker of brain endocrine activity though it is also secreted by peripheral organs. 5-HT was detected in blood of rats in a biologically active concentration at any studied age, from the 21st embryonic day till the 30th postnatal day. The brain was proven to be a source of circulating 5-HT before the BBB closure by showing that the 5-HT concentration in blood decreased significantly after the inhibition of 5-HT synthesis in the brain of neonates. The 5-HT concentration in blood was not diminished after the BBB closure, apparently due to compensatory increase of 5-HT secretion by peripheral sources. Thus, brain-derived 5-HT is delivered to the general circulation before the BBB closure being potentially capable of providing endocrine regulation of target organs. PMID:24952115

Yulia, Zubova; Diana, Nasyrova; Anna, Sapronova; Michael, Ugrumov



Intra- and extraneuronal metabolism of 5-hydroxytryptamine in the isolated saphenous vein of the dog.  


The uptake and metabolism of 3H-5-hydroxytryptamine (5-HT) in the isolated saphenous vein of the dog was studied, as well as the sensitivity to 5-HT and its termination of action (as determined by oil immersion experiments). After exposure of the vein to 0.23 mumol/1 5-HT for 30 min, about one half of the 5-HT removed was accumulated in the tissue, the other half appearing in the form of metabolites. Cocaine, chlorimipramine or denervation reduced the accumulation, but not the metabolism, of 5-HT; hydrocortisone reduced both accumulation and metabolism. Hydrocortisone plus cocaine (or phenoxybenzamine alone) caused a greater reduction of accumulation and metabolism than hydrocortisone or cocaine alone. Pargyline caused an increase in accumulation and virtually abolished metabolism; amezinium also abolished metabolism, but reduced accumulation (the same effects as caused by cocaine plus pargyline). Cocaine (12 mumol/l) caused supersensitivity to 5-HT and a prolongation of the half-time for relaxation in oil; hydrocortisone (40 mumol/l) had no effect on sensitivity, but prolonged somewhat the half-time for relaxation in oil, showing supra-additive effects with cocaine. 5-HT, taken up into adrenergic nerve terminals, was released by electrical stimulation; no appreciable reduction in fractional release occurred during repeated stimulations. Exposure to cocaine prior to incubation with 5-HT prevented the neuronal uptake of 5-HT. Compartmental analysis, done with the help of washout curves of strips pretreated with pargyline and loaded with 3H-5-HT, shows that 3H-5-HT distributed into 3 compartments plus a bound fraction.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6709075

Paiva, M Q; Caramona, M; Osswald, W




PubMed Central

A study was made of the effect of the administration of reserpine and parachlorophenylalanine, an inhibitor of 5-hydroxytryptamine (serotonin; 5-HT), on the capacity of thyroid parafollicular cells to synthesize and store 5-HT. The two drugs were given to nonhibernating bats in doses which produced an equivalent degree of depletion of 5-HT from the thyroid. Tritiated 5-hydroxytryptophan, the precursor of 5-HT, was then given intravenously to assess the ability of parafollicular cell granules to take up and retain newly synthesized 5-HT. Reserpine, but not parachlorophenylalanine, decreased the amount of labeled 5-HT found in the thyroid and prevented autoradiographic labeling of parafollicular cell granules. Quantitative ultrastructural and stereological analysis demonstrated that the granules in untreated animals appeared to be nearly spherical prolate ellipsoids, with a uniformly electron-opaque inner matrix. In animals given reserpine, the axial ratio of the ellipsoidal granules increased greatly and a faint internal striation parallel to the long axis of the granules became apparent. Similar changes were not induced by parachlorophenylalanine. No other morphological changes in the thyroid epithelium were detected after administration of reserpine. This study confirms the association of 5-HT with the mature small secretory granules of thyroid parafollicular cells. PMID:4265815

Gershon, Michael D.; Nunez, Eladio A.



5-hydroxytryptamine-induced relaxation of neonatal porcine vena cava in vitro.  


5-hydroxytryptamine (5-HT) caused concentration-dependent relaxation of isolated rings from porcine vena cava contracted with alpha-methyl 5-HT or prostaglandin F2 alpha. Relaxation was not blocked by propranolol (1 micron), atropine (1 micron), indomethacin (3 microns), mepyramine (1 micron), cimetidine (1 micron), or cocaine (10 microns). Further receptor analysis could not be performed by antagonism of the relaxant response but was possible using 5-HT induced increases in cyclic AMP. Methysergide (1 micron) but not cyproheptadine (0.1 micron), specifically antagonised the 5-HT induced increase in cyclic AMP with an estimated pA2 of 7.19. The alpha-methyl analogue of 5-HT, a potent agonist at M and D receptors, did not cause relaxation or elevate cyclic AMP. These results suggest that the 5-HT receptor described here is not of the classical M or D type and unlike that described thus far in the vasculature. This receptor shares some similarities with brain 5-HT1 receptors since both may be linked with adenylate cyclase. PMID:6205240

Trevethick, M A; Feniuk, W; Humphrey, P P




PubMed Central

The two largest cells in a typical ganglion of the leech (Hirudo medicinalis) nervous system are the colossal cells of Retzius. These cells show a positive chromaffin reaction, and it has been suggested that they contain 5-hydroxytryptamine (5-HT). In this study, the presence of 5-HT in the colossal cells was confirmed by microspectrofluorometry and by thin-layer chromatography and spectrofluorometry of extracts of individually dissected and pooled colossal cell bodies. A single colossal cell body was found to contain, on the average, 3.8 x 10-10 g (6mM) 5-HT. Electron microscopy shows that the colossal cells are distinguished by the presence of 1000 A granules with irregular, electron-opaque cores. Since the granules are distributed in the same pattern as the 5-HT fluorescence, we have suggested that they contain 5-HT. Furthermore, a chromaffin reaction modified for the electron microscope provides evidence that 5-HT is present in the granule cores. These data can now serve as a basis for further studies on the metabolism, distribution, and function of 5-HT in these identified neurons. PMID:4305885

Rude, Sonia; Coggeshall, Richard E.; Van Orden, Lucas S.



5-HT3 and 5-HT4 antagonists inhibit peristaltic contractions in guinea-pig distal colon by mechanisms independent of endogenous 5-HT.  


Recent studies have shown that endogenous serotonin is not required for colonic peristalsis in vitro, nor gastrointestinal (GI) transit in vivo. However, antagonists of 5-Hydroxytryptamine (5-HT) receptors can inhibit peristalsis and GI-transit in mammals, including humans. This raises the question of how these antagonists inhibit GI-motility and transit, if depletion of endogenous 5-HT does not cause any significant inhibitory changes to either GI-motility or transit? We investigated the mechanism by which 5-HT3 and 5-HT4 antagonists inhibit distension-evoked peristaltic contractions in guinea-pig distal colon. In control animals, repetitive peristaltic contractions of the circular muscle were evoked in response to fixed fecal pellet distension. Distension-evoked peristaltic contractions were unaffected in animals with mucosa and submucosal plexus removed, that were also treated with reserpine (to deplete neuronal 5-HT). In control animals, peristaltic contractions were blocked temporarily by ondansetron (1-10 ?M) and SDZ-205-557 (1-10 ?M) in many animals. Interestingly, after this temporary blockade, and whilst in the continued presence of these antagonists, peristaltic contractions recovered, with characteristics no different from controls. Surprisingly, similar effects were seen in mucosa-free preparations, which had no detectable 5-HT, as detected by mass spectrometry. In summary, distension-evoked peristaltic reflex contractions of the circular muscle layer of the guinea-pig colon can be inhibited temporarily, or permanently, in the same preparation by selective 5-HT3 and 5-HT4 antagonists, depending on the concentration of the antagonists applied. These effects also occur in preparations that lack any detectable 5-HT. We suggest caution should be exercised when interpreting the effects of 5-HT3 and 5-HT4 antagonists; and the role of endogenous 5-HT, in the generation of distension-evoked colonic peristalsis. PMID:23935564

Sia, Tiong C; Whiting, Malcolm; Kyloh, Melinda; Nicholas, Sarah J; Oliver, John; Brookes, Simon J; Dinning, Phil G; Wattchow, David A; Spencer, Nick J



5-HT3 and 5-HT4 antagonists inhibit peristaltic contractions in guinea-pig distal colon by mechanisms independent of endogenous 5-HT  

PubMed Central

Recent studies have shown that endogenous serotonin is not required for colonic peristalsis in vitro, nor gastrointestinal (GI) transit in vivo. However, antagonists of 5-Hydroxytryptamine (5-HT) receptors can inhibit peristalsis and GI-transit in mammals, including humans. This raises the question of how these antagonists inhibit GI-motility and transit, if depletion of endogenous 5-HT does not cause any significant inhibitory changes to either GI-motility or transit? We investigated the mechanism by which 5-HT3 and 5-HT4 antagonists inhibit distension-evoked peristaltic contractions in guinea-pig distal colon. In control animals, repetitive peristaltic contractions of the circular muscle were evoked in response to fixed fecal pellet distension. Distension-evoked peristaltic contractions were unaffected in animals with mucosa and submucosal plexus removed, that were also treated with reserpine (to deplete neuronal 5-HT). In control animals, peristaltic contractions were blocked temporarily by ondansetron (1–10 ?M) and SDZ-205–557 (1–10 ?M) in many animals. Interestingly, after this temporary blockade, and whilst in the continued presence of these antagonists, peristaltic contractions recovered, with characteristics no different from controls. Surprisingly, similar effects were seen in mucosa-free preparations, which had no detectable 5-HT, as detected by mass spectrometry. In summary, distension-evoked peristaltic reflex contractions of the circular muscle layer of the guinea-pig colon can be inhibited temporarily, or permanently, in the same preparation by selective 5-HT3 and 5-HT4 antagonists, depending on the concentration of the antagonists applied. These effects also occur in preparations that lack any detectable 5-HT. We suggest caution should be exercised when interpreting the effects of 5-HT3 and 5-HT4 antagonists; and the role of endogenous 5-HT, in the generation of distension-evoked colonic peristalsis. PMID:23935564

Sia, Tiong C.; Whiting, Malcolm; Kyloh, Melinda; Nicholas, Sarah J.; Oliver, John; Brookes, Simon J.; Dinning, Phil G.; Wattchow, David A.; Spencer, Nick J.



Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study  

PubMed Central

Background—Increased concentrations of 5-hydroxytryptamine (5-HT) can be detected in the systemic circulation after a meal and may be involved in the physiological control of gastrointestinal motility. Abnormalities of 5-HT release after a meal might explain some of the postprandial symptoms associated with the irritable bowel syndrome (IBS). ?Aim—To investigate the effect of a standard meal on plasma 5-HT and urinary 5-hydroxyindole acetic acid (5-HIAA) concentrations in patients with diarrhoea predominant IBS and in healthy volunteers. ?Methods—After an overnight fast, six volunteers and five patients with IBS were given a carbohydrate-rich meal. Blood and urine samples were taken before and for four hours after the meal. Platelet-poor plasma 5-HT and urinary 5-HIAA were analysed by reversed phase high performance liquid chromatography with fluorometric detection. 5-HIAA was expressed as a ratio with urinary creatinine concentration, which was measured by spectrophotometry. ?Results—During the four hour postprandial period, 5-HT concentrations were significantly higher in patients with IBS than in healthy volunteers at 0.5 hours (p<0.05), 2 hours (p<0.05) and 2.5 hours (p<0.05). 5-HT was not detected in the plasma in the fasting state in patients or volunteers. Median peak 5-HT in patients with IBS (359 (198-796) nmol/l) was significantly greater than volunteers (83 (7-190)) (p<0.05). "Area under the curve" for 5-HT detection was greater for patients with IBS (317(138-771)) than for healthy volunteers (51 (4-129); p<0.05).The duration of the 5-HT peak was significantly longer in patients with IBS (3 (1-3) hours) than in the healthy volunteers (1 (1-1) hours; p<0.01). Postprandial urinary median 5-HIAA values in controls (5.6 (5.5-5.8) µmol/mmol creatinine) and patients with IBS (3.0(2.5-6.8) µmol/mmol creatinine) were not significantly different from preprandial values (controls: 5.9 (5.5-6.6) µmol/mmol creatinine; patients with IBS: (6.2 (2.4-9.3) µmol/mmol creatinine). ?Conclusion—These findings indicate that there may be a difference in the way that 5-HT is released in patients with diarrhoea predominant IBS, and could suggest a possible role for 5-HT in the postprandial symptoms of these patients. ?? Keywords: 5-hydroxytryptamine; postprandial; diarrhoea predominant irritable bowel syndrome PMID:9505884

Bearcroft, C; Perrett, D; Farthing, M



5-HT7 receptor signaling: improved therapeutic strategy in gut disorders  

PubMed Central

Serotonin (5-hydroxytryptamine; 5-HT) is most commonly known for its role as a neurotransmitter in the central nervous system (CNS). However, the majority of the body’s 5-HT is produced in the gut by enterochromaffin (EC) cells. Alterations in 5-HT signaling have been associated with various gut disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and enteric infections. Recently, our studies have identified a key role for 5-HT in the pathogenesis of experimental colitis. 5-HT7 receptors are expressed in the gut and very recently, we have shown evidence of 5-HT7 receptor expression on intestinal immune cells and demonstrated a key role for 5-HT7 receptors in generation of experimental colitis. This review summarizes the key findings of these studies and provides a comprehensive overview of our current knowledge of the 5-HT7 receptor in terms of its pathophysiological relevance and therapeutic potential in intestinal inflammatory conditions, such as IBD.

Kim, Janice J.; Khan, Waliul I.



Serotonin (5-hydroxytryptamine, 5HT) enhances migration of rat aortic smooth muscle cells through 5HT 2 receptors  

Microsoft Academic Search

The effects of serotonin on migration of cultured rat aortic smooth muscle cells (SMC) were studied to clarify the role of this substance in the pathogenesis of atherosclerosis. Serotonin alone did not stimulate SMC migration but stimulated it at physiological concentrations in the presence of other migration factors such as SMC-derived migration factor, platelet-derived migration factor and fibronectin. Checker-board analysis

Ken Tamura; Tetsuto Kanzaki; Yuji Saito; Masako Otabe; Yasushi Saito; Nobuhiro Morisaki



Chronic tryptophan deprivation attenuates gating deficits induced by 5-HT(1A), but not 5-HT? receptor activation.  


The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts a multifaceted function in the modulation of information processing, through the activation of multiple receptor families. In particular, stimulation of 5-HT(1A) and 5-HT(2A) receptors leads to sensorimotor gating impairments and perceptual perturbations. Previous evidence has shown that chronic deprivation of L-tryptophan (TRP), the precursor of 5-HT, results in marked reductions of 5-HT brain levels, as well as neuroplastic alterations in 5-HT(1A) and 5-HT(2A) expression and/or signaling. Building on these premises, in the present study we tested whether a prolonged TRP deprivation may differentially impact the roles of these receptors in the regulation of the prepulse inhibition (PPI) of the acoustic startle reflex, a dependable index of gating. Male Sprague-Dawley rats were fed for 14 days with either a regimen with negligible TRP content (TR-) or the same diet supplemented of TRP (TR+). At the end of this schedule, rats were treated with the prototypical 5-HT(1A) receptor agonist 8-OH-DPAT (62.5-250 ?g/kg, subcutaneous, s.c.) or the 5-HT? receptor agonist DOI (0.25-1 mg/kg, s.c.). Notably, the PPI deficits induced by 8-OH-DPAT in TR- rats were significantly milder than those observed in their TR+ counterparts; these effects were fully prevented by the 5-HT(1A) antagonist WAY-100135 (10 mg/kg, intraperitoneal). Conversely, TRP deprivation did not affect the PPI-disrupting properties of DOI. These findings suggest that prolonged 5-HT depletion attenuates the influence of 5-HT(1A), but not 5-HT? receptors on sensorimotor gating, confirming the distinct mechanisms of these two targets in PPI regulation. PMID:23141373

Stancampiano, Roberto; Frau, Roberto; Bini, Valentina; Collu, Maria; Carta, Manolo; Fadda, Fabio; Bortolato, Marco



The inhibitory effects of 5-hydroxytryptamine on gastric acid secretion by the rat isolated stomach.  

PubMed Central

1 The effect of 5-hydroxytryptamine (5-HT) on acid secretion by a rat isolated stomach preparation has been studied. 2 5-HT at 10(-5)M in the serosal bathing fluid produced significant inhibition of the acid secretory responses to histamine, pentagastrin and isoprenaline but was without effect on basal secretion or that due to bethanechol, dibutryl cyclic adenosine 3',5'-monophosphate (db cyclic AMP) or phosphodiesterase inhibition with ICI63197. Increasing the concentration of 5-HT to 5 x 10(-5) M did not change this pattern of response whilst 5-HT at 10(-6) M did not cause consistent inhibition. 3 The inhibitory action of 5-HT could be prevented by the antagonist methysergide (2.5 x 10(-5) M). This concentration of methysergide alone did not affect responses to secretagogues or basal acid output. 4 Neither propranolol (2.5 x 10(-5) M) nor tetrodotoxin (10(-6) M) antagonized the inhibitory action of 5-HT. 5 Both indomethacin (2.8 x 10(-5) M) and ibuprofen (2.4 x 10(-4) M) antagonized the action of 5-HT. Indomethacin alone had no effect upon secretagogue responses. 6 5-HT at 10(-5) M had no inhibitory action when applied to the mucosal side of the preparation. 7 The results indicate that 5-HT can act directly on the stomach of the rat to produce inhibition of acid output. This inhibition is selective and may involve the products of cyclo-oxygenase activity. PMID:6824810

Canfield, S. P.; Spencer, J. E.



Menthol inhibits 5-HT3 receptor-mediated currents.  


The effects of alcohol monoterpene menthol, a major active ingredient of the peppermint plant, were tested on the function of human 5-hydroxytryptamine type 3 (5-HT3) receptors expressed in Xenopus laevis oocytes. 5-HT (1 ?M)-evoked currents recorded by two-electrode voltage-clamp technique were reversibly inhibited by menthol in a concentration-dependent (IC50 = 163 ?M) manner. The effects of menthol developed gradually, reaching a steady-state level within 10-15 minutes and did not involve G-proteins, since GTP?S activity remained unaltered and the effect of menthol was not sensitive to pertussis toxin pretreatment. The actions of menthol were not stereoselective as (-), (+), and racemic menthol inhibited 5-HT3 receptor-mediated currents to the same extent. Menthol inhibition was not altered by intracellular 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid injections and transmembrane potential changes. The maximum inhibition observed for menthol was not reversed by increasing concentrations of 5-HT. Furthermore, specific binding of the 5-HT3 antagonist [(3)H]GR65630 was not altered in the presence of menthol (up to 1 mM), indicating that menthol acts as a noncompetitive antagonist of the 5-HT3 receptor. Finally, 5-HT3 receptor-mediated currents in acutely dissociated nodose ganglion neurons were also inhibited by menthol (100 ?M). These data demonstrate that menthol, at pharmacologically relevant concentrations, is an allosteric inhibitor of 5-HT3 receptors. PMID:23965380

Ashoor, Abrar; Nordman, Jacob C; Veltri, Daniel; Yang, Keun-Hang Susan; Shuba, Yaroslav; Al Kury, Lina; Sadek, Bassem; Howarth, Frank C; Shehu, Amarda; Kabbani, Nadine; Oz, Murat



Pharmacological characterization of an adenylyl cyclase-coupled 5-HT receptor in aplysia: comparison with mammalian 5-HT receptors.  


We attempted to identify compounds that are effective in blocking the serotonin (5-hydroxytryptamine, 5-HT) receptor(s) that activate adenylyl cyclase (AC) in Aplysia CNS. We call this class of receptor 5-HT(apAC). Eight of the 14 antagonists tested were effective against 5-HT(apAC) in CNS membranes with the following rank order of potency: methiothepin > metergoline approximately fluphenazine > clozapine > cyproheptadine approximately risperidone approximately ritanserin > NAN-190. GR-113808, olanzapine, Ro-04-6790, RS-102221, SB-204070, and spiperone were inactive. Methiothepin completely blocked 5-HT stimulation of AC with a K(b) of 18 nM. Comparison of the pharmacological profile of the 5-HT(apAC) receptor with those of mammalian 5-HT receptor subtypes suggested it most closely resembles the 5-HT(6) receptor. AC stimulation in Aplysia sensory neuron (SN) membranes was also blocked by methiothepin. Methiothepin substantially inhibited two effects of 5-HT on SN firing properties that are mediated by a cAMP-dependent reduction in S-K(+) current: spike broadening in tetraethylammonium/nifedipine and increased excitability. Consistent with cyproheptadine blocking 5-HT stimulation of AC, cyproheptadine also blocked the 5-HT-induced increase in SN excitability. Methiothepin was less effective in blocking AC-mediated modulatory effects of 5-HT in electrophysiological experiments on SNs than in blocking AC stimulation in CNS or SN membranes. This reduction in potency appears to be due to effects of the high ionic strength of physiological saline on the binding of this antagonist to the receptor. Methiothepin also antagonized AC-coupled dopamine receptors but not AC-coupled small cardioactive peptide receptors. In conjunction with other pharmacological probes, this antagonist should be useful in analyzing the role of 5-HT in various forms of neuromodulation in Aplysia. PMID:12611939

Cohen, Jonathan E; Onyike, Chiadi U; McElroy, Virginia L; Lin, Allison H; Abrams, Thomas W



The role of the 5HT 2A and 5HT 2C receptors in the stimulus effects of hallucinogenic drugs III: the mechanistic basis for supersensitivity to the LSD stimulus following serotonin depletion  

Microsoft Academic Search

The present study was designed to determine the effects ofp-chlorophenylalanine (PCPA) andp-chloroamphetamine (PCA) administration on (1) the levels of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in rat brain, (2) the sensitivity of LSD-trained rats to the stimulus effects of LSD, and (3) the maximal levels of 5-HT2A and 5-HT2C receptor mediated phosphoinositide (PI) hydrolysis in rat brain. PCA and

D. Fiorella; S. Helsley; D. S. Lorrain; R. A. Rabin; J. C. Winter



Water-soluble jack-knife prawn extract inhibits 5-hydroxytryptamine-induced vasoconstriction and platelet aggregation in humans.  


Coronary artery spasm plays an important role in the pathogenesis of various ischemic heart diseases or serious arrhythmia. The aim of this study is to look for functional foods which have physiologically active substances preventing 5-hydroxytryptamine (5-HT)-related vasospastic diseases including peri- and postoperative ischemic complications of coronary artery bypass grafting (CABG) from ocean resources in Japanese coastal waters. First, we evaluated the effect of water-soluble ocean resource extracts on the response to 5-HT in HEK293 cells which have forcibly expressed cyan fluorescent protein-fused 5-HT2A receptors (5-HT2A-CFP). Among 5 different water-soluble extracts of ocean resources, the crude water-soluble jack-knife prawn extract (WJPE) significantly reduced maximal Ca(2+) influx induced by 0.1 ?M 5-HT in a concentration-dependent manner. The Crude WJPE significantly inhibited, in a concentration-dependent manner, 5-HT-induced constriction of human saphenous vein. 5-HT released from activated platelets plays a crucial roles in the constriction of coronary artery. Next the WJPE was purified for applying the experiment of 5-HT-induced human platelet aggregation. The purified WJPE significantly inhibited 5-HT-induced human platelet aggregation also in a concentration-dependent manner. Based on our findings, jack-knife prawn could be one of a functional food with health-promoting benefits for most people with vasospastic diseases including patients who have gone CABG. PMID:25464143

Gamoh, Shuji; Kanai, Tasuku; Tanaka-Totoribe, Naoko; Ohkura, Masamichi; Kuwabara, Masachika; Nakamura, Eisaku; Yokota, Atsuko; Yamasaki, Tetsuo; Watanabe, Akiko; Hayashi, Masahiro; Fujimoto, Shouichi; Yamamoto, Ryuichi



5-Hydroxytryptamine 4(a) receptor expressed in Sf9 cells is palmitoylated in an agonist-dependent manner.  

PubMed Central

The mouse 5-hydroxytryptamine 4(a) receptor [5-HT(4(a))] was expressed with a baculovirus system in insect cells and analysed for acylation. [(3)H]Palmitic acid was effectively incorporated into 5-HT(4(a)) and label was sensitive to the treatment with reducing agents indicating a thioester-type bond. Analysis of protein-bound fatty acids revealed that 5-HT(4(a)) contains predominantly palmitic acid. Treatment of infected Sf9 (Spodoptera frugiperda) cells with BIMU8 [(endo-N-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dehydro-2-oxo-3-(prop-2-yl)-1H-benzimid-azole-1-carboxamide], a 5-HT(4) receptor-selective agonist, generated a dose-dependent increase in [(3)H]palmitate incorporation into 5-HT(4(a)) with an EC(50) of approx. 10 nM. The change in receptor labelling after stimulation with agonist was receptor-specific and did not result from general metabolic effects. We also used both pulse labelling and pulse-chase labelling to address the dynamics of 5-HT(4(a)) palmitoylation. Incorporation studies revealed that the rate of palmitate incorporation was increased approx. 3-fold after stimulation with agonist. Results of pulse-chase experiments show that activation with BIMU8 promoted the release of radiolabel from 5-HT(4(a)), thereby reducing the levels of receptor-bound palmitate to approximately one-half. Taken together, our results demonstrate that palmitoylation of 5-HT(4(a)) is a reversible process and that stimulation of 5-HT(4(a)) with agonist increases the turnover rate for receptor-bound palmitate. This provides evidence for a regulated cycling of receptor-bound palmitate and suggests a functional role for palmitoylation/depalmitoylation in 5-hydroxytryptamine-mediated signalling. PMID:11171060

Ponimaskin, E G; Schmidt, M F; Heine, M; Bickmeyer, U; Richter, D W



Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs  

Microsoft Academic Search

The tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid (DMXAA) causes dramatic haemorrhagic necrosis in murine tumours, but activity is seen only at doses close to the toxic limit. This study investigates two approaches for increasing the therapeutic ratio of DMXAA. The first approach combines DMXAA with a second tumour blood flow inhibitor, 5-hydroxytryptamine (5-HT). Co-administration of 5-HT (700 micromol kg(-1)) to

CJ Lash; AE Li; M Rutland; BC Baguley; LJ Zwi; WR Wilson



Effects of short-term lithium administration on tryptophan levels and 5-hydroxytryptamine synthesis in whole brain and brain regions in rats  

Microsoft Academic Search

Summary The effects of short-term lithium administration on tryptophan levels and 5-hydroxytryptamine (5-HT) synthesis in whole brain and brain regions in rats were studied. Short-term lithium administration was found to increase whole brain tryptophan levels without affecting whole brain 5-HT synthesis. However, the increase of tryptophan varied between various brain regions, which may possibly be due to differences in the

U. Berggren



Comparative Study of Pre and Postsynaptic 5HT1A Receptor Modulation of Anxiety in Two Ethological Animal Tests  

Microsoft Academic Search

The purpose of this study was to determine the roles of the presynaptic 5-hydroxytryptamine1A (5-HT1A) receptors in the median raphenucleus (MRN) and of the postsynaptic 5-HT1A receptors in its projection area of the dorsal hippocampus in the social interaction and elevated plus-maze tests of anxiety. Direct administration of the 5-HT1A receptor agonist (6)-8- hydroxy-dipropylaminotetralin (8-OH-DPAT, 200 ng) into the MRN

Sandra E. File; Luis E. Gonzalez; Nick Andrews



Antagonism of serotonergic 5HT 2A\\/2C receptors: mutual improvement of sleep, cognition and mood?  

Microsoft Academic Search

Serotonin (5-hydroxytryptamine (5-HT)) and 5-HT receptors are involved in sleep and in waking functions such as cognition and mood. Animal and human studies support a particular role for the 5-HT2A receptor in sleep, which has led to renewed interest in this receptor subtype as a target for the development of novel pharmacological agents to treat insomnia. Focusing primarily on findings

H.-P. Landolt; R. Wehrle



The role of the 5-HT1D receptor as a presynaptic autoreceptor in the guinea pig.  


The present study investigated the role of the 5-hydroxytryptamine (5-HT, serotonin)1D receptor as a presynaptic autoreceptor in the guinea pig. In keeping with the literature, the 5-HT1B selective antagonist, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine]oxalate (SB224289) potentiated [3H]5-HT outflow from pre-labelled slices of guinea pig cerebral cortex confirming its role as a presynaptic autoreceptor in this species. In addition, the 5-HT1D receptor-preferring antagonists, 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl]-3-pyridin-4-yl-methyl-tetrahydro-pyrimidin-2-one (LY367642), (R)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456219), (S)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456220) and 1-[2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl]-3,3-dimethyl-1,2-dihydro-indol-2-one (LY310762), potentiated [3H]5-HT outflow from this preparation with potencies (EC50 values=31-140 nM) in the same range as their affinities for the guinea pig 5-HT1D receptor (Ki values=100-333 nM). The selective 5-HT1D receptor agonist, R-2-(4-fluoro-phenyl)-2-[1-[3-(5-[1,2,4]triazol-4-yl-1H-indol-3-yl)-propyl]-piperidin-4-ylamino]-ethanol dioxylate (L-772,405), inhibited [3H]5-HT outflow. In microdialysis studies, administration of either SB224289 or LY310762 at 10 mg/kg by the intraperitoneal (i.p.) route, potentiated the increase in extracellular 5-HT concentration produced by a maximally effective dose of the selective serotonin re-uptake inhibitor, fluoxetine (at 20 mg/kg i.p.). In addition, the 5-HT1D receptor-preferring antagonist and 5-HT transporter inhibitor, LY367642 (at 10 mg/kg i.p.), elevated extracellular 5-HT concentrations to a greater extent than a maximally effective dose of fluoxetine. It is concluded that the 5-HT1D receptor, like the 5-HT1B receptor, may be a presynaptic autoreceptor in the guinea pig. PMID:15189767

Pullar, Ian A; Boot, John R; Broadmore, Richard J; Eyre, Tina A; Cooper, Jane; Sanger, Graham J; Wedley, Susan; Mitchell, Stephen N



Pharmacological characterization of the 5-hydroxytryptamine receptor mediating relaxation in the rat isolated ileum.  

PubMed Central

1 The aim of the present study was to investigate a 5-HT4 receptor involvement in the mediation of a 5-HT-induced relaxation response in the rat isolated ileum in vitro. 2 Ileal segments were taken at regular intervals from the ileo-caecal junction to duodenum. 5-HT (1 microM) induced a relaxation or contraction response in segments taken from the terminal ileum: the relaxation decreased and finally disappeared as contractions dominated in the proximal tissues. The 5-HT-induced relaxations were enhanced in the terminal segments and the contractions attenuated in both terminal and proximal segments, in the presence of methysergide (1 microM) and atropine (0.1 microM). 3 In the presence of methysergide (1 microM) and atropine (0.1 microM), a cumulative addition of 5-HT (0.01-1 microM) induced a concentration-dependent relaxation in the terminal (1-20 cm from the ileo-ceacal junction) ileal segments which at higher concentrations of 5-HT (3-30 microM) reverted to contraction. 4 The rank order of potency of indole agonists in inducing a concentration-related relaxation response in tissues of the terminal ileum (pretreated with pargyline (100 microM) and in the presence of methysergide (1 or 100 microM) and atropine (0.1 microM) was 5-hydroxytryptamine (6.97 +/- 0.06), 5-methoxytryptamine (6.50 +/- 0.07), alpha-methyl-5-hydroxytryptamine (5.53 +/- 0.17), 5-carboxamidotryptamine (5.51 +/- 0.12) and 2-methyl-5-hydroxytryptamine (< 5), the pEC50 values (mean +/- s.e.mean) being shown in parentheses. 5 Pretreatment of tissues with pargyline (100 microM) selectively enhanced the potency of 5-methoxytryptamine by a factor of 19 but failed to modify the potency of the other indole agonists. 6 The 5-HT4 receptor antagonists, tropisetron, SDZ 205-557 and GR 113808 antagonized the relaxation response to 5-HT (in the presence of methysergide (1 or 10 microM) and atropine (0.1 microM)) with pKB values (95% CL) of 6.09 (5.94-6.24), 7.0 (6.9-7.09) and 8.95 (8.81-9.1) respectively. Apparent pKB values estimations for tropisetron (1 microM) and GR 113808 (10 nM) using the agonists 5-methoxytryptamine and 5-carboxamidotryptamine were 6.37 +/- 0.31, 5.91 +/- 0.38 and 8.83 +/- 0.11, 8.82 +/- 0.22 respectively. 7 Tropisetron (10 microM), SDZ 205-557 (3 microM) and GR 113808 (10-100 nM) caused an increase in basal tone of the rat terminal ileum when administered in the presence of methysergide and atropine. 8 The relaxation response to 5-HT in the rat terminal ileum was not antagonized by ritanserin (1 microM), ondansetron (1 microM) or N omega-nitro-L-arginine methyl ester (100 microM) and with only a twofold dextral shift of the concentration-response curve by tetrodotoxin (1 microM). 9 It is concluded that the relaxant response to 5-HT in the terminal region of the ileum is mediated directly at the smooth muscle; a ranked indole agonist potency and selective antagonism by 5-HT4 receptor antagonists tropisetron, SDZ 205-557 and GR 113808 indicate a 5-HT4 receptor involvement in the relaxation response. PMID:8886413

Tuladhar, B. R.; Costall, B.; Naylor, R. J.



Inhibition by 5-hydroxytryptamine and noradrenaline in substantia gelatinosa of guinea-pig spinal trigeminal nucleus.  

PubMed Central

1. Whole-cell and intracellular recordings were made from neurons in slices of guinea-pig spinal trigeminal nucleus pars caudalis. 2. 5-Hydroxytryptamine (5-HT) hyperpolarized 70% of neurons by activating 5-HT1A receptors. The effect was mimicked by 5-carboxamidotryptamine (5-CT) and (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronapthalene hydrobromide (8-OH-DPAT) and antagonized by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)-butyl]-piperazine hydrobromide (NAN 190) and pindobind-5-HT1A. Nine per cent of the neurons were depolarized by 5-HT. 3. In about 20% of recordings, 5-HT also evoked repetitive inhibitory postsynaptic potentials that were mediated by glycine. 4. Noradrenaline (NA) hyperpolarized 71% of neurons. This effect was mediated by activation of alpha 2-adrenoceptors, since 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK14304) also caused a hyperpolarization and idazoxan (1 microM) blocked the hyperpolarization to both NA and UK14304. Phenylephrine depolarized a subset of neurons and this depolarization was blocked by prazosin, suggesting an action mediated by activation of alpha 1-adrenoceptors. 5. NA also evoked repetitive GABAA-mediated inhibitory postsynaptic potentials in about 20% of recordings. The increase in synaptic activity was mimicked by phenylephrine and blocked by prazosin. 6. These results indicate that there are at least two mechanisms through which 5-HT and NA inhibit neurons: (i) in many cells both 5-HT and NA mediate a hyperpolarization through an increase of a potassium conductance; (ii) 5-HT and NA also activated GABA- and glycine-containing interneurons to cause IPSPs in separate groups of cells. PMID:7658366

Grudt, T J; Williams, J T; Travagli, R A



The 5-hydroxytryptamine 4 Receptor Agonist-induced Actions and Enteric Neurogenesis in the Gut  

PubMed Central

We explored a novel effect of 5-hydroxytryptamine 4 receptor (5-HT4R) agonists in vivo to reconstruct the enteric neural circuitry that mediates a fundamental distal gut reflex. The neural circuit insult was performed in guinea pigs and rats by rectal transection and anastomosis. A 5-HT4R-agonist, mosapride citrate (MOS) applied orally and locally at the anastomotic site for 2 weeks promoted the regeneration of the impaired neural circuit or the recovery of the distal gut reflex. MOS generated neurofilament-, 5-HT4R- and 5-bromo-2'-deoxyuridine-positive cells and formed neural network in the granulation tissue at the anastomosis. Possible neural stem cell markers increased during the same time period. These novel actions by MOS were inhibited by specific 5-HT4R-antagonist such as GR113808 (GR) or SB-207266. The activation of enteric neural 5-HT4R promotes reconstruction of an enteric neural circuit that involves possibly neural stem cells. We also succeeded in forming dense enteric neural networks by MOS in a gut differentiated from mouse embryonic stem cells. GR abolished the formation of enteric neural networks. MOS up-regulated the expression of mRNA of 5-HT4R, and GR abolished this upregulation, suggesting MOS differentiated enteric neural networks, mediated via activation of 5-HT4R. In the small intestine in H-line: Thy1 promoter green fluorescent protein (GFP) mice, we obtained clear 3-dimensional imaging of enteric neurons that were newly generated by oral application of MOS after gut transection and anastomosis. All findings indicate that treatment with 5-HT4R-agonists could be a novel therapy for generating new enteric neurons to rescue aganglionic disorders in the whole gut. PMID:24466442

Goto, Kei; Kawahara, Isao



5-HT receptor subtypes as key targets in mediating pigment dispersion within melanophores of teleost, Oreochromis mossambicus.  


The presence of distinct class of 5-HT receptors in the melanophores of tilapia (Oreochromis mossambicus) is reported. The cellular responses to 5-HT (5-hydroxytryptamine), 5-HT(1), and 5-HT(2), agonists on isolated scale melanophores were observed with regard to pigment translocation within the cells. It was found that 5-HT exerted rapid and strong concentration dependent pigment granule dispersion within the melanophores. The threshold pharmacological dose of 5-HT that could elicit a measurable response was as low as 4.7×10(-12) M/L. Selective 5-HT(1) and 5-HT(2) agonists, sumatriptan and myristicin were investigated and resulted in dose-dependent pigment dispersion. The dispersing effects were effectively antagonized by receptor specific antagonists. It is suggested that 5-HT-induced physiological effects are mediated via distinct classes of receptors that possibly participate in modulation of pigmentary responses of the fish. PMID:23195131

Salim, Saima; Ali, Ayesha S; Ali, Sharique A



5-Hydroxytryptamine-induced microvascular pressure transients in lungs of anaesthetized rabbits.  


We determined lung microvascular pressure transients induced by 5-hydroxytryptamine (5HT), by the micropuncture technique. We mechanically ventilated anaesthetized (halothane 0.8%), open-chested rabbits, in which we recorded pulmonary artery (PA), left atrial (LA) and carotid artery pressures and cardiac output. For 4-min periods of stopped ventilation, we constantly inflated the lung with airway pressure of 7 cmH2O, then micropunctured the lung to determine pressures in arterioles and venules of 20-25 microm diameter. An intravenous bolus infusion of 5HT (100 microg), increased total pulmonary vascular resistance by 59%. Prior to 5HT infusion, the arterial, microvascular and venous segments comprised 30, 50 and 19% of the total pulmonary vascular pressure drop, respectively. However 14 s after 5HT infusion, the PA-arteriole pressure difference (arterial pressure drop) increased 46%, while the venule-LA pressure difference (venous pressure drop) increased >100%. The arteriole-venule pressure difference (microvascular pressure drop) was abolished. The increase in the arterial pressure drop was maintained for 4.8 min, whereas the increased venous pressure drop reverted to baseline in <1 min. We conclude that in the rabbit lung in situ, a 5HT bolus causes sustained arterial constriction and a strong but transient venous constriction. PMID:11442447

Sen, N; Glucksberg, M R; Bhattacharya, S



Brain tissue transplanted to the anterior chamber of the eye: 2. Fluorescence histochemistry of immature catecholamine and 5-hydroxytryptamine neurons innervating the rat vas deferens  

Microsoft Academic Search

Small pieces of the wall of the rat vas deferens were homologously transplanted to the anterior chamber of the eye together with small pieces of embryonic brain stem containing either developing noradrenaline (NA) cells of the locus coeruleus or 5-hydroxytryptamine (5-HT) neurons of the developing raphe system. The eyes of the recipients were sympathetically denervated. The double transplants became rapidly

Lars Olson; Åke Seiger



Physiologically identified 5-HT2-like receptors at the crayfish neuromuscular junction.  


The model synaptic preparation of the crayfish opener neuromuscular junction is known to be responsive to exogenous application of 5-HT. The primary effect of 5-HT is an enhancement of vesicular release from the presynaptic motor nerve terminal. 5-HT is known to act through an IP(3) cascade which suggests the presence of a 5-HT(2) receptor subtype; however, this is based on vertebrate 5-HT receptor classification. We examined this possibility by using a selective agonist and two antagonists of the vertebrate 5-HT(2) receptor subtypes. The antagonist ketanserin and spiperone reduce the responsiveness of 5-HT in a dose-dependent manner. The broad 5-HT(2) receptor agonist, alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT) enhances synaptic transmission, in a concentration-dependent manner, but it is not as potent as 5-HT. These results support the notion that a 5-HT(2) receptor subtype is present presynaptically on the crayfish motor nerve terminals. By knowing the types of 5-HT receptors present on the presynaptic motor nerve terminals in this model synaptic preparation, a better understanding of the mechanisms of action of 5-HT on vesicular release will be forthcoming. PMID:11911865

Tabor, Jami N; Cooper, Robin L



Origin of 5-hydroxytryptamine-induced hyperpolarization of the rat superior cervical ganglion and vagus nerve.  

PubMed Central

1 5-Hydroxytryptamine (5-HT)-induced membrane potential changes were recorded extracellularly from rat superior cervical ganglia (SCG) and cervical vagus nerves in vitro. 2 On the SCG, low concentrations of 5-HT (1 X 10(-8)-3 X 10(-7) M) induced concentration-related hyperpolarization responses. Higher concentrations of 5-HT (1 X 10(-6) 1 X 10(-4) M) induced complex responses which typically consisted of an initial hyperpolarization, followed by a depolarization and subsequent after-hyperpolarization. The depolarization, but not the initial hyperpolarization, was blocked by metoclopramide (3 X 10(-5) M), quipazine (1 X 10(-6) M) or MDL 72222 (1 X 10(-5) M). 3 5-HT-induced hyperpolarization of the SCG was potentiated when the amount of calcium chloride added to the superfusion medium was reduced from 2.5 to 0.15 mmol l-1. Hyperpolarization responses recorded from SCG preparations superfused with this low-calcium medium were unaffected by the substitution of lithium chloride for sodium chloride and were potentiated by the omission of potassium ions. Ouabain (1 X 10(-3) M) abolished both the hyperpolarization and the depolarization induced by 5-HT. 4 On the vagus nerve, 5-HT (1 X 10(-7) - 3 X 10(-5)M) did not induce initial hyperpolarization in either normal or low-calcium Krebs-Henseleit medium. However, in the latter solution only, depolarization responses induced by 5-HT at concentrations of 1 X 10(-6)M or greater were followed by hyperpolarization. Both the depolarization and the post-5-HT hyperpolarization were blocked by metoclopramide (3 X 10(-5)M) but were unaffected by spiperone (1 X 10(-7)M). 5 On the vagus nerve, post-5-HT hyperpolarization responses were selectively and reversibly inhibited by ouabain, and by superfusion with Krebs-Henseleit medium that was either potassium-free or contained lithium chloride in place of sodium chloride. 7 These results demonstrate the generation in the rat SCG of a 5-HT-induced hyperpolarization response that is not mediated through 5-HT3 receptors and is unlikely to be a consequence of depolarization. In contrast, on the rat vagus nerve, the post-5-HT hyperpolarization observed in the present study had the characteristics expected of depolarization-dependent activation of a sodium ion pump. PMID:3676601

Ireland, S. J.



Effect of 5-hydroxytryptamine on sodium- and potassium-dependent adenosine triphosphatase and its reactivity toward ouabain.  


Activity of vertebrate Na+,K+-ATPase was inhibited by 5-hydroxytryptamine. Inhibition was reversible, and activity could be restored by dilution of 5-hydroxytryptamine (5HT). The ability of indole derivatives to inhibit depended on the presence of a net charge on the third atom of the indole C-3 side chain. Indoles with a net positive charge, such as 5HT, were stronger inhibitors than those with a net negative charge. Derivatives with a net charge of zero were not inhibitors. The ability of indole derivatives to inhibit Na+, K+-ATPase activity decreased in the order 5HT > tryptamine > tryptophanamide > tryptophol > N-acetyl-5-methoxytryptamine > indole-3-acetic acid. Trp did not inhibit either ATPase or pNPPase activity. Charged indole derivatives also inhibited the pNPPase activity of Na+,K+-ATPase. 5HT and tryptophanamide were stronger inhibitors of pNPPase activity than indole-3-acetic acid. Binding of [3H]ouabain was inhibited by 5HT and tryptophanamide. Trp did not inhibit [3H]ouabain binding. The near equilibrium level of [3H]-ouabain binding in the presence of ATP, Mg2+, and Na+ was decreased by 5HT in the manner characteristic of a competitive inhibitor. Enzyme-bound [3H]ouabain could be displaced by 5HT. 5HT was a complex mixed inhibitor of K+ with interactions at two sites, Tris was a competitive inhibitor with interactions at three sites, and ouabain was a simple noncompetitive inhibitor. The data are explained through a model indole binding site containing oppositely charged residues. PMID:8990266

Stepp, L R; Novakoski, M A



Perinatal growth restriction is not related to higher intestinal distribution and increased serum levels of 5-hydroxytryptamin in piglets.  


Serotonin [5-hydroxytryptamin (5-HT)] is abundantly present in intestinal enteroendocrine cells and neurons and plays a crucial role in gastrointestinal functions (i.e., motility and mucosal secretion). Increased concentrations of 5-HT and its precursor l-Trp are present in plasma and brain tissues in case of intrauterine growth retardation (IUGR). Therefore, 5-HT might be involved in the impaired gastrointestinal function associated with IUGR. Small-for-gestational-age (SGA) piglets have been widely used as animal model for IUGR. Hence, the density of intestinal 5-HT cells in fetal and neonatal SGA piglets was compared with serotonergic cell density in normal weight (NW) littermates. Furthermore, 5-HT serum concentrations of the neonatal piglets were analyzed. Stereological analysis showed that fetal piglets have higher (P < 0.01) volume densities of 5-HT enteroendocrine cells compared to 3-d-old piglets irrespective of BW. Serum concentrations did not differ in relation to postnatal age (P = 0.637) and BW (P = 0.892). These results contrast with serum and brain 5-HT and l-Trp levels in human and guinea pig SGA individuals and seemingly contest the fact that 5-HT plays an important role in gut impairment in SGA. PMID:23365362

Willemen, S; Che, L; De Vos, M; Huygelen, V; Tambuyzer, B; Casteleyn, C; Van Cruchten, S; Zhang, K; Van Ginneken, C



Dual dopamine–5HT releasers: potential treatment agents for cocaine addiction  

Microsoft Academic Search

Biogenic amine transporters (BATs) are integral membrane proteins that translocate biogenic amine neurotransmitters (norepinephrine, dopamine (DA) and 5-hydroxytryptamine (5-HT)) across cell mem- branes. BATs are the principal sites of action for many psychotropic drugs, including abused stimulants such as cocaine and methamphetamine. Preclinical and human data demonstrate that withdrawal from long-term cocaine administration produces a dual deficit of synap- tic

Richard B. Rothman; Bruce E. Blough; Michael H. Baumann



5-HT4 receptor agonists: similar but not the same.  


5-Hydroxytryptamine(4) (5-HT(4)) receptors are an interesting target for the management of patients in need of gastrointestinal (GI) promotility treatment. They have proven therapeutic potential to treat patients with GI motility disorders. Lack of selectivity for the 5-HT(4) receptor has limited the clinical success of the agonists used until now. For instance, next to their affinity for 5-HT(4) receptors, both cisapride and tegaserod have appreciable affinity for other receptors, channels or transporters [e.g. cisapride: human ether-a-go-go-related gene (hERG) is K(+) channel and tegaserod: 5-HT(1) and 5-HT(2) receptors]. Adverse cardiovascular events observed with these compounds are not 5-HT(4) receptor-related. Recent efforts have led to the discovery of a series of selective 5-HT(4) receptor ligands, with prucalopride being the most advanced in clinical development. The selectivity of these new compounds clearly differentiates them from the older generation compounds by minimizing the potential of target-unrelated side effects. The availability of selective agonists enables the focus to shift to the exploration of 5-HT(4) receptor-related differences between agonists. Based on drug- and tissue-related properties (e.g. differences in receptor binding, receptor density, effectors, coupling efficiency), 5-HT(4) receptor agonists are able to express tissue selectivity, i.e. behave as a partial agonist in some and as a full agonist in other tissues. Furthermore, the concept of ligand-directed signalling offers great opportunities for future drug development by enlarging the scientific basis for the generation of agonist-specific effects in different cell types, tissues or organs. Selective 5-HT(4) receptor agonists might thus prove to be innovative drugs with an attractive safety profile for better treatment of patients suffering from hypomotility disorders. PMID:18199093

De Maeyer, J H; Lefebvre, R A; Schuurkes, J A J



Neuronal localization of the 5-HT2 receptor family in the amygdaloid complex  

PubMed Central

The amygdaloid complex (or amygdala), a heterogeneous structure located in the medial portion of the temporal lobe, is composed of deep, superficial, and “remaining” nuclei. This structure is involved in the generation of emotional behavior, in the formation of emotional memories and in the modulation of the consolidation of explicit memories for emotionally arousing events. The serotoninergic fibers originating in the dorsal and medial raphe nuclei are critically involved in amygdalar functions. Serotonin (5-hydroxytryptamine, 5-HT) regulates amygdalar activity through the activation of the 5-HT2 receptor family, which includes three receptor subtypes: 5-HT2A, 5-HT2B, and 5-HT2C. The distribution and the functional activity of the 5-HT2 receptor family has been studied more extensively than that of the 5-HT2A receptor subtypes, especially in the deep nuclei. In these nuclei, the 5-HT2A receptor is expressed on both pyramidal and non-pyramidal neurons, and could play a critical role in the formation of emotional memories. However, the exact role of the 5-HT2A receptor subtypes, as well as that of the 5-HT2B and 5-HT2C receptor subtypes, in the modulation of the amygdalar microcircuits requires additional study. The present review reports data concerning the distribution and the functional roles of the 5-HT2 receptor family in the amygdala. PMID:24782772

Bombardi, Cristiano



The actions of 5-hydroxytryptamine receptor agonists and antagonists at pre- and postjunctional level on the canine saphenous vein.  


The prejunctional and postjunctional 5-HT receptors of the canine saphenous vein were studied. The release of 3H-noradrenaline (3H-NA) from incubated saphenous vein strips was inhibited by 5-hydroxytryptamine (5-HT) in a concentration-dependent way (5-HT concentrations: 0.01, 0.1 and 1.0 mumol.l-1), but not by the selective 5-HT1A agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT; 1 and 10 mumol.l-1). The inhibitory effect of 5-HT was antagonized by metitepine and methysergide, but not by yohimbine, (-)-pindolol or ketanserin. In strips preincubated with 5-HT (1.2 mumol.l-1), the fractional release of 3H-NA was slightly reduced (paired experiments). 5-HT and 8-OH-DPAT caused concentration-dependent contractions of the saphenous smooth muscle. A parallel shift of the concentration-response curve for 8-OH-DPAT to the right was caused by metitepine and yohimbine, but not by ketanserin. The contractions caused by 5-HT were antagonized by metitepine and yohimbine (parallel displacement of the curves to the right), as well as by ketanserin and methysergide (with a depression of the upper part of the curve). Blockade of alpha-adrenoceptors (due to prazosin plus a low concentration of yohimbine) also resulted in a weak antagonistic effect. Ketanserin and metitepine displaced the noradrenaline concentration-response curve to the right. We conclude that the saphenous vein of the dog is endowed with prejunctional receptors of the 5-HT1 type which can not be classified as belonging either to the 1A or 1B subtype; and that at the postjunctional level 5-HT1 (possibly of the 1D subtype) and 5-HT2 receptors are present.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2977424

Paiva, M Q; Caramona, M M; Osswald, W



Enhanced coronary vasoconstrictor responses to 5-hydroxytryptamine in the presence of a coronary artery stenosis in anaesthetized dogs.  

PubMed Central

1. In the anaesthetized dog, left circumflex coronary artery blood flow and external diameter were measured and the vascular responses to an injection of 5-hydroxytryptamine (5-HT, 0.02-2 micrograms kg-1) assessed, before and after a screw clamp had been placed on the artery to produce a severe stenosis. 2. In the normal coronary circulation, intra-coronary (i.c.) injection of 5-HT increased coronary blood flow (CBF) but decreased the external diameter of the large coronary artery (CD), without affecting systemic mean arterial pressure or heart rate. 3. In the normal coronary circulation, the 5-HT-induced increases in CBF were unaffected by blockade of 5-HT2-receptors with ketanserin (0.1 mg kg-1 i.c.) but were significantly attenuated by blockade of 5-HT1-like receptors with methysergide (0.1 mg kg-1 i.c.). 4. In the presence of a severe stenosis, the increase in CBF produced by 5-HT was markedly attenuated and a secondary decrease in CBF was revealed. The stenosis also caused a marked enhancement of the 5-HT-induced constriction of the large artery, such that the reduction of the CD was approximately doubled at all doses of 5-HT tested. The enhanced 5-HT-induced reduction in CD was similar with placement of the stenosis either proximal or distal to the site of diameter measurement. 5. In the presence of the stenosis, blockade of 5-HT 2-receptors with ketanserin (0.1 mg kg-1 i.c.) significantly attenuated the 5-HT-induced decreases in CD and CBF.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2372656

Woodman, O. L.



Dogmas and controversies in the handling of nitrogenous wastes: 5HT2-like receptors are involved in triggering pulsatile urea excretion in the gulf toadfish, Opsanus beta  

Microsoft Academic Search

When injected arterially, serotonin (5- hydroxytryptamine; 5-HT) has been shown to elicit naturally sized urea pulse events in the gulf toadfish, Opsanus beta. The goal of the present study was to determine which 5-HT receptor(s) was involved in mediating this serotonergic stimulation of the pulsatile excretion mechanism. Toadfish were surgically implanted with caudal arterial catheters and intraperitoneal catheters and injected

M. Danielle McDonald; Patrick J. Walsh



Both exogenous 5-HT and endogenous 5-HT, released by fluoxetine, enhance distension evoked propulsion in guinea-pig ileum in vitro  

PubMed Central

The roles of 5-HT3 and 5-HT4 receptors in the modulation of intestinal propulsion by luminal application of 5-HT and augmentation of endogenous 5-HT effects were studied in segments of guinea-pig ileum in vitro. Persistent propulsive contractions evoked by saline distension were examined using a modified Trendelenburg method. When 5-HT (30 nM), fluoxetine (selective serotonin reuptake inhibitor; 1 nM), 2-methyl-5-HT (5-HT3 receptor agonist; 1 mM), or RS 67506 (5-HT4 receptor agonist, 1 ?M) was infused into the lumen, the pressure needed to initiate persistent propulsive activity fell significantly. A specific 5-HT4 receptor antagonist, SB 207266 (10 nM in lumen), abolished the effects of 5-HT, fluoxetine, and RS 67506, but not those of 2-methyl-5-HT. Granisetron (5-HT3 receptor antagonist; 1 ?M in lumen) abolished the effect of 5-HT, fluoxetine, RS 67506, and 2-methyl-5-HT. The NK3 receptor antagonist SR 142801 (100 nM in lumen) blocked the effects of 5-HT, fluoxetine, and 2-methyl-5-HT. SB 207266, granisetron, and SR 142801 had no effect by themselves. Higher concentrations of fluoxetine (100 and 300 nM) and RS 67506 (3 and 10 ?M) had no effect on the distension threshold for propulsive contractions. These results indicate that luminal application of exogenous 5-HT, or increased release of endogenous mucosal 5-HT above basal levels, acts to lower the threshold for propulsive contractions in the guinea-pig ileum via activation of 5-HT3 and 5-HT4 receptors and the release of tachykinins. The results further indicate that basal release of 5-HT is insufficient to alter the threshold for propulsive motor activity. PMID:25285066

Gwynne, Rachel M.; Clarke, Amanda J.; Furness, John B.; Bornstein, Joel C.



Role of 5-hydroxytryptamine in the regulation of brain neuropeptides in normal and diabetic rat  

NASA Technical Reports Server (NTRS)

The effect of 5-hydroxytryptamine (5-HT) alteration on brain dopamine (DA), norepinephrine (NE), beta-endorphin (beta-E), and immunoreactive insulin was studied in Sprague-Dawley diabetic and control rats. Diabetes was induced using alloxan (45 mg/kg), 15 days prior to sacrificing. Both control and diabetic animals were treated with either p-chlorophenylalanine (PCPA, 300 mg/kg) three days prior to sacrificing or fluoxetine (10 mg/kg) twice daily for three days. PCPA treatment significantly decreased brain content of 5-HT and 5-hydroxyindolel acetic acid, while it caused significant increase and decrease in brain beta-E and insulin levels, respectively, in both normal and diabetic rat. Meanwhile, the administration of fluoxetine resulted in significant increase in brain content of 5-HT, DA, NE and insulin but significant decline of beta-E in diabetic and saline control rats. The results of this experiment indicate that 5-HT may be regulating both beta-E and insulin regardless of the availability of pancreatic insulin.

Kolta, Malak G.; Williams, Byron B.; Soliman, Karam F. A.



5-HT is a potent relaxant in rat superior mesenteric veins  

PubMed Central

Serotonin (5-HT, 5-hydroxytryptamine) reduces blood pressure of the conscious rat when administered chronically (1 week). 5-HT does not directly relax isolated arteries, and microsphere experiments in 5-HT-infused rats suggested that 5-HT increased flow to the splanchnic bed. We hypothesized that 5-HT increased splanchnic flow because of direct venous relaxation; our focus was thus on the superior mesenteric vein (SMV) as an important vein in splanchnic circulation. Real-time RT-PCR, immunohistochemistry and Western analyses supported the predominant expression of the 5-HT2B and 5-HT7 receptor in the SMV. The SMV was mounted in tissue baths for measurement of isometric contraction. 5-HT caused a concentration-dependent relaxation of the endothelin-1 (ET-1)-contracted vein. The threshold of 5-HT-induced venous relaxation was significantly lower than for 5-HT-induced venous contraction (?2 vs. 700 nmol/L, respectively). A series of serotonergic agonists established in their use of receptor characterization was tested, and the following rank order of potency found for agonist-induced relaxation (receptor selectivity): 5-CT (5-HT1/5-HT7)>5-HT = LP-44 (5-HT7)>PNU109291 (5-HT1D) = BW723C86 (5-HT2B). 8-OH-DPAT (5-HT1A/7), CP93129 (5-HT1B), mCPBG (5-HT3/4), AS19 (5-HT7) and TCB-2 (5-HT2A) did not relax the isolated vein. Consistent with these findings, two different 5-HT7 receptor antagonists SB 269970 and LY215840 but not the 5-HT2B receptor antagonist LY272015 nor the nitric oxide synthase inhibitor LNNA abolished 5-CT-induced relaxation of the isolated SMV. 5-CT (1 ?g kg?1 min?1, sc) also reduced blood pressure over 7 days. These findings suggest that 5-HT directly relaxes the SMV primarily through activation of the 5-HT7 receptor.

Watts, Stephanie W; Darios, Emma S; Seitz, Bridget M; Thompson, Janice M



Peptide YY3–36 and 5-Hydroxytryptamine Mediate Emesis Induction by Trichothecene Deoxynivalenol (Vomitoxin)  

PubMed Central

Deoxynivalenol (DON, vomitoxin), a trichothecene mycotoxin produced by Fusarium sp. that frequently occurs in cereal grains, has been associated with human and animal food poisoning. Although a common hallmark of DON-induced toxicity is the rapid onset of emesis, the mechanisms for this adverse effect are not fully understood. Recently, our laboratory has demonstrated that the mink (Neovison vison) is a suitable small animal model for investigating trichothecene-induced emesis. The goal of this study was to use this model to determine the roles of two gut satiety hormones, peptide YY3–36 (PYY3–36) and cholecystokinin (CCK), and the neurotransmitter 5-hydroxytryptamine (5-HT) in DON-induced emesis. Following ip exposure to DON at 0.1 and 0.25mg/kg bw, emesis induction ensued within 15–30min and then persisted up to 120min. Plasma DON measurement revealed that this emesis period correlated with the rapid distribution and clearance of the toxin. Significant elevations in both plasma PYY3–36 (30–60min) and 5-HT (60min) but not CCK were observed during emesis. Pretreatment with the neuropeptide Y2 receptor antagonist JNJ-31020028 attenuated DON- and PYY-induced emesis, whereas the CCK1 receptor antagonist devezapide did not alter DON’s emetic effects. The 5-HT3 receptor antagonist granisetron completely suppressed induction of vomiting by DON and the 5-HT inducer cisplatin. Granisetron pretreatment also partially blocked PYY3–36-induced emesis, suggesting a potential upstream role for this gut satiety hormone in 5-HT release. Taken together, the results suggest that both PYY3–36 and 5-HT play contributory roles in DON-induced emesis. PMID:23457120

Pestka, James J.



Rostrocaudal distribution of 5-HT innervation in the lamprey spinal cord and differential effects of 5-HT on fictive locomotion.  


5-hydroxytryptamine (5-HT) is known to modulate the locomotion generator network in the lamprey spinal cord, but little is known about the pattern of 5-HT innervation along the spinal cord. The distribution of 5-HT-immunoreactive (5-HT-ir) cells and fibers, as well as the effects of 5-HT on the locomotor network in the rostral and caudal parts of the spinal cord were compared in two lamprey species, Lampetra fluviatilis and Petromyzon marinus. Intraspinal 5-HT cells form a very dense ventromedial plexus in which the dendrites of neurons forming the locomotor network are distributed. The number of 5-HT cells and varicosities in this plexus decreases in the fin area (segments 70-90), and then increases somewhat in the most caudal segments. The descending 5-HT fibers from the rhombencephalon are located in the lateral and ventral columns, and their numbers gradually decrease to around 50% in the tail part of the spinal cord. In contrast, the number of 5-HT-ir axons in the dorsal column remains the same along the spinal cord. Bath application of both N-methyl-D-aspartic acid (NMDA, 20-250 microM) and D-glutamate (250-1000 microM) was used to induce fictive locomotion in the isolated spinal cord. Bath application of 5-HT (1 microM) reduced the burst frequency in the presence of NMDA. The 5-HT effect was, however, significantly greater in the rostral as compared to the caudal part. With D-glutamate, the 5-HT effects was instead more pronounced in the caudal spinal cord. To account for this difference in 5-HT effects on NMDA- and D-glutamate-induced fictive locomotion, the cellular effect of D-glutamate was further investigated. It activates not only NMDA, but also alpha amino-3-hydroxy-5-methyl-4-isoxyl propionate (AMPA)/kainate and metabotropic glutamate receptors. In contrast to NMDA, D-glutamate did not elicit tetrodotoxin (TTX)-resistant membrane potential oscillations. This difference in action between NMDA (selective NMDA receptor agonist) and D-glutamate (mixed agonist) may partially account for the differences in effect of 5-HT on the locomotor pattern. PMID:8906499

Zhang, W; Pombal, M A; el Manira, A; Grillner, S



Distribution of cells responsive to 5-HT6 receptor antagonist-induced hypophagia  

PubMed Central

The central 5-hydroxytryptamine (5-HT; serotonin) system is well established as an important regulator of appetite and continues to remain a focus of obesity research. While much emphasis has focussed on the 5-HT2C receptor (5-HT2CR) in 5-HT's anorectic effect, pharmacological manipulation of the 5-HT6 receptor (5-HT6R) also reduces appetite and body weight and may be amenable to obesity treatment. However, the neurological circuits that underlie 5-HT6R-induced hypophagia remain to be identified. Using c-fos immunoreactivity (FOS-IR) as a marker of neuronal activation, here we mapped the neuroanatomical targets activated by an anorectic dose of the 5-HT6R antagonist SB-399885 throughout the brain. Furthermore, we quantified SB-399855 activated cells within brain appetitive nuclei, the hypothalamus, dorsal raphe nucleus (DRN) and nucleus of the solitary tract (NTS). Our results reveal that 5-HT6R antagonist-induced hypophagia is associated with significantly increased neuronal activation in two nuclei with an established role in the central control of appetite, the paraventricular nucleus of the hypothalamus (PVH) and the NTS. In contrast, no changes in FOS-IR were observed between treatment groups within other hypothalamic nuclei or DRN. The data presented here provide a first insight into the neural circuitry underlying 5-HT6R antagonist-induced appetite suppression and highlight the PVH and NTS in the coordination of 5-HT6R hypophagia. PMID:24566060

Garfield, Alastair S.; Burke, Luke K.; Shaw, Jill; Evans, Mark L.; Heisler, Lora K.



Characterization of 5-HT receptors mediating contraction of canine and primate basilar artery by use of GR43175, a selective 5-HT1-like receptor agonist.  

PubMed Central

1. The aim of this study was to characterize the 5-hydroxytryptamine (5-HT) receptor which mediates contraction of canine and primate isolated basilar artery by use of a variety of selective 5-HT agonists and antagonists. 2. 5-HT, alpha-methyl 5-HT and the selective 5-HT1-like receptor agonists, GR43175 and 5-carboxamidotryptamine (5-CT), each caused contraction of canine and primate basilar artery with a rank order of agonist potency of 5-CT greater than or equal to 5-HT greater than GR43175 greater than alpha-methyl 5-HT. The 5-HT1-like receptor agonists, GR43175 and 5-CT, produced maximum effects which were less than that produced by 5-HT or alpha-methyl 5-HT. 3. In canine basilar artery, ketanserin (0.1-1 microM) caused some depression of the maximum effect of 5-HT but produced little or no shift of the concentration-effect curve. The contractile effects of GR43175 were not modified by ketanserin (1 microM), MDL72222 (1 microM) or cyanopindolol (1 microM). However, the effects of 5-HT and GR43175 were specifically antagonized by methiothepin (0.1 microM); the mean agonist concentration-ratios were 33 and 48 respectively. 4. In primate basilar artery, ketanserin (1 microM) again caused a small depression of the 5-HT maximum response but had not effect against GR43175-induced contractions. In contrast, methiothepin (0.1 microM) antagonized both 5-HT- and GR43175-induced contractions; the mean agonist concentration-ratios were 35 for both.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2538191

Connor, H. E.; Feniuk, W.; Humphrey, P. P.



5-hydroxytryptamine-mediated neurotransmission modulates spontaneous and vagal-evoked glutamate release in the nucleus of the solitary tract effect of uptake blockade.  


The effect of blockade of either 5-hydroxytryptamine (5-HT)/serotonin transporter (SERT) with citalopram or the organic cation transporter 3 (OCT3)/plasma membrane monoamine transporter (PMAT) with decynium-22 (D-22) on spontaneous and evoked release of 5-HT in the nucleus tractus solitarius (NTS) was investigated in rat brainstem slices treated with gabazine. 5-HT release was measured indirectly by changes in the frequency and amplitude of glutamatergic miniature excitatory postsynaptic currents (mEPSCs) [in the presence of tetrodotoxin (TTX)] and evoked EPSCs. Blockade of 5-HT3 receptors with granisetron reduced, whereas the 5-HT3 agonist phenylbiguanide increased, the frequency of mEPSCs. 5-HT decreased mEPSC frequency at low concentrations and increased frequency at high concentrations. This inhibition was blocked by the 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635), which was ineffective on its own, whereas the excitation was reversed by granisetron. The addition of citalopram or D-22 caused inhibition, which was prevented by 5-HT1A blockade. Thus, in the NTS, the spontaneous release of 5-HT is able to activate 5-HT3 receptors, but not 5-HT1A receptors, as the release in their vicinity is removed by uptake. The ineffectiveness of corticosterone suggests that the low-affinity, high-capacity transporter is PMAT, not OCT3. For evoked 5-HT release, only D-22 caused an increase in the amplitude of EPSCs, with a decrease in the paired pulse ratio, and increased the number of spontaneous EPSCs after 20-Hz stimulation. Thus, for the evoked release of 5-HT, the low-affinity, high-capacity transporter PMAT, but not 5-HT transporter (5-HTT)/SERT, is important in the regulation of changes in 5-HT extracellular concentration. PMID:24618127

Hosford, Patrick S; Mifflin, Steve W; Ramage, Andrew G



The action of 5-hydroxytryptamine and related compounds on the activity of retzius cells of the leech Hirudo medicinalis  

PubMed Central

1 The equipotent molar ratios of a range of tryptamine analogues, as compared with 5-hydroxytryptamine (5-HT), have been determined on the basis of their ability to hyperpolarize the membrane potential of the Retzius cell of the leech, Hirudo medicinalis. 2 The substitution of methyl, fluoro, chloro, methoxy or acetyl groups onto the 5-HT molecule progressively reduced the potency. 3 5-Methoxylation or terminal N-methylation of tryptamine considerably increased the potency of tryptamine but these compounds tended to depolarize cells rather than cause hyperpolarization. In some experiments they were ineffective on preparations pretreated with 5-HT. 4 It is suggested that these compounds may act by a different mechanism from the 5-hydroxylated indoles, perhaps involving a different receptor. PMID:4441793

Smith, P.A.; Walker, R.J.



Glutamate release in human cerebral cortex and its modulation by 5-hydroxtryptamine acting at h 5-HT1D receptors  

PubMed Central

The release of glutamic acid and its modulation by 5-hydroxytryptamine (5-HT) in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply sited tumours.The Ca2+-dependent K+ (15?mM)-evoked overflow of glutamate was inhibited by 5-HT in a concentration-dependent manner (EC50=2.9?nM; maximal effect ?50%). The inhibition caused by 5-HT was antagonized by the 5-HT1/5-HT2 receptor antagonist methiothepin. The 5-HT1B/5-HT1D receptor agonist sumatriptan mimicked 5-HT (EC50=6.4?nM; maximal effect ?50%); the effect of sumatriptan was also methiothepin-sensitive. Selective 5-HT1A receptor antagonists could not prevent the inhibition of glutamate release by 5-HT.The 5-HT1B/5-HT1D receptor ligand GR 127935 and the 5-HT2C/5-HT1B/5-HT1D receptor ligand metergoline were unable to prevent the 5-HT effect; instead they inhibited glutamate release, their effects being abolished by methiothepin. Some 5-HT1A receptor antagonists also displayed intrinsic agonist activity.The effect of sumatriptan was prevented by ketanserin, a drug known to display much higher affinity for recombinant h 5-HT1D than for h 5-HT1B receptors.We propose that neocortical glutamatergic nerve terminals in human brain cortex possess release-inhibiting presynaptic heteroreceptors that appear to belong to the h 5-HT1D subtype. PMID:9484853

Maura, Guido; Marcoli, Manuela; Tortarolo, Massimo; Andrioli, Gian Carlo; Raiteri, Maurizio



Modulation of 5-hydroxytryptamine efflux from rat cortical synaptosomes by opioids and nociceptin.  


The modulation of [(3)H]-5-hydroxytryptamine ([(3)H]-5-HT) efflux from superfused rat cortical synaptosomes by delta, kappa, mu and ORL(1) opioid receptor agonists and antagonists was studied. Spontaneous [(3)H]-5-HT efflux was reduced (20% inhibition) by either 0.5 microM tetrodotoxin or Ca(2+)-omission. Ten mM K(+)-evoked [(3)H]-5-HT overflow was largely Ca(2+)-dependent (90%) and tetrodotoxin-sensitive (50%). The delta receptor agonist, deltorphin-I, failed to modulate the K(+)-evoked neurotransmitter efflux up to 0.3 microM. The kappa and the mu receptor agonists, U-50,488 and endomorphin-1, inhibited K(+)-evoked [(3)H]-5-HT overflow (EC(50)=112 and 7 nM, respectively; E(max)=28 and 29% inhibition, respectively) in a norBinaltorphimine- (0.3 microM) and naloxone- (1 microM) sensitive manner, respectively. None of these agonists significantly affected spontaneous [(3)H]-5-HT efflux. The ORL(1) receptor agonist nociceptin inhibited both spontaneous (EC(50)=67 nM) and K(+)-evoked (EC(50)=13 nM; E(max)=52% inhibition) [(3)H]-5-HT efflux. The effect of NC was insensitive to naloxone (up to 10 microM), but was antagonized by [Nphe(1)]nociceptin(1-13)NH(2) (a novel selective ORL(1) receptor antagonist; pA(2)=6.7) and by naloxone benzoylhydrazone (pA(2)=6.3). The ORL(1) ligand [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) also inhibited K(+) stimulated [(3)H]-5-HT overflow (EC(50)=64 nM; E(max)=31% inhibition), but its effect was partially antagonized by 10 microM naloxone. It is concluded that the ORL(1) receptor is the most important presynaptic modulator of neocortical 5-HT release within the opioid receptor family. This suggests that the ORL(1)/nociceptin system may have a powerful role in the control of cerebral 5-HT-mediated biological functions. PMID:10807682

Sbrenna, S; Marti, M; Morari, M; Calo', G; Guerrini, R; Beani, L; Bianchi, C



Modulation of 5-hydroxytryptamine efflux from rat cortical synaptosomes by opioids and nociceptin  

PubMed Central

The modulation of [3H]-5-hydroxytryptamine ([3H]-5-HT) efflux from superfused rat cortical synaptosomes by delta, kappa, mu and ORL1 opioid receptor agonists and antagonists was studied. Spontaneous [3H]-5-HT efflux was reduced (20% inhibition) by either 0.5??M tetrodotoxin or Ca2+-omission. Ten mM K+-evoked [3H]-5-HT overflow was largely Ca2+-dependent (90%) and tetrodotoxin-sensitive (50%). The delta receptor agonist, deltorphin-I, failed to modulate the K+-evoked neurotransmitter efflux up to 0.3??M. The kappa and the mu receptor agonists, U-50,488 and endomorphin-1, inhibited K+-evoked [3H]-5-HT overflow (EC50=112 and 7?nM, respectively; Emax=28 and 29% inhibition, respectively) in a norBinaltorphimine- (0.3??M) and naloxone- (1??M) sensitive manner, respectively. None of these agonists significantly affected spontaneous [3H]-5-HT efflux. The ORL1 receptor agonist nociceptin inhibited both spontaneous (EC50=67?nM) and K+-evoked (EC50=13?nM; Emax=52% inhibition) [3H]-5-HT efflux. The effect of NC was insensitive to naloxone (up to 10??M), but was antagonized by [Nphe1]nociceptin(1-13)NH2 (a novel selective ORL1 receptor antagonist; pA2=6.7) and by naloxone benzoylhydrazone (pA2=6.3). The ORL1 ligand [Phe1?(CH2-NH)Gly2]nociceptin(1-13)NH2 also inhibited K+ stimulated [3H]-5-HT overflow (EC50=64?nM; Emax=31% inhibition), but its effect was partially antagonized by 10??M naloxone. It is concluded that the ORL1 receptor is the most important presynaptic modulator of neocortical 5-HT release within the opioid receptor family. This suggests that the ORL1/nociceptin system may have a powerful role in the control of cerebral 5-HT-mediated biological functions. PMID:10807682

Sbrenna, S; Marti, M; Morari, M; Calo', G; Guerrini, R; Beani, L; Bianchi, C



5-HT1-like receptors requiring functional cyclo-oxygenase and 5-HT2 receptors independent of cyclo-oxygenase mediate contraction of the human umbilical artery.  

PubMed Central

1. The interactions between 5-hydroxytryptamine (5-HT) and the antagonists ketanserin, methysergide and phentolamine were studied in isolated preparations of human umbilical artery (HUA) at physiological oxygen tension (Po2 approximately 15 mmHg) and at high PO2 (approximately 120 mmHg). 2. At physiological Po2 ketanserin, methysergide and phentolamine behaved as silent competitive antagonists of the 5-HT-induced contraction of HUA. pA2 values calculated by Schild analysis were 8.92, 8.52 and 6.37, respectively. 3. At high Po2, 5-HT-induced contractions were antagonised in a biphasic manner by ketanserin (0.1 microM); the response to low but not to high concentrations of 5-HT was resistant to blockade by ketanserin. The ketanserin-resistant component was abolished following cyclo-oxygenase inhibition by indomethacin (1 microM). 4. At high Po2, methysergide behaved as a partial agonist. Methysergide-induced contractions were inhibited but not abolished by indomethacin, and resistant to 5-HT2 receptor and alpha 1-adrenoceptor blockade. 5. At high Po2 the component of the response to 5-HT mediated by the ketanserin-resistant receptor was mimicked by the selective 5-HT1-like receptor agonist 5-carboxamidotryptamine (5-CT): 5-CT was 7 fold more potent than 5-HT. 6. At high Po2 the component of the response to 5-HT mediated by the ketanserin-resistant receptor was antagonised by phentolamine and the selective alpha 2-adrenoceptor antagonist Wy 26703. 7. These results suggest that (i) at physiological Po2 5-HT2 receptors almost exclusively mediate contractions induced by 5-HT, and (ii) at high Po2 the agonist potency order of 5-CT greater than 5-HT greater than methysergide suggests that ketanserin-resistant responses are mediated by 5-HT1-like receptors which require functional cyclo-oxygenase. PMID:2503229

MacLennan, S. J.; Whittle, M. J.; McGrath, J. C.



5-Carboxamidotryptamine is a selective agonist at 5-hydroxytryptamine receptors mediating vasodilatation and tachycardia in anaesthetized cats.  

PubMed Central

We have attempted to characterize the 5-hydroxytryptamine (5-HT) receptors mediating bronchoconstriction, vasodilatation, vasodepression and tachycardia in anaesthetized cats following bilateral vagosympathectomy and beta-adrenoceptor blockade with propranolol. 5-HT (1-100 micrograms/kg-1 i.v.) caused dose-related bronchoconstriction and tachycardia but variable and complex effects on diastolic blood pressure and carotid arterial vascular resistance. In contrast, 5-carboxamidotryptamine (5-CT; 0.01-1 micrograms kg-1 i.v.) caused consistent, dose-related decreases in diastolic blood pressure and carotid arterial vascular resistance and increases in heart rate. 5-CT did not cause bronchoconstriction. The 5-HT-induced bronchoconstriction was dose-dependently antagonized by methiothepin, methysergide and ketanserin (10-100 micrograms kg-1 i.v.). The highest doses used of these antagonists did not antagonize bronchoconstriction induced by prostaglandin F2 alpha. The high potency of all three antagonists indicate a 5-HT2-receptor mediated effect. The 5-HT- and 5-CT-induced tachycardia as well as the 5-CT-induced vasodepressor and carotid arterial vasodilator responses were dose-dependently antagonized by low doses of methiothepin (10-100 micrograms kg-1 i.v.) and by high doses of methysergide (100-1000 micrograms kg-1 i.v.) but were little affected by ketanserin in doses up to 1000 micrograms kg-1 i.v. These selective effects of 5-CT appear to be mediated by '5-HT1-like' receptors. PMID:2937503

Connor, H. E.; Feniuk, W.; Humphrey, P. P.; Perren, M. J.



Dissipation mechanisms for 5-hydroxytryptamine in the coronary circulation of the isolated perfused heart of the rat.  

PubMed Central

1. The contribution of uptake into vascular endothelial cells, of neuronal uptake and of extraneuronal uptake in the dissipation of 5-hydroxytryptamine (5-HT) perfused through the coronary circulation of the rat heart was examined. 2. Hearts from reserpine-pretreated rats were isolated and perfused in vitro with 5-HT, in the absence or presence of inhibitors, and rates of appearance of the deaminated metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in the venous effluent were measured using an h.p.l.c. assay. 3. The steady-state rates of 5-HIAA appearance in the venous effluent in hearts perfused with 1 microM 5-HT (422 +/- 8.48 pmol g-1 min-1, n = 12) were reduced by pretreatment of the rats with 6-hydroxydopamine (22% inhibition), and by inclusion in the perfusion solution of 30 microM cocaine (28% inhibition), 100 microM 3-O-methylisoprenaline (64% inhibition), 100 microM corticosterone (58% inhibition), or 30 microM cocaine and 100 microM 3-O-methylisoprenaline (87% inhibition). 4. The extraneuronal deamination of 5-HT in the heart was saturable (Km = 101 microM, Vmax = 31.2 nmol g-1 min-1). The neuronal deamination of 5-HT was saturated by about 50 fold lower concentrations of 5-HT than was extraneuronal deamination, but Km and Vmax values could not be determined. 5. In the coronary circulation of the rat heart, 5-HT was dissipated by the uptake processes for catecholamines, extraneuronal uptake (predominantly) and neuronal uptake, and subsequent metabolism by monoamine oxidase. There was no evidence that a cocaine-sensitive uptake of 5-HT into vascular endothelial cells made any significant contribution to 5-HT dissipation in the heart. PMID:2474344

Bryan, L. J.; O'Donnell, S. R.; Williams, A. M.



Assessment of 5-hydroxytryptamine efflux in rat brain during a mild, moderate and severe serotonin-toxicity syndrome  

PubMed Central

Serotonin (5-hydroxytryptamine; 5-HT)-toxicity syndrome, an iatrogenic brain disorder induced by excessive efflux of 5-HT, has received much attention because of increasing incidents of serotonergic antidepressants. However, the neural mechanism by which extracellular 5-HT is elevated to a toxic level for the syndrome remains to be determined. The goal of the present study was to test the hypothesis that extracellular 5-HT is composed of two component effluxes responsible for distinct aspects of the syndrome. The first set of experiments was to characterize the syndrome by measuring changes in neuromuscular signs, body-core temperature and mortality rate. Our results indicate that the syndrome severity can be categorized into mild, moderate and severe levels. The second set of experiments was to determine a threshold of extracellular 5-HT for induction of each level of the syndrome. Our results demonstrate that there were an 11-fold increase in the mild syndrome and an over 55-fold increase in the severe syndrome. In the last series of experiments, the excessive increases in 5-HT were pharmacologically separated into primary and secondary component effluxes with the 5-HT2A receptor antagonists cyproheptadine and ketanserin and NMDA receptor antagonist (+)-MK-801. Our results suggest primary component efflux was caused by direct drug effects on 5-HT biosynthetic and metabolic pathways and secondary efflux ascribed to indirect drug effect on a positive feedback circuit involving 5-HT2A and NMDA receptors. In summary, the primary efflux could be an initial cause for the induction of the syndrome while the secondary efflux might involve deterioration of the syndrome. PMID:19464285

Zhang, Gongliang; Krishnamoorthy, Swapna; Ma, Zhiyuan; Vukovich, Nick P.; Huang, Xupei; Tao, Rui



Effects of monoamine uptake inhibitors on extracellular and platelet 5-hydroxytryptamine in rat blood: different effects of clomipramine and fluoxetine.  

PubMed Central

1. The concentration of 5-hydroxytryptamine (5-HT) in rat platelet-free plasma increased significantly 30 min after a single i.p. injection (10 mg kg-1) of each of six inhibitors of the high-affinity 5-HT uptake (fluvoxamine, fluoxetine, alaproclate, paroxetine, sertraline and clomipramine). The increases ranged from 226% to 776% of control values. In contrast, imipramine, desipramine and femoxetine had no significant effect. The increase elicited by paroxetine was dependent on the dose (1, 5 and 10 mg kg-1) and returned to control values after 4 h. That observed after clomipramine was also transient and paralleled the plasma concentration of the drug (Spearman-rank correlation r = 0.43). 2. In vivo, the rat pulmonary vascular endothelium removed trace amounts (8.8 nmol in a bolus) of intravenously injected [14C]-5-HT. Paroxetine pretreatment (10 mg kg-1, 30 min before-hand) reduced this uptake by 73%. 3. Repeated fluoxetine treatments reduced rat whole blood 5-HT concentration (ca. -60% after daily 2 x 5 mg kg-1, i.p. during 14 days). However, plasma (extracellular) 5-HT was not increased. 4. Various repeated treatments with clomipramine (i.p. injections or osmotic minipumps, up to 30 mg kg-1 day-1), failed to decrease rat whole blood 5-HT concentrations. Platelet-free plasma 5-HT was also unchanged, even after treatments yielding plasma clomipramine levels 2.7 times higher than those that increased it acutely. 5. These results indicate that the extracellular pool of 5-HT in rat blood (measured in the platelet-free plasma) is physiologically under the control of high-affinity 5-HT uptake systems.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1387022

Ortiz, J.; Artigas, F.



[ 3H]Sumatriptan binding sites in human brain: regional-dependent labelling of 5HT 1D and 5HT 1F receptors  

Microsoft Academic Search

The general properties of [3H]sumatriptan binding sites in postmortem human brain tissue sections are described. High concentrations of autoradiographic grains were seen in globus pallidus = substantia nigra > cortex > putamen > hippocampus. While 5-HT (5-hydroxytryptamine) displaced in all regions more than 90% of [3H]sumatriptan binding, the level of binding inhibited by 5-CT (5-carboxamidotryptamine) varied in each region. Although

Julio Pascual; Carmen Del Arco; Tamara Romón; Elena Del Olmo; Angel Pazos



Methotrexate causes a change in intestinal 5-hydroxytryptamine metabolism in rats.  


The effects of methotrexate on 5-hydroxytryptamine (5-HT) metabolism in the intestinal tissue of rats were investigated during the delayed phase after a single administration. Rats were i.p. injected with methotrexate or with saline as a control, and kaolin and food intakes were measured by an automatic monitoring apparatus. At 96 h after administration, dissected-out ileal tissue was frozen rapidly in liquid nitrogen for further analysis or fixed for immunohistochemical staining. Methotrexate at a dose of 50 mg/kg caused a time-dependent increase in kaolin intake lasting up to 72 h after administration, which returned to the control level at 96 h after administration. This dose of methotrexate caused a gradual decrease in body weight, food intake, and water intake lasting up to 72 h, which approached the control level at 96 h. Methotrexate caused pathologic changes, including a moderate inflammatory response in the ileal tissue and an increase in the number of L-tryptophan hydroxylase (TPH)-expressing cells in the ileal mucosa. Methotrexate also caused a significant increase in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content and in TPH1 mRNA expression in the ileal tissues. It had no significant effects on mRNA expression of serotonin transporter, COX-1, or COX-2 or on myeloperoxidase activity. This study demonstrated, for the first time, that methotrexate caused a change in the ileal 5-HT metabolism associated with hyperplasia of mucosal enterochromaffin cells. PMID:24975094

Takano, Yuho; Machida, Takuji; Obara, Yusuke; Hirano, Megumi; Kudo, Sae; Takagi, Minako; Hamaue, Naoya; Iizuka, Kenji; Hirafuji, Masahiko



5-Hydroxytryptamine release from platelets by different red wines: implications for migraine.  


We have confirmed our earlier finding that most red wines are able to bring about 5-hydroxytryptamine (5-HT, serotonin) release from platelets in vitro. Platelets from individual subjects manifested varying degrees of releasing ability but responded to different wines with a similar rank ordering. There was a high correlation (r = 0.87) between the effect of red wine and that of reserpine in different individuals. Some types of red wine caused a consistently higher release of 5-HT than others in all subjects; one red wine in particular resulted in negligible release. When several brands of this 'low-releasing' red wine were further examined, they all showed a lower activity than all the brands of a 'high-releasing' red wine type. This variation in releasing power was not related to intensity of red colour. Partial purification of red wine was achieved by column chromatography and showed releasing activity to be associated with a low molecular weight orange fraction. Preliminary studies, using solid phase extraction methods, showed that the active components lie mainly in a subgroup of the flavonoid fraction. If any of the adverse effects of red wine, such as headache induction, derive from this 5-HT releasing ability, then it may be possible to prepare red wines free from the chemical substances responsible. PMID:7720790

Pattichis, K; Louca, L L; Jarman, J; Sandler, M; Glover, V



5-HT inhibits calcium current and synaptic transmission from sensory neurons in lamprey.  


In the lamprey spinal cord, 5-hydroxytryptamine (5-HT) immunoreactivity (ir) is present in the ventromedial plexus originating from intraspinal neurons, ventrolateral column arising from the brainstem, and dorsal column. The latter 5-HT system originates from small dorsal root ganglion neurons. Combined Lucifer yellow intracellular labeling of the intraspinal sensory neurons, dorsal cells, and 5-HT immunohistochemistry showed close appositions between 5-HT-ir fibers and dorsal cell axons. Application of 5-HT depressed monosynaptic EPSPs evoked in giant interneurons by stimulation of single dorsal cells, dorsal roots, or dorsal column without any detectable change in the input resistance of postsynaptic neurons. Furthermore, the amplitude of AMPA-evoked depolarizations in giant interneurons was unaffected by 5-HT. The lack of postsynaptic effects of 5-HT indicates that the decrease of the amplitude of sensory monosynaptic EPSPs by 5-HT is mediated by presynaptic mechanisms. The inhibition of monosynaptic EPSPs by 5-HT was not counteracted by an antagonist of 5-HT1A receptors. 5-HT also reduced the amplitude of the calcium current recorded in isolated dorsal cells and slowed down its kinetics. The inhibition of calcium channels could represent the mechanism mediating the depression of synaptic transmission at the axonal level. These results show that activation of 5-HT receptors on dorsal cell axons as well as on other sensory neurons mediates inhibition of sensory synaptic transmission to giant interneurons. In intact animals, 5-HT could be released from small 5-HT neurons in dorsal root ganglia, which thus may underlie direct sensory-sensory interactions. PMID:9030637

El Manira, A; Zhang, W; Svensson, E; Bussières, N



Evidence for excitatory 5-HT2-receptors on rat brainstem neurones.  

PubMed Central

1. The technique of microiontophoresis was used to investigate the identity of the receptor mediating the excitatory effects of 5-hydroxytryptamine (5-HT) upon neurones in the midline of the medullary brainstem of the rat in vivo. 2. The 5-HT1-like receptor agonists 5-carboxamidotryptamine (5-CT) and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) failed to excite the majority of neurones excited by 5-HT. The mobilities of 5-CT and 8-OH-DPAT when tested in vitro were found not to differ significantly from that of 5-HT, suggesting that the lack of effect of these agonists was not due to a lower rate of release from the microelectrodes. 3. The excitatory responses to 5-HT were attenuated by the 5-HT 2-receptor antagonists ketanserin and methysergide when applied microiontophoretically or administered intravenously (0.3 and 1 mg kg-1 respectively). Excitatory responses to glutamate and noradrenaline were not reduced. 4. The 5-HT3-receptor antagonist MDL 72222 failed to attenuate selectively the excitatory response to 5-HT when applied either by microiontophoresis or administered intravenously (1 mg kg-1). 5. Microiontophoretic application of the alpha 1-adrenoceptor antagonist prazosin did not attenuate excitatory responses to either 5-HT or noradrenaline. Intravenously administered prazosin (0.8 mg kg-1) also failed to attenuate excitatory responses to 5-HT, but did block excitatory responses to noradrenaline. 6. These results suggest that 5-HT2-receptors, but not 5-HT1-like receptors, 5-HT3-receptors or alpha 1-adrenoceptors, are involved in the excitatory response of midline medullary neurones to 5-HT. PMID:3395786

Davie, M.; Wilkinson, L. S.; Roberts, M. H.



Increased hypothalamic 5-HT2A receptor gene expression and effects of pharmacologic 5-HT2A receptor inactivation in obese A{sup y} mice  

SciTech Connect

Serotonin (5-hydroxytryptamine; 5-HT) 2A receptors contribute to the effects of 5-HT on platelet aggregation and vascular smooth muscle cell proliferation, and are reportedly involved in decreases in plasma levels of adiponectin, an adipokine, in diabetic subjects. Here, we report that systemic administration of sarpogrelate, a 5-HT2A receptor antagonist, suppressed appetite and increased hypothalamic pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript, corticotropin releasing hormone, 5-HT2C, and 5-HT1B receptor gene expression. A{sup y} mice, which have ectopic expression of the agouti protein, significantly increased hypothalamic 5-HT2A receptor gene expression in association with obesity compared with wild-type mice matched for age. Systemic administration of sarpogrelate suppressed overfeeding, body weight gain, and hyperglycemia in obese A{sup y} mice, whereas it did not increase plasma adiponectin levels. These results suggest that obesity increases hypothalamic 5-HT2A receptor gene expression, and pharmacologic inactivation of 5-HT2A receptors inhibits overfeeding and obesity in A{sup y} mice, but did not increase plasma adiponectin levels.

Nonogaki, Katsunori [Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan)]. E-mail:; Nozue, Kana [Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan); Oka, Yoshitomo [Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan)



The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin mouse  

PubMed Central

A decreased level of brain 5-hydroxytryptamine (5-HT) has been theorized to be a core pathogenic factor in depression for half a century. The theory arose from clinical observations that drugs enhancing extracellular levels of 5-HT (5-HTExt) have antidepressant effects in many patients. However, whether such drugs indeed correct a primary deficit remains unresolved. Still, a number of anomalies in putative biomarkers of central 5-HT function have been repeatedly reported in depression patients over the past 40 years, collectively indicating that 5-HT deficiency could be present in depression, particularly in severely ill and/or suicidal patients. This body of literature on putative 5-HT biomarker anomalies and depression has recently been corroborated by data demonstrating that such anomalies indeed occur consequent to severely reduced 5-HTExt levels in a mouse model of naturalistic 5-HT deficiency, the tryptophan hydroxylase 2 His439 knockin (Tph2KI) mouse. In this review, we will critically assess the evidence for 5-HT deficiency in depression and the possible role of polymorphisms in the Tph2 gene as a causal factor in 5-HT deficiency, the latter investigated from a clinical as well as preclinical angle. PMID:22826344

Jacobsen, Jacob P. R.; Medvedev, Ivan O.; Caron, Marc G.



5-HT7 receptor-mediated relaxation of the oviduct in nonpregnant proestrus pigs.  


The effects of 5-hydroxytryptamine (5-HT) on the muscle tonus of the ampulla and isthmus of the oviduct isolated from nonpregnant proestrus pigs were investigated, and the 5-HT receptor subtype and mechanisms of the responses were analyzed. 5-HT (1 nM-10 microM) caused a relaxation of longitudinal and circular muscles of the isthmus in a concentration-dependent manner. Tetrodotoxin did not change the relaxation, indicating a direct action of 5-HT on smooth muscle cells. The EC(50) value in the longitudinal muscle was significantly lower than that in the circular muscle but the maximum relaxations were similar. 5-HT also caused a relaxation of both muscle layers in the ampulla but the maximum relaxation of both muscles was smaller than that of the isthmus. 5-Carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT) and (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) mimicked the relaxation of the isthmic longitudinal muscle by 5-HT, and the ranking order was 5-CT>5-HT>5-MeOT>8-OH-DPAT. On the other hand, oxymethazoline, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT), alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT), [endo-N-8-methyl-8-azabicyclo-(3,2,1) oct-3-yl]-2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1-carboxamide (BIMU-1), ergotamine and dihydroergotamine were less effective. The relaxation by 5-HT was not decreased by ketanserin, 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester (tropisetron) or [1[2-(methylsulphonyl) amino ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate (GR113808) but was antagonized by the following compounds in a competitive manner (with pK(b) values in parentheses): 2a-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-2a,3,4,5-tetrahydro-benzo[cd]indol-2(1H)-one (DR4004, 9.31), methiothepin (8.91), methysergide (7.95), metergoline (7.98), mianserin (7.69), mesulergine (8.4), spiperone (6.86) and clozapine (7.4). The correlation of these pK(b) values with pK(i) values of cloned 5-HT(7) receptor or pA(2) values of porcine uterus was high and significant. 4-(3-Butoxy-4-methoxybenzyl)-imidazolidin-2-one (Ro20-1724) significantly enhanced the relaxation by 5-HT but zaprinast, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and L-nitroarginine methylester (L-NAME) did not change the responses to 5-HT. 5-HT increased cyclic AMP in the isthmic oviduct. Ampulla and isthmus contained a single class of [3H]5-CT binding sites with a similar K(d) value (0.4 nM), but the density of the receptors in the isthmus was 2.4 times higher than that in the ampulla. A significant correlation was found between the pK(i) values in the oviduct and those of the cloned 5-HT(7) receptors. Isoprenaline, sodium nitroprusside, vasoactive intestinal peptide and pituitary adenylate cyclase activating peptide were less effective in causing the relaxation of the oviduct. In conclusion, the 5-HT receptor, functionally correlated to the 5-HT(7) type, mediates the relaxation of the porcine oviduct by 5-HT through an increase in intracellular cyclic AMP. The degrees of 5-HT-induced relaxation in the isthmus and ampulla of the oviduct were different due to the heterogeneous distribution of 5-HT(7) receptors. The strongest relaxation through 5-HT(7) receptor activation suggests that 5-HT plays an important physiological role in the regulation of porcine oviduct contractility. PMID:12586216

Inoue, Mayuko; Kitazawa, Takio; Cao, Jinshan; Taneike, Tetsuro



Inhibition of platelet aggregation and 5HT release by extracts of Australian plants used traditionally as headache treatments  

Microsoft Academic Search

To identify potential migraine therapeutics, extracts of eighteen plants were screened to detect plant constituents affecting ADP induced platelet aggregation and [14C]5-hydroxytryptamine (5-HT) release. Extracts of the seven plants exhibiting significant inhibition of platelet function were reanalysed in the presence of polyvinyl pyrrolidone (PVP) to remove polyphenolic tannins that precipitate proteins. Two of these extracts no longer exhibited inhibition of

Kelly L. Rogers; I. Darren Grice; Lyn R. Griffiths



Molecular cloning, functional expression, and pharmacological characterization of 5-hydroxytryptamine3 receptor cDNA and its splice variants from guinea pig.  


Polymerase chain reaction and rapid amplification of cDNA ends were used to isolate cDNAs encoding a 5-hydroxytryptamine3 (5-HT3) receptor subunit and its splice variants from guinea pig intestine. The amino acid sequence predicted from this cDNA is 81% homologous to the murine 5-HT3 receptor subunits cloned from NCB20 and N1E-115 cells. The splice variants code for two proteins differing by a deletion of six amino acids located in the large intracellular loop between transmembrane domains M3 and M4. For characterization, the cloned 5-HT3 cDNA was expressed in HEK 293 cells, and the electrophysiological and pharmacological properties of the recombinant ion/channel/receptor complex were investigated by patch clamping. Our data reveal that the cloned cDNAs code for guinea pig 5-HT3 receptors, which functionally assemble as homo-oligomers. The kinetic behavior of the ion channel and its sensitivity to several agonists and antagonists were markedly different from those of the cloned 5-HT3 receptors from mouse and human under similar experimental conditions. The agonists used were 5-hydroxytryptamine, 2-methyl-5-hydroxytryptamine, 1-phenylbiguanide (PBG), m-chlorophenylbiguanide, and the antagonists tropisetron and metoclopramide. In addition, 5-HT, PBG, and tropisetron were investigated through radioligand binding to isolated membranes. Compared with the human and murine 5-HT3 receptors, the guinea pig receptor showed prolonged desensitization kinetics. In addition, the guinea pig 5-HT3 receptor did not respond to the selective 5-HT3 receptor agonist PBG. Construction of chimeric receptors between guinea pig and human 5-HT3 receptor sequences localized the differences in desensitization kinetics to the carboxyl-terminal domain and the ligand binding site to the amino-terminal domain of the receptor protein. Molecular determinants of the PBG binding site of the human 5-HT3 receptor were localized to a 28-amino-acid spanning region adjacent to the M1 region. PMID:9463477

Lankiewicz, S; Lobitz, N; Wetzel, C H; Rupprecht, R; Gisselmann, G; Hatt, H



Discriminative stimulus properties of indorenate, a 5-HT1A, 5-HT1B and 5-HT2C agonist: a study in rats.  


Indorenate (INDO), initially described as an antihypertensive agent, also has some effects on behaviour, with anxiolytic and anorectic actions being reported. The aim of the present experiment was to examine the activity of INDO at the behavioural level at various serotonin (5-hydroxytryptamine, 5-HT) receptor sites by comparing its stimulus properties with those of other 5-HT receptor agonists and by examining its interactions with some 5-HT antagonists. Rats were trained to discriminate between 10.0 mg/kg INDO (administered intraperitoneally (90 min before the start of the session) from saline. A Fixed Ratio 10 (FR10) schedule of reinforcement was in effect in each drug condition. During generalization test sessions, the discrimination index (DI, responses to drug lever/responses to drug + saline lever) was calculated from the responses emitted before the first reinforcer of the session. DI was a function of the dose of INDO employed. Generalization to the discriminative stimulus properties of INDO was observed with the 5-HT1A receptor agonist 8-OH-DPAT (1.0 mg/kg produced 90% generalization) and the 5-HT(1B/2C) receptor agonist 1-(3-trifluoromethylphenyl) piperazine (TFMPP) (3.0 mg/kg produced up to 75% generalization). Yohimbine (5.6 mg/kg), buspirone (1.0 mg/kg), 6-chloro-2-(1-piperaziny)pyrazine (1.0 mg/kg) and m-chlorophenylpiperazine (mCPP) (1.0 mg/kg) induced a DI of 70%, 50% and 48% and 55%, respectively. In generalization tests, ritanserin (0.01-1.0 mg/kg) induced saline-like responding. NAN-190 (3.0 mg/kg), a 5-HT1A receptor antagonist, was able to reduce the DI of INDO to 50%. Although the 5-HT(2C/2A) receptor antagonists cinanserin (10.0 mg/kg) and metergoline (0.3 mg/kg) were able to reduce the stimulus properties of INDO to 60% and 30%, respectively, only ritanserin (1.0 mg/kg) reduced the stimulus properties of INDO to 25% with a clear dose-response relationship. The results suggest that INDO acts as an agonist at 5-HT1A receptor sites, but its activity at 5-HT(1B/2C) receptor sites also contributes to its discriminative function. PMID:11277605

Sánchez, H; Velázquez-Martínez, D N



Simultaneous determination of 5-hydroxyindoleacetic acid and 5-hydroxytryptamine in urine samples from patients with acute appendicitis by liquid chromatography using poly(bromophenol blue) film modified electrode  

Microsoft Academic Search

The fabrication and application of a novel electrochemical detection (ED) system with a poly(bromophenol blue) (PBPB) film chemically modified electrode (CME) for high performance liquid chromatography (HPLC) were described. The electrochemical behaviors of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) at this CME were investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). It was found that the PBPB CME

Haihong Xu; Wen Zhang; Dan Wang; Wei Zhu; Litong Jin



Translating 5-HT receptor pharmacology.  


Since metoclopramide was first described (in 1964) there have been several attempts to develop compounds which retained gastrointestinal prokinetic activity (via 5-HT(4) receptor activation) but without the limiting side effects associated with dopamine D(2) receptor antagonism. Early compounds (mosapride, cisapride, renzapride, tegaserod) were identified before several of the 5-HT receptors were even described (including 5-HT(4) and 5-HT(2B)), whereas prucalopride came later. Several compounds were hampered by non-selectivity, introducing cardiac liability (cisapride: activity at human Ether-a-go-go Related Gene) or potentially, a reduced intestinal prokinetic activity caused by activity at a second 5-HT receptor (renzapride: antagonism at the 5-HT(3) receptor; tegaserod: antagonism at the 5-HT(2B) receptor). Poor intrinsic activity at gastrointestinal 5-HT(4) receptors has also been an issue (mosapride, tegaserod). Perhaps prucalopride has now achieved the profile of good selectivity of action and high intrinsic activity at intestinal 5-HT(4) receptors, without clinically-meaningful actions on 5-HT(4) receptors in the heart. The progress of this compound for treatment of chronic constipation, as well as competitor molecules such as ATI-7505 and TD-5108, will now be followed with interest as each attempts to differentiate themselves from each other. Perhaps at last, 5-HT(4) receptor agonists are being given the chance to show what they can do. PMID:19906028

Sanger, G J



Effects of morphine, physostigmine and raphe nuclei stimulation on 5-hydroxytryptamine release from the cerebral cortex of the cat.  

PubMed Central

1. The release of 5-hydroxytryptamine (5-HT) from the cerebral cortex and caudate nucleus of brainstem-transected cats and from the cerebral cortex of rats anaesthetized with urethane was determined by radioenzymatic and biological assay. 2. The stimulation of nucleus linearis intermedius of raphe doubles the basal 5-HT release in the caudate nucleus and increases it 3 fold in the cerebral cortex. The effects of the electrical stimulation of the raphe are potentiated by chlorimipramine. 3. Brain 5-HT release is greatly increased by morphine hydrochloride (6 mg/kg i.v.) and by physostigmine (100 microgram/kg i.v.), but not by DL-DOPA (50 mg/kg i.v.). 4. It is suggested that the 5-HT releasing action of physostigmine can contribute to some of its pharmacological effects such as the analgesic effect so far attributed exclusively to its indirect cholinomimetic activity. 5. The 5-HT releasing action of physostigmine seems unrelated to its anticholinesterase activity. PMID:435680

Aiello-Malmberg, P; Bartolini, A; Bartolini, R; Galli, A



Differential activation of the 5-hydroxytryptamine-containing neurons of the midbrain raphe of the rat in response to randomly presented inescapable sound.  


Estimates of 5-hydroxytryptamine (5-HT) turnover in response to 30 min of inescapable, randomly presented, loud sound (sound stress) were obtained for regions of rat brain containing 5-HT perikarya by means of 5-hydroxytryptophan (5-HTP) accumulation after administration of an inhibitor of aromatic amino acid decarboxylase (100 mg/kg i.p., m-hydroxybenzylhydrazine, NSD 1015). Sound stress increased 5-HTP accumulation in the median raphe nucleus (MRN) twofold over that from sham-stressed controls, but did not change 5-HTP accumulation significantly in dorsal raphe nucleus (DRN) or hindbrain. These findings indicate that the 5-HT perikarya of the MRN but not those of the DRN or hindbrain are activated by sound stress, thus, provide further evidence for a functional distinction between the 5-HT neurons of these two midbrain nuclei. PMID:8584232

Dilts, R P; Boadle-Biber, M C



Secondhand Smoke Exposure Causes Bronchial Hyperreactivity via Transcriptionally Upregulated Endothelin and 5-hydroxytryptamine 2A Receptors  

PubMed Central

Background Cigarette smoke exposure is strongly associated with airway hyperreactivity (AHR) which is the main characteristic seen in asthma. The intracellular MAPK signaling pathways are suggested to be associated with the airway damage to the AHR. In the present study, we hypothesize that secondhand cigarette smoke (SHS) exposure upregulates the bronchial contractile receptors via activation of the Raf/ERK/MAPK pathway. Methodology/Principal Findings Rats were exposed to SHS for 3 h daily for up to 8 weeks. The receptor agonists-induced bronchial contractile reactivity was analyzed with a sensitive myograph system. The mRNA transcription and protein translation of the target receptors and the kinases in Raf/ERK/MAPK pathway were investigated by real-time PCR, Western blotting and immunofluorescence, respectively. Compared with exposure to fresh air, SHS induced enhanced bronchial contractile responses mediated by the 5-hydroxytryptamine 2A (5-HT2A) receptors as well as the endothelin type B (ETB) and type A (ETA) receptors. The response curves were shifted toward the left with an increased maximal contraction (Emax) demonstrating that SHS induced AHR. Additionally, the mRNA and protein levels of the 5-HT2A, ETB and ETA receptors were increased. Furthermore, SHS exposure increased the phosphorylation of Raf-1 and ERK1/2, but it did not alter p38 or JNK. A Raf-1 inhibitor (GW5074) suppressed the SHS-induced increase in the expression of 5-HT2A and ETA receptors and the receptor-mediated AHR. Conclusions/Significance Our findings show that SHS exposure induces transcriptional upregulation of the 5-HT2A, ETB and ETA receptors in rat bronchial smooth muscle cells, which mediates AHR. The Raf/ERK/MAPK pathway is involved in SHS-associated receptor upregulation and AHR. PMID:22952915

Cao, Lei; Zhang, Yaping; Cao, Yong-Xiao; Edvinsson, Lars; Xu, Cang-Bao



QGP-1 cells release 5HT via TRPA1 activation; a model of human enterochromaffin cells  

Microsoft Academic Search

Recently, we discovered that transient receptor potential ankyrin1 channel (TRPA1) is highly expressed in human and rat enterochromaffin\\u000a (EC) cells, and those TRPA1 agonists such as allyl isothiocyanates (AITC) and cinnamaldehyde (CA) enhance the release of serotonin\\u000a (5-hydroxytryptamine; 5-HT) from EC cells in vitro. In this study, QGP-1 cells, a human pancreatic endocrine cell line, were\\u000a found to highly express

Hitoshi Doihara; Katsura Nozawa; Ryosuke Kojima; Eri Kawabata-Shoda; Toshihide Yokoyama; Hiroyuki Ito



A role for 5-hydroxytryptamine in the GABA-mimetic potentiation of alpha-flupenthixol-induced catalepsy in the rat.  

PubMed Central

1 alpha-Flupenthixol (alpha-FPT)-induced catalepsy in the rat was potentiated by diaminobutyric acid (DABA), an inhibitor of the neuronal high affinity uptake of gamma-aminobutyric acid (GABA). 2 The depletion of 5-hydroxytryptamine (5-HT) with p-chlorophenylalanine (PCPA) abolished the DABA potentiation of alpha-FPT-induced catalepsy; this response was restored with 5-hydroxytryptophan. 3 Potentiation of alpha-FPT-induced catalepsy by clonazepam was significantly reduced by methysergide. Conversely, the potentiation of catalepsy by clomipramine was significantly reduced by picrotoxin. 4 These results are interpreted as evidence supporting a role for 5-HT in modifying the GABA-ergic inhibition of dopaminergic pathways, possibly by regulating the release of GABA. PMID:6681721

Davies, J. A.; Williams, J.



Predicted structures and dynamics for agonists and antagonists bound to serotonin 5-HT2B and 5-HT2C receptors  

PubMed Central

Subtype 2 Serotonin (5-Hydroxytryptamine, 5-HT) receptors are major drug targets for schizophrenia, feeding disorders, perception, depression, migraines, hypertension, anxiety, hallucinogens, and gastrointestinal dysfunctions.1 We report here the predicted structure of 5-HT2B and 5-HT2C receptor bound to highly potent and selective 5-HT2B antagonist PRX-08066 3, (pKi: 30 nM), including the key binding residues [V103 (2.53), L132 (3.29), V190 (4.60), and L347 (6.58)] determining the selectivity of binding to 5-HT2B over 5-HT2A. We also report structures of the endogenous agonist (5-HT) and a HT2B selective antagonist 2 (1-methyl-1-1,6,7,8-tetrahydropyrrolo[2,3-g]quinoline-5-carboxylic acid pyridine-3-ylamide). We examine the dynamics for the agonist-bound and the antagonist-bound HT2B receptors in explicit membrane and water finding dramatically different patterns of water migration into the NPxxY motif and the binding site that correlates with the stability of ionic locks in the D(E)RY region PMID:21299232

Kim, Soo-Kyung; Li, Youyong; Abrol, Ravinder; Heo, Jiyoung; Goddard, William A.



Intrathecal nefopam-induced antinociception through activation of descending serotonergic projections involving spinal 5-HT7 but not 5-HT3 receptors.  


We examined the involvement of spinal 5-HT(5-hydroxytryptamine) receptor 3(5-HT3R) and 7(5-HT7R) as well as the overall role of descending serotonergic projections in the analgesic effects of intrathecal(i.t.) nefopam for two rat models of formalin and paw incision test. I.t. nefopam produced an antinociceptive effect in a dose-dependent manner in both tests. Lesioning the spinal serotonergic projections using i.t. 5,7-dihydroxytryptamine(5,7-DHT) did not influence the intensity of allodynia in the paw incision test, but i.t. 5,7-DHT abolished the effect of nefopam. In the formain test, i.t. 5,7-DHT alone significantly diminished the flinches, but the effect of nefopam was not affected by i.t. 5,7-DHT. Antagonism study showed that i.t. 5-HT7R antagonist, SB269970 significantly blocked the antinociceptive effect of nefopam in both tests, but i.t. 5-HT3R antagonist, ondansetron has no influence on the effect of nefopam. The present study demonstrates that descending spinal serotonergic projections play a vital role in antinociceptive effect of i.t. nefopam in the paw incision test, but indeterminate in the formalin test. In both tests, the antinociceptive effect of i.t. nefopam involves the spinal 5-HT7R, but not 5-HT3R. PMID:25534502

Lee, Hyung Gon; Kim, Woong Mo; Kim, Joung Min; Bae, Hong-Beom; Choi, Jeong Il



Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder.  


Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder. PMID:25505168

Howell, Leonard L; Cunningham, Kathryn A



A 5-hydroxytryptamine receptor antagonist, sarpogrelate, reduces renal tubulointerstitial fibrosis by suppressing PAI-1.  


A selective 5-hydroxytryptamine (5-HT) 2A receptor antagonist sarpogrelate (SG) blocks serotonin-induced platelet aggregation. It has been used clinically for the treatment of peripheral arterial disease. SG might be able to improve chronic ischemia, which contributes to renal fibrosis progression by maintaining renal microcirculation. This study investigated whether SG suppresses renal fibrosis. C57BL/6 mice fed a 0.2% adenine-containing diet for 6 wk developed severe tubulointerstitial fibrosis with kidney dysfunction. Subsequent SG treatment (30 mg·kg(-1)·day(-1)) for 4 wk improved these changes significantly by increasing peritubular blood flow in the fibrotic area, as evaluated by intravital microscopy and decreasing fibrin deposition. Urinary L-type fatty acid-binding protein, up-regulated by renal hypoxia, was also reduced by SG. Additionally, results showed that mRNA expression of plasminogen activator inhibitor-1 (PAI-1), which is known to promote fibrosis by mediating and enhancing transforming growth factor (TGF)-?1 signaling, was suppressed by SG treatment in the kidney. In vitro experiments using cultured murine proximal tubular epithelial (mProx) cells revealed that incubation with TGF-?1 and 5-HT increased PAI-1 mRNA expression; SG significantly reduced it. In conclusion, SG reduces renal fibrosis not only by the antithrombotic effect of maintaining peritubular blood flow but also by suppressing PAI-1 expression in renal tubular cells. PMID:24107419

Hamasaki, Yoshifumi; Doi, Kent; Maeda-Mamiya, Rui; Ogasawara, Emi; Katagiri, Daisuke; Tanaka, Tamami; Yamamoto, Tokunori; Sugaya, Takeshi; Nangaku, Masaomi; Noiri, Eisei



Silencing of p21-activated kinase attenuates vimentin phosphorylation on Ser-56 and reorientation of the vimentin network during stimulation of smooth muscle cells by 5-hydroxytryptamine  

PubMed Central

Vimentin intermediate filaments undergo spatial reorganization in endothelial cells and fibroblasts in response to stimulation with platelet-derived growth factor and epidermal growth factor. In the present study, the vimentin network exhibited a curved filamentous structure in unstimulated smooth muscle cells. Vimentin filaments became straight and were arranged along the long axis of cells upon stimulation with 5-hydroxytryptamine (5-HT; serotonin). Stimulation of smooth muscle cells with 5-HT also induced phosphorylation of vimentin on Ser-56. Treatment of cells with small interfering RNA selectively down-regulated the expression of PAK1 (p21-activated kinase 1) without affecting the content of smooth muscle ?-actin. The silencing of PAK1 inhibited the site-specific phosphorylation and spatial rearrangement of the vimentin network in response to stimulation with 5-HT. Neither the disruption of stress fibres by cytochalasin D nor the inhibition of protein tyrosine phosphorylation affects the spatial reorganization of vimentin intermediate filaments in response to stimulation with 5-HT. In addition, stimulation of smooth muscle cells with 5-HT increased the ratio of soluble to insoluble vimentin. PAK1 silencing attenuated increases in the ratio of soluble to insoluble vimentin upon stimulation with 5-HT. These results suggest that the PAK-mediated site-specific phosphorylation of vimentin may play a role in regulating the reorganization of vimentin intermediate filaments during stimulation of smooth muscle cells with 5-HT. PMID:15766329



Potential vascular alpha1-adrenoceptor blocking properties of an array of 5-HT receptor ligands in the rat.  


This study set out to analyse the potential ability of some 5-hydroxytryptamine (5-HT) receptor ligands widely used in cardiovascular experimental models to interact with vascular alpha1-adrenoceptors in the pithed rat. These ligands included: methiothepin, methysergide and metergoline (5-HT(1)/5-HT2); WAY-100635, buspirone, ipsapirone and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (5-HT(1A)); GR127935 (5-HT(1B/1D)); ketanserin, ritanserin, spiperone and pizotifen (5-HT2); granisetron and metoclopramide (5-HT3); tropisetron (5-HT3/5-HT4); ergotamine (5-HT(1B/1D), 5-ht(5A/5B)); clozapine (5-HT6/5-HT7); as well as LY215840 and mesulergine (5-HT2/5-HT7). For this purpose, the increases in diastolic blood pressure produced by the selective alpha1-adrenoceptor agonist, phenylephrine, were analysed before and after the above antagonists or saline. The adrenoceptor antagonist properties of prazosin (alpha1) and yohimbine (alpha2) were also analysed for comparison. Thus, the phenylephrine-induced vasopressor responses were dose-dependently antagonised with the following apparent rank order of potency by: prazosin > or = methiothepin > ketanserin > clozapine > or = lisuride > buspirone; this potency correlates with the affinity of these compounds for alpha1-adrenoceptor binding sites. In contrast, the other compounds were either devoid of any blocking effect on--or even potentiated (i.e. lisuride, methysergide, 8-OH-DPAT, granisetron and GR127935)--the responses to phenylephrine. These results show that methiothepin, ketanserin, clozapine, lisuride and buspirone can block alpha1-adrenoceptors in the rat systemic vasculature. PMID:16545797

Centurión, David; Mehotra, Suneet; Sánchez-López, Araceli; Gupta, Saurabh; MaassenVanDenBrink, Antoinette; Villalón, Carlos M



The relationship between the degree of neurodegeneration of rat brain 5HT nerve terminals and the dose and frequency of administration of MDMA (`ecstasy')  

Microsoft Academic Search

The effect of varying the dose and frequency of administration of 3,4-methylenedioxymethamphetamine (MDMA or `ecstasy') on both the acute hyperthermic response and the long term neurodegeneration of 5-hydroxytryptamine (5-HT) nerve terminals in the brain has been studied in Dark Agouti rats. A single injection (4–15 mg\\/kg i.p.) of MDMA produced immediate dose-related hyperthermia and a dose-related decrease in 5-HT, 5-hydroxyindoleacetic

E O'Shea; R Granados; B Esteban; M. I Colado; A. R Green



The effects of 5-HT and m-chlorophenylpiperazine (m-CPP) on the efflux of [3H]-5-HT from human perfused platelets.  

PubMed Central

1. m-Chlorophenylpiperazine (m-CPP), a 5-HT1c-receptor agonist, induces migraine-like headaches when taken orally by migraine sufferers. The present study was undertaken to see what effects m-CPP had on 5-HT function in platelets. 2. Platelets from healthy male volunteers were loaded with [3H]-5-HT and continuously perfused in vitro with carboxygenated Krebs solution at 37 degrees C. After 30 min washout the effects of m-CPP, thrombin, 5-HT and ADP on the efflux of [3H]-5-HT were recorded. 3. m-CPP (0.5-500 microM) did not evoke an increase in the efflux of [3H]-5-HT over that occurring spontaneously whereas thrombin, unlabelled 5-HT and ADP did. The effects of 5-HT were potentiated by ADP. The results were identical whether or not the 5-HT reuptake blocker paroxetine (1 microM) was present. 4. m-CPP inhibited the increase in the efflux of [3H]-5-HT evoked by different concentrations of unlabelled 5-HT in the presence of ADP (2.5 microM) and displaced the 5-HT log concentration response curve to the right. A similar result was obtained with the 5-HT2-receptor antagonist ketanserin. 5. We conclude that m-CPP is a 5-HT2-receptor antagonist on human platelets, which is unlikely to account for its headache-inducing property, as many drugs effective in migraine prophylaxis have this action. PMID:8512759

Carver, J G; Grahame-Smith, D G; Johnson, E S; Madgwick, Z



The effects of putative 5-hydroxytryptamine antagonists on the behaviour produced by administration of tranylcypromine and L-tryptophan or tranylcypromine and L-DOPA to rats.  

PubMed Central

1 The putative 5-hydroxytryptamine (5-HT) receptor blocking drugs methysergide (10 mg/kg) and methergoline (5 mg/kg) were found to abolish some components of the hyperactivity syndrome, including head weaving and forepaw treading, which follow administration to rats of tranylcypromine (20 mg/kg) and L-tryptophan (100 mg/kg). Hyperactivity and hyper-reactivity were potentiated with a resultant increase in automated locomotor activity counts. In contrast (-)-propranolol (20 mg/kg) inhibited all features of the syndrome. The same results were obtained with these drugs when the behaviour was elicited by p-chloroamphetamine (10 mg/kg) or by tranylcypromine and tryptamine (10 mg/kg). 2 Methysergide and methergoline had similar effects on the syndrome produced by tranylcypromine and L-DOPA (50 mg/kg) whereas propranolol was without effect. 3 None of the putative 5-HT receptor antagonists affected brain 5-HT turnover as assessed by rate of accumulation of 5-HT following monoamine oxidase inhibition with tranylcypromine. 4 Microinjections of 5,7-dihydroxytryptamine into the spinal cord resulted in a 70% fall in cord 5-HT concentrations without an effect on brain 5-HT concentrations. The behavioural response to the putative 5-HT receptor agonist, 5-methoxy N,N-dimethyltryptamine (2 mg/kg), was potentiated in these animals suggesting that 5-HT receptors become supersensitive on denervation, and that some components of the behavioural syndrome are mediated by spinal cord 5-HT receptors. 5 Pretreatment with alpha-methyl p-tyrosine (2 X 200 mg/kg) delayed the onset of all components of the behaviour elicited by tranylcypromine/L-tryptophan by 60 min, indicating an involvement of catecholamines in the syndrome. 6 p-Chloroamphetamine-induced 5-HT depletion had no effect on any component of the tranylcypromine-L-DOPA behaviour. PMID:708990

Deakin, J F; Green, A R



Structure-based discovery of selective serotonin 5-HT(1B) receptor ligands.  


The development of safe and effective drugs relies on the discovery of selective ligands. Serotonin (5-hydroxytryptamine [5-HT]) G protein-coupled receptors are therapeutic targets for CNS disorders but are also associated with adverse drug effects. The determination of crystal structures for the 5-HT1B and 5-HT2B receptors provided an opportunity to identify subtype selective ligands using structure-based methods. From docking screens of 1.3 million compounds, 22 molecules were predicted to be selective for the 5-HT1B receptor over the 5-HT2B subtype, a requirement for safe serotonergic drugs. Nine compounds were experimentally verified as 5-HT1B-selective ligands, with up to 300-fold higher affinities for this subtype. Three of the ligands were agonists of the G protein pathway. Analysis of state-of-the-art homology models of the two 5-HT receptors revealed that the crystal structures were critical for predicting selective ligands. Our results demonstrate that structure-based screening can guide the discovery of ligands with specific selectivity profiles. PMID:25043551

Rodríguez, David; Brea, José; Loza, María Isabel; Carlsson, Jens



How does displacement of albumin-bound tryptophan cause sustained increases in the free tryptophan concentration in plasma and 5-hydroxytryptamine synthesis in brain?  

PubMed Central

Models of tryptophan catabolism and binding to serum albumin are presented to explain the observed effect of displacement of tryptophan from albumin on the concentrations of free and bound tryptophan and on the rate of 5-hydroxytryptamine (5-HT) synthesis from tryptophan in the brain. A rapid rate of dissociation of tryptophan from albumin (compared to the transit time of tryptophan through the liver) and a large fractional extraction of the free pool of tryptophan during passage through the liver are shown to be necessary factors in determining the effects observed. Because of the low fractional extraction of free tryptophan in the brain, the synthesis of 5-HT will be dependent only upon the free pool of tryptophan. Dissociation of tryptophan from albumin only causes a sustained increase in 5-HT synthesis in the brain because of the effect that this dissociation has on hepatic tryptophan catabolism and thereby on the free pool of tryptophan. PMID:2818573

Salter, M; Knowles, R G; Pogson, C I



5-HT1A Receptor Function in Major Depressive Disorder  

PubMed Central

Dysfunction of the serotonin 1A receptor (5-HT1A) may play a role in the genesis of major depressive disorder (MDD). Here we review the pharmacological, post-mortem, positron-emission tomography (PET), and genetic evidence in support of this statement. We also touch briefly on two MDD-associated phenotypes, cognitive impairment and somatic pain. The results of pharmacological challenge studies with 5-HT1A receptor agonists are indicative of blunted endocrine responses in depressed patients. Lithium, valproate, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and other treatment, such as electroconvulsive shock therapy (ECT), all increase post-synaptic 5-HT1A receptor signaling through either direct or indirect effects. Reduced somatodendritic and postsynaptic 5-HT1A receptor numbers or affinity have been reported in some post-mortem studies of suicide victims, a result consistent with well-replicated PET analyses demonstrating reduced 5-HT1A receptor binding potential in diverse regions such as the dorsal raphe, medial prefrontal cortex (mPFC), amygdala and hippocampus. 5-HT1A receptor knockout (KO) mice display increased anxiety-related behavior, which, unlike in their wild-type counterparts, cannot be rescued with AD treatment. In humans, the G allele of a single nucleotide polymorphism (SNP) in the 5-HT1A receptor gene (HTR1A; rs6295), which abrogates a transcription factor binding site for Deaf-1 and Hes5, has been reported to be over-represented in MDD cases. Conversely, the C allele has been associated with better response to AD drugs. We raise the possibility that 5-HT1A receptor dysfunction represents one potential mechanism underpinning MDD and other stress-related disorders. PMID:19428959

Savitz, Jonathan; Lucki, Irwin; Drevets, Wayne C



Positive allosteric modulator of the human 5-HT2C receptor.  


The human 5-hydroxytryptamine-2C (5-HT2C) receptor has been the target of potential anxiolytics and antiobesity drugs, and its positive allosteric modulator was discovered to be l-threo-alpha-d-galacto-octopyranoside, methyl-7-chloro-6,7,8-trideoxy-6-[[(4-undecyl-2-piperidinyl)carbonyl]amino]-1-thiomonohydrochloride (2S-cis) (PNU-69176E). The drug at low micromolar concentrations (<25 microM) markedly enhanced [3H]5-HT binding (more than 300%) by increasing its affinity for low-affinity sites but with no appreciable effect on antagonist ([3H]mesulergine) binding. Functionally, PNU-69176E alone rendered receptors constitutively active, producing the pheno-types of 5-HT-activated receptors, as measured with mesulergine-sensitive guanosine 5'-O-(3-[35S]thio)triphosphate binding, transient inositol 1,4,5-triphosphate release, and [3H]inositol phosphate accumulation. These actions of PNU-69176E were observed with the human 5-HT2C receptor expressed in several mammalian cell lines (human embryonic kidney 293, NIH3T3, and SH-EP) at variable receptor densities (6 to 45 pmol/mg of protein), but not with analogous 5-HT and dopamine receptors (human 5-HT2A, 5-HT2B, 5-HT6, 5-HT7, and dopamine D2-long and D3 receptors). Structurally, PNU-69176E consists of a long alkyl chain and a polar moiety, including the alpha-d-galactopyranoside. Its analogs with shorter alkyl chains (methyl to n-hexyl instead of n-undecyl group) failed to enhance [3H]5-HT binding, and also long alkyl amides are without allosteric modulation. We propose that PNU-69176E may represent a new class of membrane receptor modulators, which probably need a long alkyl chain as a membrane anchor and target a selective polar head group to receptor modulatory sites near the membrane surface. PMID:12815163

Im, Wha Bin; Chio, Christopher L; Alberts, Glen L; Dinh, Dac M



From obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists.  


The recent US Food and Drug Administration (FDA) approval of the serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor agonist lorcaserin for the treatment of obesity represents a new therapeutic drug class available to the clinic. Preclinical evidence supports the potential for this drug class to treat other related conditions such as substance abuse. In the present article we review this evidence and further suggest that overlapping neurobiological systems may contribute to an anti-addictive and anti-obesity profile. The availability of selective 5-HT2C agonists provides an opportunity to evaluate their potential as treatments for nicotine dependence or psychostimulant abuse, conditions for which there is significant medical need but only limited available treatment options. PMID:24041919

Higgins, Guy A; Sellers, Edward M; Fletcher, Paul J



Simultaneous quantification of 5-hydroxyindoleacetic acid and 5-hydroxytryptamine by capillary electrophoresis with quantum dot and horseradish peroxidase enhanced chemiluminescence detection.  


A capillary electrophoresis (CE) with chemiluminescence (CL) detection method was developed for the simultaneous quantification of 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxytryptamine (5-HT). In this method, CdTe quantum dot (QD) and horseradish peroxidase (HRP) were used as enhancing reagents to co-catalyze the post-column CL reaction between luminol and hydrogen peroxide, achieving highly efficient CL emission. 5-HIAA and 5-HT inhibit the CL emission resulting to the formation of negative peaks in electropherogram. The degree of CL suppression is proportional to the concentration of 5-HT and 5-HIAA. The linear ranges for the determination of 5-HIAA and 5-HT were 2.5×10(-8)-2.5×10(-6) M and 2.5×10(-8)-5.0×10(-6) M with detection limits (signal/noise=3) of 7.0×10(-9) M and 6.0×10(-9) M, respectively. Intraday precision do not exceed 5.0%. The accuracy was confirmed by the recoveries ranged from 98% to 104%. The present method was successfully applied for the quantification of 5-HIAA and 5-HT in human urine. The concentrations of 5-HT and 5-HIAA in human urine were found to be in the range of 0.78-1.2 ?M and 3.2-5.1 ?M, respectively. PMID:25125395

Zhang, Liangliang; Zhao, Yunsha; Huang, Junming; Zhao, Shulin



5-HT2C Receptor Agonist Anorectic Efficacy Potentiated by 5-HT1B Receptor Agonist Coapplication: An Effect Mediated via Increased Proportion of Pro-Opiomelanocortin Neurons Activated  

PubMed Central

An essential component of the neural network regulating ingestive behavior is the brain 5-hydroxytryptamine2C receptor (5-HT2CR), agonists of which suppress food intake and were recently approved for obesity treatment by the US Food and Drug Administration. 5-HT2CR-regulated appetite is mediated primarily through activation of hypothalamic arcuate nucleus (ARC) pro-opiomelanocortin (POMC) neurons, which are also disinhibited through a 5-HT1BR-mediated suppression of local inhibitory inputs. Here we investigated whether 5-HT2CR agonist anorectic potency could be significantly enhanced by coadministration of a 5-HT1BR agonist and whether this was associated with augmented POMC neuron activation on the population and/or single-cell level. The combined administration of subanorectic concentrations of 5-HT2CR and 5-HT1BR agonists produced a 45% reduction in food intake and significantly greater in vivo ARC neuron activation in mice. The chemical phenotype of activated ARC neurons was assessed by monitoring agonist-induced cellular activity via calcium imaging in mouse POMC-EGFP brain slices, which revealed that combined agonists activated significantly more POMC neurons (46%) compared with either drug alone (~25% each). Single-cell electrophysiological analysis demonstrated that 5-HT2CR/5-HT1BR agonist coadministration did not significantly potentiate the firing frequency of individual ARC POMC-EGFP cells compared with agonists alone. These data indicate a functional heterogeneity of ARC POMC neurons by revealing distinct subpopulations of POMC cells activated by 5-HT2CRs and disinhibited by 5-HT1BRs. Therefore, coadministration of a 5-HT1BR agonist potentiates the anorectic efficacy of 5-HT2CR compounds by increasing the number, but not the magnitude, of activated ARC POMC neurons and is of therapeutic relevance to obesity treatment. PMID:23739976

Doslikova, Barbora; Garfield, Alastair S.; Shaw, Jill; Evans, Mark L.; Burdakov, Denis; Billups, Brian; Heisler, Lora K.



Among its many roles in the body, serotonin (5-hydroxytryptamine, or 5-HT) mediates an animal's behavioral  

E-print Network

circuits typically alters aggressive and subordinate behaviors in a manner consistent with this view (for show a short-term activation of serotonin circuits, followed by a long-term cessation, whereas of communication behavior in gymnotiform electric fish. Weakly electric fish produce electric organ discharges

Stoddard, Philip


The alteration of 5-HT(2A) and 5-HT(2C) receptors is involved in neuronal apoptosis of goldfish cerebellum following traumatic experience.  


5-HT receptor changes remain controversial in posttraumatic stress disorder (PTSD) models. This study looks at the relationship between traumatic injuries and the alterations in 5-HT(2A) and 5-HT(2C) receptors in the goldfish brain. The effect of treatment with doxepin and fluoxetine, known to be selective serotonin reuptake inhibitor (SSRI) antidepressants, on 5-HT receptor expression in goldfish with fin ablation was also investigated. We demonstrated that fin ablation induced anxiety-like behavioural alterations and significant up-regulation of c-fos expression in goldfish cerebellum. The behavioural alterations correlated well with an increased expression of 5-HT(2A) receptors in the cerebellum of the fish with traumatic injury. An increase in the number of apoptotic cells and a higher caspase-8 protein level was present in the brains of goldfish with fin ablation compared to the control. Our findings suggest that neuronal apoptosis occured in the cerebellum as a result of fin ablation and may be related to the alterations of 5-HT(2A) and 5-HT(2C) levels and that the beneficial clinical effects of doxepin/fluoxetine treatment are due to the down-regulation of 5-HT(2A) and up-regulation of 5-HT(2C) receptors in the brain. PMID:22561958

Hu, Xueqing; Li, Yan; Hu, Zhiying; Rudd, John A; Ling, Shucai; Jiang, Fangzhen; Davies, Henry; Fang, Marong



Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK.  


The vasoconstrictor substance named serotonin was identified as 5-hydroxytryptamine (5-HT) by Maurice Rapport in 1949. In 1951, Rapport gave Gaddum samples of 5-HT substance allowing him to develop a bioassay to both detect and measure the amine. Gaddum and colleagues rapidly identified 5-HT in brain and showed that lysergic acid diethylamide (LSD) antagonized its action in peripheral tissues. Gaddum accordingly postulated that 5-HT might have a role in mood regulation. This review examines the role of UK scientists in the first 20 years following these major discoveries, discussing their role in developing assays for 5-HT in the CNS, identifying the enzymes involved in the synthesis and metabolism of 5-HT and investigating the effect of drugs on brain 5-HT. It reviews studies on the effects of LSD in humans, including Gaddum's self-administration experiments. It outlines investigations on the role of 5-HT in psychiatric disorders, including studies on the effect of antidepressant drugs on the 5-HT concentration in rodent and human brain, and the attempts to examine 5-HT biochemistry in the brains of patients with depressive illness. It is clear that a rather small group of both preclinical scientists and psychiatrists in the UK made major advances in our understanding of the role of 5-HT in the brain, paving the way for much of the knowledge now taken for granted when discussing ways that 5-HT might be involved in the control of mood and the idea that therapeutic drugs used to alleviate psychiatric illness might alter the function of cerebral 5-HT. PMID:18516072

Green, A R



Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK  

PubMed Central

The vasoconstrictor substance named serotonin was identified as 5-hydroxytryptamine (5-HT) by Maurice Rapport in 1949. In 1951, Rapport gave Gaddum samples of 5-HT substance allowing him to develop a bioassay to both detect and measure the amine. Gaddum and colleagues rapidly identified 5-HT in brain and showed that lysergic acid diethylamide (LSD) antagonized its action in peripheral tissues. Gaddum accordingly postulated that 5-HT might have a role in mood regulation. This review examines the role of UK scientists in the first 20 years following these major discoveries, discussing their role in developing assays for 5-HT in the CNS, identifying the enzymes involved in the synthesis and metabolism of 5-HT and investigating the effect of drugs on brain 5-HT. It reviews studies on the effects of LSD in humans, including Gaddum's self-administration experiments. It outlines investigations on the role of 5-HT in psychiatric disorders, including studies on the effect of antidepressant drugs on the 5-HT concentration in rodent and human brain, and the attempts to examine 5-HT biochemistry in the brains of patients with depressive illness. It is clear that a rather small group of both preclinical scientists and psychiatrists in the UK made major advances in our understanding of the role of 5-HT in the brain, paving the way for much of the knowledge now taken for granted when discussing ways that 5-HT might be involved in the control of mood and the idea that therapeutic drugs used to alleviate psychiatric illness might alter the function of cerebral 5-HT. PMID:18516072

Green, A R



GR43175, a selective agonist for the 5-HT1-like receptor in dog isolated saphenous vein.  

PubMed Central

1. We describe the actions of a novel and selective 5-HT1-like receptor agonist, GR43175, in a range of isolated tissue preparations containing different 5-hydroxytryptamine (5-HT) receptor types. 2. GR43175 was a potent agonist at 5-HT1-like receptors mediating contraction of the dog isolated saphenous vein and also at those inhibiting neuronally mediated contractions in the same preparations. For both actions, GR43175 was approximately four times weaker than 5-HT. 3. GR43175 was devoid of agonist properties at 5-HT1-like receptors mediating relaxation of the cat isolated saphenous vein. 4. GR43175 was devoid of agonist properties at 5-HT2 receptors mediating contraction of the rabbit isolated aorta, pig coronary artery, greyhound coronary artery and beagle femoral artery. 5. GR43175 was devoid of agonist properties at 5-HT3 receptors mediating depolarization of the rat isolated vagus nerve. 6. The contractile response to GR43175 in the dog isolated saphenous vein was selectively antagonized by methiothepin but was resistant to antagonism by the 5-HT2 receptor blocking drug ketanserin and the 5-HT3 receptor blocking drug MDL 72222. Methiothepin antagonized the contractile action of 5-HT and GR43175 to an equal extent suggesting that both agonists act at the same receptor. 7. The results demonstrate that GR43175 is a highly selective agonist for the 5-HT1-like receptors found in the dog saphenous vein. The absence of an action of GR43175 at 5-HT1-like receptors mediating relaxation of the cat isolated saphenous vein provides further evidence that 5-HT1-like receptors are heterogeneous. PMID:2850055

Humphrey, P. P.; Feniuk, W.; Perren, M. J.; Connor, H. E.; Oxford, A. W.; Coates, L. H.; Butina, D.



Agonism of the 5-Hydroxytryptamine 1F Receptor Promotes Mitochondrial Biogenesis and Recovery from Acute Kidney Injury  

PubMed Central

Many acute and chronic conditions, such as acute kidney injury, chronic kidney disease, heart failure, and liver disease, involve mitochondrial dysfunction. Although we have provided evidence that drug-induced stimulation of mitochondrial biogenesis (MB) accelerates mitochondrial and cellular repair, leading to recovery of organ function, only a limited number of chemicals have been identified that induce MB. The goal of this study was to assess the role of the 5-hydroxytryptamine 1F (5-HT1F) receptor in MB. Immunoblot and quantitative polymerase chain reaction analyses revealed 5-HT1F receptor expression in renal proximal tubule cells (RPTC). A MB screening assay demonstrated that two selective 5-HT1F receptor agonists, LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide) and LY344864 (N-[(3R)-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-4-fluorobenzamide; 1–100 nM) increased carbonylcyanide-p-trifluoromethoxyphenylhydrazone–uncoupled oxygen consumption in RPTC, and validation studies confirmed both agonists increased mitochondrial proteins [e.g., ATP synthase ?, cytochrome c oxidase 1 (Cox1), and NADH dehydrogenase (ubiquinone) 1? subcomplex subunit 8 (NDUFB8)] in vitro. Small interfering RNA knockdown of the 5-HT1F receptor blocked agonist-induced MB. Furthermore, LY344864 increased peroxisome proliferator–activated receptor coactivator 1-?, Cox1, and NDUFB8 transcript levels and mitochondrial DNA (mtDNA) copy number in murine renal cortex, heart, and liver. Finally, LY344864 accelerated recovery of renal function, as indicated by decreased blood urea nitrogen and kidney injury molecule 1 and increased mtDNA copy number following ischemia/reperfusion-induced acute kidney injury (AKI). In summary, these studies reveal that the 5-HT1F receptor is linked to MB, 5-HT1F receptor agonism promotes MB in vitro and in vivo, and 5-HT1F receptor agonism promotes recovery from AKI injury. Induction of MB through 5-HT1F receptor agonism represents a new target and approach to treat mitochondrial organ dysfunction. PMID:24849926

Garrett, Sara M.; Whitaker, Ryan M.; Beeson, Craig C.



The 5-HT4 receptor subtype inhibits K+ current in colliculi neurones via activation of a cyclic AMP-dependent protein kinase.  

PubMed Central

1. The aim of the present study was to examine the effect of 5-hydroxytryptamine (5-HT) on K+ current in primary culture of mouse colliculi neurones and to identify the 5-HT receptor subtype that could be involved in this effect. 2. The voltage-activated K+ current of the neurones was partially blocked by 8-bromo adenosine 3':5'-cyclic monophosphate (8-bromo-cyclic AMP). This effect was mimicked by 5-HT and the action of 5-HT could be antagonized by H7, a non specific protein kinase inhibitor, and by PKI, the specific cyclic AMP-dependent protein kinase blocker. 3. A similar cyclic AMP-dependent blockade of the K+ current was found with renzapride (BRL 24,924) and other 5-HT4 receptor agonists such as cisapride, BIMU 8, zacopride and 5-methoxytryptamine (5-MeOT). ICS 205,930, the classical 5-HT4 receptor blocker, could not be used in this study because it inhibited the studied K+ current by itself. However, the novel 5-HT4 receptor antagonist, DAU 6285 blocked the effects of 5-HT and renzapride on the K+ current. 4. The current was insensitive to the 5-HT1 and 5-HT3 receptor agonists (8-hydroxy-2-(di-n-propylamino) tetralin, RU 24,969, carboxamidotryptamine, 2-CH3-5-HT) as well as to 5-HT1, 5-HT2 and 5-HT3 antagonists (methiothepin, ketanserin, ondansetron [GR 38,032]). Moreover, these antagonists did not affect the actions of the tested 5-HT4 receptor agonists. 5. The present results show that part of the voltage-activated K+ current in mouse colliculi neurones is cyclic AMP-sensitive and the blockade of the current by 5-HT involves the 5-HT4 receptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1324059

Fagni, L.; Dumuis, A.; Sebben, M.; Bockaert, J.



Role of prucalopride, a serotonin (5-HT(4)) receptor agonist, for the treatment of chronic constipation.  


Constipation affects up to a quarter of the population in developed countries and is associated with poor quality of life and significant economic burden. Many patients with chronic constipation are dissatisfied with current therapy due to lack of long-term efficacy or side effects. Previous nonselective 5-hydroxytryptamine receptor 4 (5-HT(4)) agonists have been associated with significant interactions with other receptors (5-HT(1B), 5-HT(1D), and 5-HT(2B) for tegaserod; hERG for cisapride), leading to adverse cardiovascular events resulting in withdrawal of these drugs from the market. Prucalopride is a novel gastrointestinal prokinetic agent. It acts as a high affinity, highly-selective 5-HT(4) agonist. Its efficacy in patients with chronic constipation has been demonstrated in several phase II and phase III clinical trials showing significant improvements in bowel transit, bowel function, gastrointestinal symptoms, and quality of life, with benefit maintained for up to 24 months in open label, multicenter, follow-up studies. Prucalopride's high selectivity for the 5-HT(4) receptor may explain its favorable safety and tolerability profiles, even in elderly subjects with stable cardiovascular disease. Prucalopride is a well tolerated and efficacious prokinetic medication that should enhance the treatment of chronic constipation unresponsive to first-line treatments. PMID:21694846

Wong, Banny S; Manabe, Noriaki; Camilleri, Michael



5-HT4 receptors located on cholinergic nerves in human colon circular muscle.  


5-Hydroxytryptamine 4 (5-HT4) receptor agonists promote colonic propulsion. The alteration of circular muscle (CM) motility underlying this involves inhibition of contractility via smooth muscle 5-HT4 receptors and proximal colonic motility stimulation, the mechanism of the latter not having been characterized. Our aim was to identify and characterize a 5-HT4 receptor-mediated stimulation of human colon CM contractile activity. 5-HT4 receptor ligands were tested on electrical field stimulation (EFS)-induced contractions of human colonic muscle strips cut in the circular direction (called 'whole tissue' strips). Additionally, after incubation of tissues with [3H]-choline these compounds were tested on EFS-induced release of tritium in whole tissue strips and in 'isolated' CM strips, obtained by superficial cutting in the CM layer. Tetrodotoxin and atropine blocked EFS-induced contractions of whole tissue CM strips. Prucalopride (0.3 micromol L-1) evoked a heterogenous response on EFS-induced contraction, ranging from inhibition (most frequently observed) to enhancement. In the release experiments, EFS-induced tritium efflux was blocked by tetrodotoxin. Prucalopride increased EFS-induced tritium and [3H]-acetylcholine efflux in whole tissue and in isolated CM strips. All effects of prucalopride were antagonized by the selective 5-HT4 receptor antagonist GR113808. The results obtained indicate the presence of excitatory 5-HT4 receptors on cholinergic nerves within the CM of human colon. PMID:15916624

Leclere, P G; Prins, N H; Schuurkes, J A J; Lefebvre, R A



Peripheral 5-HT2-like receptors. Can they be classified with the available antagonists?  

PubMed Central

Interactions between 5-hydroxytryptamine (5-HT) and the so-called 5-HT2 receptor antagonists ketanserin, spiperone, trazodone and methysergide were studied in isolated preparations of the rabbit aorta, rat jugular vein, and rat caudal artery. Trazodone and spiperone were apparently simple competitive antagonists since they produced antagonism that was surmountable over the concentration range studied and, in each tissue, their apparent affinity appeared to be independent of the antagonist concentration. Furthermore, concentration-ratios obtained with the two antagonists in combination suggested that antagonism was additive, implying mutual competition with a single population of 5-HT receptors. Ketanserin was a non-surmountable antagonist of 5-HT in the rat caudal artery and methysergide demonstrated surmountable, competitive antagonism only in the rabbit aorta. Antagonist dissociation constants estimated for apparently competitive interactions showed that ketanserin, spiperone and trazodone expressed affinities which differed according to the tissue used. In the case of trazodone, affinity estimates differed by as much as 12 fold. These discrepancies were independent of the 5-HT receptor agonist used and could not be attributed to an inadequate equilibration of the antagonist. These results can be interpreted in two ways: either the receptors in the different tissues are heterogeneous or the antagonists used here must be considered as unreliable probes for the classification of 5-HT2-like receptors. PMID:2943354

Leff, P.; Martin, G. R.



Inhibitory effect of nociceptin on [3H]-5-HT release from rat cerebral cortex slices  

PubMed Central

The effect of nociceptin (NC) on 5-hydroxytryptamine (5-HT) release was studied in rat cerebral cortex slices preincubated with [3H]-5-HT and electrically stimulated (3?Hz, for 2?min) at the 45th (St1) and the 75th (St2) min of superfusion. NC (0.1–3??M), present in the medium from the 70th min onward, concentration-dependently reduced electrically evoked [3H]-5-HT efflux (pEC50=6.54, Emax ?54%). The inhibition was not antagonized by naloxone (1??M) ruling out the involvement of opioid receptors. Phe1?(CH2-NH2)Gly2]NC(1-13)NH2, which acts as an opioid-like receptor (ORL1) antagonist at the peripheral level, behaved as a partial agonist in cerebral cortex slices i.e. it inhibited [3H]-5-HT efflux when added before St2, however, when present in the medium throughout the whole experiment, [Phe1?(CH2-NH2)Gly2]NC(1-13)NH2 prevented the action of NC added at the 70th min. The non-selective ORL1 receptor antagonist, naloxone benzoylhydrazone (3??M), in the presence of 10??M naloxone, did not modify the St2/St1 ratio but completely abolished the NC effect. These findings demonstrate that NC inhibits 5-HT release from rat cerebral cortex slices via ORL1 receptors, suggesting its involvement in central processes mediated by 5-HT. PMID:10498842

Siniscalchi, Anna; Rodi, Donata; Beani, Lorenzo; Bianchi, Clementina



Dual role of serotonin in the acquisition and extinction of reward-driven learning: Involvement of 5-HT1A, 5-HT2A and 5-HT3 receptors.  


Serotonin (5-HT) has been proposed as a possible encoder of reward. Nevertheless, the role of this neurotransmitter in reward-based tasks is not well understood. Given that the major serotonergic circuit in the rat brain comprises the dorsal raphe nuclei and the medial prefrontal cortex (mPFC), and because the latter structure is involved in the control of complex behaviors and expresses 1A (5-HT1A), 2A (5-HT2A), and 3 (5-HT3) receptors, the aim was to study the role of 5-HT and of these receptors in the acquisition and extinction of a reward-dependent operant conditioning task. Long Evans rats were trained in an operant conditioning task while receiving fluoxetine (serotonin reuptake inhibitor, 10mg/kg), tianeptine (serotonin reuptake enhancer, 10mg/kg), buspirone (5-HT1A partial agonist, 10mg/kg), risperidone (5-HT2A antagonist, 1mg/kg), ondansetron (5-HT3 antagonist, 2mg/kg) or vehicle. Then, animals that acquired the operant conditioning without any treatment were trained to extinct the task in the presence of the pharmacological agents. Fluoxetine impaired acquisition but improved extinction. Tianeptine administration induced the opposite effects. Buspirone induced a mild deficit in acquisition and had no effects during the extinction phase. Risperidone administration resulted in learning deficits during the acquisition phase, although it promoted improved extinction. Ondansetron treatment showed a deleterious effect in the acquisition phase and an overall improvement in the extinction phase. These data showed a differential role of 5-HT in the acquisition and extinction of an operant conditioning task, suggesting that it may have a dual function in reward encoding. PMID:24949809

Frick, Luciana Romina; Bernardez-Vidal, Micaela; Hocht, Christian; Zanutto, Bonifacio Silvano; Rapanelli, Maximiliano



Pharmacological analysis of the novel, rapid, and potent inactivation of the human 5-Hydroxytryptamine7 receptor by risperidone, 9-OH-Risperidone, and other inactivating antagonists.  


In a previous publication, using human 5-hydroxytryptamine(7) (h5-HT(7)) receptor-expressing human embryonic kidney (HEK) 293 cells, we reported the rapid, potent inactivation of the h5-HT(7) receptor stimulation of cAMP production by three antagonists: risperidone, 9-OH-risperidone, and methiothepin (Smith et al., 2006). To better understand the drug-receptor interaction producing the inactivation, we 1) expanded the list of inactivating drugs, 2) determined the inactivating potencies and efficacies by performing concentration-response experiments, and 3) determined the potencies and efficacies of the inactivators as irreversible binding site inhibitors. Three new drugs were found to fully inactivate the h5-HT(7) receptor: lisuride, bromocryptine, and metergoline. As inactivators, these drugs displayed potencies of 1, 80, and 321 nM, respectively. Pretreatment of 5-HT(7)-expressing HEK cells with increasing concentrations of the inactivating drugs risperidone, 9-OH-risperidone, methiothepin, lisuride, bromocriptine, and metergoline potently inhibited radiolabeling of the h5-HT(7) receptor, with IC(50) values of 9, 5.5, 152, 3, 73, and 10 nM, respectively. We were surprised to find that maximal concentrations of risperidone and 9-OH-risperidone inhibited only 50% of the radiolabeling of h5-HT(7) receptors. These results indicate that risperidone and 9-OH risperidone may be producing 5-HT(7) receptor inactivation by different mechanisms than lisuride, bromocryptine, metergoline, and methiothepin. These results are not interpretable using the conventional model of G-protein-coupled receptor function. The complex seems capable of assuming a stable inactive conformation as a result of the interaction of certain antagonists. The rapid, potent inactivation of the receptor-G-protein complex by antagonists implies a constitutive, pre-existing complex between the h5-HT(7) receptor and a G-protein. PMID:18996971

Knight, Jessica A; Smith, Carol; Toohey, Nicole; Klein, Michael T; Teitler, Milt



Pharmacological Analysis of the Novel, Rapid, and Potent Inactivation of the Human 5-Hydroxytryptamine7 Receptor by Risperidone, 9-OH-Risperidone, and Other Inactivating Antagonists  

PubMed Central

In a previous publication, using human 5-hydroxytryptamine7 (h5-HT7) receptor-expressing human embryonic kidney (HEK) 293 cells, we reported the rapid, potent inactivation of the h5-HT7 receptor stimulation of cAMP production by three antagonists: risperidone, 9-OH-risperidone, and methiothepin (Smith et al., 2006). To better understand the drug-receptor interaction producing the inactivation, we 1) expanded the list of inactivating drugs, 2) determined the inactivating potencies and efficacies by performing concentration-response experiments, and 3) determined the potencies and efficacies of the inactivators as irreversible binding site inhibitors. Three new drugs were found to fully inactivate the h5-HT7 receptor: lisuride, bromocryptine, and metergoline. As inactivators, these drugs displayed potencies of 1, 80, and 321 nM, respectively. Pretreatment of 5-HT7-expressing HEK cells with increasing concentrations of the inactivating drugs risperidone, 9-OH-risperidone, methiothepin, lisuride, bromocriptine, and metergoline potently inhibited radiolabeling of the h5-HT7 receptor, with IC50 values of 9, 5.5, 152, 3, 73, and 10 nM, respectively. We were surprised to find that maximal concentrations of risperidone and 9-OH-risperidone inhibited only 50% of the radiolabeling of h5-HT7 receptors. These results indicate that risperidone and 9-OH risperidone may be producing 5-HT7 receptor inactivation by different mechanisms than lisuride, bromocryptine, metergoline, and methiothepin. These results are not interpretable using the conventional model of G-protein-coupled receptor function. The complex seems capable of assuming a stable inactive conformation as a result of the interaction of certain antagonists. The rapid, potent inactivation of the receptor-G-protein complex by antagonists implies a constitutive, pre-existing complex between the h5-HT7 receptor and a G-protein. PMID:18996971

Knight, Jessica A.; Smith, Carol; Toohey, Nicole; Klein, Michael T.; Teitler, Milt



Selective recognition of 5-hydroxytryptamine and dopamine on a multi-walled carbon nanotube-chitosan hybrid film-modi?ed microelectrode array.  


It is dif?cult to determine dopamine (DA) and 5-hydroxytryptamine (5-HT) accurately because of the interference of ascorbic acid (AA) in vitro, which has a high concentration and can be oxidized at a potential close to DA and 5-HT at a conventional electrode, combined with the overlapping voltammetric signal of DA and 5-HT at a bare electrode. Herein, chitosan (CS) was used as a stabilizing matrix by electrochemical reaction, and multi-walled carbon nanotubes (MWCNTs) were modified onto the microelectrode array (MEA). The CS-MWCNT hybrid film-modified MEA was quite effective at simultaneously recognizing these species in a mixture and resolved the overlapping anodic peaks of AA, DA and 5-HT into three well-de?ned oxidation peaks in differential pulse voltammetry (DPV) at -80 mV, 105 mV and 300 mV (versus Ag|AgCl), respectively. The linear responses were obtained in the range of 5 × 10-6 M to 2 × 10-4 M for DA (r = 0.996) and in the range of 1 × 10-5 M to 3 × 10-4 M for 5-HT (r = 0.999) using the DPV under the presence of a single substance. While DA coexisted with 5-HT in the interference of 3 × 10-4 M AA, the linear responses were obtained in the range of 1 × 10-5 M to 3 × 10-4 M for selective molecular recognition of DA (r = 0.997) and 5-HT (r = 0.997) using the DPV. Therefore, this proposed MEA was successfully used for selective molecular recognition and determination of DA and 5-HT using the DPV, which has a potential application for real-time determination in vitro experiments. PMID:25580900

Xu, Huiren; Wang, Li; Luo, Jinping; Song, Yilin; Liu, Juntao; Zhang, Song; Cai, Xinxia



Modeling [18F]MPPF Positron Emission Tomography Kinetics for the Determination of 5Hydroxytryptamine(1A) Receptor Concentration With Multiinjection  

Microsoft Academic Search

The selectivity of [18F]MPPF (fluorine-18–labeled 4-(2´-methoxyphenyl)-1-[2´-(N-2?-pirydynyl)-p-fluorobenzamido]ethylpiperazine) for serotonergic 5-hydroxytryptamine(1A) (5-HT1A) receptors has been established in animals and humans. The authors quantified the parameters of ligand-receptor exchanges using a double-injection protocol. After injection of a tracer and a coinjection dose of [18F]MPPF, dynamic positron emission tomography (PET) data were acquired during a 160-minute session in five healthy males. These PET and

Nicolas Costes; Isabelle Merlet; Luc Zimmer; Franck Lavenne; Luc Cinotti; Jacques Delforge; Didier Le Bars



Antidepressant-like responses to the combined sigma and 5HT 1A receptor agonist OPC14523  

Microsoft Academic Search

The antidepressant-like activity of a novel compound, OPC-14523, was investigated in comparison with the conventional antidepressants, fluoxetine and imipramine. OPC-14523 bound with nanomolar affinities to sigma receptors (IC50=47–56nM), the 5-HT1A receptor (IC50=2.3nM), and the 5-HT transporter (IC50=80nM). OPC-14523 inhibited the in vitro reuptake of 3H-5-HT (IC50=27nM), but it showed very weak inhibitory activity on 3H-NE and 3H-DA reuptake. OPC-14523 did

K Tottori; T Miwa; Y Uwahodo; S Yamada; M Nakai; Y Oshiro; T Kikuchi; C. A Altar



5-HT radioligands for human brain imaging with PET and SPECT.  


The serotonergic system plays a key modulatory role in the brain and is the target for many drug treatments for brain disorders either through reuptake blockade or via interactions at the 14 subtypes of 5-HT receptors. This review provides the history and current status of radioligands used for positron emission tomography (PET) and single photon emission computerized tomography (SPECT) imaging of human brain serotonin (5-HT) receptors, the 5-HT transporter (SERT), and 5-HT synthesis rate. Currently available radioligands for in vivo brain imaging of the 5-HT system in humans include antagonists for the 5-HT(1A), 5-HT(1B), 5-HT(2A), and 5-HT(4) receptors, and for SERT. Here we describe the evolution of these radioligands, along with the attempts made to develop radioligands for additional serotonergic targets. We describe the properties needed for a radioligand to become successful and the main caveats. The success of a PET or SPECT radioligand can ultimately be assessed by its frequency of use, its utility in humans, and the number of research sites using it relative to its invention date, and so these aspects are also covered. In conclusion, the development of PET and SPECT radioligands to image serotonergic targets is of high interest, and successful evaluation in humans is leading to invaluable insight into normal and abnormal brain function, emphasizing the need for continued development of both SPECT and PET radioligands for human brain imaging. PMID:21674551

Paterson, Louise M; Kornum, Birgitte R; Nutt, David J; Pike, Victor W; Knudsen, Gitte M



Noradrenaline and 5-hydroxytryptamine modulation of brain dopamine function  

PubMed Central

1 Dopamine deficiency in the brain is the prime biochemical deficit in Parkinson's disease, but loss of noradrenaline and 5HT also may contribute. 2 In rats, 5HT-containing neurones originating from the dorsal and median raphe nuclei innervate forebrain dopamine-containing areas so as to impose an inhibitory regulatory tone on dopamine function. However, this interaction between brain dopamine and 5HT-containing neuronal systems is complex, and the effect produced appears dependent on the relative activity of each system. 3. Anatomical evidence for innervation of dopamine-containing brain regions by noradrenaline fibres in the rat is scanty, but functional studies suggest the existence of inputs which facilitate dopamine function. 4 Drug therapy designed to increase or decrease brain 5HT function has had no consistent effect in Parkinson's disease. 5 Manipulation of brain noradrenergic activity in Parkinson's disease had little effect, although the noradrenaline precursor L-threo-DOPS may reduce freezing attacks. 6 Until more specific drug molecules are available the role of brain noradrenergic and 5HT mechanisms in Parkinson's disease remains uncertain. PMID:6337612

Jenner, P.; Sheehy, M.; Marsden, C. D.



Characterization of putative 5-HT7 receptors mediating tachycardia in the cat  

PubMed Central

It has been suggested that the tachycardic response to 5-hydroxytryptamine (5-HT) in the spinal-transected cat is mediated by ‘5-HT1-like' receptors since this effect, being mimicked by 5-carboxamidotryptamine (5-CT), is not modified by ketanserin or MDL 72222, but it is blocked by methiothepin, methysergide or mesulergine. The present study was set out to reanalyse this suggestion in terms of the IUPHAR 5-HT receptor classification schemes proposed in 1994 and 1996. Intravenous (i.v.) bolus injections of the tryptamine derivatives, 5-CT (0.01, 0.03, 0.1, 0.3, 1, 3, 10 and 30??g?kg?1), 5-HT (3, 10 and 30??g?kg?1) and 5-methoxytryptamine (3, 10 and 30??g?kg?1) as well as the atypical antipsychotic drug, clozapine (1000 and 3000??g?kg?1) resulted in dose-dependent increases in heart rate, with a rank order of agonist potency of 5-CT >> 5-HT > 5-methoxytryptamine >> clozapine. The tachycardic effects of 5-HT and 5-methoxytryptamine were dose-dependently antagonized by i.v. administration of lisuride (30 and 100??g?kg?1), ergotamine (100 and 300??g?kg?1) or mesulergine (100, 300 and 1000??g?kg?1); the highest doses of these antagonists used also blocked the tachycardic effects of 5-CT. Clozapine (1000 and 3000??g?kg?1) did not affect the 5-HT-induced tachycardia, but attenuated, with its highest dose, the responses to 5-methoxytryptamine and 5-CT. However, these doses of clozapine as well as the high doses of ergotamine (300??g?kg?1) and mesulergine (300 and 1000??g?kg?1) also attenuated the tachycardic effects of isoprenaline. In contrast, 5-HT-, 5-methoxytryptamine- and 5-CT-induced tachycardia were not significantly modified after i.v. administration of physiological saline (0.1 and 0.3?ml?kg?1), the 5-HT1B/1D receptor antagonist, GR127935 (500??g?kg?1) or the 5-HT3/4 receptor antagonist, tropisetron (3000??g?kg?1). Intravenous injections of the 5-HT1 receptor agonists, sumatriptan (30, 100 and 300??g?kg?1) and indorenate (300 and 1000??g?kg?1) or the 5-HT4 receptor (partial) agonist cisapride (300 and 1000??g?kg?1) were devoid of effects on feline heart rate per se and failed to modify significantly 5-HT-induced tachycardic responses. Based upon the above rank order of agonist potency, the failure of sumatriptan, indorenate or cisapride to produce cardioacceleration and the blockade by a series of drugs showing high affinity for the cloned 5-ht7 receptor, the present results indicate that the 5-HT receptor mediating tachycardia in the cat is operationally similar to other putative 5-HT7 receptors mediating vascular and non-vascular responses (e.g. relaxation of the rabbit femoral vein, canine external carotid and coronary arteries, rat systemic vasculature and guinea-pig ileum). Since these responses represent functional correlates of the 5-ht7 gene product, the 5-HT7 receptor appellation is reinforced. Therefore, the present experimental model, which is not complicated by the presence of other 5-HT receptors, can be utilized to characterize and develop new drugs with potential agonist and antagonist properties at functional 5-HT7 receptors. PMID:9249256

Villalón, Carlos M; Heiligers, Jan P C; Centurión, David; De Vries, Peter; Saxena, Pramod R



Actions of general anaesthetics on 5-HT3 receptors in N1E-115 neuroblastoma cells.  

PubMed Central

1. NIE-115 mouse neuroblastoma cells were studied under voltage clamp in the whole-cell patch-clamp configuration. Peak currents induced by bath application of 5-hydroxytryptamine (5-HT) were inwardly rectifying, reversed at 0.4 +/- 0.2 mV (mean +/- s.e.mean), and were approximately half-inhibited (at 1 microM 5-HT) by 2 nM of the 5-HT3 selective antagonist MDL-72222 (3-tropanyl-3,5-dichlorobenzoate). 2. Peak inward currents activated by a low concentration of 5-HT at a holding potential of -50 mV were potentiated by volatile general anaesthetics. At their human minimum alveolar concentrations (MACs), the degree of potentiation increased in the order isoflurane < halothane < enflurane < methoxyflurane. Potentiation by methoxyflurane was independent of membrane potential in the range -70 mV to +40 mV. The reversal potential was the same in the presence and absence of methoxyflurane. 3. Methoxyflurane shifted the 5-HT dose-response curve to lower 5-HT concentrations, without significantly changing the Hill coefficient or maximum response. The EC50 concentration for 5-HT decreased from 1.86 +/- 0.02 microM to 1.07 +/- 0.11 microM (means +/- s.e.mean) due to the presence of 1 MAC (270 microM) methoxyflurane. 4. In contrast to the volatile anaesthetics, the barbiturate anaesthetic, thiopentone, inhibited the 5-HT3 receptor. Hill analysis of thiopentone dose-response data gave an average IC50 = 117 +/- 8 microM thiopentone and Hill coefficient = 1.6 +/- 0.2 (means +/- s.e.mean). These parameters were not significantly different for data obtained at 5-HT concentrations above and below the control EC50 concentration for 5-HT, consistent with non-competitive inhibition. 5. The n-alcohols occupied an intermediate position between the volatile and barbiturate anaesthetics. The lower alcohols (butanol and hexanol) potentiated 5-HT responses at low alcohol concentrations but inhibited them at high concentrations. In contrast, the higher alcohols (octanol, decanol, dodecanol, tridecanol, tetradecanol and pentadecanol) produced no potentiation, but only inhibition, at all alcohol concentrations. 6. Inhibition of the 5-HT3 receptor by the n-alcohols exhibited a cutoff in potency similar to those previously found for tadpoles, luciferase enzymes and a neuronal nicotinic acetylcholine receptor channel. PMID:8730747

Jenkins, A.; Franks, N. P.; Lieb, W. R.



Expression of 5-HT1A receptor mRNA in rat dorsal raphe nucleus and ventrolateral periaqueductal gray neurons after peripheral inflammation.  


In the present study we observed the expression of 5-hydroxytryptamine (5-HT)1A receptor mRNA in the dorsal raphe nucleus (DRN) and ventrolateral periaqueductal gray (vlPAG) neurons, especially in 5-HT immunoreactive neurons (5-HT-IR), using in situ hybridization (ISH) and double staining with fluorescent ISH (FISH) and immunohistochemical (FIH) techniques. The findings of this study demonstrated that 5-HT1A receptor mRNA was expressed with moderate to high level in the DRN and vlPAG neurons. Following carrageenan inflammation, the expression of 5-HT1A receptor mRNA in the DRN and bilateral vlPAG neurons was significantly increased. The peak occurred at 3-8h followed by a clear decrease at 24 h, which basically corresponded to the time-course of behavioral hyperalgesia. Moderate 5-HT1A receptor mRNA and 5-HT immunoreactive (5-HT-IR) double-labeled cells were observed in the DRN and vlPAG, suggesting that some of 5-HT1A receptors in the DRN and vlPAG may be autoreceptors. Eight hours after carrageenan injection, the number of the double labeled cells was significantly increased. These results suggest that the synthesis of 5-HT1A receptors, including autoreceptors, is increased in the DRN and vlPAG during peripheral inflammation. PMID:11059903

Zhang, Y Q; Gao, X; Huang, Y L; Wu, G C



A behavioural and biochemical study in rats of 5-hydroxytryptamine receptor agonists and antagonists, with observations on structure-activity requirements for the agonists  

PubMed Central

1 The effect of the putative 5-hydroxytryptamine (5-HT) receptor antagonists, methysergide, methergoline, mianserin, cyproheptadine, cinanserin (all at 10 mg/kg), methiothepin (5 mg/kg) and (-)-propranolol (20 mg/kg) on the behavioural responses to tranylcypromine (10 mg/kg) followed 30 min later by L-tryptophan (100 mg/kg) was examined. 2 Methysergide, methergoline, methiothepin and (-)-propranolol inhibited head weaving, forepaw treading and hind-limb abduction. Methysergide and methergoline increased reactivity. In contrast, cypropheptadine, cinanserin and mianserin had no effects on the behaviour. 3 Similar findings were obtained when the behaviours were elicited by administration of tranylcypromine (10 mg/kg) followed by the putative 5-HT receptor agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (2 mg/kg). 4 When the behaviours were elicited by the putative 5-HT receptor agonist, quipazine (50 mg/kg), all the drugs effectively inhibited head weaving and forepaw treading. 5 When the dose of cypropheptadine was doubled to 20 mg/kg an inhibition of the tranylcypromine/L-tryptophan induced behaviours was seen. 6 Methiothepin produced a marked inhibition of apomorphine-induced locomotor activity whilst all the others enhanced this response, suggesting that only methiothepin inhibits the 5-HT behaviours by dopamine antagonism and that the increased reactivity seen following tranylcypromine/L-tryptophan after pretreatment with methysergide or methergoline might be due to enhanced dopamine function. 7 Pretreatment with p-chlorophenylalanine resulted in enhanced behavioural responses to both 5-MeODMT and quipazine. 8 Both methergoline and methiothepin decreased the rate of 5-HT synthesis in whole brain but not spinal cord and methergoline decreased spinal cord 5-HIAA concentration. None of the other drugs had any significant effects on the concentration of 5-HT, 5-HIAA or 5-HT synthesis rate in brain or spinal cord. 9 Experiments with compounds structurally related to quipazine and with molecular models suggested that quipazine produces behavioural changes probably by stimulating the 5-HT receptor in a similar way to 5-HT but that it would bind weakly, in agreement with ligand-receptor binding studies. 10 It is suggested, therefore, that cyproheptadine, cinanserin and mianserin fail to inhibit 5-HT and 5-MeODMT-induced behaviours because they are weak antagonists whilst they are able to inhibit the same behaviours induced by quipazine because it is a weak agonist. 11 These data indicate that extreme care should be taken in accepting or rejecting 5-HT as a mediator of behaviours or of other responses unless several antagonists or agonists have been examined. ImagesFigure 9 PMID:6166345

Green, A.R.; Hall, J.E.; Rees, A.R.



Investigation of the role of 5-HT3 and 5-HT4 receptors in ascending and descending reflexes to the circular muscle of guinea-pig small intestine.  

PubMed Central

1. The present study was undertaken to ascertain whether 5-hydroxytryptamine (5-HT) acting at either 5-HT3 or 5-HT4 receptors plays a significant role in motility reflexes in the guinea-pig small intestine. 2. An isolated segment of small intestine was opened along its mesenteric border and pinned, mucosa uppermost, in a three chambered organ bath so that the oral, middle and anal regions of a single preparation could be separately superfused. 3. Conventional intracellular recording methods were used to monitor the responses of the circular muscle in the oral or the anal end chambers when distension was applied in either of the other two chambers or the mucosal villi were compressed in the middle chamber. Drugs were added to the middle chamber. 4. 5-HT3 receptor antagonists (tropisetron, 0.1-10 microM; granisetron, 1 microM and BRL 46470, 1 microM) depressed the ascending excitatory reflex evoked by these stimuli but had no effect on the descending inhibitory reflex. The depression of the excitatory reflex was observed whether the reflex was evoked from the chamber containing the drug or was simply conducted, via interneurones, through this chamber. 5. The 5-HT4 receptor antagonist, SDZ 205-557 (1 microM), had no significant effect on either the ascending or descending reflex pathways. However, 5-HT4 receptors were present as cisapride (0.1 microM) significantly enhanced the ascending excitation without affecting the descending inhibition. This effect of cisapride was converted to a significant depression of the ascending reflex by SDZ 205-557.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7952869

Yuan, S. Y.; Bornstein, J. C.; Furness, J. B.



Further characterization of the 5-HT receptor mediating vascular relaxation and elevation of cyclic AMP in porcine isolated vena cava.  

PubMed Central

1. 5-Hydroxytryptamine (5-HT) and 5-carboxamidotryptamine (5-CT) produce both smooth muscle relaxation and elevation of tissue adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels in isolated rings of neonatal porcine vena cava. We now present studies attempting to characterize in more detail the 5-HT receptor mediating these responses. 2. Both 5-HT and 5-CT relaxed porcine isolated vena cava rings (EC50 values 200 nM and 4 nM respectively) and elevated tissue cyclic AMP levels (EC50 values 1500 nM and 16 nM respectively). For both responses 5-CT was approximately 50-100 fold more potent than 5-HT. 3. Both 5-CT-induced smooth muscle relaxation and cyclic AMP elevation were potently and specifically antagonized to a similar extent by methiothepin, methysergide and spiperone. 4. At concentrations up to 1 microM, 8-hydroxy-2-(di-n-propylamino) tetralin, buspirone, ipsapirone, n,n-dipropyl-5-CT, cyanopindolol, RU24969, ketanserin, GR38032 and GR43175 were devoid of both agonist and antagonist activity for both responses. 5. These findings suggest that the same 5-HT1-like receptor mediates both smooth muscle relaxation and elevation of cyclic AMP. This receptor is unlike any known 5-HT1 ligand binding site or adenylate cyclase-coupled 5-HT receptor in brain tissues. PMID:2541857

Sumner, M. J.; Feniuk, W.; Humphrey, P. P.



Quantal corelease of histamine and 5-hydroxytryptamine from mast cells and the effects of prior incubation.  


Corelease of histamine and 5-hydroxytryptamine from individual mast cells has been measured with fast-scan cyclic voltammetry using a carbon-fiber electrode placed next to a single cell. Release events, induced by exposure of the cells to the calcium ionophore, A23187, were resolved at the level of individual exocytotic events. Changes in the relative concentrations secreted from individual granules were observed after incubation with 5-hydroxytryptamine, histamine, and tryptophan. In contrast, an alteration in individual cell content after such incubations, analyzed with capillary chromatography, was only found after incubation with 5-hydroxytryptamine. Cells incubated with 5-hydroxytryptamine or its precursor, tryptophan, released more 5-hydroxytryptamine and less histamine per secretory event relative to controls. Coincubation of the cells with pargyline and 5-hydroxytryptamine further reduced the release of histamine. Since cell content of histamine is unchanged, the reduction in its release must be due to its displacement to a nonreleasable compartment induced by 5-hydroxytryptamine granular uptake. Incubation with histamine increased histamine secretion and, surprisingly, also increased 5-hydroxytryptamine release without changing its cell content. This result is consistent with a relaxation of the storage matrix accompanying histamine granular uptake allowing more 5-hydroxytryptamine to be released. These results demonstrate that the intragranular mode of storage as well as granular uptake of biogenic amines affects the stoichiometry of their release. PMID:9454595

Pihel, K; Hsieh, S; Jorgenson, J W; Wightman, R M



Peptide Inhibitors Disrupt the Serotonin 5-HT2C Receptor Interaction with Phosphatase and Tensin Homolog to Allosterically Modulate Cellular Signaling and Behavior  

PubMed Central

Serotonin (5-hydroxytryptamine; 5-HT) signaling through the 5-HT2C receptor (5-HT2CR) is essential in normal physiology, whereas aberrant 5-HT2CR function is thought to contribute to the pathogenesis of multiple neural disorders. The 5-HT2CR interacts with specific protein partners, but the impact of such interactions on 5-HT2CR function is poorly understood. Here, we report convergent cellular and behavioral data that the interaction between the 5-HT2CR and protein phosphatase and tensin homolog (PTEN) serves as a regulatory mechanism to control 5-HT2CR-mediated biology but not that of the closely homologous 5-HT2AR. A peptide derived from the third intracellular loop of the human 5-HT2CR [3L4F (third loop, fourth fragment)] disrupted the association, allosterically augmented 5-HT2CR-mediated signaling in live cells, and acted as a positive allosteric modulator in rats in vivo. We identified the critical residues within an 8 aa fragment of the 3L4F peptide that maintained efficacy (within the picomolar range) in live cells similar to that of the 3L4F peptide. Last, molecular modeling identified key structural features and potential interaction sites of the active 3L4F peptides against PTEN. These compelling data demonstrate the specificity and importance of this protein assembly in cellular events and behaviors mediated by 5-HT2CR signaling and provide a chemical guidepost to the future development of drug-like peptide or small-molecule inhibitors as neuroprobes to study 5-HT2CR allostery and therapeutics for 5-HT2CR-mediated disorders. PMID:23345234

Anastasio, Noelle C.; Gilbertson, Scott R.; Bubar, Marcy J.; Agarkov, Anton; Stutz, Sonja J.; Jeng, Yowjiun; Bremer, Nicole M.; Smith, Thressa D.; Fox, Robert G.; Swinford, Sarah E.; Seitz, Patricia K.; Charendoff, Marc N.; Craft, John W.; Laezza, Fernanda M.; Watson, Cheryl S.; Briggs, James M.; Cunningham, Kathryn A.



5-HT Obesity Medication Efficacy via POMC Activation is Maintained During Aging  

PubMed Central

The phenomenon commonly described as the middle-age spread is the result of elevated adiposity accumulation throughout adulthood until late middle-age. It is a clinical imperative to gain a greater understanding of the underpinnings of age-dependent obesity and, in turn, how these mechanisms may impact the efficacy of obesity treatments. In particular, both obesity and aging are associated with rewiring of a principal brain pathway modulating energy homeostasis, promoting reduced activity of satiety pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus (ARC). Using a selective ARC-deficient POMC mouse line, here we report that former obesity medications augmenting endogenous 5-hydroxytryptamine (5-HT) activity d-fenfluramine and sibutramine require ARC POMC neurons to elicit therapeutic appetite-suppressive effects. We next investigated whether age-related diminished ARC POMC activity therefore impacts the potency of 5-HT obesity pharmacotherapies, lorcaserin, d-fenfluramine, and sibutramine and report that all compounds reduced food intake to a comparable extent in both chow-fed young lean (3–5 months old) and middle-aged obese (12–14 months old) male and female mice. We provide a mechanism through which 5-HT anorectic potency is maintained with age, via preserved 5-HT–POMC appetitive anatomical machinery. Specifically, the abundance and signaling of the primary 5-HT receptor influencing appetite via POMC activation, the 5-HT2CR, is not perturbed with age. These data reveal that although 5-HT obesity medications require ARC POMC neurons to achieve appetitive effects, the anorectic efficacy is maintained with aging, findings of clinical significance to the global aging obese population. PMID:25051442

Burke, Luke K.; Doslikova, Barbora; D'Agostino, Giuseppe; Garfield, Alastair S.; Farooq, Gala; Burdakov, Denis; Low, Malcolm J.; Rubinstein, Marcelo; Evans, Mark L.; Billups, Brian



5-HT obesity medication efficacy via POMC activation is maintained during aging.  


The phenomenon commonly described as the middle-age spread is the result of elevated adiposity accumulation throughout adulthood until late middle-age. It is a clinical imperative to gain a greater understanding of the underpinnings of age-dependent obesity and, in turn, how these mechanisms may impact the efficacy of obesity treatments. In particular, both obesity and aging are associated with rewiring of a principal brain pathway modulating energy homeostasis, promoting reduced activity of satiety pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus (ARC). Using a selective ARC-deficient POMC mouse line, here we report that former obesity medications augmenting endogenous 5-hydroxytryptamine (5-HT) activity d-fenfluramine and sibutramine require ARC POMC neurons to elicit therapeutic appetite-suppressive effects. We next investigated whether age-related diminished ARC POMC activity therefore impacts the potency of 5-HT obesity pharmacotherapies, lorcaserin, d-fenfluramine, and sibutramine and report that all compounds reduced food intake to a comparable extent in both chow-fed young lean (3-5 months old) and middle-aged obese (12-14 months old) male and female mice. We provide a mechanism through which 5-HT anorectic potency is maintained with age, via preserved 5-HT-POMC appetitive anatomical machinery. Specifically, the abundance and signaling of the primary 5-HT receptor influencing appetite via POMC activation, the 5-HT2CR, is not perturbed with age. These data reveal that although 5-HT obesity medications require ARC POMC neurons to achieve appetitive effects, the anorectic efficacy is maintained with aging, findings of clinical significance to the global aging obese population. PMID:25051442

Burke, Luke K; Doslikova, Barbora; D'Agostino, Giuseppe; Garfield, Alastair S; Farooq, Gala; Burdakov, Denis; Low, Malcolm J; Rubinstein, Marcelo; Evans, Mark L; Billups, Brian; Heisler, Lora K



Evidence for postsynaptic mediation of the hypothermic effect of 5-HT1A receptor activation.  

PubMed Central

1. The 5-HT1A ligand BMY 7378 (8-[2[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]8-azaspirol [4,5]-decane-7,9-dione dihydrochloride, 0.032-2 mg kg-1, s.c.) caused hyperphagia, a response to the activation of presynaptic 5-HT1A receptors. 2. BMY 7378 (8 mg kg-1, s.c.) and the 5-HT1A agonist (8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), 0.10 and 0.25 mg kg-1 s.c.) also caused hypothermia. This was inhibited by (-)-pindolol (1-mg kg-1, i.p.) and not prevented by pretreatments with p-chlorophenylalanine which grossly depleted 5-hydroxytryptamine (5-HT) from terminal regions. The hypothermic effects are explicable by activation of postsynaptic 5-HT1A receptors. Infusion of BMY 7378 (8-64 micrograms) into the dorsal raphe was without convincing hypothermic effect. 3. BMY 7378 (8 mg kg-1, s.c.) inhibited another effect of activation of postsynaptic 5-HT1A receptors, i.e., the induction of components of the 5-HT syndrome by 8-OH-DPAT (0.5, 1.0 mg kg-1, s.c.) which suggests that BMY 7378 has antagonistic as well as agonistic effects at these sites. 4. Partial agonist properties of BMY 7378 at postsynaptic sites were also indicated by doses for hypothermia being much greater than those for hyperphagia i.e., ED50 (hypothermia) greater than 2 mg kg-1, ED50 (hyperphagia) = 0.010 mg kg-1. This contrasts with the similar ED50 values for both the hypothermic (ED50 = 0.08-0.10 mg kg-1) and hyperphagic (ED50 = 0.06-0.10 mg kg-1) effects of 8-OH-DPAT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1387027

O'Connell, M. T.; Sarna, G. S.; Curzon, G.



Further evidence that the discriminative stimulus properties of indorenate are mediated by 5-HT 1A/1B/2C receptors.  


Indorenate (5-methoxytryptamine beta-methylcarboxylate, INDO) is a serotonin (5-hydroxytryptamine, 5-HT) agonist that has affinity for 5-HT(1A/1B/2C) receptors. Unlike other anxiolytics such as 5-HT receptor agonists, INDO may not share tolerance or dependency with the benzodiazepine anxiolytics. It has been reported that the discriminative stimulus properties of 5-HT(1A/1B/2C) agonists, but not those of 5-HT(3/4) agonists, generalize to INDO. Therefore, the aim of the present study was to obtain further evidence on the differential involvement of 5-HT(1A/1B/2C) receptors in the discriminative stimulus properties of INDO by evaluating its interactions with antagonists of the 5-HT(1A), 5-HT(1B), 5-HT(2C), and 5-HT(3/4) receptor subtypes. Rats were trained to discriminate INDO from saline in a conditioned taste aversion paradigm. For Group D(+)S(-), administration of INDO signalled that saccharin flavour was followed by LiCl, while injection of vehicle signalled safe consumption of saccharin solution. Group D(-)S(+) had the contingencies reversed. After this training, rats had generalization tests where INDO administration was preceded by different doses of the following antagonists: WAY100635 (5-HT(1A)), NAN190 (5-HT(1A)), methiothepin (5-HT(1A/1B/2C)), GR127935 (5-HT(1B/1D)), ketanserin (5-HT(2A/2C)), ritanserin (5-HT(2C/2A)), mesulergine (5-HT(2C/2A)), metergoline (5-HT(2C/2A)), SB206553 (5-HT(2B/2C)), and tropisetron (5-HT(3/4)). In Group D(+)S(-), the order of potency to block the discriminative stimulus properties of INDO was WAY100635>ketanserin>ritanserin>GR127935>mesulergine congruent with SB206553>metergoline>methiothepin>NAN190, while in Group D(-)S(+), the order was WAY100635>GR127935>ketanserin>ritanserin>mesulergine congruent with SB206553>metergoline>methiothepin>NAN190. Tropisetron did not produce any alteration of the discriminative control by INDO. These results suggest that the discriminative signal of INDO is mediated by 5-HT(1A/2C/1B) receptors and that blockade of any of its components produces a degradation of its discriminative effects. PMID:12479957

Miranda, F; Hong, E; Sánchez, H; Velázquez-Martínez, D N



Simultaneous determination of 5-hydroxyindoleacetic acid and 5-hydroxytryptamine in urine samples from patients with acute appendicitis by liquid chromatography using poly(bromophenol blue) film modified electrode.  


The fabrication and application of a novel electrochemical detection (ED) system with a poly(bromophenol blue) (PBPB) film chemically modified electrode (CME) for high performance liquid chromatography (HPLC) were described. The electrochemical behaviors of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) at this CME were investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). It was found that the PBPB CME efficiently exhibited electrocatalytic effect on the current responses of 5-HT and 5-HIAA with relatively high sensitivity, stability and long life of activity. In HPLC-ED, the two analytes had good and stable current responses at the CME and their linear ranges were over four orders of magnitude (R> or =0.9992) with the detection limits being 0.25 nmol L(-1) for 5-HT and 0.50 nmol L(-1) for 5-HIAA. The application of this method for the determination of 5-HT and 5-HIAA in urine samples from patients with acute appendicitis (AA) was satisfactory. PMID:16949889

Xu, Haihong; Zhang, Wen; Wang, Dan; Zhu, Wei; Jin, Litong



Changes in 5-hydroxytryptamine and cortisol plasma levels in menopausal women after inhalation of clary sage oil.  


The purpose of this study was to examine the antidepressant-like effects of clary sage oil on human beings by comparing the neurotransmitter level change in plasma. The voluntary participants were 22 menopausal women in 50's. Subjects were classified into normal and depression tendency groups using each of Korean version of Beck Depression Inventory-I (KBDI-I), KBDI-II, and Korean version of Self-rating Depression Scale. Then, the changes in neurotransmitter concentrations were compared between two groups. After inhalation of clary sage oil, cortisol levels were significantly decreased while 5-hydroxytryptamine (5-HT) concentration was significantly increased. Thyroid stimulating hormone was also reduced in all groups but not statistically significantly. The different change rate of 5-HT concentration between normal and depression tendency groups was variable according to the depression measurement inventory. When using KBDI-I and KBDI-II, 5-HT increased by 341% and 828% for the normal group and 484% and 257% for the depression tendency group, respectively. The change rate of cortisol was greater in depression tendency groups compared with normal groups, and this difference was statistically significant when using KBDI-II (31% vs. 16% reduction) and Self-rating Depression Scale inventory (36% vs. 8.3% reduction). Among three inventories, only KBDI-II differentiated normal and depression tendency groups with significantly different cortisol level. Finally, clary sage oil has antidepressant-like effect, and KBDI-II inventory may be the most sensitive and valid tool in screening for depression status or severity. PMID:24802524

Lee, Kyung-Bok; Cho, Eun; Kang, Young-Sook



An in vivo dialysis and behavioural study of the release of 5-HT by p-chloroamphetamine in reserpine-treated rats.  

PubMed Central

1. Reserpine (2.5 mg kg-1 i.p.) decreased rat brain 5-hydroxytryptamine (5-HT) by 86% 24 h later but most components of the 5-HT-dependent behavioural syndrome induced by p-chloroamphetamine (PCA, 5 mg kg-1 i.p.) or 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 5 mg kg-1 i.p.) over 1 h after administration were unaffected. However, Straub tail was increased after giving PCA or 5-MeODMT and head weaving was decreased after giving 5-MeODMT. 2. Frontal cortex extracellular 5-HT concentrations of vehicle pretreated rats before injection of PCA, as calculated from dialysate 5-HT concentrations, were about 1/1000th of corresponding brain values. Extracellular 5-hydroxyindoleacetic acid (5-HIAA) and brain values were comparable with each other. Dialysate 5-HT increased after PCA with peak values at 20-40 min. 3. Reserpine pretreatment reduced dialysate 5-HT concentration before PCA was given but the net increase (AUC) over the 1 h after PCA did not differ significantly from that seen in animals pretreated with vehicle. Dialysate 5-HIAA values slowly decreased after PCA injection in both reserpine and vehicle pretreated groups. 4. The results suggest that PCA causes the 5-HT syndrome by releasing 5-HT from the neuronal cytoplasm but that physiological release of 5-HT occurs from vesicular stores. PMID:2720308

Adell, A.; Sarna, G. S.; Hutson, P. H.; Curzon, G.



Doxazosin selectively potentiates contraction to serotonin via 5-HT?A receptors in longitudinal muscle strips of the rabbit gastric body.  


The aims of this study were to examine the effects of doxazosin on contractile responses to 5-hydroxytryptamine (5-HT), carbachol, and histamine, and to compare them with those of prazosin, alfuzosin, and terazosin, and then characterize a pharmacological profile of the 5-HT-induced contractile response using preparations of isolated longitudinal muscle strips from the rabbit gastric body. The results from these preparations showed that the contraction response to 5-HT, but not to carbachol or histamine, was found to be dose-dependently potentiated by doxazosin and its enantiomers. The specific potentiation effect on 5-HT was not observed in the preparations that were treated with prazosin, terazosin, or alfuzosin. The contractile response to 5-HT and its potentiation by doxazosin were not affected by treatment with phenoxybenzamine. However, 5-HT-induced contraction was competitively antagonized by nefazodone (with pA? value of 8.64 ± 0.17), and was almost completely inhibited by treatment with indomethacin. In conclusion, doxazosin, but not prazosin, alfuzosin, or terazosin, selectively potentiates 5-HT-induced contraction in the rabbit gastric body strips via an ??-adrenoceptor-independent mechanism, without chiral recognition of its enantiomers. Additionally, the contraction to 5-HT was found to be mediated via 5-HT(?) receptors, and was similar to PGs synthesis in the preparations. PMID:24593784

Zhao, Yan; Cao, Xue-Bin; Ren, Lei-Ming



Differential effects of 5-hydroxytryptamine4 receptor agonists at gastric versus cardiac receptors: an operational framework to explain and quantify organ-specific behavior.  


Quantification of different levels of 5-hydroxytryptamine4 (5-HT4) receptor agonism expression across animal species as well as across organs within the same animal species offers substantial potential for the separation of desired gastrointestinal versus undesired cardiac pharmacological activity of compounds in development. Since a detailed investigation of such properties is lacking to date, we set out to quantify gastric and cardiac effects of 5-HT4 receptor ligands in the pig, a model considered to be representative for the human situation. An in vitro test was developed to study the potentiating effect of 5-HT, prucalopride, tegaserod, R149402 (4-amino-5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid [3-hydroxy-1-(3-methoxy-propyl)-piperidin-4ylmethyl]-amide), and R199715 (4-amino-5-chloro-2,3-dihydro-benzofuran-7-carboxylic acid [3-hydroxy-1-(3-methoxy-propyl)-piperidin-4ylmethyl]-amide) on electrically induced cholinergic contractions in longitudinal muscle strips of the proximal stomach. The results were compared with inotropic and chronotropic effects of these compounds in the electrically paced left atrium and spontaneously beating right atrium, respectively. To quantify the observed tissue-dependent responses, a nonlinear mixed-effects model based on the operational model of agonism was developed and successfully fitted to the data. The model quantified the tissue-dependent partial agonism of the selective 5-HT4 receptor agonists prucalopride, R149402, and R199715, whereas tegaserod and 5-HT were equiefficacious. The model was further extended to incorporate the responses to prucalopride in the presence of the 5-HT4 receptor antagonist GR113808 ([1-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl-]methyl 1-methyl-1H-indole-3-carboxylate). The results indicate that these interactions do not follow a simple competitive pattern and that they differ between stomach and left atrium. PMID:16501067

De Maeyer, Joris H; Prins, Nicolaas H; Schuurkes, Jan A J; Lefebvre, Romain A



The 5-hydroxytryptamine4 receptor agonists prucalopride and PRX-03140 increase acetylcholine and histamine levels in the rat prefrontal cortex and the power of stimulated hippocampal ? oscillations.  


5-Hydroxytryptamine (5-HT)(4) receptor agonists reportedly stimulate brain acetylcholine (ACh) release, a property that might provide a new pharmacological approach for treating cognitive deficits associated with Alzheimer's disease. The purpose of this study was to compare the binding affinities, functional activities, and effects on neuropharmacological responses associated with cognition of two highly selective 5-HT(4) receptor agonists, prucalopride and 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-[3-(piperidin-1-yl)propyl]thieno[2,3-b]pyridine-5-carboxamide (PRX-03140). In vitro, prucalopride and PRX-03140 bound to native rat brain 5-HT(4) receptors with K(i) values of 30 nM and 110 nM, respectively, and increased cAMP production in human embryonic kidney-293 cells expressing recombinant rat 5-HT(4) receptors. In vivo receptor occupancy studies established that prucalopride and PRX-03140 were able to penetrate the brain and bound to 5-HT(4) receptors in rat brain, achieving 50% receptor occupancy at free brain exposures of 330 nM and 130 nM, respectively. Rat microdialysis studies revealed that prucalopride maximally increased ACh and histamine levels in the prefrontal cortex at 5 and 10 mg/kg, whereas PRX-03140 significantly increased cortical histamine levels at 50 mg/kg, failing to affect ACh release at doses lower than 150 mg/kg. In combination studies, donepezil-induced increases in cortical ACh levels were potentiated by prucalopride and PRX-03140. Electrophysiological studies in rats demonstrated that both compounds increased the power of brainstem-stimulated hippocampal ? oscillations at 5.6 mg/kg. These findings show for the first time that the 5-HT(4) receptor agonists prucalopride and PRX-03140 can increase cortical ACh and histamine levels, augment donepezil-induced ACh increases, and increase stimulated-hippocampal ? power, all neuropharmacological parameters consistent with potential positive effects on cognitive processes. PMID:22408061

Johnson, David E; Drummond, Elena; Grimwood, Sarah; Sawant-Basak, Aarti; Miller, Emily; Tseng, Elaine; McDowell, Laura L; Vanase-Frawley, Michelle A; Fisher, Katherine E; Rubitski, David M; Stutzman-Engwall, Kim J; Nelson, Robin T; Horner, Weldon E; Gorczyca, Roxanne R; Hajos, Mihaly; Siok, Chester J



Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs.  


The tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid (DMXAA) causes dramatic haemorrhagic necrosis in murine tumours, but activity is seen only at doses close to the toxic limit. This study investigates two approaches for increasing the therapeutic ratio of DMXAA. The first approach combines DMXAA with a second tumour blood flow inhibitor, 5-hydroxytryptamine (5-HT). Co-administration of 5-HT (700 micromol kg(-1)) to C3H mice caused marked enhancement of DMXAA effects against MDAH-MCa-4 tumours, with dose-modifying factors (DMFs) of >3 for blood flow inhibition (at 4 h), 2.3 for necrosis (at 12 h) and 2.0 for growth delay, without compromising the maximum tolerated dose of DMXAA (90 micromol kg(-1)). The data are consistent with ischaemic injury to the tumour being the major mechanism of anti-tumour activity. The second approach combines DMXAA (+/- 5-HT) with hypoxia-selective bioreductive drugs. Anti-tumour activity of all three bioreductive drugs tested (tirapazamine, CI-1010, SN 23816) was strongly potentiated by DMXAA, suggesting that there is a population of reversibly hypoxic tumour cells after DMXAA treatment. Co-administration of 5-HT further potentiated anti-tumour activity, but also increased host toxicity of tirapazamine and CI-1010 so that little therapeutic benefit was achieved. In contrast, the host toxicity of the dinitrobenzamide mustard SN 23816 was only slightly increased by DMXAA/5-HT, whereas the tumour growth delay at the maximum tolerated dose of SN 23816 was increased from 3.5 to 26.5 days. This study demonstrates that 5-HT and/or bioreductive drugs can improve the therapeutic activity of DMXAA in mice, and that with SN 23816 both approaches can be used together to provide considerably enhanced anti-tumour activity. PMID:9716024

Lash, C J; Li, A E; Rutland, M; Baguley, B C; Zwi, L J; Wilson, W R



Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs.  

PubMed Central

The tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid (DMXAA) causes dramatic haemorrhagic necrosis in murine tumours, but activity is seen only at doses close to the toxic limit. This study investigates two approaches for increasing the therapeutic ratio of DMXAA. The first approach combines DMXAA with a second tumour blood flow inhibitor, 5-hydroxytryptamine (5-HT). Co-administration of 5-HT (700 micromol kg(-1)) to C3H mice caused marked enhancement of DMXAA effects against MDAH-MCa-4 tumours, with dose-modifying factors (DMFs) of >3 for blood flow inhibition (at 4 h), 2.3 for necrosis (at 12 h) and 2.0 for growth delay, without compromising the maximum tolerated dose of DMXAA (90 micromol kg(-1)). The data are consistent with ischaemic injury to the tumour being the major mechanism of anti-tumour activity. The second approach combines DMXAA (+/- 5-HT) with hypoxia-selective bioreductive drugs. Anti-tumour activity of all three bioreductive drugs tested (tirapazamine, CI-1010, SN 23816) was strongly potentiated by DMXAA, suggesting that there is a population of reversibly hypoxic tumour cells after DMXAA treatment. Co-administration of 5-HT further potentiated anti-tumour activity, but also increased host toxicity of tirapazamine and CI-1010 so that little therapeutic benefit was achieved. In contrast, the host toxicity of the dinitrobenzamide mustard SN 23816 was only slightly increased by DMXAA/5-HT, whereas the tumour growth delay at the maximum tolerated dose of SN 23816 was increased from 3.5 to 26.5 days. This study demonstrates that 5-HT and/or bioreductive drugs can improve the therapeutic activity of DMXAA in mice, and that with SN 23816 both approaches can be used together to provide considerably enhanced anti-tumour activity. PMID:9716024

Lash, C. J.; Li, A. E.; Rutland, M.; Baguley, B. C.; Zwi, L. J.; Wilson, W. R.



High-Throughput Multiplexed Transcript Analysis Yields Enhanced Resolution of 5-Hydroxytryptamine2C Receptor mRNA Editing ProfilesS?  

PubMed Central

RNA editing is a post-transcriptional modification in which adenosine residues are converted to inosine (adenosine-to-inosine editing). Commonly used methodologies to quantify RNA editing levels involve either direct sequencing or pyrosequencing of individual cDNA clones. The limitations of these methods lead to a small number of clones characterized in comparison to the number of mRNA molecules in the original sample, thereby producing significant sampling errors and potentially erroneous conclusions. We have developed an improved method for quantifying RNA editing patterns that increases sequence analysis to an average of more than 800,000 individual cDNAs per sample, substantially increasing accuracy and sensitivity. Our method is based on the serotonin 2C receptor (5-hydroxytryptamine2C; 5HT2C) transcript, an RNA editing substrate in which up to five adenosines are modified. Using a high-throughput multiplexed transcript analysis, we were able to quantify accurately the expression of twenty 5HT2C isoforms, each representing at least 0.25% of the total 5HT2C transcripts. Furthermore, this approach allowed the detection of previously unobserved changes in 5HT2C editing in RNA samples isolated from different inbred mouse strains and dissected brain regions, as well as editing differences in alternatively spliced 5HT2C variants. This approach provides a novel and efficient strategy for large-scale analyses of RNA editing and may prove to be a valuable tool for uncovering new information regarding editing patterns in specific disease states and in response to pharmacological and physiological perturbation, further elucidating the impact of 5HT2C RNA editing on central nervous system function. PMID:20181818

Morabito, Michael V.; Ulbricht, Randi J.; O'Neil, Richard T.; Airey, David C.; Lu, Pengcheng; Zhang, Bing; Wang, Lily



Medicinal chemistry strategies to 5-HT(6) receptor ligands as potential cognitive enhancers and antiobesity agents.  


Although the 5-hydroxytryptamine(6) (5-HT(6)) receptor was discovered only recently, its almost exclusive distribution in the brain makes it a promising, novel, target for central nervous system (CNS)-mediated diseases such as Alzheimer's disease (cognitive function), schizophrenia, anxiety and obesity. In the past few years a significant research interest has advanced the understanding of the functional roles and the pharmacophore requirements of this receptor. Two 5-HT(6) receptor antagonists have already entered Phase II clinical trials for the enhancement of cognitive function. Since the first discovery of selective ligands for the 5-HT(6) receptor by HTS in 1998, several medicinal-chemistry-driven approaches have delivered highly selective lead structures with well-defined functionalities, starting from either the endogenous ligand 5-HT or the chemical structures identified by HTS. The concept of 'scaffold hopping' has been employed to expand the variability of the available chemical scaffolds and to generate patentable ligands. Supported by pharmacophore models, which have been established recently, the binding and functionality (structure-activity relationships) of the lead structures have been optimized further. PMID:16580970

Holenz, Jörg; Pauwels, Petrus J; Díaz, José Luis; Mercè, Ramon; Codony, Xavier; Buschmann, Helmut



Activation of serotonin 5-HT7 receptor induces coronary flow increase in isolated rat heart.  


Serotonin (5-Hydroxytryptamine, 5-HT) can elicit both vasoconstrictive and relaxant responses on rat coronary artery. The constrictive response has been well discussed, but the mechanism of relaxant response is less studied. In the present study, we found serotonin (0.3 and 1?M) increased coronary flow on isolated rat hearts, and treatment of nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) 300?M reduced but not totally blocked this coronary flow increasing effect. In l-NAME 10?M treated heart, treatment of selective serotonin 5-HT7 receptor antagonist SB269970 0.1?M blocked serotonin induced coronary flow increasing response, and in the presence of 1?M SB269970, serotonin turned into reducing coronary flow. Treatment of TCW295 (8-(2,4-Dimethoxyphenyl)-6-methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol hydrochloride), a novel serotonin 5-HT2A/7 receptor antagonist, inhibited both serotonin induced coronary flow increasing and decreasing effects. In conclusion, we found serotonin increases coronary flow of isolated rat heart by activating serotonin 5-HT7 receptor activation, and this effect can be, at least partially, resistant to l-NAME. PMID:25196212

Chang Chien, Ching-Chia; Hsin, Ling-Wei; Su, Ming-Jai



Mediation of 5-HT-induced external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs by the putative 5-HT7 receptor  

PubMed Central

The vasodilator effects of 5-hydroxytryptamine (5-HT) in the external carotid bed of anaesthetized dogs with intact sympathetic tone are mediated by prejunctional sympatho-inhibitory 5-HT1B/1D receptors and postjunctional 5-HT receptors. The prejunctional vasodilator mechanism is abolished after vagosympathectomy which results in the reversal of the vasodilator effect to vasoconstriction. The blockade of this vasoconstrictor effect of 5-HT with the 5-HT1B/1D receptor antagonist, GR 127935, unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this postjunctional vasodilator 5-HT receptor in the external carotid bed of vagosympathectomized dogs pretreated with GR 127935 (20??g?kg?1, i.v.).One-minute intracarotid (i.c.) infusions of 5-HT (0.330??g?min?1), 5-carboxamidotryptamine (5-CT; 0.010.3??g?min?1), 5-methoxytryptamine (1100??g?min?1) and lisuride (31000??g?min?1) resulted in dose-dependent increases in external carotid blood flow (without changes in blood pressure or heart rate) with a rank order of agonist potency of 5-CT>>5-HT?5-methoxytryptamine>lisuride, whereas cisapride (1001000??g?min?1, i.c.) was practically inactive. Interestingly, lisuride (mean dose of 85±7??g?kg?1, i.c.), but not cisapride (mean dose of 67±7??g?kg?1, i.c.), specifically abolished the responses induced by 5-HT, 5-CT and 5-methoxytryptamine, suggesting that a common site of action may be involved. In contrast, 1?min i.c. infusions of 8-OH-DPAT (33000??g?min?1) produced dose-dependent decreases, not increases, in external carotid blood flow and failed to antagonize (mean dose of 200±33??g?kg?1, i.c.) the agonist-induced vasodilator responses.The external carotid vasodilator responses to 5-HT, 5-CT and 5-methoxytryptamine were not modified by intravenous (i.v.) pretreatment with either saline, (±)-pindolol (4?mg?kg?1) or ritanserin (100??g?kg?1) plus granisetron (300??g?kg?1), but were dose-dependently blocked by i.v. administration of methiothepin (10 and 30??g?kg?1, given after ritanserin plus granisetron), mesulergine (10 and 30??g?kg?1), metergoline (1 and 3?mg?kg?1), methysergide (1 and 3?mg?kg?1) or clozapine (0.3 and 1?mg?kg?1). Nevertheless, the blockade of the above responses, not significant after treatment with the lower of the two doses of metergoline and mesulergine, was nonspecific after administration of the higher of the two doses of methysergide and clozapine.Based upon the above rank order of agonist potencies and the antagonism produced by a series of drugs showing high affinity for the cloned 5-ht7 receptor, our results indicate that the 5-HT receptor mediating external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs is operationally similar to the putative 5-HT7 receptor mediating relaxation of vascular and non-vascular smooth muscles (e.g. rabbit femoral vein, canine coronary artery, rat systemic vasculature and guinea-pig ileum) as well as tachycardia in the cat. PMID:9105708

Villalón, Carlos M; Centurión, David; Luján-Estrada, Miguel; Terrón, José A; Sánchez-López, Araceli



Expression of 5-HT1A receptor mRNA in rat lumbar spinal dorsal horn neurons after peripheral inflammation.  


The present study observed the expression of the 5-hydroxytryptamine (5-HT) (1A) receptor mRNA in the lumbar spinal dorsal horn neurons following carrageenan inflammation using in situ hybridization (ISH). We also studied the co-localization of 5-HT(1A) receptor mRNA and gamma-amino butyric acid (GABA) or enkephalin (ENK) immunoreactivities using a combined fluorescent ISH and immunofluorescent histochemical double-staining technique. The finding of this study demonstrated that 5-HT(1A) receptor mRNA was widely distributed in the spinal dorsal horn with the highest density in laminae III-VI. Following carrageenan-induced inflammation, the 5-HT(1A) receptor mRNA expression in all layers of ipsilateral dorsal horn was significantly enhanced, and the peak occurred after 8h. Furthermore, the number of 5-HT(1A) receptor mRNA and GABA or ENK immunoreactive double-labeled cells was also markedly increased 8h after carrageenan injection. These findings suggested that following peripheral inflammation, the synthesis of 5-HT(1A) receptor was increased in the lumbar spinal dorsal horn neurons, especially in spinal GABA and ENK neurons. PMID:12127030

Zhang, Yu-Qiu; Gao, Xiu; Ji, Guang-Chen; Huang, Ya-Lin; Wu, Gen-Cheng; Zhao, Zhi-Qi



5-HT1A receptor-dependent control of nigrostriatal dopamine neurotransmission in the pharmacotherapy of Parkinson's disease and schizophrenia.  


Dysfunctions of the basal ganglia are associated with a number of neurological and psychiatric conditions including Parkinson's disease and schizophrenia. Current treatments of these disorders are mostly symptomatic and inadequate, and are often associated with a number of unwanted side-effects. The striatum, the terminal region of the nigrostriatal dopamine pathway, is the main input nucleus of the basal ganglia, and dopamine neurotransmission through the nigrostriatal pathway plays a crucial role in the modulation of basal ganglia output and mediated behaviors. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the modulation of dopamine neurotransmission and in improving pharmacotherapy in schizophrenia and Parkinson's disease. This review concerns the role of 5-HT1A receptors in the modulation of nigrostriatal dopamine neurotransmission, with the aim of providing guidelines for future research to improve pharmacotherapy. The current state of knowledge suggests that drugs simultaneously targeting dopamine D2 and 5-HT1A receptors may improve pharmacotherapy for schizophrenia and Parkinson's disease. Activation of somatodendritic 5-HT1A receptors in the dorsal raphe nucleus has an important role in the alleviation of extrapyramidal symptoms and levodopa-induced dyskinesia induced by antipsychotic treatment. Drugs acting exclusively through dopamine D2 and 5-HT1A receptors are highly needed to validate the potential role of 5-HT1A receptors in improving therapeutics for Parkinson's disease and schizophrenia. PMID:25503261

Haleem, Darakhshan J



Diurnal rhythm in the levels of the serotonin 5-HT1A receptors in the crayfish eyestalk.  


The crayfish eyestalk (ES) has been postulated as a possible circadian clock. 5-Hydroxytryptamine (5-HT) has been shown to play the role of a neurotransmitter or a modulator in the ES. However, little is known about the 5-HT receptors in the ES. The purpose of this work is to determine the specific binding sites using [(3)H]8-hydroxy-2(di-n-propylamino)tetralin ([(3)H]8-OH-DPAT), a specific agonist of the 5-HT(1A) receptor, and to characterize the diurnal rhythm in the binding by an autoradiography procedure in the crayfish ES. Data show the presence of a circadian rhythmicity in the level of the 5-HT(1A) receptors, principally in two regions: (a) the complex retina (R)-lamina ganglionaris (LG), with the acrophase at dusk and (b) the medulla terminalis (MT), where it was in antiphase. It is suggested that (1) the expression of levels of 5-HT(1A) receptors is modulated by light-dark (LD) cycles, (2) the level of 5-HT(1A) receptors in the R-LG and MT are in antiphase during the 24-h cycle, and (3) there is a different mechanism of action of LD cycles in each of these two anatomical regions of the crayfish ES. PMID:16447179

Calderón-Rosete, Gabina; Flores, Gonzalo; Rodríguez-Sosa, Leonardo



Influence of excitatory amino acids on basal and sensory stimuli-induced release of 5-HT in the locus coeruleus  

PubMed Central

The interactions between 5-hydroxytryptaminergic neurones and excitatory amino acid utilizing neurones were studied in the locus coeruleus of conscious, freely moving rats. The locus coeruleus was superfused with artificial cerebrospinal fluid through a push-pull cannula and 5-hydroxytryptamine (5-HT) was determined in the superfusate that was continuously collected in time periods of 10?min. Superfusion of the locus coeruleus with the NMDA receptor antagonist AP5 (10??M), kynurenic acid (1?mM), or the AMPA/kainate receptor antagonist DNQX (10??M) reduced the 5-HT release in the locus coeruleus. Superfusion with the agonists NMDA (50??M), kainic acid (50??M) or AMPA (10??M) enhanced the release rate of 5-HT. AP5 (10??M) blocked the stimulant effect of NMDA, while tetrodotoxin (1??M) failed to influence the NMDA-induced release of 5-HT. In the presence of 10??M DNQX, the releasing effect of 50??M kainic acid was abolished. Pain elicited by tail pinch, as well as noise-induced stress, increased the release of 5-HT. Superfusion of the locus coeruleus with 10??M AP5 reduced the tail pinch-induced 5-HT release. AP5 (10??M) did not affect the noise-induced release of 5-HT which was reduced, when the locus coeruleus was superfused simultaneously with this concentration of AP5 and 1??M kynurenic acid. DNQX (10?mM) failed to influence the release of 5-HT induced by tail pinch or noise. The findings suggest that 5-hydroxytryptaminergic neurones of the locus coeruleus are tonically modulated by excitatory amino acids via NMDA and AMPA/kainate receptors. The release of 5-HT elicited by tail pinch and noise is mediated to a considerable extent through endogenous excitatory amino acids acting on NMDA receptors, while AMPA/kainate receptors are not involved in this process. PMID:9517395

Singewald, Nicolas; Kaehler, Stefan T; Hemeida, Ramadan; Philippu, Athineos



Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor  

PubMed Central

Exposure to UV radiation induces skin cancer and suppresses the immune response. To induce immune suppression, the electromagnetic energy of UV radiation must be absorbed by an epidermal photoreceptor and converted into a biologically recognizable signal. Two photoreceptors have been recognized: DNA and trans-urocanic acid (UCA). Trans-UCA is normally found in the outermost layer of skin and isomerizes to the cis isomer upon exposure to UV radiation. Although UCA was identified as a UV photoreceptor years ago, and many have documented its ability to induce immune suppression, its exact mode of action remains elusive. Particularly vexing has been the identity of the molecular pathway by which cis-UCA mediates immune suppression. Here we provide evidence that cis-UCA binds to the serotonin [5-hydroxytryptamine (5-HT)] receptor with relatively high affinity (Kd = 4.6 nM). Anti-cis-UCA antibody precipitates radiolabeled 5-HT, and the binding is inhibited by excess 5-HT and/or excess cis-UCA. Similarly, anti-5-HT antibody precipitates radiolabeled cis-UCA, and the binding is inhibited by excess 5-HT or excess cis-UCA. Calcium mobilization was activated when a mouse fibroblast line, stably transfected with the human 5-HT2A receptor, was treated with cis-UCA. Cis-UCA-induced calcium mobilization was blocked with a selective 5-HT2A receptor antagonist. UV- and cis-UCA-induced immune suppression was blocked by antiserotonin antibodies or by treating the mice with 5-HT2A receptor antagonists. Our findings identify cis-UCA as a serotonin receptor ligand and indicate that the immunosuppressive effects of cis-UCA and UV radiation are mediated by activation of the 5-HT2A receptor. PMID:17085585

Walterscheid, Jeffrey P.; Nghiem, Dat X.; Kazimi, Nasser; Nutt, Leta K.; McConkey, David J.; Norval, Mary; Ullrich, Stephen E.



Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 1.  


A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT(1A) receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinity at the 5-HT(1A) receptor and serotonin reuptake inhibition at nanomolar concentrations for dual activities. PMID:12749894

Takeuchi, Kumiko; Kohn, Todd J; Honigschmidt, Nicholas A; Rocco, Vincent P; Spinazze, Patrick G; Koch, Daniel J; Nelson, David L; Wainscott, D Bradley; Ahmad, Laura J; Shaw, Janice; Threlkeld, Penny G; Wong, David T



Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5HT 1A receptor antagonism\\/SSRI activities. Part 1  

Microsoft Academic Search

A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinity at the 5-HT1A receptor and serotonin reuptake inhibition at nanomolar concentrations for dual activities.

Kumiko Takeuchi; Todd J Kohn; Nicholas A Honigschmidt; Vincent P Rocco; Patrick G Spinazze; Daniel J Koch; David L Nelson; D. Bradley Wainscott; Laura J Ahmad; Janice Shaw; Penny G Threlkeld; David T Wong



MDMA Induces EPSP–Spike Potentiation in Rat Ventral Hippocampus In Vitro Via Serotonin and Noradrenaline Release and Coactivation of 5HT4 and ?1 Receptors  

Microsoft Academic Search

It is well documented that N-methyl-3,4-methylenedioxyamphetamine (MDMA, ecstasy) releases brain serotonin (5-HT; 5-hydroxytryptamine), noradrenaline (NE; norepinephrine), and dopamine, but the consequent effect on brain functioning remains elusive. In this study, we characterized the effects of MDMA on electrically evoked responses in the ventral CA1 region of a rat hippocampal slice preparation. Superfusion with MDMA (10 ?M, 30 min) increased the

Boris Mlinar; Simona Mascalchi; Raffaella Morini; Filippo Giachi; Renato Corradetti



Overexpression of 5HT1B Receptor in Dorsal Raphe Nucleus Using Herpes Simplex Virus Gene Transfer Increases Anxiety Behavior after Inescapable Stress  

Microsoft Academic Search

5-HT1B autoreceptors have been implicated in animal models of stress and are regulated selectively by serotonin-selective reuptake inhibitors such as fluoxetine. These terminal autore- ceptors regulate serotonin release from dorsal raphe nucleus (DRN) projections throughout rat forebrain. However, it has not been previously possible to manipulate 5-HT1B autoreceptor activity selectively without also changing 5-HT1B activity in other neurons mediating different

Michael S. Clark; Timothy J. Sexton; Molly McClain; Daniel Root; Ruth Kohen; John F. Neumaier



Advances Toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT(1A) receptor antagonism/SSRI activities. Part 2.  


Potent 5-HT1A/SSRIs at low nanomolar and subnanomolar concentrations were identified in a series of 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols. Incorporation of an alpha-Me group in the piperidine ring with its specific stereochemistry enhanced binding affinity at the 5-HT reuptake site and in vitro 5-HT(1A) antagonist functional activity. PMID:12824042

Takeuchi, Kumiko; Kohn, Todd J; Honigschmidt, Nicholas A; Rocco, Vincent P; Spinazze, Patrick G; Koch, Daniel J; Atkinson, Steven T; Hertel, Larry W; Nelson, David L; Wainscott, D Bradley; Ahmad, Laura J; Shaw, Janice; Threlkeld, Penny G; Wong, David T



Advances Toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5HT 1A receptor antagonism\\/SSRI activities. Part 2  

Microsoft Academic Search

Potent 5-HT1A\\/SSRIs at low nanomolar and subnanomolar concentrations were identified in a series of 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols. Incorporation of an ?-Me group in the piperidine ring with its specific stereochemistry enhanced binding affinity at the 5-HT reuptake site and in vitro 5-HT1A antagonist functional activity.

Kumiko Takeuchi; Todd J Kohn; Nicholas A Honigschmidt; Vincent P Rocco; Patrick G Spinazze; Daniel J Koch; Steven T Atkinson; Larry W Hertel; David L Nelson; D. Bradley Wainscott; Laura J Ahmad; Janice Shaw; Penny G Threlkeld; David T Wong



A novel 5HT 2A receptor antagonist exhibits antidepressant-like effects in a battery of rodent behavioural assays: Approaching early-onset antidepressants  

Microsoft Academic Search

Collective evidence suggests that inhibition of neuronal 5-hydroxytryptamine type 2A (5-HT2A) receptors contributes to the assuagement of depression-like behaviour in rodents. The present study evaluated the antidepressant-like effect of the 5-((4-benzo [?] isothiazol-3-yl) piperazin-1-yl) methyl)-6-chloroindolin-2-one (BIP-1), a compound having affinity to 5-HT2A receptors, using a rodent behavioural test battery. Acute BIP-1 (0.25–4mg\\/kg) pretreatment reduced the quipazine-induced head twitches in mice

Dilip Kumar Pandey; Radhakrishnan Mahesh; Akutota Ashok kumar; V. Sambasiva Rao; Muralidharan Arjun; Ramamoorthy Rajkumar



The Traditional Japanese Medicine Rikkunshito Promotes Gastric Emptying via the Antagonistic Action of the 5-HT3 Receptor Pathway in Rats  

PubMed Central

The traditional Japanese medicine rikkunshito ameliorates the nitric oxide-associated delay in gastric emptying. Whether rikkunshito affects gastric motility associated with 5-hydroxytryptamine (serotonin: 5-HT) receptors or dopamine receptors is unknown. We examined the effects of rikkunshito on the delay in gastric emptying induced by 5-HT or dopamine using the phenol red method in male Wistar rats. 5-HT (0.01–1.0?mg?kg?1, i.p.) dose dependently delayed gastric emptying, similar to the effect of the 5-HT3 receptor agonist 1-(3-chlorophenyl) biguanide (0.01–1.0?mg?kg?1, i.p.). Dopamine also dose dependently delayed gastric emptying. The 5-HT3 receptor antagonist ondansetron (0.04–4.0?mg?kg?1) and rikkunshito (125–500?mg?kg?1) significantly suppressed the delay in gastric emptying caused by 5-HT or 1-(3-chlorophenyl) biguanide. Hesperidin (the most active ingredient in rikkunshito) suppressed the 5-HT-induced delayed gastric emptying in a dose-dependent manner, the maximum effect of which was similar to that of ondansetron (0.4?mg?kg?1). The improvement obtained by rikkunshito or ondansetron in delaying gastric emptying was completely blocked by pretreatment with atropine. Rikkunshito appears to improve delay in gastric emptying via the antagonistic action of the 5-HT3 receptor pathway. PMID:19861508

Tominaga, K.; Kido, T.; Ochi, M.; Sadakane, C.; Mase, A.; Okazaki, H.; Yamagami, H.; Tanigawa, T.; Watanabe, K.; Watanabe, T.; Fujiwara, Y.; Oshitani, N.; Arakawa, T.



Antiphlogistische Wirkung von 5-HT3 Antagonisten.  

E-print Network

??Da in Tierversuchen sowie klinischen Studien festgestellt werden konnte, dass 5-HT3 Antagonisten wie Tropisetron (Navoban®) und Ondansetron (Zofran®) neben einer analgetischen auch eine antiphlogistische Wirkung… (more)

Geyer, Verena Judith



Essential role for orbitofrontal 5-HT1B receptors in OCD-like behavior and SRI response in mice  

PubMed Central

Background Perseveration and sensorimotor gating deficits are core features of obsessive-compulsive disorder (OCD). Serotonin 1B receptor (5-HT1BR) agonists exacerbate OCD symptoms in patients, and induce perseveration and sensorimotor gating deficits in mice. Serotonin reuptake inhibitors (SRIs), but not noradrenaline reuptake inhibitors (NRIs), reduce OCD symptoms following 4–8 weeks of treatment. Using mice, we compared the effects of chronic SRI versus NRI treatment on 5-HT1BR-induced OCD-like behavior, and 5-HT1BR sensitivity in orbitofrontal-subcortical “OCD circuits”. Furthermore, we localized the 5-HT1BR population that mediates OCD-like behavior. Methods Mice chronically received the SRI clomipramine or the NRI desipramine and were examined for 5-HT1BR-induced OCD-like behavior, or 5-HT1BR binding and G-protein-coupling in caudate-putamen, nucleus accumbens, and orbitofrontal cortex. Separate mice were tested for OCD- or depression-like behavior following 4, 14, 21, 28 or 56 days of SRI treatment. Finally, OCD-like behavior was assessed following intra-orbitofrontal 5-HT1BR agonist infusion, or intra-orbitofrontal 5-HT1BR antagonist infusion coupled with systemic 5-HT1BR agonist treatment. Results Effective, but not ineffective, OCD treatments reduced OCD-like behavior in mice with a time-course that parallels the delayed therapeutic onset in OCD patients, and downregulated 5-HT1BR expression in the orbitofrontal cortex. Intra-orbitofrontal 5-HT1BR agonist infusion induced OCD-like behavior, and intra-orbitofrontal 5-HT1BR antagonist infusion blocked OCD-like effects of systemic 5-HT1BR agonist treatment. Conclusions These results indicate that orbitofrontal 5-HT1BRs are necessary and sufficient to induce OCD-like behavior in mice, and that SRI pharmacotherapy reduces OCD-like behavior by desensitizing orbitofrontal 5-HT1BRs. Our findings suggest an essential role for orbitofrontal 5-HT1BRs in OCD pathophysiology and treatment. PMID:21920503

Shanahan, Nancy A; Velez, Lady P; Masten, Virginia L; Dulawa, Stephanie C



Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 5.  


A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT1A receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demonstrated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the initial acute activation of 5-HT1A somatodendritic autoreceptors. PMID:16298130

Takeuchi, Kumiko; Kohn, Todd J; Honigschmidt, Nicholas A; Rocco, Vincent P; Spinazze, Patrick G; Hemrick-Luecke, Susan K; Thompson, Linda K; Evans, David C; Rasmussen, Kurt; Koger, Deanna; Lodge, David; Martin, Laura J; Shaw, Janice; Threlkeld, Penny G; Wong, David T



Reduced sensitivity to both positive and negative reinforcement in mice over-expressing the 5-hydroxytryptamine transporter.  


The 5-hydroxytryptamine (5-HT) transporter (5-HTT) is believed to play a key role in both normal and pathological psychological states. Much previous data suggest that the s allele of the polymorphic regulatory region of the 5-HTT gene promoter is associated with reduced 5-HTT expression and vulnerability to psychiatric disorders, including anxiety and depression. In comparison, the l allele, which increases 5-HTT expression, is generally considered protective. However, recent data link this allele to both abnormal 5-HT signalling and psychopathic traits. Here, we studied the processing of aversive and rewarding cues in transgenic mice that over-express the 5-HTT (5-HTTOE mice). Compared with wild-type mice, 5-HTTOE mice froze less in response to both a tone that had previously been paired with footshock, and the conditioning context. In addition, on a decision-making T-maze task, 5-HTTOE mice displayed reduced preference for a larger, delayed reward and increased preference for a smaller, immediate reward, suggesting increased impulsiveness compared with wild-type mice. However, further inspection of the data revealed that 5-HTTOE mice displayed a relative insensitivity to reward magnitude, irrespective of delay. In contrast, 5-HTTOE mice appeared normal on tests of spatial working and reference memory, which required an absolute choice between options associated with either reward or no reward. Overall, the present findings suggest that 5-HTT over-expression results in a reduced sensitivity to both positive and negative reinforcers. Thus, these data show that increased 5-HTT expression has some maladaptive effects, supporting recent suggestions that l allele homozygosity may be a potential risk factor for disabling psychiatric traits. PMID:25283165

Line, Samantha J; Barkus, Chris; Rawlings, Nancy; Jennings, Katie; McHugh, Stephen; Sharp, Trevor; Bannerman, David M



Serotonin (5-HT3) receptor antagonists for the reduction of symptoms of low anterior resection syndrome  

PubMed Central

Purpose Serotonin (5-hydroxytryptamine [5-HT])3 receptor antagonists are effective for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), in which exaggerated intestinal/colonic hypermotility is often observed. Recent studies have suggested that the motility disorder, especially spastic hypermotility, seen in the neorectum following sphincter-preserving operations for rectal cancer may be the basis of the postoperative defecatory malfunction seen in these patients. We investigated the efficacy of 5-HT3 receptor antagonists in patients suffering from severe low anterior resection syndrome. Patients and methods A total of 25 male patients with complaints of uncontrollable urgency or fecal incontinence following sphincter-preserving operations were enrolled in this study. Defecatory status, assessed on the basis of incontinence score (0–20), urgency grade (0–3), and number of toilet visits per day, was evaluated using a questionnaire before and 1 month after the administration of the 5-HT3 antagonist ramosetron. Results All the parameters assessed improved significantly after taking ramosetron for 1 month. The effect was more prominent in cases whose anastomotic line was lower, ie, inside the anal canal. Defecatory function was better in patients who commenced ramosetron therapy within 6 months postoperatively, as compared to those who were not prescribed ramosetron for more than 7 months postoperatively. Conclusion These results suggest that 5-HT3 antagonists are effective for the treatment of low anterior resection syndrome, as in diarrhea-predominant irritable bowel syndrome. The improvement in symptoms is not merely time dependent, but it is related to treatment with 5-HT3 antagonists. PMID:24648748

Itagaki, Ryohei; Koda, Keiji; Yamazaki, Masato; Shuto, Kiyohiko; Kosugi, Chihiro; Hirano, Atsushi; Arimitsu, Hidehito; Shiragami, Risa; Yoshimura, Yukino; Suzuki, Masato



Antagonist interaction with the human 5-HT7 receptor mediates the rapid and potent inhibition of non-G-protein-stimulated adenylate cyclase activity: a novel GPCR effect  

PubMed Central

BACKGROUND AND PURPOSE The human 5-hydroxytryptamine7 (h5-HT7) receptor is Gs-coupled and stimulates the production of the intracellular signalling molecule cAMP. Previously, we reported a novel property of the h5-HT7 receptor: pseudo-irreversible antagonists irreversibly inhibit forskolin-stimulated (non-receptor-mediated) cAMP production. Herein, we sought to determine if competitive antagonists also affect forskolin-stimulated activity and if this effect is common among other Gs-coupled receptors. EXPERIMENTAL APPROACH Recombinant cell lines expressing h5-HT7 receptors or other receptors of interest were briefly exposed to antagonists; cAMP production was then stimulated by forskolin and quantified by an immunocompetitive assay. KEY RESULTS In human embryonic kidney 293 cells stably expressing h5-HT7 receptors, all competitive antagonists inhibited nearly 100% of forskolin-stimulated cAMP production. This effect was insensitive to pertussis toxin, that is, not Gi/o-mediated. Potency to inhibit forskolin-stimulated activity strongly correlated with h5-HT7 binding affinity (r2= 0.91), indicating that the antagonists acted through h5-HT7 receptors to inhibit forskolin. Potency and maximal effects of clozapine, a prototypical competitive h5-HT7 antagonist, were unaffected by varying forskolin concentration. Antagonist interaction with h5-HT6, human ?1, ?2, and ?3 adrenoceptors did not inhibit forskolin's activity. CONCLUSIONS AND IMPLICATIONS The inhibition of adenylate cyclase, as measured by forskolin's activity, is an underlying property of antagonist interaction with h5-HT7 receptors; however, this is not a common property of other Gs-coupled receptors. This phenomenon may be involved in the roles played by h5-HT7 receptors in human physiology. Development of h5-HT7 antagonists that do not elicit this effect would aid in the elucidation of its mechanisms and shed light on its possible physiological relevance. PMID:21198551

Klein, MT; Teitler, M



Pharmacological characterization of 8-OH-DPAT-induced inhibition of rat hippocampal 5-HT release in vivo as measured by microdialysis.  

PubMed Central

1. We have previously found that the putative 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) decreases hippocampal 5-hydroxytryptamine (5-HT) release in the anaesthetized rat, as measured by brain microdialysis. The present study attempted to characterize the receptor involved in this response using a range of monoamine receptor antagonists. 2. The classical 5-HT receptor antagonists, metergoline (5 mg kg-1 s.c.), methysergide (10 mg kg-1 s.c.) and methiothepin (10 mg kg-1 s.c.) each reduced dialysate levels of 5-HT which complicated their use as antagonists in these experiments. Nevertheless, pretreatment with metergoline but not methiothepin and methysergide partially reduced the 5-HT response to a maximally effective dose of 8-OH-DPAT (0.25 mg kg-1 s.c.). 3. The mixed 5-HT 1/beta-adrenoceptor antagonist pindolol (8 mg kg-1 s.c.) was without effect on spontaneous 5-HT output but attenuated the effect of both maximally (0.25 mg kg-1 s.c.) and submaximally (0.05 mg kg-1 s.c.) effective dose of 8-OH-DPAT. In comparison, propranolol (10 mg kg-1 s.c.) did not affect 5-HT output when injected alone and did not alter the response to 8-OH-DPAT (0.25 mg kg-1 s.c.). 4. The 5-HT2 receptor antagonist ritanserin (0.2 mg kg-1 s.c.) and the 5-HT3 receptor antagonist BRL 43694 (0.5 mg kg-1 s.c.) neither altered 5-HT output alone nor significantly changed the response to 8-OH-DPAT (0.25 mg kg-1 s.c.).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2574066

Sharp, T.; Bramwell, S. R.; Hjorth, S.; Grahame-Smith, D. G.



Platelet-induced neurogenic coronary contractions due to accumulation of the false neurotransmitter, 5-hydroxytryptamine.  

PubMed Central

The purpose of this study was to determine if 5-hydroxytryptamine released from aggregating platelets could be accumulated and released by canine coronary adrenergic nerves, and if the false neurotransmitter resulted in an abnormal response of the smooth muscle to nerve stimulation. Isometric tension was measured in rings of epicardial coronary suspended in organ chambers filled with physiological salt solution. The response to electrical stimulation or exogenously added norepinephrine was elicited after contraction with prostaglandin F2 alpha. Electrical stimulation and exogenous norepinephrine caused beta-adrenergic relaxation of control rings. However, after rings were exposed for 2 h to aggregating platelets or 5-hydroxytryptamine, electrical stimulation caused frequency-dependent contractions. These contractions were prevented by the serotonergic antagonists, cyproheptadine or ketanserin, or by the neuronal uptake inhibitor, cocaine. The relaxation caused by exogenously added norepinephrine was unchanged after exposure to platelets or 5-hydroxytryptamine, indicating that smooth muscle alpha- and beta-adrenergic responsiveness was unchanged. The electrically stimulated overflow of radiolabeled norepinephrine from superfused strips of coronary artery was not altered by prior exposure to 5-hydroxytryptamine, indicating that the effect of exposure on the response to electrical stimulation is primarily at smooth muscle serotonergic receptors. Canine coronary arteries accumulated and metabolized radiolabeled 5-hydroxytryptamine in vitro. The accumulation of 5-hydroxytryptamine was inhibited by cocaine or by adrenergic denervation with 6-hydroxydopamine but unaffected by removal of endothelium, indicating that the adrenergic nerves were the primary site of accumulation. Electrical stimulation of superfused strips of coronary artery preincubated with radiolabeled 5-hydroxytryptamine caused the release of the intact indoleamine; this was blocked by the neurotoxin, tetrodotoxin. These studies suggest that 5-hydroxytryptamine liberated from aggregating platelets may be accumulated by coronary adrenergic nerve endings. Upon its release from the nerves as a false transmitter, the amine can activate serotonergic receptors on the smooth muscle and reverse the action of the adrenergic nerves from dilator to constrictor. Images PMID:3965509

Cohen, R A



QGP-1 cells release 5-HT via TRPA1 activation; a model of human enterochromaffin cells.  


Recently, we discovered that transient receptor potential ankyrin1 channel (TRPA1) is highly expressed in human and rat enterochromaffin (EC) cells, and those TRPA1 agonists such as allyl isothiocyanates (AITC) and cinnamaldehyde (CA) enhance the release of serotonin (5-hydroxytryptamine; 5-HT) from EC cells in vitro. In this study, QGP-1 cells, a human pancreatic endocrine cell line, were found to highly express TRPA1 and EC cell marker genes, such as tryptophan hydroxylase 1 (TPH1), chromogranin A (CgA), synaptophysin, ATP-dependent vesicular monoamine transporter 1 (VMAT1), metabotropic glutamate receptor 4 (mGluR4), beta1-adrenergic receptor (ADB1), muscarinic 4 acetylcholine receptor (ACM4), substance P, serotonin transporter (SERT), and guanylin. Furthermore, the TRPA1 agonists AITC, CA, and acrolein concentration dependently evoked an increase in intracellular Ca(2+) influx and the release of 5-HT in QGP-1 cells. The effects of these TRPA1 agonists were inhibited by ruthenium red, a TRPA1 antagonist, and TRPA1-specific siRNA. These results indicate that the Ca(2+) influx increase and 5-HT release induced by AITC, CA and acrolein in QGP-1 cells were mediated by TRPA1, and that the QGP-1 cell line could be a new model for the investigation of TRPA1 function in the human EC cell. PMID:19507004

Doihara, Hitoshi; Nozawa, Katsura; Kojima, Ryosuke; Kawabata-Shoda, Eri; Yokoyama, Toshihide; Ito, Hiroyuki



Low-dose prazosin in combination with 5-HT6 antagonist PRX-07034 has antipsychotic effects.  


An extensive amount of research has focused on the development of new pharmacological agents to treat schizophrenia. Varying from person to person, schizophrenia is a heterogeneous disease with symptoms of positive, negative, and cognitive deficits. PRX-07034, a 5-hydroxytryptamine6 (5-HT6) receptor antagonist has been evaluated for its potential in treating obesity and cognitive deficits. This study evaluated PRX-07034 (0.1, 0.3, and 1.0 mg/kg body mass, by intraperitoneal (i.p.) injection), in combination with a low dose of prazosin (0.3 mg/kg, i.p.), for its antipsychotic potential. The research utilized a stereotypy assay, an open field test, an object recognition task, and prepulse inhibition. Dizocilpine, a non-competitive N-methyl-d-aspartate (NMDA) antagonist, was also administered in the above-mentioned assays as a psychomimetic. The combination of PRX-07034 and prazosin alleviated stereotypy and hyperlocomotor activity while enhancing memory in an object recognition task, and reversed sensory-gating deficits induced by dizocilpine. Examination of the medial prefrontal cortex revealed that a combination of PRX-07034 and prazosin reduced the dizocilpine-mediated increase of 5-HT. These results suggest that the combination of a 5-HT6 antagonist with low doses of prazosin could have therapeutic potential in the treatment of schizophrenia. PMID:25429515

Abraham, Renny; Nirogi, Ramakrishna; Shinde, Anil; Irupannanavar, Shantaveer



The Type 7 Serotonin Receptor, 5-HT7, Is Essential in the Mammary Gland for Regulation of Mammary Epithelial Structure and Function  

PubMed Central

Autocrine-paracrine activity of serotonin (5-hydroxytryptamine, 5-HT) is a crucial homeostatic parameter in mammary gland development during lactation and involution. Published studies suggested that the 5-HT7 receptor type was important for mediating several effects of 5-HT in the mammary epithelium. Here, using 5-HT7 receptor-null (HT7KO) mice we attempt to understand the role of this receptor in mediating 5-HT actions within the mammary gland. We demonstrate for the first time that HT7KO dams are inefficient at sustaining their pups. Histologically, the HT7KO mammary epithelium shows a significant deviation from the normal secretory epithelium in morphological architecture, reduced secretory vesicles, and numerous multinucleated epithelial cells with atypically displaced nuclei, during lactation. Mammary epithelial cells in HT7KO dams also display an inability to transition from lactation to involution as normally seen by transition from a columnar to a squamous cell configuration, along with alveolar cell apoptosis and cell shedding. Our results show that 5-HT7 is required for multiple actions of 5-HT in the mammary glands including core functions that contribute to changes in cell shape and cell turnover, as well as specialized secretory functions. Understanding these actions may provide new interventions to improve lactation performance and treat diseases such as mastitis and breast cancer. PMID:25664318

Pai, Vaibhav P.; Hernandez, Laura L.; Stull, Malinda A.; Horseman, Nelson D.



Suppressive Effects of D-Glucosamine on the 5-HT Sensitive Nociceptive Units in the Rat Tooth Pulpal Nerve  

PubMed Central

It is well known that D-glucosamine hydrochloride (DGL) has a variety of biological activities and is regarded as a nutritional supplement effective in improving various disorders, including osteoarthritis and atherosclerosis. Although it has been reported that DGL has a significant pain relief effect in treating osteoarthritis, little is known about the characteristics of the effects of this compound on dental pain. The present study was undertaken to evaluate the applicability of DGL as a medicament to control pulpalgia. Using an in vitro rat mandible-inferior alveolar nerve preparation (jaw-nerve preparation), we evaluated the effects of DGL on 5-hydroxytryptamine (5-HT) sensitive nociceptive responses in the tooth pulpal nerve. 5-HT-induced nociceptive responses were fairly suppressed by direct application of DGL, suggesting that DGL have a pain relief effect on patients with dental pain. PMID:24818130

Kaida, Kei; Yamashita, Hiromi; Toda, Kazuo



The Pharmacology of TD-8954, a Potent and Selective 5-HT4 Receptor Agonist with Gastrointestinal Prokinetic Properties  

PubMed Central

This study evaluated the in vitro and in vivo pharmacological properties of TD-8954, a potent and selective 5-HT4 receptor agonist. TD-8954 had high affinity (pKi?=?9.4) for human recombinant 5-HT4(c) (h5-HT4(c)) receptors, and selectivity (>2,000-fold) over all other 5-hydroxytryptamine (5-HT) receptors and non-5-HT receptors, ion channels, enzymes and transporters tested (n?=?78). TD-8954 produced an elevation of cAMP in HEK-293 cells expressing the h5-HT4(c) receptor (pEC50?=?9.3), and contracted the guinea pig colonic longitudinal muscle/myenteric plexus preparation (pEC50?=?8.6). TD-8954 had moderate intrinsic activity in the in vitro assays. In conscious guinea pigs, subcutaneous administration of TD-8954 (0.03–3?mg/kg) increased the colonic transit of carmine red dye, reducing the time taken for its excretion. Following intraduodenal dosing to anesthetized rats, TD-8954 (0.03–10?mg/kg) evoked a dose-dependent relaxation of the esophagus. Following oral administration to conscious dogs, TD-8954 (10 and 30??g/kg) produced an increase in contractility of the antrum, duodenum, and jejunum. In a single ascending oral dose study in healthy human subjects, TD-8954 (0.1–20?mg) increased bowel movement frequency and reduced the time to first stool. It is concluded that TD-8954 is a potent and selective 5-HT4 receptor agonist in vitro, with robust in vivo stimulatory activity in the gastrointestinal (GI) tract of guinea pigs, rats, dogs, and humans. TD-8954 may have clinical utility in patients with disorders of reduced GI motility. PMID:21687517

Beattie, David T.; Armstrong, Scott R.; Vickery, Ross G.; Tsuruda, Pamela R.; Campbell, Christina B.; Richardson, Carrie; McCullough, Julia L.; Daniels, Oranee; Kersey, Kathryn; Li, Yu-Ping; Kim, Karl H. S.



Prevention of 5-hydroxytryptamine2C receptor RNA editing and alternate splicing in C57BL/6 mice activates the hypothalamic-pituitary-adrenal axis and alters mood  

PubMed Central

The 5-hydroxytryptamine2C (5-HT)2C receptor is widely implicated in the aetiology of affective and eating disorders as well as regulation of the hypothalamo-pituitary-adrenal axis. Signalling through this receptor is regulated by A-to-I RNA editing, affecting three amino acids in the protein sequence, with unedited transcripts encoding a receptor (INI) that, in vitro, is hyperactive compared with edited isoforms. Targeted alteration (knock-in) of the Htr2c gene to generate ‘INI’ mice with no alternate splicing, solely expressing the full-length unedited isoform, did not produce an overt metabolic phenotype or altered anxiety behaviour, but did display reduced depressive-like and fear-associated behaviours. INI mice exhibited a hyperactive hypothalamo-pituitary-adrenal axis, with increased nadir plasma corticosterone and corticotrophin-releasing hormone expression in the hypothalamus but responded normally to chronic stress and showed normal circadian activity and activity in a novel environment. The circadian patterns of 5-HT2C receptor mRNA and mbii52, a snoRNA known to regulate RNA editing and RNA splicing of 5-HT2C receptor pre-mRNA, were altered in INI mice compared with wild-type control mice. Moreover, levels of 5-HT1A receptor mRNA were increased in the hippocampus of INI mice. These gene expression changes may underpin the neuroendocrine and behavioural changes observed in INI mice. However, the phenotype of INI mice was not consistent with a globally hyperactive INI receptor encoded by the unedited transcript in the absence of alternate splicing. Hence, the in vivo outcome of RNA editing may be neuronal cell type specific. PMID:25257581

Bombail, Vincent; Qing, Wei; Chapman, Karen E; Holmes, Megan C



The murine serotonin syndrome - evaluation of responses to 5-HT-enhancing drugs in NMRI mice.  


In humans, the ingestion of the combination of two or more serotonin (5-HT)-enhancing drugs but also of a single drug in overdose can induce serious adverse effects, which are characteristics of the serotonin syndrome (SS). In mice, acute administration of direct and indirect 5-HT agonists also leads to behavioral and autonomic responses, but in literature different responses are thought to be essential. In order to detect common behavioral SS responses induced by 5-HT-enhancing drugs with different mechanisms of action, we investigated the effects of the 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX), and the monoaminooxidase (MAO) inhibitor tranylcypromine (TCP) in male NMRI mice. The drugs were administered alone or in combination to investigate additive effects or drug potentiation. Moreover, we compared the 5-HT responses to the effects induced by the dopamine, noradrenaline, and cholinergic agonists, apomorphine (APO), atomoxetine (ATO), and oxotremorine (OXO). Our results show that the studied 5-HT-enhancing drugs induced a different number of concomitant responses. The following five responses consistently and dose-dependently occurred in NMRI mice: flat body posture, hindlimb abduction, piloerection, tremor, and decreased rearings. Like in humans, the combination of 5-HT-enhancing drugs leads to a potentiation of drug effects. With the exception of flat body posture the responses are not specific for serotonergic hyperactivity. The findings demonstrate that the SS in NMRI mice is a suitable animal model for preclinical research, if it is taken into account that the spectrum of typical responses to 5-HT enhancing drugs may differ depending on drug and mouse strain and that some responses might be evoked by activation of other transmission systems, too. PMID:24780865

Haberzettl, Robert; Fink, Heidrun; Bert, Bettina



Short communication: Circulating serotonin (5-HT) concentrations on day 1 of lactation as a potential predictor of transition-related disorders.  


The monoamine serotonin (5-hydroxytryptamine; 5-HT) has been described as a homeostatic regulator of lactation. Recently, our laboratory determined that 5-HT is involved in the regulation of calcium and glucose homeostasis during the transition period in rodents. More specifically, we demonstrate that 5-HT is responsible for calcium mobilization from bone and upregulation of hepatic gluconeogenic enzymes and mammary gland glucose transporters. Our objective was to investigate the correlation between circulating 5-HT concentrations and circulating ionized calcium, parathyroid hormone-related protein (PTHrP), and glucose concentrations on d 1 postpartum. We also investigated the correlation between circulating 5-HT and milk fever and ketosis incidence and severity in multiparous Holstein cows at the onset of lactation. Blood samples were collected from 42 multiparous cows on d 1 of lactation and analyzed for 5-HT, calcium, glucose, and PTHrP. Milk fever (determined subjectively for each cow on d 1 postpartum) and ketosis incidence and severity (scale 1 to 4, determined objectively for each cow during the first 10 d postpartum) were recorded for all animals. Serum 5-HT was positively correlated with serum calcium and with plasma PTHrP (r>0.37). Serum 5-HT was negatively correlated with milk fever incidence and with ketosis severity (most severe ketosis incidence recorded during the first 10 d postpartum; r<-0.33). Serum calcium and plasma glucose concentrations were negatively correlated with milk fever and ketosis severity, respectively (r<-0.39). These data indicate that 5-HT potentially plays a role in the regulation of calcium and glucose homeostasis during the transition period in cattle, which we previously demonstrated in rodents. Increased circulating concentrations of 5-HT might decrease milk fever at the onset of lactation and ketosis severity during the first 10 d postpartum in dairy cows. Understanding this physiological axis could help describe the underlying mechanisms associated with these periparturient metabolic disorders in dairy cows. PMID:23746592

Laporta, J; Moore, S A E; Peters, M W; Peters, T L; Hernandez, L L



Antidepressants are functional antagonists at the serotonin type 3 (5HT3) receptor  

Microsoft Academic Search

Antidepressants are commonly supposed to enhance serotonergic and\\/or noradrenergic neurotransmission by inhibition of neurotransmitter reuptake through binding to the respective neurotransmitter transporters or through inhibition of the monoamine oxidase. Using the concentration-clamp technique and measurements of intracellular Ca2+, we demonstrate that different classes of antidepressants act as functional antagonists at the human 5-HT3A receptor stably expressed in HEK 293 cells

B Eisensamer; G Rammes; G Gimpl; M Shapa; U Ferrari; G Hapfelmeier; B Bondy; C Parsons; K Gilling; W Zieglgänsberger; F Holsboer; R Rupprecht



Mutant 5-hydroxytryptamine 1A receptor D116A is a receptor activated solely by synthetic ligands with a rich pharmacology.  


Like other biogenic amine G protein-coupled receptors, mutation of the conserved aspartatic residue into alanine at position 116 (D116A(3.32)) in the 5-hydroxytryptamine (5-HT)(1A) receptor greatly affects 5-HT binding and signal transduction. [(3)H]8-Hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and [(3)H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100,635) are capable to bind the 5-HT(1A)-D116A mutant and, using these radioligands, we show here that this mutation dramatically reduces the affinities of the selective 5-HT(1A) agonists N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methylpyridin-2-yl)-methylamino methyl]piperidine (F13640), 3-chloro-4-fluorophenyl-(4-fluorophenyl-4-{[(5-methyl-6 methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone (F13714), and 2-[5-[3-(4-methylsulfonylamino)benzyl-1,4-oxadiazol-5-yl]-1H-indole-3-yl]ethylamine (L694247) and that of 5-carboxamidotryptamine. Although to a lesser extent, the binding of buspirone, (+)-flesinoxan, (-)-pindolol, and (-)-8-OH-DPAT are also highly decreased. In contrast, affinities of the 5-HT(1A) ligands WAY100,635, spiperone, (-)-4-(dipropylamino)-1,3,4,5-tetrahydrobenz {c,d}indole-6-carboxamide (LY228,729), and 1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl) piperazine (S14506) and the prototypical 5-HT(1A) agonist (+)-8-OH-DPAT are only slightly affected by the mutation, suggesting a moderate contribution of Asp116 to the binding pocket for these latter. Furthermore, LY228,729, S14506, and (+)-8-OH-DPAT induce a potent and efficacious coupling of the 5-HT(1A)-D116A receptor to G protein activation as measured by Ca(2+) mobilization and guanosine 5'-O-(3-[(35)S]thio)triphosphate binding in Chinese hamster ovary cells as well as by G protein-coupled inwardly rectifying potassium channel current activation in Xenopus laevis oocytes. It is interesting that the selective 5-HT(1A) antagonist WAY100,635 shows potent partial agonist activity at the 5-HT(1A)-D116A mutant, whereas spiperone maintains its inverse agonist properties. The pharmacological approach reported here re-evaluates the binding and functional properties of the 5-HT(1A)-D116A receptor and describes for the first time this mutant as a receptor activated solely by synthetic ligands (RASSL), with a rich pharmacology. By bioengineering animal models incorporating this RASSL, one may further explore the role of 5-HT(1A) receptor signaling in the central nervous system as well as G(i) protein-mediated signaling pathways in other tissues. PMID:19605522

Cussac, Didier; Palmier, Christiane; Finana, Frédéric; De Vries, Luc; Tardif, Stéphanie; Léger, Céline; Bernois, Sophie; Heusler, Peter



5-Hydroxytryptamine synthesis in HL-1 cells and neonatal rat cardiocytes  

E-print Network

in HL-1 cardiomyocytes and neonatal rat cardio- myocytes (MCs), not in NMCs. mRNAs of 5-HT2A receptor were detected in both MCs and NMCs, and those of 5-HT2B receptor in NMCs. These findings definitively- iology [1­4]. We previously showed that sarpogrelate, a specific inhibitor of 5-HT2A receptor, attenuated

Wojcik, Edward J.


5-HT4 receptor agonists enhance both cholinergic and nitrergic activities in human isolated colon circular muscle.  


Previous studies have demonstrated mixed inhibitory and facilitatory effects of 5-hydroxytryptamine-4 (5-HT(4)) receptor agonists on electrical field stimulation (EFS)-induced responses in human isolated colon. Here we report three types of responses to EFS in human isolated colon circular muscle: monophasic cholinergic contraction during EFS, biphasic response (nitrergic relaxation during EFS followed by cholinergic contraction after termination of EFS) and triphasic response (cholinergic contraction followed by nitrergic relaxation during EFS and a tachykininergic contraction after EFS). The effects of two 5-HT(4) receptor agonists, prucalopride and tegaserod were then investigated on monophasic responses only. Each compound inhibited contractions during EFS in a concentration-dependent manner. In the presence of N(omega)-nitro-l-arginine methyl ester (l-NAME) however, prucalopride and tegaserod enhanced the contractions in a concentration-dependent manner. In strips where the tone was elevated with substance-P and treated with scopolamine, EFS-induced relaxations were enhanced by the two agonists. The above observed effects by the two agonists were abolished by 5-HT(4) receptor antagonist SB-204070. The two agonists did not alter the tone raised by substance-P in the presence of scopolamine and l-NAME and did not affect carbachol-induced contractions in the presence of tetrodotoxin. These results suggest that in the circular muscle of human colon, 5-HT(4) receptor agonists simultaneously facilitate the activity of neurones which release the inhibitory and excitatory neurotransmitters, nitric oxide and acetylcholine respectively. PMID:16918765

Cellek, S; John, A K; Thangiah, R; Dass, N B; Bassil, A K; Jarvie, E M; Lalude, O; Vivekanandan, S; Sanger, G J



Changes in the 5-hydroxytryptamine content of rat, rabbit and human brain after death  

PubMed Central

The fall in 5-hydroxytryptamine concentration which occurs in brain tissues in the first 48 hr after death varies in different areas of the brain and is of the same order of magnitude in those areas of the rat and rabbit in which it was estimated, namely, hypothalamus, hippocampal gyrus and frontal cortex, and also in human frontal cortex. The loss of 5-hydroxytryptamine is greater in the hypothalamus than in the cerebral cortex. The extent of this change depends on the temperature and conditions of storage of tissues. It is least in tissues which remain within the skull after death before chemical extraction and in tissues stored at —17° C. Comparison of cerebral 5-hydroxytryptamine content in control animals and animals pretreated with iproniazid suggests that the differences are for the greater part due to the action of mono-amine oxidase. PMID:14452643

Joyce, Daphné



Association of the C(-1019)G 5-HT1A functional promoter polymorphism with antidepressant response.  


Antidepressants, such as serotonin or noradrenaline reuptake inhibitors (e.g. fluoxetine, nefadozone) or 5-HT1A agonists (flibanserin), desensitize the 5-HT1A autoreceptor, which may contribute to their clinical efficacy. The 5-HT1A receptor gene is repressed by NUDR/DEAF-1 in raphe cells at the C-, but not at the G-allele of the C(-1019)G polymorphism that is associated with major depression and suicide. Depressed patients (n=118) were treated with antidepressants including fluoxetine or nefadozone combined with pindolol or flibanserin alone. The severity of depression was assesssed using the Hamilton Rating Scale for Depression. Although patients had similar severity initially, those with the homozygous G(-1019) genotype responded significantly less to flibanserin (p=0.039) and in pooled antidepressant treatment groups (p=0.0497) and were approximately twice as likely to be non-responders as those with the C(-1019)C genotype. These results implicate the C(-1019)G 5-HT1A gene polymorphism as a potential marker for antidepressant response, suggesting a role for repression of the 5-HT1A gene. PMID:15447813

Lemonde, Sylvie; Du, Lisheng; Bakish, David; Hrdina, Pavel; Albert, Paul R



Cerebral 5-HT2A receptor binding, but not mGluR2, is increased in tryptophan hydroxylase 2 decrease-of-function mice  

PubMed Central

Transgenic mice with knock-in (KI) of a tryptophan hydroxylase 2 (Tph2) R439H mutation, analogous to the Tph2 R441H single-nucleotide polymorphism originally identified in a late life depression cohort, have markedly reduced levels of 5-hydroxytryptamine (5-HT). These Tph2KI mice are therefore interesting as a putative translational model of low endogenous 5-HT function that allows for assessment of adaptive changes in different anatomical regions. Here, we determined 5-HT2A receptor binding in several brain regions using in vitro receptor autoradiography and two different radioligands. When using the 5-HT2A receptor selective antagonist radioligand 3H-MDL100907, we found higher binding in the prefrontal cortex (10%, P=0.009), the striatum (26%, P=0.005), and the substantia nigra (21%, P=0.027). The increase was confirmed in the same regions with the 5-HT2A/C receptor agonist, 3H-CIMBI-36 (2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine). 5-HT2A receptors establish heteromeric functional receptor complexes with metabotropic glutamate 2 receptors (mGluR2), but binding levels of the mGluR2/3 ligand 3H-LY341495 were unaltered in brain areas with increased 5-HT2A receptor levels. These data show that in distinct anatomical regions, 5-HT2A receptor binding sites are up-regulated in 5-HT deficient mice, and this increase is not associated with changes in mGluR2 binding. PMID:24055299

Jørgensen, Christinna V; Jacobsen, Jacob P; Caron, Marc G; Klein, Anders Bue; Knudsen, Gitte M; Mikkelsen, Jens D



Peripheral 5-HT2A receptor antagonism attenuates primary thermal hyperalgesia and secondary mechanical allodynia after thermal injury in rats.  


Inflammation or injury of peripheral tissue causes release of chemical mediators, including 5-hydroxytryptamine (5-HT), which is involved in the facilitation of nociceptive transmission and the induction of hyperalgesia. The present study examined the effect of a selective 5-HT2A receptor antagonist, sarpogrelate, on hyperalgesia and allodynia induced by thermal injury in rats. Mild thermal injury to the hindpaw produces thermal hyperalgesia in the injured area (primary thermal hyperalgesia) and mechanical allodynia in sites adjacent to the primary area (secondary mechanical allodynia). Mechanical allodynia was assessed by paw withdrawal thresholds using von Frey filaments, and thermal hyperalgesia was assessed by paw withdrawal latencies upon exposure to a radiant heat source. Intraperitoneal administration (30-100 mg/kg) or local injection (30-300 microg) of sarpogrelate 10 min prior to thermal injury attenuated secondary mechanical allodynia in a dose-dependent manner. Intraperitoneal administration (3-100 mg/kg) or local injection (30-300 microg) of sarpogrelate 10 min prior to thermal injury attenuated primary thermal hyperalgesia in a dose-dependent manner. Intraplantar injection of sarpogrelate (300 microg) to the contralateral hindpaw had no effect on primary thermal hyperalgesia or secondary mechanical allodynia in the ipsilateral paw. The tissue concentration of 5-HT was measured using microdialysis. Concentrations of 5-HT increased after thermal injury in both primary and secondary areas, and the increase was not attenuated by pretreatment with sarpogrelate (100 mg/kg, i.p.). These data suggest that 5-HT released in peripheral tissues after thermal injury sensitizes primary afferent neurons and produces mechanical allodynia and thermal hyperalgesia via peripheral 5-HT2A receptors. PMID:16527395

Sasaki, Masayuki; Obata, Hideaki; Kawahara, Kunie; Saito, Shigeru; Goto, Fumio



Pharmacological profile of engineered 5-HT? receptors and identification of 5-HT? receptor-biased ligands.  


G protein-coupled receptors (GPCRs) can activate simultaneously multiple signaling pathways upon agonist binding. The combined use of engineered GPCRs, such as the receptors activated solely by synthetic ligands (RASSLs), and of biased ligands that activate only one pathway at a time might help deciphering the physiological role of each G protein signaling. In order to find serotonin type 4 receptor (5-HT?R) biased ligands, we analyzed the ability of several compounds to activate the Gs and G(q/11) pathways in COS-7 cells that transiently express wild type 5-HT?R, the 5-HT?R-D(100)A mutant (known also as 5-HT?-RASSL, or Rs1) or the 5-HT?R-T(104)A mutant, which modifies agonist-induced 5-HT?R activation. This analysis allowed completing the pharmacological profile of the two mutant 5-HT?Rs, but we did not find any biased ligand for the mutant receptors. Conversely, we identified the first biased agonists for wild type 5-HT?R. Indeed, RS 67333 and prucalopride acted as partial agonists to induce cAMP accumulation, but as antagonists on inositol phosphate production. Moreover, they showed very different antagonist potencies that could be exploited to study the activation of the G(s) pathway, with or without concomitant block of G(q/11) signaling. This article is part of a Special Issue entitled Optogenetics (7th BRES). PMID:23148949

Gaven, Florence; Pellissier, Lucie P; Queffeulou, Emilie; Cochet, Maud; Bockaert, Joël; Dumuis, Aline; Claeysen, Sylvie



Vasomotor effects of acetylcholine, bradykinin, noradrenaline, 5-hydroxytryptamine, histamine and angiotensin II on the mouse basilar artery.  


We investigated the responsiveness of the mouse basilar artery to acetylcholine (ACh), bradykinin (BK), noradrenaline (NA), 5-hydroxytryptamine (5-HT), histamine (His) and angiotensin (Ang) II in order to characterize the related receptor subtypes in vitro. ACh and BK induced endothelium-dependent relaxation of precontracted arteries with U-46619 (a thromboxane A2 analogue). Atropine (a non-selective muscarinic receptor antagonist) and N?-nitro-L-arginine (a NO synthase inhibitor, L-NNA) shifted the concentration-response curve for ACh to the right, whereas pirenzepine, methoctramine and pFHHSiD (muscarinic M1, M2 and M3 antagonists, respectively) had no significant effect. L-NNA and HOE140 (a B2 antagonist) shifted the concentration-response curve for BK to the right, whereas des-Arg(9)-[Leu(8)]-BK (a B1 antagonist) and indomethacin (a cyclooxygenase inhibitor) had no significant effect. NA failed to produce any vasomotor action. His and Ang II induced concentration-dependent contraction. Diphenhydramine (a H1 antagonist) shifted the concentration-response curve for His to the right, whereas cimetidine (a H2 antagonist) had no significant effect. Losartan (an AT1 antagonist) shifted the concentration-response curve for Ang II to the right, whereas PD123319 (an AT2 antagonist) had no significant effect. These results suggest that the H1 and AT1 receptor subtypes might play an important role in arterial contraction, whereas muscarinic receptor subtypes apart from M1, M2 and M3, and B2 receptors on the endothelium, might modify these contractions to relaxations. PMID:24942113

Islam, Md Zahorul; Watanabe, Yutaka; Nguyen, Ha Thi Thanh; Yamazaki-Himeno, Emi; Obi, Takeshi; Shiraishi, Mitsuya; Miyamoto, Atsushi



Bombesin-, gastrin/CCK-, 5-hydroxytryptamine-, neurotensin-, somatostatin-, and VIP-like immunoreactivity and catecholamine fluorescence in the gut of the elasmobranch, Squalus acanthias.  


The presence of peptides and 5-hydroxytryptamine (5-HT) in neurons and endocrine cells in the gastrointestinal tract of the spiny dogfish, Squalus acanthias, was investigated by means of immunohistochemistry, and the distribution of catecholamines by use of the Falck-Hillarp fluorescence-histochemical technique. Bombesin-like immunoreactivity was present in numerous nerves in all layers and all parts of the gut, and also in endocrine cells in the mucosa throughout the stomach, rectum and intestine. VIP-like immunoreactivity occurred in an abundance of nerve fibres and in nerve cell bodies in all parts of the gut except the oesophagus, while 5-HT-like immunoreactivity was found sparsely in nerve fibres and more frequently in endocrine cells throughout the gut. Gastrin/CCK-like immunoreactivity was present in numerous nerve fibres in the rectum, but only in scattered fibres in the other parts of the gut. Endocrine cells showing gastrin/CCK-like immunoreactivity were present in the intestine only. Somatostatin-like immunoreactivity occurred in both nerve fibres and endocrine cells of the stomach and intestine, but only in nerves in the rectum. Neurotensin-like immunoreactivity was confined to endocrine cells of the intestine. Falck-Hillarp fluorescence histochemistry revealed 5-HT in endocrine cells and catecholamines in nerve fibres (and possibly also in endocrine cells) throughout the gut. Bombesin-, VIP-, gastrin/CCK- and somatostatin-like immunoreactivities and catecholamine fluorescence were present in nerve fibres of the rectal gland and, with the exception of gastrin/CCK-like immunoreactivity, also in nerve bundles in the walls of the coeliac and mesenteric arteries. The findings of the present study form an anatomical basis for the assumption that several of the neuropeptides and amines could function as neurotransmitters or neuromodulators in the gut of Squalus. PMID:6362887

Holmgren, S; Nilsson, S



Cocaine acts on accumbens monoamines and locomotor behavior via a 5HT 2A\\/2C receptor mechanism as shown by ketanserin: 24-h follow-up studies  

Microsoft Academic Search

It is well known that cocaine's psychomotor stimulant properties derive from enhanced monoamines via synaptic transporter\\/reuptake inhibition and release mechanisms. However, to further understand mechanisms of action for cocaine, which may be receptor-related, ketanserin, a selective 5-HT2A\\/2C antagonist was used to ascertain a possible mediation for 5-HT2A\\/\\/2C receptors in the monoamine and behavioral responses to cocaine. The studies were performed

Patricia A Broderick; Opeyemi A Olabisi; David N Rahni; Yueping Zhou



GPR30 is necessary for estradiol-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the rat hypothalamus  

PubMed Central

Estrogen therapy used in combination with selective serotonin reuptake inhibitor (SSRI) treatment improves SSRI efficacy for the treatment of mood disorders. Desensitization of serotonin 1A (5-HT1A) receptors, which takes one to two weeks to develop in animals, is necessary for SSRI therapeutic efficacy. Estradiol modifies 5-HT1A receptor signaling and induces a partial desensitization in the paraventricular nucleus (PVN) of the rat within two days, but the mechanisms underlying this effect are currently unknown. The purpose of this study was to identify the estrogen receptor necessary for estradiol-induced 5-HT1A receptor desensitization. We previously showed that estrogen receptor ? is not necessary for 5-HT1A receptor desensitization and that selective activation of estrogen receptor GPR30 mimics the effects of estradiol in rat PVN. Here, we used a recombinant adenovirus containing GPR30 siRNAs to decrease GPR30 expression in the PVN. Reduction of GPR30 prevented estradiol-induced desensitization of 5-HT1A receptor as measured by hormonal responses to the selective 5-HT1A receptor agonist, (+)8-OH-DPAT. To determine the possible mechanisms underlying these effects, we investigated protein and mRNA levels of 5-HT1A receptor signaling components including 5-HT1A receptor, G?z, and RGSz1. We found that two days of estradiol increased protein and mRNA expression of RGSz1, and decreased 5-HT1A receptor protein but increased 5-HT1A mRNA; GPR30 knockdown prevented the estradiol-induced changes in 5-HT1A receptor protein in the PVN. Taken together, these data demonstrate that GPR30 is necessary for estradiol-induced changes in the 5-HT1A receptor signaling pathway and desensitization of 5-HT1A receptor signaling. PMID:22265196

McAllister, C.E.; Creech, R.; Kimball, P.; Muma, N.; Li, Q.



Serotonin reuptake inhibitors do not prevent 5,7-dihydroxytryptamine-induced depletion of serotonin in rat brain.  


Although the selective toxicity of 5,7-dihydroxytryptamine (5,7-DHT) is thought to depend on the drug's transport into serotonin (5HT) neurons via the 5HT transporter, few studies have critically examined this postulation. We therefore evaluated if 5,7-DHT-induced reductions in 5HT concentrations and synthesis rate in rat brain are blocked by pretreatment with 5HT-selective reuptake inhibitors. Rats pretreated with desipramine (DMI) (to prevent norepinephrine depletion) received intracerebroventricular injections of 5,7-DHT (5, 50, 100, 200 microg/rat) 30 min after fluoxetine (20 mg/kg ip). Forty-eight hours later, they received m-hydroxybenzylhydrazine 30 min before sacrifice. The concentrations of 5HT and 5-hydroxytryptophan (5HTP, an index of 5HT synthesis) were measured in hypothalamus, cortex and brainstem. Each 5,7-DHT dose produced significant reductions in 5HT and 5HTP concentrations in all regions examined (5 microg reduced 5HT but not 5HTP), effects that were not blocked by fluoxetine. Two other 5HT reuptake blockers (chlorimipramine, alaproclate) also failed to block the 5HT and 5HTP depleting actions of 5,7-DHT. Desipramine blocked 5,7-DHT-induced norepinephrine (NE) depletion. Pretreatment with the 5HT receptor antagonist metergoline, or the 5HT(1A) agonist 8-hydroxy-(di-n-propylamino)tetralin (to slow 5HT neuronal firing rate) also failed to antagonize the 5HT depleting action of 5,7-DHT. Together, the data strongly suggest that the mechanism by which 5,7-DHT depletes the brain of serotonin does not involve 5HT-transporter-mediated concentration of neurotoxin in 5HT neurons, may not involve 5HT receptor interaction, and does not depend on the firing rate of the 5HT neuron. PMID:15064132

Choi, SuJean; Jonak, Elizabeth; Fernstrom, John D



Potentiation of chloride responses to glycine by three 5-HT3 antagonists in rat spinal neurones.  

PubMed Central

1. Modulations of Cl- responses to glycine by 5-hydroxytryptamine ligands were studied in cultured spinal neurones, by the whole-cell recording technique. 2. Three 5-HT3 antagonists were found to potentiate reversibly responses to low concentrations of glycine. Potentiations were induced by micromolar concentrations of LY-278,584 (1-10 microM) and by concentrations of MDL-72222 or ICS-205,930 between 10 nM and 1 microM. 3. Potentiations were observed over the whole voltage range without any change in the reversal potential of the glycine responses and without affecting the resting conductance. 4. The degree of potentiation was variable among cells. It increased with the concentration of the modulator, but only up to 100 nM for MDL-72222 and ICS-205,930. 5. The potentiation appeared to result from an increase in the affinity for glycine of glycine receptors. 6. Neither the blockade of glycine uptake by Na+ removal, nor the excision of membrane patches prevented the potentiation. 7. At high concentrations (10 microM), both MDL-72222 and ICS-205,930 had, in contrast, a blocking effect on glycine responses. 8. Potentiation by LY-278,584 and a dose-dependent modulation by MDL-72222 were also observed for taurine responses. 9. The effects on glycine responses of various ligands of 5-HT3 receptors (including agonists) are discussed. The ability of LY-278,584, MDL-72222 and ICS-205,930 to potentiate glycine responses appears to be independent of their known 5-HT3 receptor antagonist properties. It would be interesting to look for chemically related drugs that would be specific potentiators of glycine responses. PMID:8864550

Chesnoy-Marchais, D.



Advances toward new antidepressants beyond SSRIs: 1Aryloxy3-piperidinylpropan-2-ols with dual 5HT 1A receptor antagonism\\/SSRI activities. Part 5  

Microsoft Academic Search

A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT1A receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demonstrated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the

Kumiko Takeuchi; Todd J. Kohn; Nicholas A. Honigschmidt; Vincent P. Rocco; Patrick G. Spinazze; Susan K. Hemrick-Luecke; Linda K. Thompson; David C. Evans; Kurt Rasmussen; Deanna Koger; David Lodge; Laura J. Martin; Janice Shaw; Penny G. Threlkeld; David T. Wong



R-fluoxetine increases extracellular DA, NE, as well as 5-HT in rat prefrontal cortex and hypothalamus: an in vivo microdialysis and receptor binding study.  


The selective serotonin reuptake inhibitor fluoxetine consists of equal amounts of R and S stereoisomers. In this study, we investigated the pharmacologic properties of the stereoisomers using transporter and receptor binding assays and in vivo microdialysis in freely moving rats. Binding to the transporter confirmed selectivity of R- and S-fluoxetine for the 5-HT transporter versus the dopamine (DA) and norepinephrine (NE) human transporters. Receptor binding studies demonstrated significant affinity of R-fluoxetine, but not S-fluoxetine, for human 5-HT(2A) and 5-HT(2C) receptor subtypes. Functional GTPgammaS binding studies indicated that R-fluoxetine is an antagonist at 5-HT(2A) and 5-HT(2C) receptors. In microdialysis studies, acute R- and S-fluoxetine increased extracellular levels of 5-HT, DA, and NE in prefrontal cortex (PFC), but R-fluoxetine caused significantly greater increases of catecholamines. R-fluoxetine increased extracellular levels of 5-HT and NE in PFC, nucleus accumbens, and hypothalamus, whereas it increased dopamine in PFC and hypothalamus, but not in DA-rich nucleus accumbens and striatum, thus indicating a regionally selective effect. The unexpected increases of extracellular catecholamines by a selective 5-HT uptake inhibitor like R-fluoxetine may be due to its antagonism of 5-HT(2C) receptors. PMID:12464452

Koch, Susanne; Perry, Kenneth W; Nelson, David L; Conway, Richard G; Threlkeld, Penny G; Bymaster, Frank P



Voltage-dependent inhibition of recombinant NMDA receptor-mediated currents by 5-hydroxytryptamine  

PubMed Central

The effect of 5-HT and related indolealkylamines on heteromeric recombinant NMDA receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp recording technique. In the absence of external Mg2+ ions, 5-HT inhibited NMDA receptor-mediated currents in a concentration-dependent manner. The inhibitory effect of 5-HT was independent of the NR1a and NR2 subunit combination. The inhibition of glutamate-evoked currents by 5-HT was use- and voltage-dependent. The voltage sensitivity of inhibition for NR1a+NR2 subunit combinations by 5-HT was similar, exhibiting an e-fold change per ?20?mV, indicating that 5-HT binds to a site deep within the membrane electric field. The inhibition of the open NMDA receptor by external Mg2+ and 5-HT was not additive, suggesting competition between Mg2+ and 5-HT for a binding site in the NMDA receptor channel. The concentration-dependence curves for 5-HT and 5-methoxytryptamine (5-MeOT) inhibition of NMDA receptor-mediated currents are shifted to the right in the presence of external Mg2+. The related indolealkylamines inhibited glutamate-evoked currents with the following order of inhibitory potency: 5-MeOT=5-methyltryptamine>tryptamine>7-methyltryptamine>5-HT?tryptophan=melatonin. Taken together, these data suggest that 5-HT and related compounds can attenuate glutamate-mediated excitatory synaptic responses and may provide a basis for drug treatment of excitoxic neurodegeneration. PMID:15655527

Kloda, Anna; Adams, David J



Piperazine Analogs of Naphthyridine-3-carboxamides and Indole-2-carboxamides: Novel 5-HT3 Receptor Antagonists with Antidepressant-Like Activity.  


Series of piperazine analogs of naphthyridine-3-carboxamides and indole-2-carboxamides were designed using a ligand-based approach with consideration of the pharmacophoric requirements for 5-HT3 receptor antagonists. The title carboxamides were synthesized using appropriate synthetic routes. Initially, the 5-HT3 receptor antagonistic activity of all the compounds was determined on isolated guinea pig ileum tissue against the 5-HT3 agonist, 2-methyl-5-hydroxytryptamine, which was denoted in the form of pA2 values. The structure-activity relationship regarding the influence of the aromatic part and basic moiety as features in the 5-HT3 pharmacophore was derived. Among all the compounds screened, the piperazine derivatives of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h exhibited prominent 5-HT3 receptor antagonism with pA2 values of 7.5 and 7.3, respectively. Subsequent investigation of the antidepressant activities of selected compounds in the mouse forced swim test (FST) led to the identification of the piperazine analogs of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h as the most promising compounds. Both 13i and 8h demonstrated significant reduction in the duration of immobility as compared to the control. Importantly, none of the tested compounds affected the baseline locomotion of mice at the tested dose levels. PMID:25581677

Dhar, Arghya K; Mahesh, Radhakrishnan; Jindal, Ankur; Bhatt, Shvetank



Isomerization of the proline in the M2-M3 linker is not required for activation of the human 5-HT3A receptor.  


Each subunit of the cation-selective members of the Cys-loop family of ligand-gated ion channels contains a conserved proline residue in the extracellular loop between the second and third transmembrane domains. In the mouse homomeric 5-hydroxytryptamine type 3A (5-HT(3)A) receptor, the effects of substitution of this proline by unnatural amino acids led to the suggestion that trans-cis isomerization of the protein backbone at this position is integral to agonist-induced channel opening [Nature (2005) vol. 438, pp. 248-252]. We explored the generality of this conclusion using natural amino acid mutagenesis of the homologous human 5-HT(3)A receptor. The conserved proline (P303) was substituted by either a histidine or tryprophan and the mutant receptors were expressed in Xenopus oocytes. These mutations did not significantly affect the magnitude of agonist-mediated currents, compromise channel gating by 5-HT or inhibition of 5-HT-induced currents by either picrotoxin or d-tubocurarine. The mutations did, however, result in altered dependence on extracellular Ca(2+) concentration and a 10-fold increase in the rate of receptor desensitization. These results demonstrate an important role for P303 in 5-HT(3)A receptor function but indicate that trans-cis isomerization at this proline is unlikely to be a general mechanism underlying the gating process. PMID:19457066

Paulsen, Isabelle M; Martin, Ian L; Dunn, Susan M J



Effect of cold exposure on brain 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in some vertebrate species.  


1. The changes in 5-HT and 5-HIAA levels were studied in the brain regions of Gerbillus pyramidum, Streptopelia senegalensis aegyptiaca and Agama stellio following exposure to cold. 2. In general, the 5-HT levels increased in the Gerbillus brain parts and decreased in those of Streptopelia. 3. Cold exposure in the Agama brain regions caused a transient decrease in the 5-HT levels of the cerebral hemispheres, midbrain and pons plus medulla after 6 hr and a general increase after 12, 24 and 48 hr. 4. It is concluded that cold exposure may be associated with increased activity of 5-HT ergic neurons and the rate of turnover of 5-HT to 5-HIAA. PMID:6184195

Mohamed, M I; Rahman, T A



Serotonin 5-HT(2) and 5-HT(1A)-like receptors differentially modulate aggressive behaviors in Drosophila melanogaster.  


Aggressive behavior is widespread throughout the animal kingdom, and is a complex social behavior influenced by both genetics and environment. Animals typically fight over resources that include food, territory, and sexual partners. Of all the neurotransmitters, serotonin (5-HT) has been the most implicated in modulating aggressive behaviors in mammalian systems. In the fruit fly, Drosophila melanogaster, the involvement of 5-HT itself in aggressive behaviors has been recently established, however, the underlying mechanisms have largely remained elusive. Here we describe the influence of different 5-HT receptor subtypes on aggressive behaviors in Drosophila. Drosophila express homologs of three mammalian 5-HT receptors: the 5-HT(1A), 5-HT(2), and 5-HT(7) receptors. Significantly, these receptors mediate important behaviors in mammalian systems ranging from feeding, aggression, and sleep, to cognition. To examine the role of the 5-HT(2)Dro receptor, we utilized the selective 5-HT(2) receptor agonist (R)-1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI), and the 5-HT(2) receptor antagonist, ketanserin. To examine the role of 5-HT(1A)-like receptors we used the 5-HT(1A) receptor agonist 8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT), and the 5-HT(1A) receptor antagonist WAY100635. We find that activation of 5-HT(2) receptors with (R)-DOI appears to decrease overall aggression, whereas activation of 5-HT(1A)-like receptors with 8-OH-DPAT increases overall aggression. Furthermore, the different 5-HT receptor circuitries appear to mediate different aspects of aggression: 5-HT(2) receptor manipulation primarily alters lunging and boxing, whereas 5-HT(1A)-like receptor manipulation primarily affects wing threats and fencing. Elucidating the effects of serotonergic systems on aggression in the fly is a significant advancement not only in establishing the fly as a system to study aggression, but as a system relevant to elucidating molecular mechanisms underlying aggression in mammals, including humans. PMID:19041376

Johnson, O; Becnel, J; Nichols, C D



Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene  

Microsoft Academic Search

Obsessive compulsive disorder (OCD) is a common illness, characterized by anxiety- provoking thoughts and the need to perform rituals. OCD is most commonly treated with a class of pharmacological agents known as serotonin reuptake inhibitors (SRIs). SRIs block the reuptake of serotonin (5-HT) into the presynaptic neuron, a process mediated by the serotonin transporter (5-HTT). The successful use of SRIs

E A Billett; M A Richter; N King; A Heils; K P Lesch; J L Kennedy



Role of 5Hydroxytryptamine in Mental Diseases and its Antagonism to Lysergic Acid Derivatives  

Microsoft Academic Search

THE possibility that 5-hydroxytryptamine plays a part in abnormal mental processes has been discussed by Gaddum1 and by Woolley and Shaw2. The hypothesis is based on the findings that this substance is a natural constituent of nervous tissue, particularly of the brain3, and that certain of its actions are antagonized by lysergic acid diethylamide4, a drug which on oral application

A. Cerletti; E. Rothlin



Effects of U46619 on contractions to 5-HT, sumatriptan and methysergide in canine coronary artery and saphenous vein in vitro.  

PubMed Central

1. The aim of this study was to investigate the mechanism of enhanced reactivity to 5'-hydroxytryptamine (5-HT) and sumatriptan previously observed in human isolated coronary arteries when active force was raised with the thromboxane A2-mimetic, U46619. 2. Ring segments of dog isolated coronary artery and saphenous vein were suspended in organ baths and cumulative concentration-contraction curves to 5-HT, sumatriptan and methysergide were constructed in the absence and presence of low concentrations of U46619. 3. In both endothelium-intact and endothelium-denuded rings of coronary artery, precontraction with U46619 to low (< 10% Fmax; the contraction to a maximum depolarizing 125 mM KCl Krebs solution; KPSS) levels of active force had no effect on either the maximum contraction or sensitivity (pEC50) to 5-HT, sumatriptan and methysergide. 4. Ketanserin (1 microM) had no effect on contractions to sumatriptan and methysergide in endothelium-denuded coronary artery rings, but reduced the maximum contraction to 5-HT by approximately 90% to a value (5% Fmax) similar to that for sumatriptan and methylsergide. Under these conditions, U46619 precontraction had no effect on either pEC50 or maximum for 5-HT, sumatriptan or methysergide. 5. In rings of saphenous vein with endothelium and treated with ketanserin (1 microM), 5-HT and sumatriptan caused equal maximum responses of 65% Fmax which were approximately double that of methysergide (32% Fmax). The maximum responses and sensitivity to 5-HT, sumatriptan, methysergide and noradrenaline were unaffected by precontraction with U46619.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8564247

Kemp, B. K.; Cocks, T. M.



Human 5-HT7 receptor-induced inactivation of forskolin-stimulated adenylate cyclase by risperidone, 9-OH-risperidone and other "inactivating antagonists".  


We have previously reported on the unusual human 5-hydroxytryptamine(7) (h5-HT(7)) receptor-inactivating properties of risperidone, 9-OH-risperidone, bromocriptine, methiothepin, metergoline, and lisuride. Inactivation was defined as the inability of 10 microM 5-HT to stimulate cAMP accumulation after brief exposure and thorough removal of the drugs from HEK293 cells expressing h5-HT(7) receptors. Herein we report that brief exposure of the h5-HT(7) receptor-expressing cells to inactivating drugs, followed by removal of the drugs, results in potent and efficacious irreversible inhibition of forskolin-stimulated adenylate cyclase activity. Pretreatment, followed by removal of the inactivating drugs inhibited 10 microM forskolin-stimulated adenylate cyclase activity with potencies similar to the drugs' affinities for the h5-HT(7) receptor. The actions of the inactivating drugs were pertussis toxin-insensitive, indicating the lack of G(i) in their mechanism(s) of action. Methiothepin and bromocriptine maximally inhibited 10 microM forskolin-stimulated adenylate cyclase, whereas the other drugs produced partial inhibition, indicating the drugs are inducing slightly different inactive conformations of the h5-HT(7) receptor. Maximal effects of these inactivating drugs occurred within 15 to 30 min of exposure of the cells to the drugs. A G(s)-mediated inhibition of forskolin-stimulated activity has never been reported. The inactivating antagonists seem to induce a stable conformation of the h5-HT(7) receptor, which induces an altered state of G(s), which, in turn, inhibits forskolin-mediated stimulation of adenylate cyclase. These and previous observations indicate that the inactivating antagonists represent a unique class of drugs and may reveal GPCR regulatory mechanisms previously unknown. These drugs may produce innovative approaches to the development of therapeutic drugs. PMID:19509219

Toohey, Nicole; Klein, Michael T; Knight, Jessica; Smith, Carol; Teitler, Milt



Human 5-HT7 Receptor-Induced Inactivation of Forskolin-Stimulated Adenylate Cyclase by Risperidone, 9-OH-Risperidone and Other “Inactivating Antagonists”  

PubMed Central

We have previously reported on the unusual human 5-hydroxytryptamine7 (h5-HT7) receptor-inactivating properties of risperidone, 9-OH-risperidone, bromocriptine, methiothepin, metergoline, and lisuride. Inactivation was defined as the inability of 10 ?M 5-HT to stimulate cAMP accumulation after brief exposure and thorough removal of the drugs from HEK293 cells expressing h5-HT7 receptors. Herein we report that brief exposure of the h5-HT7 receptor-expressing cells to inactivating drugs, followed by removal of the drugs, results in potent and efficacious irreversible inhibition of forskolin-stimulated adenylate cyclase activity. Pretreatment, followed by removal of the inactivating drugs inhibited 10 ?M forskolin-stimulated adenylate cyclase activity with potencies similar to the drugs' affinities for the h5-HT7 receptor. The actions of the inactivating drugs were pertussis toxin-insensitive, indicating the lack of Gi in their mechanism(s) of action. Methiothepin and bromocriptine maximally inhibited 10 ?M forskolin-stimulated adenylate cyclase, whereas the other drugs produced partial inhibition, indicating the drugs are inducing slightly different inactive conformations of the h5-HT7 receptor. Maximal effects of these inactivating drugs occurred within 15 to 30 min of exposure of the cells to the drugs. A Gs-mediated inhibition of forskolin-stimulated activity has never been reported. The inactivating antagonists seem to induce a stable conformation of the h5-HT7 receptor, which induces an altered state of Gs, which, in turn, inhibits forskolin-mediated stimulation of adenylate cyclase. These and previous observations indicate that the inactivating antagonists represent a unique class of drugs and may reveal GPCR regulatory mechanisms previously unknown. These drugs may produce innovative approaches to the development of therapeutic drugs. PMID:19509219

Toohey, Nicole; Klein, Michael T.; Knight, Jessica; Smith, Carol; Teitler, Milt



Serotonin 5HT 3 receptors in the central nervous system  

Microsoft Academic Search

The 5-HT3 receptor is a ligand-gated ion channel activated by serotonin (5-HT). Although originally identified in the peripheral nervous system, the 5-HT3 receptor is also ubiquitously expressed in the central nervous system. Sites of expression include several brain stem nuclei and higher cortical areas such as the amygdala, hippocampus, and cortex. On the subcellular level, both presynaptic and postsynaptic 5-HT3

Pascal Chameau; Johannes A. van Hooft



5HT4 receptors in isolated human corpus cavernosum?  

Microsoft Academic Search

The novel serotonin subtype-4 (5-HT4) receptor agonist, SC53116 (SC), produced a limited relaxation of noradrenaline (NA) pre-contracted human corpus cavernosum (CC) smooth muscle in vitro. This effect was not significantly attenuated by the 5-HT4 antagonist SDZ250557 (SDZ). In the presence of (±) pindolol (1 ?M) and methysergide (1 ?M), employed to mask 5-HT1 and ?-adrenergic, and 5-HT2 receptors respectively, SC

ES Hayes; PG Adaikan; SS Ratnam; SC Ng



The 5-HT3B subunit affects high-potency inhibition of 5-HT3 receptors by morphine  

PubMed Central

BACKGROUND AND PURPOSE Morphine is an antagonist at 5-HT3A receptors. 5-HT3 and opioid receptors are expressed in many of the same neuronal pathways where they modulate gut motility, pain and reinforcement. There is increasing interest in the 5-HT3B subunit, which confers altered pharmacology to 5-HT3 receptors. We investigated the mechanisms of inhibition by morphine of 5-HT3 receptors and the influence of the 5-HT3B subunit. EXPERIMENTAL APPROACH 5-HT-evoked currents were recorded from voltage-clamped HEK293 cells expressing human 5-HT3A subunits alone or in combination with 5-HT3B subunits. The affinity of morphine for the orthosteric site of 5-HT3A or 5-HT3AB receptors was assessed using radioligand binding with the antagonist [3H]GR65630. KEY RESULTS When pre-applied, morphine potently inhibited 5-HT-evoked currents mediated by 5-HT3A receptors. The 5-HT3B subunit reduced the potency of morphine fourfold and increased the rates of inhibition and recovery. Inhibition by pre-applied morphine was insurmountable by 5-HT, was voltage-independent and occurred through a site outside the second membrane-spanning domain. When applied simultaneously with 5-HT, morphine caused a lower potency, surmountable inhibition of 5-HT3A and 5-HT3AB receptors. Morphine also fully displaced [3H]GR65630 from 5-HT3A and 5-HT3AB receptors with similar potency. CONCLUSIONS AND IMPLICATIONS These findings suggest that morphine has two sites of action, a low-affinity, competitive site and a high-affinity, non-competitive site that is not available when the channel is activated. The affinity of morphine for the latter is reduced by the 5-HT3B subunit. Our results reveal that morphine causes a high-affinity, insurmountable and subunit-dependent inhibition of human 5-HT3 receptors. PMID:21740409

Baptista-Hon, Daniel T; Deeb, Tarek Z; Othman, Nidaa A; Sharp, Douglas; Hales, Tim G



The effect of diet on the 5-hydroxytryptamine content of the small intestine and other organs in rats and mice  

PubMed Central

In rats, a diet of meat or liver caused a rise in the amount of 5-hydroxytryptamine in the small intestine, an increase in the weight of the intestine and a 10-fold increase in anaerobic bacteria in the rectum. A diet containing added tryptophan did not affect tissue levels of 5-hydroxytryptamine in rats, but in mice there was a rise of 5-hydroxytryptamine in various tissues. The significance of these findings is discussed together with the possible role of intestinal bacteria in mediating the effects caused by a meat diet. No change was observed in the 5-hydroxytryptamine content of brain or in the distribution of argentaffin cells in the jejunum as a result of these diets. PMID:19108138

Sullivan, T. J.



Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 4.  


A series of 1-(1H-indol-4-yloxy)-3-(4-arylpiperidinyl)propan-2-ols possessing potent dual 5-HT(1A) receptor antagonism and serotonin reuptake inhibition was discovered. The fused aryl ring moiety contributed to the robust dual activities irrespective of the regiochemistry associated with its connectivity to the piperidine central ring. PMID:15109671

Rocco, Vincent P; Spinazze, Patrick G; Kohn, Todd J; Honigschmidt, Nicholas A; Nelson, David L; Bradley Wainscott, D; Ahmad, Laura J; Shaw, Janice; Threlkeld, Penny G; Wong, David T; Takeuchi, Kumiko



Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5-HT1A receptor antagonism/SSRI activities. Part 3.  


A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT(1A) receptor antagonism and serotonin reuptake inhibition was discovered. Modification of potential metabolic sites of 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols further improved the in vitro binding affinities and functional antagonism. PMID:14592479

Takeuchi, Kumiko; Kohn, Todd J; Honigschmidt, Nicholas A; Rocco, Vincent P; Spinazze, Patrick G; Atkinson, Steven T; Hertel, Larry W; Nelson, David L; Wainscott, D Bradley; Ahmad, Laura J; Shaw, Janice; Threlkeld, Penny G; Wong, David T



Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5HT 1A receptor antagonism\\/SSRI activities. Part 3  

Microsoft Academic Search

A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. Modification of potential metabolic sites of 1-(1H-indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols further improved the in vitro binding affinities and functional antagonism.

Kumiko Takeuchi; Todd J Kohn; Nicholas A Honigschmidt; Vincent P Rocco; Patrick G Spinazze; Steven T Atkinson; Larry W Hertel; David L Nelson; D. Bradley Wainscott; Laura J Ahmad; Janice Shaw; Penny G Threlkeld; David T Wong



Advances toward new antidepressants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual 5HT 1A receptor antagonism\\/SSRI activities. Part 4  

Microsoft Academic Search

A series of 1-(1H-indol-4-yloxy)-3-(4-arylpiperidinyl)propan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. The fused aryl ring moiety contributed to the robust dual activities irrespective of the regiochemistry associated with its connectivity to the piperidine central ring.

Vincent P. Rocco; Patrick G. Spinazze; Todd J. Kohn; Nicholas A. Honigschmidt; David L. Nelson; D. Bradley Wainscott; Laura J. Ahmad; Janice Shaw; Penny G. Threlkeld; David T. Wong; Kumiko Takeuchi



Motoneuron Excitability and Muscle Spasms Are Regulated by 5-HT2B and 5-HT2C Receptor Activity  

PubMed Central

Immediately after spinal cord injury (SCI), a devastating paralysis results from the loss of brain stem and cortical innervation of spinal neurons that control movement, including a loss of serotonergic (5-HT) innervation of motoneurons. Over time, motoneurons recover from denervation and function autonomously, exhibiting large persistent calcium currents (Ca PICs) that both help with functional recovery and contribute to uncontrolled muscle spasms. Here we systematically evaluated which 5-HT receptor subtypes influence PICs and spasms after injury. Spasms were quantified by recording the long-lasting reflexes (LLRs) on ventral roots in response to dorsal root stimulation, in the chronic spinal rat, in vitro. Ca PICs were quantified by intracellular recording in synaptically isolated motoneurons. Application of agonists selective to 5-HT2B and 5-HT2C receptors (including BW723C86) significantly increased the LLRs and associated Ca PICs, whereas application of agonists to 5-HT1, 5-HT2A, 5-HT3, or 5-HT4/5/6/7 receptors (e.g., 8-OH-DPAT) did not. The 5-HT2 receptor agonist–induced increases in LLRs were dose dependent, with doses for 50% effects (EC50) highly correlated with published doses for agonist receptor binding (Ki) at 5-HT2B and 5-HT2C receptors. Application of selective antagonists to 5-HT2B (e.g., RS127445) and 5-HT2C (SB242084) receptors inhibited the agonist-induced increase in LLR. However, antagonists that are known to specifically be neutral antagonists at 5-HT2B/C receptors (e.g., RS127445) had no effect when given by themselves, indicating that these receptors were not activated by residual 5-HT in the spinal cord. In contrast, inverse agonists (such as SB206553) that block constitutive activity at 5-HT2B or 5-HT2C receptors markedly reduced the LLRs, indicating the presence of constitutive activity in these receptors. 5-HT2B or 5-HT2C receptors were confirmed to be on motoneurons by immunolabeling. In summary, 5-HT2B and 5-HT2C receptors on motoneurons become constitutively active after injury and ultimately contribute to recovery of motoneuron function and emergence of spasms. PMID:20980537

Murray, Katherine C.; Stephens, Marilee J.; Ballou, Edmund W.; Heckman, Charles J.



VUF10166, a Novel Compound with Differing Activities at 5-HT3A and 5-HT3AB Receptors  

PubMed Central

The actions of a novel, potent 5-HT3 receptor ligand, [2-chloro-(4-methylpiperazine-1-yl)quinoxaline (VUF10166)], were examined at heterologously expressed human 5-HT3A and 5-HT3AB receptors. VUF10166 displaced [3H]granisetron binding to 5-HT3A receptors expressed in human embryonic kidney cells with high affinity (Ki = 0.04 nM) but was less potent at 5-HT3AB receptors (Ki = 22 nM). Dissociation of [3H]granisetron in the presence of VUF10166 was best fit with a single time constant (t1/2 = 53 min) at 5-HT3A receptors, but with two time constants (t1/2 = 55 and 2.4 min) at 5-HT3AB receptors. Electrophysiological studies in oocytes revealed that VUF10166 inhibited 5-HT-induced responses at 5-HT3A receptors at nanomolar concentrations, but inhibition and recovery were too slow to determine an IC50. At 5-HT3AB receptors, inhibition and recovery were faster, yielding an IC50 of 40 nM. Cysteine substitutions in the complementary (?), but not the principal (+), face of the 5-HT3B subunit produced heteromeric receptors in which the actions of VUF10166 resembled those at homomeric receptors. At 5-HT3A receptors, VUF10166 at higher concentrations also behaved as a partial agonist (EC50 = 5.2 ?M; Rmax = 0.24) but did not elicit significant responses at 5-HT3AB receptors at ?100 ?M. Thus, we propose that VUF10166 binds to the common A+A? site of both receptor types and to a second A+B? modulatory site in the heteromeric receptor. The ability of VUF10166 to distinguish between 5-HT3A and 5-HT3AB receptors could help evaluate differences between these receptor types and has potential therapeutic value. PMID:22306960

Thompson, A. J.; Verheij, M. H. P.; de Esch, I. J. P.



Muramyl dipeptide (MDP) and 5-HT receptors. Neuroimmunomodulatory effects of MDP are probably not mediated through 5-HT4 or 5-HT1A receptors.  


A possible interaction of immunomodulator muramyl dipeptide (MDP) with 5-HT4 and 5-HT1A receptors was investigated. The activation of 5-HT4 receptors releases acetylcholine from nerve terminals, thereby contracting the guinea-pig distal ileum. The whole ileum segments were therefore cut and placed into the bath. The preparations were contracted by 5-HT (10 nM-3.2 microM); these contractions were totally abolished in the presence of atropine (1 microM) and significantly attenuated in the presence of SDZ-205,557 (320 nM). The 5-HT evoked contractions remained unchanged in the presence of MDP (5, 50 or 500 nM). MDP (l0 nM-3.2 microM) could not directly contract the preparations. In further experiments, the possible interaction of MDP with 5-HT1A receptors was investigated. The activation of 5-HT1A receptors inhibits the release of acetylcholine from nerve terminals, thereby decreasing the height of electrically evoked neurogenic twitches of guinea-pig ileum. The whole ileum segments were cut, placed into the bath and stimulated electrically. Selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) decreased the height of twitches and this effect was significantly attenuated in the presence of 5-HT antagonist metergoline (1 microM). The effect of 8-OH-DPAT remained unchanged in the presence of MDP (5, 50 or 500 nM). MDP (10 nM-3.2 microM) did not exert any direct effect on the preparations. These results suggest that MDP interacts with neither 5-HT4 nor 5-HT1A receptors. PMID:12022444

Sevcík, Jan; R?icka, Vladimír; Sláinský, Josef; Masek, Karel



Differences in signal transduction of two 5-HT4 receptor splice variants: compound specificity and dual coupling with Galphas- and Galphai/o-proteins.  


This study documents differences in ligand binding and signal transduction properties between the human (h) 5-hydroxytryptamine (5-HT)4a and h5-HT4b receptor splice variants stably expressed in human embryonic kidney 293 cells. The fraction of the [3H]5-HT high-affinity site relative to the whole receptor population measured with [3H]GR113808 was higher for the h5-HT4a isoform (around 0.4) than for the 5-HT4b isoform (around 0.2) and was independent of the level of expression. The potency and efficacy of reference compounds tested for the cAMP response differed slightly but significantly between both variants. Most remarkably, 5-methoxytryptamine and prucalopride were found more potent on the 5-HT4b variant, whereas SDZ-HTF 919 and SB204070 were more potent on the 5-HT(4a) variant. Guanosine-5'-O-(3-[35S]thio)triphosphate binding on membranes and cAMP assays in whole cells revealed that only the h5-HT4b isoform coupled to Galphai/o-proteins in addition to its well-documented Galphas coupling. In contrast, the h5-HT4a receptor coupled only to Galphas-proteins, however, was able to trigger an increase in the intracellular calcium concentration ([Ca(2+)]i). The observed [Ca(2+)]i increase did not occur through inositol phosphate formation and was not sensitive to Bordetella pertussis toxin, forskolin, or 3-isobutyl-1-methylxanthine (pre)treatment but was due to Ca(2+) influx from the extracellular environment. Interestingly, the Ca(2+) pathway was dependent on high receptor expression levels and was compound-specific, because benzamide-like compounds triggered two to three times higher responses than indoleamines. Taken together, these data provide the first evidence for fine functional differences between C-terminal splice variants of the h5-HT4 receptor, which may contribute to a better understanding of the functional diversity of this receptor class. PMID:11752209

Pindon, Armelle; van Hecke, Geert; van Gompel, Paul; Lesage, Anne S; Leysen, Josée E; Jurzak, Mirek



The mouse 5HT5 receptor reveals a remarkable heterogeneity within the 5HT1D receptor family.  

PubMed Central

Serotonin (5-HT) is a neuromodulator that mediates a wide range of physiological functions by activating multiple receptors. Using a strategy based on amino acid sequence homology between 5-HT receptors that interact with G proteins, we have isolated a cDNA encoding a new serotonin receptor from a mouse brain library. Amino acid sequence comparisons revealed that this receptor was a distant relative of all previously identified 5-HT receptors; we therefore named it 5HT5. When expressed in Cos-7 cells and NIH-3T3 cells, the 5HT5 receptor displayed a high affinity for the serotonergic radioligand [125I]LSD. Surprisingly, its pharmacological profile resembled that of the 5HT1D receptor, which is a 5-HT receptor subtype which has been shown to inhibit adenylate cyclase and which is predominantly expressed in basal ganglia. However, unlike 5HT1D receptors, the 5HT5 receptor did not inhibit adenylate cyclase and its mRNA was not found in basal ganglia. On the contrary, in situ hybridization experiments revealed that the 5HT5 mRNA was expressed predominantly in cerebral cortex, hippocampus, habenula, olfactory bulb and granular layer of the cerebellum. Our results therefore demonstrate that the 5HT1D receptors constitute a heterogeneous family of receptors with distinct intracellular signalling properties and expression patterns. Images PMID:1464308

Plassat, J L; Boschert, U; Amlaiky, N; Hen, R



Electrochemical monitoring of 5-hydroxytryptamine release in vitro and related in vivo measurements of indoleamines.  


1. Electrochemical techniques have been used to measure release of endogenous 5HT from brain regions in vitro and to record electrochemical changes induced by drugs acting on 5HT neurones in the anaesthetised and unanaesthetised rat in vivo. 2. 5HT release in vitro was observed in all regions studied. The highest level of basal release was observed in the nucleus accumbens/septal region and hypothalamus and the lowest in the striatum. 3. High potassium (55 mM) increased release of 5HT in all regions, where their basal release was observed. 5HT release was also increased by p-chloroamphetamine (1-10 microM). 4. In rats anaesthetised with pentobarbitone, three electrochemical peaks were observed in the striatum, nucleus accumbens and frontal cortex at + 0.12 V, +0.2 V and + 0.35 V using a micro-graphite paste electrode and differential pulse voltammetry. 5. The peak at + 0.12 V was increased by micro-infusion of ascorbic acid (5 X 10(-6) M) and that at + 0.35 V by micro-infusion of 5HT (5 X 10(-6) M) and 5-hydroxyindole acetic acid (5HIAA) (5 X 10(-6) M). 6. p-Chlorophenylalanine (2 X 150 mg/kg) caused the loss of the peak at + 0.35 V. Fenfluramine (10 mg/kg) also decreased the peak at + 0.35 V. 7. The results indicate the validity of the in vitro technique and demonstrate the future potential of the in vivo method, though further studies are needed to determine the precise chemical nature of the changes in oxidation following administration of drugs acting on 5HT neurones. PMID:7288649

Marsden, C A; Bennett, G W; Brazell, M; Sharp, T; Stolz, J F



RGS inhibition at G?i2 selectively potentiates 5-HT1A–mediated antidepressant effects  

PubMed Central

Elevating serotonin (5-HT) levels with selective serotonin reuptake inhibitors (SSRIs) is the most widely used treatment for depression. However, current therapies are ineffective, have delayed benefit, or cause side effects in many patients. Here, we define a mechanism downstream of 5-HT1A receptors that mediates antidepressant-like behavior and is profoundly and selectively enhanced by genetic disruption of regulators of G protein signaling (RGS) activity at G?i2. Animals rendered insensitive to RGS protein regulation through a mutation in G?i2 (G184S) exhibited spontaneous antidepressant- and anxiolytic-like behaviors. Mice expressing RGS-insensitive G?i2 also exhibited increased cortical and hippocampal phosphorylation of glycogen synthase kinase-3?, a constitutively active proapoptotic kinase that is inhibited through phosphorylation in response to serotonin, SSRIs, and 5-HT1 receptor agonists. Both behavioral and biochemical phenotypes were blocked by treatment with WAY 100635, a 5-HT1A–selective antagonist. RGS-insensitive mice were also 5–10 times more responsive to the antidepressant-like effects of the SSRI fluvoxamine and 5-HT1A–selective agonist 8-hydroxy-2-dipropylaminotetralin. In contrast, the antidepressant potency of agents acting through nonserotonergic mechanisms was unchanged as was 5-HT1A action on body temperature. The findings point to a critical role for endogenous RGS proteins to suppress the antidepressant-like effects of 5-HT1A receptor activation. By selectively enhancing the beneficial effects of serotonin, inhibition of RGS proteins represents a therapeutic approach for the treatment of mood disorders. PMID:20534514

Talbot, Jeffery N.; Jutkiewicz, Emily M.; Graves, Steven M.; Clemans, Crystal F.; Nicol, Melanie R.; Mortensen, Richard M.; Huang, Xinyan; Neubig, Richard R.; Traynor, John R.



The effects of benzofury (5-APB) on the dopamine transporter and 5-HT2-dependent vasoconstriction in the rat.  


5-APB, commonly marketed as 'benzofury' is a new psychoactive substance and erstwhile 'legal high' which has been implicated in 10 recent drug-related deaths in the UK. This drug was available on the internet and in 'head shops' and was one of the most commonly sold legal highs up until its recent UK temporary ban (UK Home Office). Despite its prominence, very little is known about its pharmacology. This study was undertaken to examine the pharmacology of 5-APB in vitro. We hypothesised that 5-APB would activate the dopamine and 5-HT systems which may underlie its putative stimulant and hallucinogenic effects. Autoradiographic studies showed that 5-APB displaced both [(125)I] RTI-121 and [(3)H] ketanserin from rat brain tissue suggesting affinity at the dopamine transporter and 5-HT2 receptor sites respectively. Voltammetric studies in rat accumbens brain slices revealed that 5-APB slowed dopamine reuptake, and at high concentrations caused reverse transport of dopamine. 5-APB also caused vasoconstriction of rat aorta, an effect antagonised by the 5-HT2A receptor antagonist ketanserin, and caused contraction of rat stomach fundus, which was reversed by the 5-HT2B receptor antagonist RS-127445. These data show that 5-APB interacts with the dopamine transporter and is an agonist at the 5-HT2A and 5-HT2B receptors in the rat. Thus 5-APB's pharmacology is consistent with it having both stimulant and hallucinogenic properties. In addition, 5-APB's activity at the 5-HT2B receptor may cause cardiotoxicity. PMID:24012617

Dawson, Patrick; Opacka-Juffry, Jolanta; Moffatt, James D; Daniju, Yusuf; Dutta, Neelakshi; Ramsey, John; Davidson, Colin



Gamma aminobutyric acid B and 5-hydroxy tryptamine 2A receptors functional regulation during enhanced liver cell proliferation by GABA and 5-HT chitosan nanoparticles treatment.  


Liver is one of the major organs in vertebrates and hepatocytes are damaged by many factors. The liver cell maintenance and multiplication after injury and treatment gained immense interest. The present study investigated the role of Gamma aminobutyric acid (GABA) and serotonin or 5-hydroxytryptamine (5-HT) coupled with chitosan nanoparticles in the functional regulation of Gamma aminobutyric acid B and 5-hydroxy tryptamine 2A receptors mediated cell signaling mechanisms, extend of DNA methylation and superoxide dismutase activity during enhanced liver cell proliferation. Liver injury was achieved by partial hepatectomy of male Wistar rats and the GABA and 5-HT chitosan nanoparticles treatments were given intraperitoneally. The experimental groups were sham operated control (C), partially hepatectomised rats with no treatment (PHNT), partially hepatectomised rats with GABA chitosan nanoparticle (GCNP), 5-HT chitosan nanoparticle (SCNP) and a combination of GABA and 5-HT chitosan nanoparticle (GSCNP) treatments. In GABA and 5-HT chitosan nanoparticle treated group there was a significant decrease (P<0.001) in the receptor expression of Gamma aminobutyric acid B and a significant increase (P<0.001) in the receptor expression of 5-hydroxy tryptamine 2A when compared to PHNT. The cyclic adenosine monophosphate content and its regulatory protein, presence of methylated DNA and superoxide dismutase activity were decreased in GCNP, SCNP and GSCNP when compared to PHNT. The Gamma aminobutyric acid B and 5-hydroxy tryptamine 2A receptors coupled signaling elements played an important role in GABA and 5-HT chitosan nanoparticles induced liver cell proliferation which has therapeutic significance in liver disease management. PMID:23748019

Shilpa, Joy; Pretty, Mary Abraham; Anitha, Malat; Paulose, Cheramadathikudyil Skaria



[Determination of 6-hydroxy-1-methyl-1,2,3,4-tetrahydro-beta-carboline, 5-hydroxytryptamine and 5-hydroxyindole acetic acid in the neonatal rat brains using high performance iquid chromatography-electrochemical detection].  


A simple method was developed for the analysis of 6-hydroxy-1-methyl-1,2,3,4-tetrahydro-beta-carboline (6-OH-MTHbetaC), 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in rat brain by high performance liquid chromatography with electrochemical detection (HPLC-ECD). The separation of the sample was performed on a Discovery HS F5 column (250 mm x 4.6 mm, 5 microm) with a mobile phase of the buffer (40 mmol/L citric acid + 20 mmol/L Na2HPO4 + 0.3 mmol/L EDTA2Na, pH 4.0)-methanol (78:22, v/v) at a flow rate of 1.0 mL/min. The electrochemical detector was Coularray Detector-4. This method showed good linearity (r > 0.9992) for the quantification of 6-OH-MTHbetaC, 5-HT and 5-HIAA in the concentration range of 1.0-500.0 microg/L. The limits of detection were 0.56, 0.26 and 0.53 microg/L, respectively. The recoveries of 6-OH-MTHbetaC, 5-HT and 5-HIAA spiked in rat brain samples were 87.1%-98.2%, 87.0%-95.3%, 90.1%-97.7%, respectively, and the relative standard deviations of intra-day and inter-day determinations were both less than 6.1%. In comparison with the control, the analysis of alcohol-exposed neonatal rat brain samples revealed a significant difference in the level of 6-OH-MTHbetaC (P < 0.05). The method was proved to be simple, highly sensitive, and could be applied in the analysis of 6-OH-MTHbetaC, 5-HT and 5-HIAA in the rat brain. PMID:19626852

Mao, Jian; Su, Yang; Luan, Yujing; Chen, Xuechai; Deng, Yulin



SLC6A4 markers modulate platelet 5-HT level and specific behaviors of autism: a study from an Indian population.  


Presence of platelet hyperserotonemia and effective amelioration of behavioral dysfunctions by selective serotonin reuptake inhibitors (SSRI) in autism spectrum disorders (ASD) indicate that irregularities in serotonin (5-HT) reuptake and its homeostasis could be the basis of behavioral impairments in ASD patients. SLC6A4, the gene encoding serotonin transporter (SERT) is considered as a potential susceptibility gene for ASD, since it is a quantitative trait locus for blood 5-HT levels. Three functional polymorphisms, 5-HTTLPR, STin2 and 3'UTR-SNP of SLC6A4 are extensively studied for possible association with the disorder, with inconclusive outcome. In the present study, we investigated association of these polymorphisms with platelet 5-HT content and symptoms severity as revealed by childhood autism rating scale in ASD children from an Indian population. Higher 5-HT level observed in ASD was highly significant in children with heterozygous and homozygous genotypes comprising of minor alleles of the markers. Quantitative transmission disequilibrium test demonstrated significant genetic effect of STin2 allele as well as STin2/3'UTR-SNP and 5-HTTLPR/3'UTR-SNP haplotypes on 5-HT levels, but no direct association with overall CARS score and ASD phenotype. Significant genetic effect of the markers on specific behavioral phenotypes was observed for various sub-phenotypes of CARS in quantitative trait analysis. Even though the 5-HT level was not associated with severity of behavioral CARS score, a significant negative relationship was observed for 5-HT levels and level and consistency of intellectual response and general impression in ASD children. Population-based study revealed higher distribution of the haplotype 10/G of STin2/3'UTR-SNP in male controls, suggesting protective effect of this haplotype in male cases. Overall results of the study suggest that SLC6A4 markers have specific genetic effect on individual ASD behavioral attributes, might be through the modulation of 5-HT content. PMID:25261775

Jaiswal, Preeti; Guhathakurta, Subhrangshu; Singh, Asem Surindro; Verma, Deepak; Pandey, Mritunjay; Varghese, Merina; Sinha, Swagata; Ghosh, Saurabh; Mohanakumar, Kochupurackal P; Rajamma, Usha



Inhibition of platelet aggregation and 5-HT release by extracts of Australian plants used traditionally as headache treatments.  


To identify potential migraine therapeutics, extracts of eighteen plants were screened to detect plant constituents affecting ADP induced platelet aggregation and [14C]5-hydroxytryptamine (5-HT) release. Extracts of the seven plants exhibiting significant inhibition of platelet function were reanalysed in the presence of polyvinyl pyrrolidone (PVP) to remove polyphenolic tannins that precipitate proteins. Two of these extracts no longer exhibited inhibition of platelet activity after removal of tannins. However, extracts of Crataegus monogyna, Ipomoea pes-caprae, Eremophila freelingii, Eremophila longifolia, and Asteromyrtus symphyocarpa still potently inhibited ADP induced human platelet [14C]5-HT release in vitro, with levels ranging from 62 to 95% inhibition. I. pes-caprae, and C. monogyna also caused significant inhibition of ADP induced platelet aggregation. All of these plants have been previously used as traditional headache treatments, except for C. monogyna which is used primarily for protective effects on the cardiovascular system. Further studies elucidating the compounds that are responsible for these anti-platelet effects are needed to determine their exact mechanism of action. PMID:10664475

Rogers, K L; Grice, I D; Griffiths, L R



Effect of heat stress on brain 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in some vertebrate species.  


1. The variations in 5-HT and 5-HIAA levels following heat exposure and split heat doses were determined in the different brain regions of Gerbillus pyramidum, Streptopelia senegalensis aegyptiaca and Agama stellio. 2. Heat exposure was found to be associated with an increase in the levels of the two indole compounds. 3. The 5-HT concentrations increased markedly in the three species following the first heat dose and decreased following the second dose in the various brain regions except in the cerebellum of Agama. 4. The increased 5-HT levels when animals are exposed to high temperature probably represent a response to activate heat-loss mechanisms and to depress heat production. PMID:6184194

Mohamed, M I; Rahman, T A



Differential Distribution of [ 3H]Sumatriptan Binding Sites (5HT 1B, 5HT 1D and 5HT 1F Receptors) in Human Brain: Focus on Brainstem and Spinal Cord  

Microsoft Academic Search

We report on the autoradiographic distribution of 5-HT1B, 5-HT1D and 5-HT1F receptor subtypes in human brain, focusing on the brainstem and cervical spinal cord. We have used [3H]sumatriptan as a radioligand in the presence of suitable concentrations of 5-CT (5-carboxamidotryptamine) to define 5-HT1F receptors, and ketanserin, to discriminate between 5-HT1B and 5-HT1D receptors. In the brainstem the highest concentrations of




Fluoxetine and all other SSRIs are 5-HT2B Agonists - Importance for their Therapeutic Effects  

PubMed Central

Fluoxetine and other serotonin-specific re-uptake inhibitors (SSRIs) are generally thought to owe their therapeutic potency to inhibition of the serotonin transporter (SERT). However, research in our laboratory showed that it affects, with relatively high affinity the 5-HT2B receptor in cultured astrocytes; this finding was confirmed by independent observations showing that fluoxetine loses its ability to elicit SSRI-like responses in behavioral assays in mice in which the 5-HT2B receptor was knocked-out genetically or inhibited pharmacologically. All clinically used SSRIs are approximately equipotent towards 5-HT2B receptors and exert their effect on cultured astrocytes at concentrations similar to those used clinically, a substantial difference from their effect on SERT. We have demonstrated up-regulation and editing of astrocytic genes for ADAR2, the kainate receptor GluK2, cPLA2 and the 5-HT2B receptor itself after chronic treatment of cultures, which do not express SERT and after treatment of mice (expressing SERT) for 2 weeks with fluoxetine, followed by isolation of astrocytic and neuronal cell fractionation. Affected genes were identical in both experimental paradigms. Fluoxetine treatment also altered Ca2+ homeostatic cascades, in a specific way that differs from that seen after treatment with the anti-bipolar drugs carbamazepine, lithium, or valproic acid. All changes occurred after a lag period similar to what is seen for fluoxetine’s clinical effects, and some of the genes were altered in the opposite direction by mild chronic inescapable stress, known to cause anhedonia, a component of major depression. In the anhedonic mice these changes were reversed by treatment with SSRIs. PMID:25342944

Peng, Liang; Gu, Li; Li, Baoman; Hertz, Leif



Serotonin 5HT2A and 5HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients  

Microsoft Academic Search

BACKGROUND: It has been hypothesized that alterations of the serotonergic system contribute to neuropsychiatric symptoms in Alzheimer disease (AD). Cellular expressions of the two serotonergic receptors 5-HT2A and 5-HT6 have therefore been determined by immunohistochemistry in the prefrontal cortex of patients with AD (n=6) and normal age-matched controls (n = 7). RESULTS: In normal aging patients, 5-HT2A label was mainly

Dietrich E Lorke; Gang Lu; Eric Cho; David T Yew



Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors  

Microsoft Academic Search

Evidence from studies with phenylisopropylamine hallucinogens indicates that the 5HT2A receptor is the likely target for the initiation of events leading to hallucinogenic activity associated with LSD?and related\\u000a drugs. Recently, lisuride (a purported non-hallucinogenic congener of LSD) was reported to be a potent antagonist at the 5HT2C receptor and an agonist at the 5HT2A receptor. LSD exhibited agonist activity at

Christina T. Egan; Katharine Herrick-Davis; Keith Miller; Richard A. Glennon; M. Teitler



Postnatal development of serotonergic innervation, 5-HT1A receptor expression, and 5-HT responses in rat motoneurons.  


We compared the electrophysiological responses to serotonin (5-HT) of neonatal and juvenile rat hypoglossal motoneurons (HMs) by using intracellular recording techniques in a brainstem slice preparation. In neonatal HMs (5-HT caused a substantial decrease in the amplitude of spike afterhyperpolarization (AHP) that was associated with an increase in the minimal repetitive firing frequency (Fmin). Previous work has shown that this effect of 5-HT was mediated by the 5-HT1A receptor and may be secondary to inhibition of N- and P/Q-type calcium channels. In contrast to results from neonates, we found that 5-HT did not inhibit the AHP in juvenile HMs (>/= P20). Application of a cocktail of calcium channel toxins (omega-Conotoxin-GVIA and omega-Agatoxin-IVA) to juvenile HMs substantially inhibited the AHP, indicating that calcium entry through N- and P/Q-type channels supports the AHP in juvenile HMs, as it does in neonates. In addition, intracellular injection of the long-lasting GTP analog GTPgammaS induced an agonist-independent increase in Fmin similar to that seen in neonates in the presence of 5-HT. Together, these results suggested that intracellular mechanisms downstream of the 5-HT1A receptor capable of inhibiting the AHP were intact in juvenile HMs. Therefore, we investigated the possibility that age-related changes in effects of 5-HT on the AHP resulted from altered expression of the 5-HT1A receptor. To this end, we performed ligand-binding autoradiography using [3H]8-OH-DPAT, a 5-HT1A agonist, and in situ hybridization using radiolabeled oligonucleotide probes specific for the 5-HT1A receptor. The two approaches gave remarkably similar results. The highest levels of 5-HT1A receptor expression were found in neonatal HMs, with maximal binding and hybridization at approximately postnatal day 7 (P7) and only low levels of receptor expression by P28. Finally, immunohistochemistry for 5-HT revealed that these developmental changes in 5-HT1A receptor expression occurred coincident with a postnatal increase in serotonergic innervation of the hypoglossal nucleus (nXII). Together, these findings indicate that developmental changes occur in the serotonergic innervation of nXII and in the expression of 5-HT1A receptors in HMs during the early postnatal period, resulting in markedly different effects of 5-HT on firing behavior in neonatal and juvenile HMs. PMID:9151764

Talley, E M; Sadr, N N; Bayliss, D A



RU 24969-induced emesis in the cat - 5-HT1 sites other than 5-HT1A, 5-HT1B or 5-HT1C implicated  

NASA Technical Reports Server (NTRS)

RU 24969 was administered s.c. to cats and found to elicit emesis with a maximally effective dose of 1.0 mg/kg 5-Methoxytryptamine was found to have lower efficacy and to produce a higher incidence of nonspecific effects while trifluoromethylphenylpiperizine (TFMPP) was devoid of emetic effects. The emesis elicited by 1.0 mg/kg of RU 24969 was not altered by pretreatment with phentolamine, haloperidol, yohimbine or (-)-propranolol, indicating that catecholamines played no role in this response. The emesis was prevented by metergoline and methysergide but not by ketanserin, cyproheptadine, mesulergine, ICS 205 930, methiothepin, trimethobenzamide or BMY 7378. An indirect argument is presented that implicates a role for 5-HT1D sites. This conclusion must remain tentative until drugs selective for this site are synthesized and tested. The emesis was also prevented by 8-hydroxy-2-(di-n-propylamine)tetralin (8-OH-DPAT), confirming that this drug has a general antiemetic effect in cats.

Lucot, James B.




PubMed Central

The lung is able to rapidly remove 5-hydroxytryptamme (5-HT) from the circulation by a Na+-dependent transport mechanism. In order to identify the sites of uptake, radioautographic studies were done on rat lungs which had been isolated and perfused with 5-HT-3H and 0 5 mM iproniazid, a monoamine oxidase inhibitor. In control experiments 10-4 M imipramine was added to the perfusate to inhibit the membrane transport of 5-HT At the light microscope level, silver grains were seen concentrated near capillaries and in the endothelium of large vessels From electron microscope radioautographs a semiquantitative grain count was made and 90% of the silver grains were observed over capillary endothelial cells. The grains were found over the nucleus and cytoplasm of the cell and shewed no preferential association with any particular cytoplasmic inclusion bodies, organelles, or vesicles Other cell types were unlabeled except for a few mast cells, certain vascular smooth muscle cells, and one nerve ending. This radioautographic demonstration of the cell type responsible for the rapid removal of 5-HT from the lung circulation clearly establishes the existence of a new metabolic role for pulmonary endothelial cells. PMID:5044755

Strum, Judy M.; Junod, Alain F.



Activation of cortical 5-HT3 receptor-expressing interneurons induces NO mediated vasodilatations and NPY mediated vasoconstrictions  

PubMed Central

GABAergic interneurons are local integrators of cortical activity that have been reported to be involved in the control of cerebral blood flow (CBF) through their ability to produce vasoactive molecules and their rich innervation of neighboring blood vessels. They form a highly diverse population among which the serotonin 5-hydroxytryptamine 3A receptor (5-HT3A)-expressing interneurons share a common developmental origin, in addition to the responsiveness to serotonergic ascending pathway. We have recently shown that these neurons regroup two distinct subpopulations within the somatosensory cortex: Neuropeptide Y (NPY)-expressing interneurons, displaying morphological properties similar to those of neurogliaform cells and Vasoactive Intestinal Peptide (VIP)-expressing bipolar/bitufted interneurons. The aim of the present study was to determine the role of these neuronal populations in the control of vascular tone by monitoring blood vessels diameter changes, using infrared videomicroscopy in mouse neocortical slices. Bath applications of 1-(3-Chlorophenyl)biguanide hydrochloride (mCPBG), a 5-HT3R agonist, induced both constrictions (30%) and dilations (70%) of penetrating arterioles within supragranular layers. All vasoconstrictions were abolished in the presence of the NPY receptor antagonist (BIBP 3226), suggesting that they were elicited by NPY release. Vasodilations persisted in the presence of the VIP receptor antagonist VPAC1 (PG-97-269), whereas they were blocked in the presence of the neuronal Nitric Oxide (NO) Synthase (nNOS) inhibitor, L-NNA. Altogether, these results strongly suggest that activation of neocortical 5-HT3A-expressing interneurons by serotoninergic input could induces NO mediated vasodilatations and NPY mediated vasoconstrictions. PMID:22907992

Perrenoud, Quentin; Rossier, Jean; Férézou, Isabelle; Geoffroy, Hélène; Gallopin, Thierry; Vitalis, Tania; Rancillac, Armelle



Contextual fear conditioning modulates hippocampal AMPA-, GluN1- and serotonin receptor 5-HT1A-containing receptor complexes.  


Although the roles of AMPAR (?-amino-3-hydroxyl-5-methyl-4-isoxazole propionate receptor), NMDAR (N-methyl-d-aspartate receptor) and 5HT1AR (5-hydroxytryptamine sub type 1A) in contextual fear conditioning (cFC) have been studied, information about receptor-containing complexes (RC) is not available. Moreover, there are no data on membrane or endosomal NMDA-, 5HT1A- or AMPA-RC levels, which would likely be indicative of the trafficking of these receptors. cFC was carried out in C57BL/6j mice and animals were sacrificed in the individual phases and hippocampi were taken for the determination of receptor complex and subunit levels using BN- and SDS-PAGE with subsequent Western blotting. GluA1-4, GluN1 (NMDAR subunit NR1)- and 5HT1A-RC were differentially regulated during the individual phases and differentially regulated in the membrane and endosomal fractions. GluA1-RC levels in the membrane were increased in acquisition, consolidation and retrieval phases; GluA2-RC and GluA3-RC membrane levels were reduced and modulated in early endosomes during these phases. GluA4-RC and GluN1-RC levels as well as their subunits showed the same pattern in the membrane during consolidation while 5HT1A-RC membrane and endosome levels were mainly increased during consolidation and retrieval. Taken together, the results suggest that levels of 5-HT1A-RC, NMDA-RC and AMPA-RC and subunits in membrane and endosomal preparations are paralleling individual phases of cFC. The findings from the current study suggest phase-specific receptor complex and subunit formation and propose that receptor complexes should be examined in parallel with receptor subunits to aid the interpretation of previous work and to design future work on neurotransmitter receptors in memory paradigms. PMID:25264576

Sase, Sunetra; Stork, Oliver; Lubec, Gert; Li, Lin



Desensitization of pre and post synaptic 5-HT-1A receptor responses following long term consumption of sugar rich diet: implications for sugar-induced obesity.  


The present study concerns the effectiveness of a selective 5-hydroxytryptamine (5-HT)-1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in long term sugar diet treated rats. Male albino wistar rats were divided into control and test groups. Test animals were given sugar (5 g/10 ml water) orally for three weeks. Food intakes and body weight of all rats were measured weekly. After three weeks control and test animals were further divided into two groups i.e. saline injected and drug injected. 8-OH-DPAT at a dose of 0.25mg/Kg was injected to a group of normal diet treated and another group of sugar diet treated rats. Other two groups were injected with saline. 5-HT syndrome and food intakes at 2h and 4h were monitored. Then animals were decapitated to collect brain samples for the estimation of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) levels by HPLC-EC method. We observed that weekly cumulative food intakes increased and body weights decreased in sugar diet treated rats. 8-OH-DPAT produced hyperactivity syndrome in both control and sugar treated rats. But these values were smaller in sugar diet than normal diet treated rats. Hyperphagic effects of 8-OH-DPAT were greater in normal diet than sugar diet treated rats. 5-HT and 5-HIAA levels were not altered. The results suggesting a desensitization of pre as well as postsynaptic 5-HT-1A receptors in rats treated with sugar diet are discussed in the context of a role of sugar diet in the precipitation of obesity and other neuropsychiatric illnesses. PMID:18930850

Jabeen, Bushra; Haleem, Darakhshan J



The 5-HT2C receptor gene Cys23Ser polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation  

PubMed Central

It has been postulated that the persistent short intravaginal ejaculation latency time (IELT) of men with lifelong premature ejaculation (LPE) is related to 5-hydroxytryptamine (HT)2C receptor functioning. The aim of this study was to investigate the relationship of Cys23Ser 5-HT2C receptor gene polymorphism and the duration of IELT in men with LPE. Therefore, a prospective study was conducted in 64 Dutch Caucasian men with LPE. Baseline IELT during coitus was assessed by stopwatch over a 1-month period. All men were genotyped for Cys23Ser 5-HT2C receptor gene polymorphism. Allele frequencies and genotypes of Cys and Ser variants of 5-HT2C receptor gene polymorphism were determined. Association between Cys/Cys and Ser/Ser genotypes and the natural logarithm of the IELT in men with LPE were investigated. As a result, the geometric mean, median and natural mean IELT were 25.2, 27.0, 33.9 s, respectively. Of all men, 20.0%, 10.8%, 23.1% and 41.5% ejaculated within 10, 10–20, 20–30 and 30–60 s after vaginal penetration. Of the 64 men, the Cys/Cys and Ser/Ser genotype frequency for the Cys23Ser polymorphism of the 5-HT2C receptor gene was 81% and 19%, respectively. The geometric mean IELT of the wildtypes (Cys/Cys) is significantly lower (22.6 s; 95% CI 18.3–27.8 s) than in male homozygous mutants (Ser/Ser) (40.4 s; 95% CI 20.3–80.4 s) (P = 0.03). It is concluded that Cys23Ser 5-HT2C receptor gene polymorphism is associated with the IELT in men with LPE. Men with Cys/Cys genotype have shorter IELTs than men with Ser/Ser genotypes. PMID:24799636

Janssen, Paddy KC; van Schaik, Ron; Olivier, Berend; Waldinger, Marcel D




PubMed Central

Several studies have reported decreased platelet 5-HT uptake in patients of major depression. The mechanism of antidepressant action of ECT is not clear. The present work was undertaken with the aim to study the active platelet 5-HT uptake and the effect of ECT on it in patients of major depression. 15 patients of major depression (DSM-lll-R) and equal number of age and sex-matched controls were included in the study. Active platelet 5-HT uptake was determined before ECT, after a course of ECT and 7 days after last ECT. Platelet 5-HT uptake was. significantly lower in der essives than normal controls. After ECT treatment there was significant increase in 5-HT uptake which came down to pretreatment level after 1 week of last ECT. The effect of ECT on serotonergic system is discussed. PMID:21584091

Dalal, P.K.; Lal, Narottam; Trivedi, J.K.; Seth, P.K.; Agarwal, A.K.; Khalid, Abdul



The Impact of 5-HT3RA Use on Cost and Utilization in Patients with Chemotherapy-Induced Nausea and Vomiting: Systematic Review of the Literature  

PubMed Central

Background Individual studies have assessed the impact of standard prophylactic therapy with 5-hydroxytryptamine receptor antagonists (5-HT3RAs) for chemotherapy-induced nausea and vomiting (CINV) on cost and utilization, but no synthesis of the findings exists. Objective To systematically review published literature on costs and utilization associated with CINV prophylaxis with palonosetron and other 5-HT3RAs. Methods PubMed and the National Institute for Health Research Centre for Reviews and Dissemination databases, conferences of 4 organizations (ie, Academy of Managed Care Pharmacy, American Society of Clinical Oncology, International Society for Pharmacoeconomics and Outcomes Research, and Multinational Association of Supportive Care in Cancer), and the bibliographies of relevant articles were queried for the medical subject headings and key terms of “ondansetron,” “granisetron,” “palonosetron,” “dolasetron mesylate,” “costs,” “cost analysis,” and “economics.” We included records published (full-length articles after 1997 and conference presentations after 2010) in English and with human patients, reporting data on cost and utilization (rescue medication, outpatient and inpatient services) associated with the use of 5-HT3RAs for the treatment or prevention of CINV. Results Of the 434 identified studies, 32 are included in the current analysis: 7 studies report costs, 18 report utilization, and 7 studies report both. The costs are reported in US dollars (7 studies), in Euros (5 studies), and in Canadian dollars (2 studies). The studies vary in designs, patients, 5-HT3RA regimens, and the definition of outcomes. The US studies report higher drug costs for CINV prophylaxis with palonosetron compared with ondansetron, lower medical outpatient and inpatient costs for palonosetron versus other 5-HT3RAs, and higher acquisition costs for palonosetron versus ondansetron or other 5-HT3RAs. Fewer patients receiving palonosetron versus with ondansetron or other 5-HT3RAs required rescue medication or used outpatient or inpatient care. In Europe and in Canada, the total pharmacy costs and use of rescue medications reported are lower for patients receiving prophylaxis with palonosetron. Conclusions This analysis shows that prophylaxis with palonosetron for the treatment of CINV is associated with higher acquisition treatment costs, but also with lower use of rescue medications and outpatient and inpatient services compared with ondansetron or other 5-HT3RAs in the United States. Therefore, the use of palonosetron as a standard treatment may lead to reduced service utilization for CINV. PMID:24991400

Broder, Michael S.; Faria, Claudio; Powers, Annette; Sunderji, Jehangeer; Cherepanov, Dasha



Decreased Hippocampal 5-HT and DA Levels Following Sub-Chronic Exposure to Noise Stress: Impairment in both Spatial and Recognition Memory in Male Rats  

PubMed Central

Mankind is exposed to a number of stressors, and among them noise is one which can cause intense stress. High levels of background noise can severely impair one’s ability to concentrate. The present study was aimed to investigate the effect of sub-chronic noise stress on cognitive behavior and hippocampal monoamine levels in male rats. The study was performed on 12 male Wistar rats, divided into two groups; the control and noise-exposed. The rats in the test group were subjected to noise stress, 4h daily for 15 days. Cognitive testing was performed by the Elevated Plus Maze test (EPM) and Novel Object Recognition test (NOR). HPLC-EC was used to determine hippocampal monoamine levels and their metabolites. The data obtained revealed a significant decrease in hippocampal serotonin (5-hydroxytryptamine; 5-HT) and dopamine (DA) levels, whereas turnover ratios of 5-HT and DA were significantly increased compared to the controls. Rats exposed to noise exhibited a significant decrement in spatial memory. A significantly decreased recognition index of rats exposed to noise as compared to the control was also observed in the NOR test. Results of the present findings suggest the role of decreased hippocampal 5-HT and DA in the impairment of cognitive function following noise exposure. PMID:23264946

Haider, Saida; Naqvi, Fizza; Batool, Zehra; Tabassum, Saiqa; Perveen, Tahira; Saleem, Sadia; Haleem, Darakhshan Jabeen



Quantitative analysis of immunolabeling for serotonin and for glutamate transporters after administration of imipramine and citalopram  

Microsoft Academic Search

Serotonin (5-hydroxytryptamine, 5-HT) is an amine neurotransmitter derived from tryptophan and is important in brain systems regulating mood, emotional behavior, and sleep. Selective serotonin reuptake inhibitor (SSRI) drugs are used to treat disorders such as depression, stress, eating disorders, autism, and schizophrenia. It is thought that these drugs act to prolong the action of 5-HT by blocking reuptake. This may

Susan M. Williams; Lesley J. Bryan-Lluka; David V. Pow



Attenuation of phencyclidine-induced object recognition deficits by the combination of atypical antipsychotic drugs and pimavanserin (ACP 103), a 5-hydroxytryptamine(2A) receptor inverse agonist.  


Subchronic administration of the N-methyl-d-aspartate receptor antagonist, phencyclidine (PCP), in rodents has been shown to produce impairment in novel object recognition (NOR), a model of visual learning and memory. We tested the hypothesis that the selective 5-HT(2A) inverse agonists, pimavanserin and (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4-piperidinemethanol (M100907), would potentiate subeffective doses of atypical antipsychotic drugs (APDs) to reverse the NOR deficits. Female rats received vehicle or PCP (2 mg/kg b.i.d.) for 7 days, followed by a 7-day washout. Pimavanserin (3 mg/kg) or M100907 (1 mg/kg) alone, or four atypicial APDs, risperidone (0.05-0.1 mg/kg), melperone (1-3 mg/kg), olanzapine (1-2 mg/kg), or N-desmethylclozapine (1-2 mg/kg), and the typical APD, haloperidol (0.05-0.1 mg/kg), were administered alone, or in combination with pimavanserin or M100907, before NOR testing. The exploration times of objects during 3-min acquisition and retention trials, separated by a 1-min interval, were compared by analysis of variance. Vehicle-, but not PCP-treated, animals, explored the novel object significantly more than the familiar in the retention trial (p < 0.05-0.01). Pretreatment with the higher doses of the atypical APDs, but not pimavanserin, M100907, or haloperidol alone, reversed the effects of PCP. The effect of risperidone was blocked by haloperidol pretreatment. Coadministration of pimavanserin or M100907, with ineffective doses of the atypical APDs, but not haloperidol, also reversed the PCP-induced deficit in NOR. These results support the importance of 5-hydroxytryptamine(2A) receptor blockade relative to D(2) receptor blockade in the ability of atypicals to ameliorate the effect of subchronic PCP, a putative measure of cognitive dysfunction in schizophrenia. PMID:19864614

Snigdha, S; Horiguchi, M; Huang, M; Li, Z; Shahid, M; Neill, J C; Meltzer, H Y



5-HT4 receptors exert a frequency-related facilitatory control on dorsal raphé nucleus 5-HT neuronal activity.  


We investigated, using single-unit recordings in chloral hydrate-anaesthetized rats, the role of serotonin 4 (5-HT4) receptors in the control of dorsal raphé nucleus (DRN) 5-HT neuron activity. About one-half (36) of the 76 neurons recorded were affected by either the preferential 5-HT4 agonist cisapride (500 and 1000 micro g/kg, i.v.) or the selective 5-HT4 antagonist, GR 125487 (200- 2000 micro g/kg, i.v.). Responding neurons displayed a significantly higher mean basal firing rate (1.93 +/- 0.1 Hz) than non-responders (1.31 +/- 0.1 Hz). The firing rate of responding 5-HT neurons was enhanced dose-dependently by cisapride (+47 and +94% at 500 and 1000 micro g/kg, respectively), an effect abolished by GR 125487 (500 micro g/kg) and reduced by the 5-HT4 antagonist, SDZ 205557 (500 micro g/kg, i.v). Conversely, GR 125487 induced a dose-dependent inhibition of responders activity, which was almost completely suppressed at the dose of 2000 micro g/kg. In a separate set of experiments, the selective 5-HT4 agonist, prucalopride (500 micro g/kg, i.v), increased the firing activity (+35%) of 5-HT neurons displaying a high basal firing rate; subsequent injection of GR 125487 (500 micro g/kg, i.v.) suppressed this effect. These results indicate that 5-HT4 receptors exert both a tonic and a phasic, positive, frequency-related control on DRN 5-HT neuronal activity. The existence of such a control might open new avenues for therapeutic research in the antidepressant field. PMID:12372017

Lucas, Guillaume; Debonnel, Guy



Systemic cannabinoids produce CB 1-mediated antinociception by activation of descending serotonergic pathways that act upon spinal 5HT 7 and 5HT 2A receptors  

Microsoft Academic Search

Serotonin (5-HT) plays an important role in the descending control of pain. We evaluated the role of descending serotonergic pathways and spinal 5-HT7 and 5-HT2A receptors in comparison to that of 5-HT1A and 5-HT3 receptors in the antinociceptive effects of systemically administered cannabinoids. Antinociceptive effects were evaluated by radiant heat tail-flick and hot plate tests in Balb-C mice. The selective

Melik Seyrek; Serdar Kahraman; Mehmet Salih Deveci; Ozgur Yesilyurt; Ahmet Dogrul



Role of 5HT in stress, anxiety, and depression  

Microsoft Academic Search

There are conflicting results on the function of 5-HT in anxiety and depression. To reconcile this evidence, Deakin and Graeff have suggested that the ascending 5-HT pathway that originates in the dorsal raphe nucleus (DRN) and innervates the amygdala and frontal cortex facilitates conditioned fear, while the DRN-periventricular pathway innervating the periventricular and periaqueductal gray matter inhibits inborn fight\\/flight reactions

Frederico G. Graeff; Francisco S. Guimarães; Telma G. C. S. De Andrade; John F. W. Deakin



The 5-HT3 receptor as a therapeutic target  

PubMed Central

The 5-HT3 receptor is a neurotransmitter-gated ion channel. It is a member of the Cys-loop family of receptors, which also includes nicotinic acetylcholine, glycine and GABAA receptors. Each member of the family consists of an arrangement of five subunits surrounding a central ion-conducting pore. The 5-HT3 receptor binding site is composed of six loops from two adjacent subunits, and the critical ligand binding residues within these loops are well documented. There are a range of 5-HT3 receptor agonists and competitive antagonists, but it is the antagonists that dominate their clinical use. Studies have proposed a range of disease symptoms that might be amenable to 5-HT3 receptor selective compounds; however, so far only the treatment of emesis and irritable bowel syndrome have been fully realised. In this review, the authors look at the structure, function and distribution of 5-HT3 receptors and how this may influence their role in disease. The authors also describe the existing clinical applications of 5-HT3 antagonists and the future potential of these drugs. PMID:17373882

Thompson, Andrew J; Lummis, Sarah CR



Myenteric 5-HT-containing neurones activate the descending cholinergic excitatory pathway to the circular muscle of guinea-pig ileum.  

PubMed Central

1. Participation of myenteric 5-hydroxytryptamine (5-HT)-containing neurones in the ascending and descending pathways of the guinea-pig isolated ileum was investigated in a new preparation. Transmural electrical stimulation of the longitudinal muscle-myenteric plexus (LM-MP) portion of the preparation caused ascending and descending contractions of circular or longitudinal muscle in the attached, intact segments situated orally or anally to the point of stimulation. 2. All contractions of LM-MP stimulation were abolished by tetrodotoxin (0.2 microM). The ascending and descending contractions of circular muscles were also abolished by atropine and inhibited to about 50% by hexamethonium. They were not affected by desensitization to substance P (SP) or by the SP antagonist, (D-Pro2,D-Trp7,9)-substance P. The contractions of longitudinal muscles were inhibited by about 45% by hexamethonium and abolished by a combination of atropine with SP desensitization or the SP antagonist, (D-Pro2,D-Trp7,9)-substance P. 3. Desensitization to 5-HT, ICS 205-930 (1 microM) or cocaine (1 microM) reduced the descending contraction of circular muscle by 80-90%, without significantly affecting the ascending contraction. Methysergide (0.2 microM) failed to alter either contraction. 4. 5-HT desensitization, ICS 205-930 and cocaine only partially reduced the descending contraction of longitudinal muscle. A similar reduction of the ascending contraction (20-30%) was also observed. Methysergide had no effects on either contraction. 5. Contractions of either circular or longitudinal muscle produced by field stimulation of the intact segment were not significantly affected by any of the 5-HT receptor antagonists tested.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2480172

Jin, J. G.; Neya, T.; Nakayama, S.



Differential responses to acute administration of a new 5-HT7-R agonist as a function of adolescent pre-treatment: phMRI and immuno-histochemical study  

PubMed Central

LP-211 is a new, selective agonist of serotonin (5-hydroxytryptamine, 5-HT) receptor 7 (5-HT7-R), which is part of a neuro-transmission system with a proposed role in neural plasticity and in mood, cognitive and sleep regulation. Adolescent subchronic LP-211 treatment produces some persisting changes in rats' forebrain structural and functional parameters. Here, using pharmacological MRI (phMRI), we investigated the effect of acute administration with LP-211 (10 mg/kg i.p.), or vehicle, to adult rats previously exposed to the same drug (0.25 mg/kg/day for 5 days), or vehicle, during adolescence (44–48 post-natal days); histology and immuno-histochemistry were performed ex vivo to evaluate neuro-anatomical and physiological long-term adaptation to pharmacological pre-treatment. The phMRI signal reveals forebrain areas (i.e., hippocampus, orbital prefrontal cortex), activated in response to LP-211 challenge independently of adolescent pre-treatment. In septum and nucleus accumbens, sensitized activation was found in adolescent pre-treated rats but not in vehicle-exposed controls. Immuno-histochemical analyses showed marked differences in septum as long-term consequence of the adolescent pre-treatment: increased level of 5-HT7-R, increased number of 5-HT7-R positive cells, and enhanced astrocyte activation. For nucleus accumbens, immuno-histochemical analyses did not reveal any difference between adolescent pre-treated rats and vehicle-exposed controls. In conclusion, subchronic LP-211 administration during adolescence is able to induce persistent physiological changes in the septal 5-HT7-R expression and astrocyte response that can still be observed in adulthood. Data shed new insights into roles of 5-HT7-R for normal and pathologic behavioral regulations. PMID:25565998

Altabella, Luisa; Sbriccoli, Marco; Zoratto, Francesca; Poleggi, Anna; Vinci, Ramona; Lacivita, Enza; Leopoldo, Marcello; Laviola, Giovanni; Cardone, Franco; Canese, Rossella; Adriani, Walter



Release of endogenous serotonin from two identified serotonin-containing neurones and the physiological role of serotonin re-uptake  

PubMed Central

1. The amounts of endogenous serotonin (5-HT) released into the medium by the cerebro-buccal ganglionic ring of Aplysia californica incubated in artificial sea water (ASW) were measured. The rate of spontaneous 5-HT release varied between 0·4 and 1·2 p-mole per hour, which is less than 1% of the total 5-HT present in this preparation. 2. Direct stimulation of the ordinarily silent 5-HT-containing giant cerebral neurones resulted in a 80-100% increase of the 5-HT released, but only when the 5-HT uptake was blocked by chlorimipramine (1-10 ?M). 3. High K+ media (50 mM) also caused a significant increase in the amount of 5-HT released from the preparation provided that chlorimipramine (1-10 ?M) was present in the incubation fluid. 4. Co2+ ions (10-30 mM) added to the incubating medium blocked the spontaneous leak of endogenous 5-HT as well as the release, in the presence of chlorimipramine, evoked either by stimulation of the 5-HT-giant cerebral neurones or high K+-media. 5. In the presence of chlorimipramine or desmethylimipramine, the duration and/or the amplitude of the excitatory or the inhibitory synaptic potentials evoked in the buccal neurones by the stimulation of the 5-HT giant cerebral neurones were markedly enhanced. 6. These results strongly support the idea that 5-HT is the synaptic transmitter released at the excitatory and inhibitory junctions established by the 5-HT giant cerebral neurones in the ipsilateral buccal ganglia. In addition, they underline the role of amine re-uptake in the physiological inactivation of 5-HT as a transmitter. PMID:203673

Hamon, M.; Gerschenfeld, H. M.; Paupardin-Tritsch, Daniele



Modification of 5-hydroxytryptophan-evoked 5-hydroxytryptamine formation of guinea pig colonic mucosa by reactive oxygen species.  


We studied whether reactive oxygen species (ROS) generated by normal colonic mucosa affect 5-hydroxytryptophan (5-HTP)-evoked 5-HT formation (measured as the sum of 5-HT plus 5-hydroxyindole acetic acid (5-HIAA) accumulation) of guinea pig's isolated colonic mucosa. Catalase (3000-6000 U/ml), a hydrogen peroxide (H2O2) scavenger or diphenylene iodonium (DPI, 10-100 microM), an NADPH oxidase inhibitor, concentration-dependently caused an increase of the sum of 5-HT plus 5-HIAA accumulation in the presence of 5-HTP (10 microM), but these drugs did not significantly affect the 5-HT-metabolite in the colonic mucosa measured as the ratio of 5-HIAA/5-HT. Exogenously applied H2O2 (10-100 microM) concentration-dependently inhibited the sum of 5-HT plus 5-HIAA accumulation. In contrast, neither superoxide dismutase (SOD, 100-300 U/ml), superoxide anion scavenger, nor dimetyl sulfoxide (1-5%, DMSO), a hydroxyl radical scavenger affected the sum of 5-HT plus 5-HIAA accumulation. Moreover, mucosa ROS generation was estimated using the chemiluminescence technique. SOD (100-300 U/ml), catalase (3000-6000 U/ml) or DPI (10-100 microM), concentration-dependently reduced luminol-enhanced chemiluminescence signal from the colonic mucosa, while allopurinol (10-100 microM), a xanthine oxidase inhibitor, did not affect the chemiluminescence signal. These results suggest that ROS is formed through an NADPH oxidase system in the guinea pig colonic mucosa, where it exerts a modulatory effect on mucosal 5-HT formation upon addition of 5-HTP. Thus, ROS formation from normal colonic mucosa could be considered to contribute to the control of 5-HT production in mucosa enterochromaffin cells. PMID:11855670

Kojim, Shu-ichi; Ikeda, Masashi; Shibukawa, Asako; Kamikawa, Yuichiro



Serotonin (5-HT) Affects Expression of Liver Metabolic Enzymes and Mammary Gland Glucose Transporters during the Transition from Pregnancy to Lactation  

PubMed Central

The aim of this experiment was to demonstrate the ability of feeding serotonin (5-HT; 5-hydroxytryptamine) precursors to increase 5-HT production during the transition from pregnancy to lactation and the effects this has on maternal energy metabolism in the liver and mammary gland. Pregnant rats (n?=?45) were fed one of three diets: I) control (CON), II) CON supplemented with 0.2% 5-hydroxytryptophan (5-HTP) or III) CON supplemented with 1.35% L-tryptophan (L-TRP), beginning on d13 of pregnancy through d9 of lactation (d9). Serum (pre and post-partum), milk (daily), liver and mammary gland tissue (d9) were collected. Serum 5-HT was increased in the 5-HTP fed dams beginning on d20 of gestation and remained elevated through d9, while it was only increased on d9 in the L-TRP fed dams. 5-HT levels were increased in mammary gland and liver of both groups. Additionally, 5-HTP fed dams had serum and milk glucose levels similar to the CON, while L-TRP had decreased serum (d9) and milk glucose (all dates evaluated). Feeding 5-HTP resulted in increased mRNA expression of key gluconeogenic and glycolytic enzymes in liver and glucose transporters 1 and 8 (GLUT-1, -8) in the mammary gland. We demonstrated the location of GLUT-8 in the mammary gland both in the epithelial and vascular endothelial cells. Finally, phosphorylated 5? AMP-activated protein kinase (pAMPK), a known regulator of intracellular energy status, was elevated in mammary glands of 5-HTP fed dams. Our results suggest that increasing 5-HT production during the transition from pregnancy to lactation increases mRNA expression of enzymes involved in energy metabolism in the liver, and mRNA abundance and distribution of glucose transporters within the mammary gland. This suggests the possibility that 5-HT may be involved in regulating energy metabolism during the transition from pregnancy to lactation. PMID:23469086

Laporta, Jimena; Peters, Tonia L.; Merriman, Kathryn E.; Vezina, Chad M.; Hernandez, Laura L.



Effects of Sustained Administration of Quetiapine Alone and in Combination with a Serotonin Reuptake Inhibitor on Norepinephrine and Serotonin Transmission  

PubMed Central

Quetiapine is now used in the treatment of unipolar and bipolar disorders, both alone and in combination with other medications. In the current study, the sustained administration of quetiapine and N-Desalkyl quetiapine (NQuet) in rats in a 3?:?1 mixture (hQuetiapine (hQuet)) was used to mimic quetiapine exposure in patients because rats do not produce the latter important metabolite of quetiapine. Sustained administration of hQuet for 2 and 14 days, respectively, significantly enhanced the firing rate of norepinephrine (NE) neurons by blocking the cell body ?2-adrenergic autoreceptors on NE neurons, whether it was given alone or with a serotonin (5-HT) reuptake inhibitor. The 14-day regimen of hQuet enhanced the tonic activation of postsynaptic ?2- but not ?1-adrenergic receptors in the hippocampus. This increase in NE transmission was attributable to increased firing of NE neurons, the inhibition of NE reuptake by NQuet, and the attenuated function of terminal ?2-adrenergic receptors on NE terminals. Sustained administration of hQuet for 2 and 14 days, respectively, significantly inhibited the firing rate of 5-HT, whether it was given alone or with a 5-HT reuptake inhibitor, because of the blockade of excitatory ?1-adrenergic receptors on 5-HT neurons. Nevertheless, the 14-day regimen of hQuet enhanced the tonic activation of postsynaptic 5-HT1A receptors in the hippocampus. This increase in 5-HT transmission was attributable to the attenuated inhibitory function of the ?2-adrenergic receptors on 5-HT terminals and possibly to direct 5-HT1A receptor agonism by NQuet. The enhancement of NE and 5-HT transmission by hQuet may contribute to its antidepressant action in mood disorders. PMID:22373941

Chernoloz, Olga; El Mansari, Mostafa; Blier, Pierre



Selectivity of 3H-MADAM binding to 5-hydroxytryptamine transporters in vitro and in vivo in mice; correlation with behavioural effects  

PubMed Central

Binding of the novel radioligand 3H-2-(2-dimethylaminomethyl-phenylsulphanyl)-5-methyl-phenylamine (3H-MADAM) to the serotonin transporter (SERT) was used to characterise a range of selective serotonin re-uptake inhibitors (SSRIs) in vitro and in vivo. 3H-MADAM bound with high affinity in a saturable manner to both human SERT expressed in CHO cells (Kd=0.20 nM (pKd=9.74±0.12), Bmax=35±4 fmol mg?1 protein) and mouse cerebral cortex membranes (Kd=0.21 nM (pKd=9.66±0.10), Bmax=50±24 fmol mg?1 protein). Binding of 3H-MADAM was highly selective for SERT in vitro as demonstrated by the in vitro profile of MADAM tested at 75 different receptors, ion channels and transporters. This was further substantiated by the pharmacological profile of the binding. Hence, the binding of 3H-MADAM was potently inhibited by SSRIs but not by selective inhibitors of noradrenaline transport and dopamine transport. Likewise, a 5-HT2A/2C receptor antagonist did not inhibit 3H-MADAM binding. 3H-MADAM binding in vivo was inhibited only by compounds which also inhibited the binding of 3H-MADAM in vitro (the SSRIs, mixed SERT/noradrenaline transport inhibitors and clomipramine), confirming the selectivity of 3H-MADAM for SERT also in vivo. Moreover, compounds effective in inhibiting 3H-MADAM binding were the only ones found to be active in the mouse 5-HTP potentiation test confirming the model as a behavioural correlate to in vivo 5-HT uptake. Finally, it was found that a SERT occupancy of 85–95% was necessary to produce 50% of the maximum behavioural response (ED50). PMID:14993096

Larsen, A K; Brennum, L T; Egebjerg, J; Sánchez, C; Halldin, C; Andersen, P H



5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver  

Technology Transfer Automated Retrieval System (TEKTRAN)

Mice lacking 5-HT 2C receptors displayed hepatic insulin resistance, a phenotype normalized by re-expression of 5-HT2CRs only in pro-opiomelanocortin (POMC) neurons. 5-HT2CR deficiency also abolished the anti-diabetic effects of meta-chlorophenylpiperazine (a 5-HT2CR agonist); these effects were re...


Regulating prefrontal cortex activation: an emerging role for the 5-HT?A serotonin receptor in the modulation of emotion-based actions?  


The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala and the striatal circuitry, areas involved in emotion and reward processing. The PFC, however, is able to modulate amygdala reactivity via a feedback loop to this area. A role for serotonin in adjusting for this circuitry of cognitive regulation of emotion has long been suggested based primarily on the positive pharmacological effect of elevating serotonin levels in anxiety regulation. Recent animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-hydroxytryptamine (5-HT)2A serotonin receptor in the PFC feedback regulatory projection onto the amygdala. This receptor is highly expressed in the prefrontal cortex areas, playing an important role in modulating cortical activity and neural oscillations (brain waves). This makes it an interesting potential pharmacological target for the treatment of neuropsychiatric modes characterized by lack of inhibitory control of emotion-based actions, such as addiction and other impulse-related behaviors. In this review, we give an overview of the 5-HT2A receptor distribution (neuronal, intracellular, and anatomical) along with its functional and physiological effect on PFC activation, and how that relates to more recent findings of a regulatory effect of the PFC on the emotional control of our actions. PMID:23696058

Aznar, Susana; Klein, Anders B



Electrochemical measurements of serotonin (5-HT) release from the guinea pig mucosa using continuous amperometry with a boron-doped diamond microelectrode  

PubMed Central

Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by chronic abdominal discomfort, including pain, bloating and changes in bowel habits. The exact cause of IBS is not entirely understood. Recent studies have shown that IBS may be associated with altered serotonin (5-hydroxytryptamine, 5-HT) levels within the GI tract. About 90% of 5-HT in the human body is produced and stored in enterochromaffin (EC) cells that reside in the mucosal layer of the intestine. Measurements of serotonin availability locally in the mucosa can provide insight on the functionality of these cells and potentially the pathophysiology of the disease. In this study, we used continuous amperometry with a diamond microelectrode to record serotonin levels in vitro in the ileum mucosa as an oxidation current. The boron-doped diamond (BDD) microelectrode is quite practical for these measurements because if its low background signal, low sensitivity to solution pH changes, and excellent resistance to fouling by adsorbed serotonin oxidation reaction products. In fact, the measurements are only possible because of the unique properties of diamond. We present electrochemical data that demonstrate the diamond microelectrode’s utility for assessment of enterochromaffin cell function. Confirmation that the oxidation current was associated with indogenous serotonin release came from pharmacological studies. We are hopeful that these types of in vitro electrochemical measurements will lead to a better understanding of the pathophysiology of IBS. PMID:20209031

Zhao, Hong; Bian, Xiaochun; Galligan, James J.; Swain, Greg M.



Synthesis and structure-activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT?B and 5-HT? receptor antagonists. Part 2.  


We previously reported that the novel dual 5-HT?B and 5-HT7 receptor antagonist N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (4) exerted a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs. To develop a synthetic strategy, we performed docking studies of lead compound 4 bound to 5-HT?B and 5-HT? receptors, and observed that the carbonyl guanidine group forms a tight interaction network with an active center Asp (D135:5-HT2B, D162:5-HT?), Tyr (Y370:5-HT?B, Y374:5-HT?) and aromatic residue (W131:5-HT2B, F158:5-HT?). Based on molecular modeling results, we optimized the substituents at the 5- to 8-position and 9-position of the fluorene ring and identified N-(diaminomethylene)-9-hydroxy-9-methyl-9H-fluorene-2-carboxamide (24a) exhibits potent affinity for 5-HT?B (Ki=4.3 nM) and 5-HT7 receptor (Ki=4.3 nM) with high selectivity over 5-HT?A, 5-HT?C, ??, D? and M? receptors. Compound 24a reversed the hypothermic effect of 5-carboxamidotryptamine (5-CT) in mice and also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered at 30 mg/kg. Compound 24a is therefore a promising candidate for a novel class of anti-migraine agent without any adverse effects. PMID:24916029

Moritomo, Ayako; Yamada, Hiroyoshi; Watanabe, Toshihiro; Itahana, Hirotsune; Koga, Yuji; Akuzawa, Shinobu; Okada, Minoru



Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide.  


Inhibition of serotonergic raphe neurons is mediated by somatodendritic 5-HT1A autoreceptors, which may be increased in depressed patients. We report an association of the C(-1019)G 5-HT1A promoter polymorphism with major depression and suicide in separate cohorts. In depressed patients, the homozygous G(-1019) allele was enriched twofold versus controls (p = 0.0017 and 0.0006 for G/G genotype and G allele distribution, respectively), and in completed suicide cases the G(-1019) allele was enriched fourfold (p = 0.002 and 0.00008 for G/G genotype and G allele distribution, respectively). The C(-1019) allele was part of a 26 bp imperfect palindrome that bound transcription factors nuclear NUDR [nuclear deformed epidermal autoregulatory factor (DEAF-1)]/suppressin and Hairy/Enhancer-of-split-5 (Drosophila) (Hes5) to repress 5-HT1A or heterologous promoters, whereas the G(-1019) allele abolished repression by NUDR, but only partially impaired Hes5-mediated repression. Recombinant NUDR bound specifically to the 26 bp palindrome, and endogenous NUDR was present in the major protein-DNA complex from raphe nuclear extracts. Stable expression of NUDR in raphe cells reduced levels of endogenous 5-HT1A protein and binding. NUDR protein was colocalized with 5-HT1A receptors in serotonergic raphe cells, hippocampal and cortical neurons, and adult brain regions including raphe nuclei, indicating a role in regulating 5-HT1A autoreceptor expression. Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism. We suggest a novel transcriptional model in which the G(-1019) allele derepresses 5-HT1A autoreceptor expression to reduce serotonergic neurotransmission, predisposing to depression and suicide. PMID:14507979

Lemonde, Sylvie; Turecki, Gustavo; Bakish, David; Du, Lisheng; Hrdina, Pavel D; Bown, Christopher D; Sequeira, Adolfo; Kushwaha, Neena; Morris, Stephen J; Basak, Ajoy; Ou, Xiao-Ming; Albert, Paul R



Studies on a series of potent, orally bioavailable, 5-HT(1) receptor ligands--part II.  


A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration. PMID:19071020

Ward, Simon E; Eddershaw, Peter; Flynn, Sean T; Gordon, Laurie; Lovell, Peter J; Moore, Susan H; Scott, Claire M; Smith, Paul W; Thewlis, Kevin M; Wyman, Paul A



A novel class of 5HT 2a receptor antagonists: Aryl aminoguanidines  

Microsoft Academic Search

Local delivery of serotonin (5-HT) produces a rapid edematous response in soft tissues via increased fluid extravasation which is prevented by 5-HT2 antagonists such as ketanserin or mianserin. Here we report the effects of a new class of aminoguanidine 5-HT2 antagonists, with relative selectivity for 5-HT2A receptors which are potent inhibitors of 5-HT-induced paw edema in the rat. Radioligand binding

Henry U. Bryant; David L. Nelson; Donald Button; Harlan W. Cole; Melvyn B. Baez; Virginia L. Lucaites; David B. Wainscott; Cecilia Whitesitt; Jon Reel; Richard Simon; Gary A. Koppel



Itch-associated response induced by intradermal serotonin through 5HT 2 receptors in mice  

Microsoft Academic Search

Serotonin (5-HT) is pruritogenic in humans and suggested to be involved in some pruritic diseases. Our experiments were carried out to determine whether an intradermal injection of 5-HT would elicit itch-associated response in mice and to elucidate the 5-HT receptor subtypes involved in this 5-HT action. 5-HT (14.1–235 nmol site?1) injected intradermally into the rostral back elicited scratching of the

Tomomi Yamaguchi; Tetsuro Nagasawa; Masamichi Satoh; Yasushi Kuraishi



Oxidation of tryptamine and 5-hydroxytryptamine: a pulse radiolysis and quantum chemical study.  


The reactions of oxidizing radicals (*)OH, N(3)(*), Br(2)(*-), and NO(2)(*) with tryptamine (Tpe) and 5-hydroxytryptamine (HTpe) were studied by pulse radiolysis and analyzed by quantum chemical calculations. Barring NO(2)(*) radical, the rate constants for their reaction with Tpe and HTpe were found to be diffusion controlled and the rates in the NO(2)(*) radical reaction with HTpe are lower by 2 orders of magnitude with k approximately 1 x 10(7) dm(3) mol(-1) s(-1). The transient spectra formed on oxidation of Tpe and HTpe exhibited peaks at 330 and 530 nm (indolyl radical) and 420 nm (indoloxyl radical), respectively, and the latter is in reasonable agreement with the calculated value (407 nm). Both radicals decay through direct recombination, but only the indoloxyl radical was observed to react with the parent molecule to give a (HTpe-Ind)(*) radical adduct for [HTpe] > or = 50 x 10(-6) mol dm(-3). The calculated optimized geometries in water revealed the formation of two distinct types of radical adducts, one through the H-O bond and the other by C-C linkage. The H-O bonded radical adduct was found to be exothermic with a reaction enthalpy of -4 kcal mol(-1) and bond length 0.1819 nm and the C-C bonded radical adducts are endothermic and rate determining but are finally driven by exothermic processes involving intermolecular H transfer followed by intramolecular reorganization through H shift resulting in stable C4-C4' and C2-C4' dimers with reaction enthalpies of -39 and -44 kcal mol(-1), respectively, and this process was found to be thermodynamically as efficient as direct recombination of indoloxyl radicals. The formation of the two dimer products was also seen in steady-state radiolysis. The lack of adduct formation in the case of indolyl radical with Tpe is due to the positive free energy change (DeltaG = 10 kcal mol(-1)). The energetics for the (*)OH addition have shown dependence on the site of activation with (HTpe-OH)(*) adducts at C2 and C4 and the (Tpe-OH)(*) adduct at C2 being more thermodynamically stable and the water elimination to give the indoloxyl radical proceeds fast from (HTpe-OH)(*) adduct at C4 due to favorable geometry. PMID:19569709

Gaikwad, P; Priyadarsini, K I; Naumov, S; Rao, B S M



Serotonin (5HT) in Veins: Not All in Vain  

Microsoft Academic Search

The circulatory system consists of veins and arteries. Com- pared with arteries, veins have been neglected in cardiovascu- lar research. Although veins are significantly less muscular than similarly sized arteries, the contribution of veins to cardiovas- cular homeostasis cannot be left un-noted because veins ac- commodate 70% of the circulating blood. Circulating blood platelets contain the majority of systemic 5-HT

A. Elizabeth Linder; Wei Ni; Jessica L. Diaz; Theodora Szasz; Robert Burnett; Stephanie W. Watts



Novel brain penetrant benzofuropiperidine 5-HT? receptor antagonists.  


7-Arylsulfonyl substituted benzofuropiperidine was discovered as a novel scaffold for 5HT(6) receptor antagonists. Optimization by substitution at C-1 position led to identification of selective, orally bioavailable, brain penetrant antagonists with reduced hERG liability. An advanced analog tested in rat social recognition model showed significant activity suggesting potential utility in the enhancement of short-term memory. PMID:22153937

Sundar, Babu G; Bailey, Thomas R; Dunn, Derek D; Bacon, Edward R; Salvino, Joseph M; Morton, George C; Aimone, Lisa D; Zeqi, Huang; Mathiasen, Joanne R; Dicamillo, Amy; Huffman, Mark J; McKenna, Beth A; Kopec, Karla; Lu, Lily D; Brown, Rebecca; Qian, Jie; Angeles, Thelma; Connors, Thomas; Spais, Chrysanthe; Holskin, Beverly; Galinis, Deborah; Duzic, Emir; Schaffhauser, Herve; Rosse, Gerard C



5-HT1A and 5-HT1B receptors differentially modulate rate and timing of auditory responses in the mouse inferior colliculus  

PubMed Central

Serotonin is a physiological signal that translates both internal and external information about behavioral context into changes in sensory processing through a diverse array of receptors. The details of this process, particularly how receptors interact to shape sensory encoding, are poorly understood. In the inferior colliculus, a midbrain auditory nucleus, serotonin (5-HT) 1A receptors have suppressive and 5-HT1B receptors have facilitatory effects on evoked responses of neurons. We explored how these two receptor classes interact by testing three hypotheses: that they 1) affect separate neuron populations, 2) affect different response properties, or 3) have different endogenous patterns of activation. The first two hypotheses were tested by iontophoretic application of 5-HT1A and 5-HT1B receptor agonists individually and together to neurons in vivo. 5-HT1A and 5-HT1B agonists affected overlapping populations of neurons. During co-application, 5-HT1A and 5-HT1B agonists influenced spike rate and frequency bandwidth additively, with each moderating the effect of the other. In contrast, although both agonists individually influenced latencies and interspike intervals, the 5-HT1A agonist dominated these measurements during co-application. The third hypothesis was tested by applying antagonists of the 5-HT1A and 5-HT1B receptors. Blocking 5-HT1B receptors was complementary to activation of the receptor, but blocking 5-HT1A receptors was not, suggesting the endogenous activation of additional receptor types. These results suggest that cooperative interactions between 5-HT1A and 5-HT1B receptors shape auditory encoding in the IC, and that the effects of neuromodulators within sensory systems may depend nonlinearly on the specific profile of receptors that are activated. PMID:20646059

Ramsey, Lissandra Castellan Baldan; Sinha, Shiva R.; Hurley, Laura M.



Prucalopride is a partial agonist through human and porcine atrial 5-HT4 receptors: comparison with recombinant human 5-HT4 splice variants.  


Prucalopride is a gastrointestinal prokinetic drug that acts through 5-HT4 receptors, but its potential effects on cardiac atrial function are unknown. We investigated the effects of prucalopride on human right atrium, piglet left atrium, and piglet sinoatrial node. The effects of prucalopride on 5-HT4 receptor splice variants a, b, g and i, known to be expressed in human atrium, were studied for comparison. Prucalopride was an inotropic partial agonist, compared with 5-HT, on paced human atrial trabeculae (-logEC50M=7.4) and porcine left atria (-logEC50M=7.2), with intrinsic activity of 0.77 and 0.63 respectively. Prucalopride (1 microM) surmountably antagonized the positive inotropic effects of 5-HT on human (pK(P)=7.2) and porcine (pK(P)=7.1) atrium. Prucalopride was also a chronotropic partial agonist (-logEC50M=7.4, intrinsic activity=0.72 with respect to 5-HT) on spontaneously beating piglet atria. The cardiostimulant effects of prucalopride were prevented by GR113808 (1 microM), consistent with mediation through 5-HT4 receptors. Prucalopride bound to recombinant 5-HT4(a), 5-HT4(b), 5-HT4(g), and 5-HT4(i) receptors, labeled by [3H]GR113808, with pKi values of 7.6, 7.5, 7.4, and 7.8 respectively. Prucalopride stimulated adenylyl cyclase as a partial agonist on 5-HT4(a), 5-HT4(b), and 5-HT4(i) receptors with intrinsic activities of 0.82, 0.86, and 0.78 and -logEC50 values of 7.2, 7.3, and 7.2 respectively. At the 5-HT4(g) receptor prucalopride acted as a full agonist (-logEC50M=8.0) compared with 5-HT in the cell line tested, which was probably due to high receptor expression levels. We conclude that prucalopride is a cardiostimulatory partial agonist through human and porcine 5-HT4 receptors. Since prucalopride acts similarly through 5-HT4(a), 5-HT4(b), 5-HT4(g), and 5-HT4(i) receptors, any of these variants could be involved in the mediation of cardiostimulation. PMID:16012870

Krobert, Kurt A; Brattelid, Trond; Levy, Finn Olav; Kaumann, Alberto J



5HT 2C receptors inhibit and 5HT 1A receptors activate the generation of spike–wave discharges in a genetic rat model of absence epilepsy  

Microsoft Academic Search

The present study was conducted to investigate the role of 5-HT2C and 5-HT1A receptors in the generation of spike–wave discharges (SWD) in the genetic absence epilepsy model Wistar Albino Glaxo rats from Rijswijk, Netherlands (WAG\\/Rij rats). We have determined the effects of the 5-HT2C receptor preferring agonist m-chlorophenyl-piperazine (m-CPP), the selective 5-HT2C receptor antagonist SB-242084, the selective 5-HT1A receptor antagonist

Rita Jakus; Marton Graf; Gabriella Juhasz; Katalin Gerber; Gyorgy Levay; Peter Halasz; Gyorgy Bagdy



5-Hydroxytryptamine1A receptor-activation hyperpolarizes pyramidal cells and suppresses hippocampal gamma oscillations via Kir3 channel activation.  


Rhythmic cortical neuronal oscillations in the gamma frequency band (30-80 Hz, gamma oscillations) have been associated with cognitive processes such as sensory perception and integration, attention, learning, and memory. Gamma oscillations are disrupted in disorders for which cognitive deficits are hallmark symptoms such as schizophrenia and Alzheimer's disease.In vitro, various neurotransmitters have been found to modulate gamma oscillations. Serotonin(5-HT) has long been known to be important for both behavioural and cognitive functions such as learning and memory. Multiple 5-HT receptor subtypes are expressed in the CA3 region of the hippocampus and high doses of 5-HT reduce the power of induced gamma oscillations.Hypothesizing that 5-HT may have cell- and receptor subtype-specific modulatory effects, we investigated the receptor subtypes, cell types and cellular mechanisms engaged by 5-HT in the modulation of gamma oscillations in mice and rats. We found that 5-HT decreases the power of kainate-induced hippocampal gamma oscillations in both species via the 5-HT1A receptor subtype. Whole-cell patch clamp recordings demonstrated that this decrease was caused by a hyperpolarization of CA3 pyramidal cells and a reduction of their firing frequency, but not by alteration of inhibitory neurotransmission. Finally, our results show that the effect on pyramidal cells is mediated via the G protein-coupled receptor inwardly rectifying potassium channel Kir3.Our findings suggest this novel cellular mechanism as a potential target for therapies that are aimed at alleviating cognitive decline by helping the brain to maintain or re-establish normal gamma oscillation levels in neuropsychiatric and neurodegenerative disorders. PMID:25107925

Johnston, April; McBain, Chris J; Fisahn, André



Synthesis and structure-activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists.  


To identify potent dual 5-HT2B and 5-HT7 receptor antagonists, we synthesized a series of novel carbonyl guanidine derivatives and examined their structure-activity relationships. Among these compounds, N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (10) had a good in vitro profile, that is, potent affinity for human 5-HT2B and 5-HT7 receptor subtypes (Ki=1.8 nM and Ki=17.6 nM, respectively) and high selectivity over 5-HT2A, 5-HT2C, ?1, D2 and M1 receptors. Compound 10 also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered. PMID:24189186

Moritomo, Ayako; Yamada, Hiroyoshi; Watanabe, Toshihiro; Itahana, Hirotsune; Akuzawa, Shinobu; Okada, Minoru; Ohta, Mitsuaki



Using Cerebral White Matter for Estimation of Nondisplaceable Binding of 5-HT1A Receptors in Temporal Lobe Epilepsy  

PubMed Central

The estimation of nondisplaceable binding from cerebellar white matter, rather than from whole cerebellum, was proposed for the PET tracer carbonyl-11C-WAY-100635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridyl)cyclohexane-carboxamidel]) because of the heterogeneity of total ligand binding in this region. For the 5-hydroxytryptamine receptor 1A (5-HT1A) antagonist 18F-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-2-pyridyl)trans-4-fluorocyclohexanecarboxamide (18F-FCWAY), the estimation of nondisplaceable binding from cerebellum (VND) may be additionally biased by spillover of 18F-fluoride activity from skull. We aimed to assess the effect of using cerebral white matter as reference region on detection of group differences in 5-HT1A binding with PET and 18F-FCWAY. Methods In 22 temporal lobe epilepsy patients (TLE) and 10 healthy controls, 18F-FCWAY distribution volume in cerebral white matter (VWM) was computed using an extrapolation method as part of a partial-volume correction (PVC) algorithm. To assess the feasibility of applying this method to clinical studies in which PVC is not performed, VWM was also calculated by placing circular, 6-mm-diameter regions of interest (ROIs) in the centrum semiovalis on parametric images. Binding potentials were BPF = (VT ? VND)/fP and BPF-WM = (VT ? VWM)/fP, where VT is total distribution volume and fP = 18F-FCWAY plasma free fraction. Statistical analysis was performed using t tests and linear regression. Results In the whole group, VWM was 14% ± 19% lower than VND (P < 0.05). VWM/fP was significantly (P < 0.05) lower in patients than in controls. All significant (P < 0.05) reductions of 5-HT1A receptor availability in TLE patients detected by BPF were also detected using BPF-WM. Significant (P < 0.05) reductions of 5-HT1A specific binding were detected by BPF-WM, but not BPF, in ipsilateral inferior temporal cortex, contralateral fusiform gyrus, and contralateral amygdala. However, effect sizes were similar for BPF-WM and BPF. The value of VWM calculated with the ROI approach did not significantly (P > 0.05) differ from that calculated with the extrapolation approach (0.67 ± 0.32 mL/mL and 0.72 ± 0.34 mL/mL, respectively). Conclusion Cerebral white matter can be used for the quantification of nondisplaceable binding of 5-HT1A without loss of statistical power for detection of regional group differences. The ROI approach is a good compromise between computational complexity and sensitivity to spillover of activity, and it appears suitable to studies in which PVC is not performed. For 18F-FCWAY, this approach has the advantage of avoiding spillover of 18F-fluoride activity onto the reference region. PMID:19837769

Giovacchini, Giampiero; Conant, Shielah; Herscovitch, Peter; Theodore, William H.



The 5-HT4 receptor: molecular cloning and pharmacological characterization of two splice variants.  

PubMed Central

Molecular cloning efforts have provided primary amino acid sequence and signal transduction data for a large collection of serotonin receptor subtypes. These include five 5-HT1-like receptors, three 5-HT2 receptors, one 5-HT3 receptor, two 5-HT5 receptors, one 5-HT6 receptor and one 5-HT7 receptor. Molecular biological information on the 5-HT4 receptor is notably absent from this list. We now report the cloning of the pharmacologically defined 5-HT4 receptor. Using degenerate oligonucleotide primers, we identified a rat brain PCR fragment which encoded a '5-HT receptor-like' amino acid sequence. The corresponding full length cDNA was isolated from a rat brain cDNA library. Transiently expressed in COS-7 cells, this receptor stimulates adenylyl cyclase activity and is sensitive to the benzamide derivative cisapride. The response is also blocked by ICS-205930. Interestingly, we isolated two splice variants of the receptor, 5-HT4L and 5-HT4S, differing in the length and sequence of their C-termini. In rat brain, the 5-HT4S transcripts are restricted to the striatum, but the 5-HT4L transcripts are expressed throughout the brain, except in the cerebellum where it was barely detectable. In peripheral tissues, differential expression was also observed in the atrium of the heart where only the 5-HT4S isoform was detectable. Images PMID:7796807

Gerald, C; Adham, N; Kao, H T; Olsen, M A; Laz, T M; Schechter, L E; Bard, J A; Vaysse, P J; Hartig, P R; Branchek, T A



Bi-directional modulation of BNST neurons by 5-HT: Molecular expression and functional properties of excitatory 5-HT receptor subtypes  

PubMed Central

Activation of neurons in the anterolateral bed nucleus of the stria terminalis (BNSTALG) plays an important role in mediating the behavioral response to stressful and anxiogenic stimuli. Application of 5-HT elicits complex postsynaptic responses in BNSTALG neurons, which includes 1) membrane hyperpolarization (5-HTHyp), 2) hyperpolarization followed by depolarization (5-HTHyp-Dep), 3) depolarization (5-HTDep) or 4) no response (5-HTNR). We have shown that the inhibitory response is mediated by activation of postsynaptic 5-HT1A receptors. Here, we used a combination of in vitro whole-cell patch-clamp recording and single cell reverse transcriptase polymerase chain reaction (RT-PCR) to determine the pharmacological properties and molecular profile of 5-HT receptor subtypes mediating the excitatory response to 5-HT in BNSTALG neurons. We show that the depolarizing component of both the 5-HTHyp/Dep and the 5-HTDep response was mediated by activation of 5-HT2A, 5-HT2C and/or 5-HT7 receptors. Single cell RT-PCR data revealed that 5-HT7 receptors (46%) and 5-HT1A receptors (41%) are the most prevalent receptor subtypes expressed in BNSTALG neurons. Moreover, 5-HT receptor subtypes are differentially expressed in Type I – III BNSTALG neurons. Hence, 5-HT2C receptors are almost exclusively expressed by Type III neurons, whereas 5-HT7 receptors are expressed by Type I and II neurons, but not Type III neurons. Conversely, 5-HT2A receptors are found predominantly in Type II neurons. Finally, bi-directional modulation of individual neurons occurs only in Type I and II neurons. Significantly the distribution of 5-HT receptor subtypes in BNSTALG neurons predicted the observed expression pattern of 5-HT responses determined pharmacologically. Together, these results suggest that 5-HT can differentially modulate the excitability of Type I – III neurons, and further suggest that bi-directional modulation of BNSTALG neurons occurs primarily through an interplay between 5-HT1A and 5-HT7 receptors. Hence, modulation of 5-HT7 receptor activity in the BNSTALG may offer a novel avenue for the design of anxiolytic medications. PMID:19778589

Guo, Ji-Dong; Hammack, Sayamwong E.; Hazra, Rimi; Levita, Liat; Rainnie, Donald G.



Fluvoxamine, a selective serotonin reuptake inhibitor, suppresses tetrahydrobiopterin in the mouse hippocampus.  


In the present study, we investigated the effects of fluvoxamine, a selective serotonin reuptake inhibitor, on brain tetrahydrobiopterin (BH4) levels. We directly measured levels of BH4 by Tani and Ohno's direct method as well as the serotonin (5-HT) turnover ratio, i.e. 5-hydroxyindoleacetic acid (5-HIAA)/5-HT, after sub-acute s.c. injection of fluvoxamine in the hippocampus of mice. Our animal model incorporated two risk factors of depression, social isolation and acute environmental change. Male ddY mice (6W) were housed in isolation (1 per cage; 35 days), injected with fluvoxamine (20 or 40 mg/kg; days 29-35), and exposed to novelty stress (20 min; day 35). In the stress session, behavioral parameters, i.e. total distance and rearing behavior, were measured. Isolation housing increased both behaviors. Fluvoxamine attenuated rearing behavior, but did not influence total distance. Isolation housing increased BH4 levels. Novelty stress increased BH4 levels in group housing, although it did not change them in isolation housing. Fluvoxamine suppressed BH4 levels. In isolation housing, fluvoxamine increased 5-HT turnover ratios, while it decreased them in group housing. In conclusion, fluvoxamine, housing condition, and novelty stress regulated BH4 levels. Fluvoxamine may have changed behavior and 5-HT turnover by suppressing BH4 levels as well as by inhibiting 5-HT reuptake. PMID:14975689

Miura, H; Qiao, H; Kitagami, T; Ohta, T



Antidepressant drug development: Focus on triple monoamine reuptake inhibition.  


Many patients with major depressive disorder (MDD) only partially respond, and some have no clinically meaningful response, to current widely used antidepressant drugs. Due to the purported role of dopamine in the pathophysiology of depression, triple-reuptake inhibitors (TRIs) that simultaneously inhibit serotonin (5-HT), norepinephrine (NE) and dopamine reuptake could be a useful addition to the armamentarium of treatments for MDD. A TRI should more effectively activate mesolimbic dopamine-related reward-networks, restore positive mood and reduce potent 5-HT reuptake blockade associated "hypodopaminergic" adverse effects of decreased libido, weight gain and "blunting" of emotions. On the other hand, dopaminergic effects raise concern over abuse liability and TRIs may have many of the cardiovascular effects associated with NET inhibition. Several clinical development programs for potential TRI antidepressants have failed to demonstrate significantly greater efficacy than placebo or standard of care. Successful late-stage clinical development of a TRI is more likely if experimental research studies in the target population of depressed patients have demonstrated target engagement that differentially and dose-dependently improves assessments of reward-network dysfunction relative to existing antidepressants. TRI treatment could be individualized on the basis of predictive markers such as the burden of decreased positive mood symptoms and/or neuroimaging evidence of reward network dysfunction. This review focuses on how the next generation of monoamine-based treatments could be efficiently developed to address unmet medical need in MDD. PMID:25315829

Lane, Roger M



Evidence that d -fenfluramine anorexia is mediated by 5HT 1 receptors  

Microsoft Academic Search

The effects of eight serotonin (5-HT) receptor antagonists on the anorectic effect of d-fenfluramine (3.0 mg\\/kg, IP) were examined in a test of sweet mash consumption, using non-deprived male rats. d-Fenfluramine's effect was attenuated by the mixed 5-HT1\\/5-HT2 receptor antagonists, methiothepin and metergoline; by the 5-HT2 receptor antagonist ritanserin; and by (±)cyanopindolol, a mixed 5-HT1A\\/5-HT1B receptor antagonist. In contrast, d-fenfluramine's

J. C. Neill; S. J. Cooper



Expression of the 5-HT1A Serotonin Receptor in the Hippocampus Is Required for Social Stress Resilience and the Antidepressant-Like Effects Induced by the Nicotinic Partial Agonist Cytisine.  


Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders. PMID:25288485

Mineur, Yann S; Einstein, Emily B; Bentham, Matthew P; Wigestrand, Mattis B; Blakeman, Sam; Newbold, Sylvia A; Picciotto, Marina R



Butyrophenone analogues in the carbazole series as potential atypical antipsychotics: synthesis and determination of affinities at D(2), 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors.  


We describe practical and efficient routes for synthesis of 2-aminomethyl-1,2,3,9-tetrahydro-4H-carbazol-4-ones using the Fischer indole synthesis or palladium-catalysed cyclization methodologies, as well as their affinities for D(2), 5-HT(2A) and 5-HT(2C) receptors, and their activity at the 5-HT(2B) receptor. The most active compounds, 4b (QF 2003B) and 4c (QF 2004B), with a pK(i) (5-HT(2A)/D(2)) ratio of 1.28 show a potential antipsychotic profile according to Meltzer's classification. PMID:10733606

Masaguer, C F; Raviña, E; Fontenla, J A; Brea, J; Tristán, H; Loza, M I



Evidence for the existence of FGFR1-5-HT1A heteroreceptor complexes in the midbrain raphe 5-HT system.  


The ascending midbrain 5-HT neurons known to contain 5-HT1A autoreceptors may be dysregulated in depression due to a reduced trophic support. With in situ proximity ligation assay (PLA) and supported by co-location of the FGFR1 and 5-HT1A immunoreactivities in midbrain raphe 5-HT cells, evidence for the existence of FGFR1-5-HT1A heteroreceptor complexes were obtained in the dorsal and median raphe nuclei of the Sprague-Dawley rat. Their existence in the rat medullary raphe RN33B cell cultures was also established. After combined FGF-2 and 8-OH-DPAT treatment, a marked and significant increase in PLA positive clusters was found in the RN33B cells. Similar results were reached upon coactivation by agonists in HEK293T cells using the Fluorescent Resonance Energy Transfer (FRET) technique resulting in increased FRETmax and reduced FRET50 values. The heteroreceptor complex formation was dependent on TMV of the 5-HT1A receptor since it was blocked by incubation with TMV but not with TMII. Taken together, the 5-HT1A autoreceptors by being recruited into a FGFR1-5-HT1A heteroreceptor complex in the midbrain raphe 5-HT nerve cells may develop a novel function, namely a trophic role in many midbrain 5-HT neuron systems originating from the dorsal and medianus raphe nuclei. PMID:25485703

Borroto-Escuela, Dasiel O; Narvaez, Manuel; Pérez-Alea, Mileidys; Tarakanov, Alexander O; Jiménez-Beristain, Antonio; Mudó, Giuseppa; Agnati, Luigi F; Ciruela, Francisco; Belluardo, Natale; Fuxe, Kjell



Pharmacological evidence for the 5-HT7 receptor mediating smooth muscle relaxation in canine cerebral arteries  

PubMed Central

We investigated in the present study whether 5-HT is able to exert direct relaxant responses in canine basilar and middle cerebral arteries via the 5-HT7 receptor. In arterial rings deprived of endothelium and pre-contracted with prostaglandin?F2? (2??M), 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine, sumatriptan or ?-methyl-5-HT produced further increase in tone and/or slight relaxation. Blockade of 5-HT1B/1D and 5-HT2A receptors with GR127935 (1??M) and ketanserin (0.1??M), respectively, antagonized the vasoconstrictor component of the response and unmasked a concentration-dependent relaxation to 5-HT, 5-CT and 5-methoxytryptamine; sumatriptan and ?-methyl-5-HT remained inactive as relaxant agonists. The rank order of agonist potency in both arteries was 5-CT>5-HT>5-methoxytryptamine>>sumatriptan??-methyl-5-HT. In dog basilar artery, pre-incubated with GR127935 (1??M) and ketanserin (0.1??M) and pre-contracted with prostaglandin?F2? (2??M), the 5-HT7 ligands, clozapine (1??M), mesulergine (0.3??M), methiothepin (3?nM), risperidone (3?nM), spiperone (1??M) and LY215840 (10–100?nM), produced significant rightward shifts of the concentration-response curves for 5-HT and 5-CT. Only methiothepin and risperidone reduced significantly the maximum relaxant response (Emax), whilst the other drugs behaved as competitive antagonists with affinity values (pKB) that significantly correlated with their binding affinity (pKi) at recombinant 5-HT7 receptors. These data disclosing the involvement of the 5-HT7 receptor in cerebrovascular relaxation may be strongly relevant in the light of : (1) the involvement of 5-HT in migraine; (2) the putative linkage between cephalovascular vasodilatation and migraine headache; and (3) the relatively high 5-HT7 receptor affinity of migraine prophylactic 5-HT antagonists. PMID:10401550

Terrón, José A; Falcón-Neri, Alicia



5-hydroxytryptamine 2C receptors in the basolateral amygdala are involved in the expression of anxiety after uncontrollable traumatic stress  

PubMed Central

Background Exposure to uncontrollable stressors often increases anxiety-like behavior in both humans and rodents. In rat, this effect depends upon stress-induced activity within the dorsal raphé nucleus (DRN). However, the role of serotonin in DRN projection regions is largely unknown. The goals of the current study were to 1) determine if DRN activity during a post-stress anxiety test is involved in anxiety-like behavior, 2) assess the effect of uncontrollable stress on extracellular serotonin in the basolateral amygdala during the anxiety test, and 3) determine the role of the serotonin 2C receptor (5-HT2C) in uncontrollable stress-induced anxiety. Method Rats were exposed to tailshocks that were uncontrollable. On the following day anxiety-like behavior was assessed in a JSE test. BLA extracellular serotonin concentrations were assessed during JSE by in vivo microdialysis 24 h after uncontrollable stress, controllable stress or no stress. In separate experiments drugs were administered before the JSE test to inhibit the DRN or to block 5-HT2C receptors. Results Exposure to uncontrollable shock reduced later social exploration. Prior uncontrollable stress potentiated serotonin efflux in the BLA during social exploration, but controllable stress did not. Intra-DRN 8-OH-DPAT and systemic and intra-BLA 5-HT2C receptor antagonist SB 242084 prevented the expression of potentiated anxiety in uncontrollably stressed rats. Intra-BLA injection of the 5-HT2C agonist CP 809101 mimicked the effect of stress. Conclusion These results suggest that the anxiety-like behavior observed after uncontrollable stress is mediated by exaggerated 5-HT acting at BLA 5-HT2C receptors. PMID:19914601

Christianson, John P.; Ragole, Thomas; Amat, Jose; Greenwood, Benjamin N.; Strong, Paul V.; Paul, Evan D.; Fleshner, Monika; Watkins, Linda R.; Maier, Steven F.



Signal transduction by the 5-HT2A receptor and its H452Y polymorphic variant   

E-print Network

The 5-HT2A receptor (5-HT2AR) is implicated in neuropsychiatric disorders such as schizophrenia and is thought to mediate the actions of a number of hallucinogenic and antipsychotic drugs. Additionally, certain polymorphic ...

Barclay, Zoë Jade



In-vitro acetylcholine release is not a straightforward model to study hippocampal 5-HT? receptors.  


5-HT? receptor (5-HT?R) activation induces procognitive effects. This might be related to stimulation of hippocampal acetylcholine release, which has been shown for 5-HT?R agonists in in-vivo models. We investigated the influence of the 5-HT?R agonists, prucalopride and BIMU-8, on acetylcholine release in rat hippocampal brain slices. In contrast to the report by Siniscalchi et al., no facilitating effect of 5-HT?R agonists on electrically evoked acetylcholine could be shown. The in our hands absence of an effect by 5-HT?R agonists illustrates that an in-vitro evaluation of 5-HT?R agonists on hippocampal acetylcholine release is not a straightforward model to study the relationship between hippocampal 5-HT?Rs and hippocampal acetylcholine release. PMID:21946331

de Vin, Filip; De Maeyer, Joris H; Lefebvre, Romain A



Disruption of 5-HT2A Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats  

PubMed Central

Despite common pathophysiological mechanisms, inflammatory and neuropathic pain do not respond equally to the analgesic effect of antidepressants, except for selective serotonin reuptake inhibitors (SSRIs), which show a limited efficacy in both conditions. We previously demonstrated that an interfering peptide (TAT-2ASCV) disrupting the interaction between 5-HT2A receptors and its associated PDZ proteins (e.g. PSD-95) reveals a 5-HT2A receptor-mediated anti-hyperalgesic effect and enhances the efficacy of fluoxetine (a SSRI) in diabetic neuropathic pain conditions in rats. Here, we have examined whether the same strategy would be useful to treat inflammatory pain. Sub-chronic inflammatory pain was induced by injecting ?-carrageenan (100 µl, 2%) into the left hind paw of the rat. Mechanical hyperalgesia was assessed after acute treatment with TAT-2ASCV or/and fluoxetine (SSRI) 2.5 h after ?-carrageenan injection. Possible changes in the level of 5-HT2A receptors and its associated PDZ protein PSD-95 upon inflammation induction were quantified by Western blotting in dorsal horn spinal cord. Administration of TAT-2ASCV peptide (100 ng/rat, intrathecally) but not fluoxetine (10 mg/kg, intraperitoneally) relieves mechanical hyperalgesia (paw pressure test) in inflamed rats. This anti-hyperalgesic effect involves spinal 5-HT2A receptors and GABAergic interneurons as it is abolished by a 5-HT2A antagonist (M100907, 150 ng/rat, intrathecally) and a GABAA antagonist, (bicuculline, 3 µg/rat, intrathecally). We also found a decreased expression of 5-HT2A receptors in the dorsal spinal cord of inflamed animals which could not be rescued by TAT-2ASCV injection, while the amount of PSD-95 was not affected by inflammatory pain. Finally, the coadministration of fluoxetine does not further enhance the anti-hyperalgesic effect of TAT-2ASCV peptide. This study reveals a role of the interactions between 5-HT2A receptors and PDZ proteins in the pathophysiological pathways of inflammatory pain and opens new perspectives in its control thanks to molecules disrupting 5-HT2A receptor/PDZ protein interactions. PMID:24058620

Wattiez, Anne-Sophie; Pichon, Xavier; Dupuis, Amandine; Hernández, Alejandro; Privat, Anne-Marie; Aissouni, Youssef; Chalus, Maryse; Pelissier, Teresa; Eschalier, Alain; Marin, Philippe; Courteix, Christine



A 5HT 1B receptor agonist inhibits light-induced suppression of pineal melatonin production  

Microsoft Academic Search

Serotonin (5-HT) modulates the phase adjusting effects of light on the mammalian circadian clock through the activation of presynaptic 5-HT1B receptors located on retinal terminals in the suprachiasmatic nucleus (SCN). The current study was conducted to determine whether activation of 5-HT1B receptors also alters photic regulation of nocturnal pineal melatonin production. Systemic administration of the 5-HT1B receptor agonist TFMPP attenuated

Michael A. Rea; Gary E. Pickard



The human 5-HT7 serotonin receptor splice variants: constitutive activity and inverse agonist effects.  


1. Using membranes from stably or transiently transfected HEK293 cells cultured in 5-HT-free medium and expressing the recombinant human 5-HT(7) receptor splice variants (h5-HT(7(a)), h5-HT(7(b)) and h5-HT(7(d))), we compared their abilities to constitutively activate adenylyl cyclase (AC). 2. All h5-HT(7) splice variants elevated basal and forskolin-stimulated AC. The basal AC activity was reduced by the 5-HT(7) antagonist methiothepin and this effect was blocked by mesulergine (neutral 5-HT(7) antagonist) indicating that the inhibitory effect of methiothepin is inverse agonism at the 5-HT(7) receptor. 3. Receptor density correlated poorly with constitutive AC activity in stable clonal cell lines and transiently transfected cells. Mean constitutive AC activity as a percentage of forskolin-stimulated AC was significantly higher for the h5-HT(7(b)) splice variant compared to the h5-HT(7(a)) and h5-HT(7(d)) splice variants but only in stable cell lines. 4. All eight 5-HT antagonists tested inhibited constitutive AC activity of all splice variants in a concentration-dependent manner. No differences in inverse agonist potencies (pIC(50)) were observed between the splice variants. The rank order of potencies was in agreement and highly correlated with antagonist potencies (pK(b)) determined by antagonism of 5-HT-stimulated AC activity (methiothepin >metergoline> mesulergine > or = clozapine > or = spiperone > or = ritanserin > methysergide > ketanserin). 5. The efficacy of inverse agonism was not receptor level dependent and varied for several 5-HT antagonists between membrane preparations of transiently and stably transfected cells. 6. It is concluded that the h5-HT(7) splice variants display similar constitutive activity and inverse agonist properties. PMID:11906971

Krobert, Kurt A; Levy, Finn Olav



Treatment of severe, drug resistant obsessive compulsive disorder with the 5HT 1D agonist sumatriptan  

Microsoft Academic Search

The serotonergic system has been implicated in both the aetiology and pharmacological treatment of obsessive compulsive disorder. In pharmacological challenge tests, mCPP, a 5-HT agonist, with an affinity for 5HT2C as well as 5HT1A and 5HT1D, receptors, was associated with a transient exacerbation of obsessive compulsive symptoms. Chronic administration of mCPP was found to bring about some relief of these

Liat Stern; Joseph Zohar; Rivka Cohen; Yehuda Sasson