These are representative sample records from related to your search topic.
For comprehensive and current results, perform a real-time search at

Migraine association and linkage analyses of the human 5-hydroxytryptamine (5HT 2A) receptor gene  

E-print Network

Migraine association and linkage analyses of the human 5-hydroxytryptamine (5HT 2A) receptor gene. Migraine association and linkage analyses of the human 5-hydroxytryptamine (5HT2A) receptor gene linked microsatellite marker (D13S126),for linkage and association with common migraine

Nyholt, Dale R.


5Hydroxytryptamine (5HT) contracts the guinea-pig isolated iliac artery via 5HT 1 -like and 5HT 2 receptors  

Microsoft Academic Search

The characterization of 5-hydroxytryptamine (5-HT) receptors mediating contractions of the guinea-pig isolated iliac artery was studied when the basal tone was slightly increased by prostaglandin F2a (PGF2a).

H. Pertz



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.



Potentiation of RSU-1069 tumour cytotoxicity by 5-hydroxytryptamine (5HT)  

Microsoft Academic Search

It is known that many solid animal tumours have a lower oxygenation level than most normal tissues and, in addition, that this level of oxygenation can be further decreased by systemic administration of 5-hydroxytryptamine (5-HT). The present study has investigated if such selective decrease in tumour oxygenation can be exploited by using the hypoxic cell cytotoxin, RSU-1069. The results obtained

D J Chaplin



5-Hydroxytryptamine (5-HT) contracts the guinea-pig isolated iliac artery via 5-HT1-like and 5-HT2 receptors.  


The characterization of 5-hydroxytryptamine (5-HT) receptors mediating contractions of the guinea-pig isolated iliac artery was studied when the basal tone was slightly increased by prostaglandin F2 alpha (PGF2 alpha). In the presence of ketanserin (1 mumol/l), 5-HT and several 5-HT receptor agonists induced contractile responses with the rank order of agonist potency: 5-HT = 5-carboxyamidotryptamine (5-CT) = lysergol > ergometrine = methylergometrine > RU 24969 approximately 5-methoxytryptamine (5-MeOT) > methysergide > sumatriptan > tryptamine. Concentration-effect curves to the ergot alkaloids, lysergol, ergometrine, methylergometrine and methylsergide, were biphasic. In the presence of ketanserin (1 mumol/l), contractile responses to 5-HT, 5-CT, RU 24969, 5-MeOT, sumatriptan and tryptamine were antagonized by methiothepin (30 nmol/l) and flesinoxan (3 mumol/l) with approximate pKB values of 8.5-9.0 and 6.0-6.3, respectively. The first phase of contraction produced by the ergot alkaloids, lysergol, ergometrine, methylergometrine and methysergide, were blocked by methiothepin (30 nmol/l) and flesinoxan (3 mumol/l), respectively, with approximate pKB values about 8.4-8.7 and 6.2-6.4, respectively. The mechanism underlying the second phase of contraction remains to be established. Maximum responses of the concentration-effect curves to 5-HT (1 nmol/l-1 mumol/l) were concentration-dependently depressed by ketanserin (1 nmol/l-1 mumol) and spiperone (30 nmol/l-0.3 mumol/l) and reached approximately 60% of the 5-HT maximum response in the presence of ketanserin (1 mumol/l) and spiperone (0.1 mumol/l), respectively. Agonist potency of 5-HT was not affected by the antagonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8133899

Pertz, H



Predictive In Silico Studies of Human 5-hydroxytryptamine Receptor Subtype 2B (5-HT2B) and Valvular Heart Disease  

PubMed Central

Serotonin (5-HT) receptors are neuromodulator neurotransmitter receptors which when activated generate a signal transduction pathway within cells resulting in cell-cell communication. 5-hydroxytryptamine (serotonin) receptor 2B (5-HT2B) is a subtype of the seven members of 5-hydroxytrytamine (5-HT) family of receptors which is the largest member of the super family of 7-transmembrane G-protein coupled receptors (GPCRs). Not only do 5-HT receptors play physiological roles in the cardiovascular system, gastrointestinal and endocrine function and the central nervous, but they also play a role in behavioral functions. In particular 5-HT2B receptor is wide spread with regards to its distribution throughout bodily tissues and is expressed at high levels in the lungs, peripheral tissues, liver, kidney and prostate just to name a few. Hence 5-HT2B participates in multiple biological functions including CNS regulation, regulation of gastrointestinal motality, cardiovascular regulation and 5-HT transport system regulation. While 5-HT2B is a viable drug target and has therapeutic indications for treating obesity, psychotherapy, Parkinson’s disease etc. there is a growing concern regarding adverse drug reactions, specifically valvulopathy associated with 5-HT2B agonists. Due to the sequence homology experienced by 5-HT2 subtypes there is also a concern regarding the off target effects of 5-HT2A and 5-HT2C agonists. The concept of subtype selectivity is of paramount importance and can be tackled with the aid of in silico studies, specifically cheminformatics, to develop models to predict valvulopathy associated toxicity of drug candidates prior to clinical trials. This review has highlighted three in silico approaches thus far that have been successful in either predicting 5-HT2B toxicity of molecules or identifying important interactions between 5-HT2B and drug molecules that bring about valvulopathy related toxicities. PMID:23675941

Reid, Terry-Elinor; Kumar, Krishna



Estradiol induces expression of 5-hydroxytryptamine (5-HT) 4, 5-HT5, and 5-HT6 receptor messenger ribonucleic acid in rat anterior pituitary cell aggregates and allows prolactin release via the 5-HT4 receptor.  


Serotonin [5-hydroxytryptamine (5-HT)] is known to control prolactin (PRL) release at a hypothalamic level, but a pituitary site of action remains poorly studied. The present study explores the acute effect of 5-HT on PRL release in rat anterior pituitary aggregate cell cultures, the influence of steroid and thyroid hormones, and the 5-HT receptor (5-HTR) subtype(s) involved. 5-HT elicited a prompt increase in basal PRL release, an effect strongly potentiated by estradiol (E(2)) in the culture medium (dose response 1-100 nm). In E(2) condition, the PRL response was not affected by the nonselective 5-HTR antagonists methysergide and methiothepin nor by 5-HTR1, 5-HTR2, 5-HTR3, 5-HTR6, and 5-HTR7/5 antagonists, but was fully blocked by the 5-HTR4 antagonist GR 113808. Among various agonist analogs, only the 5-HTR4 agonist cisapride and the 5-HTR2 agonist alpha-methyl-5-HT evoked PRL release. The effect of alpha-methyl-5-HT also required E(2) during culture and was abolished by GR 113808 but not by combined 5-HTR2A, B, and C blockade. In E(2)-treated aggregates, 5-HT caused a 5-fold increase in cAMP levels. The intact anterior pituitary expressed mRNA of all known members of the 5-HTR family. In aggregates, 5-HTR4, 5-HTR5, and 5-HTR6 mRNA expression required E(2) during culture. The effect of 5-HT on PRL release was not affected by blocking the serotonin transporter or the vesicular monoamine transporter. The present data suggest a widespread expression of 5-HTRs in the rat anterior pituitary, several of which are up-regulated by estrogen, and that, in the presence of estrogen, one of these, the 5-HTR4, mediates acute PRL release. PMID:17122082

Papageorgiou, A; Denef, C



High-level stable expression of recombinant 5-HT1A 5-hydroxytryptamine receptors in Chinese hamster ovary cells.  

PubMed Central

The human 5-hydroxytryptamine 5-HT1A receptor gene was transfected into Chinese hamster ovary cells. A series of recombinant monoclonal cell lines expressing the receptor were isolated and the properties of one cell line that expressed receptors at a high level (2.8 pmol/mg) were studied in detail. In ligand binding assays with the selective 5-HT1A receptor agonist 2-(NN-di[3H]propylamino)-8-hydroxy-1,2,3,4-tetrahydronaphthalene ([3H]8-OH-DPAT) only a single class of saturable high-affinity binding sites was detected, with a pharmacological profile in competition experiments essentially identical to that of the 5-HT1A receptor of bovine hippocampus. [3H]8-OH-DPAT binding to the recombinant cell membranes was inhibited by GTP, showing that the receptors in the transfected cells couple to G-proteins. A series of 5-hydroxytryptamine agonists inhibited forskolin-stimulated adenylate cyclase activity in the cells and, despite the high level of receptor expression, their apparent efficacies were similar to those observed for inhibition of adenylate cyclase in brain. This recombinant cell line provides a complete model system for studying the 5-HT1A receptor and its transmembrane signalling system. The recombinant cells can also be grown in suspension culture for long periods but, whereas 5-HT1A receptor numbers and receptor regulation by guanine nucleotides are maintained in suspension-grown cells, the inhibition of adenylate cyclase by the 5-HT1A receptor is gradually lost. Images Fig. 1. PMID:1386736

Newman-Tancredi, A; Wootton, R; Strange, P G



Further characterization of 5-hydroxytryptamine receptors (putative 5-HT2B) in rat stomach fundus longitudinal muscle.  

PubMed Central

1. The present study was undertaken to isolate and characterize pharmacologically homogeneous populations of 5-hydroxytryptamine (5-HT) receptors from a possible mixed receptor population mediating concentration of the longitudinal muscle of rat stomach fundus. Our aim was to extend the pharmacological characterization of the 5-HT2B receptor which is reported to be expressed in this preparation. 2. To minimize spontaneous activity and any influence of circular muscle on the contractile response, narrow (1-1.5 x 20 mm) segments of mucosa-denuded longitudinal muscle were used. Under these conditions, blockade of monoamine oxidase with pargyline (100 microM for 15 min) caused a leftward displacement of concentration-effect curves for both 5-methoxytryptamine (5-MeO-T) and tryptamine. Neither pargyline nor a number of uptake inhibitors affected responses to 5-HT. 3. In pargyline pretreated preparations, the order of potency of a number of tryptamine analogues was as follows: 5-MeO-T > or = alpha-Me-5-HT > or = 5-HT > 5-carboxamidotryptamine (5-CT) > tryptamine > 2-Me-5-HT. In addition several ligands known to act as agonists at either 5-HT2A or 5-HT2C receptors including 1-m-chlorophenylpiperazine (m-CPP), Ru 24969, MK 212 and SCH 23390 were also agonists in rat fundus whilst sumatriptan, renzapride and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) were very weak or inactive. With the exception of 2-Me-5-HT and m-CPP, most agonists produced monophasic concentration-effect curves consistent with an interaction at a single site.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8032658

Baxter, G. S.; Murphy, O. E.; Blackburn, T. P.



Actions of 5-hydroxytryptamine and 5-HT1A receptor ligands on rat dorso-lateral septal neurones in vitro.  

PubMed Central

1. The actions of 5-hydroxytryptamine (5-HT) and some 5-HT1A receptor ligands on neurones in the rat dorso-lateral septal nucleus were recorded in vitro by intracellular recording techniques. 2. In the presence of tetrodotoxin (1 microM) to block any indirect effects, bath application of 5-HT (0.3-30 microM) hyperpolarized the neurones in a concentration-dependent manner and reduced membrane resistance. The hyperpolarization did not exhibit desensitization and was sometimes followed by a small depolarization. 3. The 5-HT1A receptor ligands, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) and buspirone but not the non-selective 5-HT1 receptor agonist, 1-m-trifluoromethylphenylpiperazine (TFMPP), also hyperpolarized the neurones. 4. 5-HT, 8-OH-DPAT and DP-5-CT appeared to act as full agonists whereas buspirone behaved as a partial agonist. The estimated EC50S were: DP-5-CT 15 nM, 8-OH-DPAT 110 nM, 5-HT 3 microM and buspirone 110 nM. 5. At a concentration of 3 microM, the putative 5-HT1A receptor antagonists, spiperone, methiothepin, NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl]piperazine) and MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8- azaspiro[4,5]decane-7,9-dione methyl sulphonate), produced a parallel rightward shift in the concentration-response curve to 5-HT with no significant reduction in the maximum response. The estimated pA2 values were: NAN-190 6.79, MDL 73005EF 6.59, spiperone 6.54 and methiothepin 6.17.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1393288

Van den Hooff, P.; Galvan, M.



Inhibition of 5-hydroxytryptamine-induced and-amplified human platelet aggregation by ketanserin (R 41 468), a selective 5HT 2 -receptor antagonist  

Microsoft Academic Search

Ketanserin, a selective 5-HT2-receptor antagonist, inhibits the reversible aggregation induced by 5-hydroxytryptamine (5-HT) in human platelet-rich plasma (PRP). In this respect, the compound is equipotent to cyproheptadine and more active than methysergide (IC50: 1.66×10?8M, 1.44×10?8M and 5.62×10?8M respectively). Ketanserin is active against 5-HT-induced platelet aggregation after bothin vitro and oral administration to human volunteers. At concentrations up to 500 times

Fred de Clerck; Jean-Louis David; Paul A. J. Janssen



5-Hydroxytryptamine drives apoptosis in biopsylike Burkitt lymphoma cells: reversal by selective serotonin reuptake inhibitors.  


Serotonin (5-HT), a well-known neurotransmitter of the central nervous system, has been implicated in diverse aspects of immune regulation. Here we show that 5-HT can efficiently drive programmed cell death in established Burkitt lymphoma (BL) lines that remain faithful to the original biopsy phenotype (group 1). Group 1 BL cells cultured in the presence of 5-HT exhibited marked suppression of DNA synthesis that was accompanied by extensive apoptosis-serotonin-driven apoptosis was complete within 24 hours, was preceded by early caspase activation, and was accompanied by a decline in mitochondrial membrane potential. BL cells that had drifted to a lymphoblastic group 3 phenotype were relatively resistant to these actions of serotonin, and the forced ectopic expression of either bcl-2 or bcl-x(L) provided substantial protection from 5-HT-induced apoptosis. 5-HT receptor antagonists (SDZ205-557, granisetron, methysergide) failed to inhibit serotonin-induced apoptosis, whereas the selective serotonin reuptake inhibitors (SSRI)-fluoxetine (Prozac), paroxetine (Paxil), and citalopram (Celexa)-substantially blocked the monoamine actions. Western blot analysis showed that BL cells expressed protein for the 5-HT transporter, and transport assays confirmed active uptake of serotonin by the cells. Unlike what was suggested for neuronal cells, there was no evidence that intracellular oxidative metabolites were responsible for the 5-HT-induced programmed death of BL cells. These data indicate that serotonin drives apoptosis in biopsylike BL cells after its entry through an active transport mechanism, and they suggest a novel therapeutic modality for Burkitt lymphoma. PMID:11895792

Serafeim, Adamantios; Grafton, Gillian; Chamba, Anita; Gregory, Christopher D; Blakely, Randy D; Bowery, Norman G; Barnes, Nicholas M; Gordon, John



Long-term 5HT reuptake blockade, but not monoamine oxidase inhibition, decreases the function of terminal 5HT autoreceptors: an electrophysiological study in the rat brain  

Microsoft Academic Search

5-HT-containing terminals possess autoreceptors which modulate the release of 5-HT into the synaptic cleft. Tritiated imipramine ([3H]IMI), and more specifically [3H]citalopram and [3H]paroxetine, bind to a site associated with the 5-HT reuptake carrier on the 5-HT terminals. The function of terminal 5-HT autoreceptors is decreased following long-term treatment with the 5-HT reuptake blocker citalopram. The present study was undertaken to

Pierre Blier; Yves Chaput; Claude de Montigny



Effect of a novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist, GK-128, on 5-HT3 receptors mediating contractions and relaxations in guinea-pig distal colon.  


1. We investigated 5-hydroxytryptamine3 (5-HT3) receptor-mediating contractions and relaxations in the guinea-pig isolated distal colon using various 5-HT3 receptor agonists and antagonists, including GK-128 (2-[(2-methylimidazol-1-yl) methyl] benzo[f] thiochromen-1-one monohydrochloride hemihydrate). 2. Selective 5-HT3 receptor agonists, 2-methyl-5-HT and m-chlorophenylbiguanide, produced spantide-insensitive contraction and atropine-insensitive contraction and the relaxation. These agonists showed a small, but significant, difference of potency between contraction and relaxation. 3. GK-128 competitively blocked both 2-methyl-5-HT- and m-chlorophenylbiguanide-induced responses with similar potency. The affinities of GK-128 for spantide-insensitive contraction and atropine-insensitive contraction were ten-fold higher than for relaxation. 4. Other selective 5-HT3 receptor antagonists, azasetron and tropisetron, also exhibited higher affinity in contraction than in relaxation, but the extent of their affinity differences was smaller than that observed in GK-128. In contrast, granisetron, ramosetron and ondansetron exhibited no significant differences in their affinity values among the three responses. 5. These results suggest that the 5-HT3 receptors which mediate contraction and relaxation in the guinea-pig distal colon may not be the same, and that GK-128 is a 5-HT3 receptor antagonist with a stronger potency for contraction. PMID:9378239

Ito, C; Kawamura, R; Isobe, Y; Tsuchida, K; Muramatsu, M; Higuchi, S



Two amino acid differences in the sixth transmembrane domain are partially responsible for the pharmacological differences between the 5-HT1D beta and 5-HT1E 5-hydroxytryptamine receptors.  


5-Hydroxytryptamine elicits its physiological effects by interacting with a diverse group of receptors. Two of these receptors, the 5-HT1D beta and the 5-HT1E receptors, are approximately 60% identical in the transmembrane domains that presumably form the ligand binding site yet have very different pharmacological properties. Analysis of the pharmacological properties of a series of chimeric 5-HT1D beta/5-HT1E receptors indicates that sequences in the sixth and seventh transmembrane domains are responsible for the differential affinity of 5-carboxamidotryptamine for these two receptors. More detailed analysis shows that two amino acid differences in the sixth transmembrane domain (Ile333 and Ser334 in the 5-HT1D beta receptor, corresponding to Lys310 and Glu311 in the 5-HT1E receptor) are largely responsible for the differential affinities of some, but not all, ligands for the 5-HT1D beta and 5-HT1E receptors. It is likely that these two amino acids subtly determine the overall three-dimensional structure of the receptor rather than interact directly with individual ligands. PMID:8863519

Parker, E M; Izzarelli, D G; Lewis-Higgins, L; Palmer, D; Shapiro, R A



The effect of the selective 5-HT1A agonists alnespirone (S-20499) and 8-OH-DPAT on extracellular 5-hydroxytryptamine in different regions of rat brain  

PubMed Central

We have examined the effects of the systemic administration of the selective 5-HT1A agonist alnespirone (S-20499) on in vivo 5-hydroxytryptamine (5-HT) release in the dorsal raphe nucleus, the median raphe nucleus and four forebrain areas innervated differentially by both (dorsal striatum, frontal cortex, ventral hippocampus and dorsal hippocampus). Alnespirone (0.1–3?mg?kg?1, s.c.) dose-dependently reduced extracellular 5-HT in the six areas examined. In forebrain, the maximal reductions occurred in striatum and frontal cortex (maximal reduction to 23 and 29% of baseline, respectively). Those in dorsal and ventral hippocampus were more moderate (to ca 65% of baseline). In contrast, the decrease in 5-HT elicited in the median raphe nucleus was more marked than that in the dorsal raphe nucleus (to ca 30 and 60% of baseline, respectively). The selective 5-HT1A antagonist WAY-100635 (0.5?mg?kg?1, s.c.) prevented the decrease in 5-HT induced by alnespirone (0.3?mg?kg?1, s.c.) in frontal cortex. 8-OH-DPAT (0.025, 0.1 and 0.3?mg?kg?1, s.c.) also reduced extracellular 5-HT in a regionally-selective manner (e.g., to 32% of baseline in striatum and to 69% in dorsal hippocampus at 0.1?mg?kg?1, s.c.). In midbrain, 8-OH-DPAT reduced the dialysate 5-HT slightly more in the median than in the dorsal raphe nucleus at all doses examined. Doses of both compounds close to their respective ED50 values (0.3?mg?kg?1 alnespirone, 0.025?mg?kg?1 8-OH-DPAT) reduced 5-HT to a comparable extent in all regions examined. However, the reductions attained at higher doses were more pronounced for 8-OH-DPAT. These data show that the reduction of 5-HT release elicited by alnespirone and 8-OH-DPAT is more important in forebrain areas innervated by 5-hydroxytryptaminergic neurones of the dorsal raphe nucleus. This regional selectivity seems unlikely to be accounted for by differences in the sensitivity of 5-HT1A autoreceptors controlling 5-HT release, given the dissimilar effects of these two 5-HT1A agonists in regions rich in cell bodies and nerve terminals. This suggests the presence of complex mechanisms of control of 5-HT release by 5-HT1A receptors. PMID:9375971

Casanovas, J M; Lésourd, M; Artigas, F



Comparison of the performance of different DFT methods in the calculations of the molecular structure and vibration spectra of serotonin (5-hydroxytryptamine, 5-HT)  

NASA Astrophysics Data System (ADS)

Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter which plays an important role in treating acute or clinical stress. The comparative performance of different density functional theory (DFT) methods at various basis sets in predicting the molecular structure and vibration spectra of serotonin was reported. The calculation results of different methods including mPW1PW91, HCTH, SVWN, PBEPBE, B3PW91 and B3LYP with various basis sets including LANL2DZ, SDD, LANL2MB, 6-31G, 6-311++G and 6-311+G* were compared with the experimental data. It is remarkable that the SVWN/6-311++G and SVWN/6-311+G* levels afford the best quality to predict the structure of serotonin. The results also indicate that PBEPBE/LANL2DZ level show better performance in the vibration spectra prediction of serotonin than other DFT methods.

Yang, Yue; Gao, Hongwei



5HT 1 A autoreceptors and the mode of action of selective serotonin reuptake inhibitors (SSRI)  

Microsoft Academic Search

The clinical efficacy of antidepressant drugs that block serotonin (5-HT) reuptake may be restrained in the short term by the indirect activation of autoreceptors. In vivo microdialysis in rat hippocampus was used to study the putative release-inhibitory properties of the SSRI citalopram and paroxetine. With 5-HT reuptake first blocked by local ‘reverse-dialysis’ infusion of citalopram (1?M) into the hippocampus, acute

S. Hjorth; S. B. Auerbach



The interplay between brain 5-hydroxytryptamine levels and cocaine addiction  

Microsoft Academic Search

Cocaine addiction is a major health problem that affects millions of people. Cocaine acts by inhibiting dopamine, noradrenaline and serotonin [5-hydroxytryptamine(5-HT)] reuptake. The dopaminergic system is generally assumed to be involved in the reinforcing aspects of the drug, but the role of 5-HT in the addictive potential of cocaine is unclear. In light of pharmacological manipulations and cocaine use-related disease

L. J. P. Nonkes; I. P. van Bussel; M. M. M. Verheij; J. R. Homberg



Synergistic Action of 5HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders  

Microsoft Academic Search

Recently, the addition of drugs with prominent 5-HT2 receptor antagonist properties (risperidone, olanzapine, mirtazapine, and mianserin) to selective serotonin reuptake inhibitors (SSRIs) has been shown to enhance therapeutic responses in patients with major depression and treatment-refractory obsessive–compulsive disorder (OCD). These 5-HT2 antagonists may also be effective in ameliorating some symptoms associated with autism and other pervasive developmental disorders (PDDs). At

Gerard J Marek; Linda L Carpenter; Christopher J McDougle; Lawrence H Price



Effects of a selective 5HT reuptake blocker, citalopram, on the sensitivity of 5HT autoreceptors: Electrophysiological studies in the rat brain  

Microsoft Academic Search

Citalopram (CIT), is a selective serotonin (5-HT) reuptake blocker and a clinically effective antidepressant. The present electrophysiological studies were undertaken to investigate in vivo the acute and long-term effects of CIT administration on 5-HT neurotransmission. In a first series of experiments, a single dose of CIT (0.05–0.5 mg\\/kg) was administered intravenously to naive rats while recording the activity of a

Yves Chaput; Claude de Montigny; Pierre Blier



Fluvoxamine, a specific 5-hydroxytryptamine uptake inhibitor.  

PubMed Central

1. On the basis of both in vitro and in vivo experiments fluvoxamine has been characterized as a potential anti-depressant drug with almost exclusively 5-hydroxytryptamine (5-HT) uptake inhibiting properties. 2. Fluvoxamine is effective in inhibiting 5-ht uptake by blood platelets and brain synaptosomes. Due to inhibition of the membrane pump the compound prevents 5-HT depletion by the tyramine-derivatives H 75/12 and H 77/77. As a result of the interference with the neuronal re-uptake mechanism for 5-HT, fluvoxamine produces a decreased 5-HT turnover in the brain. Effects of 5-hydroxytryptophan (5-HTP) are potentiated in mice and in combination with pargyline, fluvoxamine induces 5-HT-like behavioural effects. 3. In contrast to tricyclic antidepressants, noradrenaline uptake processes are either unaffected or only slightly inhibited by fluvoxamine. The noradrenaline depleting effects of tyramine derivates are not influenced by fluvoxamine. Reserpine effects, such as ptosis are affected only at very high doses of the test compound. The antagonism by fluvoxamine of the reserpine-induced lowering of the pentamethylenetetrazole convulsive threshold can be regarded as due to an effect upon 5-HT uptake. In contrast to the effects of desmethylimipramine and imipramine, no stimulatory effects are found in rats when rapidly acting reserpine-like compounds are given following a dose of fluvoxamine. PMID:302726

Claassen, V; Davies, J E; Hertting, G; Placheta, P



Identification of Three Residues Essential for 5-Hydroxytryptamine 2A-Metabotropic Glutamate 2 (5-HT2A?mGlu2) Receptor Heteromerization and Its Psychoactive Behavioral Function*  

PubMed Central

Serotonin and glutamate G protein-coupled receptor (GPCR) neurotransmission affects cognition and perception in humans and rodents. GPCRs are capable of forming heteromeric complexes that differentially alter cell signaling, but the role of this structural arrangement in modulating behavior remains unknown. Here, we identified three residues located at the intracellular end of transmembrane domain four that are necessary for the metabotropic glutamate 2 (mGlu2) receptor to be assembled as a GPCR heteromer with the serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor in the mouse frontal cortex. Substitution of these residues (Ala-6774.40, Ala-6814.44, and Ala-6854.48) leads to absence of 5-HT2A·mGlu2 receptor complex formation, an effect that is associated with a decrease in their heteromeric ligand binding interaction. Disruption of heteromeric expression with mGlu2 attenuates the psychosis-like effects induced in mice by hallucinogenic 5-HT2A agonists. Furthermore, the ligand binding interaction between the components of the 5-HT2A·mGlu2 receptor heterocomplex is up-regulated in the frontal cortex of schizophrenic subjects as compared with controls. Together, these findings provide structural evidence for the unique behavioral function of a GPCR heteromer. PMID:23129762

Moreno, Jose L.; Muguruza, Carolina; Umali, Adrienne; Mortillo, Steven; Holloway, Terrell; Pilar-Cuellar, Fuencisla; Mocci, Giuseppe; Seto, Jeremy; Callado, Luis F.; Neve, Rachael L.; Milligan, Graeme; Sealfon, Stuart C.; Lopez-Gimenez, Juan F.; Meana, J. Javier; Benson, Deanna L.; Gonzalez-Maeso, Javier



Localization of serotoni (5-hydroxytryptamine, 5-HT) with partial purification and characterization of a serotonin binding protein in the intestinal tissue of the nematode Ascaris suum  

SciTech Connect

An intracellular 5-HT binding protein (SBP) from intestinal tissue was partially purified and characterized. Binding of ({sup 3}H) 5-HT to the protein appeared to be Fe{sup +2}-sensitive and maximal (20.8pmol/mg protein) at 5 {times} 10{sup {minus}4}M Fe{sup +2} and 10{sup {minus}7}M ({sup 3}H) 5-HT. There were two 5-HT binding sites present at optimum Fe{sup +2} concentrations. The Bmax values of these sites were more sensitive to Fe{sup +2} than Kd values. Sulfhydryl reducing agents, cation chelators, Fe{sup +3}, Ca{sup +2} and antagonists of 5-HT uptake and storage inhibited binding of 5-HT to SBP. Gel exclusion chromatography indicated the presence of a 45Kda SBP that in 5 {times} 10{sup {minus}5}M Fe{sup +2} may form aggregates ranging in size from approximately 80 to >1000Kda. The data indicate these in vitro aggregates may correspond to the electron-opaque patches observed in situ. Ascaris suum may provide a model system to further elucidate the physiological role of analogous serotonin binding proteins that have been identified in mammalian systems.

Martin, R.E.



Hydrogen peroxide (H/sub 2/O/sub 2/) stimulates the active transport of 5-hydroxytryptamine (5-HT) into platelets  

SciTech Connect

Platelets function in a variety of physiological and pathological processes which may be altered by oxidant injury. One such process is the active transport 5-HT, which is an important mechanism in the control of circulating 5-HT levels. Exposure of mouse platelets (10/sup 8//ml) to H/sub 2/O/sub 2/ caused a time-dependent and dose-dependent increase in 5-HT (10/sup -7/M) uptake. The uptake 4 and 10 min following H/sub 2/O/sub 2/ (50 was 228% and 145% of control values, respectively. Fluoxetine (10/sup -6/M) blocked all 5-HT uptake and catalase (1500 U/ml) blocked the H/sub 2/O/sub 2/-stimulated uptake. Enzymatically produced H/sub 2/O/sub 2/ (glucose/glucose oxidase) and xanthine (X)/xanthine oxidase (XO) generated oxygen radicals produced quantitatively and qualitatively similar results. The stimulatory response of platelets to X/XO generated oxidants was unaffected by superoxide dismutase (250 U/ml) but, was inhibited using heat-denatured XO, allopurinol (0.5 mM) and catalase; fluoxetine inhibited all 5-HT uptake. Platelets exposed to X/XO in the presence of chelated (EDTA, 100 or unchelated FeSO/sub 4/, FeNH/sub 4/(SO/sub 4/)/sub 2/ or CuCl (50 did not have altered 5-HT uptake. These data indicate that brief exposure of platelets to physiological levels of H/sub 2/O/sub 2/ results in marked, reversible stimulation of active 5-HT uptake which may represent a homeostatic defense mechanism when H/sub 2/O/sub 2/ is elevated in the platelet microenvironment.

Bosin, T.R.



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))



Disrupting 5HT2A Receptor\\/PDZ Protein Interactions Reduces Hyperalgesia and Enhances SSRI Efficacy in Neuropathic Pain  

Microsoft Academic Search

Antidepressants are one of the first-line treatments for neuropathic pain. Despite the influence of serotonin (5-hydroxytryptamine, 5-HT) in pain modulation, selective serotonin reuptake inhibitors (SSRIs) are less effective than tricyclic antidepressants. Here, we show, in diabetic neuropathic rats, an alteration of the antihyperalgesic effect induced by stimulation of 5-HT2A receptors, which are known to mediate SSRI-induced analgesia. 5-HT2A receptor density

Xavier Pichon; Anne S Wattiez; Carine Becamel; Ingrid Ehrlich; Joel Bockaert; Alain Eschalier; Philippe Marin; Christine Courteix



The inactivation of 5-hydroxytryptamine by blood platelets in mental deficiency with elevated serum 5-hydroxytryptamine  

Microsoft Academic Search

The mentally defective patients were divided into two groups according to the 5-hydroxytryptamine (5HT) content in serum. In the first (“normal”) group were those with values 200 ng\\/ml (7 cerebral palsies, 5 encephalopathies).

M. K. Paasonen; E. Kivalo



The effect of altered 5-hydroxytryptamine levels on beta-endorphin  

NASA Technical Reports Server (NTRS)

The purpose of the present study was to examine the effect of altering the concentration of 5-hydroxytryptamine (5-HT) on beta-endorphin (beta-Ep) content in the hypothalamus, thalamus, and periaqueductal gray (PAG)-rostral pons regions of the rat brain. The selective 5-HT reuptake inhibitor, fluoxetine (10 mg/kg), significantly lowered beta-Ep content in the hypothalamus and the PAG. Parachlorophenylalanine, which inhibits 5-HT synthesis, significantly elevated beta-Ep in all brain parts studied. Intracisternal injections of the neurotoxin 5-prime, 7-prime-dihydroxytryptamine with desmethylimipramine pretreatment significantly increased beta-Ep content in the hypothalamus and the PAG. In adrenalectomized rats, fluoxetine significantly decreased beta-Ep levels in the hypothalamus and increased the levels in the PAG. The results indicate that 5-HT may modulate the levels of brain beta-Ep.

Soliman, Karam F. A.; Mash, Deborah C.; Walker, Charles A.



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, Gael; Gautron, Sophie; Sanchez, Connie; Gardier, Alain M



5Hydroxytryptamine receptors in the human cardiovascular system  

Microsoft Academic Search

The human cardiovascular system is exposed to plasma 5-hydroxytryptamine (5-HT, serotonin), usually released from platelets. 5-HT can produce harmful acute and chronic effects. The acute cardiac effects of 5-HT consist of tachycardia (preceded on occasion by a brief reflex bradycardia), increased atrial contractility and production of atrial arrhythmias. Acute inotropic, lusitropic and arrhythmic effects of 5-HT on human ventricle become

Alberto J. Kaumann; Finn Olav Levy



5-hydroxytryptamine receptors in uterine smooth muscle.  


When studying some of the properties of 5-hydroxytryptamine (5HT) receptors in the rat uterine muscle using phenoxybenzamine (PBZ) as an antagonist it was found that the specific receptors for 5HT in the smooth muscle were selectively blocked by PBZ; a period of 20-minute exposure to the antagonist was required for maximal effect. The blockade produced was of long duration and the recovery of response was relatively slow; it was incomplete throughout the 4-hour observation period. A concentration of 1 X 10(-8) g/ml PBZ produced a parallel shift of the dose-response effects while higher concentrations reduced both the slope and maximal response. The reasons for such a shift were discussed. 5HT produced a rapid onset and offset of effect suggesting that the site of 5HT receptor is on the surface of the cell membrane. Moreover, 5HT could protect its own receptor against PBZ blockade. PMID:1228247

Osman, F H; Ammar, E M



Endogenous Serotonin Excites Striatal Cholinergic Interneurons via the Activation of 5HT 2C, 5HT6, and 5HT7 Serotonin Receptors: Implications for Extrapyramidal Side Effects of Serotonin Reuptake Inhibitors  

Microsoft Academic Search

The striatum is richly innervated by serotonergic afferents from the raphe nucleus. We explored the effects of this input on striatal cholinergic interneurons from rat brain slices, by means of both conventional intracellular and whole-cell patch-clamp recordings. Bath-applied serotonin (5-HT, 3–300 ?M), induced a dose-dependent membrane depolarization and increased the rate of spiking. This effect was mimicked by the 5-HT

Paola Bonsi; Dario Cuomo; Jun Ding; Giuseppe Sciamanna; Sasha Ulrich; Anne Tscherter; Giorgio Bernardi; D James Surmeier; Antonio Pisani



Comparative studies of the effects of 5-hydroxytryptamine and noradrenaline on the rat anococcygeus muscle  

Microsoft Academic Search

The effects of 5-hydroxytryptamine (5HT) and noradrenaline (NA) have been studied on rat anococcygeus muscle.1.5HT and NA produced a dose-dependent contraction of rat anococcygeus muscle. Cyproheptadine (1.0×10?6M), a specific 5HT receptor blocker, failed to inhibit the responses to either 5HT or NA.2.However, phentolamine, a specificalpha receptor antagonist competitively blocked the responses to 5HT and NA.3.The responses to 5HT were inhibited

Ramesh K. Goyal; Natvar M. Patel; Subhash C. Verma



The role of activation of the 5-HT1A receptor and adenylate cyclase in the antidepressant-like effect of YL-0919, a dual 5-HT1A agonist and selective serotonin reuptake inhibitor.  


This study aimed to explore the possible mechanisms underlying the antidepressant-like effect of YL-0919, a novel antidepressant candidate with dual activity as a 5-HT1A receptor agonist and a selective serotonin reuptake inhibitor. The animal models commonly used to evaluate potential antidepressants, i.e., tail suspension (TST) in mice and forced swimming test (FST) in mice were used to evaluate the antidepressant effect of YL-0919. The activity of adenylate cyclase (AC) on the synaptic membrane was determined by the homogeneous time-resolved fluorescence resonance energy transfer (TR-FRET) immunoassay. The results indicated that YL-0919 (1.25-2.5mg/kg, i.g.) significantly decreased the immobility time in both the tail suspension test and the forced swim test in a dose-dependent manner, demonstrating the antidepressant-like effect of YL-0919. Furthermore, this effect was completely antagonized by the co-administration of WAY-100635 (0.3mg/kg, s.c.), a 5-HT1A selective antagonist. YL-0919 (10(-9)-10(-5)mol/L) was also shown to activate AC in vitro in a dose-dependent manner in synaptic membranes extracted from the rat prefrontal cortex, and this effect (10(-7)-10(-5)mol/L) was antagonized by WAY-100635 (10(-7)mol/L). Finally, the antidepressant-like effect of YL-0919 (2.5mg/kg, i.g.) was also blocked by the co-administration of H-89 (3?g/site, i.c.v.), a protein kinase A (PKA) selective inhibitor. These results indicate that the activation of 5-HT1A receptors and the subsequent activation of the AC-cAMP-PKA signaling pathway in the frontal cortex play a critical role in the antidepressant-like effect of YL-0919. PMID:25220701

Qin, Juan-Juan; Chen, Hong-Xia; Zhao, Nan; Yuan, Li; Zhang, You-Zhi; Yang, Ri-Fang; Zhang, Li-Ming; Li, Yun-Feng



5-HT3 Receptors*  

PubMed Central

5-Hydroxytryptamine type 3 (5-HT3) receptors are cation-selective Cys loop receptors found in both the central and peripheral nervous systems. There are five 5-HT3 receptor subunits (A–E), and all functional receptors require at least one A subunit. Regions from noncontiguous parts of the subunit sequence contribute to the agonist-binding site, and the roles of a range of amino acid residues that form the binding pocket have been identified. Drugs that selectively antagonize 5-HT3 receptors (the “setrons”) are the current gold standard for treatment of chemotherapy-induced and postoperative nausea and vomiting and have potential for the treatment of a range of other conditions. PMID:23038271

Lummis, Sarah C. R.



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



Acute effects of Sceletium tortuosum (Zembrin), a dual 5-HT reuptake and PDE4 inhibitor, in the human amygdala and its connection to the hypothalamus.  


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



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



Arterial expression of 5HT2B and 5HT1B receptors during development of DOCA-salt hypertension  

Microsoft Academic Search

BACKGROUND: 5-hydroxytryptamine (5-HT)2B and 5-HT1B receptors are upregulated in arteries from hypertensive DOCA-salt rats and directly by mineralocorticoids. We hypothesized that increased 5-HT2B and 5-HT1B receptor density and contractile function would precede increased blood pressure in DOCA-high salt rats. We performed DOCA-salt time course (days 1, 3, 5 and 7) studies using treatment groups of: DOCA-high salt, DOCA-low salt, Sham

Amy KL Banes; Stephanie W Watts



Role of uptake inhibition and autoreceptor activation in the control of 5-HT release in the frontal cortex and dorsal hippocampus of the rat  

PubMed Central

Using brain microdialysis, we compared the relative role of 5-hydroxytryptamine (5-HT; serotonin) blockade and somatodendritic 5-HT1A and/or terminal 5-HT1B autoreceptor activation in the control of 5-HT output.Fluoxetine (10?mg?kg?1 i.p.) doubled the 5-HT output in frontal cortex and dorsal hippocampus. The 5-HT1A receptor antagonist WAY 100635, (0.3?mg?kg?1 s.c.) potentiated the effect of fluoxetine only in frontal cortex (to ?500 % of baseline).Methiothepin (10?mg?kg?1 s.c.) further enhanced the 5-HT rise induced by fluoxetine+WAY 100635, to 835±179% in frontal cortex and 456±24% in dorsal hippocampus. Locally applied, methiothepin potentiated the fluoxetine-induced 5-HT rise more in the former area.The selective 5-HT1B receptor antagonist SB-224289 (4?mg?kg?1 i.p.) enhanced the effect of fluoxetine (10?mg?kg?1 i.p.) in both areas. As with methiothepin, SB-224289 (4?mg?kg?1 i.p.) further enhanced the 5-HT increase produced by fluoxetine+WAY 100635 more in frontal cortex (613±134%) than in dorsal hippocampus (353±59%).Locally applied, fluoxetine (10–300??M; EC50=28–29??M) and citalopram (1–30??M; EC50=1.0–1.4??M) increased the 5-HT output two to three times more in frontal cortex than in dorsal hippocampus.These data suggest that the comparable 5-HT increase produced by systemic fluoxetine in frontal cortex and dorsal hippocampus results from a greater effect of reuptake blockade in frontal cortex that is offset by a greater autoreceptor-mediated inhibition of 5-HT release. As a result, 5-HT autoreceptor antagonists preferentially potentiate the effect of fluoxetine in frontal cortex. PMID:10781012

Hervas, Ildefonso; Queiroz, Claudio M T; Adell, Albert; Artigas, Francesc



Ocular Hypotension: Involvement of Serotonergic 5HT 2 Receptors  

Microsoft Academic Search

\\u000a Serotonergic nerves innervate various parts of the eye, including the ciliary body, and serotonin (5-hydroxytryptamine, or\\u000a 5-HT) has been found in the aqueous humor in the anterior chamber of animal and human eyes. 5-HT2A-C receptor mRNAs are present in human ocular tissues involved in modulation of intraocular pressure (IOP) including ciliary\\u000a body (5-HT2A > 5-HT2B > 5-HT2C), ciliary epithelium (5-HT2A

Najam A. Sharif


The 5-HT{sub 2A} serotoninergic receptor is expressed in the MCF-7 human breast cancer cell line and reveals a mitogenic effect of serotonin  

SciTech Connect

Serotonin (5-hydroxytryptamine, 5-HT) has been described as a mitogen in a variety of cell types and carcinomas. It exerts its mitogenic effect by interacting with a wide range of 5-HT receptor types. Certain studies suggest that some selective serotonin re-uptake inhibitors promote breast cancer in animals and humans. This study attempts to clarify the role of serotonin in promoting the growth of neoplastic mammary cells. Expression of the 5-HT{sub 2A} serotoninergic receptor subtype in MCF-7 cells was determined by RT-PCR, Western blotting, and immunofluorescence analysis. The mitogenic effect of 5-HT on MCF-7 cells was determined by means of the MTT proliferation assay. We have demonstrated that the 5-HT{sub 2A} receptor subtype is fully expressed in the MCF-7 human breast cancer cell line, in terms of encoding mRNA and receptor protein. Automated sequencing has confirmed that the 5-HT{sub 2A} receptor present in this cell line is identical to the 5-HT{sub 2A} receptor found in human platelets and in human cerebral cortex. Furthermore, this receptor was found by immunofluorescence to be on the plasma membrane. MTT proliferation assays revealed that 5-HT and DOI, a selective 5-HT{sub 2A} receptor subtype agonist, stimulated MCF-7 cell. These results indicate that 5-HT plays a mitogenic role in neoplastic mammary cells. Our data also indicate that 5-HT exerts this positive growth effect on MCF-7 cells through, in part, the 5-HT{sub 2A} receptor subtype, which is fully expressed in this cell line.

Sonier, Brigitte [Department of Chemistry and Biochemistry, Universite de Moncton, Moncton, NB (Canada); Arseneault, Madeleine [Department of Chemistry and Biochemistry, Universite de Moncton, Moncton, NB (Canada); Institut National de la Recherche Scientifique-Institut Armand-Frappier, Montreal, Que. (Canada); Lavigne, Carole [Department of Biology, Universite de Moncton, Moncton, NB (Canada); Ouellette, Rodney J. [Beausejour Medical Research Institute, Moncton, NB (Canada); Vaillancourt, Cathy [Department of Chemistry and Biochemistry, Universite de Moncton, Moncton, NB (Canada) and Institut National de la Recherche Scientifique-Institut Armand-Frappier, Montreal, Que. (Canada)]. E-mail:



5-HT spatial distribution imaging with multiphoton excitation of 5-HT correlative visible fluorescence in live cells  

NASA Astrophysics Data System (ADS)

The autofluorescence of 5-Hydroxytryptamine (5-HT) loaded rat mucosal mast cells (RBL-2H3 cells) is imaged with multiphoton excitation laser scanning microscope (MPELSM). 5-HT correlative visible fluorescence (Fco-vis) excited with 740-nm multiphoton excitation is observed in live cells for the first time, and the generating mechanism of 5-HT Fco-vis is studied. The spatial distribution of 5-HT in live cells is imaged at high spatial resolution in our experiment, which provides a new way to study the correlation between 5-HT spatial distribution and content, and the cellular functional state in live tissue or cells.

Zhang, Zhihong; Zeng, Shaoqun; Liu, Yafeng; Zhou, Wei; Chen, Tongsheng; Luo, Qingming



Voltammetric detection of 5-hydroxytryptamine release in the rat brain.  


5-Hydroxytryptamine (5-HT) is an important molecule in the brain that is implicated in mood and emotional processes. In vivo, its dynamic release and uptake kinetics are poorly understood due to a lack of analytical techniques for its rapid measurement. Whereas fast-scan cyclic voltammetry with carbon fiber microelectrodes is used frequently to monitor subsecond dopamine release in freely moving and anesthetized rats, the electrooxidation of 5-HT forms products that quickly polymerize and irreversibly coat the carbon electrode surface. Previously described modifications of the electrochemical waveform allow stable and sensitive 5-HT measurements in mammalian tissue slice preparations and in the brain of fruit fly larvae. For in vivo applications in mammals, however, the problem of electrode deterioration persists. We identify the root of this problem to be fouling by extracellular metabolites such as 5-hydoxyindole acetic acid (5-HIAA), which is present in 200-1000 times the concentration of 5-HT and displays similar electrochemical properties, including filming of the electrode surface. To impede access of the 5-HIAA to the electrode surface, a thin layer of Nafion, a cation exchange polymer, has been electrodeposited onto cylindrical carbon-fiber microelectrodes. The presence of the Nafion film was confirmed with environmental scanning electron microscopy and was demonstrated by the diminution of the voltammetric signals for 5-HIAA as well as other common anionic species. The modified microelectrodes also display increased sensitivity to 5-HT, yielding a characteristic cyclic voltammogram that is easily distinguishable from other common electroactive brain species. The thickness of the Nafion coating and a diffusion coefficient (D) in the film for 5-HT were evaluated by measuring permeation through Nafion. In vivo, we used physiological, anatomical, and pharmacological evidence to validate the signal as 5-HT. Using Nafion-modified microelectrodes, we present the first endogenous recording of 5-HT in the mammalian brain. PMID:19827792

Hashemi, Parastoo; Dankoski, Elyse C; Petrovic, Jelena; Keithley, Richard B; Wightman, R M



5-Hydroxytryptamine receptors that facilitate excitatory neuromuscular transmission in the guinea-pig isolated detrusor muscle.  

PubMed Central

1. In isolated detrusor strips from the guinea-pig urinary bladder, contractile responses to electrical field stimulation were mostly mediated by neurally released acetylcholine (ACh) and adenosine 5'-triphosphate (ATP). 2. 5-Hydroxytryptamine (5-HT) produced a concentration-dependent increase in the amplitude of stimulated detrusor strip contractions. The 5-HT concentration-response curve showed a biphasic profile: the high potency phase was obtained at sub-micromolar concentrations (10-300 nM), while the low potency phase in the range 1-30 microM. The maximum response of the first phase was 30% of the total 5-HT response. 3. Like 5-HT, the 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT: 0.3-100 microM), the 5-HT2 receptor agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI: 30 nM-3 microM) and the 5-HT4 receptor agonist, 5-methoxytryptamine (5-MeOT: 0.1-30 microM) potentiated, though with lower potency, detrusor contractions. The resulting concentration-response curves were monophasic in nature. 2-Methyl-5-HT had a maximum effect comparable to that of 5-HT. By contrast, the maximal effects of DOI and 5-MeOT were only 20% and 30% of that elicited by 30 microM 5-HT, respectively. 4. The 5-HT3 receptor antagonist, granisetron (0.3 microM) had no effect on the high potency phase, but caused a rightward parallel shift of the low potency phase of the 5-HT curve (pKB = 7.3).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582490

Messori, E.; Rizzi, C. A.; Candura, S. M.; Lucchelli, A.; Balestra, B.; Tonini, M.



Effects of chronic treatment with fluoxetine and citalopram on 5HT uptake, 5HT1B autoreceptors, 5HT3 and 5HT4 receptors in rats  

Microsoft Academic Search

The effect in rats of chronic treatment with two specific 5-HT reuptake inhibitors (SSRI) with antidepressant properties,\\u000a citalopram (10 mg\\/kg, i.p. twice a day for 14 days, one day washout) and fluoxetine (15 mg\\/kg, p.o. twice a day for 21 days,\\u000a 7 days washout), was evaluated on some mechanisms involved in central 5-HT neurotransmission. No adaptive modifications of\\u000a brain 5-HT

Marco Gobbi; Daniela Crespi; Maria Cristina Foddi; Claudia Fracasso; Laura Mancini; Luca Parotti; Tiziana Mennini



Allosteric modulation of the 5-HT3 receptor  

PubMed Central

5-Hydroxytryptamine type 3 (5-HT3) receptors are ligand-gated ion channels that play important roles in depression, anxiety, substance abuse, emesis, inflammatory pain, spinal nociception, gastrointestinal function, and cardiovascular reflexes. Probably the most studied modulators of 5-HT3 receptors are the high affinity competitive ‘setron’ antagonists typified by ondansetron. However, there exists a broad range of compounds that modulate the 5-HT3 receptor, not through the orthosteric site but by binding to allosteric sites. Most notable are therapeutic compounds ascribed to certain targets but that allosterically modulate 5-HT3 receptors at clinically relevant concentrations. PMID:21342788

Davies, Paul Andrew



Species differences in the responses of pulmonary vascular preparations to 5-hydroxytryptamine.  


5-Hydroxytryptamine (5-HT) has been implicated in pulmonary hypertension, hypoxic pulmonary vasoconstriction, and the pulmonary side-effects of some drugs. 5-HT contracts bovine, ovine, canine, caprine, feline, rabbit, guinea-pig and rat isolated pulmonary arteries mainly by activation of 5-HT2A receptors but relaxes porcine pulmonary artery through activation of endothelial 5-HT2B receptors. Pharmacological responses of the pulmonary veins to 5-HT have been less studied and comprise both contraction (bovine, canine, feline, equine, rabbit) and relaxation (ovine, caprine). Functional and radioligand binding studies in human isolated intrapulmonary arteries and veins have demonstrated a mixed population of 5-HT1B/1D and 5-HT2A receptors mediating vasoconstriction but no evidence of involvement of 5-HT1A, 5-HT3 and 5-HT4 receptors. Remarkable differences exist in the in vitro pulmonary vasoreactivity to 5-HT and related drugs in humans compared with other mammals. Therefore, the use of human tissues is to be preferred to study pathophysiological responses of pulmonary circulation with clinical relevance. PMID:10216431

Morcillo, E J; Cortijo, J



5HT 1B\\/D receptors in anxiety  

Microsoft Academic Search

\\u000a The last 30 years have seen the virtual monopoly of the anxiolytic market by benzodiazepines and more recently by the compounds\\u000a which constitute the first part of this book. Among other neurotransmitters potentially involved in anxiety, serotonin (5-hydroxytryptamine,\\u000a 5-HT) of course has a very prominent place. The neuropharmacology of 5-HT has been fundamentally revised in recent years with\\u000a the discovery

Chantal Moret


The activity of dihydropyrimidine dehydrogenase from rat liver was not affected by any of five 5-hydroxytryptamine antagonists.  


We estimate the influence of five 5-hydroxytryptamine receptor (5-HT3) antagonists on the activity of dihydropyrimidine dehydrogenase (DPDase), the rate-limiting enzyme in 5-fluorouracil (5FU) metabolism. The activity of DPDase from the rat liver was compared in the cytosol mixture of 5FU incubated with or without each of five 5-HT3 antagonists. DPDase activity was not altered in the presence of any 5-HT3 antagonist studied here. It may be inferred from these results that the any 5-HT3 receptor antagonist examined in this study has little or no effect on fluorouracil catabolism. PMID:8950202

Tateishi, T; Nakura, H; Watanabe, M; Tanaka, M; Kumai, T; Kobayashi, S



Pulmonary hypertension, anorexigens and 5HT: pharmacological synergism in action?  

Microsoft Academic Search

In pulmonary hypertension (PHT), pulmonary vascular resistance is elevated as a result of increased pulmonary vascular tone and pulmonary vascular remodelling. Certain diet pills, such as the fenfluramines, have been associated with the development of PHT. This class of drugs act as indirect 5-HT receptor agonists and can inhibit 5-HT reuptake and cause the release of 5-HT from platelets. Many

Margaret R MacLean



Immunocytochemical demonstration of 5-hydroxytryptamine (serotonin) in the nervous system of the liver fluke, Fasciola hepatica (Trematoda, Digenea)  

Microsoft Academic Search

The localisation and distribution of 5-hydroxytryptamine (5-HT or serotonin) in the nervous system ofFasciola hepatica has been determined by an indirect immunofluorescence technique. Cell bodies and nerve fibres immunoreactive to 5-HT are present in the anterior ganglia, and the longitudinal nerve cords and their commissures in the central nervous system. In the peripheral nervous system, similar immunoreactivity occurs in the

I. Fairweather; A. G. Maule; S. H. Mitchell; C. F. Johnston; D. W. Halton



Activation of Human 5-Hydroxytryptamine Type 3 Receptors via an Allosteric Transmembrane Site.  


In common with other members of the Cys-loop family of pentameric ligand-gated ion channels, 5-hydroxytryptamine type 3 receptors (5-HT3Rs) are activated by the binding of a neurotransmitter to an extracellular orthosteric site, located at the interface of two adjacent receptor subunits. In addition, a variety of compounds have been identified that modulate agonist-evoked responses of 5-HT3Rs, and other Cys-loop receptors, by binding to distinct allosteric sites. In this study, we examined the pharmacological effects of a group of monoterpene compounds on recombinant 5-HT3Rs expressed in Xenopus oocytes. Two phenolic monoterpenes (carvacrol and thymol) display allosteric agonist activity on human homomeric 5-HT3ARs (64 ± 7% and 80 ± 4% of the maximum response evoked by the endogenous orthosteric agonist 5-HT, respectively). In addition, at lower concentrations, where agonist effects are less apparent, carvacrol and thymol act as potentiators of responses evoked by submaximal concentrations of 5-HT. By contrast, carvacrol and thymol have no agonist or potentiating activity on the closely related mouse 5-HT3ARs. Using subunit chimeras containing regions of the human and mouse 5-HT3A subunits, and by use of site-directed mutagenesis, we have identified transmembrane amino acids that either abolish the agonist activity of carvacrol and thymol on human 5-HT3ARs or are able to confer this property on mouse 5-HT3ARs. By contrast, these mutations have no significant effect on orthosteric activation of 5-HT3ARs by 5-HT. We conclude that 5-HT3ARs can be activated by the binding of ligands to an allosteric transmembrane site, a conclusion that is supported by computer docking studies. PMID:25338672

Lansdell, Stuart J; Sathyaprakash, Chaitra; Doward, Anne; Millar, Neil S



5-Hydroxytryptamine Generates Tonic Inward Currents on Pacemaker Activity of Interstitial Cells of Cajal from Mouse Small Intestine  

PubMed Central

In this study we determined whether or not 5-hydroxytryptamine (5-HT) has an effect on the pacemaker activities of interstitial cells of Cajal (ICC) from the mouse small intestine. The actions of 5-HT on pacemaker activities were investigated using a whole-cell patch-clamp technique, intracellular Ca2+ ([Ca2+]i) analysis, and RT-PCR in ICC. Exogenously-treated 5-HT showed tonic inward currents on pacemaker currents in ICC under the voltage-clamp mode in a dose-dependent manner. Based on RT-PCR results, we found the existence of 5-HT2B, 3, 4, and 7 receptors in ICC. However, SDZ 205557 (a 5-HT4 receptor antagonist), SB 269970 (a 5-HT7 receptor antagonist), 3-tropanylindole - 3 - carboxylate methiodide (3-TCM; a 5-HT3 antagonist) blocked the 5-HT-induced action on pacemaker activity, but not SB 204741 (a 5-HT2B receptor antagonist). Based on [Ca2+]i analysis, we found that 5-HT increased the intensity of [Ca2+]i. The treatment of PD 98059 or JNK II inhibitor blocked the 5-HT-induced action on pacemaker activity of ICC, but not SB 203580. In summary, these results suggest that 5-HT can modulate pacemaker activity through 5-HT3, 4, and 7 receptors via [Ca2+]i mobilization and regulation of mitogen-activated protein kinases. PMID:21860590

Shahi, Pawan Kumar; Choi, Seok; Zuo, Dong Chuan; Yeum, Cheol Ho; Yoon, Pyung Jin; Lee, Jun; Kim, Young Dae; Park, Chan Guk; Kim, Man Yoo; Shin, Hye Rang; Oh, Hyun Jung



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



Influence of 5-hydroxytryptamine uptake on the apparent 5-hydroxytryptamine antagonist potency of metoclopramide in the rat isolated superior cervical ganglion.  

PubMed Central

Metoclopramide, 1 X 10(-6) -1 X 10(-4) M, was found to behave as a reversible, competitive antagonist of 5-hydroxytryptamine (5-HT)-induced depolarization of the rat isolated vagus nerve (VN) and superior cervical ganglion (SCG). The pKB values were 6.60 (+/- 0.04) and 5.74 (+/- 0.07), respectively. The possibility that this apparent difference in potency was due to saturable 5-HT uptake was investigated. The SCG, but not the VN, accumulated tritium-labelled 5-HT via a saturable, sodium- and temperature-dependent mechanism. Ganglionic 5-HT uptake was blocked by desmethylimipramine (IC50 1.4 X 10(-6)M), chlorimipramine (8.7 X 10(-9) M), zimelidine (1.5 X 10(-7) M), paroxetine (4.3 X 10(-8) M) and citalopram (6.2 X 10(-8) M). The 5-HT uptake inhibitor paroxetine, 1 X 10(-6) M, did not modify the apparent 5-HT antagonist potency of metoclopramide on the VN, but raised the pKB obtained against 5-HT on the SCG from 5.74 (+/- 0.07) to 6.25 (+/- 0.03). It is suggested that the observed difference in the potency of metoclopramide as a 5-HT antagonist on the rat VN and SCG was due to saturable 5-HT uptake in the latter preparation. The results do not support a difference in the 5-HT receptors mediating depolarization on the VN and SCG. PMID:3814917

Ireland, S. J.; Straughan, D. W.; Tyers, M. B.



A reverse-phase HPLC and fluorescence detection method for measurement of 5-hydroxytryptamine (serotonin) in Planaria  

Microsoft Academic Search

Introduction:Planaria have proven to be a good model system in which to investigate mammalian behaviors and responses to drugs. We have recently studied the response of planarians to dopaminergic ligands and to the effects of cocaine and opioids. To correlate behavior (specifically, drug withdrawal) with neurotransmitter levels, we developed a method to quantify 5-hydroxytryptamine (5-HT; serotonin) in planarians. Methods: Following

Sumiyo Umeda; Gregory W. Stagliano; Michael R. Borenstein; Robert B. Raffa



Expression of the 5HT receptors in rat brain during memory consolidation  

Microsoft Academic Search

Serotonin (5-hydroxytryptamine, 5-HT) system displays more than 14 receptors subtypes on brain areas involved in learning and memory processes, and pharmacological manipulation of specific receptors selectively affects memory formation. In order to begin the search of 5-HT receptors expression during memory formation, in this work, we aimed to determine, by autoradiography (using [3H] 5-HT as ligand, 2nM, specific activity 123Ci\\/mmol),

A Meneses; L Manuel-Apolinar; L Rocha; E Castillo; C Castillo



Antidepressant activity: contribution of brain microdialysis in knock-out mice to the understanding of BDNF/5-HT transporter/5-HT autoreceptor interactions  

PubMed Central

Why antidepressants vary in terms of efficacy is currently unclear. Despite the leadership of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression, the precise neurobiological mechanisms involved in their therapeutic action are poorly understood. A better knowledge of molecular interactions between monoaminergic system, pre- and post-synaptic partners, brain neuronal circuits and regions involved may help to overcome limitations of current treatments and identify new therapeutic targets. Intracerebral in vivo microdialysis (ICM) already provided important information about the brain mechanism of action of antidepressants first in anesthetized rats in the early 1990s, and since then in conscious wild-type or knock-out mice. The principle of ICM is based on the balance between release of neurotransmitters (e.g., monoamines) and reuptake by selective transporters [e.g., serotonin transporter for serotonin 5-hydroxytryptamine (5-HT)]. Complementary to electrophysiology, this technique reflects pre-synaptic monoamines release and intrasynaptic events corresponding to ?80% of whole brain tissue content. The inhibitory role of serotonergic autoreceptors infers that they limit somatodendritic and nerve terminal 5-HT release. It has been proposed that activation of 5-HT1A and 5-HT1B receptor sub-types limits the antidepressant-like activity of SSRIs. This hypothesis is based partially on results obtained in ICM experiments performed in naïve, non-stressed rodents. The present review will first remind the principle and methodology of ICM performed in mice. The crucial need of developing animal models that display anxiety and depression-like behaviors, neurochemical and brain morphological phenotypes reminiscent of these mood disorders in humans, will be underlined. Recently developed genetic mouse models have been generated to independently manipulate 5-HT1A auto and heteroreceptors and ICM helped to clarify the role of the pre-synaptic component, i.e., by measuring extracellular levels of neurotransmitters in serotonergic nerve terminal regions and raphe nuclei. Finally, we will summarize main advantages of using ICM in mice through recent examples obtained in knock-outs (drug infusion through the ICM probe allows the search of a correlation between changes in extracellular neurotransmitter levels and antidepressant-like activity) or alternatives (infusion of a small-interfering RNA suppressing receptor functions in the mouse brain). We will also focus this review on post-synaptic components such as brain-derived neurotrophic factor in adult hippocampus that plays a crucial role in the neurogenic and anxiolytic/antidepressant-like activity of chronic SSRI treatment. Limitations of ICM will also be considered. PMID:23964240

Gardier, Alain M.



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



Metabolic kinetics of 5-hydroxytryptamine and the research targets of functional gastrointestinal disorders.  


5-Hydroxytryptamine (5-HT) is an important neurotransmitter in both the central and enteric nervous systems. It has diverse functions in regulating gastrointestinal motility and visceral sensitivity, emotion, appetite, pain and sensory perception, cognition, sexual activity and sleep. These functions are mainly associated with the metabolic kinetics of 5-HT in different tissues. Tryptophan hydroxylase is the rate-limiting enzyme and modulates serotonin synthesis. Vesicular monoamine transporter 1 plays a role in 5-HT storage and release. Degradation of 5-HT is mediated by monoamine oxidase-A. All these factors influence the action of 5-HT in vivo. Functional gastrointestinal disorders (FGIDs) are characterized by a series of symptoms including abdominal pain, diarrhea, constipation, anxiety and depression, in the absence of identifiable structural or biochemical abnormalities. They are frequently accompanied by changed gut motility or visceral sensitivity. An increasing body of research has found FGIDs to be closely associated with 5-HT, and drugs such as citalopram, paroxetine, venlafaxine, alosetron, tegaserod, prucalopride and mosapride have all been developed or discovered from the perspective of the metabolic kinetics of 5-HT. This review discusses the relationship between the metabolic kinetics of 5-HT and research targets in the field of FGIDs and suggests areas of future study that may be useful for understanding these disorders and identification of potential therapeutic targets. PMID:24916714

Jing, Fuchun; Zhang, Jun



Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice.  


Serotonin [5-hydroxytryptamine (5-HT)] neurotransmission in the central nervous system modulates depression and anxiety-related behaviors in humans and rodents, but the responsible downstream receptors remain poorly understood. We demonstrate that global disruption of 5-HT2A receptor (5HT2AR) signaling in mice reduces inhibition in conflict anxiety paradigms without affecting fear-conditioned and depression-related behaviors. Selective restoration of 5HT2AR signaling to the cortex normalized conflict anxiety behaviors. These findings indicate a specific role for cortical 5HT2AR function in the modulation of conflict anxiety, consistent with models of cortical, "top-down" influences on risk assessment. PMID:16873667

Weisstaub, Noelia V; Zhou, Mingming; Lira, Alena; Lambe, Evelyn; González-Maeso, Javier; Hornung, Jean-Pierre; Sibille, Etienne; Underwood, Mark; Itohara, Shigeyoshi; Dauer, William T; Ansorge, Mark S; Morelli, Emanuela; Mann, J John; Toth, Miklos; Aghajanian, George; Sealfon, Stuart C; Hen, René; Gingrich, Jay A



Plasma 5-hydroxytryptamine constricts equine digital blood vessels in vitro: implications for pathogenesis of acute laminitis.  


Cumulative concentration response curves to 5-hydroxytryptamine (5-HT; 10(-10)-10(-4) mol/l) were constructed using isolated rings of equine digital, facial, tail and coronary arteries (endothelium intact). 5-HT was 17.7 and 41 times more potent as a vasoconstrictor of digital arteries than facial and tail arteries respectively. Removal of the endothelium increased the vasoconstrictor potency of 5-HT in the facial artery by 3.7-fold (P<0.05) but did not alter the sensitivity of digital arteries to 5-HT. Coronary arteries failed to contract to 5-HT. Coronary arteries pre-contracted with U44069 showed concentration dependent relaxation to 5-HT, a response which was partially dependent on the presence of the endothelium. No vasorelaxant effects were found in the digital or facial arteries. The concentration of 5-HT in platelet poor and platelet rich equine plasma was found to be 6.70+/-1.1 x 10(-8) mol/l and 1.77+/-0.36 x 10(-6) mol/l (mean +/-s.e.) respectively by high performance liquid chromatography (HPLC). Plasma which contained no detectable platelets had a 5-HT concentration of 1.12+/-0.48 x 10(-8) mol/l. Isolated digital arteries constricted when exposed to dilutions of platelet poor and platelet depleted equine plasma. These plasma induced contractions were almost completely inhibited by 5-HT receptor antagonists, ketanserin and methiothepin. The change in isometric tension in rings of equine digital artery in vitro was therefore used as a bioassay for plasma 5-HT and the results obtained by this method showed an excellent correlation (r2 = 97.2%, P<0.001) with the concentration estimated by HPLC. Circulating free concentrations of 5-HT in normal horses may be sufficient to constrict digital blood vessels partially in vivo but are well below the threshold for contraction of other peripheral blood vessels examined. PMID:9535068

Bailey, S R; Elliott, 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.



CART peptides increase 5-hydroxytryptamine in the dorsal raphe and nucleus accumbens of freely behaving rats  

PubMed Central

Cocaine and amphetamine-regulated transcript peptides (CART) are implicated in the antidepressant effect. This may involve in 5-hydroxytryptamine (5-HT) in the CNS. The aim of the present studies was to investigate the effect of CART peptides on extracellular 5-HT in the dorsal raphe nucleus (DRN) and nucleus accumbens (NAcc) using a microdialysis approach in freely-behaving rats. Reverse infusion of CART61–102 in the DRN produced a concentration (10 µM–100 µM) -dependent increase in 5-HT in the DRN. Similarly, CART62–76 (10 µM–100 µM) infused into the DRN and NAcc elevated 5-HT in the DRN and NAcc, respectively. Thus, CART increases extracellular 5-HT in both the DRN and NAcc. In addition, infusion of CART62–76 (100 µM) in the DRN produced a significant increase in 5-HT in the NAcc, implying an existence of CART receptors responsible for the depolarization-dependent release. In summary, the results of the present studies suggest that CART peptides may have an antidepressant effect through increases in extracellular 5-HT. PMID:17346884

Ma, Zhiyuan; Pearson, Elliot; Tao, Rui



5-Hydroxytryptamine participation in the vagal inhibitory innervation of the stomach  

PubMed Central

1. Intraluminal pressure was recorded from the isolated guinea-pig and mouse stomach with the vagus and sympathetic nerves attached. 2. The response to vagal stimulation, which consists of an excitatory and an inhibitory component, resembled the response to 5-hydroxytryptamine (5-HT), which has no direct action on the muscle but acts on intrinsic excitatory and inhibitory ganglia. 3. In the presence of hyoscine, the effect of vagal stimulation, of nicotinic compounds and of 5-HT were all purely relaxant. Competitive block of ganglionic receptors for acetylcholine reduced the vagal relaxation without antagonizing 5-HT. Specific desensitization of ganglionic receptors for 5-HT reduced the vagal relaxation without antagonizing nicotinic compounds. 4. During the early phase of the blocking action of nicotine, responses to vagal stimulation and to 5-HT were both abolished. As the non-specific antagonism changed to the later phase of specific antagonism to acetylcholine, the inhibitory (but not the excitatory) component of the vagal response recovered partially, in parallel with the recovery of the relaxant effect of 5-HT. 5. The vagal inhibitory effect was completely abolished only when competitive block of acetylcholine receptors was combined with desensitization of 5-HT receptors. 6. Stimulation of the mouse stomach (after asphyxiation of the mucosa and exclusion of the luminal content) in the presence of hyoscine caused the release of 5-HT; this release was blocked by tetrodotoxin. 7. The results, together with previous observations that 5-HT is contained within preganglionic nerve fibres in the myenteric plexus, are consistent with the hypothesis that 5-HT, with acetylcholine, may be a neurotransmitter in the vagal inhibitory innervation of the stomach. PMID:4383454

Bulbring, Edith; Gershon, M. D.



Hypothalamic paraventricular 5-hydroxytryptamine inhibits the effects of ghrelin on eating and energy substrate utilization  

PubMed Central

Ghrelin microinjections into discrete regions of the hypothalamus, including the paraventricular nucleus (PVN), stimulate eating and promote carbohydrate oxidation, effects similar to PVN microinjection of neuropeptide Y (NPY). We have also reported that NPY’s orexigenic and metabolic effects are antagonized by pretreatment with 5-hydroxytryptamine (5-HT) or 5-HT receptor agonists. In order to determine whether 5-HT also inhibits ghrelin’s orexigenic and metabolic actions, the present study examined the effects of 5-HT pretreatment on ghrelin-induced alterations in eating and energy substrate utilization following direct injections into the hypothalamic PVN. Both 5-HT (5–20 nmol) and ghrelin (100 pmol) were administered at the onset of the dark cycle. Food intake was measured 2 h postinjection. A separate group of rats (n=8) was injected with 5-HT paired with ghrelin and respiratory quotient (RQ; VCO2/VO2) was measured over 2 h using an open circuit calorimeter. PVN injections of ghrelin increased food intake and increased RQ, reflecting a shift in energy substrate utilization in favor of carbohydrate oxidation. 5-HT effectively blocked the effects of ghrelin on both food intake and RQ. We then administered the 5-HT2A/2C, receptor agonist, DOI, immediately prior to ghrelin. Similar to 5-HT, PVN DOI blocked ghrelin-induced eating and inhibited the peptide’s effect on substrate utilization. These data are in agreement with other evidence suggesting that ghrelin functions as a gut-brain peptide in the control of food intake and energy metabolism, and indicate that 5-HT acts within the PVN to modulate ghrelin’s orexigenic and metabolic signaling. PMID:20573591

Currie, Paul J.; John, Catherine S.; Nicholson, Marjorie L.; Chapman, Colin D.; Loera, Katherine E.



Functional antagonism of gonadal steroids at the 5-hydroxytryptamine type 3 receptor.  


Steroid hormone action involves binding to cognate intracellular receptors that, in turn, bind to respective response elements and thus modulate gene expression. The present study shows that the gonadal steroids, 17beta-estradiol and progesterone, may also act as functional antagonists at the 5-hydroxytryptamine type 3 (5-HT3) receptor in whole-cell voltage-clamp recordings of HEK 293 cells stably expressing the 5-HT3 receptor. Functional antagonistic properties at this ligand-gated ion channel could also be shown for 17alpha-estradiol, 17alpha-ethinyl-17beta-estradiol, mestranol, R 5020, testosterone, and allopregnanolone but not for pregnenolone sulfate and cholesterol. An antagonism at the 5-HT3 receptor could further be observed with the aromatic alcohol 4-dodecylphenol but not with phenol or ethanol. Thus, the modulation of 5-HT3 receptor function by steroids or alcohols is dependent on their respective molecule structure. The antagonistic action of steroids at the 5-HT3 receptor is not mediated via the serotonin binding site because the steroids did not alter the binding affinity of [3H]GR65630 to the 5-HT3 receptor, and kinetic experiments revealed a quite different response pattern to 17beta-estradiol when compared with the competitive antagonist metoclopramide. BSA-conjugated gonadal steroids labeled with fluorescein isothiocyanate bound to membranes of HEK 293 cells expressing the 5-HT3 receptor in contrast to native HEK 293 cells. However, there was no dose-dependent displacement of the binding of gonadal steroids to membranes of cells expressing the 5-HT3 receptor in binding experiments or fluorescence studies. Thus, gonadal steroids probably interact allosterically with the 5-HT3 receptor at the receptor-membrane interface. The functional antagonism of gonadal steroids at the 5-HT3 receptor may play a role for the development and course of nausea during pregnancy and of psychiatric disorders. PMID:9731711

Wetzel, C H; Hermann, B; Behl, C; Pestel, E; Rammes, G; Zieglgänsberger, W; Holsboer, F; Rupprecht, R



Effects of repeated lithium administration on the subcellular distribution of 5-hydroxytryptamine in rat brain.  

PubMed Central

1 The content and distribution of 5-hydroxytryptamine (5-HT) between subcellular fractions from rat whole brain (excluding cerebellum) were examined following repeated lithium administration. 2 Lithium chloride (3 mEq/kg body wt. s.c.) administered twice daily for 3 days produced no change in the 5-HT content of primary subcellular fractions (P1-nuclear; P2-crude synaptosomal; SNT-soluble) measured on the 4th day. 3 Similarly, repeated lithium treatment alone did not appear to produce increases in the 5-HT content of either cytoplasmic (S) or vesicular (M2) fractions derived from hypo-osmotically disrupted synaptosomes (P2) when compared to control rats receiving NaCl only. 4 One hour after monoamine oxidase inhibition with tranylcypromine, there was a further selective 25% increase in 5-HT accumulation in the lithium-treated rats over control values in the soluble cytoplasmic fraction (S) and in fractions containing occluded cytoplasm only. This increase did not occur in the synaptic vesicle fraction (M2). This corresponds to an increase in 5-HT turnover rate due to the lithium treatment of approx. 50%. 5 These findings lend additional support to the hypothesis that lithium treatment alters the intraneuronal storage or compartmentation of 5-HT between vesicles and cytoplasm. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:7104517

Atterwill, C. K.; Tordoff, A. F.



5-Hydroxytryptamine stimulates fluid secretion in locust malpighian tubules independently of cAMP.  


5-Hydroxytryptamine (5-HT) stimulates fluid secretion by semi-isolated Malpighian tubules of Locusta in a dose-dependent manner. The threshold of stimulation is between 10(-8) and 10(-7) M 5-HT; maximal activation occurs at doses greater than 10(-6) M. Relative to the activation induced by diuretic hormone (storage lobe extracts), 5-HT increases the rate of fluid secretion by only 65%. Phentolamine, the alpha-adrenergic blocker, failed to inhibit either DH or 5-HT stimulated secretion. Diuretic hormone raises the levels of intracellular of cAMP, and activates adenylate cyclase in plasma membrane preparations of Locusta Malpighian tubules. 5-HT (10(-4) M) has no effect in either assay system. Thus 5-HT can stimulate fluid secretion independently of cAMP. A hypothetical model for hormone stimulated fluid secretion by Locusta Malpighian tubules, involving dual-receptor activation, is proposed. Other biogenic amines, including octopamine, adrenalin, dopamine, synephrine and the formamidine chlordimeform were tested for their ability to stimulate fluid secretion. Only dopamine showed a weakly stimulatory effect. PMID:6151458

Morgan, P J; Mordue, W



5-Carboxamide tryptamine, a compound with high affinity for 5-hydroxytryptamine1 binding sites, dilates arterioles and constricts arteriovenous anastomoses.  

PubMed Central

The effects of 5-carboxamide tryptamine, which activates non-5-hydroxytryptamine2-'atypical' receptors for 5-hydroxytryptamine (5-HT) in the dog saphenous vein, was studied on the complete distribution of cardiac output and common carotid blood flow in anaesthetized pigs. The drug was infused for 10 min at the rate of 0.025, 0.1 and 0.4 micrograms kg-1 min-1 either intravenously (cardiac output distribution) or intra-arterially (carotid distribution). 5-Carboxamide tryptamine decreased arterial blood pressure due to a reduction of cardiac output. This reduction was confined to its arteriovenous anastomotic component; the component used for the tissue perfusion (nutrient part) in fact increased. Similar changes were observed in the carotid blood flow distribution. Vasodilation was observed in several tissues, but the skin, ears and stomach responded most prominently. The effects of 5-carboxamide tryptamine on the carotid distribution were not significantly modified by cyproheptadine (1 mg kg-1). It is concluded that, like 5-HT, 5-carboxamide tryptamine constricts arteriovenous anastomoses and dilates arterioles by activating non-5-HT2-'atypical' receptors. These 'atypical' 5-HT receptors appear to be of the 5-HT1 type since both 5-carboxamide tryptamine and BEA 1654, a new piperazine derivative, produced similar vascular effects in the carotid bed of the pig and also showed a high and selective affinity for the 5-HT1 binding sites. PMID:3978321

Saxena, P. R.; Verdouw, P. D.



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



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



Interaction of ketanserin and its metabolite ketanserinol with 5HT 2 receptors in pulmonary and coronary arteries of calf  

Microsoft Academic Search

A comparison of 5-hydroxytryptamine (5HT)-induced contractions was made on cocaine-treated strips of bovine pulmonary arteries and large coronary arteries. The affinities of the 5HT2 antagonist ketanserin, its metabolite ketanserinol, yohimbine and rauwolscine were estimated for both arteries.1.Ketanserin was a competitive antagonist of the effects of 5HT in both arteries. The KB values (-log mol\\/l) were 9.5 for large coronary arteries

Michael Frenken; Alberto J. Kaumann



Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro.  

PubMed Central

1. Tramadol is a centrally acting analgesic with low opioid receptor affinity and therefore presumably other mechanisms of analgesic action. Tramadol inhibits noradrenaline uptake but since 5-hydroxytryptamine (5-HT) is also involved in the modulation of pain perception, we tested the effects of tramadol on 5-HT uptake and release in vitro. 2. Tramadol inhibited the uptake of [3H]-5-HT into purified rat frontal cortex synaptosomes with an IC50 of 3.1 microM. The (+)-enantiomer was about four times more potent than the (-)-enantiomer; the main metabolite of tramadol, O-desmethyltramadol, was about ten times less potent. 3. Rat frontal cortex slices were preincubated with [3H]-5-HT, then superfused and stimulated electrically. Tramadol facilitated the basal outflow of [3H]-5-HT, at concentrations greater than 1 microM, while the uptake inhibitor 5-nitroquipazine enhanced both basal and stimulation-evoked overflow. Effects of the (+)-enantiomer were more potent than either the racemate, the (-)-enantiomer or the principal metabolite. 4. The effects of tramadol on the basal outflow of [3H]-5-HT were almost completely abolished when the superfusion medium contained a high concentration of the selective 5-HT uptake blocker, 6-nitroquipazine. 5. The results provide evidence for an interaction of tramadol with the neuronal 5-HT transporter. An intact uptake system is necessary for the enhancement of extraneuronal 5-HT concentrations by tramadol indicating an intraneuronal site of action. PMID:1596676

Driessen, B.; Reimann, W.



Phylogenetic Analysis and Selection Pressures of 5HT Receptors in Human and Non-human Primates: Receptor of an Ancient Neurotransmitter  

Microsoft Academic Search

Neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) an ancient neurotransmitter, involved in several neurophysiological and behavioral functions, acts by interacting with multiple receptors (5-HT1-5-HT7). Alterations in serotonergic signalling have also been implicated in various psychiatric disorders. The availability of the genome data of nonhuman primates permits comparative analysis of human 5-HT receptors with sequences of non-human primates to understand evolutionary divergence. We compared

Padmanabhan Anbazhagan; Meera Purushottam; H. B. Kiran Kumar; Odity Mukherjee; Sanjeev Jain; Ramanathan Sowdhamini



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



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



Multiple 5-HT receptors in the guinea-pig superior cervical ganglion.  

PubMed Central

1. We have studied the pharmacology of the depolarization by 5-hydroxytryptamine (5-HT) of the guinea-pig isolated superior cervical ganglion (SCG) using the grease-gap technique. We studied the effects of selective and non-selective antagonists on the responses to 5-HT and other 5-HT receptor agonists. 2. We have extended the pharmacology of the 5-HT3 receptor in this preparation by studying the effects of granisetron, BRL 46470 and mianserin on the concentration-response curve (CRC) to 2-methyl-5-HT. As with other 5-HT3 receptor antagonists, these compounds exhibited a lower affinity for guinea-pig 5-HT3 receptors than for rat 5-HT3 receptors. 3. We have confirmed that low concentrations of 5-HT (< or = 1 microM) mediate ketanserin-sensitive responses and higher concentrations of 5-HT also recruit 5-HT3 receptors. The responses to low concentrations of 5-HT were antagonized by low concentrations of ketanserin, spiperone, mianserin, DOI and LSD indicating probably mediation by 5-HT2A receptors. At high concentrations, the hallucinogen, DOI, but not LSD, evoked a ketanserin-sensitive depolarization. 4. Although mianserin could bind to the 5-HT2A receptors in this preparation, we could not demonstrate a down-regulation of depolarizations evoked by these receptors after a 10 day oral treatment with mianserin (10 mg kg-1, daily). 5. 5-Carboxamidotryptamine (5-CT) evoked a prolonged depolarization. Although high concentrations of 5-CT (> or = microM) appeared to activate 5-HT2A receptors, lower concentrations of 5-CT evoked a response with a distinct pharmacology. After studying the action of 20 selective and non-selective 5-HT receptor ligands we believe that this response may be mediated by a novel receptor; but its pharmacology is closest to that of receptors in the 5-HT2 receptor family. Like 5-CT, 5-HT (3-300 microM) could evoke an LSD-sensitive response in the presence of the 5-HT2 receptor antagonist, ketanserin and the 5-HT3 receptor antagonist, tropisetron (all 1 microM). 6. We conclude that 5-HT activates three pharmacologically distinct receptors to depolarize the guinea-pig SCG. Low concentrations of 5-HT appear to activate 5-HT2A receptors. Higher concentrations of 5-HT also activate 5-HT3 receptors and a possible novel 5-HT receptor. The novel receptor could be a species homologue of a 5-HT2 receptor or an, as yet, unclassified 5-HT receptor. PMID:8825338

Watkins, C. J.; Newberry, N. R.



The nature of the acetylcholine and 5-hydroxytryptamine receptors in buccal smooth muscle of the pest slug Deroceras reticulatum  

Microsoft Academic Search

The characteristics of the acetylcholine (ACh) and 5-hydroxytryptamine (5-HT) receptors of Deroceras buccal muscle were examined using specific pharmacological probes and sucrose gap electrophysiological analysis. ACh induced concentration-dependent smooth tonic contractures coupled with considerable depolarisation from the normal resting membrane potential of -30.6 mV. The use of choline ester analogues such as carbachol, propionylcholine and butyrylcholine, specific cholinergic agonists such

T. Wright; H. Huddart



Binding interactions of antagonists with 5-hydroxytryptamine3A receptor models.  


Homology modeling was performed on the N-terminal extracellular regions of human, mouse, and guinea pig 5-hydroxytryptamine type 3A receptors (5-HT3R) based on the 24% sequence homology with and on the crystal structure of the snail acetylcholine binding protein (AChBP). Docking of 5-HT3 antagonists granisetron, tropisetron, ondansetron, dolasetron ('setrons), and (+)-tubocurarine suggests an aromatic binding cleft behind a hydrophilic vestibule. Several intra- and interface interactions, H-bonds, and salt bridges stabilize the pentameric structure and the binding cleft. The planar rings of antagonists are intercalated between aromatic side-chains (W183-Y234, Y143-Y153). S227 donates H-bonds to the carbonyl groups of 'setrons. The tertiary ammonium ions interact with E236, N128 or E129, and/or W90 (cation-pi interaction). This offers a molecular explanation of the pharmacophore models of 5-HT3R antagonists. Docking artifacts suggest some ambiguities in the binding loops A and C of the 5-HT3AR models. Lower potencies of (+)-tubocurarine for human, and those of tropisetron for guinea pig 5-HT3ARs can be attributed to steric differences of I/S230 in the binding cleft and to distinct binding interactions with E229 and S227, respectively. Ligand binding interferes with crucial intra- and interface interactions along the binding cleft. PMID:14626451

Maksay, Gábor; Bikádi, Zsolt; Simonyi, Miklós



5-Hydroxytryptamine and cholera secretion: a histochemical and physiological study in cats.  

PubMed Central

The effect of cholera toxin on the content of 5-hydroxytryptamine (5-HT) in the enterochromaffin cells of the cat small intestine was estimated by cytofluorimetry of individual enterochromaffin cells at varying times after exposing the intestinal mucosa to the toxin. The observed changes in 5-HT levels in the enterochromaffin cells were correlated with the simultaneously measured rate of net fluid transport across the intestinal epithelium. Intestinal segments exposed to cholera toxin showed a statistically significant decrease in 5-HT levels of enterochromaffin cells compared with segments exposed to heat-inactivated cholera toxin. A good correlation (r = 0.73) was found between relative 5-HT fluorescence in enterochromaffin cells and net fluid transport across the intestinal epithelium. Thus, a diminished 5-HT content was associated with a decreased rate of fluid absorption or an increased rate of secretion. A hypothesis is presented for explaining the possible role of the enterochromaffin cells in the pathophysiology of cholera secretion. Images Fig. 2 PMID:6852634

Nilsson, O; Cassuto, J; Larsson, P A; Jodal, M; Lidberg, P; Ahlman, H; Dahlstrom, A; Lundgren, O



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



Acetaminophen-induced antinociception via central 5HT 2A receptors  

Microsoft Academic Search

Acetaminophen is one of the most widely used analgesic drugs. Although the mechanism of analgesic action of acetaminophen is still not known, the involvement of the central serotonin (5-hydroxytryptamine: 5-HT) system is one possibility. In the present study, we examined the antinociceptive effect of acute and chronic intraperitoneally (i.p.) administered acetaminophen by tail flick latency measurements in the rat. A

Anan Srikiatkhachorn; Naovarut Tarasub; Piyarat Govitrapong



Novel Role of the JAK-STAT Pathway in Mediating the Effects of Atypical Antipsychotics on 5-HT2A Receptor Signaling  

E-print Network

reuptake inhibitor (SSRIs), such as fluoxetine (Prozac), the 5-HT system became the focus of a large body of literature implicating 5-HT neurotransmitter disturbances in the pathophysiology of depression. Of the 16 different classes of 5-HT receptors... Biosynthesis and Metabolism 10 Serotonin Receptors 11 5-HT Receptors 12 5-HT 2A Receptors 14 Depression and 5-HT 2A Receptors 16 Schizophrenia and 5-HT 2A Receptors 18 Signaling...

Singh, Rakesh K.



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



Involvement of 5-HT3 receptors in the nucleus accumbens in the potentiation of cocaine-induced behaviours in the rat  

PubMed Central

The present study investigated the central effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the role of 5-hydroxytryptamine3 (5-HT3) receptors in the core of the nucleus accumbens (NAc) on cocaine-induced behavioural changes in rats. The 5-HT3 receptor antagonist ondansetron (1 or 10?ng) was microinjected bilaterally into the core of the NAc 60?min prior to peripheral cocaine (15?mg?kg?1, i.p.) administration followed by the assessment of locomotor activity, rearing activity and head bobs. Both doses of ondansetron attenuated cocaine's stimulatory effect on behaviours. Fluoxetine (0.05 or 5??g) microinjected bilaterally into the core of the NAc 30?min before peripheral administration of cocaine produced dose-dependent biphasic effects on cocaine-induced behaviours. Intra-NAc administration of 0.05??g fluoxetine resulted in a potentiation of cocaine-induced behaviours, while the higher dose of the SSRI (5??g) attenuated the stimulant effect of cocaine on behaviours. To investigate a possible involvement of 5-HT3 receptors in fluoxetine's facilitatory action, ondansetron (10?ng) was microinjected 30?min prior to fluoxetine (0.05??g), which resulted in a significant attenuation of the facilitatory effect of fluoxetine on cocaine-induced behaviours. Thus, 5-HT3 receptors in the core of the NAc appear to mediate stimulatory effects on cocaine-induced locomotor activity, rears and head bobs, whereas the attenuation of cocaine-induced behaviours by fluoxetine at the higher dose, suggests the involvement of a different 5-HT receptor subtype. PMID:11090100

Herges, Sonja; Taylor, David A



Liberation of catecholamines and 5-hydroxytryptamine from human blood-platelets.  


Spontaneous and drug-induced liberation of 14C-5-hydroxytryptamine (14C-5HT), 3H-dopamine (3H-DA) and 3H-noradrenaline (3H-NA) from normal and reserpinized human blood-platelets has been determined from measurements of the amine contents before and after incubation in tris-buffer. In normal platelets the spontaneous liberation of 3H-catecholamines was more marked than that of 14C-5HT, but was less in percent for all these labelled amines than in reserpinized platelets. Thrombin lowered amine contents more in normal than in reserpinized platelets. The initial thrombin-induced decrease of 14C-5HT, in contrast to that of 3H-catecholamines, showed a partial recovery after 30 min which was abolished by imipramine. The benzoquinolizine Ro 4-1284 diminished all the amines in normal, but not in reserpinized platelets. In normal platelets tryamine affected 14C-5HT and 3H-DA about equally, whereas 3H-NA much less. Octopamine showed a similar pattern as tryamine, but was less potent. P-chlormethamphetamine (PCMA) and amphetamine decreased 3H-DA less markedly than 14C-5HT and 3H-NA not at all. In reserpinized platelets these arylalkylamines induced a decrease of 14C-5HT but not of 3H-catecholamines. It is concluded that (a) 3H-catecholamines like 14C-5HT are mainly localized in the granular pool of normal human platelets, (b) the pattern of action of a drug on intra- and extragranular amines depends not only on the nature of the drug and the amine to be liberated, but in comparison with previous results also on the species, (c) platelets are not completely satisfactory models for monoaminergic neurons, especially catecholaminergic ones regarding drug-induced amine liberation. PMID:6912385

Peyer, M; Pletscher, A



Pharmacological Characterization of a 5-HT1-Type Serotonin Receptor in the Red Flour Beetle, Tribolium castaneum  

PubMed Central

Serotonin (5-hydroxytryptamine, 5-HT) is known for its key role in modulating diverse physiological processes and behaviors by binding various 5-HT receptors. However, a lack of pharmacological knowledge impedes studies on invertebrate 5-HT receptors. Moreover, pharmacological information is urgently needed in order to establish a reliable classification system for invertebrate 5-HT receptors. In this study we report on the molecular cloning and pharmacological characterization of a 5-HT1 receptor from the red flour beetle, Tribolium castaneum (Trica5-HT1). The Trica5-HT1 receptor encoding cDNA shows considerable sequence similarity with members of the 5-HT1 receptor class. Real time PCR showed high expression in the brain (without optic lobes) and the optic lobes, consistent with the role of 5-HT as neurotransmitter. Activation of Trica5-HT1 in mammalian cells decreased NKH-477-stimulated cyclic AMP levels in a dose-dependent manner, but did not influence intracellular Ca2+ signaling. We studied the pharmacological profile of the 5-HT1 receptor and demonstrated that ?-methylserotonin, 5-methoxytryptamine and 5-carboxamidotryptamine acted as agonists. Prazosin, methiothepin and methysergide were the most potent antagonists and showed competitive inhibition in presence of 5-HT. This study offers important information on a 5-HT1 receptor from T. castaneum facilitating functional research of 5-HT receptors in insects and other invertebrates. The pharmacological profiles may contribute to establish a reliable classification scheme for invertebrate 5-HT receptors. PMID:23741451

Vleugels, Rut; Lenaerts, Cynthia; Baumann, Arnd; Vanden Broeck, Jozef; Verlinden, Heleen



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.  


The effect of 5-hydroxytryptamine (5-HT) alteration on brain dopamine (DA), norepinephrine (NE), beta-endorphin (beta E) and immunoreactive insulin (IRI) 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) 3 days prior to sacrificing or fluoxetine (10 mg/kg) twice daily for 3 days. PCPA treatment significantly decreased brain content of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) 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. PMID:2935473

Kolta, M G; Soliman, K F; Williams, B B



5-Hydroxytryptamine causes depression of twitch height in the partially curarized rat phrenic nerve hemidiaphragm preparation.  


5-Hydroxytryptamine (5-HT) has significant effects on the skeletal neuromuscular junction. We have evaluated the potential neuromodulatory effects of 5-HT on the rat hemidiaphragm using a non-fatiguing pattern of stimulation (0.3 Hz) in a partially curarized preparation using tubocurarine (EC50 = 560 (range 400-650) nmol litre-1). 5-HT was added to the partially curarized preparation in the following concentrations: 0, 12.5, 25, 50, 100, 200 and 400 nmol litre-1 and the twitch response was recorded at each concentration. These measurements were expressed as a ratio of control values, plotted against time and the area under the curve (AUC) calculated. The AUC values for test and control hemidiaphragms were compared by paired t test analysis accepting a 5% significance level. The mean AUC for test (3327 mm2) and control (4102 mm2) preparations were significantly different (P = 0.003). We have shown that the addition of low concentrations of 5-HT to the indirectly stimulated partially curarized rat diaphragm preparation caused depression of twitch height. PMID:9505786

Hindle, A T; Hopkins, P M



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.



The role of 5-hydroxytryptamine as a transmitter between identified leech neurones in culture.  

PubMed Central

The synthesis, storage, release and synaptic actions of 5-hydroxytryptamine (5-HT or serotonin) were studied in order to characterize the synaptic connexion that develops between pairs of identified neurones dissected from the central nervous system of the leech and maintained in culture. Experiments were made with Retzius cells (which are known to contain 5-HT in vivo) and pressure sensory neurones on which they form chemical synapses in culture. Individual, isolated Retzius cells in culture synthesized [3H]5-HT from either [3H]tryptophan or [3H]5-hydroxytryptophan [( 3H]5-HTP). These cells did not synthesize other putative neurotransmitters, such as acetylcholine, dopamine, octopamine, noradrenaline or gamma-aminobutyric acid from their respective precursors. The monoaminergic character of Retzius cells was also demonstrated by staining with Neutral Red and by histofluorescence. Individual, isolated Retzius cells that had synthesized and accumulated [3H]5-HT released this compound when depolarized. Transmitter release was calcium-dependent and was blocked by magnesium. When incubated with [3H]5-HT and washed, Retzius cells in culture accumulated approximately 100 times more labelled 5-HT than did non-serotonergic cells, and 10 times more than Retzius cell somata acutely isolated from the animal and incubated in vitro. Chlorimipramine, a blocker of 5-HT uptake, decreased the amount of [3H]5-HT accumulated by Retzius cells and also caused a reversible increase in the amplitude of the synaptic response in the pressure sensory cell elicited by stimulation of the Retzius cell. Pressure sensory neurones in culture and in vivo responded to 5-HT focally applied by pressure ejection from a micropipette. Small pulses elicited a small, slow hyperpolarization. This response was due, at least in part, to an increase in chloride conductance and desensitized rapidly. With larger pulses, a larger, faster non-desensitizing depolarization was elicited. Together, these results provide evidence that 5-HT released from Retzius cells could be responsible for the chemical synaptic potentials seen in pressure sensory neurones in culture. Images Fig. 9 PLATE 1 PLATE 2 PMID:6310087

Henderson, L P



5-hydroxytryptamine release in the anterior hypothalamic and the hippocampal areas of cholestatic rats.  


Cholestasis contributes to the genesis of fatigue through several mechanisms. Among these mechanisms, affected serotonergic neurotransmission is important in the pathogenesis of central fatigue. Previously, elevated levels of 5-hydroxyindole acetic acid (5-HIAA), the metabolite of 5-hydroxytryptamine (5-HT) and increased 5-HT(2) receptor density were demonstrated in the anterior hypothalamus and in the hippocampus of bile duct resected rats (BDR), respectively. The aim of this paper is to demonstrate evoked 5-HT release in selected brain regions like anterior hypothalamus and hippocampal CA1 regions of cholestatic rats using BDR rats as an experimental model for cholestasis. In this study, we analyzed the K+ evoked 5-HT and its metabolite 5-HIAA levels by using HPLC with electrochemical detection in the microdialysis samples collected from anterior hypothalamic and hippocampal CA1 regions of sham-operated and BDR rats (n = 6). The ratios of [5-HIAA] to [5-HT] following perfusion with 100 mM K+ artificial cerebrospinal fluid was used for the comparison of the evoked release of 5-HT. Locomotor activity was used to assess the signs of cholestasis associated fatigue in the BDR rats. The vertical and horizontal activity counts within 15 min were found to be decreased in the BDR rats compared to sham-operated rats (p < 0.05). Besides, the number of fecal boli (an index of emotionality) was also significantly fewer in the cholestatic rats (p < 0.05). No significant difference between the sham-operated and the BDR rats was detected in the basal 5-HT and 5-HIAA levels of anterior hypothalamus. K+ stimulation yielded a more profound increase in the [5-HIAA]/[5-HT] in the BDR rats (p < 0.05). The basal levels of 5-HT in CA1 region of the BDR rats was found to be lower than that of sham-operated group (p < 0.05), but no significant difference was observed in terms of evoked 5-HT release in both sham-operated and BDR rats. These findings imply the presence of affected serotonergic system in cholestasis. PMID:16185717

Terzio?lu, Berna; Aypak, Cenk; Yananli, Hasan Raci; Küçükibrahimo?lu, Esra; Yurdaydin, Cihan; Gören, M Zafer



Cellular mechanisms of the 5-HT7 receptor-mediated signaling  

PubMed Central

Serotonin (5-hydroxytryptamine or 5-HT) is an important neurotransmitter regulating a wide range of physiological and pathological functions via activation of heterogeneously expressed 5-HT receptors. The 5-HT7 receptor is one of the most recently described members of the 5-HT receptor family. Functionally, 5-HT7 receptor is associated with a number of physiological and pathological responses, including serotonin-induced phase shifting of the circadian rhythm, control of memory as well as locomotor and exploratory activity. A large body of evidence indicates involvement of the 5-HT7 receptor in anxiety and depression, and recent studies suggest that 5-HT7 receptor can be highly relevant for the treatment of major depressive disorders. The 5-HT7 receptor is coupled to the stimulatory Gs-protein, and receptor stimulation results in activation of adenylyl cyclase (AC) leading to a rise of cAMP concentration. In addition, this receptor is coupled to the G12-protein to activate small GTPases of the Rho family. This review focuses on molecular mechanisms responsible for the 5-HT7 receptor-mediated signaling. We provide detailed overview of signaling cascades controlled and regulated by the 5-HT7 receptor and discuss the functional impact of 5-HT7 receptor for the regulation of different cellular and subcellular processes. PMID:25324743

Guseva, Daria; Wirth, Alexander; Ponimaskin, Evgeni



Peptide YY3-36 and 5-hydroxytryptamine mediate emesis induction by trichothecene deoxynivalenol (vomitoxin).  


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

Wu, Wenda; Bates, Melissa A; Bursian, Steven J; Flannery, Brenna; Zhou, Hui-Ren; Link, Jane E; Zhang, Haibin; Pestka, James J



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.



The 5-HT(7) receptor as a mediator and modulator of antidepressant-like behavior.  


The 5-HT(7) receptor has been suggested as a target for treating depression since inactivation or blockade of the receptor has an antidepressant-like behavioral effect. The present study investigated possible interactions between various classes of drugs with antidepressant properties and blockade or inactivation of the 5-HT(7) receptor. Immobility despair in the tail suspension test and the forced swim test was evaluated in mice lacking the 5-HT(7) receptor (5-HT(7)(-/-)) and in wild-type controls (5-HT(7)(+/+)) following acute drug treatments. Citalopram, a selective serotonin reuptake inhibitor and widely used antidepressant, dose-dependently reduced immobility in the tail suspension test in both 5-HT(7)(+/+) and 5-HT(7)(-/-) mice. Combining doses of citalopram and the 5-HT(7) receptor antagonist SB-269970 that by themselves did not affect behavior, reduced immobility in 5-HT(7)(+/+) mice in both the tail suspension test and the forced swim test. No effect was seen in 5-HT(7)(-/-) mice. Desipramine and reboxetine, two norepinephrine reuptake inhibitors, dose-dependently reduced immobility in the tail suspension test in 5-HT(7)(+/+) mice, but had no effect in 5-HT(7)(-/-) mice. A synergistic effect between desipramine and SB-269970 was found in both behavioral tests in 5-HT(7)(+/+) mice. Reboxetine combined with SB-269970 had effect only in the forced swim test. GBR 12909, a dopamine reuptake inhibitor, dose-dependently reduced tail suspension test immobility in both genotypes. There was no interaction between GBR 12909 and SB-269970. Aripiprazole, an antipsychotic, reduced immobility in both tests in 5-HT(7)(+/+) mice, but not in 5-HT(7)(-/-) mice. The results show that the 5-HT(7) receptor is required for the observed interaction between this receptor and antidepressants such as citalopram. The data furthermore support the hypothesis that the 5-HT(7) receptor might be a suitable target for treating depression. PMID:20097233

Sarkisyan, Gor; Roberts, Amanda J; Hedlund, Peter B



Responsiveness of 5HT 2C receptors in repeatedly diazepam-injected rats: a behavioral and neurochemical study  

Microsoft Academic Search

The role of 5-hydroxytryptamine (serotonin; 5-HT)2C receptors in anxiety and the anxiolytic effects of drugs is well documented. In view of the withdrawal anxiety associated with repeated diazepam intake, the present study concerns the efficacy of 5-HT2C re- ceptors in rats treated with diazepam. Results show that diazepam injections at a dose of 2 mg\\/kg daily for two weeks increased

Asma Khan; Darakhshan J. Haleem



Early postnatal stress affects 5HT 1A receptor function in the medial prefrontal cortex in adult rats  

Microsoft Academic Search

Traumatic events in early life are associated with an increased risk of psychiatric diseases in adulthood. 5-hydroxytryptamine (5-HT)1A receptors are known to play a pivotal role in the 5-HTergic mechanisms associated with the etiology of stress-related disorders. The goal of the present study was to investigate whether early postnatal stress influences 5-HT1A receptor function in the medial prefrontal cortex in

Hirokazu Matsuzaki; Takeshi Izumi; Machiko Matsumoto; Hiroko Togashi; Taku Yamaguchi; Takayuki Yoshida; Masahiko Watanabe; Mitsuhiro Yoshioka



The nature of the acetylcholine and 5-hydroxytryptamine receptors in buccal smooth muscle of the pest slug Deroceras reticulatum.  


The characteristics of the acetylcholine (ACh) and 5-hydroxytryptamine (5-HT) receptors of Deroceras buccal muscle were examined using specific pharmacological probes and sucrose gap electrophysiological analysis. ACh induced concentration-dependent smooth tonic contractures coupled with considerable depolarisation from the normal resting membrane potential of -30.6 mV. The use of choline ester analogues such as carbachol, propionylcholine and butyrylcholine, specific cholinergic agonists such as nicotine, muscarine, bethanecol and pilocarpine and antagonists such as d-tubocurarine, succinylcholine, hexamethomium, atropine, gallamine, pirenzepine and scopolamine indicated that the ACh receptor showed both nicotinic and muscarinic characteristics; the muscarinic activity resembled that of a mammalian M(2)-like receptor. Alternatively, it can not be ruled out that both mammalian types of receptor may be present in this preparation since both nicotine and muscarine induced noticeable tension. 5-HT application induced characteristic dose-dependent phasic contractions accompanied by small but quite consistent depolarisations. Serotonergic agonist and antagonist experiments using 1-(3-chlorophenyl) piperazine, 1-(m-chlorophenyl) biguanide, methiothepin, methysergide and metoclopramide strongly suggested that the 5-HT receptor showed closest pharmacological affinity with the 5-HT(1) receptor class of mammals but with some 5-HT(2) activity. In view of the phylogenetic gap between molluscs and mammals it is not surprising that the ACh and 5-HT receptors of Deroceras can not be properly classified by conventional mammalian terminology. PMID:11919705

Wright, T J; Huddart, H



Induction of hypoglycaemia and accumulation of 5-hydroxytryptamine in the liver after the injection of mitogenic substances into mice.  

PubMed Central

Various mitogenic substances (concanavalin A, pokeweed mitogen, polyI : polyC and a phorbol diester), as well as lipopolysaccharides (LPS or endotoxins), produced hypoglycaemia after being injected into mice. However, non-mitogenic immuno-stimulants (zymosan, carrageenan, an adjuvant peptide and interferon) did not induce hypoglycaemia. All of the mitogenic substances also induced an increase in 5-hydroxytryptamine (5-HT) in liver, but the non-mitogenic substances did not have this effect. The time course of the development of hypoglycaemia was similar to that of the increase in liver 5-HT. The dose-dependence of the hypoglycaemia induced by LPS was similar to that of the increase in liver 5-HT. In C3H/HeJ mice, the macrophages and/or lymphocytes of the mice are known to be less responsive to LPS, and both the LPS-induced hypoglycaemia and increase in 5-HT were less in these mice than in control mice (C3H/He and ddI mice). These results suggest that macrophages and/or lymphocytes may participate in the induction of hypoglycaemia and the increase in 5-HT induced by mitogenic substances and LPS. A possible correlation between hypoglycaemia and the increase in hepatic 5-HT is discussed, although the relationship is not substantiated. PMID:6722393

Endo, Y.



Inhibition of rat platelet 5-hydroxytryptamine uptake by chlorpyrifos and carbaryl.  


The organophosphate insecticide chlorpyrifos and the carbamate insecticide carbaryl were investigated in adult male rats in terms of their effects on the activity of brain monoamine oxidase-A (MAO-A) activity and on the platelet uptake of 5-hydroxytryptamine (5-HT). The activities of brain acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE) were also determined. For each compound two different dosage regimens were employed. In the acute study, chlorpyrifos or carbaryl was administered at a single intraperitoneal dose of 100 mg/kg or 50 mg/kg, respectively In the subacute study, chlorpyrifos was injected at a daily dose of 20 mg/kg for 7 days, while carbaryl was given at a daily dose of 10 mg/kg for 14 days. Acute chlorpyrifos administration produced a 85.01% inhibition of AChE and a 43.4% inhibition of BuChE but had no effect on MAO-A activity and 5-HT uptake. In contrast, subacute chlorpyrifos exposure caused a 94.96% inhibition of AChE and a 85.8% inhibition of BuChE and, also, elicited a significant (35.02%) reduction in the platelet uptake of 5-HT. MAO-A activity was not affected. Acute carbaryl administration produced a 56.38% AChE inhibition and a 55.95% BuChE inhibition and also caused a significant (26.36%) decrease in 5-HT uptake but no change in MAO-A. Subacute carbaryl exposure failed to affect significantly any of the biochemical parameters determined. Interference with the 5-HT system by chlorpyrifos and carbaryl could contribute to the toxicity of these pesticides. PMID:11881970

Sachana, M; Flaskos, J; Nikolaidis, E; Hargreaves, A; Alexaki-Tzivanidou, E



L-694,247: a potent 5-HT1D receptor agonist.  

PubMed Central

1. The 5-hydroxytryptamine (5-HT) receptor binding selectivity profile of a novel, potent 5-HT1D receptor agonist, L-694,247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl ]- 1H-indole-3-yl]ethylamine) was assessed and compared with that of the 5-HT1-like receptor agonist, sumatriptan. 2. L-694,247 had an affinity (pIC50) of 10.03 at the 5-HT1D binding site and 9.08 at the 5-HT1B binding site (sumatriptan: pIC50 values 8.22 and 5.94 respectively). L-694,247 retained good selectivity with respect to the 5-HT1A binding site (pIC50 = 8.64), the 5-HT1C binding site (6.42), the 5-HT2 binding site (6.50) and the 5-HT1E binding site (5.66). The pIC50 values for sumatriptan at these radioligand binding sites were 6.14, 5.0, < 5.0 and 5.64 respectively. Both L-694,247 and sumatriptan were essentially inactive at the 5-HT3 recognition site. 3. L-694,247, like sumatriptan, displayed a similar efficacy to 5-HT in inhibiting forskolin-stimulated adenylyl cyclase in guinea-pig substantia nigra although L-694,247 (pEC50 = 9.1) was more potent than sumatriptan (6.2) in this 5-HT1D receptor mediated functional response. L-694,247 (pEC50 = 9.4) was also more potent than sumatriptan (6.5) in a second 5-HT1D receptor mediated functional response, the inhibition of K(+)-evoked [3H]-5-HT release from guinea-pig frontal cortex slices.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8298808

Beer, M. S.; Stanton, J. A.; Bevan, Y.; Heald, A.; Reeve, A. J.; Street, L. J.; Matassa, V. G.; Hargreaves, R. J.; Middlemiss, D. N.



Ion permeation through 5-hydroxytryptamine-gated channels in neuroblastoma N18 cells  

PubMed Central

Ionic currents induced by 5-hydroxytryptamine (5-HT) in cultured neuroblastoma N18 cells were studied using whole-cell voltage clamp. The response was blocked by 1-10 nM 5-HT3 receptor-specific antagonists MDL 7222 or ICS 205-930, but not by 1 microM 5-HT1/5-HT2 receptor antagonist spiperone or 5-HT2 receptor-specific antagonist ketanserin. These 5-HT3 receptors seem to be ligand-gated channels because the response (a) did not require internal ATP or GTP, (b) persisted with long internal dialysis of CsF (90 mM), A1F4- (100 microM), or GTP gamma S (100 microM), and (c) with ionophoretic delivery of 5-HT developed with a delay of less than 10 ms and rose to a peak in 34-130 ms. Fluctuation analysis yielded an apparent single-channel conductance of 593 fS. The relative permeabilities of the channel for a variety of ions were determined from reversal potentials. The channel was only weakly selective among small cations, with permeability ratios PX/PNa of 1.22, 1.10, 1.01, 1.00, and 0.99 for Cs+, K+, Li+, Na+, and Rb+, and 1.12, 0.79, and 0.73 for Ca2+, Ba2+, and Mg2+ (when studied in mixtures of 20 mM divalent ions and 120 mM N-methyl-D-glucamine). Apparent permeability ratios for the divalent ions decreased as the concentration of divalent ions was increased. Small monovalent organic cations were highly permeant. Large organic cations such as Tris and glucosamine were measurably permeant with permeability ratios of 0.20 and 0.08, and N-methyl-D-glucamine was almost impermeant. Small anions, NO3-, Cl-, and F-, were slightly permeant with permeability ratios of 0.08, 0.04, and 0.03. The results indicate that the open 5-HT3 receptor channel has an effective minimum circular pore size of 7.6 A and that ionic interactions in the channel may involve negative charges near the pore mouth. PMID:2286832



Increase by visual stimuli in turnover of 5-hydroxytryptamine in the superior colliculi of the rabbit.  

PubMed Central

1. Irregular light falshes were played on to one eye of dark adapted rabbits for periods of 20-80 min. The concentration of 5-hydroxyindol-3-ylacetic acid (5-HIAA) and of 5-hydroxytryptamine (5-HT) were estimated in left and right superior colliculi, thalami and hippocampi. 2. In rabbits exposed to such visual stimuli for 30-60 min, there was an increase in the 5-HIAA content of the colliculus contralateral to the stimulated retina which aberaged 17% (P = 0-02), but no rise was seen if the exposure was shortened to 20 or prolonged to 80 min. At no time was there a difference in 5-HIAA content between right and left thalamus or right and left hippocampus. 3. Stationary or strictly repetitive visual stimuli produced no difference between the 5-HIAA content of left and right superior colliculus. 4. No difference in 5-HT concentration between the two colliculi was found after any form of visual stimulation, nor did any changes occur in the other parts of the brain which were examined. 5. Irregular, prolonged visual stimualtion thus appears to activate tryptaminergic neurones terminating in the colliculi. The possibility is discussed that the 5-HT released at this site might act as a brake to neuronal activity under conditions when habituation to the stimuli is not yet complete. PMID:1249785

Fukui, K; Vogt, M



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)



5-Hydroxytryptamine2B receptor signaling in rat stomach fundus: role of voltage-dependent calcium channels, intracellular calcium release and protein kinase C.  


The rat stomach fundus is enriched with the 5-hydroxytryptamine (5-HT)2B receptor, the newest subtype of the 5-HT2 receptor family to be cloned. Although the 5-HT2A and 5-HT2C receptor subtypes couple to phosphatidylinositol hydrolysis, such a coupling has not been established for the 5-HT2B receptor in tissues. Thus, the purpose of this study was to characterize further the signal transduction mechanism of the 5-HT2B receptor in rat stomach fundus. Nitrendipine (1 microM) inhibited the maximal contraction to 5-HT (1 microM) by approximately 50%. Removal of extracellular calcium did not inhibit 5-HT contraction to a greater extent than that produced by nitrendipine, indicating that calcium influx through voltage-dependent calcium channels was predominantly responsible for the dependence of the 5-HT contraction on extracellular calcium. Depletion of both extracellular calcium and intracellular calcium stores abolished 5-HT contraction. Ryanodine (30 microM), a compound which inhibits calcium release from intracellular stores, significantly inhibited the maximal contraction to carbamylcholine (3 microM). In contrast, ryanodine (30 microM) did not inhibit the maximal contraction to 5-HT (1 microM) in the absence of nitrendipine. However, ryanodine (30 microM) did significantly inhibit the nitrendipine-insensitive 5-HT contraction, suggesting that this component of the contraction was due in part to calcium release from a ryanodine-sensitive store. Bisindolylmaleimide (5 microM), a specific inhibitor of protein kinase C (PKC), inhibited 5-HT contraction in either the absence or presence of nitrendipine, suggesting that activation of PKC is also involved.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7815326

Cox, D A; Cohen, M L



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



Therapeutics of 5-HT3 Receptor Antagonists: Current Uses and Future Directions  

PubMed Central

The 5-Hydroxytryptamine3 (5-HT3) receptor is a member of the cys-loop family of ligand gated ion channels, of which the nicotinic acetylcholine receptor is the prototype. All other 5-HT receptors identified to date are metabotropic receptors. The 5-HT3 receptor is present in the central and peripheral nervous systems, as well as a number of non-nervous tissues. As an ion channel that is permeable to the cations, Na+, K+, and Ca2+, the 5-HT3 receptor mediates fast depolarizing responses in pre- and post-synaptic neurons. As such, 5-HT3 receptor antagonists that are used clinically block afferent and efferent synaptic transmission. The most well established physiological roles of the 5-HT3 receptor are to coordinate emesis and regulate gastrointestinal motility. Currently marketed 5-HT3 receptor antagonists are indicated for treatment of chemotherapy, radiation, and anesthesia-induced nausea and vomiting, as well as irritable bowel syndrome. Other therapeutic uses that have been explored include pain and drug addiction. The 5-HT3 receptor is one of a number of receptors that play a role in mediating nausea and vomiting, and as such, 5-HT3 receptor antagonists demonstrate greatest anti-emetic efficacy when administered in combination with other drug classes. PMID:21356241

Machu, Tina K.



Physiologically active compounds interacting with serotonin (5-hydroxytryptamine) receptors  

NASA Astrophysics Data System (ADS)

The data on the structures of organic compounds active with respect to serotonin (5-hydroxytryptamine) receptors are systematised. Various aspects of their design are considered. The bibliography includes 296 references.

Zefirova, Ol'ga N.; Zefirov, Nikolai S.



5-Hydroxytryptamine 2B receptor regulates cell-cycle progression: Cross-talk with tyrosine kinase pathways  

PubMed Central

In this paper, we present evidence that activation of 5-hydroxytryptamine 2B (5-HT2B) receptors by serotonin (5-HT) leads to cell-cycle progression through retinoblastoma protein hyperphosphorylation and through activation of both cyclin D1/cdk4 and cyclin E/cdk2 kinases by a mechanism that depends on induction of cyclin D1 and cyclin E protein levels. The induction of cyclin D1 expression, but not that of cyclin E, is under mitogen-activated protein kinase (MAPK) control, indicating an independent regulation of these two cyclins in the 5-HT2B receptor mitogenesis. Moreover, by using the specific platelet-derived growth factor receptor (PDGFR) inhibitor AG 1296 or by overexpressing a kinase-mutant PDGFR, we show that PDGFR kinase activity is essential for 5-HT2B-triggered MAPK/cyclin D1, but not cyclin E, signaling pathways. 5-HT2B receptor activation also increases activity of the Src family kinase, c-Src, Fyn, and c-Yes. Strikingly, c-Src, but not Fyn or c-Yes, is the crucial molecule between the Gq protein-coupled 5-HT2B receptor and the cell-cycle regulators. Inhibition of c-Src activity by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) or depletion of c-Src is sufficient to abolish the 5-HT-induced (i) PDGFR tyrosine kinase phosphorylation and MAPK activation, (ii) cyclin D1 and cyclin E expression levels, and (iii) thymidine incorporation. This paper elucidates a model of 5-HT2B receptor mitogenesis in which c-Src acts alone to control cyclin E induction and in concert with the receptor tyrosine kinase PDGFR to induce cyclin D1 expression via the MAPK/ERK pathway. PMID:10688905

Nebigil, Canan G.; Launay, Jean-Marie; Hickel, Pierre; Tournois, Claire; Maroteaux, Luc



Dissociation of Intracellular Ca 2+ Release and Ca 2+ Entry Response to 5Hydroxytryptamine in Cultured Canine Tracheal Smooth Muscle Cells  

Microsoft Academic Search

The relationship between the agonist-sensitive Ca2+ pool and those discharged by the Ca2+-ATPase inhibitor thapsigargin (TG) were investigated in canine tracheal smooth muscle cells (TSMCs). In fura-2-loaded TSMCs, 5-hydroxytryptamine (5-HT) stimulated a rapid increase in intracellular Ca2+ ([Ca2+]i), followed by a sustained plateau phase that was dependent on extracellular Ca2+. In such cells, TG produced a concentration-dependent increase in [Ca2+]i,

Chuen-Mao Yang



Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting.  


Postoperative nausea and vomiting (PONV) affects approximately one third of patients and may lead to aspiration, dehiscence, esophageal rupture, and increased treatment costs if inadequately controlled. An important therapeutic option for prevention of PONV is 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists. Nonetheless, therapeutic failure sometimes occurs. Metabolism by the cytochrome P450 (CYP) system differs among the 5-HT3 receptor antagonists, and provides a rational explanation for decreased therapeutic efficacy in some patients. Four of the 5-HT3 receptor antagonist agents (dolasetron, ondansetron, palonosetron, and tropisetron) are metabolized in various degrees via CYP2D6, an isoform subject to marked genetic polymorphism. In patients with duplicate CYP2D6 alleles, degradation into inactive metabolites occurs rapidly with these four 5-HT3 receptor antagonists, resulting in decreased efficacy for preventing PONV. Granisetron is the only agent in this class that is not metabolized via CYP2D6. Instead, granisetron is metabolized via the CYP3A4 isoform, which is not subject to significant genetic polymorphism. CYP2D6 genotype screening prior to PONV treatment may allow for modification of antiemetic dosing. An alternative is to use a 5-HT3 agent that is metabolized independently of the CYP2D6 isoform, such as granisetron, that would obviate the need for genotyping and may lead to improved prophylaxis of PONV. PMID:16192915

Janicki, Piotr K



Thyrotrophin releasing hormone--5-hydroxytryptamine interactions in the brain studied using chronic immunization and chemical lesioning techniques.  


This study investigates the effects of chemically lesioning 5-hydroxytryptamine (5HT) neurones and chronic passive immunization of central thyrotrophin releasing hormone (TRH) on 5HT and TRH mediated behavioural responses. 5HT lesions produced by 5,7-dihydroxytryptamine (5,7-DHT) enhanced the behavioural response produced by the 5HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MEODMT) while decreasing the locomotor hyperactivity observed following administration of the TRH analogue CG 3509 but having no effect on the reversal of pentobarbitone sleep-time produced by CG 3509. Chronic intracerebroventricular infusion of the purified TRH antibody markedly increased the length of pentobarbitone-induced sleep-time while enhancing the effects of CG 3509 both on locomotor activity and pentobarbitone-induced sleep. TRH antibody infusion also increased the response produced by 5-MEODMT. The results indicate that chronic passive immunization of central TRH induces changes in TRH receptor responsiveness and that there is a functional interaction between TRH and 5HT neuronal systems. PMID:3040985

Bennett, G W; Edwards, R M; Lighton, C; Marsden, C A



5-HT2 Receptors Facilitate JC Polyomavirus Entry  

PubMed Central

The human JC polyomavirus (JCPyV) causes the rapidly progressing demyelinating disease progressive multifocal leukoencephalopathy (PML). The disease occurs most often in individuals with AIDS but also occurs in individuals receiving immunomodulatory therapies for immune-related diseases such as multiple sclerosis. JCPyV infection of host cells requires the pentasaccharide lactoseries tetrasaccharide c (LSTc) and the serotonin receptor 5-hydroxytryptamine (5-HT) receptor 5-HT2AR. While LSTc is involved in the initial attachment of virus to cells via interactions with VP1, the mechanism by which 5-HT2AR contributes to infection is not clear. To further define the roles of serotonin receptors in infection, HEK293A cells, which are poorly permissive to JCPyV, were transfected with 14 different isoforms of serotonin receptor. Only 5-HT2 receptors were found to support infection by JCPyV. None of the other 11 isoforms of serotonin receptor supported JCPyV infection. Expression of 5-HT2 receptors did not increase binding of JCPyV to cells, but this was not unexpected, given that the cells uniformly expressed the major attachment receptor, LSTc. Infection of these cells remained sensitive to inhibition with soluble LSTc, confirming that LSTc recognition is required for JCPyV infection. Virus internalization into HEK293A cells was significantly and specifically enhanced when 5HT2 receptors were expressed. Taken together, these data confirm that the carbohydrate LSTc is the attachment receptor for JCPyV and that the type 2 serotonin receptors contribute to JCPyV infection by facilitating entry. PMID:24089568

Assetta, Benedetta; Maginnis, Melissa S.; Gracia Ahufinger, Irene; Haley, Sheila A.; Gee, Gretchen V.; Nelson, Christian D. S.; O'Hara, Bethany A.; Allen Ramdial, Stacy-ann A.



Conditioned taste aversion: modulation by 5HT receptor activity and corticosterone  

Microsoft Academic Search

Two experiments were designed to elucidate the involvement of the hypothalamic–pituitary–adrenal axis and the 5-hydroxytryptamine (5-HT) system in the acquisition of lithium chloride-conditioned taste aversion. In Experiment 1, rats were administered either vehicle or 50 mg\\/kg nefazodone daily for 4 weeks. Rats were treated with 22 mg\\/kg of lithium chloride in order to produce conditioned taste aversion to a sucrose

Boris Gorzalka; Laura Hanson; Jennifer Harrington; Sisley Killam; Dan Campbell-Meiklejohn



5-HT precursor loading, but not 5-HT receptor agonists, increases motor function after spinal cord contusion in adult rats.  


Serotonergic (5-HT) receptors are upregulated following spinal cord transection. Stimulation by administration of serotonergic receptor agonists has been successful in improving hindlimb function. We tested whether this strategy would be successful in incomplete injury models (moderate or severe thoracic contusion) where descending projections are partially spared which should produce less denervation-induced receptor upregulation. Adult rats received midthoracic moderate (MOD: 25 mm drop) or severe (SEV: 50 mm drop) contusion injuries. Distribution of 5-HT and its transporter and expression of 5-HT(2C) receptors were evaluated in lumbar spinal cord and motor response to 5-HT receptor activation was assessed using open field locomotion (BBB) score, percent weight supported treadmill stepping (%WS) and evaluation of hindlimb muscle activation (tremor and serotonin syndrome). 5-HT immunostaining 3 months post-contusion revealed few 5-HT fibers caudal to the severe contusion, and more spared caudal to the moderate contusion. The distribution of 5-HT transporter paralleled 5-HT staining, but was more greatly reduced. Thus serotonin reuptake may be less efficient in the injured spinal cord. Immunostaining for the 5-HT(2C) receptor in the dorsal and ventral horns at L5 showed significant upregulation in SEV, compared to sham or MOD rats. Neither 5-HT(2C) nor 5-HT(1A) receptor agonists, alone or in combination, nor the serotonin transporter inhibitor d-fenfluramine modified BBB scores or %WS in either group. Despite the increased sensitivity of post-synaptic targets, agonist treatment did not improve function in SEV rats. We conclude that selective 5-HT(2C) or 5-HT(1A) receptor activation was not effective in improving hindlimb function after incomplete lesions. In contrast, the 5-HT precursor 5-hydroxytryptophan (L-5-HTP), which leads to activation of all classes of 5-HT receptors, increased both %WS and hindlimb activity in the MOD group. While no side effects were observed in normal or MOD rats, SEV rats displayed hindlimb tremors and 33% mortality, indicating hypersensitivity to the precursor. PMID:19840787

Hayashi, Y; Jacob-Vadakot, S; Dugan, E A; McBride, S; Olexa, R; Simansky, K; Murray, M; Shumsky, J S



Effect of Pindolol on the Function of Pre and Postsynaptic 5HT1A Receptors: In Vivo Microdialysis and Electrophysiological Studies in the Rat Brain  

Microsoft Academic Search

In microdialysis studies, somatodendritic 5-HT1A receptors in the dorsal raphe nucleus (DRN) were activated by the local infusion of 50 ?M citalopram, a selective 5-HT reuptake inhibitor (SSRI). This reduced extracellular 5-HT by about 50% in dorsal striatum, an area receiving 5-HT afferents exclusively from the DRN. (?)Pindolol dose-dependently attenuated this citalopram-induced reduction of striatal extracellular 5-HT. Consistent with its

L Romero; N Bel; F Artigas; C de Montigny; P Blier



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



Pharmacological characterization of the 5-HT receptor-mediated contraction in the mouse isolated ileum.  


The pharmacological characterization of a 5-HT receptor-mediated contractile response in the mouse isolated ileum is described. In the presence of methysergide (1 microM), 5-hydroxytryptamine (5-HT, 0.3 - 100 microM) produced phasic concentration-dependent contractions of segments of the mouse isolated ileum with a pEC(50) value of 5.47+/-0.09. The 5-HT(3) receptor selective agonists m-chlorophenylbiguanide (0.3 - 100 microM, pEC(50) 5.81+/-0.04), 1-phenylbiguanide (3 - 100 microM, pEC(50) 5.05+/-0.06) and 2-methyl-5-HT (3 - 100 microM, pEC(50) 5.00+/-0.07) acted as full agonists to induce contractile responses. 5-methoxytryptamine (0.1 - 100 microM), RS 67506 (0.1 - 100 microM) and alpha-methyl-5-HT (0.1 - 100 microM) failed to mimic the 5-HT responses. The contractile response to 5-HT was not antagonized by either 5-HT(2) receptor antagonists ritanserin (0.1 microM) or ketanserin (1 microM) nor the 5-HT(4) receptor antagonist SB 204070 (0.1 microM). The 5-HT(3) receptor selective antagonists granisetron (0.3 - 1 nM), tropisetron (1 - 10 nM), ondansetron (10 nM - 1 microM) and MDL 72222 (10 nM - 1 microM) caused rightward displacement of the concentration-response curves to 5-HT. The lower concentrations of the antagonists caused approximate parallel rightward shifts of the concentration-response curves to 5-HT with apparent pK(B) values for granisetron (9.70+/-0. 39), tropisetron (9.18+/-0.20), ondansetron (8.84+/-0.24) and MDL 72222 (8.65+/-0.35). But higher concentrations of antagonists resulted in a progressive reduction in the maximum responses. The contractile response to 5-HT was abolished by tetrodotoxin (0.3 microM); atropine (0.1 and 1 microM) decreased the maximum response of the 5-HT concentration-response curve by approximately 65%. It is concluded that a neuronally located 5-HT(3) receptor mediates a contractile response to 5-HT in the mouse ileum. The 5-HT(3) receptor in the mouse ileum has a different pharmacological profile to that reported for the guinea-pig ileum. PMID:11139451

Tuladhar, B R; Womack, M D; Naylor, R J



Increased contractile responses to 5-hydroxytryptamine and Angiotensin II in high fat diet fed rat thoracic aorta  

PubMed Central

Background Feeding normal rats with high dietary levels of saturated fat leads to pathological conditions, which are quite similar to syndrome X in humans. These conditions such as hypertriglyceridemia, hypercholesterolemia, obesity, and hyperglycemia might induce hypertension through various mechanisms. Metabolic syndrome and the resulting NIDDM represent a major clinical challenge because implementation of treatment strategies is difficult. Vascular abnormalities probably contribute to the etiology of many diabetic complications including nephropathy, neuropathy, retinopathy, and cardiomyopathy. It has been shown that in Streptozotocin induced diabetic animals there is an increase in maximal responses to 5-Hydroxytryptamine and Angiotensin II. The purpose of this study was to evaluate High fat diet fed rats for the development of hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperglycemia and to assess their vascular responses to 5-Hydroxytryptamine and Angiotensin II. Methods Male Sprague Dawley rats were used for this study and were divided into two equal groups. One of the groups was fed with normal pellet diet and they served as the control group, whereas the other group was on a high fat diet for 4 weeks. Body weight, plasma triglycerides, plasma cholesterol, and plasma glucose were measured every week. Intraperitoneal glucose tolerance test was performed after 4 weeks of feeding. At the end of fourth week of high fat diet feeding, thoracic aortae were removed, and cut into helical strips for vascular reactivity studies. Dose-response curves of 5-Hydroxytryptamine and Angiotensin II were obtained. Results There was no significant difference in pD2, with 5-Hydroxytryptamine and Angiotensin II in both groups but Emax was increased. Conclusions These results suggest that hypertension in high fat diet rats is associated with increased in vitro vascular reactivity to 5-HT and Ang II. PMID:15287987

Ghatta, Srinivas; Ramarao, Poduri



Ag ion irradiated based sensor for the electrochemical determination of epinephrine and 5-hydroxytryptamine in human biological fluids.  


A promising and highly sensitive voltammetric method has been developed for the first time for the determination of epinephrine (EP) and 5-hydroxytryptamine (5-HT) using 120 MeV Ag ion irradiated multi-walled carbon nano tube (MWCNT) based sensor. The MWCNT were irradiated at various fluences of 1e12, 3e12 and 1e13 ions cm(-2) using palletron accelerator. The simultaneous determination of EP and 5-HT has been carried out in phosphate buffer solution of pH 7.20 using square wave voltammetry and cyclic voltammetry. Experimental results suggested that irradiation of MWCNT by Ag ions enhanced the electrocatalytic activity due to increase in effective surface area and insertion of Ag ions, leading to a remarkable enhancement in peak currents and shift of peak potentials to less positive values as compared to the unirradiated MWCNT (pristine). The developed sensor exhibited a linear relationship between peak current and concentration of EP and 5-HT in the range 0.1-105 ?M with detection limit (3?/b) of 2 nM and 0.75 nM, respectively. The practical utility of irradiation based MWCNT sensor has been demonstrated for the determination of EP and 5-HT in human urine and blood samples. PMID:22882821

Goyal, Rajendra N; Agrawal, Bharati



2-(2-Aminoethyl)-quinoline (D-1997): a novel agonist at 5-hydroxytryptamine1-like receptors in the canine basilar artery.  


This study aimed to investigate the mechanisms involved in the contractile effects produced by the novel quinoline derivative, 2-(2-aminoethyl)-quinoline (D-1997), in the canine isolated basilar artery. For comparison, the effects of D-1997 were also evaluated on rat aorta. Canine basilar artery and rat aortic rings were prepared and mounted in organ baths to record isometric tension changes. The contractile effects of D-1997 in the basilar artery were compared with those produced by 5-hydroxytryptamine (5-HT) and the 5-HT receptor agonist quipazine. Thus, 4-HT (10(-10)-10(-6)M), D-1997 (3.1 x 10(-8)-10(-4) M) and quipazine (3.1 x 10(-7)-10(-4) M) each caused concentration-dependent contractions of the canine basilar artery with a rank order of agonist potency of 5-HT > D-1997 > quipazine. 5-HT and D-1997 exhibited similar maximum effects which were higher than that of quipazine. Similar concentrations of D-1997 failed to produce contraction in rat aorta. The effects of D-1997 in the basilar artery were not modified by incubation with either the 5-HT2 receptor antagonist ketanserin (0.01-1 microM), the 5-HT3 and 5-HT4 receptor antagonist ICS205930 (tropisetron; 0.1-10 microM), the 5-HT1A receptor antagonist spiroxatrine (0.01-1 microM), the beta-adrenoceptor blocker with high affinity for 5-HT1A and 5-HT1B binding sites (+/-)-pindolol (0.01-1 microM), or the alpha 1-adrenoceptor antagonist prazosin (0.01-1 microM). In contrast, the D-1997-induced responses were potently and concentration-dependently antagonized by the mixed 5-HT1-like and 5-HT2 receptor antagonist methiothepin (0.01-1 microM). It is concluded that D-1997 contracts the canine basilar artery by stimulating 5-HT1-like receptors unrelated to either the 5-HT1A or 5-HT1B receptor subtypes. The compound seems to be devoid of 5-HT2 receptor agonist properties in rat aorta. PMID:7944828

Terrón, J A; López-Muñoz, F J; Hong, E; Villalón, C 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



A review of granisetron, 5-hydroxytryptamine3 receptor antagonists, and other antiemetics.  


Nausea and vomiting are 2 of the most upsetting adverse reactions of chemotherapy. Current guidelines propose 5-hydroxytryptamine3 (5-HT3) receptor antagonists as a pharmacologic intervention for acute and delayed nausea and vomiting [chemotherapy-induced nausea and vomiting (CINV)] associated with moderately and highly emetogenic chemotherapy. Meanwhile, both postoperative nausea and vomiting (PONV) and postdischarge nausea and vomiting are challenging situations after surgeries and procedures. Prophylactic and therapeutic combinations of antiemetics are recommended in patients at high risk of suffering from PONV and postdischarge nausea and vomiting. Granisetron (Kytril) is a selective 5-HT3 receptor antagonist that does not induce or inhibit the hepatic cytochrome P-450 system in vitro. There are also 4 other antagonists of 5-HT3 receptor (dolasetron, ondansetron, palonosetron, and tropisetron) being metabolized via the CYP2D6 and are subject to potential genetic polymorphism. The launch of a new class of antiemetics, the substance P/neurokinin1 receptor antagonists, was attributed to the scientific update on the central generator responsible for emesis and role of substance P. There has been mounting interest in exploring integrative medicine, either acupuncture or acustimulation of P6 (Nei-Kuwan), to complement the western medicine for prevention and management of nausea and vomiting. The potential application of cannabinoids, either alone or in combination with other agents of different mechanism, could contribute further to improve outcome in CINV. Implementation of future treatment guidelines for more effective management of CINV and PONV could certainly improve the efficacy and outcome of cancer and postoperative care. PMID:20844345

Hsu, Eric S



Sequential onset of three 5-HT receptors during the 5-hydroxytryptaminergic differentiation of the murine 1C11 cell line.  

PubMed Central

1. The murine 1C11 clone, which derives from a multipotential embryonal carcinoma cell line, has the features of a neuroectodermal precursor. When cultured in the presence of dibutyryl cyclic AMP, the 1C11 cells extend bipolar extensions and express neurone-associated markers. After 4 days, the resulting cells have acquired the ability to synthesize, take up, store and catabolize 5-hydroxytryptamine (5-HT). We have thus investigated the presence of 5-HT receptors during the 5-hydroxytryptaminergic differentiation of this inducible 1C11 cell line. 2. As shown by the binding of [125I]-GTI and the CGS 12066-dependent inhibition of the forskolin-induced cyclic AMP production, functional 5-HT1B/1D receptors become expressed on day 2 of 1C11 cell differentiation. The density of these receptors remained unchanged until day 4. 3. The same holds true for the 5-HT2B receptor, also identified by its pharmacological profile and its positive coupling to the phosphoinositide cascade. 4. On day 4 of 1C11 cell differentiation, a third 5-HT receptor, pharmacologically and functionally similar to 5-HT2A, had become induced. 5. Strikingly, the amounts of each transcript encoding 5-HT1B, 5-HT2A and 5-HT2B receptor did not very significantly during the time course of the 1C11 5-hydroxytryptaminergic differentiation. 6. The clone 1C11 may thus provide a useful in vitro model for studying regulation(s) between multiple G-linked receptors as well as the possible role of 5-HT upon the expression of a complete 5-hydroxytryptamine phenotype. Images Figure 5 PMID:8818339

Kellermann, O.; Loric, S.; Maroteaux, L.; Launay, J. M.



Chronic stress-induced alterations in mouse colonic 5-HT and defecation responses are strain dependent.  


Mood disorders and chronic stress are frequently associated with gastrointestinal (GI) symptoms including diarrhoea or constipation. Locally produced serotonin [5-hydroxytryptamine (5-HT)] regulates GI motility and is a key factor in the pathophysiology of stress-associated GI disorders. We aimed to establish whether chronic stress can differentially affect faecal output and colon 5-HT concentration in two inbred mouse strains: BALB/c and C57BL/6 which differ in their ability to cope with stress. Adult male BALB/c and C57BL/6 mice were restrained for 2 h daily for 10 days. Defecation was monitored during each stress session. Twenty-four hours after the last session of stress, plasma corticosterone concentration was higher than control in both strains, indicative of a physiological effect of chronic stress; however, stress-induced diarrhoea was more persistent in C57BL/6 mice. Basal concentration of colon 5-HT was higher in C57BL/6 mice, and stress elicited an increase in colon 5-HT only in this strain. Finally, naïve BALB/c mice had a higher sensitivity (incidence of diarrhoea) to 5-HT (0.33 mg/kg, i.p.) than C57BL/6 mice. Our results suggest that differential defecation responses to stress may be associated with colon 5-HT concentration, which may in turn reflect the individual sensitivity to 5-HT. In addition, C57BL/6 mice emerge as a relevant model for studying GI alterations induced by chronic stress. PMID:21875301

Julio-Pieper, Marcela; O'Mahony, Cliona M; Clarke, Gerard; Bravo, Javier A; Dinan, Timothy G; Cryan, John F



Meta-analysis of 5-hydroxytryptamine type 2A receptor polymorphisms and migraine susceptibility.  


Epidemiologic studies have investigated the association of polymorphisms in 5-hydroxytryptamine type 2A receptor (5HT2A) gene and migraine susceptibility, but the results of those studies are inconclusive. To obtain a more systematic estimation of the association, we conducted a comprehensive search to examine all the eligible studies of 5HT2A polymorphisms and migraine risk. The odd ratios (ORs) with 95% confidence intervals (CIs) were used to determine the strength of the association. Publication bias was analyzed by Begg's funnel plots. Seven eligible studies regarding 5HT2A T102C and A-1438G polymorphisms with 721 cases and 713 controls were included in this meta-analysis. Overall, no significant associations were found between 5HT2A T102C (for T vs. C: OR = 1.029, 95% CI = 0.870-1.217, p = 0.739; for TT vs. CC: OR = 1.083, 95% CI = 0.760-1.544, p = 0.657; for TT + TC vs. CC: OR = 1.066, 95% CI = 0.802-1.416, p = 0.662; for TT vs. TC + CC: OR = 1.017, 95% CI = 0.774-1.336, p = 0.904) or A-1438G (for T vs. C: OR = 0.996, 95% CI = 0.726-1.365, p = 0.979; for TT vs. CC: OR = 0.983, 95% CI = 0.511-1.891, p = 0.960; for TT + TC vs. CC: OR = 1.118, 95% CI = 0.654-1.910, p = 0.684; for TT vs. TC + CC: OR = 0.890, 95% CI = 0.528-1.499, p = 0.661) polymorphisms and migraine risk. The further subgroup analysis by ethnicity, assay and disease type also found no significant association using four genetic models. Meanwhile, the publication bias analysis suggests that there is no publication bias in these studies. In conclusion, our current meta-analysis implies that 5HT2A T102C and A-1438G polymorphisms may be not risk factors in the pathogenesis of migraine. PMID:25019276

Peng, Jian-Ming; Yu, You-Jiang; Su, Lan-Di; Luo, Xue



Subcellular distribution of 5-hydroxytryptamine2A and N-methyl-D-aspartate receptors within single neurons in rat motor and limbic striatum.  


The dorsolateral caudate-putamen nucleus (CPN) and the nucleus accumbens (NAc) shell, respectively, are involved in many motor and limbic functions that are affected by activation of the 5-hydroxytryptamine2A receptor (5HT2AR) and the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR). We examined the functional sites for 5HT2AR activation and potential interactions involving the NMDAR subunit NR1 (NMDAR1) within these striatal regions. For this examination, sequence-specific antipeptide antisera against these receptors were localized by electron microscopic dual-labeling immunocytochemistry in the rat brain. In the dorsolateral CPN and the NAc shell, the 5HT2AR-labeled profiles were mainly dendrites, but somata and axons were also immunoreactive. The neuronal somata contained round unindented nuclei that are typical of spiny striatal neurons, although few dendritic spines were 5HT2AR immunolabeled. In all neuronal profiles, the 5HT2AR labeling was primarily associated with cytoplasmic organelles and more rarely was localized to synaptic or nonsynaptic plasma membranes. Colocalization of 5HT2AR and NMDAR1 was seen primarily in somata and dendrites. Significantly greter numbers of 5HT2AR- or 5HT2AR- and NMDAR1-containing dendrites were seen in the dorsolateral CPN than in the NAc shell. As compared with 5HT2AR, NMDAR1 labeling was more often observed in dendritic spines, and these were also more numerous in the CPN. These results indicate that 5HT2A and NMDA receptors are coexpressed but differentially targeted in single spiny striatal neurons and are likely to play a major role in control of motor functions involving the dorsolateral CPN. PMID:10524335

Rodríguez, J J; Garcia, D R; Pickel, V M



Methylene blue inhibits function of the 5-HT transporter  

PubMed Central

BACKGROUND AND PURPOSE Methylene blue (MB) is commonly employed as a treatment for methaemoglobinaemia, malaria and vasoplegic shock. An increasing number of studies indicate that MB can cause 5-HT toxicity when administered with a 5-HT reuptake inhibitor. MB is a potent inhibitor of monoamine oxidases, but other targets that may contribute to MB toxicity have not been identified. Given the role of the 5-HT transporter (SERT) in the regulation of extracellular 5-HT concentrations, the present study aimed to characterize the effect of MB on SERT. EXPERIMENTAL APPROACH Live cell imaging, in conjunction with the fluorescent SERT substrate 4-(4-(dimethylamino)-styryl)-N-methylpyridinium (ASP+), [3H]5-HT uptake and whole-cell patch-clamp techniques were employed to examine the effects of MB on SERT function. KEY RESULTS In EM4 cells expressing GFP-tagged human SERT (hSERT), MB concentration-dependently inhibited ASP+ accumulation (IC50: 1.4 ± 0.3 µM). A similar effect was observed in N2A cells. Uptake of [3H]5-HT was decreased by MB pretreatment. Furthermore, patch-clamp studies in hSERT expressing cells indicated that MB significantly inhibited 5-HT-evoked ion currents. Pretreatment with 8-Br-cGMP did not alter the inhibitory effect of MB on hSERT activity, and intracellular Ca2+ levels remained unchanged during MB application. Further experiments revealed that ASP+ binding to cell surface hSERT was reduced after MB treatment. In whole-cell radioligand experiments, exposure to MB (10 µM; 10 min) did not alter surface binding of the SERT ligand [125I]RTI-55. CONCLUSIONS AND IMPLICATIONS MB modulated SERT function and suggested that SERT may be an additional target upon which MB acts to produce 5-HT toxicity. PMID:21542830

Oz, Murat; Isaev, Dmytro; Lorke, Dietrich E; Hasan, Muhammed; Petroianu, Georg; Shippenberg, Toni S



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



Autoradiographic localization of 3 H-5HTP and 3 H-5HT in the pineal organ and circumventricular areas in the rainbow trout, Salmo gairdneri Richardson  

Microsoft Academic Search

The time course of incorporation and cellular localization of 3H-5-hydroxytryptophan (3H-5-HTP) and 3H-5-hydroxytryptamine (3H-5-HT) in the pineal and some brain regions in rainbow trout, Salmo gairdneri, were studied by quantitative and qualitative autoradiography.

M. A. Hafeez; L. Zerihun



Modulation of synaptic transmission and excitation-contraction coupling in the opener muscle of the crayfish, Astacus leptodactylus, by 5-hydroxytryptamine and octopamine.  


The modulatory actions of 5-hydroxytryptamine (5-HT) and octopamine (OA) were investigated in the opener nerve-muscle preparation of the crayfish, Astacus leptodactylus. Membrane resistance and resting potential were unaltered by 5-HT and OA at concentrations up to 2.5 X 10(-5) M; but EPSP-amplitudes were increased, up to 3-fold by OA and up to 18-fold by 5-HT. The lowest effective concentration was 2.5 X 10(-9) M; a maximal effect was produced at 2.5 X 10(-6) M. The effect was reversible only after prolonged washing. The enhancement of EPSPs by 5-HT or OA is due to an increased amplitude of the synaptic current; the current duration is not altered. The facilitation ratio (ratio of amplitudes of a pair of EPSPs) is not significantly affected by 5-HT or OA despite the often enormous increase of the absolute EPSP-amplitudes. The modulatory action also affects the excitation-contraction (e-c) coupling process: the effectiveness of e-c coupling was increased 7.4-fold by 5-HT (2.5 X 10(-6) M) and 18.7-fold by OA (5 X 10(-6) M). The threshold potential of e-c coupling was not affected. PMID:6300277

Fischer, L; Florey, E



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



Suppressive effects of isorhynchophylline on 5-HT2A receptor function in the brain: behavioural and electrophysiological studies.  


Isorhynchophylline is a major oxindole alkaloid found in Uncaria species which have long been used in traditional Chinese medicine. Here, we investigated the effects of isorhynchophylline and isorhynchophylline-related alkaloids on 5-hydroxytryptamine (5-HT) receptor-mediated behavioural responses in mice and 5-HT-evoked current responses in Xenopus oocytes expressing 5-HT2A or 5-HT2C receptors. Isorhynchophylline dose-dependently inhibited 5-HT2A receptor-mediated head-twitch but not 5-HT1A receptor-mediated head-weaving responses evoked by 5-methoxy-N,N-dimethyltryptamine. Pretreatment with reserpine, a monoamine-depleting agent, enhanced the head-twitching, but did not influence the effect of isorhynchophylline on the behavioural response. Isocorynoxeine, an isorhynchophylline-related alkaloid in which the configuration of the oxindole moiety is the same as in isorhynchophylline, also reduced the head-twitch response in reserpinized mice over the same dose range as isorhynchophylline, while both rhynchophylline and corynoxeine, stereoisomers of isorhynchophylline and isocorynoxeine, did not. None of the alkaloids tested had an effect on meta-chlorophenylpiperazine-induced hypolocomotion, a 5-HT2C receptor-mediated behavioural response. In experiments in vitro, isorhynchophylline and isocorynoxeine dose-dependently and competitively inhibited 5-HT-evoked currents in Xenopus oocytes expressing 5-HT2A receptors, but had less of a suppressive effect on those in oocytes expressing 5-HT2C receptors. These results indicate that isorhynchophylline and isocorynoxeine preferentially suppress 5-HT2A receptor function in the brain probably via a competitive antagonism at 5-HT2A receptor sites and that the configuration of the oxindole moiety of isorhynchophylline is essential for their antagonistic activity at the 5-HT2A receptor. PMID:15963493

Matsumoto, Kinzo; Morishige, Ryo; Murakami, Yukihisa; Tohda, Michihisa; Takayama, Hiromitsu; Sakakibara, Iwao; Watanabe, Hiroshi



Calcium influx through presynaptic 5-HT3 receptors facilitates GABA release in the hippocampus: in vitro slice and synaptosome studies.  


Serotonin 5-hydroxytryptamine type 3 receptors (5HT3R) are Ca2+-permeant, non-selective cation channels that have been localized to presynaptic terminals and demonstrated to modulate neurotransmitter release. In the present study the effect of 5-HT on GABA release in the hippocampus was characterized using both electrophysiological and biochemical techniques. 5-HT elicited a burst-like, 6- to 10-fold increase in the frequency of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) measured with whole-cell voltage-clamp recordings of CA1 neurons in hippocampal slices. When tetrodotoxin was used to block action potential propagation, the 5-HT-induced burst of IPSCs was still observed. Stimulation of hippocampal synaptosomes with 5-HT resulted in a significant increase in the amount of [3H]GABA released by hyperosmotic saline. In both preparations, the 5-HT effect was shown to be mediated by 5HT3Rs, as it was mimicked by the selective 5HT3R agonist m-chlorophenyl biguanide and blocked by the selective 5HT3R antagonist 3-tropanylindole-3-carboxylate hydrochloride. The 5HT3R-mediated increase in GABA release was blocked by 100 microM cadmium or by omitting Ca2+ in external solutions, indicating the Ca2+-dependence of the effect. The high voltage-activated Ca2+ channel blockers omega-conotoxin GVIA and omega-conotoxin MVIIC and 10 microM cadmium had no significant effect on the 5-HT3R-mediated enhancement of GABA release, indicating that Ca2+ influx through the 5-HT3R facilitates GABA release. Taken together, these data provide direct evidence that Ca2+ entry via presynaptic 5HT3Rs facilitates the release of GABA from hippocampal interneurons. PMID:15541891

Turner, T J; Mokler, D J; Luebke, J I



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



Evidence that 5-hydroxytryptamine7 receptors play a role in the mediation of afferent transmission within the nucleus tractus solitarius in anaesthetized rats  

PubMed Central

Background and purpose: Central 5-hydroxytryptamine (5-HT)-containing pathways utilizing 5-HT7 receptors are known to be critical for the mediation of cardiovascular reflexes. The nucleus tractus solitarius (NTS) is a site involved in the integration of cardiovascular afferent information. The present experiments examined the involvement of the 5-HT7 receptor in the processing of cardiovascular reflexes in the NTS. Experimental approach: In anaesthetized rats extracellular recordings were made from 104 NTS neurones that were excited by electrical stimulation of the vagus nerve and/or activation of cardiopulmonary afferents. Drugs were applied ionophoretically in the vicinity of these neurones. Key results: The non-selective 5-HT7 receptor agonist 5-carboxamidotryptamine maleate (5-CT) applied to 78 neurones increased the firing rate in 18 by 59% and decreased it in 38 neurones by 47%. Similarly, the 5-HT1A agonist 8-OH-DPAT applied to 20 neurones had an excitatory (8), inhibitory (7) or no effect (5) on the 20 neurones tested. In the presence of the 5-HT7 antagonist SB 258719 the 5-CT excitation was attenuated. Furthermore, the excitatory response of NTS neurones evoked by electrical stimulation of the vagus nerve or activation of cardiopulmonary afferents with intra atrial phenylbiguanide was attenuated by SB 258719. The inhibitory action of 5-CT was unaffected by SB 258719 and the 5-HT1A antagonist WAY-100635. WAY-100635 failed to have any effect on 5-CT and vagal afferent-evoked excitations. Conclusions and implications: Vagal afferent-evoked excitation of NTS neurones can be blocked by SB 258719, a selective 5-HT7 antagonist. This observation further supports the involvement of 5-HT neurotransmission in NTS afferent processing. PMID:19785653

Oskutyte, Diana; Jordan, David; Ramage, Andrew G



Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors.  


Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that is believed to modulate numerous sensory, motor and behavioural processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signalling system and the paucity of selective drugs have made it difficult to define specific roles for 5-HT receptor subtypes, or to determine how serotonergic drugs modulate mood and behaviour. To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin. Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite. Mutant animals are also prone to spontaneous death from seizures, suggesting that 5-HT2C receptors mediate tonic inhibition of neuronal network excitability. PMID:7700379

Tecott, L H; Sun, L M; Akana, S F; Strack, A M; Lowenstein, D H; Dallman, M F; Julius, D



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



Agonism of the 5-hydroxytryptamine 1F receptor promotes mitochondrial biogenesis and recovery from acute kidney injury.  


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; Schnellmann, Rick G



Involvement of 5-hydroxytryptamine type 3 receptors in sevoflurane-induced hypnotic and analgesic effects in mice.  


In the present study, we investigated the role of 5-hydroxytryptamine type 3 (5-HT(3)) receptors in hypnosis and analgesia induced by emulsified sevoflurane. A mouse model of hypnosis and analgesia was established by an intraperitoneal or subcutaneous injection of emulsified sevoflurane.We intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administered YM-31636, a 5-HT(3) receptor agonist, to mice and observed sleep time during hypnosis. In addition, the tail withdrawal latency was measured using the tail withdrawal test, and the writhing time was determined using the acetic acid writhing test. In the hypnosis test, YM-31636 (5, 10 and 15 ?g, i.c.v.) treatment significantly decreased emulsified sevoflurane-induced mouse sleep time (p < 0.05 or p < 0.01). YM-31636 (2.5, 5 and 10 ?g, i.t.) treatment significantly and dose-dependently decreased the tail withdrawal latency (p < 0.05 or p < 0.01) and increased the writhing time (p < 0.01) of mice treated with emulsified sevoflurane. These results suggest that 5-HT(3) receptors may modulate the hypnotic and analgesic effects induced by emulsified sevoflurane. PMID:20885002

Hang, Li-Hua; Shao, Dong-Hua; Wang, Hong; Yang, Jian-Ping



Is functional upregulation of the 5HT 2B receptor in deoxycorticosterone acetate salt-treated rats blood pressure dependent?  

Microsoft Academic Search

This study tests the hypothesis that the functional upregulation of the arterial 5-hydroxytryptamine (5-HT)2B receptor in arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats depends on the development of high blood pressure. Wistar-Furth and Wistar rats were given sham or DOCA-salt treatment (200 mg\\/kg DOCA, SC; 1.0% NaCl and 0.2% KCl in drinking water). Systolic blood pressures (4 week; mm Hg)

Stephanie W. Watts; Brian Harris



Serotonin (5-HT) regulates neurite outgrowth through 5-HT1A and 5-HT7 receptors in cultured hippocampal neurons.  


Serotonin (5-HT) production and expression of 5-HT receptors (5-HTRs) occur early during prenatal development. Recent evidence suggests that, in addition to its classical role as a neurotransmitter, 5-HT regulates neuronal connectivity during mammalian development by modulating cell migration and neuronal cytoarchitecture. Given the variety of 5-HTRs, researchers have had difficulty clarifying the specific role of each receptor subtype in brain development. Signalling mediated by the G-protein-coupled 5-HT1A R and 5-HT7 R, however, has been associated with neuronal plasticity. Thus, we hypothesized that 5-HT promotes neurite outgrowth through 5-HT1A R and 5-HT7 R. The involvement of 5-HT1A R and 5-HT7 R in the morphology of rat hippocampal neurons was evaluated by treating primary cultures at 2 days in vitro with 5-HT and specific antagonists for 5-HT1A R and 5-HT7 R (WAY-100635 and SB269970, respectively). The stimulation of hippocampal neurons with 100 nM 5-HT for 24 hr produced no effect on either the number or the length of primary neurites. Nonetheless, after 5HT7 R was blocked, the addition of 5-HT increased the number of primary neurites, suggesting that 5HT7 R could inhibit neuritogenesis. In contrast, 5-HT induced secondary neurite outgrowth, an effect inhibited by 1 ?M WAY-100635 or SB269970. These results suggest that both serotonergic receptors participate in secondary neurite outgrowth. We conclude that 5-HT1A R and 5-HT7 R regulate neuronal morphology in primary hippocampal cultures by promoting secondary neurite outgrowth. PMID:24752854

Rojas, Paulina S; Neira, David; Muñoz, Mauricio; Lavandero, Sergio; Fiedler, Jenny L



The vascular responses of the isolated perfused bovine external ear to exogenous histamine and 5HT (serotonin)  

Microsoft Academic Search

The responses of the vasculature of isolated, non-sensitized, bovine external ears to histamine and serotonin (5-HT) were evaluated while they were being perfused with Krebs-Henseleit solution, Histamine (10-5 mol\\/L to 5×10-3 mol\\/L) and 5-hydroxytryptamine (5-HT) (10-9 mol\\/L to 10-2 mol\\/L) caused increased vascular resistance. Mepyramine (10-7 mol\\/L), cimetidine (10-5 mol\\/L) and atropine (10-6 mol\\/L) inhibited the responses to histamine. The

K. I. Eghianruwa; P. Eyre



Potentiation by endothelin-1 of 5-hydroxytryptamine-induced contraction in coronary artery of the pig.  

PubMed Central

1. In order to elucidate the physiological and potential pathological roles of endothelin-1 (ET-1) in coronary artery contraction and relaxation, we undertook the present study to examine the action of ET-1 itself, and the combined effects of ET-1 with vasoconstrictor agonists such as acetylcholine (ACh), histamine, and 5-hydroxytryptamine (5-HT), all of which have been implicated in the genesis of coronary spasm. 2. Isometric tension and cytosolic Ca2+ concentration ([Ca2+]i) in a ring segment of porcine coronary artery loaded with fura-2 were measured simultaneously. 3. ET-1 contracted the artery in a concentration-dependent manner; and nisoldipine, a Ca2+ channel blocking drug of the 1,4-dihydropyridine type, antagonized the ET-1 action non-competitively. A radio-receptor binding assay also indicated the mutually exclusive binding of ET-1 and (+)-[3H]-PN200-110, a Ca2+ channel ligand, to the membrane fraction of porcine coronary artery. 4. ET-1 (10-100 pM) increased tension and [Ca2+]i in a parallel manner, while at higher concentrations (1-10 nM) it produced further contraction with a small increase in [Ca2+]i. 5. ET-1 (30-100 pM) selectively potentiated the 5-HT-induced contraction 1.5 to 2 times over the control without causing a significant increase in [Ca2+]i, which seems to be qualitatively similar to a tumour promoting phorbol ester, 12-deoxyphorbol 13-isobutylate (DPB). Bay K 8644 (10 nM), on the other hand, potentiated the contraction in response to practically all agonists used and affected a concomitant increase in [Ca2+]i.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1810605

Nakayama, K.; Ishigai, Y.; Uchida, H.; Tanaka, Y.



Functional evidence for the rapid desensitization of 5-HT(3) receptors on vagal afferents mediating the Bezold-Jarisch reflex  

NASA Technical Reports Server (NTRS)

The aim of this study was to determine whether 5-hydroxytryptamine (5-HT)(3) receptors on cardiopulmonary afferents mediating the Bezold-Jarisch reflex (BJR) desensitize upon repeated exposure to selective agonists. BJR-mediated falls in heart rate, diastolic arterial blood pressure and cardiac output elicited by the 5-HT(3)-receptor agonists, phenylbiguanide (100 microg/kg, i.v.) or 2-methyl-5-HT (100 microg/kg, i.v.), progressively diminished upon repeated injection in conscious rats. The BJR responses elicited by 5-HT (40 microg/kg, i.v.) were markedly reduced in rats which had received the above injections of phenylbiguanide or 2-methyl-5-HT whereas the BJR responses elicited by L-S-nitrosocysteine (10 micromol/kg, i.v.) were similar before and after the injections of the 5-HT(3) receptor agonists. These findings suggest that tachyphylaxis to 5-HT(3) receptor agonists may be due to the desensitization of 5-HT(3) receptors on cardiopulmonary afferents rather than the impairment of the central or peripheral processing of the BJR.

Whalen, E. J.; Johnson, A. K.; Lewis, S. J.



Identification of structural determinants of ligand selectivity in 5-HT? receptor subtypes on the basis of protein-ligand interactions.  


Drug selectivity is one of the most critical improvement steps in drug development. The 5-hydroxytryptamine 2 (5-HT?) receptor has 3 subtypes that exhibit different pharmacological functions. Because of their high amino acid sequence similarity, designing small molecules that selectively activate only 1 receptor among the 3 subtypes is difficult. We performed homology modeling of the 5-HT? receptor subtypes using the ??-adrenergic receptor as a template to identify differences in active sites that may influence 5-HT? receptor agonist selectivity. A subset of selective 5-HT? agonists was docked into the modeled protein structures to investigate their interactions with each receptor. Subtype-specific active site residues at positions xl2.54, 5.39, and 5.46 interacted differently with each ligand. Molecular dynamics simulations revealed that position 5.46 of the 5-HT(2A) receptor interacted more favorably with selective 5-HT(2A) agonists than with selective 5-HT(2B) agonists. These computationally obtained insights provided clues to improving agonist selectivity for specific pharmacological action at 5-HT? receptors. PMID:23085173

Jang, Jae Wan; Kim, Min Sup; Cho, Yong Seo; Cho, Art E; Pae, Ae Nim



Expression and function of 5-HT7 receptors in smooth muscle preparations from equine duodenum, ileum, and pelvic flexure  

PubMed Central

In horses, gastrointestinal (GI) disorders occur frequently and cause a considerable demand for efficient medication. 5-Hydroxytryptamine receptors (5-HT) have been reported to be involved in GI tract motility and thus, are potential targets for treating functional bowel disorders. Our studies extend current knowledge on the 5-HT7 receptor in equine duodenum, ileum and pelvic flexure by studying its expression throughout the intestine and its role in modulating contractility in vitro by immunofluorescence and organ bath experiments, respectively. 5-HT7 immunoreactivity was demonstrated in both smooth muscle layers, particularly in the circular one, and within the myenteric plexus. Interstitial cells of Cajal (ICC), identified by c-Kit labeling, show a staining pattern similar to that of 5-HT7 immunoreactivity. The selective 5-HT7 receptor antagonist SB-269970 increased the amplitude of contractions in spontaneous contracting specimens of the ileum and in electrical field-stimulated specimens of the pelvic flexure concentration-dependently. Our in vitro experiments suggest an involvement of the 5-HT7 receptor subtype in contractility of equine intestine. While the 5-HT7 receptor has been established to be constitutively active and inhibits smooth muscle contractility, our experiments demonstrate an increase in contractility by the 5-HT7 receptor ligand SB-269970, suggesting it exerting inverse agonist properties. PMID:19364615

Prause, Andrea S.; Stoffel, Michael H.; Portier, Christopher J.; Mevissen, Meike



Molecular characterization and analysis of a putative 5-HT receptor involved in reproduction process of the pearl oyster Pinctada fucata.  


5-HT (5-hydroxytryptamine; serotonin) has been linked to a variety of biological roles including gonad maturation and sequential spawning in bivalve molluscs. To gain a better understanding of the effects of 5-HT on developmental regulation in the pearl oyster Pinctada fucata, the isolation, cloning, and expression of the 5-HT receptor was investigated in this study. A full-length cDNA (2541 bp) encoding a putative 5-HT receptor (5-HTpf) of 471 amino acids was isolated from the ovary of the pearl oyster. It shared 71% and 51% homology, respectively, with the Crassostrea gigas 5-HT receptor and the Aplysia californica 5-HT1ap. The 5-HTpf sequence possessed the typical characteristics of seven transmembrane domains and a long third inner loop. Phylogenetic analysis also indicated that 5-HTpf was classified into the 5-HT1 subtype together with other invertebrate 5-HT1 receptors. Quantitative RT-PCR showed that 5-HTpf is widely expressed in all tissues tested, is involved in the gametogenesis cycle, embryonic and larval development stages, and expression is induced by E2 in ovarian tissues. These results suggest that 5-HTpf is involved in the reproductive process, specifically in the induction of oocyte maturation and spawning of P. fucata. PMID:24852353

Wang, Qi; He, Maoxian



Histochemical Demonstration of 5.Hydroxytryptamine in Platelets and Megakaryocytes  

Microsoft Academic Search

I_I AND AND REID 1 were the first to show that circulating 5-hydroxytrypta- mine (5-HT) is concentrated in the blood platelets. Under normal con- ditions, there is no detectable 5-HT in the circulating blood components other than platelets. Clark et al.2 and Gaddum and Giarman3 showed that both spleen and bone marrow are lacking the enzyme, 5-hydroxytryptophan (5- HiP) decarboxylase,




Effect of ?-mangostin through the inhibition of 5-hydroxytryptamine2A receptors in 5-fluoro-?-methyltryptamine-induced head-twitch responses of mice  

PubMed Central

Intracerebronventricular (i.c.v.) injection of ?-mangostin (10–40?nmol/mouse), a major compound of the fruit hull of Garcinia mangostana Lin., like ketanserin (10, 20?nmol/mouse, i.c.v.) inhibited 5-fluoro-?-methyltryptamine (5-FMT) (45?mg?kg?1, i.p.)-induced head-twitch response in mice in the presence or absence of citalopram (a 5-hydroxytryptamine (5-HT)-uptake inhibitor).Neither the 5-FMT- nor the 8-hydroxy-2-(di-n-propylamino)tetralin (5-HT1A-agonist)-induced 5-HT syndrome (head weaving and hindlimb abduction) was affected by ?-mangostin or ketanserin.The locomotor activity stimulated by 5-FMT through the activation of ?1-adrenoceptors did not alter in the presence of ?-mangostin.5-HT-induced inositol phosphates accumulation in mouse brain slices was abolished by ketanserin. ?-Mangostin caused a concentration-dependent inhibition of the inositol phosphates accumulation.?-Mangostin caused a concentration-dependent inhibition of the binding of [3H]-spiperone, a specific 5-HT2A receptor antagonist, to mouse brain membranes.Kinetic analysis of the [3H]-spiperone binding revealed that ?-mangostin increased the Kd value without affecting the Bmax value, indicating the mode of the competitive nature of the inhibition by ?-mangostin.These results suggest that ?-mangostin inhibits 5-FMT-induced head-twitch response in mice by blocking 5-HT2A receptors not by blocking the release of 5-HT from the central neurone. ?-Mangostin is a promising 5-HT2A receptor antagonist in the central nervous system. PMID:9535013

Chairungsrilerd, Nattaya; Furukawa, Ken-Ichi; Tadano, Takeshi; Kisara, Kensuke; Ohizumi, Yasushi



Involvement of 5-hydroxytryptamine and prostaglandin E2 in the intestinal secretory action of Escherichia coli heat-stable enterotoxin B.  

PubMed Central

The intestinal secretory action of Escherichia coli heat-stable enterotoxin B (STb) is poorly defined. Previous work indicates that STb causes loss of intestinal fluid and electrolytes by a mechanism independent of elevated levels of cyclic nucleotides, the hallmark of other E. coli cytotonic enterotoxins. In the work described in this report, we observed that treatment of ligated rat intestinal loops with purified STb of E. coli resulted in a dose-dependent rise in intestinal secretion concomitant with dose-related increases in levels of serotonin (5-hydroxytryptamine [5-HT]) and prostaglandin E2 (PGE2). Treatment of rats with the 5-HT2 receptor antagonist ketanserin prior to STb challenge resulted in significant (P < 0.05) reduction in intestinal secretion. Blockage of 5-HT2 receptors with ketanserin also reduced (P < 0.05) the level of PGE2 observed following STb treatment, indicating that at least a portion of the PGE2 was formed in response to 5-HT2 receptor stimulation. In a similar fashion, indomethacin, an inhibitor of cyclooxygenase activity, significantly reduced the level of secretion (P < 0.05) observed following STb treatment yet had no effect on 5-HT levels. Treatment of rats with both ketanserin and indomethacin further reduced STb-mediated secretion to a level not attained by either drug alone. Taken together, our data suggest that secretion due to STb involves both 5-HT and PGE2 as intestinal secretagogues. Furthermore, PGE2 formation appears to arise through both 5-HT-dependent and 5-HT-independent pathways. PMID:7868242

Harville, B A; Dreyfus, L A



Physical Interaction of Calmodulin with the 5-Hydroxytryptamine2C Receptor C-Terminus Is Essential for G Protein-independent, Arrestin-dependent Receptor Signaling  

PubMed Central

The serotonin (5-hydroxytryptamine; 5-HT)2C receptor is a G protein-coupled receptor (GPCR) exclusively expressed in CNS that has been implicated in numerous brain disorders, including anxio-depressive states. Like many GPCRs, 5-HT2C receptors physically interact with a variety of intracellular proteins in addition to G proteins. Here, we show that calmodulin (CaM) binds to a prototypic Ca2+-dependent “1-10” CaM-binding motif located in the proximal region of the 5-HT2C receptor C-terminus upon receptor activation by 5-HT. Mutation of this motif inhibited both ?-arrestin recruitment by 5-HT2C receptor and receptor-operated extracellular signal-regulated kinase (ERK) 1,2 signaling in human embryonic kidney-293 cells, which was independent of G proteins and dependent on ?-arrestins. A similar inhibition was observed in cells expressing a dominant-negative CaM or depleted of CaM by RNA interference. Expression of the CaM mutant also prevented receptor-mediated ERK1,2 phosphorylation in cultured cortical neurons and choroid plexus epithelial cells that endogenously express 5-HT2C receptors. Collectively, these findings demonstrate that physical interaction of CaM with recombinant and native 5-HT2C receptors is critical for G protein-independent, arrestin-dependent receptor signaling. This signaling pathway might be involved in neurogenesis induced by chronic treatment with 5-HT2C receptor agonists and their antidepressant-like activity. PMID:18768750

Labasque, Marilyne; Reiter, Eric; Becamel, Carine; Bockaert, Joel



Characterization of 5-HT receptors on human pulmonary artery and vein: functional and binding studies  

PubMed Central

This study aimed to investigate the 5-hydroxytryptamine (5-HT) receptors mediating contraction of ring preparations isolated from human pulmonary arteries and veins. In functional studies, the responses to 5-HT, sumatriptan, ergotamine, serotonin-O-carboxymethyl-glycyl-tyrosinamide (SCMGT), ?-methyl 5-HT (?-Me) and 2-methyl 5-HT (2-Me) were studied with WAY100635, GR127935, ritanserin, zacopride and SB204070 as antagonists.All agonists produced concentration-dependent contractions of human pulmonary artery and vein preparations. The order of potency (?log EC50 values) was ergotamine (6.88)>5-HT (6.41)?SCMGT (6.20)=sumatriptan (6.19) ??-Me (6.04) in the artery, and ergotamine (7.84)>5-HT (6.96)>sumatriptan (6.60)=?-Me (6.56)>SCMGT (6.09) in the vein. The potency of each agonist, except for SCMGT, was greater in vein than in artery preparations. Contractile responses to 5-HT were similar in intact and endothelium-denuded preparations but responses to sumatriptan were enhanced in artery rings without endothelium.GR127935 (1?nM to 0.5??M) produced an unsurmountable antagonism of the response to 5-HT, sumatriptan, ergotamine and SCMGT. Ritanserin (1?nM to 1??M) also reduced the maximum contractile responses to 5-HT, ergotamine and ?-Me in artery and vein preparations without affecting those to sumatriptan and SCMGT. In endothelium-denuded preparations, surmountable antagonism of sumatriptan by GR127935 (in the presence of ritanserin) and of ?-Me by ritanserin (in the presence of GR127935) allowed for the calculation of the apparent pKB values of GR127935 (9.17±0.11 in artery and 9.11±0.05 in vein) and ritanserin (8.82±0.09 in artery and 8.98±0.12 in vein).WAY100635 (1?nM to 1??M), zacopride (1?nM to 1??M), or SB204070 (1?nM) did not significantly alter the concentration-response curves for 5-HT, sumatriptan, ergotamine, SCMGT or 2-Me in human pulmonary artery or vein thus indicating that 5-HT1A, 5-HT3 and 5-HT4 receptors are presumably not involved in the contractile response to these agonists.Binding studies using selective radioligands for different 5-HT receptors could not detect the presence of 5-HT1A receptor binding in human pulmonary blood vessels whereas the 5-HT1B/1D radioligand [3H]-5-CT significantly labelled a population of specific binding sites in both vessel types. The presence of 5-HT2A receptors could also be inferred from the level of binding of [3H]-ketanserin to membranes obtained from human pulmonary vessels, although significance could not be reached for arteries. 5-HT4 specific receptor binding was scarce in veins and absent in the case of arteries.These findings indicate that the human pulmonary artery and vein have a mixed functional population of 5-HT1B/1D and 5-HT2A receptors mediating the contractile response to 5-HT which is consistent with results of the binding studies. PMID:9421295

Cortijo, Julio; Martí-Cabrera, Miguel; Bernabeu, Eva; Domènech, Teresa; Bou, Josep; Fernández, Andrés G; Beleta, Jorge; Palacios, José M; Morcillo, Esteban J



5-HT Radioligands for Human Brain Imaging With PET and SPECT  

PubMed Central

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-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 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.



Serotonin contracts the rat mesenteric artery by inhibiting 4-aminopyridine-sensitive Kv channels via the 5-HT2A receptor and Src tyrosine kinase  

PubMed Central

Serotonin (5-hydroxytryptamine (5-HT)) is a neurotransmitter that regulates a variety of functions in the nervous, gastrointestinal and cardiovascular systems. Despite such importance, 5-HT signaling pathways are not entirely clear. We demonstrated previously that 4-aminopyridine (4-AP)-sensitive voltage-gated K+ (Kv) channels determine the resting membrane potential of arterial smooth muscle cells and that the Kv channels are inhibited by 5-HT, which depolarizes the membranes. Therefore, we hypothesized that 5-HT contracts arteries by inhibiting Kv channels. Here we studied 5-HT signaling and the detailed role of Kv currents in rat mesenteric arteries using patch-clamp and isometric tension measurements. Our data showed that inhibiting 4-AP-sensitive Kv channels contracted arterial rings, whereas inhibiting Ca2+-activated K+, inward rectifier K+ and ATP-sensitive K+ channels had little effect on arterial contraction, indicating a central role of Kv channels in the regulation of resting arterial tone. 5-HT-induced arterial contraction decreased significantly in the presence of high KCl or the voltage-gated Ca2+ channel (VGCC) inhibitor nifedipine, indicating that membrane depolarization and the consequent activation of VGCCs mediate the 5-HT-induced vasoconstriction. The effects of 5-HT on Kv currents and arterial contraction were markedly prevented by the 5-HT2A receptor antagonists ketanserin and spiperone. Consistently, ?-methyl 5-HT, a 5-HT2 receptor agonist, mimicked the 5-HT action on Kv channels. Pretreatment with a Src tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, prevented both the 5-HT-mediated vasoconstriction and Kv current inhibition. Our data suggest that 4-AP-sensitive Kv channels are the primary regulator of the resting tone in rat mesenteric arteries. 5-HT constricts the arteries by inhibiting Kv channels via the 5-HT2A receptor and Src tyrosine kinase pathway. PMID:24336234

Sung, Dong Jun; Noh, Hyun Ju; Kim, Jae Gon; Park, Sang Woong; Kim, Bokyung; Cho, Hana; Bae, Young Min



Serotonin contracts the rat mesenteric artery by inhibiting 4-aminopyridine-sensitive Kv channels via the 5-HT2A receptor and Src tyrosine kinase.  


Serotonin (5-hydroxytryptamine (5-HT)) is a neurotransmitter that regulates a variety of functions in the nervous, gastrointestinal and cardiovascular systems. Despite such importance, 5-HT signaling pathways are not entirely clear. We demonstrated previously that 4-aminopyridine (4-AP)-sensitive voltage-gated K(+) (Kv) channels determine the resting membrane potential of arterial smooth muscle cells and that the Kv channels are inhibited by 5-HT, which depolarizes the membranes. Therefore, we hypothesized that 5-HT contracts arteries by inhibiting Kv channels. Here we studied 5-HT signaling and the detailed role of Kv currents in rat mesenteric arteries using patch-clamp and isometric tension measurements. Our data showed that inhibiting 4-AP-sensitive Kv channels contracted arterial rings, whereas inhibiting Ca(2+)-activated K(+), inward rectifier K(+) and ATP-sensitive K(+) channels had little effect on arterial contraction, indicating a central role of Kv channels in the regulation of resting arterial tone. 5-HT-induced arterial contraction decreased significantly in the presence of high KCl or the voltage-gated Ca(2+) channel (VGCC) inhibitor nifedipine, indicating that membrane depolarization and the consequent activation of VGCCs mediate the 5-HT-induced vasoconstriction. The effects of 5-HT on Kv currents and arterial contraction were markedly prevented by the 5-HT2A receptor antagonists ketanserin and spiperone. Consistently, ?-methyl 5-HT, a 5-HT2 receptor agonist, mimicked the 5-HT action on Kv channels. Pretreatment with a Src tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, prevented both the 5-HT-mediated vasoconstriction and Kv current inhibition. Our data suggest that 4-AP-sensitive Kv channels are the primary regulator of the resting tone in rat mesenteric arteries. 5-HT constricts the arteries by inhibiting Kv channels via the 5-HT2A receptor and Src tyrosine kinase pathway. PMID:24336234

Sung, Dong Jun; Noh, Hyun Ju; Kim, Jae Gon; Park, Sang Woong; Kim, Bokyung; Cho, Hana; Bae, Young Min



Prefrontal/amygdalar system determines stress coping behavior through 5-HT/GABA connection.  


Coping is defined as the behavioral and physiological effort made to master stressful situations. The ability to cope with stress leads either to healthy or to pathogenic outcomes. The medial prefrontal cortex (mpFC) and amygdala are acknowledged as having a major role in stress-related behaviors, and mpFC has a critical role in the regulation of amygdala-mediated arousal in response to emotionally salient stimuli. Prefrontal cortical serotonin (5-hydroxytryptamine (5-HT)) is involved in corticolimbic circuitry, and GABA has a major role in amygdala functioning. Here, using mice, it was assessed whether amygdalar GABA regulation by prefrontal 5-HT is involved in processing stressful experiences and in determining coping outcomes. First (experiment 1), bilateral selective 5-HT depletion in mpFC of mice reduced GABA release induced by stress in basolateral amygdala (BLA) and passive coping in the Forced Swimming Test (FST) (experiment 2). Moreover, prefrontal-amygdala disconnection procedure that combined a selective unilateral 5-HT depletion of mpFC and infusion of an inhibitor of GABA synthesis into the contralateral BLA, thereby to disrupt prefrontal-amygdalar serial connectivity bilaterally, showed that disconnection selectively decreases immobility in the FST. These results point to prefrontal/amygdala connectivity mediated by 5-HT and GABA transmission as a critical neural mechanism in stress-induced behavior. PMID:23636466

Andolina, Diego; Maran, Dario; Valzania, Alessandro; Conversi, David; Puglisi-Allegra, Stefano



Application of quantitative structure-activity relationship models of 5-HT1A receptor binding to virtual screening identifies novel and potent 5-HT1A ligands.  


The 5-hydroxytryptamine 1A (5-HT1A) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification quantitative structure-activity relationship (QSAR) models of 5-HT1A receptor binding activity using data retrieved from the PDSP Ki database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the World of Molecular Bioactivity database. These validated models were then used to mine three major types of chemical screening libraries, i.e., drug-like libraries, GPCR targeted libraries, and diversity libraries, to identify novel computational hits. The five best hits from each class of libraries were chosen for further experimental testing in radioligand binding assays, and nine of the 15 hits were confirmed to be active experimentally with binding affinity better than 10 ?M. The most active compound, Lysergol, from the diversity library showed very high binding affinity (Ki) of 2.3 nM against 5-HT1A receptor. The novel 5-HT1A actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential antischizophrenic drugs. PMID:24410373

Luo, Man; Wang, Xiang Simon; Roth, Bryan L; Golbraikh, Alexander; Tropsha, Alexander



On the nature of the 5-HT receptor subtype inhibiting acetylcholine release in the guinea-pig ileum.  

PubMed Central

1. The nature of the 5-hydroxytryptamine (5-HT) receptor subtype controlling acetylcholine release and contraction induced by stimulation of the neurokinin NK3 receptor has been studied in the longitudinal muscle-myenteric plexus preparation from guinea-pig ileum. 2. In preparations preloaded with [3H]-choline, the selective NK3 agonist, senktide, produced a concentration-dependent increase in tritium overflow, an index of [3H]-acetylcholine release. Low concentrations of neurokinin B, also markedly increased tritium efflux. 3. The senktide-induced acetylcholine release was markedly increased by the same concentration of methysergide and mesulergine. The 5-HT2A/2C agonist DOI (1 microM) inhibited the tritium overflow while 8-OH-DPAT, sumatriptan and ketanserin (1 microM each) were without effect on the senktide-induced tritium efflux. 4. The contractile response to senktide in the guinea-pig ileum was attenuated by atropine, 0.1 microM. Methysergide, a 5-HT1/2 receptor antagonist, and mesulergine, a 5-HT2A/2B/2C receptor antagonist, (1 microM each), enhanced the contractile effect of the NK3 receptor agonist. 5. It is concluded that the acetylcholine release induced by a NK3 receptor agonist is inhibited by stimulation of a 5-HT receptor, possibly of the 5-HT2C or 5-HT2C subtype. PMID:7529115

Ramírez, M J; Del Río, J; Cenarruzabeitia, E; Lasheras, B



Conformational toggle switches implicated in basal constitutive and agonist-induced activated states of 5-hydroxytryptamine-4 receptors.  


The extended classic ternary complex model predicts that a G protein-coupled receptor (GPCR) exists in only two interconvertible states: an inactive R, and an active R(*). However, different structural active R(*) complexes may exist in addition to a silent inactive R ground state (Rg). Here we demonstrate, in a cellular context, that several R(*) states of 5-hydroxytryptamine-4 (5-HT(4)) receptors involve different side-chain conformational toggle switches. Using site-directed mutagenesis and molecular modeling approaches, we show that the basal constitutive receptor (R(*)basal) results from stabilization of an obligatory double toggle switch (Thr3.36 from inactive g- to active g+ and Trp6.48 from inactive g+ to active t). Mutation of either threonine or tryptophan to alanine resulted in a lowering of the activity of the R(*)basal similar to the Rg. The T3.36A mutation shows that the Thr3.36 toggle switch plays a minor role in the stabilization of R(*) induced by 5-HT (R(*)-5-HT) and BIMU8 (R(*)-BIMU8) and is fully required in the stabilization of R(*) induced by (S)-zacopride, cisapride, and 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-butyl-4-piperidinyl)-1-propanone (RS 67333) (R(*)-benzamides). Thus, benzamides stabilize R(*)-benzamides by forming a specific hydrogen bond with Thr3.36 in the active g+ conformation. Conversely, R(*)-BIMU8 was probably the result of a direct conformational transition of Trp6.48 from inactive g+ to active t by hydrogen bonding of this residue to a carboxyl group of BIMU8. We were surprised that the Trp6.48 toggle switch was not necessary for receptor activation by the natural agonist 5-HT. R(*)-5-HT is probably attained through other routes of activation. Thus, different conformational arrangements occur during stabilization of R(*)basal, R(*)-5-HT, R(*)-benzamides, and R(*)-BIMU8. PMID:19168624

Pellissier, Lucie P; Sallander, Jessica; Campillo, Mercedes; Gaven, Florence; Queffeulou, Emilie; Pillot, Marion; Dumuis, Aline; Claeysen, Sylvie; Bockaert, Joël; Pardo, Leonardo



The Antimalarial Drug Proguanil Is an Antagonist at 5-HT3 Receptors.  


Proguanil is an antimalarial prodrug that is metabolized to 4-chlorophenyl-1-biguanide (CPB) and the active metabolite cycloguanil (CG). These compounds are structurally related to meta-chlorophenyl biguanide (mCPBG), a 5-hydroxytryptamine 3 (5-HT3) receptor agonist. Here we examine the effects of proguanil and its metabolites on the electrophysiology and ligand-binding properties of human 5-HT3A receptors expressed in Xenopus oocytes and human embryonic kidney 293 cells, respectively. 5-HT3 receptor responses were reversibly inhibited by proguanil, with an IC50 of 1.81 ?M. Competitive antagonism was shown by a lack of voltage-dependence, Schild plot (Kb = 1.70 ?M), and radioligand competition (Ki = 2.61 ?M) with the 5-HT3 receptor antagonist [(3)H]granisetron. Kinetic measurements (kon = 4.0 × 10(4) M(-1) s(-1) ; koff = 0.23 s(-1)) were consistent with a simple bimolecular reaction scheme with a Kb of 4.35 ?M. The metabolites CG and CPB similarly inhibited 5-HT3 receptors as assessed by IC50 (1.48 and 4.36 ?M, respectively), Schild plot (Kb = 2.97 and 11.4 ?M), and radioligand competition (Ki = 4.89 and 0.41 ?M). At higher concentrations, CPB was a partial agonist (EC50 = 14.1 ?M; I/Imax = 0.013). These results demonstrate that proguanil competitively inhibits 5-HT3 receptors, with an IC50 that exceeds whole-blood concentrations following its oral administration. They may therefore be responsible for the occasional gastrointestinal side effects, nausea, and vomiting reported following its use. Clinical development of related compounds should therefore consider effects at 5-HT3 receptors as an early indication of possible unwanted gastrointestinal side effects. PMID:25277140

Lochner, Martin; Thompson, Andrew J



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.



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



The spike generator in the labellar taste receptors of the blowfly is differently affected by 4-aminopyridine and 5-hydroxytryptamine.  


In taste chemoreception of invertebrates the interaction of taste stimuli with specific membrane receptors and/or ion channels located in the apical membrane of taste receptor cells results in the generation of a receptor potential which, in turn, activates the 'encoder' region to produce action potentials which propagate to the CNS. This study investigates, in the labellar chemosensilla of the blowfly, Protophormia terraenovae, the voltage-gated K(+) currents involved in the action potential repolarization and repetitive firing of the neurons by way of the K(v) channel inhibitors, 4-aminopyridine and 5-hydroxytryptamine. The receptor potential and the spike activity were simultaneously recorded from the 'salt', 'sugar' and 'deterrent' cells, by means of the extracellular side-wall technique, in response to 150 mM NaCl, 100 mM sucrose and 1 mM quinine HCl, before, 0÷10 min after apical administration of 4-AP (0.01-10 mM) or 5-HT (0.1-100 mM). The results show that the receptor potential in all three cells is neither affected by 4-AP nor by 5-HT. Instead, spike activity is significantly decreased, by way of blocking different K(v) channel types: an inactivating A-type K(+) current (KA) modulating repetitive firing of the cells and responsible for the after hyperpolarization, and a sustained K(+) current that resembles the delayed rectifier (DKR) and contributes to action potential repolarization. PMID:23085554

Sollai, Giorgia; Solari, Paolo; Corda, Valentina; Masala, Carla; Crnjar, Roberto



Anpirtoline, a novel, highly potent 5-HT1B receptor agonist with antinociceptive/antidepressant-like actions in rodents.  

PubMed Central

1. The purpose of the present study was to relate the effects of the novel drug, anpirtoline, on 5-hydroxytryptamine (5-HT) receptor subtypes to its antinociceptive and antidepressant-like actions in rodents. 2. Binding assays with rat brain membranes have shown that anpirtoline bound with a much higher affinity to 5-HT1B receptor (Ki = 28 nM) than to 5-HT1A (Ki = 150 nM) and 5-HT2 (Ki = 1.49 microM) receptors. 3. Like 5-HT, anpirtoline concentration-dependently inhibited forskolin-stimulated adenylate cyclase activity in homogenates from the rat substantia nigra. Both effects were not additive, and could be prevented by 5-HT1B receptor antagonists such as propranolol and penbutolol. 4. In superfused rat and pig brain cortex slices preincubated with [3H]-5-HT, the electrically evoked tritium overflow was inhibited by anpirtoline and 5-HT. Whereas 5-HT was equipotent in both tissues (EC50 = 69 nM), anpirtoline was markedly less potent in pig brain cortex slices (EC50 = 1190 nM) than in rat brain cortex slices (EC50 = 55 nM). The concentration-response curve for anpirtoline was shifted to the right by metitepine in both preparations. 5. In the social behaviour deficit test, anpirtoline and trifluoromethylphenyl-piperazine were effective in reversing the isolation-induced impairments in mice, an effect shown only by compounds with agonist properties at the 5-HT1B receptor. 6. In the electrostimulated pain test using mice, anpirtoline dose-dependently increased the pain threshold with an ED50 of 0.52 mg kg-1, i.p. The antinociceptive activity of anpirtoline was abolished by pretreatment with cyproheptadine or propranolol.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1628159

Schlicker, E.; Werner, U.; Hamon, M.; Gozlan, H.; Nickel, B.; Szelenyi, I.; Göthert, M.



5-HT4-Receptors Modulate Induction of Long-Term Depression but Not Potentiation at Hippocampal Output Synapses in Acute Rat Brain Slices  

PubMed Central

The subiculum is the principal target of CA1 pyramidal cells and mediates hippocampal output to various cortical and subcortical regions of the brain. The majority of subicular pyramidal cells are burst-spiking neurons. Previous studies indicated that high frequency stimulation in subicular burst-spiking cells causes presynaptic NMDA-receptor dependent long-term potentiation (LTP) whereas low frequency stimulation induces postsynaptic NMDA-receptor-dependent long-term depression (LTD). In the present study, we investigate the effect of 5-hydroxytryptamine type 4 (5-HT4) receptor activation and blockade on both forms of synaptic plasticity in burst-spiking cells. We demonstrate that neither activation nor block of 5-HT4 receptors modulate the induction or expression of LTP. In contrast, activation of 5-HT4 receptors facilitates expression of LTD, and block of the 5-HT4 receptor prevents induction of short-term depression and LTD. As 5-HT4 receptors are positively coupled to adenylate cyclase 1 (AC1), 5-HT4 receptors might modulate PKA activity through AC1. Since LTD is blocked in the presence of 5-HT4 receptor antagonists, our data are consistent with 5-HT4 receptor activation by ambient serotonin or intrinsically active 5-HT4 receptors. Our findings provide new insight into aminergic modulation of hippocampal output. PMID:24505387

Wawra, Matthias; Fidzinski, Pawel; Heinemann, Uwe; Mody, Istvan; Behr, Joachim



A Chemocentric Informatics Approach to Drug Discovery: Identification and Experimental Validation of Selective Estrogen Receptor Modulators as ligands of 5-Hydroxytryptamine-6 Receptors and as Potential Cognition Enhancers  

PubMed Central

We have devised a chemocentric informatics methodology for drug discovery integrating independent approaches to mining biomolecular databases. As a proof of concept, we have searched for novel putative cognition enhancers. First, we generated Quantitative Structure- Activity Relationship (QSAR) models of compounds binding to 5-hydroxytryptamine-6 receptor (5HT6R), a known target for cognition enhancers, and employed these models for virtual screening to identify putative 5-HT6R actives. Second, we queried chemogenomics data from the Connectivity Map ( with the gene expression profile signatures of Alzheimer’s disease patients to identify compounds putatively linked to the disease. Thirteen common hits were tested in 5-HT6R radioligand binding assays and ten were confirmed as actives. Four of them were known selective estrogen receptor modulators that were never reported as 5-HT6R ligands. Furthermore, nine of the confirmed actives were reported elsewhere to have memory-enhancing effects. The approaches discussed herein can be used broadly to identify novel drug-target-disease associations. PMID:22537153

Hajjo, Rima; Setola, Vincent; Roth, Bryan L.; Tropsha, Alexander



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. Copyright © 2014 John Wiley & Sons, Ltd. PMID:24802524

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



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



Association between 5-hydroxytryptamine 1A receptor gene polymorphism and suicidal behavior.  


Suicidal behavior is highly correlated with many emotional disturbances and some psychiatric disorders. The biogenic amine, serotonin, is one of the most important neurotransmitter in the central nervous system believed to play a huge role in pathogenesis of some kind of mental disorders. Drugs targeting serotonin receptors like serotonin reuptake inhibitors (SSRIs) are useful in the present therapy of anxiety and depression. Recent studies have reported that genetic factors are associated with development of some psychiatric disorders. Serotonin receptor single nucleotide polymorphism (SNP) has emerged as the subject of controversial result in correlation with suicide attempt. Further studies should be performed to confirm the influence of allelic variation of serotonin receptor on elevated risk of auto-aggression behavior. The aim of our study was to examine the frequency and genotype distribution of C(-1019)G polymorphism of regulatory region 5-HT1A receptor in the group of 65 suicide attempters and 63 persons in the control group. Using allele specific amplification PCR (ASA-PCR), we found that allele G was higher in suicidal attempters. The genotype frequency was significantly different between hospitalized patients and control subjects. The most common intoxication causes were antidepressants (56.9%), analgesics (18.5%) and cardiologic drugs (10.8%). Our data support hypothesis which indicate role of the 5-HT1A C(-1019)G SNP polymorphism in elevated risk of suicidal attempt. PMID:17724868

Sawiniec, Jaros?aw; Borkowski, Krzysztof; Ginalska, Grazyna; Lewandowska-Stanek, Hanna



Protein kinase C inhibition prevents upregulation of vascular ETB and 5HT1B receptors and reverses cerebral blood flow reduction after subarachnoid haemorrhage in rats  

Microsoft Academic Search

The pathogenesis of cerebral ischaemia after subarachnoid haemorrhage (SAH) still remains elusive. The purpose of the present study was to examine whether specific protein kinas C (PKC) inhibition in rats could alter the transcriptional SAH induced Endothelin (ET) type B and 5-hydroxytryptamine type 1B (5-HT1B) receptor upregulation and prevent the associated cerebral blood flow (CBF) reduction. The PKC inhibitor RO-31-7549

Saema S Beg; Jacob A Hansen-Schwartz; Petter J Vikman; Cang-Bao Xu; Lars I Edvinsson



Effects of the antidepressant fluoxetine on the subcellular localization of 5-HT1A receptors and SERT  

PubMed Central

Serotonin (5-HT) 5-HT1A autoreceptors (5-HT1AautoR) and the plasmalemmal 5-HT transporter (SERT) are key elements in the regulation of central 5-HT function and its responsiveness to antidepressant drugs. Previous immuno-electron microscopic studies in rats have demonstrated an internalization of 5-HT1AautoR upon acute administration of the selective agonist 8-OH-DPAT or the selective serotonin reuptake inhibitor antidepressant fluoxetine. Interestingly, it was subsequently shown in cats as well as in humans that this internalization is detectable by positron emission tomography (PET) imaging with the 5-HT1A radioligand [18F]MPPF. Further immunocytochemical studies also revealed that, after chronic fluoxetine treatment, the 5-HT1AautoR, although present in normal density on the plasma membrane of 5-HT cell bodies and dendrites, do not internalize when challenged with 8-OH-DPAT. Resensitization requires several weeks after discontinuation of the chronic fluoxetine treatment. In contrast, the SERT internalizes in both the cell bodies and axon terminals of 5-HT neurons after chronic but not acute fluoxetine treatment. Moreover, the total amount of SERT immunoreactivity is then reduced, suggesting that SERT is not only internalized, but also degraded in the course of the treatment. Ongoing and future investigations prompted by these finding are briefly outlined by way of conclusion. PMID:22826342

Descarries, Laurent; Riad, Mustaph



Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research.  


Psychiatric disorders represent a large economic burden in modern societies. However, pharmacological treatments are still far from optimal. Drugs used in the treatment of major depressive disorder (MDD) and anxiety disorders (selective serotonin [5-HT] reuptake inhibitors [SSRIs] and serotonin-noradrenaline reuptake inhibitors [SNRIs]) are pharmacological refinements of first-generation tricyclic drugs, discovered by serendipity, and show low efficacy and slowness of onset. Moreover, antipsychotic drugs are partly effective in positive symptoms of schizophrenia, yet they poorly treat negative symptoms and cognitive deficits. The present article reviews the neurobiological basis of 5-HT1A receptor (5-HT1A-R) function and the role of pre- and postsynaptic 5-HT1A-Rs in the treatment of MDD, anxiety and psychotic disorders. The activation of postsynaptic 5-HT1A-Rs in corticolimbic areas appears beneficial for the therapeutic action of antidepressant drugs. However, presynaptic 5-HT1A-Rs play a detrimental role in MDD, since individuals with high density or function of presynaptic 5-HT1A-Rs are more susceptible to mood disorders and suicide, and respond poorly to antidepressant drugs. Moreover, the indirect activation of presynaptic 5-HT1A-Rs by SSRIs/SNRIs reduces 5-HT neuron activity and terminal 5-HT release, thus opposing the elevation of extracellular 5-HT produced by blockade of the serotonin transporter (SERT) in the forebrain. Chronic antidepressant treatment desensitizes presynaptic 5-HT1A-Rs, thus reducing the effectiveness of the 5-HT1A autoreceptor-mediated negative feedback. The prevention of this process by the non-selective partial agonist pindolol accelerates clinical antidepressant effects. Two new antidepressant drugs, vilazodone (marketed in the USA) and vortioxetine (in development) incorporate partial 5-HT1A-R agonist properties with SERT blockade. Several studies with transgenic mice have also established the respective role of pre- and postsynaptic 5-HT1A-Rs in MDD and anxiety. In agreement with pharmacological studies, presynaptic and postsynaptic 5-HT1A-R activation appears necessary for anxiolytic and antidepressant effects, respectively, yet, neurodevelopmental roles for 5-HT1A-Rs are also involved. Likewise, the use of small interference RNA has enabled the showing of robust antidepressant-like effects in mice after selective knock-down of 5-HT1A autoreceptors. Postsynaptic 5-HT1A-Rs in the prefrontal cortex (PFC) also appear important for the superior clinical effects of clozapine and other second-generation (atypical) antipsychotic drugs in the treatment of schizophrenia and related psychotic disorders. Despite showing a moderate in vitro affinity for 5-HT1A-Rs in binding assays, clozapine displays functional agonist properties at this receptor type in vivo. The stimulation of 5-HT1A-Rs in the PFC leads to the distal activation of the mesocortical pathway and to an increased dopamine release in PFC, an effect likely involved in the clinical actions of clozapine in negative symptoms and cognitive deficits in schizophrenia. The anxiolytic/antidepressant properties of 5-HT1A-R agonists in preclinical tests raised expectations enormously. However, these agents have achieved little clinical success, possibly due to their partial agonist character at postsynaptic 5-HT1A-Rs, together with full agonist properties at presynaptic 5-HT1A autoreceptors, as well as their gastrointestinal side effects. The partial 5-HT1A-R agonists buspirone, gepirone, and tandospirone are marketed as anxiolytic drugs, and buspirone is also used as an augmentation strategy in MDD. The development of new 5-HT1A-R agonists with selectivity for postsynaptic 5-HT1A-Rs may open new perspectives in the field. PMID:23757185

Celada, Pau; Bortolozzi, Analía; Artigas, Francesc



Differentiation of 5-hydroxytryptamine2 receptor subtypes using sup 125 I-R-(-)2,5-dimethoxy-4-iodo-phenylisopropylamine and sup 3 H-ketanserin  

SciTech Connect

The radioligand binding characteristics of 125I-R-(-)4-iodo-2,5-dimethoxyphenylisopropylamine (125I-R-(-)DOI) and 3H-ketanserin were compared in rat and bovine cortical membranes. In rat cortex, 125I-R-(-)DOI labels a relatively low density of binding sites (Bmax = 2.5 +/- 0.2 pmol/gm tissue) with high affinity (KD = 0.63 +/- 0.09 nM). In bovine cortex, specific binding of 125I-R-(-)DOI represents less than 20% of total binding at radioligand concentrations above 0.6 nM, and, therefore, the data cannot be analyzed adequately by Scatchard transformation. By contrast, 3H-ketanserin displays saturable, specific high-affinity binding in both rat cortex (KD = 1.0 +/- 0.1 nM; Bmax = 11 +/- 0.4 pmol/gm tissue) and bovine cortex (KD = 1.2 +/- 0.2 nM; Bmax = 5.3 +/- 0.4 pmol/gm tissue). Ki values for 30 drugs were determined for 125I-R-(-)DOI-labeled sites in rat cortex and 3H-ketanserin-labeled sites in bovine cortex. 5-Hydroxytryptamine (5-HT) displays 250-fold higher selectivity for the 125I-R-(-)DOI-labeled sites (Ki = 3.0 +/- 0.7 nM) than for the 3H-ketanserin-labeled sites (Ki = 750 +/- 50 nM). Structural congeners of R-(-)DOI display 80- to 160-fold higher affinity for the 125I-R-(-)DOI binding site than for the 3H-ketanserin-labeled binding site. d-LSD and putative 5-HT2 antagonists are approximately equipotent at both sites. Significant correlations were found between drug affinities for 125I-R-(-)DOI-labeled sites in rat cortex and putative 5-HT2A sites labeled previously by 77Br-R-(-)DOB (r = 0.93, p less than 0.01), putative 5-HT2B sites labeled by 3H-ketanserin in bovine cortex (r = 0.63, p less than 0.01), and 5-HT1C binding sites that have been characterized by other investigators (r = 0.78, p less than 0.01). No significant correlations were found between drug affinities for 125I-R-(-)DOI-labeled sites in rat cortex and 5-HT1A, 5-HT1B, 5-HT1D, or 5-HT3 sites, as determined by previous investigators.

McKenna, D.J.; Peroutka, S.J. (Stanford Univ., CA (USA))



Distinct thermodynamic parameters of serotonin 5-HT3 agonists and antagonists to displace [3H]granisetron binding.  


Specific binding of [3H]granisetron was examined to serotonin 5-HT3 receptors in synaptosomal membranes of rat cerebral cortex between 1 and 37 degrees C. Displacing potencies were determined for 5-HT3 antagonists (granisetron, ondansetron, tropisetron, and d-tubocurarine) and agonists (5-hydroxytryptamine, 2-methyl-5-hydroxytryptamine, phenylbiguanide, m-chlorophenylbiguanide, and SR 57227A). Displacing potencies of the agonists decreased with decreasing temperature. In contrast, displacing potencies of all antagonists increased with decreasing temperature, whereas those of tropisetron and d-tubocurarine passed a maximum. Scatchard analysis of [3H]granisetron binding resulted in KD values lower than the IC50 values of granisetron and a decreasing number of binding sites at higher temperatures. It can be reconciled with temperature-dependent agonist and antagonist states of 5-HT3 receptors. A semiquantitative thermodynamic analysis was based on displacing potencies. The distinct patterns for the signs of entropy, enthalpy, and heat capacity changes on binding can be reconciled with ionic interactions for agonists and hydrophobic interactions for antagonists. The distinctive differences in these thermodynamic parameters exceed those for GABAA and glycine receptor-ionophore complexes. PMID:8667020

Maksay, G



Discriminating between 5-HT3A and 5-HT3AB receptors  

PubMed Central

The 5-HT3B subunit was first cloned in 1999, and co-expression with the 5-HT3A subunit results in heteromeric 5-HT3AB receptors that are functionally distinct from homomeric 5-HT3A receptors. The affinities of competitive ligands at the two receptor subtypes are usually similar, but those of non-competitive antagonists that bind in the pore often differ. A competitive ligand and allosteric modulator that distinguishes 5-HT3A from 5-HT3AB receptors has recently been described, and the number of non-competitive antagonists identified with this ability has increased in recent years. In this review, we discuss the differences between 5-HT3A and 5-HT3AB receptors and describe the possible sites of action of compounds that can distinguish between them. PMID:23489111

Thompson, AJ; Lummis, SCR



Early detection of oxygen-induced lung injury in conscious rabbits. Reduced in vivo activity of angiotensin converting enzyme and removal of 5-hydroxytryptamine  

SciTech Connect

Changes in lung endothelial metabolic function, determined in vitro, have been proposed as sensitive indexes of hyperoxic lung damage. However, it is unclear whether these changes are also seen in vivo. We studied the possibility, using conscious rabbits in which jugular and carotid catheters had previously been placed under halothane anesthesia. Approximately 24 h later, test animals were exposed to normobaric hyperoxia (96 +/- 2%), while a second group was maintained in room air. Multiple indicator dilution methods were used to study (1) metabolism of /sup 3/H-benzoyl-phe-ala-pro (BPAP), a synthetic substrate for angiotensin converting enzyme (ACE), and (2) removal of /sup 14/C-5-hydroxytryptamine (5-HT) during a single transpulmonary passage in conscious animals. Lungs of air-exposed animals hydrolyzed 81 +/- 2% of injected BPAP (0.1 to 0.15 nmoles) during a single passage. Percent metabolism was unaltered during the next 72 h. However, in test animals, ACE activity, as reflected by BPAP metabolism, was significantly reduced after 16 h of exposure to oxygen (77 +/- 2%, p less than 0.01) and continued to decrease to a nadir of 66 +/- 3% at 40 h. Single-pass lung uptake of /sup 14/C-5-HT (77 +/- 2%) was unchanged throughout the 72-h period in air-exposed rabbits. In test animals, /sup 14/C-5-HT removal decreased to 65 +/- 4% (p less than 0.01) after 24 h of oxygen exposure; 5-HT removal remained depressed compared with the 0 h control determination for the oxygen group at all subsequent measurement intervals. Light and electron microscopy of lungs from oxygen-exposed rabbits demonstrating reduced 5-HT removal and ACE activity at 24 h revealed normal endothelial and type I cell morphologic features.

Dobuler, K.J.; Catravas, J.D.; Gillis, C.N.



Triptan-induced contractile (5-HT1B receptor) responses in human cerebral and coronary arteries: relationship to clinical effect.  


Triptans are agonists at 5-HT1B and 5-HT1D (where 5-HT is 5-hydroxytryptamine; serotonin) receptors and cause vasoconstriction of isolated blood vessels. The aim of the present study was to determine vasoconstrictor potency (EC50) of triptans in human coronary and cerebral arteries and to examine whether there was any relationship with the maximal plasma concentrations (Cmax; nM) of the drugs achieved following oral administration of clinically relevant doses to man using values reported in the literature. We also examined the expression of 5-HT1B receptors in atherosclerotic and normal coronary arteries. The vasocontractile responses to sumatriptan, rizatriptan or eletriptan were characterized by in vitro pharmacology. The ratio of Cmax/EC50 was calculated. 5-HT1B and 5-HT1D receptors were visualized by immunohistochemical techniques in coronary arteries. Sumatriptan, rizatriptan and eletriptan were powerful vasoconstrictors in cerebral artery. The rank order of agonist potency was eletriptan=rizatriptan=sumatriptan. In the coronary artery, the triptans were weaker vasoconstrictors. The rank order of potency was similar. In cerebral artery the ratio of Cmax/EC50 was not significantly different from unity, indicating a relationship between these two parameters. In general for the coronary artery, the ratios were significantly less than unity, indicating no direct relationship. Immunohistochemistry showed expression of 5-HT1B receptors in the medial layer, but did not reveal any obvious difference in 5-HT1B receptor expression between normal and atherosclerotic coronary arteries. The results support the notion that triptans are selective vasoconstrictors of cerebral arteries over coronary arteries and that there is a relationship between vasoconstrictor potency in cerebral arteries and clinically relevant plasma levels. PMID:15853772

Edvinsson, Lars; Uddman, Erik; Wackenfors, Angelica; Davenport, Anthony; Longmore, Jenny; Malmsjö, Malin



5-{2-[4-(2Methyl5-quinolinyl)-1-piperazinyl]ethyl}-2(1 H)-quinolinones and 3,4-dihydro-2(1 H)-quinolinones: Dual-acting 5HT 1 receptor antagonists and serotonin reuptake inhibitors. Part 3  

Microsoft Academic Search

5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT1 autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and

Steven M. Bromidge; Roberto Arban; Barbara Bertani; Manuela Borriello; Anna-Maria Capelli; Romano Di-Fabio; Stefania Faedo; Massimo Gianotti; Laurie J. Gordon; Enrica Granci; Alessandra Pasquarello; Simone K. Spada; Angela Worby; Laura Zonzini; Valeria Zucchelli



Mice with Compromised 5-HTT Function Lack Phosphotyrosine-Mediated Inhibitory Control over Prefrontal 5-HT Responses  

PubMed Central

The activity of the prefrontal cortex is essential for normal emotional processing and is strongly modulated by serotonin (5-HT). Yet, little is known about the regulatory mechanisms that control the activity of the prefrontal 5-HT receptors. Here, we found and characterized a deregulation of prefrontal 5-HT receptor electrophysiological signaling in mouse models of disrupted serotonin transporter (5-HTT) function, a risk factor for emotional and cognitive disturbances. We identified a novel tyrosine kinase-dependent mechanism that regulates 5-HT-mediated inhibition of prefrontal pyramidal neurons. We report that mice with compromised 5-HTT, resulting from either genetic deletion or brief treatment with selective serotonin reuptake inhibitors during development, have amplified 5-HT1A receptor-mediated currents in adulthood. These greater inhibitory effects of 5-HT are accompanied by enhanced downstream coupling to Kir3 channels. Notably, in normal wild-type mice, we found that these larger 5-HT1A responses can be mimicked through inhibition of Src family tyrosine kinases. By comparison, in our 5-HTT mouse models, the larger 5-HT1A responses were rapidly reduced through inhibition of tyrosine phosphatases. Our findings implicate tyrosine phosphorylation in regulating the electrophysiological effects of prefrontal 5-HT1A receptors with implications for neuropsychiatric diseases associated with emotional dysfunction, such as anxiety and depressive disorders. PMID:24760870

Goodfellow, Nathalie M.; Sargin, Derya; Ansorge, Mark S.; Gingrich, Jay A.



Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function.  


Early-life serotonin [5-hydroxytryptamine (5-HT)] signaling modulates brain development, which impacts adult behavior, but 5-HT-sensitive periods, neural substrates, and behavioral consequences remain poorly understood. Here we identify the period ranging from postnatal day 2 (P2) to P11 as 5-HT sensitive, with 5-HT transporter (5-HTT) blockade increasing anxiety- and depression-like behavior, and impairing fear extinction learning and memory in adult mice. Concomitantly, P2-P11 5-HTT blockade causes dendritic hypotrophy and reduced excitability of infralimbic (IL) cortex pyramidal neurons that normally promote fear extinction. By contrast, the neighboring prelimbic (PL) pyramidal neurons, which normally inhibit fear extinction, become more excitable. Excitotoxic IL but not PL lesions in adult control mice reproduce the anxiety-related phenotypes. These findings suggest that increased 5-HT signaling during P2-P11 alters adult mPFC function to increase anxiety and impair fear extinction, and imply a differential role for IL and PL neurons in regulating affective behaviors. Together, our results support a developmental mechanism for the etiology and pathophysiology of affective disorders and fear-related behaviors. PMID:25209278

Rebello, Tahilia J; Yu, Qinghui; Goodfellow, Nathalie M; Caffrey Cagliostro, Martha K; Teissier, Anne; Morelli, Emanuela; Demireva, Elena Y; Chemiakine, Alexei; Rosoklija, Gorazd B; Dwork, Andrew J; Lambe, Evelyn K; Gingrich, Jay A; Ansorge, Mark S



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.



Serotonin decreases aggression via 5-HT1A receptors in the fighting fish Betta splendens.  


The role of the monoamine neurotransmitter serotonin (5-HT) in the modulation of conspecific aggression in the fighting fish (Betta splendens) was investigated using pharmacological manipulations. We used a fish's response to its mirror image as our index of aggressive behavior. We also investigated the effects of some manipulations on monoamine levels in the B. splendens brain. Acute treatment with 5-HT and with the 5-HT1A receptor agonist 8-OH-DPAT both decreased aggressive behavior; however, treatment with the 5-HT1A receptor antagonist WAY-100635 did not increase aggression. Chronic treatment with the selective serotonin reuptake inhibitor fluoxetine caused no significant changes in aggressive behavior and a significant decline in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations. Treatment with the serotonin synthesis inhibitor p-chlorophenylalanine resulted in no change in aggression, yet serotonergic activity decreased significantly. Finally, a diet supplemented with L-tryptophan (Trp), the precursor to 5-HT, showed no consistent effects on aggressive behavior or brain monoamine concentrations. These results suggest a complex role for serotonin in the expression of aggression in teleost fishes, and that B. splendens may be a useful model organism in pharmacological and toxicological studies. PMID:17553555

Clotfelter, Ethan D; O'Hare, Erin P; McNitt, Meredith M; Carpenter, Russ E; Summers, Cliff H



Effect of hemorrhagic shock on 5-hydroxytryptamine removal by the lung  

SciTech Connect

The biogenic amine, radioactive 5-hydroxytryptamine, is removed from the blood during passage through the pulmonary vasculature. After one hour of hemorrhagic shock, the extraction rate increased from 74 to 89 per cent. One and two hours after resuscitation, the lung extracted only 30 per cent of the 5-hydroxytryptamine. The relationship between the pathophysiologic state and altered amine removal is a reflection of prolonged exposure to receptor sites or increased diffusion of serotonin across the endothelium.

Kerstein, M.D.; Cronau, L.H.; Mandel, S.D.; Gillis, C.N.



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



Roles of extracellular ions and pH in 5-HT-induced sperm motility in marine bivalve.  


Factors that inhibit and stimulate the initiation of sperm motility were determined for Manila clam (Ruditapes philippinarum), Pacific oyster (Crassostrea gigas), and Japanese scallop (Patinopecten yessoensis). Compared with artificial seawater (ASW), serotonin (5-hydroxytryptamine creatinine sulfate, 5-HT) could fully trigger sperm motility and increase sperm velocity and motility duration. Sperm motility was decreased in ASW at pH 6.5-7.0 and suppressed at pH 4.0. In Manila clam and Pacific oyster, 5-HT could overcome the inhibitory effects of acidic pH on sperm motility. In the presence of nigericin (a K(+)/H(+) exchanger), sperm motility was only triggered at pH 8.3. Testicular fluid K(+) concentrations were two- to fourfold higher than that in ASW. Sperm motility and velocity were decreased in ASW or 5-HT containing ?40? mM K(+) or ?2.5? mM 4-aminopyridine, suggesting K(+) efflux requirement to initiate motility. Sperm motility and velocity were reduced in ASW or 5-HT containing EGTA or W-7, suggesting that extracellular Ca(2)(+) is required for Ca(2)(+)/calmodulin-dependent flagellar beating. Ca(2)(+) influx occurs via Ca(2)(+) channels because sperm motility and velocity were decreased in both ASW and 5-HT containing T-type and L-type Ca(2)(+) channel blockers. 5-HT-dependent initiation of sperm motility was associated with intracellular Ca(2)(+) rise, which was comparable to that seen in ASW but was not observed in the presence of EGTA or a Ca(2)(+) channel blocker. Extracellular Na(+) is also essential for sperm motility initiation via regulation of Na(+)/Ca(2)(+) exchange. Overall, 5-HT-dependent initiation of sperm motility in marine bivalve mollusks is an osmolality-independent mechanism and regulated by extracellular pH, K(+), Ca(2)(+), and Na(+). PMID:24398874

Alavi, Sayyed Mohammad Hadi; Matsumura, Natsuki; Shiba, Kogiku; Itoh, Naoki; Takahashi, Keisuke G; Inaba, Kazuo; Osada, Makoto



5-Amino-6-chloro-N-[(1-isobutylpiperidin-4-yl)methyl]-2-methylimidazo[1,2-alpha]pyridine-8-carboxamide (CJ-033,466), a novel and selective 5-hydroxytryptamine4 receptor partial agonist: pharmacological profile in vitro and gastroprokinetic effect in conscious dogs.  


5-Hydroxytryptamine (5-HT) receptors and dopamine(2) (D(2)) receptor modulate gastrointestinal motility. Gastroprokinetic agents that act on several 5-HT receptor subtypes and/or D(2) receptors are used clinically. Although the 5-HT(4) receptor is known to mediate the gastroprokinetic effects of these agents, the absence of highly selective 5-HT(4) receptor agonists has made it difficult to confirm the physiological consequences of selective 5-HT(4) receptor stimulation. In this study, we report the in vitro pharmacological profiles and the in vivo gastroprokinetic effects of 5-amino-6-chloro-N-[(1-isobutylpiperidin-4-yl)methyl]-2-methylimidazo[1,2-alpha]pyridine-8-carboxamide (CJ-033,466), a novel, potent, and selective 5-HT(4) partial agonist. Compared with preceding 5-HT(4) agonists such as cisapride, mosapride, and tegaserod, CJ-033,466 had a superior in vitro profile, with nanomolar agonistic activities for the 5-HT(4) receptor and 1000-fold greater selectivity for the 5-HT(4) receptor over other 5-HT and D(2) receptors. In vivo studies in conscious dogs showed that CJ-033,466 dose-dependently stimulated gastric antral motility in both the fasted and postprandial states at the same dose range and that it was 30 times more potent than cisapride. Furthermore, CJ-033,466 accelerated the gastric emptying rate in a gastroparesis dog model at the minimally effective dose established in the gastric motility study. In conclusion, CJ-033,466 is a potent and highly selective 5-HT(4) agonist that stimulates physiologically coordinated gastric motility, and it has no activity on other 5-HT receptor subtypes and D(2) receptors. Therefore, CJ-033,466 could be used to treat gastroparesis, providing better gastroprokinetics and reduced side effects mediated by the other receptors. PMID:18198343

Mikami, Tadayoshi; Ochi, Yasuo; Suzuki, Keiko; Saito, Toshiyuki; Sugie, Yutaka; Sakakibara, Minoru



Hypothermia induced in rabbits by intracerebroventricular taurine: specificity and relationships with central serotonin (5-HT) systems.  


The intracerebroventricular (i.c.v.) injection of taurine produced a fall in core temperature, the extent of which was dependent on the thermal gradient between the body and the environment. Concurrently, a sudden rise in ear skin temperature, which was maximal in the cold and negligible at 30 degrees C, was observed. The fever induced by i.v. injection of Escherichia coli endotoxin was antagonized by taurine. High temperatures produced by i.c.v. injection of prostaglandin E1 were also suppressed by taurine. Intracerebroventricular injections of bicuculline and strychnine, but not those of picrotoxin or pentylentetrazol, were able to reduce hypothermia induced by taurine. Intracerebroventricular injection of the taurine reuptake inhibitor guanidinoethyl sulfonate, on the contrary, did enhance the hypothermic response to taurine. Injection (i.c.v.) of serotonin (5-HT) elicited a fall in core temperature which was not accompanied by a rise in ear skin temperature, but was antagonized by the concurrent injection of the 5-HT antagonist methysergide. Pretreating animals with p-chlorophenyl-alanine caused a significant fall of brain 5-HT contents and a reduction of the hypothermic response to taurine. The latter effect was also observed when the animals were i.c.v. pretreated either the methysergide or with the 5-HT reuptake blockers chlorimipramine and Lilly 110140. These findings give support to the hypothesis that taurine-induced hypothermia in rabbits mediated by some taurine sensitive cells and, at least in part, by serotonergic synaptic mechanisms. PMID:6457908

Sgaragli, G; Carlà, V; Magnani, M; Galli, A



5HT2A and 5HT2B Receptors Contribute to Serotonin-Induced Vascular Dysfunction in Diabetes  

PubMed Central

Although 5HT2A receptors mediate contractions of normal arteries to serotonin (5HT), in some cardiovascular diseases, other receptor subtypes contribute to the marked increase in serotonin contractions. We hypothesized that enhanced contractions of arteries from diabetics to 5HT are mediated by an increased contribution from multiple 5HT receptor subtypes. We compared responses to selective 5HT receptor agonists and expression of 5HT receptor isoforms (5HT1B, 5HT2A, and 5HT2B) in aorta from nondiabetic (ND) compared to type 2 diabetic mice (DB, BKS.Cg-Dock7m+/+Leprdb/J). 5HT, 5HT2A (TCB2 and BRL54443), and 5HT2B (norfenfluramine and BW723C86) receptor agonists produced concentration-dependent contractions of ND arteries that were markedly increased in DB arteries. Neither ND nor DB arteries contracted to a 5HT1B receptor agonist. MDL11939, a 5HT2A receptor antagonist, and LY272015, a 5HT2B receptor antagonist, reduced contractions of arteries from DB to 5HT more than ND. Expression of 5HT1B, 5HT2A, and 5HT2B receptor subtypes was similar in ND and DB. Inhibition of rho kinase decreased contractions to 5HT and 5HT2A and 5HT2B receptor agonists in ND and DB. We conclude that in contrast to other cardiovascular diseases, enhanced contraction of arteries from diabetics to 5HT is not due to a change in expression of multiple 5HT receptor subtypes. PMID:23346101

Nelson, Peter M.; Harrod, Jeremy S.; Lamping, Kathryn G.




PubMed Central

Migraine and anxiety disorders are frequently co-morbid with balance disorders. This study examined the relative distribution of subtypes of serotonin (5-HT) receptor in the inner ear of monkeys and rats. Most vestibular ganglion cells were immunoreactive for 5-HT1B and 5-HT1D receptors in macaques and rats. In the inner ear, 5-HT1B and 5-HT1D receptor immunopositivity was associated with endothelial cells of the vestibular ganglion, spiral ganglion, vestibulocochlear nerve, spiral ligament and stria vascularis. It was noteworthy that 5-HT1B and 5-HT1D receptors are expressed in parallel sites in peripheral vestibular and trigeminal systems, which may be a factor underlying the efficacy of triptans in treating migraine and migrainous vertigo. Because the vestibular ganglion and trigeminal ganglion are both within the subarachnoid space, an interaction between 5-HT1B and TRPV1 receptors on blood vessel and ganglion cells may also contribute to the vasospasm and the comorbid headache, dizziness, nausea and vomiting that accompany subarachnoid hemorrhage. PMID:20510890

Ahn, Seong-Ki; Balaban, Carey D.



Central 5-HT7 receptors are critical for reflex activation of cardiac vagal drive in anaesthetized rats  

PubMed Central

5-Hydroxytryptamine (5-HT; serotonin)-containing neurones contribute to reflex activation of parasympathetic outflow in a number of species, but the 5-HT receptors mediating these effects have yet to be fully determined. The present experiments demonstrate that central 5-HT7 receptors are involved in the vagal bradycardia evoked during the cardiopulmonary reflex, baroreflexes and the chemoreflex, as well as other autonomic changes caused by these reflexes. The experiments examined the effects of the selective 5-HT7 receptor antagonists SB-269970 and SB-656104 on these reflexes. For the cardiopulmonary reflex, when compared to time-matched vehicle control experiments, intracisternal application of SB-269970 (30–300 ?g kg?1, i.c.) dose-dependently attenuated the evoked bradycardia. At the highest dose, SB-269970 also attenuated the reflex hypotension and sympathoinhibition. The structurally different 5-HT7 receptor antagonist SB-656104 (100 ?g kg?1, i.c.) similarly attenuated the reflex bradycardia and hypotension. SB-269970 (100 ?g kg?1, i.c.) also attenuated the bradycardias evoked by electrical stimulation of aortic nerve afferents and the baroreflex evoked by the pressor response to phenylephrine (3–25 ?g kg?1, i.v.). The gain of the baroreflex was also significantly attenuated (0.15 ± 0.06 versus 0.34 ± 0.06 ms mmHg?1). Finally, SB-269970 (100 ?g kg?1, i.c.) significantly attenuated both the bradycardia and sympathoexcitation evoked by the chemoreflex. These data indicate that central 5-HT7 receptors play an important facilitatory role in the reflex activation of vagal outflow to the heart. PMID:15611034

Kellett, Daniel O; Ramage, Andrew G; Jordan, David



Antagonism of serotonergic 5-HT2A/2C receptors: mutual improvement of sleep, cognition and mood?  


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-HT(2A) 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 in healthy human volunteers, a review of the available data suggests that antagonistic interaction with 5-HT(2A) receptors (and possibly also 5-HT(2C) receptors) prolongs the duration of slow wave sleep and enhances low-frequency (< 7 Hz) activity in the sleep electroencephalogram (EEG), a widely accepted marker of sleep intensity. Despite certain differences, the changes in sleep and the sleep EEG appear to be remarkably similar to those of physiologically more intense sleep after sleep deprivation. It is currently unclear whether these changes in sleep are associated with improved vigilance, cognition and mood during wakefulness. While drug-induced interaction with sleep must be interpreted cautiously, too few studies are available to provide a clear answer to this question. Moreover, functional relationships between sleep and waking functions may differ between healthy controls and patients with sleep disorders. A multimodal approach investigating subjective and objective aspects of sleep and wakefulness provides a promising research avenue for shedding light on the complex relationships among 5-HT(2A/2C) receptor-mediated effects on sleep, the sleep EEG, cognition and mood in health and various diseases associated with disturbed sleep and waking functions. PMID:19473234

Landolt, H-P; Wehrle, R



Responsiveness of 5-HT2C receptors in repeatedly diazepam-injected rats: a behavioral and neurochemical study.  


The role of 5-hydroxytryptamine (serotonin; 5-HT)2C receptors in anxiety and the anxiolytic effects of drugs is well documented. In view of the withdrawal anxiety associated with repeated diazepam intake, the present study concerns the efficacy of 5-HT2C receptors in rats treated with diazepam. Results show that diazepam injections at a dose of 2 mg/kg daily for two weeks increased weekly food intake and growth rate. Anxiolytic effects of the drug monitored in a light/dark activity box were not significant after single administration. One week and two weeks of administration elicited anxiolytic effects, which were smaller after two weeks of administration as compared to one week, suggesting the development of tolerance to the anxiolytic profile of diazepam. Moreover, three days' withdrawal from repeated administration elicited anxiogenic behavior in the light/dark activity box. The behavioral and neurochemical effects of 1-(m-chlorophenyl)piperazine (m-CPP) (3 mg/kg), a 5-HT2C agonist, were monitored following withdrawal (three days) from two weeks of diazepam administration. Results showed that hypophagic as well as anxiogenic-like effects of m-CPP were not different from repeated saline or repeated diazepam-injected animals. Administration of m-CPP increased 5-HT metabolism in repeated saline as well as repeated diazepam-injected animals. However, m-CPP-induced increases in 5-HT metabolism were greater in repeated diazepam-injected animals. Results are discussed in the context of the role of 5-HT2C receptors in the precipitation of withdrawal anxiety. PMID:19066419

Khan, Asma; Haleem, Darakhshan J



Ca2+ responses in Chinese hamster ovary-K1 cells demonstrate an atypical pattern of ligand-induced 5-HT1A receptor activation.  


Little experimental evidence has been reported for diverse signaling via 5-hydroxytryptamine (5-HT)1A receptors despite the fact that agonists seem to be more efficacious at dorsal raphe somatodendritic 5-HT1A autoreceptors than at postsynaptic 5-HT1A receptors. The present study investigated Ca2+ responses in Chinese hamster ovary (CHO)-K1 cells expressing a human 5-HT1A receptor by 5-HT, prototypical 5-HT1A agonists, N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methyl-6-; methylaminopyridin-2-yl)-methylaminomethyl]-piperidine (F 14679), and especially N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methylpyridin-2-yl)-; methylaminomethyl]piperidine (F 13640) as representative ligands of a new chemical class (methylamino-pyridine) that combines both high efficacy and selectivity for 5-HT1A receptors. 5-HT (pEC50 = 6.70 +/- 0.02) induced a pertussis toxin-sensitive, transient high-magnitude Ca2+ response. High-magnitude Ca2+ responses (Emax, percentage versus 5-HT) were also found with F 13640 (107 +/- 4), 5-carboxamidotryptamine (100 +/- 3), and F 14679 (87 +/- 3). In contrast, the prototypical 5-HT1A receptor agonists buspirone, ipsapirone, and 8-(hydroxy-2-(di-n-propylamino)tetralin, and also flesinoxan and eptapirone, were virtually inactive (< or =5). This atypical pattern of 5-HT1A receptor activation contrasts with the broad spectrum of the ligands' partial agonist properties as observed by measuring guanosine 5'-O-(3-[35 S]thio)triphosphate ([35S]GTPgammaS) binding responses with membranes of either CHO-K1 or C6-glial cells stably expressing a human 5-HT1A receptor. Remarkably, differences between ligands that seem small in the [35S]GTPgammaS binding assay translate into huge differences in the magnitude of Ca2+ responses. Therefore, some of these 5-HT1A ligands (i.e., F 13640) may in a selective way induce responses that may be not at all be achieved with other ligands (i.e., buspirone). In conclusion, the pharmacology of 5-HT1A receptor ligands seems to be codetermined by the effector pathway. PMID:12970382

Pauwels, Petrus J; Colpaert, Francis C



The use of stereotactic dissection followed by fluorimetric assay, to determine the distribution of noradrenaline, dopamine and 5-hydroxytryptamine in the preoptic hypothalamic area of rabbit brain  

PubMed Central

1 A method of stereotactic dissection followed by fluorimetric assay, has been used to determine the distribution of noradrenaline, dopamine and 5-hydroxytryptamine (5-HT) within the preoptic hypothalamic area of rabbit brain. 2 The method involved subdividing the area into a number of thin slices cut with reference to stereotactic co-ordinates. The amine content of each slice was then determined fluorimetrically. 3 Noradrenaline was shown to be concentrated (>2.0 ?g/g) in two areas within the preoptic hypothalamic area, both of which were adjacent to the mid-saggittal line: the first was close to the preoptic nucleus and the second immediately caudal to the main group of hypothalamic nuclei. 4 Dopamine was evenly distributed throughout the preoptic hypothalamic area. 5 5-HT was concentrated (>1.6 ?g/g) towards the lateral borders of the area, principally in the region which joins the preoptic area to the anterior hypothalamus. 6 The relative merits of the stereotactic approach and the histochemical approach are discussed. PMID:4609531

Metcalf, G.



Characterization of electroencephalographic and biochemical responses at 5-HT promoting drug-induced onset of serotonin syndrome in rats  

PubMed Central

Many psychotropic substances used either for medications or illicit recreational purposes are able to produce an increase in extracellular serotonin (5HT) in the CNS. 5HT is well known to improve mood, however, only when the levels of its release are in an appropriate range. Excessive 5HT is harmful, and will generally result in serotonin syndrome. To date, clinical diagnosis of serotonin syndrome relies exclusively on observation of symptoms because of a lack of available laboratory tests. The goal of the present study was to characterize the onset of the syndrome using laboratory settings to determine excessive 5HT-evoked neurological abnormalities. Experiments were carried out in rats with the syndrome being elicited by three groups of 5HT-promoting drugs: 1) (±)-3,4-methylenedioxymethamphetamine (MDMA); 2) a combination of the monoamine oxidase inhibitor clorgyline with the 5HT precursor 5-hydroxytryptophan; 3) clorgyline combined with the serotonin-selective reuptake inhibitor paroxetine. The onset of the syndrome was characterized by electroencephalography (EEG), tremor and brain/plasma 5HT tests. We found that a mild syndrome was associated with reduced EEG amplitudes while a severe syndrome strongly with seizure-like EEG activity and increased tremor activity. The occurrence of the syndrome was confirmed with microdialysis, showing excessive 5HT efflux in brain dialysate and the increased concentration of unbound 5HT in the plasma. Our findings suggest that the syndrome onset can be revealed with EEG recording, measurements of tremor activity and changes of unbound 5HT concentration in the plasma. PMID:23286698

Ma, Zhiyuan; Rudacille, Mary; Prentice, Howard M.; Tao, Rui



5-Hydroxytryptamine transport in cells and secretory granules from a transplantable rat insulinoma.  


Mechanisms of transport of 5-hydroxytryptamine in the pancreatic B-cell were investigated by using cell suspensions and secretory granules prepared from a transplantable rat insulinoma. (1) Cells incubated with 5-hydroxy[G-3H]tryptamine at concentrations ranging from 0.1 microM to 5 mM accumulated the radioisotope principally by a simple diffusion process. The incorporated radioactivity was recovered principally as the parent molecule and was recovered predominantly in soluble protein and secretory-granule fractions prepared from the tissue. (2) Isolated granules incubated in buffered iso-osmotic medium without ATP accumulated the amine to concentrations up to 38-fold that of the medium. This process was insensitive to reserpine and occurred over a wide range of 5-hydroxytryptamine concentrations (0.075 microM-25 mM). Above 5 mM, 5-hydroxytryptamine accumulation decreased in parallel with the breakdown of the delta pH across the granule membrane. Uptake was favoured by alkaline media and was reduced by the addition of (NH4)2SO4. In both cases a close correlation was observed between uptake and the transmembrane delta pH, a finding that suggested that 5-hydroxytryptamine permeated the membrane as the free base and equilibrated across the membrane with the delta pH. Binding of 5-hydroxytryptamine to granule constituents also played a part in this process. ATP caused a further doubling of granule 5-hydroxytryptamine uptake by a process that was sensitive to reserpine (0.5 microM). Inhibitor studies suggested that amine transport in this instance was linked to the activity of the granule membrane proton-translocating ATPase. (3) It was concluded that the uptake of amines driven by proton gradients across the insulin-granule membrane could account for the accumulation in vivo of amines in the B-cell. PMID:6307272

Hutton, J C; Peshavaria, M; Tooke, N E



The effects of PRX-07034, a novel 5-HT6 antagonist, on cognitive flexibility and working memory in rats  

PubMed Central

Rationale Accumulating evidence indicates that schizophrenia and autism spectrum disorder patients are marked by cognitive deficits in working memory and strategy switching. There is accumulating evidence that 5-hydroxytryptamine (5-HT)6 receptors may serve as a useful target to improve cognitive functioning. Objectives In the present experiments, the novel 5-HT6 antagonist, PRX-07034, was examined for its selectivity of the 5-HT6 receptor, as well as its effect on delayed spontaneous alternation and strategy switching. Methods The binding affinity of PRX-07034 to the 5-HT6 receptor, other 5-HT receptors, as well as other G-protein coupled receptors, ion channels, and transporters was evaluated. Cyclic AMP production was measured from transfected HEK-293 cells. In separate behavioral experiments, rats received different doses of PRX-07034 (0.1, 1, or 3 mg/kg, i.p.) 30 min prior to delayed spontaneous alternation testing or prior to the acquisition and switch phases in a place–response switch test. Results The results indicated that PRX-07034 is both a potent (Ki = 4–8 nM) and highly selective 5-HT6 receptor antagonist (?100-fold selectivity for the 5-HT6 receptor compared to 68 other GPCRs, ion channels, and transporters, except D3 (Ki = 71 nM) and 5-HT1B (Ki = 260 nM) receptors. For cyclic AMP quantification, PRX-07034 demonstrated antagonist activity (IC50 = 19 nM) without an effect on basal levels and did not show any agonist activity up to 10 µM. PRX-07034 at 1 and 3 mg/kg (but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation. The drug at 1 and 3 mg/kg also enhanced switching between a place and response strategy, but did not affect initial learning of either a place or response discrimination. Conclusions These findings demonstrate that PRX-07034 is a selective 5-HT6 receptor antagonist that may represent a novel treatment for enhancing working memory and cognitive flexibility. PMID:21989804

Mohler, Eric G.; Baker, Phillip M.; Gannon, Kimberly S.; Jones, Simon S.; Shacham, Sharon; Sweeney, John A.



Abnormalities of 5-hydroxytryptamine uptake and binding by blood platelets from children with Down's syndrome.  


1. Blood platelets from normal children and children with the trisomy 21 form of Down's syndrome (mongolism) were studied to determine the cause of the well established reduction in platelet 5-HT in the disease.2. Concentrations of endogenous 5-HT in the platelets from mongols were 25.3% of the concentrations found in normal children.3. The net accumulation of 5-HT in the mongol cells was decreased to 52.7% of normal. This reduction was probably due, in part, to a defect in 5-HT transport, because the initial rates of 5-HT uptake at plasma concentrations of 10(-6) and 10(-5)M were significantly slower.4. Experiments on the efflux of 5-HT from mongol platelets loaded with amine showed that the rate of loss was initially 2.6 and later 7.8 times faster than normal.5. Platelet ATP in mongol cells was 26% of normal, and the reduction of ATP and 5-HT was in the molar ratio of 3:1.6. It is considered that the low platelet 5-HT in Down's syndrome is due to a defective 5-HT transport mechanism and impaired 5-HT binding, resulting from a reduction in the essential binding substance, ATP. PMID:4251289

Boullin, D J; O'Brien, R A



Vasomotor Effects of Acetylcholine, Bradykinin, Noradrenaline, 5-Hydroxytryptamine, Histamine and Angiotensin II on the Mouse Basilar Artery  

PubMed Central

ABSTRACT 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-Arg9-[Leu8]-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



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



Associations of the 5-hydroxytryptamine (Serotonin) Receptor 1B Gene (HTR1B) with Alcohol, Cocaine, and Heroin Abuse  

PubMed Central

Abnormal serotonergic pathways are implicated in numerous neuropsychiatric disorders including alcohol and drug dependence (abuse). The human 5-hydroxytryptamine (serotonin) receptor 1B, encoded by the HTR1B (5-HT1B) gene, is a presynaptic serotonin autoreceptor that plays an important role in regulating serotonin synthesis and release. Although there was evidence of associations of the HTR1B gene variants in the etiologies of substance use disorders, negative findings were also reported. To clarify the roles of commonly-reported single nucleotide polymorphisms (SNPs) of the HTR1B gene underlying alcohol and drug dependence (abuse), we performed a meta-analysis based on the available genotype data from individual candidate gene-based association studies. Evidence of association was found between the functional SNP -161A>T (rs130058) and alcohol, cocaine, and heroin dependence (e.g., P = 0.03 and odds ratio = 1.2 (1.02, 1.42) in the combined European, Asian, African, and Hispanic populations). SNP -261T>G (rs11568817) also showed evidence of association but with different directions in Europeans and non-Europeans (e.g., P = 0.0018 with odds ratio = 1.42 (1.14, 1.76) and P = 0.01 with odds ratio = 0.5 (0.3, 0.85), respectively). This meta-analysis supports the associations of HTR1B -261T>G and -161A>T with alcohol and drug abuse and further investigations are warranted in larger samples. PMID:23335468

Cao, Jian; LaRocque, Emily; Li, Dawei



5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. A comparison of their pharmacology and clinical efficacy.  


In the mid-1980s it was discovered that serotonin (5-hydroxytryptamine; 5-HT) was at least partially responsible for producing chemotherapy-induced nausea and vomiting. It was therefore realised that serotonin receptor blockade with serotonin 5-HT3 receptor antagonists could inhibit chemotherapy-induced nausea and vomiting. 5-HT3 antagonists have different chemical structures and receptor binding affinity. Granisetron, dolasetron and its major metabolite are pure 5-HT3 antagonists, while ondansetron and tropisetron are weak antagonists at the 5-HT4 receptor. Ondansetron has also been demonstrated to bind at other serotonin receptors and to the opioid mu receptor. The half-lives of granisetron, tropisetron and the active metabolite of dolasetron are 2 to 3 times longer than that of ondansetron. These observations initially suggested that more frequent ondansetron administration would be required; however, it has now been shown that receptor blockade does not correlate with elimination half-life and all 5-HT3 antagonists can be effectively administered once daily. Clinical trials have been conducted that directly compare the 5-HT3 antagonists. To compare these studies, it is necessary to assess trial design, including known risk factors for the development of chemotherapy-induced nausea and vomiting, and response criteria. Stratification for risk factors, use of strict efficacy criteria and randomisation to a blinded trial using an appropriate comparative regimen are essential for a well designed antiemetic trial. Comparative clinical trials using various doses, routes and regimens of administration have been conducted with 5-HT3 antagonists. Despite some trial design shortcomings, most of the studies show equal efficacy between the agents, especially in moderately emetogenic chemotherapy and mild, infrequently occurring adverse effects. The addition of steroids also appears to improve outcome. However, since many doses and regimens of ondansetron were used, further study is needed to determine the optimal regimen. The efficacy of 5-HT3 antagonists in controlling delayed nausea and vomiting from chemotherapy is less well studied. Further, there is no good scientific rationale for the use of 5-HT3 antagonists in controlling delayed nausea and vomiting since serotonin has not been shown to be released during the delayed phase. In fact, most studies show no benefit or modest benefit of 5-HT3 antagonists over placebo. Because the 5-HT3 antagonists perform similarly in the clinical setting, pharmacological differences do not seem to translate into therapeutic differences. There is also no appreciable difference in the incidence or severity of adverse effects among the 5-HT3 antagonists. Determination of clinical use may then be driven by cost. PMID:9506240

Gregory, R E; Ettinger, D S



Further investigation into the signal transduction mechanism of the 5-HT4-like receptor in the circular smooth muscle of human colon.  


1. The nature of the receptor coupling mechanism of the 5-hydroxytryptamine4 (5-HT4) receptor in the circular smooth muscle of the human colon has been further investigated. 2. 5-HT stimulated cyclic AMP generation and caused a relaxation in a concentration-dependent fashion, with EC50 values of 175.5 and 274.9 nM respectively. DAU 6236 increased cyclic AMP formation and caused a relaxant effect but was a partial agonist relative to 5-HT. 3. The 5-HT4 receptor antagonist, GR 113808, inhibited cyclic AMP formation and relaxation induced by 5-HT with -log Ki values of 9.1 (cyclic AMP) and 8.9 (relaxation) and apparent pA2 values of 9.2 (cyclic AMP) and 9.5 (relaxation). 4. Ondansetron and methysergide failed to inhibit cyclic AMP formation or the relaxation induced by 5-HT. 5. The phosphodiesterase inhibitor, IBMX, produced a concentration-dependent relaxation (EC50 = 30 microM) and at 1 microM it enhanced the 5-HT-induced relaxation producing a leftward shift of the 5-HT concentration-effect curve with a concentration-ratio of 4.1. Rolipram caused a concentration-dependent relaxation (EC50 = 564.8 nM) and at 200 nm caused a leftward shift of the concentration-effect curve to 5-HT with a concentration-ratio of 5.5. 6. Application of the adenylyl cyclase inhibitor, SQ 22536 (0.1 mM), and the protein kinase inhibitors, H7 (100 nM) and H89 (200 nM), inhibited the relaxant effect of 5-HT inducing a rightward shift of the concentration-effect curve with concentration-ratios of 10.1, 2.7 and 4.2 respectively. 7. Forskolin stimulated cyclic AMP production and caused a relaxation. The maximum relaxant effect of forskolin (6 microM, 13.8 +/- 1.9 cm.s) was not significantly different from the maximum relaxant effect of 5-HT (10 microM, 12.7 +/- 4.9 cm.s). However, the cyclic AMP levels stimulated by forskolin (6 microM, 49.3 +/- 6.6 pmol mg-1) were markedly greater than those stimulated by 5-HT (10 microM, 7.6 +/- 2.0 pmol mg-1). 8. In conclusion, these results indicate that the 5-HT4 receptors of the circular smooth muscle of human colon mediate relaxation and inhibition of spontaneous contractions via activation of adenylyl cyclase, formation of cyclic AMP and activation of protein kinase A. PMID:8799582

McLean, P G; Coupar, I M



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.



Effects of the Co-administration of 5HT 1A Receptor Antagonists with an SSRI in Conditioned Fear Stress-Induced Freezing Behavior  

Microsoft Academic Search

The effects of the co-administration of the serotonin (5-HT) 1A receptor antagonists NAN-190 or (+)-WAY100135 with a selective 5-HT reuptake inhibitor (SSRI) citalopram on conditioned fear stress (CFS)-induced freezing behavior, which is the animal model of anxiety, were examined. The inhibitory effects of co-administration of NAN-190 (0.1–10 mg\\/kg) with citalopram on CFS-induced freezing were potent; in particular, at 0.1 and

Shinji Hashimoto; Takeshi Inoue; Tsukasa Koyama



Dissociation of intracellular Ca2+ release and Ca2+ entry response to 5-hydroxytryptamine in cultured canine tracheal smooth muscle cells.  


The relationship between the agonist-sensitive Ca2+ pool and those discharged by the Ca2+ -ATPase inhibitor thapsigargin (TG) were investigated in canine tracheal smooth muscle cells (TSMCs). In fura-2-loaded TSMCs, 5-hydroxytryptamine (5-HT) stimulated a rapid increase in intracellular Ca2+ ([Ca2+]i), followed by a sustained plateau phase that was dependent on extracellular Ca2+. In such cells, TG produced a concentration-dependent increase in [Ca2+]i, which remained elevated over basal level for several minutes and was substantially attenuated in the absence of extracellular Ca2+. Application of 5-HT after TG demonstrated that the TG-sensitive compartment partly overlapped the 5-HT-sensitive stores. Pre-treatment of TSMCs with TG significantly inhibited the increase in [Ca2+]i induced by 5-HT in a time-dependent manner. Similar results were obtained with two other Ca2+ -ATPase inhibitors, cyclopiazonic acid and 2,5-di-t-butylhydroquinone. Although these inhibitors had no effect on phosphoinositide hydrolysis, Ca2+ -influx was stimulated by these agents. These results suggest that depletion of the agonist-sensitive Ca2+ stores is sufficient for activation of Ca2+ influx. Some characteristics of the Ca2+ -influx activated by depletion of internal Ca2+ stores were compared with those of the agonist-activated pathway. 5-HT-stimulated Ca2+ influx was inhibited by La3+, membrane depolarisation, and the novel Ca2+ -influx blocker 1-¿beta-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl¿-1H-imidazole hydrochloride (SKF96365). Likewise, activation of Ca2+ influx by TG also was blocked by La3+, membrane depolarisation, and SKF96365. These results suggest that (1) in the absence of PI hydrolysis, depletion of the agonist-sensitive internal Ca2+ stores in TSMCs is sufficient for activation of Ca2+ influx, and (2) the agonist-activated Ca2+ influx pathway and the influx pathway activated by depletion of the inositol 1,4,5-trisphosphate-sensitive Ca2+ pool are indistinguishable. PMID:9884025

Yang, C M



Diurnal variation in 5-HT1B autoreceptor function in the anterior hypothalamus in vivo: effect of chronic antidepressant drug treatment  

PubMed Central

Intracerebral microdialysis was used to examine the function of the terminal 5-hydroxytryptamine (5-HT) autoreceptor in the anterior hypothalamus of anaesthetized rats at two points in the light phase of the light–dark cycle.Infusion of the 5-HT1A/1B agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU24969) 0.1, 1.0 and 10??M through the microdialysis probe led to a concentration-dependent decrease (49, 56 and 65% respectively) in 5-HT output. The effect of RU24969 (1 and 5??M) was prevented by concurrent infusion of methiothepin (1 and 10??M) into the anterior hypothalamus via the microdialysis probe. Infusion of methiothepin alone (1.0 and 10??M) increased (15 and 142% respectively) 5-HT output.Infusion of RU24969 (5??M) through the probe at mid-light and end-light resulted in a quantitatively greater decrease in 5-HT output at end-light compared with mid-light.Following treatment with either paroxetine hydrochloride (10?mg?kg?1 i.p.) or desipramine hydrochloride (10?mg?kg?1 i.p.) for 21 days the function of the terminal 5-HT1B autoreceptor was more markedly attenuated at end-light.The data show that, as defined by the response to RU24969, the function of the 5-HT1B receptors that control 5-HT output in the anterior hypothalamus is attenuated following chronic desipramine or paroxetine treatment in a time-of-day-dependent manner. PMID:10372820

Sayer, Tamsin J O; Hannon, Serina D; Redfern, Peter H; Martin, Keith F



VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux.  


Recent evidence suggests that 5-hydroxytryptamine (5-HT)(4) receptor activity enhances cognition and provides neuroprotection. Here we report the effects of VRX-03011, a novel partial 5-HT(4) agonist, that is both potent (K(i) approximately 30 nM) and highly selective (K(i) > 5 microM for all other 5-HT receptors tested). In separate experiments, rats received VRX-03011 (0.1-10 mg/kg i.p.) 30 min prior to spontaneous alternation testing in a no-delay or a 30-s delay condition. VRX-03011 (1, 5 and 10 mg/kg, but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation performance while none of the doses enhanced performance in the no-delay test. VRX-03011 (1 and 5 mg/kg) concomitantly enhanced hippocampal acetylcholine output and delayed spontaneous alternation scores compared to that of vehicle controls, but had no effect on hippocampal acetylcholine release under a resting condition. Moreover, suboptimal doses of VRX-03011 and the acetylcholinesterase inhibitor galanthamine combined to enhance memory. VRX-03011 also regulated amyloid precursor protein (APP) metabolism by inducing a concentration-dependent increase in the non-amyloidogenic soluble form of APP (sAPPalpha) with an EC(50) approximately 1--10 nM. VRX-03011 had no effect on contractile properties in guinea pig ileum or colon preparations with an EC(50) > 10 microM and did not alter rat intestinal transit at doses up to 10 mg/kg. These findings suggest that VRX-03011 may represent a novel treatment for Alzheimer's disease that reduces cognitive impairments and provides neuroprotection without gastrointestinal side effects. PMID:17692343

Mohler, Eric G; Shacham, Sharon; Noiman, Silvia; Lezoualc'h, Frank; Robert, Sylvain; Gastineau, Monique; Rutkowski, Joseph; Marantz, Yael; Dumuis, Aline; Bockaert, Joel; Gold, Paul E; Ragozzino, Michael E



Cisplatin impairs fluid and electrolyte absorption in rat small intestine: a role for 5-hydroxytryptamine  

PubMed Central

Background—The antineoplastic drug cisplatin has been widely used for the treatment of cancer in humans but its use has been limited by vomiting and diarrhoea. Cisplatin releases 5-hydroxytryptamine into the gut which is thought to be the major mediator of cisplatin induced vomiting. ?Aim—To determine whether cisplatin affects fluid and electrolyte transport in rat jejunum and whether this change can be modulated by the 5-hydroxytryptamine3 receptor antagonist, ondansetron. ?Methods—Jejunal perfusion in rats in vivo was performed one hour after intraperitoneal cisplatin (5 and 10 mg/kg) administration. The effect of pretreatment with subcutaneous ondansetron 300 µg/kg was investigated. ?Results—Median net fluid absorption after cisplatin 10 mg/kg (67 µl/min/g dry intestinal weight (interquartile range 46 to 100); n = 15) was reduced compared with controls (120 (107to 151) µl/min/g; n = 13; p<0.001). Ondansetron reversed the impairment of jejunal fluid absorption produced by cisplatin to normal (161(130 to 176) µl/min/g; n = 11; p<0.001). Electrolyte movement paralleled fluid movement. Jejunal histological examination of sections from cisplatin treated animals showed villus damage, which was not prevented by pretreatment with ondansetron. ?Conclusion—These findings suggest that diarrhoea during cisplatin therapy may be due to altered fluid transport in the small bowel. The reversal of fluid transport to normal in the presence of a 5-hydroxytryptamine3 receptor antagonist suggests that 5-hydroxytryptamine is a local mediator in the small intestine. ?? Keywords: cisplatin; 5-hydroxytryptamine; rat; ondansetron; small intestine; fluid transport PMID:9895375

Bearcroft, C; Domizio, P; Mourad, F; Andre, E; Farthing, M



Genetic linkage to the serotonin transporter protein and 5HT2A receptor genes excluded in generalized social phobia.  


Social phobia, particularly the generalized form, is strongly familial and frequently comorbid with major depression, panic disorder, and obsessive-compulsive disorder. It has also recently been shown to be responsive to selective serotonin reuptake inhibitors. We conducted a study to determine if generalized social phobia is genetically linked to either of two candidate genes: the serotonin transporter protein (5HTT) gene, or the 5HT2A receptor (5HT2AR) gene. Rates of social phobia (using several phenotype definitions) were ascertained and blood samples obtained from consenting first-degree family members of generalized social phobic probands. 5HT2AR and 5HTT genotyping was performed using the polymerase chain reaction (PCR). Linkage was tested using LINKAGE and GENEHUNTER software. No evidence of linkage was found; power analysis indicated that failure to find linkage was unlikely due to inadequate statistical power. These findings reasonably exclude linkage between generalized social phobia and the 5HTT or 5HT2AR genes in these samples, although modifier effects cannot be ruled out. Other 5HT receptor subtypes or indirect modulatory effects of 5HT on other neurotransmitter systems may be involved. PMID:9925179

Stein, M B; Chartier, M J; Kozak, M V; King, N; Kennedy, J L



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.



Differential effects of centrally-active antihypertensives on 5-HT1A receptors in rat dorso-lateral septum, rat hippocampus and guinea-pig hippocampus.  

PubMed Central

1. The electrophysiological responses elicited by 5-hydroxytryptamine1A-(5-HT1A) receptor agonists in rat and guinea-pig CA1 pyramidal neurones and rat dorso-lateral septal neurones were compared in vitro by use of conventional intracellular recording techniques. 2. In the presence of 1 microM tetrodotoxin (TTX), to prevent indirect effects, 5-HT, N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) and 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT) hyperpolarized the neurones from rat and guinea-pig brain. 3. The hypotensive drug flesinoxan, a selective 5-HT1A receptor agonist, hyperpolarized neurones in all three areas tested; however, another hypotensive agent with high affinity at 5-HT1A-receptors, 5-methyl-urapidil, hyperpolarized only the neurones in rat hippocampus and septum. 4. In guinea-pig hippocampal neurones, 5-methyl-urapidil behaved as a 5-HT1A-receptor antagonist. 5. The relative efficacies (5-HT = 1) of DP-5-CT, 8-OH-DPAT, flesinoxan and 5-methyl-urapidil at the three sites were: rat hippocampus, 1.09, 0.7, 0.5 and 0.24; rat septum, 0.88, 0.69, 0.82 and 0.7; guinea-pig hippocampus, 1.0, 0.69, 0.89 and 0, respectively. 6. It is concluded that the hypotensive agents flesinoxan and 5-methyl-urapidil appear to have different efficacies at 5-HT1A receptors located in different regions of the rodent brain. Whether these regional and species differences arise from receptor plurality or variability in intracellular transduction mechanisms remains to be elucidated. PMID:8012713

Leishman, D. J.; Boeijinga, P. H.; Galvan, M.



Modified receptor internalization upon coexpression of 5-HT1B receptor and 5-HT2B receptors.  


Serotonin 5-HT(2B) receptors are often coexpressed with 5-HT(1B) receptors, and cross-talk between the two receptors has been reported in various cell types. However, many mechanistic details underlying 5-HT(1B) and 5-HT(2B) receptor cross-talk have not been elucidated. We hypothesized that 5-HT(2B) and 5-HT(1B) receptors each affect the others' signaling by modulating the others' trafficking. We thus examined the agonist stimulated internalization kinetics of fluorescent protein-tagged 5-HT(2B) and 5-HT(1B) receptors when expressed alone and upon coexpression in LMTK(-) murine fibroblasts. Time-lapse confocal microscopy and whole-cell radioligand binding analyses revealed that, when expressed alone, 5-HT(2B) and 5-HT(1B) receptors displayed distinct half-lives. Upon coexpression, serotonin-induced internalization of 5-HT(2B) receptors was accelerated 5-fold and was insensitive to a 5-HT(2B) receptor antagonist. In this context, 5-HT(2B) receptors did internalize in response to a 5-HT(1B) receptor agonist. In contrast, co-expression did not render 5-HT(1B) receptor internalization sensitive to a 5-HT(2B) receptor agonist. The altered internalization kinetics of both receptors upon coexpression was probably not due to direct interaction because only low levels of colocalization were observed. Antibody knockdown experiments revealed that internalization of 5-HT(1B) receptors (expressed alone) was entirely clathrin-independent and Caveolin1-dependent, whereas that of 5-HT(2B) receptors (expressed alone) was Caveolin1-independent and clathrin-dependent. Upon coexpression, serotonin-induced 5-HT(2B) receptor internalization became partially Caveolin1-dependent, and serotonin-induced 5-HT(1B) receptor internalization became entirely Caveolin1-independent in a protein kinase Cepsilon-dependent fashion. In conclusion, these data demonstrate that coexpression of 5-HT(1B) and 5-HT(2B) receptors influences the internalization pathways and kinetics of both receptors. PMID:17325130

Janoshazi, Agnes; Deraet, Maud; Callebert, Jacques; Setola, Vincent; Guenther, Silke; Saubamea, Bruno; Manivet, Philippe; Launay, Jean-Marie; Maroteaux, Luc



5Hydroxytryptamine 3-receptor antagonist modulates gallbladder emptying and motilin release induced by erythromycin  

Microsoft Academic Search

In the present study we evaluated the effect of ondansetron (formerly indicated as GR38032F), a potent and selective type-3 5-hydroxytryptamine receptor antagonist, on erythromycin-induced gallbladder emptying and motilin release, as well as gallbladder emptying induced by a regular meal in healthy volunteers. Gallbladder emptying was evaluated by sonography. Ondansetron, at the dose of 0.05 mg\\/kg, significantly reduced (PP<0.001, by ANOVA).

Stefano Fiorucci; Luca Santucci; Antonio Morelli



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 5-HT3 Receptors in the Antidepressant Response  

PubMed Central

Serotonin (5-HT)3 receptors are the only ligand-gated ion channel of the 5-HT receptors family. They are present both in the peripheral and central nervous system and are localized in several areas involved in mood regulation (e.g., hippocampus or prefrontal cortex). Moreover, they are involved in regulation of neurotransmitter systems implicated in the pathophysiology of major depression (e.g., dopamine or GABA). Clinical and preclinical studies have suggested that 5-HT3 receptors may be a relevant target in the treatment of affective disorders. 5-HT3 receptor agonists seem to counteract the effects of antidepressants in non-clinical models, whereas 5-HT3 receptor antagonists, such as ondansetron, present antidepressant-like activities. In addition, several antidepressants, such as mirtazapine, also target 5-HT3 receptors. In this review, we will report major advances in the research of 5-HT3 receptor's roles in neuropsychiatric disorders, with special emphasis on mood and anxiety disorders.

Betry, Cecile; Etievant, Adeline; Oosterhof, Chris; Ebert, Bjarke; Sanchez, Connie; Haddjeri, Nasser



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.



A comparative study of functional 5-HT4 receptors in human colon, rat oesophagus and rat ileum.  


1. The pharmacological properties of 5-hydroxytryptamine (5-HT), the 5-HT4 receptor agonists, DAU 6236 and SC 53116 and the 5-HT4 receptor antagonist, GR 1130808, were studied in the rat oesophagus, rat ileum and human colon. 2. 5-HT relaxed the longitudinal muscle of the rat oesophagus and rat ileum and the circular muscle of the human colon. Absolute values of relaxation were measured and showed the order of the maximum responses, rat oesophagus > human colon > rat ileum with EC50 values of 189 +/- 15 nM, 157 +/- 4 nM, 306 +/- 72 nM, respectively. 5-HT also inhibited the spontaneous contractions of the human colon with an EC50 value of 119 +/- 1 nM. The effect of 5-HT on the human colon was not affected by methysergide (10 microM) or ondansetron (1 microM). 3. The use of the uptake and metabolism inhibitors, cocaine (30 microM) and pargyline (100 microM), did not increase the potency of 5-HT in the rat oesophagus or human colon. In the rat oesophagus, cocaine (30 microM) produced a reduction in carbachol-induced tone of 22.2 +/- 0.6% and reduced the 5-HT maximum effect by 52.0 +/- 0.4%. 4. The compounds, DAU 6236 and SC 53116, showed a different pattern of potencies and efficacies in the rat oesophagus, rat ileum and human colon compared to 5-HT. DAU 6236 relaxed the human colonic circular muscle with an EC50 value of 129 +/- 16 nM but its efficacy was less than that of 5-HT. DAU 6236 (1 microM) also antagonized the 5-HT-induced relaxation of the human colon with a dose-ratio of 9.9. In the rat oesophagus and rat ileum, DAU 6236 was inactive in the majority of tissues. In the minority of oesophagus tissues that did respond the EC50 value was 1.2 +/- 0.7 microM. DAU 6236 also antagonized the effect of 5-HT in the rat oesophagus in a non-surmountable fashion. SC 53116 relaxed the rat oesophagus with an EC50 value of 91 +/- 4 nM, with an efficacy less than that observed to 5-HT; however, at 200 nM it did not antagonize the 5-HT-induced relaxation of the rat oesophagus. SC 53116 showed no agonist activity in the rat ileum and human colon, but at 1 microM it did antagonize the effect of 5-HT in the human colon with a dose-ratio of 11.3 +/- 0.3. 5. GR 113808 competitively antagonized the 5-HT4 receptor-mediated relaxation of the rat oesophagus with a pA2 value of 8.59 (8.18-9.00) against 5-HT and 9.05 (8.79-9.31) against SC 53116. GR 113808(0.01 microM) also antagonized the 5-HT-induced relaxation of human colonic circular muscle with an apparent pA2 value of 9.02 +/- 0.12. However at 1 microM the apparent pA2 value was significantly lower than that measured at 0.01 and 0.1 microM. GR 113808 (0.01 microM) antagonized the 5-HT4 receptor-mediated relaxation of the rat ileum with an apparent pA2 value of 9.30 +/- 0.21.6. In conclusion, these studies have shown that the human colon, rat oesophagus and rat ileum contain functional 5-HT4 receptors. However, the 5-HT4 receptor agonists displayed differences in these tissues making it necessary to be cautious when extrapolating from animal to human tissue. This emphasizes the importance of the use of human tissue in the development of therapeutic drugs. PMID:7647983

McLean, P G; Coupar, I M; Molenaar, P



5-HT modulation by acute tryptophan depletion of human instrumental contingency judgements  

PubMed Central

Introduction The concept of ‘depressive realism’, that depression leads to more accurate perception of causal control, has been influential in the field of depression research, but remains controversial. Recent work testing contingency learning has suggested that contextual processing might determine realism-like effects. Serotonin (5-hydroxytryptamine, (5-HT)), which is implicated in the pathophysiology of depression, might also influence contextual processing. Using acute tryptophan depletion (ATD), we tested the hypothesis that dysfunctional serotoninergic neurotransmission influences contingency judgements in dysphoric subjects via an effect on contextual processing. Materials and methods We employed a novel contingency learning task to obtain separate measures (ratings) of the causal effect of partcipants’ responses and efficacy of the background context over an outcome. Participants, without a history of depression, completed this task on and off ATD in a double-blind, placebo-controlled, within-subjects design. Results As with other work on contingency learning, the effects of ATD were related to baseline mood levels. Although no overall effects of ATD were observed, the subgroup of participants with low Beck depression inventory (BDI) scores showed reduced ratings of contextual control and improved accuracy of contingency judgements under positive contingencies following ATD, compared to placebo. High BDI participants demonstrated low accuracy in contingency judgements, regardless of serotoninergic status. Conclusions No effect of ATD on contingency judgements was observed in the group as a whole, but effects were observed in a subgroup of participants with low BDI scores. We discuss these data in light of the context processing hypothesis, and prior research on 5-HT and depressive realism. Electronic supplementary material The online version of this article (doi:10.1007/s00213-010-1934-4) contains supplementary material, which is available to authorized users. PMID:20631992

Crockett, Molly J.; Msetfi, Rachel M.; Murphy, Robin A.; Clark, Luke; Sahakian, Barbara J.; Robbins, Trevor W.



Increased tissue concentrations of 5-hydroxytryptamine in the duodenal mucosa of patients with coeliac disease.  

PubMed Central

Tissue concentrations of 5-HT have been measured in the duodenal mucosa of adults and children with coeliac disease and were found to be significantly higher than those from a control group. This finding may be associated with hyperactivity or hyperplasia of enterochromaffin (EC) cells in the duodenum of patients with coeliac disease and could also be directly related to described abnormalities of 5-HT metabolism in this disease. PMID:590848

Challacombe, D N; Dawkins, P D; Baker, P



Involvement of 5HT3 Receptors in Anti-Inflammatory Effects of Tropisetron on Experimental TNBS-Induced Colitis in Rat  

PubMed Central

Introduction: There is a pressing need for research leading to the development of new effective drugs with lower side effects and more efficacy for treating inflammatory bowel disease (IBD). The analgesic and anti-inflammatory properties of 5-Hydroxytryptamine (5-HT)-3 receptor antagonists have been shown in in vivo and in vitro studies. The present study was designed to investigate the effects of tropisetron, a 5-HT3 receptor antagonist, on an immune-based animal model of IBD. Methods: In the present study, the trinitrobenzenesulfonic acid (TNBS) model of colitis in the rat was used. Two hours after induction of colitis in rats, tropisetron (2 mg/kg), dexamethasone (1 mg/kg), meta-chlorophenylbiguanide (mCPBG, 5 mg/kg), a 5-HT3 receptor agonist, or tropisetron + mCPBG were intraperitoneally (i.p.) administrated for 6 days. Animals were then sacrificed; macroscopic, histological, biochemical (myeloperoxidase [MPO]) assessments and ELISA test (tumor necrosis factor-alpha, interleukin-6 and interleukin-1 beta) were performed on distal colon samples. Results: Tropisetron or dexamethasone treatment significantly reduced macroscopic and microscopic colonic damages. In addition, a significant reduction in MPO activity and colonic levels of inflammatory cytokines was seen. The beneficial effects of tropisetron were antagonized by concurrent administration of mCPBG. Conclusion: The present study indicates that the protective effects of tropisetron on TNBS-induced colitis can be mediated by 5-HT3 receptors. PMID:24455480

Motavallian, Azadeh; Minaiyan, Mohsen; Rabbani, Mohammad; Andalib, Sasan; Mahzouni, Parvin



Cell-specific coupling of the cloned human 5-HT1F receptor to multiple signal transduction pathways.  


We recently described the cloning of a fifth member of the 5-hydroxytryptamine (5-HT)1 (serotonin1) receptor class that inhibits adenylyl cyclase, namely the human 5-HT1F receptor (Adham et al. 1993a). In the present study we have examined in greater detail the functional coupling of the 5-HT1F receptor in two different cell lines, NIH-3T3 and LM(tk-) fibroblasts (receptor densities of 1.7 and 4.4 pmol/mg protein, respectively). The maximal inhibitory response elicited by 5-HT was significantly greater in NIH-3T3 as compared to LM(tk-) cells, whereas the EC50 values were comparable. To investigate the relationship between receptor occupancy and inhibition of cAMP accumulation mediated by 5-HT1F receptors in NIH-3T3 cells (and hence the degree of receptor reserve), we used the irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). The half-maximal response required only about 10% receptor occupancy, consistent with a receptor reserve of 90% (88 +/- 2.1%, n = 4) for 5-HT-induced inhibition of FSCA. Despite the presence of such a high degree of receptor reserve, a range of intrinsic activities was displayed by structurally diverse classes of compounds. For example, sumatriptan and lysergol were as efficacious as 5-HT itself and thus acted as full agonists, whereas metergoline and 1-NP behaved as partial agonists and as shown previously (Adham et al. 1993a), methiothepin was a silent antagonist (Kb = 438 nM). We have also investigated activation of additional signal transduction pathways by the 5-HT1F receptor and found that the responses differ in the two cell lines with respect to stimulation of phospholipase C. For example, in NIH-3T3 cells no elevation of inositol phosphates (IP) of [Ca2+]i was observed even at very high agonist concentrations (100 microM). In contrast, in LM(tk-) cells concentrations of 5-HT as low as 10 nM induced stimulation of IP and a rapid increase of [Ca2+]i. The 5-HT1F receptor failed to alter arachidonic acid release in either cell line. The maximal increase in IP accumulation in LM(tk-) cells was modest, averaging about 100% above basal. The increases of IP and [Ca2+]i required 5-HT concentrations less than one order of magnitude greater than those inhibiting FSCA (EC50 = 17, 55 and 8 nM, respectively), and both responses were blocked by 100 microM methiothepin. All three responses (cAMP, IP, and [Ca2+]i) were sensitive to pertussis toxin pre-treatment, suggesting the involvement of Gi/Go protein(s) in these signal transduction pathways.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:8133900

Adham, N; Borden, L A; Schechter, L E; Gustafson, E L; Cochran, T L; Vaysse, P J; Weinshank, R L; Branchek, T A



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



Estradiol-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the hypothalamus is independent of estrogen receptor-beta  

PubMed Central

Summary Estradiol regulates serotonin 1A(5-HT1A) receptor signaling. Since desensitization of 5-HT1A receptors may be an underlying mechanism by which selective serotonin reuptake inhibitors (SSRIs) mediate their therapeutic effects and combining estradiol with SSRIs enhances the efficacy of the SSRIs, it is important to determine which estrogen receptors are capable of desensitizating 5-HT1A receptor function. We previously demonstrated that selective activation of the estrogen receptor, GPR30, desensitizes 5-HT1A receptor signaling in rat hypothalamic paraventricular nucleus(PVN). However, since estrogen receptor beta(ER?), is highly expressed in the PVN, we investigated the role of ER? in estradiol-induced desensitization of 5-HT1A receptor signaling. We first showed that a selective ER? agonist, diarylpropionitrile(DPN) has a 100-fold lower binding affinity than estradiol for GPR30. Administration of DPN did not desensitize 5-HT1A receptor signaling in rat PVN as demonstrated by agonist-stimulated hormone release. Second, we used a recombinant adenovirus containing ER? siRNAs to decrease ER? expression in the PVN. Reductions in ER? did not alter the estradiol-induced desensitization of 5-HT1A receptor signaling in oxytocin cells. In contrast, in animals with reduced ER?, estradiol administration, instead of producing desensitization, augmented the ACTH response to a 5-HT1A agonist. Combined with the results from the DPN treatment experiments, desensitization of 5-HT1A receptor signaling does not appear to be mediated by ER? in oxytocin cells, but that ER?, together with GPR30, may play a complex role in central regulation of 5-HT1A-mediated ACTH release. Determining the mechanisms by which estrogens induce desensitization may aid in the development of better treatments for mood disorders. PMID:20138435

Rossi, Dania V.; Dai, Ying; Thomas, Peter; Carrasco, Gonzalo A.; DonCarlos, Lydia L.; Muma, Nancy A.; Li, Qian



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



Acute and subchronic toxicities of QX100626, a 5-HT4 receptor agonist, in rodents and Beagle dogs.  


Serotonin 5-hydroxytryptamine 4(5-HT4) receptor agonists have been widely prescribed as a prokinetics drug for patients with gastro-esophageal reflux disease and functional dyspepsia. QX100626, one of the 5-HT4 receptor agonists, has been studied as a promising agent for this clinical use. The objective of the present study was to identify possible target organs of toxicity and propose a non-toxic dose of QX100626 for clinical usage. After single lethal dose oral and intravenous testing in rodents, some signs indicative of adverse CNS effects were observed. The minimum toxic dose of QX100626 for a single oral administration for dogs was 90.0mg/kgb.w., and the severe toxic dose was more than 300mg/kgb.w. The No Observed Adverse Effect Level (NOAEL) of QX100626 by daily oral administration for rats and dogs was 20mg/kg and 10mg/kg, respectively, whereas the minimum toxic dosages were 67 and 30mg/kg, respectively. All of the adverse effects suggested that kidney, digestive tract, as well as nervous, hematological, and respiratory systems might be the target organs of toxicity for humans induced by QX100626. The compound could be a safe alternative to other existing prokinetic agents for the treatment of functional bowel disorders. PMID:25108057

Zhang, Xiaofang; Yuan, Bojun; Mao, Yu; Dai, Xiaoyu; Zhang, Xiaodong; Lu, Guocai



5HT 1A receptor antagonists and lordosis behavior  

Microsoft Academic Search

In proestrous rats, serotonin 1A (5-HT1A) receptor agonists inhibit lordosis behavior within 5–15 min following infusion into the ventromedial nucleus of the hypothalamus (VMN). In the present report, the lordosis-inhibiting effects of the 5-HT1A agonist [(±) 8-hydroxy-2-(di-n-propylamino) tetralin) (8-OH-DPAT] were shown to be attenuated with 5-HT1A receptor antagonists. Two compounds, propranolol and pindolol, that function as both ?-adrenergic and 5-HT1A

Lynda Uphouse; Martha Andrade; Marjay Caldarola-Pastuszka; Astra Jackson



Role of the N-terminal region in G protein-coupled receptor functions: negative modulation revealed by 5-HT2B receptor polymorphisms.  


The putative role of the N-terminal region of rhodopsin-like 7 transmembrane biogenic amine receptors in agonist-induced signaling has not yet been clarified despite recent advances in 7 transmembrane receptor structural biology. Given the existence of N-terminal nonsynonymous polymorphisms (R6G;E42G) within the HTR2B gene in a drug-abusing population, we assessed whether these polymorphisms affect 5-hydroxytryptamine 2B (5-HT2B) receptor in vitro pharmacologic and coupling properties in transfected COS-7 cells. Modification of the 5-HT2B receptor N terminus by the R6G;E42G polymorphisms increases such agonist signaling pathways as inositol phosphate accumulation as assessed by either classic or operational models. The N-terminal R6G;E42G mutations of the 5-HT2B receptor also increase cell proliferation and slow its desensitization kinetics compared with the wild-type receptor, further supporting a role for the N terminus in transduction efficacy. Furthermore, by coexpressing a tethered wild-type 5-HT2B receptor N terminus with a 5-HT2B receptor bearing a N-terminal deletion, we were able to restore original coupling. This reversion to normal activity of a truncated 5-HT2B receptor by coexpression of the membrane-tethered wild-type 5-HT2B receptor N terminus was not observed using a membrane-tethered 5-HT2B receptor R6G;E42G N terminus. These data suggest that the N terminus exerts a negative control over basal as well as agonist-stimulated receptor activity that is lost in the R6G;E42G mutant. Our findings reveal a new and unanticipated role of the 5-HT2B receptor N terminus as a negative modulator, affecting both constitutive and agonist-stimulated activity. Moreover, our data caution against excluding the N terminus and extracellular loops in structural studies of this 7 transmembrane receptor family. PMID:24174497

Belmer, Arnauld; Doly, Stephane; Setola, Vincent; Banas, Sophie M; Moutkine, Imane; Boutourlinsky, Katia; Kenakin, Terry; Maroteaux, Luc



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


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 Ca(2+) 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



A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT1A Receptor Binding in Humans  

PubMed Central

In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [ 11C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT1A receptor gene, the influence of the common SNP [(?1018) C>G] on 5-HT1A receptor expression was examined in a group of 35 healthy individuals scanned with [ 11C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT1A receptor density. Whereas, the 5-HT1A receptor genotype did not show any significant effects on [ 11C]WAY 100635 binding, 5-HT1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT1A receptor gene, affects 5-HT1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states. PMID:15758168

David, Sean P.; Murthy, Naga Venkatesha; Rabiner, Eugenii A.; Munafo, Marcus R.; Johnstone, Elaine C.; Jacob, Robyn; Walton, Robert T.; Grasby, Paul M.



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



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.



5-Hydroxytryptamine Type 3 Receptor Modulates Opioid-induced Hyperalgesia and Tolerance in Mice  

PubMed Central

Background Opioid-induced hyperalgesia (OIH) and tolerance are challenging maladaptations associated with opioids in managing pain. Recent genetic studies and the existing literature suggest the 5-hydroxy tryptamine type 3 (5-HT3) receptor participates in these phenomena. The location of the relevant receptor populations and the interactions between the 5-HT3 system and other systems controlling OIH and tolerance have not been explored, however. We hypothesized that 5-HT3 receptors modulate OIH and tolerance, and that this modulation involves the control of expression of multiple neurotransmitter and receptor systems. Methods C57BL/6 mice were exposed to a standardized 4-day morphine administration protocol. The 5-HT3 antagonist ondansetron was administered either during or after the conclusion of morphine administration. Mechanical testing was used to quantify OIH, and thermal tail flick responses were used to measure morphine tolerance. In other experiments spinal cord and dorsal root ganglion tissues were harvested for analysis of messenger RNA levels by real-time polymerase chain reaction or immunochemistry analysis. Results The results showed 1) Systemic or intrathecal injection of ondansetron significantly prevented and reversed OIH, but not local intraplantar injection. 2) Systemic or intrathecal injection of ondansetron prevented and reversed tolerance, and 3) Ondansetron blocked morphine induced increases of multiple genes -relevant to OIH and tolerance in dorsal root ganglion and spinal cord. Conclusions Morphine acts via a 5-HT3 dependent mechanism to support multiple maladaptations to the chronic administration of morphine. Furthermore, the use of 5-HT3 receptor antagonists may provide a new avenue to prevent or reverse OIH and tolerance associated with chronic opioid use. PMID:21368652

Liang, De-Yong; Li, XiangQi; Clark, J. David



Tryptamine transport in rat brain slices: A comparison with 5-hydroxytryptamine  

Microsoft Academic Search

The uptake of [14C]tryptamine (14C-T) and [3H]serotonin (3H-5HT) into slices of rat hypothalamus (HT), fronto-parietal cortex (CX), and caudate nucleus (Cau) has been investigated. In all three brain areas, the uptake of3H-5HT at 37°C was much greater than that in an ice-bath at 1.0–1.5°C. In contrast, the uptake of14C-T at 37°C was not much greater than uptake at 1.0–1.5°C. While

Lillian E. Dyck



Phospholipase A2 and protein kinase C contribute to myofilament sensitization to 5-HT in the rabbit mesenteric artery.  

PubMed Central

1. Calcium (Ca2+, 0.1-100 microM) stimulated concentration-dependent contractions in small strips from the rabbit mesenteric artery in which the smooth muscle cells had been permeabilized with Staphylococcus aureus alpha-toxin. 2. 5-Hydroxytryptamine (5-HT) and phenylephrine, each in the presence of 10 microM guanosine 5'-triphosphate (GTP), concentration-dependently stimulated additional contractions in strips sub-maximally contracted by the presence of a buffered concentration of calcium (0.3 microM). All the additional contraction was abolished with the selective inhibitor of protein kinase C, Ro 31-8220 (10 microM). 3. Quinacrine (10-50 microM), an inhibitor of phospholipase A2, selectively inhibited the sensitization to 5-HT, but did not alter the sensitization to either phenylephrine or GTP. 4. Myofilament sensitization to calcium was mimicked by exogenous arachidonic acid (300 microM, in the presence of indomethacin, miconazole and BW755c) and the stable analogue of arachidonic acid, 5,8,11,14-eicosatetrayonic acid (ETYA, 100 microM), and in both cases did not require the additional presence of GTP. Ro 31-8220, but not quinacrine, reduced the sensitization to arachidonic acid by around 30%. 5. These results indicate that G protein-linked myofilament sensitization to calcium in the mesenteric artery that follows the activation of 5-HT receptors, but not alpha 1-receptors, involves phospholipase A2. The sensitization stimulated by each of these different receptors, and a component of the response to arachidonic acid, also appears to involve the activation of protein kinase C. PMID:8866867

Parsons, S J; Sumner, M J; Garland, C J



5-HT stimulation of heart rate in Drosophila does not act through cAMP as revealed by pharmacogenetics.  


The fruit fly, Drosophila melanogaster, is a good experimental organism to study the underlying mechanism of heart rate (HR) regulation. It is already known that many neuromodulators (serotonin, dopamine, octopamine, acetylcholine) change the HR in Drosophila melanogaster larvae. In this study, we investigated the role of cAMP-PKA signaling pathway in HR regulation and 5-HT positive chronotropic action. In order to obtain insight into the 5-HT mechanism of action in larvae cardiomyocytes, genetic and pharmacological approaches were used. We used transgenic flies that expressed the hM4Di receptor [designer receptors exclusively activated by designer drugs (DREADDs)] as one tool. Our previous results showed that activation of hM4Di receptors (modified muscarinic acetylcholine receptors) decreases or arrests the heart from beating. In this study, it was hypothesized that the positive chronotropic effect of serotonin [5-hydroxytryptamine (5-HT)] are mediated by serotonin receptors coupled to the adenylyl cyclase pathway and downstream cAMP and PKA activity. Activation of hM4Di by clozapine-N-oxide (CNO) was predicted to block the effects of serotonin by inhibiting adenylyl cyclase activity through G?i pathway activation. Interestingly, we found here that manipulation of adenylyl cyclase activity and cAMP levels had no significant effect on HR. The ability of hM4Di receptor activation to slow or stop the heart is therefore likely mediated by activation of GIRK channels to produce hyperpolarization of cardiomyocytes, and not through inhibition of adenylyl cyclase. PMID:24092690

Majeed, Zana R; Nichols, Charles D; Cooper, Robin L



Effects of venlafaxine on extracellular 5-HT, dopamine and noradrenaline in the hippocampus and on peripheral hormone concentrations in the rat in vivo.  


The purpose of the present study was to study the effect of an acute dose of the serotonin (5-HT) - noradrenaline (NA) reuptake inhibitor venlafaxine on extracellular concentrations of 5-HT, NA and dopamine (DA) in the hippocampus and on the peripheral hormone concentrations in freely moving rats. Blood obtained from a catheter placed in the vena femoralis was analyzed for adrenocorticotropin (ACTH), beta-endorphins, prolactin (PRL), growth hormone (GH) and cortisol. Collections are referred to pre and post injection of 20 mg/kg of venlafaxine. Extracellular hippocampal NA and 5-HT as determined with in vivo microdialysis increased significantly after drug injection. PRL and ACTH were significantly affected by the drug. At the selected dose venlafaxine is able to increase the release of 5-HT but also of NA in rat hippocampus. Due to the dual reuptake properties of the drug and the functional interconnection of the NA and the 5-HT systems, the observed effects on peripheral hormones are possibly mediated by a combined action of these 2 systems. PMID:12954452

Piacentini, M F; Clinckers, R; Meeusen, R; Sarre, S; Ebinger, G; Michotte, Y



Fluoxetine potentiation of methylphenidate-induced gene regulation in striatal output pathways: Potential role for 5-HT1B receptor.  


Drug combinations that include the psychostimulant methylphenidate plus a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine are increasingly used in children and adolescents. For example, this combination is indicated in the treatment of attention-deficit/hyperactivity disorder and depression comorbidity and other mental disorders. Such co-exposure also occurs in patients on SSRIs who use methylphenidate as a cognitive enhancer. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone can produce gene regulation effects that mimic addiction-related gene regulation by cocaine, consistent with its moderate addiction liability. We have previously shown that combining SSRIs with methylphenidate potentiates methylphenidate-induced gene regulation in the striatum. The present study investigated which striatal output pathways are affected by the methylphenidate + fluoxetine combination, by assessing effects on pathway-specific neuropeptide markers, and which serotonin receptor subtypes may mediate these effects. Our results demonstrate that a 5-day repeated treatment with fluoxetine (5 mg/kg) potentiates methylphenidate (5 mg/kg)-induced expression of both dynorphin (direct pathway marker) and enkephalin (indirect pathway). These changes were accompanied by correlated increases in the expression of the 5-HT1B, but not 5-HT2C, serotonin receptor in the same striatal regions. A further study showed that the 5-HT1B receptor agonist CP94253 (3-10 mg/kg) mimics the fluoxetine potentiation of methylphenidate-induced gene regulation. These findings suggest a role for the 5-HT1B receptor in the fluoxetine effects on striatal gene regulation. Given that 5-HT1B receptors are known to facilitate addiction-related gene regulation and behavior, our results suggest that SSRIs may enhance the addiction liability of methylphenidate by increasing 5-HT1B receptor signaling. PMID:25218038

Van Waes, Vincent; Ehrlich, Sarah; Beverley, Joel A; Steiner, Heinz



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


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; Schaik, Ron van; Olivier, Berend; Waldinger, Marcel D



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



Antisense Inhibition of 5-Hydroxytryptamine2a Receptor Induces an Antidepressant-Like Effect in Mice  

E-print Network

include tricyclics, SSRIs, monoamine oxidase inhibitors, and atypical antidepressants such as mi- anserin transport; and monoamine oxidase inhibitors prevent the inactivation of monoamines. These drugs can be considered indirect ago- nists because they increase the availability of monoamines, especially 5-HT

Sibille, Etienne


Characteristics of a 5-hydroxytryptamine-sensitive adenylate cyclase in intact and intracellularly perfused squid axons.  

PubMed Central

1. Cyclic AMP metabolism was studied in intact and intracellularly perfused axons. 2. Cyclic AMP content of intact axons lay within the range 10-100 nmol kg-1 axoplasm. This was increased by exposure to caffeine (2-fold) and to 5-HT (15-fold). The caffeine-sensitive cyclic AMP increase was 30-fold larger in the presence of 5-HT. 3. A reduction in sodium concentration from the sea water bathing intact axons attenuated the 5-HT-evoked increase in cyclic AMP content, but had little effect on resting cyclic AMP. This effect was partially reversed by exclusion of external calcium, and suggests that free calcium plays a role in cyclic AMP homeostasis. 4. Prolonged exposure of intact axons to 5-HT (up to 3 h) led to apparent desensitization of the cyclic AMP response. 5. Intracellular perfusion can be used as a method to study adenylate cyclase in a single axon, simply by measuring the cyclic AMP content of the emerging perfusate. 6. Intracellular perfusion revealed micromolar requirements for internal GTP (K0.5 approximately 1-10 microM) and external 5-HT (K0.5 approximately 1-10 microM); a detailed investigation of this observation was limited due to the progressive loss of 5-HT-evoked adenylate cyclase activity with time. This slow loss was not seen during Gpp(NH)p (guanylylimidodiphosphate), NaF or forskolin activation of cyclase activity. 7. In perfused axons, an increase in intracellular calcium stimulated cyclase activated by 100 microM-forskolin but inhibited cyclase activated by 500 microM-Gpp(NH)p or 10 mM-NaF. A reduction in intracellular magnesium from 10 to 4-5 mM attenuated the effects of 5-HT-evoked cyclase activity. 8. Study of the perfused axon allows characterization of the intracellular requirements of a plasmalemmal transduction system which activates adenylate cyclase, whilst maintaining ionic asymmetry across the cell membrane. PMID:2561784

Allen, T J



Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular 5-HT in the frontal cortex of freely moving rats  

PubMed Central

Evidence has recently suggested that NMDA receptors may play a role in the aetiology and possible treatment of depression and that weak noncompetitive NMDA receptor antagonists such as amantadine can synergize with conventional antidepressants in a model of the illness. To try to obtain a neurochemical rationale for these findings, we have studied the effects of acute and chronic administration of amantadine or the related drug budipine on cortical release of 5-hydroxytryptamine (5-HT) following the antidepressants reboxitine (REB), paroxetine (PAROX) and clomipramine (CLOM) in freely moving rats by using microdialysis. Acute administration of amantadine (40?mg?kg?1), budipine (10?mg?kg?1), REB (10?mg?kg?1), PAROX (10?mg?kg?1) or CLOM (10?mg?kg?1) all failed to significantly alter extracellular 5-HT in the cortex. However, when either amantadine or budipine was administered 30?min prior to any of the three antidepressants, a significant rise in 5-HT was observed. For chronic studies, the effects of the drugs were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular 5-HT at any time point. The three antidepressant drugs all elicited a gradual increase in 5-HT, which became significant after 14 days and tended to plateau thereafter. When either amantadine (20?mg?kg?1) or budipine (5?mg?kg?1) was coadministered with any of the three antidepressants, two differences were seen compared with the effects of the antidepressants alone. Firstly, the time required for significant increases in cortical 5-HT was reduced with elevated levels now being observed by 7 days. Secondly, the absolute magnitude of the increase in extracellular 5-HT was markedly greater in these rats from day 7 until the end of the experiment. If, as is widely considered, an increase in extracellular 5-HT represents a critical step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants as well as possibly enhance their efficacy. PMID:15834446

Owen, Jenny C E; Whitton, Peter S



The role of central 5-HT3 receptors in vagal reflex inputs to neurones in the nucleus tractus solitarius of anaesthetized rats  

PubMed Central

Brainstem 5-hydroxytryptamine (5-HT, serotonin)-containing neurones modulate cardiovascular reflex responses but the differing roles of the many 5-HT receptors have not been thoroughly investigated. The present experiments on anaesthetized rats investigated the role of 5-HT3 receptors in modulating vagal afferent evoked activity of nucleus tractus solitarius (NTS) neurones. Recordings were made from 301 NTS neurones receiving an input at long (> 20 ms) minimum onset latency from stimulation of the vagus nerve. These included 140 neurones excited by activating non-myelinated cardiopulmonary afferents by right atrial injection of phenylbiguanide (PBG). Ionophoretic application of PBG, a highly selective 5-HT3 receptor agonist, significantly increased activity (from 2.4 ± 0.4 to 5.5 ± 0.8 spikes s?1) in 96 of 106 neurones tested and in all 17 neurones tested the increase in activity (3.4 ± 1.1 to 7.0 ± 1.9 spikes s?1) was significantly attenuated (3.0 ± 0.9 to 3.8 ± 1.1 spikes s?1) by the selective 5-HT3 receptor antagonist granisetron. Ionophoretic application of PBG potentiated responses to vagus nerve and cardiopulmonary afferent stimulation, and granisetron significantly attenuated this cardiopulmonary input (20.2 ± 5.7 to 10.6 ± 4.1 spikes burst?1) in 9 of 10 neurones tested. Ionophoretic application of AMPA and NMDA also excited NTS neurones and these excitations could be selectively antagonized by the non-NMDA and NMDA receptor antagonists DNQX and AP-5, respectively. At these selective currents, DNQX and AP-5 also attenuated PBG- and cardiopulmonary input-evoked increases in NTS activity. These data are consistent with the hypothesis that vagal inputs, including non-myelinated cardiopulmonary inputs to the NTS, utilize a 5-HT-containing pathway which activates 5-HT3 receptors. This excitatory response to 5-HT3 receptor activation may be partly a direct postsynaptic action but part may also be due to facilitation of the release of glutamate which in turn acts on either non-NMDA or NMDA receptors to evoke excitation. PMID:15905216

Jeggo, Ross D; Kellett, Daniel O; Wang, Yun; Ramage, Andrew G; Jordan, David



Differential distribution of MAP1A isoforms in the adult mouse barrel cortex and comparison with the serotonin 5-HT2A receptor.  


Microtubule-associated protein 1A (MAP1A) is essential during the late differentiation phase of neuronal development. Here, we demonstrated the presence of two MAP1A isoforms with a differential spatial distribution in the adult mouse barrel cortex. Antibody A stained MAP1A in pyramidal and stellate cells, including dendrites that crossed layer IV in the septa between barrels. The other antibody, BW6 recognized a MAP1A isoform that was mainly confined to the barrel hollow and identified smaller caliber dendrites. Previously, an interaction of MAP1A and the serotonin 5-hydroxytryptamine 2A (5-HT(2A)) receptor was shown in the rat cortex. Here, we identified, by double-immunofluorescent labeling, MAP1A isoform and serotonin 5-HT(2A) receptor distribution. MAP1A co-localized mainly with 5-HT(2A) receptor in larger apical dendrites situated in septa. This differential staining of MAP1A and a serotonin receptor in defined barrel compartments may be due to changes in the expression or processing of MAP1A during dendritic transport as a consequence of functional differences in processing of whisker-related sensory input. PMID:15121214

Touri, F; Welker, E; Riederer, B M



Mediation of the antidepressant-like effect of 8-OH-DPAT in mice by postsynaptic 5-HT1A receptors.  

PubMed Central

1. The 5-hydroxytryptamine (5-HT)1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) has been evaluated in a mouse model for detecting potential antidepressants (Porsolt test). The effects of various receptor antagonists, lesions of brain monoaminergic neurones and chronic drug treatments on this 8-OH-DPAT-induced response have also been determined. 2. 8-OH-DPAT (0.3-10.0 mg kg-1, s.c.) dose-dependently increased the mobility of mice in the Porsolt test. Other selective 5-HT1A receptor ligands (0.3-30 mg kg-1, s.c.) either mimicked the 8-OH-DPAT response (ipsapirone, at 10 and 30 mg kg-1, s.c.) or were inactive (buspirone and gepirone). However, each of these compounds (< or = 100 mg kg-1, p.o.) inhibited the response to 8-OH-DPAT (3 mg kg-1, s.c.) when given concurrently. 3. The putative 5-HT1A antagonists, spiroxatrine (1-30 mg kg-1, p.o.), (+/-)-pindolol (30 mg kg-1, p.o.) and methiothepin (3-10 mg kg-1, p.o.), each attenuated the 8-OH-DPAT (3 mg kg-1, s.c.)-induced increase in mobility. 4. The dopamine D1 receptor antagonist, SCH 23390 (3-10 mg kg-1, p.o.), weakly reversed the 8-OH-DPAT response.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8467355

Luscombe, G. P.; Martin, K. F.; Hutchins, L. J.; Gosden, J.; Heal, D. J.



Stimulus Properties of the Selective 5HT Reuptake Inhibitor Fluvoxamine in Conditioned Taste Aversion Procedures  

Microsoft Academic Search

Previous attempts to train pigeons and rats to discriminate between the antidepressant fluvoxamine and its vehicle as assessed in a drug discrimination paradigm have been without success. The present experiments were, therefore, designed to assess in a conditioned taste aversion procedure (CTA) whether or not fluvoxamine possesses stimulus properties. Rats were exposed to a conditioned taste aversion (CTA) procedure. In

B. Olivier; J. Gommans; J. Van Der Gugten; J. A. Bouwknecht; A. H. J. Herremans; T. Patty; T. H. Hijzen



A Meta-Analysis of the Effects of the 5-Hydroxytryptamine Transporter Gene-Linked Promoter Region Polymorphism on Susceptibility to Lifelong Premature Ejaculation  

PubMed Central

Objective Premature ejaculation (PE) has been reported as the most common male sexual dysfunction with global prevalence rates estimated at approximately 30%. The neurobiogenesis of ejaculation is very complex and involves the serotoninergic (5-hydroxytryptamine, 5-HT) system. Recently, genetic polymorphisms located on SLC6A4 gene codifying for 5-HT transporter (5-HTT), the major regulator of serotonic neurotransmission, have been linked with the pathogenesis and risk of PE. Apparently studies of this type of polymorphism in PE have show conflicting results. Methods A meta-analysis was performed that are available in relation with 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism and the risk of lifelong PE (LPE) in men to clarify this relationship. We searched Pubmed and Embase (last search updated on Aug 2012) using ‘premature ejaculation’, ‘polymorphism or variant’, ‘genotype’, ‘ejaculatory function’, and ‘rapid ejaculation’ as keywords and reference lists of studies corresponded to the inclusion criteria for meta-analysis. These studies involved the total number of 481 LPE men and 466 health control men subjects. Odds ratio (OR) and 95% confidence intervals (CIs) were used to evaluate this relationship. Results In the overall analysis, significant associations between LPE risk and 5-HTTLPR polymorphism were found (L-allele vs. S-allele OR?=?0.86, 95% CI?=?0.79–0.95, P?=?0.002; LL vs. SS: OR?=?0.80, 95% CI?=?0.68–0.95, P?=?0.009; LS vs. SS: OR?=?0.85, 95% CI?=?0.76–0.97, P?=?0.012 and LL+LS vs. SS: OR?=?0.88, 95% CI?=?0.81–0.95, P?=?0.002). Moreover, in subgroup analysis based on ethnicity, similar significant associations were detected. The Egger’s test did not reveal presence of a publication bias. Conclusions Our investigations demonstrate that 5-HTTLPR (L>S) polymorphism might protect men against LPE risk. Further studies based on larger sample size and gene-environment interactions should be conducted the role of 5-HTTLPR polymorphism and LPE risk. PMID:23383022

Wu, Sheng; Shao, Hongbao; Dai, Feng; Peng, Tao; Qin, Feng; Feng, Ninghan



Effect of central 5-hydroxytryptamine depletion on changeover behaviour in concurrent schedules of reinforcement  

Microsoft Academic Search

Rationale: Previous experiments have shown that rats whose 5-hydroxytryptaminergic (5-HTergic) pathways have been destroyed exhibit\\u000a higher rates of switching between response alternatives on various temporal differentiation schedules. Objective: This paper reports two experiments investigating the effect of central 5-HT depletion on switching between concurrent schedules\\u000a of reinforcement which do not entail temporal differentiation of behaviour. Methods: Rats received injections of

A. S. A. Al-Ruwaitea; T.-J. Chiang; M.-Y. Ho; C. M. Bradshaw; E. Szabadi



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



5HT 1A receptor function in major depressive disorder  

Microsoft Academic Search

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

Jonathan Savitz; Irwin Lucki; Wayne C. Drevets



Mol Psychiatry . Author manuscript 5-HT receptors are required for serotonin-selective antidepressant2B  

E-print Network

genetic or pharmacologic inactivation of 5-HT receptors.2B Conversely, direct agonist stimulation of 5-HT in 5-HT-dependent phenotypes, including impulsivity, aggressivity and2B ­ suicidality ( ). studies have


Differential pulse voltammetry in the dorsal horn of the spinal cord of the anesthetized rat: are the voltammograms related to 5-HT and/or to 5-HIAA?  


Treated carbon fiber microelectrodes were used with the differential pulse voltammetry method for in vitro and in vivo determination of indoleamines. Under these conditions a peak of oxidation current which is characteristic of 5-hydroxyindoles is recorded at 280-300 mV. Treated carbon fiber microelectrodes respond in vitro linearly over a large range of concentrations of 5-hydroxytryptamine (5-HT) and of 5-hydroxyindoleacetic acid (5-HIAA), but are 5-8 times more sensitive to 5-HT than to 5-HIAA. In vivo, the question remains as to the exact nature of the peak because the oxidation potentials of 5-HT and 5-HIAA are close together and cannot be monitored separately. Pharmacological investigations were hence carried out in order to characterize the electrochemical signal detected at 300 mV in the dorsal horn of the lumbar spinal cord of chloral hydrate-anesthetized rats. Using 250 micron long carbon fiber microelectrodes, the electrochemical signal stabilizes at 30-90 min and the peak remains constant for up to 210 min. Administration of the monoamine oxidase inhibitor (MAOI) clorgyline produced a progressive decrease of the signal which reached a decrease of 33% of control at 180 min after injection. At this time biochemical measures demonstrated a 117% increase in 5-HT and a 32% decrease in 5-HIAA in the dorsal half of the spinal cord. Reserpine provoked an increase of 20% in the electrochemical peak and the 5-HIAA outflow blocker probenecid gave rise to a sustained plateau of about 60% above control values.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6194856

Rivot, J P; Ory-Lavollee, L; Chiang, C Y



Brain 5HT 2C receptors: potential role in anxiety disorders  

Microsoft Academic Search

\\u000a Due to their predominant brain localization [1], 5HT2Creceptors offer innovative targets for designing novel psychotropic drugs for the treatment of psychiatric disorders. 5HT2Creceptors (formerly termed 5HTic) are members of the 5HT2receptor family [2-4] which also includes 5HT2Areceptors (formerly 5HT2receptors) and 5HT2Breceptors (formerly5HT2Freceptors). This G-protein coupled receptor family activates phospholipase C as a transduction mechanism. 5HT2receptor subtypes mutually share approximately 80%

François Jenck; Jean-Luc Moreau; Jürgen Wichmann; Heinz Stadler; James R. Martin; Michael Bös


Structural basis of ligand recognition in 5-HT3 receptors  

PubMed Central

The 5-HT3 receptor is a pentameric serotonin-gated ion channel, which mediates rapid excitatory neurotransmission and is the target of a therapeutically important class of anti-emetic drugs, such as granisetron. We report crystal structures of a binding protein engineered to recognize the agonist serotonin and the antagonist granisetron with affinities comparable to the 5-HT3 receptor. In the serotonin-bound structure, we observe hydrophilic interactions with loop E-binding site residues, which might enable transitions to channel opening. In the granisetron-bound structure, we observe a critical cation–? interaction between the indazole moiety of the ligand and a cationic centre in loop D, which is uniquely present in the 5-HT3 receptor. We use a series of chemically tuned granisetron analogues to demonstrate the energetic contribution of this electrostatic interaction to high-affinity ligand binding in the human 5-HT3 receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti-emetics in the 5-HT3 receptor. PMID:23196367

Kesters, Divya; Thompson, Andrew J; Brams, Marijke; van Elk, Rene; Spurny, Radovan; Geitmann, Matthis; Villalgordo, Jose M; Guskov, Albert; Helena Danielson, U; Lummis, Sarah C R; Smit, August B; Ulens, Chris



Synthesis and structure-affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes  

PubMed Central

Efforts to develop ligands that distinguish between clinically relevant 5-HT2A and 5-HT2C serotonin receptor subtypes have been challenging, because their sequences have high homology. Previous studies reported that a novel aplysinopsin belonging to a chemical class of natural products isolated from a marine sponge was selective for the 5-HT2C over the 5-HT2A receptor subtype. Our goal was to explore the 5-HT2A/2C receptor structure-affinity relationships of derivatives based on the aplysinopsin natural product pharmacophore. Twenty aplysinopsin derivatives were synthesized, purified and tested for their affinities for cloned human serotonin 5-HT1A, 5-HT2A and 5-HT2C receptor subtypes. Four compounds in this series had >30-fold selectivity for 5-HT2A or 5-HT2C receptors. The compound (E)-5-((5,6-dichloro-1H-indol-3-yl)methylene)-2-imino-1,3-dimethylimidazolidin-4-one (UNT-TWU-22, 16) had approximately 2100-fold selectivity for the serotonin 5-HT2C receptor subtype: an affinity for 5-HT2C equal to 46 nM and no detectable affinity for the 5-HT1A or 5-HT2A receptor subtypes. The two most important factors controlling 5-HT2A or 5-HT2C receptor subtype selectivity were the combined R1, R3-alkylation of the imidazolidinone ring and the type and number of halogens on the indole ring of the aplysinopsin pharmacophore. PMID:20570529

Cummings, David F.; Canseco, Diana C.; Sheth, Pratikkumar; Johnson, James E.; Schetz, John A.



Differential Effects of 5-HT2A and 5-HT2C Receptor Blockade on Strategy-Switching  

PubMed Central

Recent experiments indicate that blockade of serotonin (5-HT) 2A and 2C receptors have differential effects on reversal learning. The present experiments investigated the effects of the 5-HT2A receptor antagonist, ketanserin and 5-HT2C receptor antagonist, SB242084 on acquisition and strategy-switching in a visual cue – response paradigm. Long-Evans rats were trained in a cross-maze to enter an arm based on color (visual cue version) or a specific turn response (response version). Systemic treatment with ketanserin did not affect initial learning of a visual cue or response discrimination, but ketanserin at 0.5 mg/kg significantly enhanced a switch between visual cue and response strategies. Ketanserin facilitated strategy-switching by inhibiting responses to a previously relevant strategy without affecting choices to never-reinforced strategies. Treatment with SB242084 (0.5, 1.0 or 2.0 mg/kg) did not affect acquisition of a visual cue or response discrimination. SB242084 treatment also did not affect strategy-switching. The present findings suggest that blockade of 5-HT2A, but not 5-HT2C, receptors enhance strategy switching. PMID:21232556

Baker, Phillip M.; Thompson, Jennifer L.; Sweeney, John A.; Ragozzino, Michael E.



Differential effects of 5-HT(2A) and 5-HT(2C) receptor blockade on strategy-switching.  


Recent experiments indicate that blockade of serotonin (5-HT) 2A and 2C receptors have differential effects on reversal learning. The present experiments investigated the effects of the 5-HT(2A) receptor antagonist, ketanserin and 5-HT(2C) receptor antagonist, SB242084 on acquisition and strategy-switching in a visual cue-response paradigm. Long-Evans rats were trained in a cross-maze to enter an arm based on color (visual cue version) or a specific turn response (response version). Systemic treatment with ketanserin did not affect initial learning of a visual cue or response discrimination, but ketanserin at 0.5 mg/kg significantly enhanced a switch between visual cue and response strategies. Ketanserin facilitated strategy-switching by inhibiting responses to a previously relevant strategy without affecting choices to never-reinforced strategies. Treatment with SB242084 (0.5, 1.0 or 2.0 mg/kg) did not affect acquisition of a visual cue or response discrimination. SB242084 treatment also did not affect strategy-switching. The present findings suggest that blockade of 5-HT(2A), but not 5-HT(2C), receptors enhance strategy switching. PMID:21232556

Baker, Phillip M; Thompson, Jennifer L; Sweeney, John A; Ragozzino, Michael E



Blockade of 5-HT(3) receptor with MDL 72222 and Y 25130 reduces beta-amyloid protein (25--35)-induced neurotoxicity in cultured rat cortical neurons.  


The present study was performed to examine neuroprotective effects of 5-hydroxytryptamine (5-HT)(3) receptor antagonists against beta-amyloid protein (25--35)-, a synthetic 25--35 amyloid peptide, induced neurotoxicity using cultured rat cortical neurons. beta-Amyloid protein (25--35) produced a concentration-dependent reduction of cell viability, which was significantly reduced by (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801), an N-methyl-d-aspartate (NMDA) receptor antagonist, verapamil, an L-type Ca(2+) channel blocker, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. The 5-HT(3) receptor antagonists, tropanyl-3,5-dichlorobenzoate (MDL-72222, 0.1--10 microM) and N-(1-azabicyclo[2.2.2.]oct-3-yl)-6-chloro-4-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide hydrochloride (Y 25130, 0.05--5 microM), decreased the beta-amyloid protein (25--35) (10 microM)-induced neuronal cell death as assessed by a colorimetric 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and the number of apoptotic nuclei, evidenced by Hoechst 33342 staining. MDL 72222 and Y 25130 inhibited the beta-amyloid protein (25--35) (10 microM)-induced elevation of cytosolic Ca(2+) concentration ([Ca(2+)](c)) and glutamate release, generation of reactive oxygen species, and caspase-3 activity. These neuroprotective effects of MDL 72222 (10 microM) and Y 25130 (5 microM) were completely blocked by the simultaneous treatment with 100 microM 1-phenylbiguanide, a 5-HT(3) receptor agonist, indicating that the protective effects of these compounds were due to 5-HT(3) receptor blockade. These results suggest that the activation of the 5-HT(3) receptor may be partially involved in beta-amyloid protein-induced neurotoxicity, by membrane depolarization for Ca(2+) influx. Therefore, the blockade of 5-HT(3) receptor with MDL 72222 and Y 25130, may ameliorate the beta-amyloid protein-induced neurotoxicity by interfering with the increase of [Ca(2+)](c), and then by inhibiting glutamate release, generation of reactive oxygen species and caspase-3 activity. PMID:16150439

Ju Yeon Ban; Yeon Hee Seong



5HT3-receptor antagonists as antiemetics in cancer.  


Effective antiemetic therapy is crucial for patients undergoing chemotherapy or radiotherapy for cancer. Severe nausea and vomiting associated with such cancer treatment can lead to anxiety, anorexia, dehydration, electrolyte disturbance and renal failure, and may interrupt cancer therapy, demoralise patients or even cause them to abandon treatment. In 1992, we welcomed the introduction of ondansetron, the first selective serotonin type 3- (5HT3-) receptor antagonist marketed in the UK, as an important advance in preventing chemotherapy-induced nausea and vomiting. Several selective 5HT3-receptor antagonists are now licensed. They are widely prescribed to patients receiving cancer treatment, but not always appropriately. Here we review their optimal use. PMID:16111085



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



Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes.  


Although certain antiparkinson agents interact with serotonin (5-HT) receptors, little information is available concerning functional actions. Herein, we characterized efficacies of apomorphine, bromocriptine, cabergoline, lisuride, piribedil, pergolide, roxindole, and terguride at human (h)5-HT(1A), h5-HT(1B), and h5-HT(1D) receptors [guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding], and at h5-HT(2A), h5-HT(2B), and h5-HT(2C) receptors (depletion of membrane-bound [(3)H]phosphatydilinositol). All drugs stimulated h5-HT(1A) receptors with efficacies (compared with 5-HT, 100%) ranging from modest (apomorphine, 35%) to high (cabergoline, 93%). At h5-HT(1B) receptors, efficacies varied from mild (terguride, 37%) to marked (cabergoline, 102%) and potencies were modest (pEC(50) values of 5.8-7.6): h5-HT(1D) sites were activated with a similar range of efficacies and greater potency (7.1-8.5). Piribedil and apomorphine were inactive at h5-HT(1B) and h5-HT(1D) receptors. At h5-HT(2A) receptors, terguride, lisuride, bromocriptine, cabergoline, and pergolide displayed potent (7.6-8.8) agonist properties (49-103%), whereas apomorphine and roxindole were antagonists and piribedil was inactive. Only pergolide (113%/8.2) and cabergoline (123%/8.6) displayed pronounced agonist properties at h5-HT(2B) receptors. At 5-HT(2C) receptors, lisuride, bromocriptine, pergolide, and cabergoline were efficacious (75-96%) agonists, apomorphine and terguride were antagonists, and piribedil was inactive. MDL100,907 and SB242,084, selective antagonists at 5-HT(2A) and 5-HT(2C) receptors, respectively, abolished these actions of pergolide, cabergoline, and bromocriptine. In conclusion, antiparkinson agents display markedly different patterns of agonist and antagonist properties at multiple 5-HT receptor subtypes. Although all show modest (agonist) activity at 5-HT(1A) sites, their contrasting actions at 5-HT(2A) and 5-HT(2C) sites may be of particular significance to their functional profiles in vivo. PMID:12388668

Newman-Tancredi, Adrian; Cussac, Didier; Quentric, Yann; Touzard, Manuelle; Verrièle, Laurence; Carpentier, Nathalie; Millan, Mark J



Investigations into the Binding Affinities of Different Human 5HT4 Receptor Splice Variants  

Microsoft Academic Search

This study examined whether the drug-receptor-binding sites of 5 selected human 5-HT4 receptor splice variants [h5-HT4(a), h5-HT4(b), h5-HT4(c), h5-HT4(d) and h5-HT4(g)] display preferential affinities towards agonists. The agonists selected on the basis of chemical diversity and clinical relevance were: 5-HT4 benzamides, renzapride, zacopride and prucalopride; the benzimidazolones, DAU 6236 and BIMU 1; the aromatic ketone, RS67333, and the indole carbazimidamide

Helen R. Irving; Nathalie Tochon-Danguy; Kenneth A. Chinkwo; Jian G. Li; Carmen Grabbe; Marina Shapiro; Colin W. Pouton; Ian M. Coupar



Effects of Hallucinogens on Locomotor and Investigatory Activity and Patterns: Influence of 5HT2A and 5HT2C Receptors  

Microsoft Academic Search

The 5-HT2A and 5-HT2C antagonists MDL 100,907 and SER-082 were tested with the 5-HT2A\\/C agonist DOI and the 5-HT1A\\/2A\\/2C agonist LSD in the Behavioral Pattern Monitor, which provides multiple measures of locomotor and investigatory activity. Previous investigations have shown that these measures load onto three independent behavioral factors: amount of activity, exploratory behavior, and behavioral organization. Rats pretreated with saline,

Kirsten Krebs-Thomson; Martin P Paulus; Mark A Geyer



5-HT(1A)-receptor over-expressing mice: genotype and sex dependent responses to antidepressants in the forced swim-test.  


Deficiencies in serotonergic neurotransmission are involved in the pathophysiology of depression. Due to its modulatory effect on serotonin (5-HT) release, the 5-HT(1A)-receptor is thought to play a decisive role in the therapy of this mood disorder. However, it is not fully understood how antidepressant effects are mediated by pre- and postsynaptic receptor sites. In this study we examined the impact of postsynaptic 5-HT(1A)-receptor over-expression in corticolimbic areas of male and female mice on the performance in the forced swim-test (FST). Furthermore, we investigated their response to the serotonin selective reuptake inhibitor (SSRI) citalopram in comparison to the selective noradrenaline reuptake inhibitor reboxetine, as well as the partial 5-HT(1A)-receptor agonists, buspirone and S 15535. Additionally, these drugs were evaluated in the open field-test in order to observe effects on motor activity. The density of 5-HT(1A)-receptors in discrete corticolimbic regions was determined in detail by quantitative autoradiography with [(3)H]8-OH-DPAT to investigate genotype as well as sex dependent differences in the expression pattern. [(3)H]8-OH-DPAT binding differed depending on sex with female mice of both genotypes displaying higher receptor binding in distinct brain areas. In the FST untreated male but not female over-expressing (OE) mice showed an antidepressant-like behaviour compared to wild-type (WT) mice. Citalopram yielded an antidepressant effect without influencing locomotor activity in OE mice but not in WT mice. Reboxetine had no antidepressant-like effect in OE mice, but sex-dependently in WT mice. The two partial agonists, buspirone and S 15535 produced no antidepressant-like activity in both genotypes and sexes, but aberrant motor effects. The antidepressant-like phenotype of male transgenic mice accounts for an involvement of postsynaptic 5-HT(1A)-receptors in the FST behaviour. In addition, the selective over-expression of postsynaptic 5-HT(1A)-receptors in mice contributes to the antidepressant response to citalopram in the FST. Although further pharmacological analysis is required, the data provide novel support for a role of postsynaptic 5-HT(1A)-receptors in the effects of SSRIs. PMID:21419787

Günther, Lydia; Rothe, Julia; Rex, André; Voigt, Jörg-Peter; Millan, Mark J; Fink, Heidrun; Bert, Bettina



Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity  

PubMed Central

Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses (‘cue reactivity') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence. PMID:24618688

Anastasio, N C; Liu, S; Maili, L; Swinford, S E; Lane, S D; Fox, R G; Hamon, S C; Nielsen, D A; Cunningham, K A; Moeller, F G



Opposing actions of 5HT1A and 5HT2-like serotonin receptors on modulations of the electric signal waveform in the electric fish Brachyhypopomus pinnicaudatus  

PubMed Central

Serotonin (5-HT) is an indirect modulator of the electric organ discharge (EOD) in the weakly electric gymnotiform fish, Brachyhypopomus pinnicaudatus. Injections of 5-HT enhance EOD waveform “masculinity”, increasing both waveform amplitude and the duration of the second phase. This study investigated the pharmacological identity of 5-HT receptors that regulate the electric waveform and their effects on EOD amplitude and duration. We present evidence that two sets of serotonin receptors modulate the EOD in opposite directions. We found that the 5HT1AR agonist 8-OH-DPAT diminishes EOD duration and amplitude while the 5HT1AR antagonist WAY100635 increases these parameters. In contrast, the 5HT2R agonist ?-Me-5-HT increases EOD amplitude but not duration, yet 5-HT-induced increases in EOD duration can be inhibited by blocking 5HT2A/2C-like receptors with ketanserin. These results show that 5-HT exerts bi-directional control of EOD modulations in B. pinnicaudatus via action at receptors similar to mammalian 5HT1A and 5HT2 receptors. The discordant amplitude and duration response suggests separate mechanisms for modulating these waveform parameters. PMID:18206154

Allee, Susan J.; Markham, Michael R.; Salazar, Vielka L.; Stoddard, Philip K.



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



5HT–2C receptor polymorphism in suicide victims  

Microsoft Academic Search

Sustainable observations suggest that suicidal behaviour by itself may have biological correlates, among which those related to the serotonergic synapse hold the key position. Based on the association of suicide and serotonergic dysfunction, it was proposed that genetic mechanisms affecting suicidal behaviour could be related to the alterations of the genes encoding the elements of 5HT synapse. The present study

J. Stefulj; A. Büttner; M. Kubat; P. Zill; M. Balija; W. Eisenmenger; B. Bondy; B. Jernej



Reevaluation of lisuride pharmacology: 5-hydroxytryptamine 1A receptor-mediated behavioral effects overlap its other properties in rats  

Microsoft Academic Search

  Abstract\\u000a \\u000a \\u000a Rationale. There is substantial evidence that lisuride can produce effects linked to 5-HT1A receptor occupancy. Nevertheless, this action has generally been ignored in the mechanism of action of lisuride, in favor\\u000a of an exclusive role for dopamine receptors in considering its antiparkinsonian effects, or an exclusive role of 5-HT2A\\/2C receptor activation in hallucinogenesis. These conclusions are surprising when one

Danuta Marona-Lewicka; Deborah M. Kurrasch-Orbaugh; Jennifer R. Selken; Medhane G. Cumbay; Joshua G. Lisnicchia; David E. Nichols



Novel arylsulfonamide derivatives with 5-HT?/5-HT? receptor antagonism targeting behavioral and psychological symptoms of dementia.  


In order to target behavioral and psychological symptoms of dementia (BPSD), we used molecular modeling-assisted design to obtain novel multifunctional arylsulfonamide derivatives that potently antagonize 5-HT(6/7/2A) and D2 receptors, without interacting with M1 receptors and hERG channels. In vitro studies confirmed their antagonism of 5-HT(7/2A) and D2 receptors and weak interactions with key antitargets (M1R and hERG) associated with side effects. Marked 5-HT6 receptor affinities were also observed, notably for 6-fluoro-3-(piperidin-4-yl)-1,2-benzoxazole derivatives connected by a 3-4 unit alkyl linker with mono- or bicyclic, lipophilic arylsulfonamide moieties. N-[4-[4-(6-Fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]butyl]benzothiophene-2-sulfonamide (72) was characterized in vitro on 14 targets and antitargets. It displayed dual blockade of 5-HT6 and D2 receptors and negligible interactions at hERG and M1 receptors. Unlike reference antipsychotics, 72 displayed marked antipsychotic and antidepressant activity in rats after oral administration, in the absence of cognitive or motor impairment. This profile is particularly attractive when targeting a fragile, elderly BPSD patient population. PMID:24805037

Ko?aczkowski, Marcin; Marcinkowska, Monika; Bucki, Adam; Paw?owski, Maciej; Mitka, Katarzyna; Ja?kowska, Jolanta; Kowalski, Piotr; Kazek, Grzegorz; Siwek, Agata; Wasik, Anna; Weso?owska, Anna; Mierzejewski, Pawe?; Bienkowski, Przemyslaw



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



A novel highly selective 5-HT6 receptor antagonist attenuates ethanol and nicotine seeking but does not affect inhibitory response control in Wistar rats.  


Recent studies suggest a potential role for 5-hydroxytryptamine(6) (5-HT(6)) receptors in the regulation of addictive behavior. In the present study, our aim was to investigate whether the novel highly selective 5-HT(6) receptor antagonist compound (CMP) 42 affected nicotine and ethanol seeking behavior in Wistar rats. We have also studied whether CMP 42 had beneficial effects in a model of impulse control, as measured in the 5-choice serial reaction time task (5-CSRTT). Rats were trained to nose poke to receive intravenous infusions of nicotine or an ethanol drop. CMP 42 (3-30 mg/kg intraperitoneally, i.p.) was administered to investigate the effects on nicotine self-administration. Rats were also tested for cue-induced reinstatement of nicotine and ethanol seeking. In addition, the effects of CMP 42 were studied on the number of anticipatory responses in the 5-CSRTT. CMP 42 was effective in reducing nicotine self-administration and reinstatement of nicotine seeking at a dose of 30 mg/kg (i.p.). CMP 42 was also effective in reducing reinstatement of ethanol seeking (30 mg/kg i.p.). In contrast, CMP 42 did not affect anticipatory responding at doses tested, indicating no effects on impulse control. These results add to a body of evidence implicating the 5-HT(6) receptor as a viable target for the control of drug abuse. Specifically, we demonstrated for the first time effects on nicotine self-administration and on nicotine and ethanol reinstatement. Further, these effects are probably not mediated by effects on impulse control. PMID:22974550

de Bruin, N M W J; McCreary, A C; van Loevezijn, A; de Vries, T J; Venhorst, J; van Drimmelen, M; Kruse, C G



Molecular basis of partial agonism: orientation of indoleamine ligands in the binding pocket of the human serotonin 5-HT2A receptor determines relative efficacy.  


Based on experiment and computational simulation, we present a structural explanation for the differing efficacies of indole agonists at the human serotonin 5-HT2A receptor (5HT2AR). We find that serotonin [5-hydroxytryptamine (5-HT)] forms hydrogen-bonds with Ser3.36 in helix 3 and Ser5.46 in helix 5. Disruption of these hydrogen bonds by methyl-substitution of the cationic primary amine or of the backbone N1-amine, respectively, leads to a reduction in agonist efficacy. Computational simulation predicts that mutation of Ser3.36 to Ala should allow a similar interaction with helix 3 both for agonists that have unmodified cationic amine side chains and for those with substituted amines. Experimentally, this mutation was found to largely eliminate the differences in efficacy caused by cationic amine substitution for a series of indole congeners. Similarly, substitution of the N1-amine, which interacts with Ser5.46, reduced efficacy more markedly at the wild-type (WT) than at the Ser5.46Ala mutant receptor. Computational modeling of binding pocket interactions of ligands with WT and mutant receptor constructs demonstrate how the Ser3.36 and Ser5.46 interactions serve to modify the agonist's favored position in the binding pocket. A striking correlation was found between differences in the position assumed by the indole ring and differences in agonist activity. These data support the hypothesis that the position of the agonist interacting with the receptor is influenced by specific interactions in helices 3 and 5 and determines the degree of receptor activation by agonist through a mechanism that is likely to be shared by other G-protein coupled receptors in this class. PMID:12488534

Ebersole, Barbara J; Visiers, Irache; Weinstein, Harel; Sealfon, Stuart C



Quantitative changes in intracellular calcium and extracellular-regulated kinase activation measured in parallel in CHO cells stably expressing serotonin (5-HT) 5-HT2A or 5-HT2C receptors  

PubMed Central

Background The serotonin (5-HT) 2A and 2C receptors (5-HT2AR and 5-HT2CR) are involved in a wide range of physiological and behavioral processes in the mammalian central and peripheral nervous systems. These receptors share a high degree of homology, have overlapping pharmacological profiles, and utilize many of the same and richly diverse second messenger signaling systems. We have developed quantitative assays for cells stably expressing these two receptors involving minimal cell sample manipulations that dramatically improve parallel assessments of two signaling responses: intracellular calcium (Cai++) changes and activation (phosphorylation) of downstream kinases. Such profiles are needed to begin to understand the simultaneous contributions from the multiplicity of signaling cascades likely to be initiated by serotonergic ligands. Results We optimized the Cai++ assay for stable cell lines expressing either 5-HT2AR or 5-HT2CR (including dye use and measurement parameters; cell density and serum requirements). We adapted a quantitative 96-well plate immunoassay for pERK in the same cell lines. Similar cell density optima and time courses were observed for 5-HT2AR- and 5-HT2CR-expressing cells in generating both types of signaling. Both cell lines also require serum-free preincubation for maximal agonist responses in the pERK assay. However, 5-HT2AR-expressing cells showed significant release of Cai++ in response to 5-HT stimulation even when preincubated in serum-replete medium, while the response was completely eliminated by serum in 5-HT2CR-expressing cells. Response to another serotonergic ligand (DOI) was eliminated by serum-replete preincubation in both cells lines. Conclusions These data expand our knowledge of differences in ligand-stimulated signaling cascades between 5-HT2AR and 5-HT2CR. Our parallel assays can be applied to other cell and receptor systems for monitoring and dissecting concurrent signaling responses. PMID:22397586



5?HT3 antiemetic therapy for patients with breast cancer  

Microsoft Academic Search

Antiemetic treatment should be considered for breast cancer patients receiving moderately emetogenic chemotherapy. Although the extent of chemotherapy-induced emesis is largely dependent on the emetogenic potential of the specific agents employed, patient characteristics such as age and sex also contribute. Recent clinical studies show that treatment with the currently available 5-HT3 antagonists effectively reduces the incidence of chemotherapy-induced nausea and

Edith A. Perez



The serotonin 5-HT7 receptors: two decades of research.  


Like most neurotransmitters, serotonin possesses a simple structure. However, the pharmacological consequences are more complex and diverse. Serotonin is involved in numerous functions in the human body including the control of appetite, sleep, memory and learning, temperature regulation, mood, behavior, cardiovascular function, muscle contraction, endocrine regulation, and depression. Low levels of serotonin may be associated with several disorders, namely increase in aggressive and angry behaviors, clinical depression, Parkinson's disease, obsessive-compulsive disorder, eating disorders, migraine, irritable bowel syndrome, tinnitus, and bipolar disease. These effects are mediated via different serotonin (5-HT) receptors. In this review, we will focus on the last discovered member of this serotonin receptor family, the 5-HT7 receptor. This receptor belongs to the G protein-coupled receptor superfamily and was cloned two decades ago. Later, different splice variants were described but no major functional differences have been described so far. All 5-HT7 receptor variants are coupled to G?s proteins and stimulate cAMP formation. Recently, several interacting proteins have been reported, which can influence receptor signaling and trafficking. PMID:24042216

Gellynck, Evelien; Heyninck, Karen; Andressen, Kjetil W; Haegeman, Guy; Levy, Finn Olav; Vanhoenacker, Peter; Van Craenenbroeck, Kathleen



5-HT3 receptor antagonists: differences and similarities.  


Differences among 5-HT3 receptor antagonists have been reported in pharmacological studies with regard to selectivity of receptor binding, potency, duration of action and dose-response curves. However, whether these pharmacological differences can affect clinical efficacy and safety remains to be determined. A careful analysis of the literature revealed 22 comparative studies among the 5-HT3 receptor antagonists available for review. Unfortunately, several of these trials have some important shortcomings especially in the study design, the size of population studied and the type of anti-emetic treatment selected, making their conclusions often difficult to interpret. However, among these studies, seven large, double-blind clinical trials have clearly shown that the antiemetic activity and tolerability of ondansetron, granisetron, tropisetron and dolasetron is almost identical at least in the prevention of cisplatin-induced emesis. Therefore, from the efficacy and safety point of view, there is no reason to prefer one with respect to the other compound. From the economic perspective, instead, differences may exist and they are strictly related to the dose and schedule of administration chosen for each compound. The information available on the use of 5-HT3 receptor antagonists in the prevention of emesis induced by moderately emetogenic chemotherapy is at best scant. Contrasting results have been reported and only one well-conducted study has been published in full. Therefore, the possible differences among the various compounds are difficult to evaluate. More studies should be carried out in this group of patients. PMID:9337675

Roila, F; Ballatori, E; Tonato, M; Del Favero, A



The role of 5-HT1A receptors in the anti-aversive effects of cannabidiol on panic attack-like behaviors evoked in the presence of the wild snake Epicrates cenchria crassus (Reptilia, Boidae).  


The potential anxiolytic and antipanic properties of cannabidiol have been shown; however, its mechanism of action seems to recruit other receptors than those involved in the endocannabinoid-mediated system. It was recently shown that the model of panic-like behaviors elicited by the encounters between mice and snakes is a good tool to investigate innate fear-related responses, and cannabidiol causes a panicolytic-like effect in this model. The aim of the present study was to investigate the 5-hydroxytryptamine (5-HT) co-participation in the panicolytic-like effects of cannabidiol on the innate fear-related behaviors evoked by a prey versus predator interaction-based paradigm. Male Swiss mice were treated with intraperitoneal (i.p.) administrations of cannabidiol (3 mg/kg, i.p.) and its vehicle and the effects of the peripheral pre-treatment with increasing doses of the 5-HT1A receptor antagonist WAY-100635 (0.1, 0.3 and 0.9 mg/kg, i.p.) on instinctive fear-induced responses evoked by the presence of a wild snake were evaluated. The present results showed that the panicolytic-like effects of cannabidiol were blocked by the pre-treatment with WAY-100635 at different doses. These findings demonstrate that cannabidiol modulates the defensive behaviors evoked by the presence of threatening stimuli, and the effects of cannabidiol are at least partially dependent on the recruitment of 5-HT1A receptors. PMID:23926240

Twardowschy, André; Castiblanco-Urbina, Maria Angélica; Uribe-Mariño, Andres; Biagioni, Audrey Francisco; Salgado-Rohner, Carlos José; Crippa, José Alexandre de Souza; Coimbra, Norberto Cysne



Serotonin (5-HT) 2C Receptor (5-HT2CR) Protein Expression is Enriched in Synaptosomal and Postsynaptic Compartments of Rat Cortex  

PubMed Central

The action of serotonin (5-HT) at the 5-HT2C receptor (5-HT2CR) in cerebral cortex is emerging as a candidate modulator of neural processes that mediate core phenotypic facets of several psychiatric and neurological disorders. However, our understanding of the neurobiology of the cortical 5-HT2CR protein complex is currently limited. The goal of the present study was to explore the subcellular localization of the 5-HT2CR in synaptosomes and the postsynaptic density, an electron-dense thickening specialized for postsynaptic signaling and neuronal plasticity. Utilizing multiples tissues (brain, peripheral tissues), protein fractions (synaptosomal, postsynaptic density), and controls (peptide neutralization, 5-HT2CR stable-expressing cells), we established the selectivity of two commercially available 5-HT2CR antibodies and employed the antibodies in Western blot and immunoprecipitation studies of PFC and motor cortex, two regions implicated in cognitive, emotional and motor dysfunction. For the first time, we demonstrated the expression of the 5-HT2CR in postsynaptic density-enriched fractions from both PFC and motor cortex. Co-immunoprecipitation studies revealed the presence of PSD-95 within the 5-HT2CR protein complex expressed in PFC and motor cortex. Taken together, these data support the hypothesis that the 5-HT2CR is localized within the postsynaptic thickening of synapses and is therefore positioned to directly modulate synaptic plasticity in cortical neurons. PMID:20345755

Anastasio, Noelle C.; Lanfranco, Maria Fe; Bubar, Marcy J.; Seitz, Patricia K.; Stutz, Sonja J.; McGinnis, Andrew G.; Watson, Cheryl S.; Cunningham, Kathryn A.



Possible involvement of 5-HT4 receptors, in addition to 5-HT3 receptors, in the emesis induced by high-dose cisplatin in Suncus murinus.  


To clarify the mechanism for the severe emesis concomitant with intensive chemotherapy, we investigated the effects of 5-HT3- and 5-HT4-receptor antagonists on the emesis induced by the high-dose of cisplatin in Suncus murinus. The emesis induced by 50 mg/kg of cisplatin was reduced by the oral pretreatment with tropisetron, which is known as a 5-HT3- and 5-HT4-receptor dual antagonist in vitro, with the ID50 value of 0.52 mg/kg. On the contrary, granisetron, a selective 5-HT3-receptor antagonist, did not markedly inhibit the emesis at up to 30 mg/kg. Moreover, GR125487, a selective 5-HT4-receptor antagonist, did not inhibit the emesis. However, co-administration of GR125487 and granisetron significantly reduced the number of emetic episodes. The study of the co-administration of GR125487 with tropisetron showed that GR125487 did not further enhance the inhibitory effect of tropisetron alone, suggesting that the anti-emetic effect of tropisetron is mediated via the blockade of both 5-HT3 and 5-HT4 receptors. These results suggest that both the 5-HT3 and 5-HT4 receptors are involved in the emesis induced by the high-dose of cisplatin in Suncus murinus. PMID:11243577

Horikoshi, K; Yokoyama, T; Kishibayashi, N; Ohmori, K; Ishii, A; Karasawa, A



Descending 5Hydroxytryptamine Raphe Inputs Repress the Expression of Serotonergic Neurons and Slow the Maturation of Inhibitory Systems in Mouse Embryonic Spinal Cord  

Microsoft Academic Search

5-HT1A receptors. Finally, to verify whether the expression of 5-HT intraspinal neurons could compensate for the lack of descending 5-HT fibers and play a role in the development of spontaneous activity, we blocked the 5-HT synthesis using p-chlorophenylalanine methyl ester in cultures devoid of the medulla. Surprisingly, we found that this pharmacological treat- ment did not prevent the development of

Pascal Branchereau; Jacqueline Chapron; Pierre Meyrand



Agonist actions of dihydroergotamine at 5-HT2B and 5-HT2C receptors and their possible relevance to antimigraine efficacy  

PubMed Central

The pharmaceutical compound, dihydroergotamine (DHE) is dispensed to prevent and reduce the occurrence of migraine attacks. Although still controversial, the prophylactic effect of this drug is believed to be caused through blockade and/or activation of numerous receptors including serotonin (5-HT) receptors of the 5-HT2 subtype. To elucidate if 5-HT2 receptors (5-HT2Rs) may be involved in DHE prophylactic effect, we performed investigations aimed to determine the respective pharmacological profile of DHE and of its major metabolite 8?-hydroxy-DHE (8?-OH-DHE) at the 5-HT2B and 5-HT2CRs by binding, inositol triphosphate (IP3) or cyclic GMP (cGMP) coupling studies in transfected fibroblasts. DHE and 8?-OH-DHE are competitive compounds at 5-HT2B and 5-HT2CRs. 8?-OH-DHE interaction at (5-HT2BRs) was best fitted by a biphasic competition curve and displayed the highest affinity with a Ki of 5 nM. These two compounds acted as agonists for both receptors in respect to cGMP production with pEC50 of 8.32±0.09 for 8?-OH-DHE at 5-HT2B and 7.83±0.06 at 5-HT2CRs. Knowing that the antimigraine prophylactic effect of DHE is only observed after long-term treatment, we chronically exposed the recombinant cells to DHE and 8?-OH-DHE. The number of 5-HT2BR-binding sites was always more affected than 5-HT2CRs. At 5-HT2BRs, 8?-OH-DHE was more effective than DHE, with an uncoupling that persisted for more than 40 h for IP3 or cGMP. By contrast, the 5-HT2CR coupling was reversible after either treatment. Chronic exposure to 8?-OH-DHE caused a persistent agonist-mediated desensitisation of 5-HT2B, but not 5-HT2CRs. This may be of relevance to therapeutic actions of the compound. PMID:12970106

Schaerlinger, B; Hickel, P; Etienne, N; Guesnier, L; Maroteaux, L



5-HT2CR blockade in the amygdala conveys analgesic efficacy to SSRIs in a rat model of arthritis pain  

PubMed Central

Background Pain, including arthritic pain, has a negative affective component and is often associated with anxiety and depression. However, selective serotonin reuptake inhibitor antidepressants (SSRIs) show limited effectiveness in pain. The amygdala plays a key role in the emotional-affective component of pain, pain modulation and affective disorders. Neuroplasticity in the basolateral and central amygdala (BLA and CeA, respectively) correlate positively with pain behaviors. Evidence suggests that serotonin receptor subtype 5-HT2CR in the amygdala contributes critically to anxiogenic behavior and anxiety disorders. In this study, we tested the hypothesis that 5-HT2CR in the amygdala accounts for the limited effectiveness of SSRIs in reducing pain behaviors and that 5-HT2CR blockade in the amygdala renders SSRIs effective. Results Nocifensive reflexes, vocalizations and anxiety-like behavior were measured in adult male Sprague–Dawley rats. Behavioral experiments were done in sham controls and in rats with arthritis induced by kaolin/carrageenan injections into one knee joint. Rats received a systemic (i.p.) administration of an SSRI (fluvoxamine, 30 mg/kg) or vehicle (sterile saline) and stereotaxic application of a selective 5-HT2CR antagonist (SB242084, 10 ?M) or vehicle (ACSF) into BLA or CeA by microdialysis. Compared to shams, arthritic rats showed decreased hindlimb withdrawal thresholds (increased reflexes), increased duration of audible and ultrasonic vocalizations, and decreased open-arm choices in the elevated plus maze test suggesting anxiety-like behavior. Fluvoxamine (i.p.) or SB242084 (intra-BLA) alone had no significant effect, but their combination inhibited the pain-related increase of vocalizations and anxiety-like behavior without affecting spinal reflexes. SB242084 applied into the CeA in combination with systemic fluvoxamine had no effect on vocalizations and spinal reflexes. Conclusions The data suggest that 5-HT2CR in the amygdala, especially in the BLA, limits the effectiveness of SSRIs to inhibit pain-related emotional-affective behaviors. PMID:23937887



Does the effect of central 5-hydroxytryptamine depletion on timing depend on motivational change?  


In a previous experiment we found that destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways by microinjection of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei resulted in impaired acquisition of temporal differentiation under an interresponse-time-greater-than-15-s (IRT > 15 s) schedule of sucrose reinforcement. This paper reports three experiments, the results of which bear on the interpretation of that finding. In Experiment 1, 32 rats were trained for 120 sessions under the IRT > 15 s schedule; then 16 received lesions of the 5HTergic pathways and 16 received sham lesions. Comparisons of the IRT frequency distributions of the two groups showed that the lesion produced a significant reduction of the mean IRT and an increase in the dispersion of IRTs, as expressed by the coefficient of variation. Obtained reinforcement rates were significantly reduced in the lesioned group, but response rates were not significantly altered. Levels of 5HT and 5-hydroxyindoleacetic acid were markedly reduced in all forebrain areas examined, without significant change in noradrenaline and dopamine levels. The results indicate that destruction of the 5HTergic pathways disrupts performance as well as acquisition of temporal differentiation. Experiments 2 and 3 examined whether changes in deprivation level and reinforcer magnitude, which are known to affect reinforcer value, would influence temporal differentiation in a similar fashion to destruction of the 5HTergic pathways. In experiment 2, 20 rats were trained under the IRT > 15 s schedule while maintained at 80% or 90% of free-feeding body weight; the more severe deprivation condition was associated with a longer mean IRT and a lower coefficient of variation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7871014

Wogar, M A; Bradshaw, C M; Szabadi, E



Stimulation of inositol phospholipid breakdown in rat cortical and hippocampal miniprisms by noradrenaline, 5-hydroxytryptamine and carbachol: some methodological aspects.  


After incubation of miniprisms from rat cerebral cortex or hippocampus with 3H-myo-inositol, labelling of the phospholipid ("Lipid") and inositol phosphate ("InsP") fractions was found. Inositol phospholipid hydrolysis ("PI breakdown") was stimulated by noradrenaline, 5-hydroxytryptamine and carbachol. Expressing data as InsP/(Lipid + InsP) was found to be a superior measure of the rate of PI breakdown compared with the more commonly used InsP d.p.m. unit, since the former was found to be independent of the volume of the miniprism aliquot used and the degree of labelling of inositol phospholipids. The PI breakdown responses to noradrenaline, 5-hydroxytryptamine and particularly carbachol were found to be enhanced by increasing the assay [K+] from 5.88 mM to 18.2 mM. Storage of hippocampal samples at -70 degrees by the "slow freeze-fast thaw" method of Hardy et al. (1983) resulted in a decreased degree of labelling of the Lipid and InsP fractions and a loss of the PI response to noradrenaline when assayed at a [K+] of 5.88 mM, but a reasonable response was seen in these samples at an assay [K+] of 18.2 mM. The temperature of the Krebs-Henseleit buffer used in the preparation of the miniprisms was found to be important for the PI breakdown response. PMID:3588525

Fowler, C J; Court, J A; Tiger, G; Björklund, P E; Candy, J M



Curcumin prevents corticosterone-induced neurotoxicity and abnormalities of neuroplasticity via 5-HT receptor pathway.  


Curcumin, a major active component of Curcuma longa, possesses antioxidant and neuroprotective activities. The present study explores the mechanisms underlying the neuroprotective effect of curcumin against corticosterone and its relation to 5-hydroxy tryptamine (5-HT) receptors. Exposure of cortical neurons to corticosterone results in decreased mRNA levels for three 5-HT receptor subtypes, 5-HT(1A), 5-HT(2A) and 5-HT(4), but 5-HT(1B,) 5-HT(2B), 5-HT(2C), 5-HT(6) and 5-HT(7) receptors remain unchanged. Pre-treatment with curcumin reversed this effect on mRNA for the 5-HT(1A) and 5-HT(4) receptors, but not for the 5-HT(2A) receptor. Moreover, curcumin exerted a neuroprotective effect against corticosterone-induced neuronal death. This observed effect of curcumin was partially blocked by either 5-HT(1A) receptor antagonist p-MPPI or 5-HT(4) receptor antagonist RS 39604 alone; whereas, the simultaneous application of both antagonists completely reversed the effect. Curcumin was also found to regulate corticosterone-induced morphological changes such as increases in soma size, dendritic branching and dendritic spine density, as well as elevate synaptophysin expression in cortical neurons. p-MPPI and RS 39604 reversed the effect of curcumin-induced change in neuronal morphology and synaptophysin expression of corticosterone-treated neurons. In addition, an increase in cyclic adenosine monophosphate (cAMP) level was observed after curcumin treatment, which was further prevented by RS 39604, but not by p-MPPI. However, curcumin-induced elevation in protein kinase A activity and phosphorylation of cAMP response element-binding protein levels were inhibited by both p-MPPI and RS 39604. These findings suggest that the neuroprotection and modulation of neuroplasticity exhibited by curcumin might be mediated, at least in part, via the 5-HT receptor-cAMP-PKA-CREB signal pathway. PMID:21689105

Xu, Ying; Li, Shan; Vernon, Matthew M; Pan, Jianchun; Chen, Ling; Barish, Philip A; Zhang, Yuan; Acharya, Abhinav P; Yu, Jie; Govindarajan, Subramaniam S; Boykin, Erin; Pan, Xiaoyu; O'Donnell, James M; Ogle, William O



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



Brief Communication A Functional Genetic Variation of the Serotonin (5-HT)  

E-print Network

Brief Communication A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic


Transcriptional regulation of the 5-HT1A receptor: implications for mental illness  

PubMed Central

The serotonin-1A (5-HT1A) receptor is an abundant post-synaptic 5-HT receptor (heteroreceptor) implicated in regulation of mood, emotion and stress responses and is the major somatodendritic autoreceptor that negatively regulates 5-HT neuronal activity. Based on animal models, an integrated model for opposing roles of pre- and post-synaptic 5-HT1A receptors in anxiety and depression phenotypes and response to antidepressants is proposed. Understanding differential transcriptional regulation of pre- versus post-synaptic 5-HT1A receptors could provide better tools for their selective regulation. This review examines the transcription factors that regulate brain region-specific basal and stress-induced expression of the 5-HT1A receptor gene (Htr1a). A functional polymorphism, rs6295 in the Htr1a promoter region, blocks the function of specific repressors Hes1, Hes5 and Deaf1, resulting in increased 5-HT1A autoreceptor expression in animal models and humans. Its association with altered 5-HT1A expression, depression, anxiety and antidepressant response are related to genotype frequency in different populations, sample homogeneity, disease outcome measures and severity. Preliminary evidence from gene × environment studies suggests the potential for synergistic interaction of stress-mediated repression of 5-HT1A heteroreceptors, and rs6295-induced upregulation of 5-HT1A autoreceptors. Targeted therapeutics to inhibit 5-HT1A autoreceptor expression and induce 5-HT1A heteroreceptor expression may ameliorate treatment of anxiety and major depression. PMID:22826341

Albert, Paul R.



Evaluation of gene expression changes of serotonin receptors, 5-HT3AR and 5-HT2AR as main stress factors in breast cancer patients.  


Breast cancer is a serious and potentially lethal multi-factor disease among 40-50 aged women in both developed and developing countries. Also, various studies have pointed to roles of neurotransmitters like serotonin in development of cancers, through action on various types of receptors. This study was conducted to evaluate serotonin receptor (5HT2AR and 5HT3AR) genes expression in peripheral blood mononuclear cells (PBMCs) of breast cancer patients in comparison with the healthy people and in the MCF7 cell line. Peripheral blood samples were obtained from 30 patients and 30 healthy individuals. Total RNA was extracted from PBMCs and MCF-7 cells. and 5HT2AR and 5HT3AR were detected by RT-PCR techniques. Finally, serotonin receptor gene expression variation in breast cancer patients and MCF-7 cells were determined by real time-PCR. This latter indicated significant promotion in expression of 5HT3AR and 5HT2AR in PBMCs in breast cancer patients but expression of 5HT2AR in the MCF-7 cell line was significantly decreased. In conclusion, after performing complimentary tests, determine of gene expression changes in serotonin receptors (5HT2AR and 5HT3AR) may be useful as a new approach in treatment of breast cancer based on use of antagonists. PMID:24969868

Hejazi, Seyed Hesam; Ahangari, Ghasem; Pornour, Majid; Deezagi, Abdolkhaleagh; Aminzadeh, Saeed; Ahmadkhaniha, Hamid Reza; Akbari, Mohamad Esmail



Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT1B Inhibitor.  


AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine (5-HT1B) receptor, was explored as a potential treatment for depression. To support clinical trials, repeat dose toxicity studies in rats and dogs were conducted. Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-month study, there were minimal neuronal vacuolation in the brain, a marked increase in liver enzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD), and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-month study, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86 days. Extensive pathologic changes were seen in all animals in retina epithelium (inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiber degeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciatic and optic nerves (degeneration). Pigment-laden macrophages were observed in the lung, kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues. Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration and pathology study showed that the concentration of AZD3783 in the brain was approximately 4 times higher than in the plasma after 4 weeks of dosing, however, they were similar in all regions examined, and did not correlate with areas with pathologic findings. Our findings with AZD3783 in dogs have not been reported previously with other CNS compounds that effect through serotonergic pharmacology. PMID:24791065

Chang, Jane C F; Ciaccio, Paul; Schroeder, Patricia; Wright, Lindsay; Westwood, Russell; Berg, Anna-Lena



Density and Function of Central Serotonin (5-HT) Transporters, 5-HT1A and 5-HT2A Receptors, and Effects of their Targeting on BTBR T+tf/J Mouse Social Behavior  

PubMed Central

BTBR mice are potentially useful tools for autism research because their behavior parallels core social interaction impairments and restricted-repetitive behaviors. Altered regulation of central serotonin (5-HT) neurotransmission may underlie such behavioral deficits. To test this, we compared 5-HT transporter (SERT), 5-HT1A and 5-HT2A receptor densities among BTBR and C57 strains. Autoradiographic [3H] cyanoimipramine (1nM) binding to SERT was 20–30% lower throughout the adult BTBR brain as compared to C57BL/10J mice. In hippocampal membrane homogenates [3H] citalopram maximal binding (Bmax) to SERT was 95 ± 13 fmol/mg protein in BTBR and 171 ± 20 fmol/mg protein in C57BL/6J mice, and the BTBR dissociation constant (KD) was 2 ± 0.3 nM vs. 1.1 ± 0.2 in C57BL/6J mice. Hippocampal 5-HT1A and 5-HT2A receptor binding was similar among strains. However, 8-OH-DPAT-stimulated [35S] GTP?S binding in the BTBR hippocampal CA1 region was 28% higher, indicating elevated 5-HT1A capacity to activate G-proteins. In BTBR mice, the SERT blocker, fluoxetine (10 mg/kg) and the 5-HT1A receptor partial-agonist, buspirone (2 mg/kg) enhanced social interactions. The D2/5-HT2 receptor antagonist, risperidone (0.1 mg/kg) reduced marble burying but failed to improve sociability. Overall, altered SERT and/or 5-HT1A functionality in hippocampus could contribute to the relatively low sociability of BTBR mice. PMID:21070242

Gould, Georgianna G.; Hensler, Julie G.; Burke, Teresa F.; Benno, Robert H.; Onaivi, Emmanuel S.; Daws, Lynette C.



Substitution of 5-HT1A Receptor Signaling by a Light-activated G Protein-coupled Receptor*  

E-print Network

-CT5-HT1A has the potential to directly cor- relate in vivo 5-HT1A signaling with 5-HT neuron activity of physiological and behavioral functions including learning and memory, sexual behavior, and aggression (4


Failed heart rate recovery at a critical age in 5-HT-deficient mice exposed to episodic anoxia: implications for SIDS  

PubMed Central

Mice deficient in the transcription factor Pet-1?/? have a ?70% deficiency of brainstem serotonin [5-hydroxytryptamine (5-HT)] neurons and exhibit spontaneous bradycardias in room air at postnatal day (P)5 and P12 and delayed gasping in response to a single episode of anoxia at P4.5 and P9.5 (Cummings KJ, Li A, Deneris ES, Nattie EE. Am J Physiol Regul Integr Comp Physiol 298: R1333–R1342, 2010; and Erickson JT, Sposato BC. J Appl Physiol 106: 1785–1792, 2009). We hypothesized that at a critical age Pet-1?/? mice will fail to autoresuscitate during episodic anoxia, ultimately dying from a failure of gasping to restore heart rate (HR). We exposed P5, P8, and P12 Pet-1?/? mice and wild-type littermates (WT) to four 30-s episodes of anoxia (97% N2-3% CO2), separated by 5 min of room air. We observed excess mortality in Pet-1?/? only at P8: 43% of Pet-1?/? animals survived past the third episode of anoxia while ?95% of WT survived all four episodes (P = 0.004). No deaths occurred at P5 and at P12, and one of six Pet-1?/? mice died after the fourth episode, while all WT animals survived. At P8, dying Pet-1?/? animals had delayed gasping, recovery of HR, and eupnea after the first two episodes of anoxia (P < 0.001 for each); death ultimately occurred when gasping failed to restore HR. Both high- and low-frequency components of HR variability were abnormally elevated in dying Pet-1?/? animals following the first episode of anoxia. Dying P8 Pet-1?/? animals had significantly fewer 5-HT neurons in the raphe magnus than surviving animals (P < 0.001). Our data indicate a critical developmental window at which a brainstem 5-HT deficiency increases the risk of death during episodes of anoxia. They may apply to the sudden infant death syndrome, which occurs at a critical age and is associated with 5-HT deficiency. PMID:21680874

Commons, Kathryn G.; Hewitt, Julie C.; Daubenspeck, John A.; Li, Aihua; Kinney, Hannah C.; Nattie, Eugene E.



Simple O-acylated derivatives of lysergol and dihydrolysergol-I: synthesis and interaction with 5-HT2A, 5-HT2C and 5-HT1B receptors, and alpha1 adrenergic receptors.  


A series of simple O-acylated derivatives of the naturally occurring clavine alkaloids lysergol and dihydrolysergol-I were synthesized and tested in-vitro for their ability to interact with 5-HT2A receptors in rat tail artery, 5-HT2C receptors in piglet choroid plexus, 5-HT1B receptors in guinea-pig iliac artery and alpha1-adrenergic receptors in rat aorta. In contrast to the classical ergoline 5-HT2A receptor antagonists methysergide and LY53857, the compounds produced competitive antagonism of the 5-HT response in rat tail artery. Affinities of ergolines 3-14 were higher (pA2 values of 7.33-8.40) than those of the parent alcohols lysergol (1) and dihydrolysergol-I (2), respectively. The introduction of an isopropyl substituent at the N(1) position of the compounds failed to enhance 5-HT2A receptor affinity. Compounds 3-14 exhibited lower affinities for alpha1-adrenergic receptors than for 5-HT2A receptors. In particular, those lysergol derivatives that had an isopropyl substituent at the N(1) position were highly specific 5-HT2A receptor antagonists (ratio 5-HT2A/alpha1 = 302-3548). Selected derivatives of lysergol (3-5, 9-11) which were assayed for radioligand binding at 5-HT2C receptors in piglet choroid plexus had affinities that were similar to those found in rat tail artery. Additionally, lysergol and its N(1)-unsubstituted derivatives were found to be partial agonists (alpha of 0.2-0.4) for 5-HT2C receptor-mediated inositol phosphate accumulation in piglet choroid plexus. On the other hand, analogues with an isopropyl substituent at N(1) showed no measurable agonist activity. The observation that N(1)-unsubstituted derivatives of lysergol possessed agonist properties at 5-HT2C receptors whereas their agonist activity at 5-HT2A receptors was marginal (alpha of 0.05 for compound 3 at 1 microM) or not measurable, suggests that these compounds have different abilities to cause conformational change at the two receptor types. Selected derivatives of lysergol (3-5, 9-11) which were examined as ligands for 5-HT1B receptors in guinea-pig iliac artery caused insurmountable blockade of the contractile effect of 5-HT. N(1)-isopropyl derivatives had 30-50-fold lower affinities for 5-HT1B receptors of this tissue than their N(1)-unsubstituted analogues. It is concluded that O-acylated derivatives of the clavine alkaloids lysergol and dihydrolysergol-I mimic therapeutically relevant ergolines due to the complexity of their pharmacological profile as partial agonists and antagonists at 5-HT2A, 5-HT2C and 5-HT1B receptors, and at alpha1-adrenergic receptors. PMID:10344634

Pertz, H H; Brown, A M; Gager, T L; Kaumann, A J



The effects of aging and chronic fluoxetine treatment on circadian rhythms and suprachiasmatic nucleus expression of neuropeptide genes and 5-HT1B receptors  

PubMed Central

Age-related changes in circadian rhythms, including attenuation of photic phase shifts, are associated with changes in the central pacemaker in the suprachiasmatic nucleus (SCN). Aging decreases expression of mRNA for vasoactive intestinal peptide (VIP), a key neuropeptide for rhythm generation and photic phase shifts, and increases expression of serotonin transporters and 5-HT1B receptors, whose activation inhibits these phase shifts. Here we describe studies in hamsters showing that aging decreases SCN expression of mRNA for gastrin-releasing peptide, which also modulates photic phase resetting. Because serotonin innervation trophically supports SCN VIP mRNA expression, and serotonin transporters decrease extracellular serotonin, we predicted that chronic administration of the serotonin-selective reuptake inhibitor, fluoxetine, would attenuate the age-related changes in SCN VIP mRNA expression and 5-HT1B receptors. In situ hybridization studies showed that fluoxetine treatment does not alter SCN VIP mRNA expression, in either age group, at zeitgeber time (ZT)6 or 13 (ZT12 corresponds to lights off). However, receptor autoradiographic studies showed that fluoxetine prevents the age-related increase in SCN 5-HT1B receptors at ZT6, and decreases SCN 5-HT1B receptors in both ages at ZT13. Therefore, aging effects on SCN VIP mRNA and SCN 5-HT1B receptors are differentially regulated; the age-related increase in serotonin transporter sites mediates the latter but not the former. The studies also showed that aging and chronic fluoxetine treatment decrease total daily wheel running without altering the phase of the circadian wheel running rhythm, in contrast to previous reports of phase resetting by acute fluoxetine treatment. PMID:20525077

Duncan, Marilyn J.; Hester, James M.; Hopper, Jason A.; Franklin, Kathleen M.



Unique serotonin receptor (5HT-1C) in choroid plexus is linked to phosphoinositide hydrolysis  

SciTech Connect

The binding of /sup 125/I-LSD to the 5HT-1C site and of /sup 3/H-ket-anserin to the 5HT-2 site was determined in choroid plexus and cerebral cortex of male Sprague-Dawley rats, respectively. As an index of phosphoinositide (PI) hydrolysis, whole choroid plexus and cerebral cortex slices were prelabelled with /sup 3/H-inositol and serotonin (5HT) stimulated release of /sup 3/H-inositol-1-phosphate was measured. 5HT stimulated PI hydrolysis in choroid plexus (6-fold) and in cerebral cortex (2.5-fold). 5HT was more potent in choroid plexus (EC/sub 50/ = 46 nM) consistent with the involvement of the 5HT-1C site. 5HT antagonists, ketanserin, mianserin and spiperone, inhibited the response to 5HT with different potencies in the two tissues. In cerebral cortex all 3 antagonists had nM affinities and a rank order (spiperone > ketanserin > mianserin) consistent with the 5HT-2 site. In choroid plexus, however, the rank order (mianserin > ketanserin > spiperone) and absolute potencies agreed with binding to the 5HT-1C site. These data suggest that the 5HT-1C site is a functional receptor which utilizes PI hydrolysis as its biochemical effector system.

Sanders-Bush, E.; Conn, P.J.; Hoffman, B.J.; Hartig, P.R.



Anticonvulsant action of hippocampal dopamine and serotonin is independently mediated by D and 5-HT receptors.  


The present microdialysis study evaluated the anticonvulsant activity of extracellular hippocampal dopamine (DA) and serotonin (5-HT) with concomitant assessment of the possible mutual interactions between these monoamines. The anticonvulsant effects of intrahippocampally applied DA and 5-HT concentrations were evaluated against pilocarpine-induced seizures in conscious rats. DA or 5-HT perfusions protected the rats from limbic seizures as long as extracellular DA or 5-HT concentrations ranged, respectively, between 70-400% and 80-350% increases compared with the baseline levels. Co-perfusion with the selective D(2) blocker remoxipride or the selective 5-HT(1A) blocker WAY-100635 clearly abolished all anticonvulsant effects. These anticonvulsant effects were mediated independently since no mutual 5-HT and DA interactions were observed as long as extracellular DA and 5-HT levels remained within these protective ranges. Simultaneous D(2) and 5-HT(1A) receptor blockade significantly aggravated pilocarpine-induced seizures. High extracellular DA (> 1000% increases) or 5-HT (> 900% increases) concentrations also worsened seizure outcome. The latter proconvulsive effects were associated with significant increases in extracellular glutamate (Glu) and mutual increases in extracellular monoamines. Our results suggest that, within a certain concentration range, DA and 5-HT contribute independently to the prevention of hippocampal epileptogenesis via, respectively, D(2) and 5-HT(1A) receptor activation. PMID:15140183

Clinckers, Ralph; Smolders, Ilse; Meurs, Alfred; Ebinger, Guy; Michotte, Yvette



5-HT1A Receptor-Regulated Signal Transduction Pathways in Brain  

PubMed Central

Serotonin is an influential monoamine neurotransmitter that signals through a number of receptors to modulate brain function. Among different serotonin receptors, the serotonin 1A (5-HT1A) receptors has been tied to a variety of physiological and pathological processes, notably in anxiety, mood, and cognition. 5-HT1A receptors couple not only to the classical inhibitory G-protein-regulated signaling pathway, but also to signaling pathways traditionally regulated by growth factors. Despite the importance of 5-HT1A receptors in brain function, little is known about how these signaling mechanisms link 5-HT1A receptors to regulation of brain physiology and behavior. Following a brief summary of the known physiological and behavioral effects of 5-HT1A receptors, this article will review the signaling pathways regulated by 5-HT1A receptors, and discuss the potential implication of these signaling pathways in 5-HT1A receptor-regulated physiological processes and behaviors. PMID:20363322

Polter, Abigail M.; Li, Xiaohua



Outcomes Associated with 5-HT3-RA Therapy Selection in Patients with Chemotherapy-Induced Nausea and Vomiting: A Retrospective Claims Analysis  

PubMed Central

Background Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of chemotherapy, and may present during the administration of chemotherapy (ie, acute CINV) or within 25 to 120 hours of chemotherapy (ie, delayed CINV). Preventing CINV with the initiation of chemotherapy is important, because the risk for CINV in future chemotherapy cycles increases if CINV occurs in the first or previous treatment cycle. Inadequately controlled CINV is associated with increased resource utilization and costs, particularly for patients receiving highly or moderately emetogenic chemotherapy. Objective To evaluate the clinical and economic impacts of delayed CINV events in patients who receive initial and maintenance therapy with the newer-generation 5-hydroxytryptamine3 receptor antagonist (5-HT3-RA) palonosetron compared with patients who receive initial and maintenance therapy with an older 5-HT3-RA agent. Methods A retrospective database analysis was conducted using the OptumInsight database covering the years 2005–2011 (96% commercially insured members, 4% Medicaid members). Patients with cancer who received initial therapy with an emetogenic single-day chemotherapy regimen and a 5-HT3-RA agent (ie, dolasetron, granisetron, ondansetron, or palonosetron) were included in the analysis. The outcomes measured included the overall rates of delayed CINV for cycles 1 to 6, by 5-HT3-RA cohort. For cycles 2 to 6, calculations were based on patients who experienced CINV in the previous cycle, maintained the same 5-HT3-RA for all cycles, and had chemotherapy with a similar level of emetic potential. The economic outcomes (ie, cost and utilization) were also collected and calculated. Results A total of 26,974 patients were included in the analysis. The overall rate for delayed CINV at cycle 1 was 15.6%, and the lowest rate was for palonosetron at 15%. The patients who initiated palonosetron had lower CINV rates throughout all cycles. The regression analysis compared individual agents to palonosetron and demonstrated higher odds of CINV in the second cycle for the older agents (ondansetron: odds ratio [OR], 1.41; 95% confidence interval [CI], 1.14–1.74; P <.002; granisetron: OR, 1.70; 95% CI, 1.39–2.08; P <.001; dolasetron: OR, 1.65; 95% CI, 1.27–2.15; P = .002). This trend continued through cycle 6, and not all ORs were significant. Over 6 cycles, ondansetron cost an additional $126,775 compared with palonosetron; granisetron an additional $169,838 versus palonosetron; and dolasetron an additional $148,960. Conclusions Current guidelines support the use of 5-HT3-RA agents for the prevention of CINV. As shown in this analysis, the selection of a specific 5-HT3-RA agent has a clinical and subsequent economic impact on patients with cancer experiencing delayed CINV. Specifically, patients receiving therapy with palonosetron had a lower incidence of delayed CINV and incurred lower overall costs. PMID:24991390

Faria, Claudio; Li, Xuan; Nagl, Norman; McBride, Ali



Characteristics of 5-HT3 binding sites in NG108-15, NCB-20 neuroblastoma cells and rat cerebral cortex using [3H]-quipazine and [3H]-GR65630 binding.  

PubMed Central

1. The biochemical and pharmacological properties of 5-HT3 receptors in homogenates of NG108-15 and NCB-20 neuroblastoma cells and rat cerebral cortex have been ascertained by the use of [3H]-quipazine and [3H]-GR65630 binding. 2. In NG108-15 and NCB-20 cell homogenates, [3H]-quipazine bound to a single class of high affinity (NG108-15: Kd = 6.2 +/- 1.1 nM, n = 4; NCB-20: Kd = 3.0 +/- 0.9 nM, n = 4; means +/- s.e.means) saturable (NG108-15: Bmax = 1340 +/- 220 fmol mg-1 protein; NCB-20: Bmax = 2300 +/- 200 fmol mg-1 protein) binding sites. In rat cortical homogenates, [3H]-quipazine bound to two populations of binding sites in the absence of the 5-hydroxytryptamine (5-HT) uptake inhibitor, paroxetine (Kd1 = 1.6 +/- 0.5 nM, Bmax1 = 75 +/- 14 fmol mg-1 protein; Kd2 = 500 +/- 300 nM, Bmax2 = 1840 +/- 1040 fmol mg-1 protein, n = 3), and to a single class of high affinity binding sites (Kd = 2.0 +/- 0.5 nM, n = 3; Bmax = 73 +/- 6 fmol mg-1 protein) in the presence of paroxetine. The high affinity (nanomolar) component probably represented 5-HT3 binding sites and the low affinity component represented 5-HT uptake sites. 3. [3H]-paroxetine bound with high affinity (Kd = 0.02 +/- 0.003 nM, n = 3) to a site in rat cortical homogenates in a saturable (Bmax = 323 +/- 45 fmol mg-1 protein, n = 3) and reversible manner.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1830236

Sharif, N. A.; Wong, E. H.; Loury, D. N.; Stefanich, E.; Michel, A. D.; Eglen, R. M.; Whiting, R. L.



The binding characteristics and orientation of a novel radioligand with distinct properties at 5-HT3A and 5-HT3AB receptors  

E-print Network

loops B and D, similar to the orientations of the closely related ligands tropisetron (2WNC) and cocaine (2PGZ) in AChBP. In contrast, in 5HTBP 5-HT hydrogen bonds with the backbone carbonyls of I104 (Y141 in 5-HT3) and 12 I116 (Y153), and has...

Thompson, Andrew J.; Verheij, Mark H. P.; Verbeek, Joost; Windhorst, Albert D.; de Esch, Iwan J. P.; Lummis, Sarah C. R.



Do imipramine and dihydroergosine possess two components - one stimulating 5-HT sub 1 and the other inhibiting 5-HT sub 2 receptors  

SciTech Connect

The mechanisms by which imipramine and dihydroergosine stimulate the 5-HT syndrome in rats and inhibit the head-twitch response in rats and mice were studied. Imipramine- and dihydroergosine-included stimulation of the 5-HT syndrome was inhibited stereoselectively by propranolol, a high affinity ligand for 5-HT{sub 1} receptor sites, but not by ritanserin, a specific 5-HT{sub 2} receptor antagonist. (-) -Propranolol potentiated the inhibitory effect of imipramine, but not of dihydroergosine on the head-twitch response, while ritanserin was without effect. As expected, 8-OH-DPAT, a selective 5-HT{sub 1A} receptor agonist, stimulated, and 5-HT{sub 1B} agonists CGS 12066B and 1-(trifluoromethylphenyl) piperazine (TFMPP) failed to stimulate the 5-HT syndrome induced in rats by pargyline and 5-HTP administration. A higher dose of ritanserin inhibited the syndrome. While 8-OH-DPAT alone produced all behavioral components of the 5-HT syndrome, dihydroergosine or imipramine alone even at very high doses never produced tremor or a more intensive forepaw padding as seen when these drugs were given in combination with pargyline and 5-HTP. A single administration of (-)-propranolol also inhibited the head-twitch response. This effect lasted in mice longer that after ritanserin administration. In in vitro experiments dihydroergosine expressed approximately twenty-fold higher affinity for {sup 3}H-ketanserin binding sites than imipramine.

Pericic, D.; Mueck-Seler, D. (Rudjer Boskovic Institute, Zagreb (Yugoslavia))



[3H]-8-OH-DPAT binding in the rat brain raphe area: involvement of 5-HT1A and non-5-HT1A receptors  

PubMed Central

The 5-HT1A agonist 8-OH-DPAT has been shown to have additional 5-HT uptake inhibiting properties. The present work was undertaken to examine further the binding of [3H]-8-OH-DPAT in the raphe area of the rat brain, a region rich in 5-HT1A receptors and 5-HT uptake sites.5-HT inhibited [3H]-8-OH-DPAT binding in a biphasic manner (pKi1: 8.82±0.01, pKi2: 6.07±0.05, n=4) with the low affinity site representing 36±4% of the total population. A biphasic inhibition curve was found also with the 5-HT1A antagonist, WAY 100635 (pKi1: 8.65±0.17, pKi2: 4.26±0.38, n=3). In the presence of 1??M WAY 100635 to mask 5-HT1A receptors, 5-HT inhibited [3H]-8-OH-DPAT binding in a monophasic manner (pKi: 6.04±0.07, n=3).The affinities of various compounds for sites labelled by [3H]-8-OH-DPAT in the presence of 1??M WAY 100635 and for sites labelled by [3H]-citalopram (a selective 5-HT uptake inhibitor) were determined. There was a significant correlation between pKi values at 5-HT uptake sites and at non-5HT1A sites labelled by [3H]-8-OH-DPAT (r=0.80, P<0.001, n=17), suggesting these latter sites to be 5-HT uptake sites.Whereas the affinities of R(+) and S(?) enantiomers of 8-OH-DPAT for the 5-HT uptake site are similar, R(+)8-OH-DPAT has 10 times higher affinity for the non-5-HT1A site than S(?)8-OH-DPAT and was considered as an outlier in the correlation. It is suggested that [3H]-8-OH-DPAT labels other, as yet unknown binding sites in the raphe. PMID:10903975

Assie, Marie-Bernadette; Koek, Wouter



In vitro and in vivo profile of SB 206553, a potent 5-HT2C/5-HT2B receptor antagonist with anxiolytic-like properties.  

PubMed Central

1. SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole) displays a high affinity (pK1 7.9) for the cloned human 5-HT2C receptor expressed in HEK 293 cells and the 5-HT2B receptor (pA2 8.9) as measured in the rat stomach fundus preparation. SB 206553 has low affinity for cloned human 5-HT2A receptors expressed in HEK 293 cells (pK1 5.8) and (pK1 < 6) for a wide variety of other neurotransmitter receptors. 2. SB 206553 appears to be a surmountable antagonist of 5-HT-stimulated phosphoinositide hydrolysis in HEK 293 cells expressing the human 5-HT2C receptor (pKB 9.0). 3. The compound potently (ID50 5.5 mg kg-1, p.o., 0.27 mg kg-1, i.v.) inhibited the hypolocomotor response to m-chlorophenylpiperazine (mCPP), a putative model of 5-HT2C/5-HT2B receptor function in vivo. 4. At similar doses (2-20 mg kg-1, p.o.) SB 206553 increased total interaction scores in a rat social interaction test and increased punished responding in a rat Geller-Seifter conflict test. These effects are consistent with the possession of anxiolytic properties. 5. SB 206553 also increased suppressed responding in a marmoset conflict model of anxiety at somewhat higher doses (15 and 20 mg kg-1, p.o.) but also reduced unsuppressed responding. 6. These results suggest that SB 206553 is a potent mixed 5-HT2C/5-HT2B receptor antagonist with selectivity over the 5-HT2A and all other sites studied and possesses anxiolytic-like properties. PMID:8821530

Kennett, G. A.; Wood, M. D.; Bright, F.; Cilia, J.; Piper, D. C.; Gager, T.; Thomas, D.; Baxter, G. S.; Forbes, I. T.; Ham, P.; Blackburn, T. P.



NMDA-induced glutamate and aspartate release from rat cortical pyramidal neurones: evidence for modulation by a 5-HT1A antagonist.  

PubMed Central

1. We have investigated an aspect of the regulation of cortical pyramidal neurone activity. Microdialysis was used to assess whether topical application of drugs (in 10 microliter) to fill a burr hole over the frontal cortex, where part of the corticostriatal pathway originates, would change concentrations of the excitatory amino acids glutamate and aspartate in the striatum of the anaesthetized rat. 2. Topical application of N-methyl-D-aspartate (NMDA, 2 and 20 mM) dose-dependently increased glutamate and aspartate concentrations in the striatum. Coapplication of tetrodotoxin (10 microM) blocked the NMDA-evoked rise in these amino acids. A calcium-free medium, perfused through the probe also blocked the rise, indicating that it was due to an exocytotic mechanism in the striatum. 3. It was hypothesized that the rise observed was due to an increase in the activity of the corticostriatal pathway. As 5-hydroxytryptamine1A (5-HT1A) receptors are enriched on cell bodies of corticostriatal neurones, a selective 5-HT1A-antagonist (WAY 100135) was coapplied with the lower dose of NMDA. Compared to NMDA alone, coapplication of 50 microM WAY 100135 significantly increased glutamate release. This effect was sensitive to tetrodotoxin and calcium-dependent. Application of 50 microM WAY 100135 alone significantly enhanced glutamate release above baseline; this was also tested at 100 microM (not significant). 4. Compared to NMDA alone, coapplication of WAY 100135 (20 microM) significantly enhanced aspartate release; the mean value was also increased (not significantly) with 50 microM. This rise was calcium-dependent, but not tetrodotoxin-sensitive. WAY 100135 (100 microM) reduced NMDA-induced aspartate release.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582540

Dijk, S. N.; Francis, P. T.; Stratmann, G. C.; Bowen, D. M.



5-HT neurons of the area postrema become c-Fos-activated after increases in plasma sodium levels and transmit interoceptive information to the nucleus accumbens.  


Serotonergic (5-hydroxytryptamine, 5-HT) neurons of the area postrema (AP) represent one neuronal phenotype implicated in the regulation of salt appetite. Tryptophan hydroxylase (Tryp-OH, synthetic enzyme-producing 5-HT) immunoreactive neurons in the AP of rats become c-Fos-activated following conditions in which plasma sodium levels are elevated; these include intraperitoneal injections of hypertonic saline and sodium repletion. Non-Tryp-OH neurons also became c-Fos-activated. Sodium depletion, which induced an increase in plasma osmolality but caused no significant change in the plasma sodium concentration, had no effect on the c-Fos activity in the AP. Epithelial sodium channels are expressed in the Tryp-OH-immunoreactive AP neurons, possibly functioning in the detection of changes in plasma sodium levels. Since little is known about the neural circuitry of these neurons, we tested whether the AP contributes to a central pathway that innervates the reward center of the brain. Stereotaxic injections of pseudorabies virus were made in the nucleus accumbens (NAc), and after 4 days, this viral tracer produced retrograde transneuronal labeling in the Tryp-OH and non-Tryp-OH AP neurons. Both sets of neurons innervate the NAc via a multisynaptic pathway. Besides sensory information regarding plasma sodium levels, the AP?NAc pathway may also transmit other types of chemosensory information, such as those related to metabolic functions, food intake, and immune system to the subcortical structures of the reward system. Because these subcortical regions ultimately project to the medial prefrontal cortex, different types of chemical signals from visceral systems may influence affective functions. PMID:24598462

Miller, Rebecca L; Loewy, Arthur D



Similar anxiolytic effects of agonists targeting serotonin 5-HT1A or cannabinoid CB receptors on zebrafish behavior in novel environments.  


The discovery that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are present and bioaccumulate in aquatic ecosystems have spurred studies of fish serotonin transporters (SERTs) and changes in SSRI-sensitive behaviors as adverse outcomes relevant for risk assessment. Many SSRIs also act at serotonin 5-HT1A receptors. Since capitalizing on this action may improve treatments of clinical depression and other psychiatric disorders, novel multimodal drugs that agonize 5-HT1A and block SERT were introduced. In mammals both 5-HT1A and CB agonists, such as buspirone and WIN55,212-2, reduce anxious behaviors. Immunological and behavioral evidence suggests that 5-HT1A-like receptors may function similarly in zebrafish (Danio rerio), yet their pharmacological properties are not well characterized. Herein we compared the density of [(3)H] 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT) binding to 5-HT1A-like sites in the zebrafish brain, to that of similarly G?i/o-coupled cannabinoid receptors. [(3)H] 8-OH-DPAT specific binding was 176±8, 275±32, and 230±36fmol/mg protein in the hypothalamus, optic tectum, and telencephalon. [(3)H] WIN55,212-2 binding density was higher in those same brain regions at 6±0.3, 5.5±0.4 and 7.3±0.3pm/mg protein. The aquatic light-dark plus maze was used to examine behavioral effects of 5-HT1A and CB receptor agonists on zebrafish novelty-based anxiety. With acute exposure to the 5-HT1A partial-agonist buspirone (50mg/L), or dietary exposure to WIN55,212-2 (7?g/week) zebrafish spent more time in and/or entered white arms more often than controls (p<0.05). Acute exposure to WIN55,212-2 at 0.5-50mg/L reduced mobility. These behavioral findings suggest that azipirones, like cannabinoid agonists, have anxiolytic and/or sedative properties on fish in novel environments. These observations highlight the need to consider potential ecological risks of azapirones and multimodal antidepressants in the future. PMID:24411165

Connors, Kristin A; Valenti, Theodore W; Lawless, Kelly; Sackerman, James; Onaivi, Emmanuel S; Brooks, Bryan W; Gould, Georgianna G



The mouse 5-HT2B receptor: possible involvement in trophic functions of serotonin.  


The novel serotonin receptor 5-HT2B shows the highest homology to the 5-HT2 family of receptors. The pharmacological profile of membranes from 5-HT2B cDNA stably transfected LMTK- cell line, corresponds to a new 5-HT2-like receptor named 5-HT2B, although some difference exists between the mouse and rat pharmacology. A similar pharmacological profile is detected on the immortalized teratocarcinoma-derived cell line 1C11 upon 2 days of serotoninergic differenciation by cAMP. In both cell lines, the analysis 125I-DOI binding reveals the presence of a single class of sites, the affinity of which is one order of magnitude lower than the one reported for the 5-HT2A receptor. This demonstrates that the 5-HT2B receptor is functionally expressed before the complete serotoninergic differentiation of 1C11 cells. These observations are in good agreement with the presence of 5-HT2B mRNA in early mouse embryonic development. Furthermore, the major sites of 5-HT2B mRNA embryonic expression are in the heart, and in the neural fold before the closure of the neural tube. Therefore, this receptor could account at least in part for the trophic functions attributed to the 5-HT2-like receptors. PMID:7920184

Choi, D S; Colas, J F; Kellermann, O; Loric, S; Launay, J M; Rosay, P; Maroteaux, L



Hyperserotonemia in autism: the potential role of 5HT-related gene variants.  


Increased platelet serotonin level (PSL) has been consistently found in a portion of autistic patients. Suggested mechanisms for hyperserotonemia in autism have been increased synthesis of serotonin (5HT) by tryptophan hydroxylase (TPH), increased uptake into platelets through 5HT transporter (5HTt), diminished release from platelets through 5HT2A receptor (5HT2Ar) and decreased metabolism by monoamine oxydase (MAOA). The allelic influence of genes, encoding the mentioned 5HT elements, on PSL was investigated in 63 autistic subjects. Our study shows that 5HTt-LPR and -1438AG 5HT(2Ar) genotypes did not significantly affect PSL. However, significantly higher PSLs were observed in subjects with "cc" genotype of a218c TPH and subjects with "4" genotype of uVNTR MAOA. In addition, when TPH-cc and MAOA-4 were combined as "high 5HT" genotypes, a correlative increase in PSL was observed with the increase in the number of "high 5HT" genotypes. These results suggest a possible synergistic effect of genes regulating 5HT synthesis/degradation in dysregulation of the peripheral 5HT homeostasis of autistic patients. PMID:18405062

Hranilovi?, Dubravka; Novak, Ruder; Babi?, Marina; Novokmet, Mislav; Bujas-Petkovi?, Zorana; Jernej, Branimir



5-HT2A receptor gene polymorphism and eating disorders.  


Recent studies have reported a genetic association between the -1438 G/A polymorphism within the promoter region of the 5-HT(2A) receptor gene and eating disorders (ED), with conflicting results. To clarify the role of the -1438 G/A polymorphism in different ED categories we have analyzed the genotype and allele frequency distribution in 54 Italian patients with Binge ED (BED) compared to 132 obese non-BED subjects. No significant differences were found between obese BED and obese non-BED individuals, suggesting that this polymorphism does not genetically distinguish these two phenotypes. Moreover, the evaluation of 148 patients with anorexia nervosa and 86 patients with bulimia nervosa revealed an association of the A allele with both these disorders. PMID:11950504

Ricca, Valdo; Nacmias, Benedetta; Cellini, Elena; Di Bernardo, Milena; Rotella, Carlo Maria; Sorbi, Sandro



Systematic review: cardiovascular safety profile of 5-HT4 agonists developed for gastrointestinal disorders  

PubMed Central

Summary Background The nonselective 5-HT4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). Aim To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Methods Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006–2008 and DDW 2008–2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Results Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT4 agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT4 agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT4 agonists with no hERG or 5-HT1 affinity (renzapride, clebopride, mosapride). Conclusions 5-HT4 agonists for GI disorders differ in chemical structure and selectivity for 5-HT4 receptors. Selectivity for 5-HT4 over non-5-HT4 receptors may influence the agent's safety and overall risk–benefit profile. Based on available evidence, highly selective 5-HT4 agonists may offer improved safety to treat patients with impaired GI motility. PMID:22356640

Tack, J; Camilleri, M; Chang, L; Chey, W D; Galligan, J J; Lacy, B E; Müller-Lissner, S; Quigley, E M M; Schuurkes, J; Maeyer, J H; Stanghellini, V



Distribution of 5-hydroxytryptamine-immunoreactive boutons on alpha-motoneurons in the lumbar spinal cord of adult cats.  


Recent studies have shown that at least some of the functional effects of serotonin (5-HT) on motoneuron excitability are direct and are mediated via postsynaptic 5-HT receptors on motoneurons. To determine the spatial distribution of direct inputs from the serotonin system on the proximal and distal dendrites of individual motoneurons, we examined identified motoneurons in vivo with a combination of immunohistochemical localization of 5-HT-immunoreactive boutons and intracellular staining with horseradish peroxidase. Seventeen intracellularly stained motoneurons from 12 adult cats were analyzed with light microscopy. Quantitative analysis of 5-HT boutons apposed to dendrites of five representative motoneurons that were entirely reconstructed in three dimensions (each from the lumbosacral spinal cord of a different animal) revealed a total of 7,848 contacts (1,570+/-487 contacts/postsynaptic neuron; mean +/- SD) over the dendrites of these cells. Analysis of contacts on the soma of two of these cells, and on the somas of an additional 12 intracellularly stained motoneurons, revealed a wide range of somatic contacts (11-211 contacts/cell) on motoneuron cell bodies, with an average of 52 contacts/cell. These results indicate that the vast majority of 5-HT-immunoreactive boutons are apposed to dendritic branches rather than to the somatic surface of motoneurons. The spatial distribution of contacts essentially matched the distribution of surface membrane area of the postsynaptic neuron, resulting in a relatively uniform density of contacts (<1/100 microm2) on proximal and distal dendrites. Consequently, the frequency of contacts was higher on the proximal dendritic compartments where available membrane area is greater. There was no preferential distribution of contacts to particular dendrites. Light/electron microscopic correlations were performed on 21 boutons that contacted dendrites (n = 7) of three motoneurons from different animals. At the electron microscope level, most appositions (18/21; 85.7%) selected by our light microscopic criteria were confirmed as direct contacts when the 5-HT boutons were examined through serial sections. Synaptic junctions, generally small and symmetric, were positively identified in only a subset of these cases (n = 6; 28.6%), in part due to the obscuring effects of the peroxidase histochemical precipitate present in both pre- and postsynaptic profiles. A few 5-HT boutons (3/21; 14.3%) selected as contacts by our light microscopic criteria were in fact separated from the adjacent labeled dendrites; in two of these three cases, the separation was due to intrusion of very thin glial lamellae (<0.3 microm in cross section). These results indicate that the bulbospinal serotonergic system(s) provide a significant, direct synaptic input to spinal motoneurons that innervate hindlimb muscles. The nature of the modulatory actions exerted by such widespread synaptic inputs will affect all regions of the somatodendritic membrane and will ultimately depend on the nature of the 5-HT receptors present over different parts of the postsynaptic neuron's dendritic tree. PMID:9520102

Alvarez, F J; Pearson, J C; Harrington, D; Dewey, D; Torbeck, L; Fyffe, R E



Inhibitors of serotonin reuptake and specific imipramine binding in human blood plasma  

SciTech Connect

This paper describes a method of extraction of endogenous inhibitors of specific IMI binding and of 5-HT reuptake, from human blood plasma and the heterogeneity of these compounds is demonstrated. Specific binding was determined as the difference between binding of /sup 3/H-IMI in the absence and in the presence of 50 microM IMI. Under these conditions, specific binding amounted to 70-80% of total binding of /sup 3/H-IMI. It is shown that extract obtained from human blood contains a material which inhibits dose-dependently both 5-HT reuptake and specific binding of /sup 3/H-IMI. Gel-chromatography of extracts of human blood plasma on Biogel P-2 is also shown.

Brusov, O.S.; Fomenko, A.M.; Katasonov, A.B.; Lidemann, R.R.



Synthesis and pharmacological investigation of aralkyl diamine derivatives as potential triple reuptake inhibitors.  


A series of aralkyl diamine derivatives were designed, synthesized, and evaluated for their triple reuptake inhibitory abilities. Compounds 18c (5-HT, NE, DA, IC50 = 389, 69, 238 nM), 36a (5-HT, NE, DA, IC50 = 378, 477, 247 nM), and 36d (5-HT, NE, DA, IC50 = 501, 206, 357 nM) showed in vivo activities in the rat forced swim test at 5, 10, and 20 mg/kg PO. 36a was identified as the most promising candidate in this study. Specifically, 36a exhibited high selectivity for monoamine transporters over a number of CNS-related targets. Furthermore, 36a showed a good pharmacokinetic properties and acceptable safety profile in preclinical studies. PMID:25164761

Zheng, Yong-Yong; Weng, Zhi-Jie; Xie, Peng; Zhu, Mei-Yu; Xing, Long-Xuan; Li, Jian-Qi



Interaction of Serotonin 5-Hydroxytryptamine Type 2C Receptors with PDZ10 of the Multi-PDZ Domain Protein MUPP1*  

E-print Network

Interaction of Serotonin 5-Hydroxytryptamine Type 2C Receptors with PDZ10 of the Multi-PDZ Domain two-hybrid system, we previously isolated a cDNA clone encoding a novel member of the multivalent PDZ protein family called MUPP1 contain- ing 13 PDZ domains. Here we report that the C terminus of the 5

Lübbert, Hermann


Presence of 5-hydroxytryptamine (serotonin) transport coupled with vacuolar-type H(+)-ATPase in neurosecretory granules from bovine posterior pituitary.  


Electrogenic H(+)-ATPase was found in neurosecretory granules from bovine posterior pituitary. This enzyme was sensitive to bafilomycin, a specific inhibitor of vacuolar H(+)-ATPase, and was inactivated completely by cold treatment in the presence of MgATP and NaNO3. Immunoblot analysis showed the presence of immunologically identical polypeptides (72, 57, and 34 kDa) in the ATPases of the neurosecretory granules and chromaffin granules. The granules showed MgATP-dependent activity for 5-hydroxytryptamine (serotonin) uptake. This uptake was temperature-dependent and showed saturation kinetics (apparent Km for 5-hydroxytryptamine, 2 microM) and counter-flow. Reserpine and tetrabenazine at 1 microM inhibited the uptake, whereas imipramine at 2 microM had no effect. Dopamine, epinephrine and norepinephrine were also inhibitory. The uptake was abolished by various treatments that dissipated the electrochemical H+ gradient or inhibited the H(+)-ATPase. These results indicate that a vacuolar type H(+)-ATPase in the neurosecretory granules forms an electrochemical H+ gradient that drives 5-hydroxytryptamine uptake by a specific transport system. A similar granular fraction from the anterior pituitary had no ATP-dependent activity for 5-hydroxytryptamine uptake. PMID:2160961

Moriyama, Y; Futai, M



Comparison of the vasoconstrictor effects of the selective 5-HT1D-receptor agonist L-775,606 with the mixed 5-HT1B/1D-receptor agonist sumatriptan and 5-HT in human isolated coronary artery  

PubMed Central

Aims Vasoconstriction in human coronary artery can be mediated via activation of both 5-HT2 and 5-HT1B-receptors. Coronary vasoconstriction is a rare, but potential adverse effect of the antimigraine drug sumatriptan. In order to investigate the receptor population involved we compared the vasoconstrictor effects of sumatriptan (a mixed 5-HT1B/1D-receptor agonist) with those of L-775,606 (a selective 5-HT1D-receptor agonist) and 5-HT (the endogenous ligand) in human isolated coronary arteries. Methods Coronary arteries were obtained from human hearts removed prior to transplant surgery. Several endothelium denuded ring segments (4 mm in length) were obtained from each artery and mounted for isometric tension recording. Each segment was first exposed to 45 mm KCl and then to 5-HT (1 nm-100 ?m?). Concentration-effect curves to L-775,606 (1-(3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)piperazine) and sumatriptan were then performed in a consecutive and random manner. The response to repeated application of 5-HT was obtained in separate segments. Results Twenty-five segments from seven different coronary arteries were studied. Concentration-effect curves were fitted to the data using nonlinear regression analysis. The maximum contraction for L-775,606 was significantly less than that for sumatriptan with Emax values (% relative to 45 mm KCl=100%) of 30.1±4.22 and 41.5±2.7, respectively. L-775,606 was significantly (30-fold) less potent than sumatriptan in causing contraction compared with sumatriptan (EC50 values were 6.0 ?m and 0.2 ?m, respectively). For comparison the Emax value for 5-HT was 77.2% and the EC50 value was 0.2 ?m. Conclusions The selective 5-HT1D-receptor agonist L-775,606 has less propensity towards vasoconstriction in human isolated coronary artery (endothelium-denuded) than was mixed 5-HT1B/1D-receptor agonist sumatriptan. The contractions produced were at concentrations where L-775,606 would be expected to occupy 5-HT1B-receptors. PMID:10671906

Longmore, J; Maguire, J J; MacLeod, A; Street, L; Schofield, W N; Hill, R G



Human platelet 5-hydroxytryptamine receptors: Binding of [ 3 H]-lysergic acid diethylamide (LSD). Effects of chronic neuroleptic and antidepressant drug administration  

Microsoft Academic Search

Summary Chronic treatment with phenothiazines and thioxanthenes has been found to enhance 5-HT-induced aggregation of human platelets. A method has been developed to study 5-HT2 receptor binding sites on platelets utilising [3H]-LSD and more recently125I\\/LSD. Results are presented which suggest that the LSD binding site is indeed the 5-HT2 binding site and that the LSD binding characterises the specific receptor

D. G. Grahame-Smith; D. P. Geaney; M. Schachter; J. M. Elliott



Effect of 5-HT2 and 5-HT3 receptor antagonists on cholera toxin-induced fluid hypersecretion in the pig jejunum.  


5-Hydroxytryptamine is a mediator in cholera toxin-induced hypersecretion in the small intestine. The aim of this study was to determine the effect of the 5-hydroxytryptamine receptor antagonists ketanserin, granisetron, ondansetron and tropisetron on cholera toxin-induced hypersecretion in the pig jejunum. Hypersecretion was induced by cholera toxin in ligated jejunal loops. The antagonists were administered subcutaneously at a dose of 100 micrograms/kg. Furthermore, the effect of intraluminally instilled ondansetron was studied. None of the antagonists altered basal absorption or caused fluid hypersecretion. Cholera toxin caused a dose-dependent electrolyte and fluid hypersecretion. The apparent maximal effect, 6.8 +/- 0.4 mg fluid x mg dry loop-1, was reduced by ondansetron, granisetron and tropisetron by about 40%, 30%, and 20%, respectively, whereas ketanserin had no effect. Intraluminal ondansetron reduced the effect of cholera toxin by about 50%. These results demonstrate that 5-hydroxytryptamine3 antagonists administered subcutaneously reduce the cholera toxin-induced hypersecretion in the pig jejunum. Finally, the results support species differences with respect to the antagonistic effect of the tested drugs in cholera toxin-induced hypersecretion. PMID:8968163

Grondahi, M L; Jensen, G M; Skadhauge, E; Hansen, M B



The binding characteristics and orientation of a novel radioligand with distinct properties at 5-HT3A and 5-HT3AB receptors.  


VUF10166 (2-chloro-3-(4-methyl piperazin-1-yl)quinoxaline) is a ligand that binds with high affinity to 5-HT3 receptors. Here we synthesise [(3)H]VUF10166 and characterise its binding properties at 5-HT3A and 5-HT3AB receptors. At 5-HT3A receptors [(3)H]VUF10166 displayed saturable binding with a Kd of 0.18 nM. Kinetic measurements gave monophasic association (6.25 × 10(7) M(-1) min(-1)) and dissociation (0.01 min(-1)) rates that yielded a similar Kd value (0.16 nM). At 5-HT3AB receptors two association (6.15 × 10(-7), 7.23 M(-1) min(-1)) and dissociation (0.024, 0.162 min(-1)) rates were seen, yielding Kd values (0.38 nM and 22 nM) that were consistent with values obtained in saturation (Kd = 0.74 nM) and competition (Ki = 37 nM) binding experiments respectively. At both receptor types, specific binding was inhibited by classical 5-HT3 receptor-selective orthosteric ligands (5-HT, allosetron, d-tubocurarine, granisetron, mCPBG, MDL72222, quipazine), but not by non-competitive antagonists (bilobalide, ginkgolide B, picrotoxin) or competitive ligands of other Cys-loop receptors (ACh, bicuculline, glycine, gabazine). To explore VUF10166 ligand-receptor interactions we used in silico modelling and docking, and tested the predictions using site directed mutagenesis. The data suggest that VUF10166 adopts a similar orientation to 5-HT3 receptor agonists bound in AChBP (varenicline) and 5HTBP (5-HT) crystal structures. PMID:25174552

Thompson, Andrew J; Verheij, Mark H P; Verbeek, Joost; Windhorst, Albert D; de Esch, Iwan J P; Lummis, Sarah C R



The binding characteristics and orientation of a novel radioligand with distinct properties at 5-HT3A and 5-HT3AB receptors  

PubMed Central

VUF10166 (2-chloro-3-(4-methyl piperazin-1-yl)quinoxaline) is a ligand that binds with high affinity to 5-HT3 receptors. Here we synthesise [3H]VUF10166 and characterise its binding properties at 5-HT3A and 5-HT3AB receptors. At 5-HT3A receptors [3H]VUF10166 displayed saturable binding with a Kd of 0.18 nM. Kinetic measurements gave monophasic association (6.25 × 107 M?1 min?1) and dissociation (0.01 min?1) rates that yielded a similar Kd value (0.16 nM). At 5-HT3AB receptors two association (6.15 × 10?7, 7.23 M?1 min?1) and dissociation (0.024, 0.162 min?1) rates were seen, yielding Kd values (0.38 nM and 22 nM) that were consistent with values obtained in saturation (Kd = 0.74 nM) and competition (Ki = 37 nM) binding experiments respectively. At both receptor types, specific binding was inhibited by classical 5-HT3 receptor-selective orthosteric ligands (5-HT, allosetron, d-tubocurarine, granisetron, mCPBG, MDL72222, quipazine), but not by non-competitive antagonists (bilobalide, ginkgolide B, picrotoxin) or competitive ligands of other Cys-loop receptors (ACh, bicuculline, glycine, gabazine). To explore VUF10166 ligand–receptor interactions we used in silico modelling and docking, and tested the predictions using site directed mutagenesis. The data suggest that VUF10166 adopts a similar orientation to 5-HT3 receptor agonists bound in AChBP (varenicline) and 5HTBP (5-HT) crystal structures. PMID:25174552

Thompson, Andrew J.; Verheij, Mark H.P.; Verbeek, Joost; Windhorst, Albert D.; de Esch, Iwan J.P.; Lummis, Sarah C.R.



Effect of treadmill exercise on 5-HT, 5-HT1A receptor and brain derived neurophic factor in rats after permanent middle cerebral artery occlusion.  


It has been well documented that exercise promotes neurological rehabilitation in patients with cerebral ischemia. However, the exact mechanisms have not been fully elucidated. This study aimed to discuss the effect of treadmill exercise on expression levels of 5-HT, 5-HT1A receptor (5-HT1AR) and brain derived neurophic factor (BDNF) in rat brains after permanent middle cerebral artery occlusion (pMCAO). A total of 55 rats were randomly divided into 3 groups: pMCAO group, pMCAO and treadmill exercise (pMCAO + Ex) group, and sham-operated group. Rats in pMCAO + Ex group underwent treadmill exercise for 16 days. Neurological function was evaluated by modified Neurological Severity Scores (mNSS). High-performance liquid chromatography-electrochemical detection system was used to determine the content of 5-HT in cortex tissues. The protein levels of 5-HT1AR, BDNF and synaptophysin were measured by Western blot. The mNSS in pMCAO + Ex group was lower than that in pMCAO group on day 19 post-MCAO (p < 0.001). The content of 5-HT dropped to 3.81 ± 1.86 ng/ml in pMCAO group (43.84 ± 2.05 ng/ml in sham-operated group), but increased in pMCAO + Ex group (10.06 ± 1.80 ng/ml). The protein expressions levels of synaptophysin, 5-HT1AR and BDNF were downregulated after cerebral ischemia (p < 0.05), and upregulated after treadmill exercise (p < 0.05). These results indicate that treadmill exercise improves neurologic function, enhances neuronal plasticity and upregulates the levels of 5-HT, 5-HT1AR and BDNF in rats with pMCAO. PMID:24326625

Lan, Xiaofang; Zhang, Meng; Yang, Wan; Zheng, Zongju; Wu, Yuan; Zeng, Qian; Liu, Shudong; Liu, Ke; Li, Guangqin



Antidepressant and antipsychotic activity of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole targeting serotonin 5-HT?A/5-HT?A/5-HT? and dopamine D?/D? receptors.  


A series of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole was synthesized to explore the influence of two structural features - replacement of ether/amide moiety with sulfonamide one, and localization of a sulfonamide group in the azine moiety. In contrast to aripiprazole, compound 33 (N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)quinoline-7-sulfonamide) and 39 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)isoquinoline-3-sulfonamide) displaying multireceptor 5-HT(1A)/5-HT(2A)/5-HT(7)/D(2)/D(3) profile, and behaving as 5-HT(1A) agonists, D(2) partial agonists, and 5-HT(2A)/5-HT(7) antagonists, produced significant antidepressant activity in FST in mice. On the other hand, their 4-isoquinolinyl analog 40 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)isoquinoline-4-sulfonamide), with similar receptor binding and functional profile, additionally displayed remarkable antipsychotic properties in the MK-801-induced hyperlocomotor activity in mice. PMID:23279866

Zajdel, Pawe?; Marciniec, Krzysztof; Ma?lankiewicz, Andrzej; Grychowska, Katarzyna; Sata?a, Grzegorz; Duszy?ska, Beata; Lenda, Tomasz; Siwek, Agata; Nowak, Gabriel; Partyka, Anna; Wróbel, Dagmara; Jastrz?bska-Wi?sek, Magdalena; Bojarski, Andrzej J; Weso?owska, Anna; Paw?owski, Maciej



Effects of repeated 5-HT? receptor stimulation on BDNF gene expression and cell survival.  


In support of the neurotrophic hypothesis of depression chronic antidepressant drug treatment increases brain-derived neurotrophic factor (bdnf) gene expression and neurogenesis. Regarding 5-HT active drugs, the 5-HT receptor behind these effects remains unidentified. Here we report the effect of repeated 5-HT?-receptor stimulation on bdnf expression and cell survival. The previously reported acute stimulatory action of the selective 5-HT? agonist LY-586713 on hippocampal bdnf expression was still present following sub-chronic (4 days), but not chronic (14 days), treatment. The effect on 5-HT?-mediated cell survival was also dependent on a similar length of treatment. Hence, our study found no support for a primary effect of 5-HT? receptors in the mediation of chronic antidepressant drug-induced up-regulation of bdnf expression or neurogenesis. PMID:23981663

de Foubert, Georgina; Khundakar, Ahmad A; Zetterström, Tyra S



Serotonin (5HT) 2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5HT, release in the frontal cortex in vivo  

Microsoft Academic Search

The novel, preferential 5-HT2C receptor agonist, Ro 60-0175 ((S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine) (2.5 mg\\/kg, s.c.), markedly suppressed dialysate levels of dopamine (DA) and noradrenaline (NA) levels in the frontal cortex of freely-moving rats without affecting levels of 5-HT. In contrast, the novel and selective 5-HT2C receptor antagonist, SB-242084 (6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline) (10.0 mg\\/kg, i.p.), markedly increased dialysate levels of DA and NA

M. J Millan; A Dekeyne; A Gobert



Serotonin (5-HT) receptor subtypes mediate specific modes of 5-HT-induced signaling and regulation of neurosecretion in gonadotropin-releasing hormone neurons.  


Serotonin (5-HT), the endogenous nonselective 5-HT receptor agonist, activates the inositol 1,4,5-triphosphate/calcium (InsP3/Ca2+) signaling pathway and exerts both stimulatory and inhibitory actions on cAMP production and GnRH release in immortalized GnRH neurons. The high degree of similarity between the signaling and secretory responses elicited by GnRH and 5-HT prompted us to target specific 5-HT receptor subtypes to deconvolute the complex actions of these agonists on signal transduction and GnRH release. Specific mRNA transcripts for 5-HT1A, 5-HT2C, 5-HT4, and 5-HT7 were identified in immortalized GnRH neurons (GT1-7). The rate of firing of spontaneous action potentials (APs) by hypothalamic GnRH neurons and cAMP production and pulsatile GnRH release in GT17 cells were profoundly inhibited during activation of the Gi-coupled 5-HT1A receptor. Treatment with a selective agonist to activate the Gq-coupled 5-HT2C receptor increased the rate of firing of spontaneous APs, stimulated InsP3 production and caused a delayed increase in GnRH release. Selective activation of the Gs-coupled 5-HT4 receptor also increased the rate of firing of APs, stimulated cAMP production, and caused a sustained and robust increase in GnRH release. The ability of 5-HT receptor subtypes expressed in GnRH neurons to activate single or multiple G proteins in a time- and dose-dependent manner differentially regulates the phospholipase C/InsP3/Ca2+, and adenylyl cyclase/cAMP signaling pathways, and thereby regulates the frequency and amplitude of pulsatile GnRH release. This process, in conjunction with the modulation of spontaneous electrical activity of the GnRH neuron, contributes to the control of the pulsatile mode of neuropeptide secretion that is characteristic of GnRH neuronal function in vivo and in vitro. PMID:16109737

Wada, Keiko; Hu, Lian; Mores, Nadia; Navarro, Carlos E; Fuda, Hirotoshi; Krsmanovic, Lazar Z; Catt, Kevin J



Sulfonyl-containing modulators of serotonin 5-HT6 receptors and their pharmacophore models  

NASA Astrophysics Data System (ADS)

Data published in recent years on the synthesis of serotonin 5-HT6 receptor modulators are summarized. Modulators with high affinity for 5-HT6 receptors exhibiting different degrees of selectivity — from highly selective to semiselective and multimodal — are described. Clinical trial results are reported for the most promising serotonin 5-HT6 receptor modulators attracting special attention of medicinal chemists. The bibliography includes 128 references.

Ivachtchenko, A. V.



Involvement of a polymorphism in the 5HT2A receptor gene in impulsive behavior  

Microsoft Academic Search

Rationale and objective  Impulsive behavior has been suggested to occur due to a dysfunction of serotonergic 5-HT neurotransmission. After evaluation by a self-reporting measure, a polymorphism in the promoter of the 5-HT2A receptor gene has been proposed to underlie the impulsive behavior; however, this hypothesis is not convincing. In this study, we examined whether this 5-HT2A receptor gene polymorphism is involved

Michio Nomura; Ichiro Kusumi; Masayuki Kaneko; Takuya Masui; Makoto Daiguji; Takeji Ueno; Tsukasa Koyama; Yasuyuki Nomura



Anti-anxiety effect of a novel 5-HT3 receptor antagonist N-(benzo[d]thiazol-2-yl)-3-ethoxyquinoxalin-2-carboxamide (6k) using battery tests for anxiety in mice  

PubMed Central

Objective: To investigate the anti-anxiety activity of “6k”, a novel 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist in in mice. Materials and Methods: Anti-anxiety activity of “6k” (1, 2, and 4 mg/kg, intraperitoneally (i.p.)) was evaluated in mice by behavioral tests such as elevated plus maze (EPM), open field test (OFT), light-dark box (L&D), and hole board test (HBT). Diazepam (2 mg/kg, i.p.) served as reference standard. Results: “6k” significantly (P < 0.05) increased the time and entries in open arm in EPM as compared to vehicle control group. Further, “6k” significantly (P < 0.05) increased the central and peripheral ambulation along with rearings and time in central area; whereas, reduced the fecal pellets in OFT as compared to vehicle control group. There was significant (P < 0.05) reduction in the latency to enter dark chamber; whereas, increased number of crossings and time in light chamber in L&D aversion test by treatment with “6k” as compared to vehicle control group. In HBT, “6k” significantly (P < 0.05) increased the number of head dipping and squares crossed; whereas, reduced the latency for first head dip and number of fecal pellets as compared to vehicle control group. Conclusion: A novel 5-HT3 receptor antagonist has anti-anxiety action. PMID:24550593

Kurhe, Yeshwant Vijay; Radhakrishnan, Mahesh; Thangaraj, Devadoss; Gupta, Deepali



New Aporphinoid 5-HT2A and ?1A Antagonists via Structural Manipulations of Nantenine  

PubMed Central

A series of C1, C2, C3 and N6 analogs of nantenine (2) was synthesized and evaluated in 5-HT2A and ?1A receptor functional assays. Alkyl substitution of the C1 and N6 methyl groups of nantenine provided selective 5-HT2A and ?1A antagonists respectively. The C2 alkyloxy analogs studied were generally selective for ?1A vs 5-HT2A. The C3 bromo analog 15 is one of the most potent aporphinoid 5-HT2A antagonists known presently. PMID:21900013

Ponnala, Shashikanth; Chaudhary, Sandeep; LeGendre, Onica; Gonzales, Junior A.; Navarro, Hernan A.; Harding, Wayne W.



5-HT and 5-HT-SO4, but not tryptophan or 5-HIAA levels in single feeding neurons track animal hunger state  

PubMed Central

Serotonin (5-HT) is an intrinsic modulator of neural network excitation states in gastropod molluscs. 5-HT and related indole metabolites were measured in single, well-charac