Sample records for 5-hydroxytryptamine 5-ht reuptake

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

    E-print Network

    Nyholt, Dale R.

    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 predominantly serves as an inhibitory neurotransmitter in the brain, has long been implicated in migraine

  2. 5Hydroxytryptamine 5HT1B and 5HT1D receptors mediating inhibition of adenylate cyclase activity

    Microsoft Academic Search

    Philippe Schoeffter; Daniel Hoyer

    1989-01-01

    5-Hydroxytryptamine1B (5-HT1B) receptor mediated-inhibition of forskolin-stimulated adenylate cyclase activity in rat substantia nigra was characterized pharmacologically and compared to 5-HT1D receptor mediated-inhibition of forskolin-stimulated adenylate cyclase activity in calf substantia nigra. Special attention was paid to the effects of drugs known to bind with high affinity to 5-HT1B (pindolol, propranolol, cyanopindolol, SDZ 21-009, isamoltane) or 5-HT1D recognition sites (yohimbine, rauwolscine).

  3. Characterization of an endothelial 5-hydroxytryptamine (5HT) receptor mediating relaxation of the porcine coronary artery

    Microsoft Academic Search

    Gerhard J. Molderings; Georg Engel; Ekkehard Roth; Manfred Göthert

    1989-01-01

    The pharmacological properties of the endothelial 5-hydroxytryptamine (5-HT) receptors involved in relaxation of vascular smooth muscle were determined in rings of pig coronary artery contracted with 10 nmol\\/1 of the thromboxane A2 receptor agonist 9,11-dideoxy-11a,9a-epoxy-methano-prostaglandin F2a (U 46619).

  4. Cisplatin increases the release of 5-hydroxytryptamine (5HT) from the isolated vascularly perfused small intestine of the guinea-pig: Involvement of 5HT 3 receptors

    Microsoft Academic Search

    H. Schwörer; K. Racké; H. Kilbinger

    1991-01-01

    Isolated segments of the guinea-pig small intestine were vascularly perfused and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) into the portal venous effluent determined by high pressure liquid chromatography with electrochemical detection. Release of acetylcholine from isolated superfused intestinal segments was determined as outflow of [3H]radioactivity from preparations preincubated with [3H]choline. Cisplatin (3 µM) increased the outflow of

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

    PubMed Central

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

    1992-01-01

    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

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

    PubMed Central

    Van den Hooff, P.; Galvan, M.

    1992-01-01

    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

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

    Microsoft Academic Search

    Fred de Clerck; Jean-Louis David; Janssen Pharmaceutica

    1994-01-01

    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

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

    Microsoft Academic Search

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

    1982-01-01

    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

  9. Increased 5-HT2 receptor number in brain as a probable explanation for the enhanced 5-hydroxytryptamine-mediated behaviour following repeated electroconvulsive shock administration to rats.

    PubMed Central

    Green, A. R.; Johnson, P.; Nimgaonkar, V. L.

    1983-01-01

    Following electroconvulsive shock (ECS) administration daily for 10 days there was an increase (35%) in 5-hydroxytryptamine2 (5-HT2) receptor number in rat frontal cortex 24 h after the last ECS, compared with handled controls. A similar increase was seen after intermittent ECS administration (5 ECS over 10 days) given during halothane anaesthesia, compared with halothane-treated controls. The dissociation constant was also increased at this time. A single ECS had no effect. Treatment of rats with pentylenetetrazol, p-chlorophenylalanine or alpha-methyl p-tyrosine during the intermittent ECS administration abolished the increase in 5-HT2 receptor binding. Since enhanced 5-HT-mediated behavioural responses are seen after repeated ECS but not when the ECS is given with the drug treatments outlined above, it is suggested that ECS-induced enhancement of 5-HT-mediated behaviour results from an increase in 5-HT2 receptor number. PMID:6228277

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

    PubMed Central

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

    2008-01-01

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

  11. Characterization of the in vitro effects of 5-hydroxytryptamine (5-HT) on identified neurones of the rat dorsal motor nucleus of the vagus (DMV).

    PubMed

    Browning, K N; Travagli, R A

    1999-11-01

    1 Whole cell patch clamp techniques were used on thin brainstem slices to investigate the effects of 5-hydroxytryptamine (5-HT) on gastrointestinal-projecting dorsal motor nucleus of the vagus (DMV) neurones. Neurones were identified as projecting to the stomach (n=122) or intestine (n=84) if they contained the fluorescent tracer Dil after it had been applied to the gastric fundus, corpus or antrum/pylorus or to the duodenum or caecum. 2 A higher proportion of intestinal neurones (69%) than gastric neurones (47%) responded to 5-HT with a concentration-dependent inward current which was antagonized fully by the 5-HT2A receptor antagonist ketanserin (1 microM). 3 Stimulation of the nucleus tractus solitarius (NTS) induced inhibitory synaptic currents that were reduced in amplitude by application of the 5-HT1A receptor agonist 8-OHDPAT (1 microM) or the 5-HT1A/1B receptor agonist TFMPP (1 microM) in 61% and 52% of gastric- and intestinal-projecting neurones, respectively. 5-HT also significantly reduced the frequency but not the amplitude of spontaneous inhibitory currents. 4 These data show that 5-HT excites directly a larger proportion of intestinal projecting neurones than gastric-projecting neurones, as well as inhibiting synaptic transmission from the NTS to the DMV. These data imply that the response to DMV neurones to 5-HT may be determined and classified by their specific projections. PMID:10578146

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

    PubMed

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

    2015-04-15

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

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

    PubMed

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

    2012-11-01

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

  14. 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

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

    1997-01-01

    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

  15. Modulation of the extracellular 5-hydroxytryptamine brain concentrations by the serotonin and noradrenaline reuptake inhibitor, milnacipran. Microdialysis studies in rats.

    PubMed

    Bel, N; Artigas, F

    1999-12-01

    We examined the effects of the administration of milnacipran, a dual inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline uptake on the 5-HT output in rat brain. Local milnacipran administration increased the 5-HT output in frontal cortex and the midbrain raphe nuclei 7- and 10-fold by a Ca(2+)- and tetrodotoxin-dependent mechanism. However, the subcutaneous administration of milnacipran (1-60 mg/kg s.c.) elevated the 5-HT output much less in these areas (200-230% of baseline at 60 mg/kg). In hypothalamus, 10 mg/kg s.c. raised 5-HT levels to 170%. The 5-HT1A antagonist WAY-100635 caused a small potentiation of the effects of milnacipran. The baseline 5-HT output was unaffected by 2-week treatments with milnacipran (30 and 60 mg/kg.day). The distinct regional profile and the lack of enhancement of its effects by WAY-100635 and prolonged treatment suggest that milnacipran does not exert its antidepressant action through an enhancement of the serotonergic function. PMID:10633480

  16. Involvement of 5-hydroxytryptamine 5-HT? serotonergic receptors in the acquisition and reinstatement of the conditioned place preference induced by MDMA.

    PubMed

    Roger-Sánchez, Concepción; Rodríguez-Arias, Marta; Miñarro, Jose; Aguilar, Maria A

    2013-08-15

    Some MDMA (3,4-methylenedioxymethamphetamine) users develop dependence as a result of chronic consumption. The present study evaluated the role of 5-hydroxytryptamine 5-HT? receptors in the acquisition, expression and reinstatement of the conditioned place preference (CPP) induced by MDMA. Adolescent male mice were conditioned with 10 mg/kg of MDMA and then treated with 1 or 3mg/kg of the 5-hydroxytryptamine 5-HT? antagonist MDL72222 during acquisition of conditioning (experiment 1), before expression of CPP in a post-conditioning test (experiment 2) or before a reinstatement test (experiment 3). MDL72222 was devoid of motivational effects but blocked acquisition of the MDMA-induced CPP. Moreover, following extinction, the low dose of MDL72222 blocked reinstatement of the CPP induced by priming with MDMA. Acute MDMA reduced levels of dihydroxypheylacetic acid (DOPAC) in the striatum and levels of acid 5-hydroxyindoleacetic (5-HIAA) in the cortex. Acute MDMA+MDL72222 also reduced striatal DOPAC. The repeated co-administration of MDMA plus MDL72222 (on PND 32-34-36-38) increased dopamine and decreased DOPAC in the striatum, and increased cortical serotonin and enhanced transporters of dopamine and serotonin. The acute administration (on PND ±55) of MDMA or MDL72222 increased levels of dopamine and reduced those of DOPAC in the striatum and co-administration of MDMA plus MDL72222 increased striatal serotonin. Our results confirm that 5-hydroxytryptamine 5-HT? receptors are involved in the acquisition of conditioned rewarding effects of MDMA and demonstrate that these receptors are also involved in reinstatement after extinction. PMID:23792143

  17. Zebra Mussel Spawning Is Induced in Low Concentrations of Putative Serotonin Reuptake Inhibitors

    Microsoft Academic Search

    PETER P. FONG

    1998-01-01

    Serotonin (5-hydroxytryptamine, 5HT) and its receptor ligands induce both oocyte maturation and spawning in zebra mussels (Dreissena polymorpha). The selective serotonin reuptake inhibitors (SSRIs) fluvoxa- mine (\\

  18. Emesis and defecations induced by the 5-hydroxytryptamine (5-HT3) receptor antagonist zacopride in the ferret.

    PubMed

    King, G L

    1990-06-01

    Three antiemetic compounds (zacopride, batanopride, granisetron [BRL43694]) were evaluated for the production of gastrointestinal side effects in the conscious ferret after i.v. or p.o. administration. Zacopride evoked multiple emetic and defecatory responses at clinically relevant doses (0.003-0.3 mg/kg) and in a dose-dependent manner. The oral route was the more potent one for eliciting emesis (ED50 0.033 mg/kg). At 0.3 mg/kg p.o., zacopride reliably evoked an 80 to 100% incidence of emesis and a 40 to 80% incidence of defecation. In contrast, batanopride and BRL43694 i.v. evoked a small (10%) incidence of these side effects, but only at 0.1 to 10 mg/kg doses. When given p.o. (0.00003-10 mg/kg), these latter compounds never evoked emesis and significantly reduced (P less than .05) the incidence of defecation below that of vehicle. Responses to zacopride (0.3 mg/kg p.o.) were challenged by i.p. pretreatment with the 5-hydroxytryptamine receptor agonist 2-methyl serotonin, the 5-hydroxytryptamine receptor antagonist BRL43694, the quaternary atropine derivative glycopyrrolate, the dopamine receptor antagonist domperidone or selective abdominal vagotomies. All compounds and either bilateral or dorsal vagotomy significantly reduced the incidence of emesis, but did not abolish it. Latency to first emesis was delayed by BRL43694, domperidone or dorsal vagotomy. The data suggest that the emetic response to p.o. zacopride is mediated in part by 5-hydroxytryptamine receptors residing on either enteric neurons or vagal afferents. However, the underlying pharmacology of the response may also include activation of cholinergic and dopaminergic pathways. PMID:2162943

  19. Antagonistic actions of renal dopamine and 5-hydroxytryptamine: increase in Na+, K(+)-ATPase activity in renal proximal tubules via activation of 5-HT1A receptors.

    PubMed Central

    Soares-da-Silva, P.; Pinto-do-O, P. C.; Bertorello, A. M.

    1996-01-01

    1. 5-Hydroxytryptamine (5-HT) is antinatriuretic. Since this effect of 5-HT is not accomplished by changes in glomerular haemodynamics, we have examined in this study whether 5-HT may influence sodium excretion by affecting the Na+, K(+)-ATPase activity in renal cortical tubules. 2. Na+, K(+)-ATPase activity was determined as the rate of [32P]-ATP hydrolysis in renal cortical tubules in suspension. Basal Na+, K(+)-ATPase activity in renal tubules was 4.8 +/- 0.4 mumol Pi mg-1 protein h-1 (n = 8). The 5-HT1A receptor agonist, (+/-)-8-hydroxy-2-(di-n-propylamino) tetraline (8-OH-DPAT) (10 to 3000 nM) induced a concentration-dependent increase (P < 0.05) in Na+, K(+)-ATPase activity with an EC50 value of 355 nM (95% confidence limits: 178, 708). Maximal stimulation elicited by 3000 nM of 8-OH-DPAT was antagonized by the selective 5-HT1A receptor antagonist, (+)-WAY 100135 10 to 1000 nM) with an IC50 value of 20 nM (14, 29); 0.3 microM (+)-WAY 100135 completely abolished (P < 0.01) the stimulatory effect of 8-OH-DPAT. The stimulatory effect of 8-OH-DPAT was found to be time-dependent (15 +/- 2% and 66 +/- 7% increase at 2.5 and 5.0 min, respectively). The 5-HT2 receptor agonist alpha-methyl-5-HT (100 to 3000 nM) did not induce any significant changes in Na+, K(+)-ATPase activity (5.0 +/- 1.5 mumol Pi mg-1 protein h-1; n = 4). 3. The stimulatory effect 8-OH-DPAT was absent when homogenates were used. Stimulation occurred at a Vmax concentration (70 mM) of sodium supporting the notion that stimulation occurs independently of increasing sodium permeability. 4. The inhibitory effect of dopamine (P < 0.05) on Na+, K(+)-ATPase activity was blunted by co-incubation with 8-OH-DPAT (0.5 microM). 5. It is concluded that activation of 5-HT1A receptors increases Na+, K(+)-ATPase activity in renal cortical tubules; this effect may represent an important cellular mechanism, at the tubule level, responsible for the antinatriuretic effect of 5-HT. Images Figure 4 PMID:8882616

  20. 5-Hydroxytryptamine 1A (5HT1A) receptors mediate increases in plasma glucose independent of corticosterone.

    PubMed

    Gehlert, Donald R; Shaw, Janice

    2014-12-15

    Hypothalamic 5HT1A receptors play an important role in the regulation of satiety, glycemia and endocrine status. In the present study, 8-OH-DP administered centrally and peripherally to C57/Bl6 mice and plasma glucose insulin and corticosterone were evaluated. In these studies, dose and time dependent increases in glucose and corticosterone were observed while no alterations in insulin were seen. The increases in plasma corticosterone were prevented by prior central or peripheral administration of LY426965, a specific 5HT1A antagonist. Intracerebroventricular coadministration of a 5HT1A antagonist with 8-OH-DPAT prevented the increase in plasma glucose establishing this response as a centrally mediated response in mice. Given that increases in plasma corticosterone are associated with increases in plasma glucose, we conducted experiments to determine if increased plasma corticosterone was the mechanism by which 8-OH-DPAT increased plasma glucose. Prior administration of the glucocorticoid antagonist mifepristone did not affect the increase in plasma glucose produced by 8-OH-DPAT. Prior administration of the glucocorticoid synthesis inhibitor, metyrapone, reduced basal corticosterone and the concentrations of corticosterone associated with 8-OH-DPAT administration. However, metyrapone administration did not affect the increases in plasma glucose. Therefore, 5HT1A receptors regulate glucose through brain mechanisms, but not through regulation of the hypophyseal-pituitary axis. Antagonism of brain 5HT1A receptors may enable discovery of novel antidiabetic agents. PMID:25446927

  1. Efflux of 3 H-5-hydroxytryptamine from rat hypothalamic slices by continuous electrical stimulation: Frequency-dependent responses to serotonergic antagonists and 5-hydroxytryptamine

    Microsoft Academic Search

    M. H. Richards

    1985-01-01

    Rat hypothalamic slices were incubated with 3H-5-hydroxytryptamine and superfused in the presence of paroxetine to inhibit 5-hydroxytryptamine (5-HT) reuptake. The slices were continuously stimulated electrically with rectangular pulses at varying frequencies.1.Continuous stimulation for up to 42 min at 1 Hz or at 3 Hz evoked a steady efflux of tritium that slowly decayed with time. The efflux produced by continuous

  2. The nature of d,l -fenfluramine-induced 5HT reuptake transporter loss in rats

    Microsoft Academic Search

    Robert Ian Westphalen; Peter Ronald Dodd

    1995-01-01

    The administration of the anorexigenic drugd,l-fenfluramine (Ponderax®) to laboratory animals results in a dose-dependent reduction in presynaptically located serotonergic reuptake transporter\\u000a protein. This long-term effect may represent an altered mechanism of synthesis of the transporter (downregulation). Alternatively,\\u000a fenfluramine may destroy the serotonergic terminals on which 5-HT transporters are located. To distinguish between these two\\u000a alternatives, we applied an assay of

  3. Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters

    Microsoft Academic Search

    Normand Lavoie; Claude de Montigny; Guy Debonnel

    1998-01-01

    In vitro radioligand binding studies were carried out in rat brain membranes to assess the affinity of various reuptake inhibitors for the serotonin (5-hydroxytryptamine, 5-HT) and the norepinephrine transporters using the selective ligands [3H]cyanoimipramine and [3H]nisoxetine, respectively. The selective 5-HT reuptake inhibitors paroxetine, indalpine and fluvoxamine displayed a high affinity for the 5-HT transporter, whereas the norepinephrine reuptake inhibitor desipramine

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

    Microsoft Academic Search

    Harald Schwörer; Heinz Hartmann; Giuliano Ramadori

    1995-01-01

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

  5. 5-hydroxytryptamine and platelet aggregation.

    PubMed

    De Clerck, F F; Herman, A G

    1983-02-01

    5-Hydroxytryptamine (5-HT) activates blood platelets of various species including humans. In contrast to cat, pig, and sheep platelets, human blood platelets respond to 5-HT mainly with a shape change and a reversible aggregation only. However, depending on the concentration and the time interval between its addition and that of another agonist, 5-HT amplifies the human platelet aggregation induced by ADP, collagen, epinephrine, and norepinephrine; the monoamine itself induces strong aggregation of platelets presensitized with norepinephrine, lysolecithin, or Thrombofax. Prolonged exposure of platelets to 5-HT results in transient tachyphylaxis. Pharmacodissection and receptor-binding studies suggest the presence of functional receptors, possibly of the 5-HT2 (S2) type, different from the ones involved in the active uptake of the monoamine by the platelets. As a modulator of platelet reactions, 5-HT may be involved in secondary platelet aggregation, hemostasis, and thrombus formation. PMID:6822293

  6. The role of 5HT receptor subtypes in the anxiolytic effects of selective serotonin reuptake inhibitors in the rat ultrasonic vocalization test

    Microsoft Academic Search

    R. Schreiber; C. Melon; Jean De Vry

    1998-01-01

    We evaluated whether the anxiolytic effects of selective serotonin reuptake inhibitors (SSRIs) in the rat ultrasonic vocalization\\u000a (USV) test are preferentially mediated by (indirect) activation of 5-HT1A, 5-HT1B\\/1D, 5-HT2A, 5-HT3 or 5-HT4 receptors. The SSRIs, paroxetine (ED50 in mg\\/kg, IP: 6.9), citalopram (6.5), fluvoxamine (11.7) and fluoxetine (>30), dose dependently reduced shock-induced USV.\\u000a The effects of paroxetine (3.0?mg\\/kg, IP) were

  7. 5-Hydroxytryptamine Receptor Subtypes and their Modulators with Therapeutic Potentials

    PubMed Central

    Pithadia, Anand B.; Jain, Sunita M.

    2009-01-01

    5-hydroxytryptamine (5-HT) has become one of the most investigated and complex biogenic amines. The main receptors and their subtypes, e.g., 5-HTI (5-HT1A, 5-HT1B, 5-HTID, 5-HTIE and 5-HT1F), 5-HT2 (5-HT2A, 5-HT2B and 5-HT2C), 5-HT3, 5-HT4, 5-HT5 (5-HT5A, 5-HT5B), 5-HT6 and 5-HT7 have been identified. Specific drugs which are capable of either selectively stimulating or inhibiting these receptor subtypes are being designed. This has generated therapeutic potentials of 5-HT receptor modulators in a variety of disease conditions. Conditions where 5-HT receptor modulators have established their use with distinct efficacy and advantages include migraine, anxiety, psychosis, obesity and cancer therapy-induced vomiting by cytotoxic drugs and radiation. Discovery of 5-HT, its biosynthesis, metabolism, physiological role and the potential of 5-HT receptor modulators in various nervous, cardiovascular and gastrointestinal tract disorders, bone growth and micturition have been discussed in this article. Keywords 5-hydroxytryptamine (5-HT) receptors; Modulators; Biogenic amines PMID:22505971

  8. 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

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

    2013-01-01

    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

  9. A Pharmacological Analysis of an Associative Learning Task: 5-HT1 to 5-HT7 Receptor Subtypes Function on a Pavlovian/Instrumental Autoshaped Memory

    PubMed Central

    Meneses, Alfredo

    2003-01-01

    Recent studies using both invertebrates and mammals have revealed that endogenous serotonin (5-hydroxytryptamine [5-HT]) modulates plasticity processes, including learning and memory. However, little is currently known about the mechanisms, loci, or time window of the actions of 5-HT. The aim of this review is to discuss some recent results on the effects of systemic administration of selective agonists and antagonists of 5-HT on associative learning in a Pavlovian/instrumental autoshaping (P/I-A) task in rats. The results indicate that pharmacological manipulation of 5-HT1-7 receptors or 5-HT reuptake sites might modulate memory consolidation, which is consistent with the emerging notion that 5-HT plays a key role in memory formation. PMID:14557609

  10. Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from in vitro and animal-based studies

    PubMed Central

    Warden, Stuart J.; Haney, Elizabeth M.

    2014-01-01

    The regulation of bone metabolism continues to be area of intense investigation, with recent evidence indicating a potential contribution from the neural system. In particular, the neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) has been hypothesized to play a role in skeletal metabolism via its transporter (5-HTT). The 5-HTT is a plasma membrane transporter that is highly specific for the uptake of extracellular 5-HT, thereby facilitating the intracellular storage and/or degradation of 5-HT. The 5-HTT is clinically important as it is the key target of pharmaceutical agents aimed at treating affective disorders, such as major depressive disorder. By antagonizing the 5-HTT, selective serotonin reuptake inhibitors (SSRIs) potentiate 5-HT activity and effectively relieve the symptoms of depression. However, questions have been raised regarding the potential skeletal effects of SSRIs given the recent identification of a functional 5-HTT and functional 5-HT receptors in bone cells. This paper discusses the preclinical evidence for the skeletal effects of 5-HT and the inhibition of the 5-HTT. In particular, it discusses the: (1) role of 5-HT and the function of the 5-HTT; (2) presence of functional 5-HTTs in bone; (3) potential sources and response mechanisms for 5-HT in bone, and; (4) in vitro and in vivo skeletal effects of 5-HT and 5-HTT inhibition. PMID:18622081

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

    PubMed Central

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

    2013-01-01

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

  12. Leech Retzius cells and 5-hydroxytryptamine.

    PubMed

    Leake, L D

    1986-01-01

    A pair of giant Retzius (R) cells in each segmental ganglion of the leech contain 5-hydroxytryptamine (5-HT). They are the only 5-HT-containing neurones in the central nervous system to send branches to the periphery, yet many peripheral tissues (e.g. body wall muscles, heart, reproductive organs, nephridia and gut) possess 5-HT-like immunoreactive nerve fibres. 5-HT and/or R cell stimulation relax basal tension of body wall muscles and reduce their relaxation times following contraction, enhance pharyngeal movements and salivary gland secretion but inhibit muscle movements of the posterior gut regions and of the reproductive tract. It is suggested that R cells are multifunction neurones modulating activity of many tissues so that feeding behaviour of the leech is carried out as efficiently as possible. PMID:2871982

  13. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract

    PubMed Central

    Gershon, Michael D.

    2013-01-01

    Purpose of review Although the gut contains most of the body’s 5-hydroxytryptamine (5-HT), many of its most important functions have recently been discovered. This review summarizes and directs attention to this new burst of knowledge. Recent findings Enteroendocrine cells have classically been regarded as pressure sensors, which secrete 5-HT to initiate peristaltic reflexes; nevertheless, recent data obtained from studies of mice that selectively lack 5-HT either in enterochromaffin cells (deletion of tryptophan hydroxylase 1 knockout; TPH1KO) or neurons (TPH2KO) imply that neuronal 5-HT is more important for constitutive gastrointestinal transit than that of enteroendocrine cells. The enteric nervous system of TPH2KO mice, however, also lacks a full complement of neurons; therefore, it is not clear whether slow transit in TPH2KO animals is due to their neuronal deficiency or absence of serotonergic neurotransmission. Neuronal 5-HT promotes the growth/maintenance of the mucosa as well as neurogenesis. Enteroendocrine cell derived 5-HT is an essential component of the gastrointestinal inflammatory response; thus, deletion of the serotonin transporter increases, whereas TPH1KO decreases the severity of intestinal inflammation. Enteroendocrine cell derived 5-HT, moreover, is also a hormone, which inhibits osteoblast proliferation and promotes hepatic regeneration. Summary New studies show that enteric 5-HT is a polyfunctional signalling molecule, acting both in developing and mature animals as a neurotransmitter paracrine factor, endocrine hormone and growth factor. PMID:23222853

  14. Platelet-vessel wall interactions: Implication of 5-hydroxytryptamine. A review

    Microsoft Academic Search

    F. De Clerck; J. M. van Nueten; R. S. Reneman

    1984-01-01

    The evidence for an impact of platelet-derived 5-hydroxytryptamine (5-HT) on local tissue perfusion is reviewed. By interacting with 5-HT2 serotonergic receptors, 5-HT, directly or through amplification, activates platelets, endothelial and vascular smooth muscle cells producing platelet aggregation, vascular permeability increase and large vessel constriction. Pharmacodissection in experimental animals with selective serotonergic 5-HT2 receptor antagonists, e.g. ketanserin, shows that 5-HT largely

  15. 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

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

    2013-12-01

    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

  16. 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

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

    2013-01-01

    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

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

    PubMed

    Mathes, Clare M; Spector, Alan C

    2014-09-01

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

  18. Antagonism of 5-hydroxytryptamine receptors by quipazine.

    PubMed Central

    Lansdown, M. J.; Nash, H. L.; Preston, P. R.; Wallis, D. I.; Williams, R. G.

    1980-01-01

    1 The antagonist actions of quipazine on 5-hydroxytryptamine (5-HT) receptors have been investigated in the rabbit isolated superior cervical ganglion and on the rat isolated spinal cord and stomach strip. 2 Changes in membrane potential induced by 5-HT or by the nicotinic agonist, 1,1-dimethyl-4-phenyl piperazinium (DMPP), were measured in the ganglion by the sucrose-gap technique. At ganglionic receptors, quipazine had little or no agonist activity, but greatly depressed depolarizations evoked by 5-HT but not depolarizations evoked by DMPP or trimethylammonium (TMA). Injections into the superfusion stream to the ganglion of 2 to 5 mumol quipazine in a small volume of Krebs solution prevented all subsequent responses to 5-HT. Superfusion of the ganglion with quipazine at a concentration of 1 microM produced complete blockade of responses to 5-HT in 3 of 6 ganglia and reduced responses by over 90% in 2 others; responses to DMPP were potentiated in amplitude and duration. Superfusion at a concentration of 0.1 microM depressed responses to 5-HT by 75% on average. The threshold concentration for the blocking action was around 0.01 microM, which depressed responses by 42% on average in 6 experiments (range 0 to 75%). 3 5-HT (1 microM or 100 microM) depressed the amplitude of the dorsal root potentials recorded from the isolated, hemisected cord of the neonate rat by 27 +/- 5% (mean +/- s.e. mean, n = 14) and by 45 +/- 6% (n = 14), respectively. In the presence of quipazine (0.01 microM), 5-HT (1 microM or 100 microM) depressed the amplitude by 6 +/- 2% (n = 15) and by 3 +/- 1% (n = 7), respectively. 4 Concentration-response curves of the contractions induced by 5-HT in the fundus of the rat stomach were obtained in the absence and presence of quipazine. Quipazine (1 microM) shifted the concentration-response curve to the right and depressed the maximum, suggesting a non-competitive mode of antagonism. pI50 values were calculated in order to assess the antagonist activity of quipazine at rat fundus 5-HT receptors; the mean pI50 was 6.91 +/- 0.2 (n = 6). 5 It is concluded that quipazine may be an effective antagonist at 5-HT receptors in various tissues. PMID:7052342

  19. Increase of noradrenaline release in the hypothalamus of freely moving rat by postsynaptic 5-hydroxytryptamine1A receptor activation.

    PubMed Central

    Suzuki, M.; Matsuda, T.; Asano, S.; Somboonthum, P.; Takuma, K.; Baba, A.

    1995-01-01

    1. 5-Hydroxytryptamine (5-HT) plays a role in the regulation of noradrenergic neurones in the brain, but the precise mechanism of regulation of noradrenaline (NA) release by 5-HT1A receptors has not been defined. The present study describes the effect of a highly potent and selective 5-HT1A receptor agonist, 5-(3-[[(2S)-1,4-benzodioxan-2-ylmethyl)]amino]propoxy)-1,3-b enzodioxole HC1 (MKC-242), on NA release in the hypothalamus using microdialysis in the freely moving rat. 2. Subcutaneous injection of MKC-242 (0.5 mg kg-1) increased extracellular levels of NA and its metabolite, 3-methoxy-4-hydroxyphenylglycol, in the hypothalamus and hippocampus. 3. The 5-HT1A receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.2 mg kg-1) and buspirone (3 mg kg-1) mimicked the effect of MKC-242 in increasing NA release in the hypothalamus. 4. The effects of MKC-242 and 8-OH-DPAT in the hypothalamus were antagonized by pretreatment with WAY100135 (10 mg kg-1), a silent 5-HT1A receptor antagonist. 5. Local administration of 8-OH-DPAT (10-100 microM), citalopram (1 microM), a 5-HT reuptake inhibitor, and MDL72222 (10 microM), a 5-HT3 receptor antagonist, into the hypothalamus, had no effect on NA release. 6. Intracerebroventricular injection with 5,7-dihydroxytryptamine caused a marked reduction in brain 5-HT content, but the treatment affected neither basal NA levels nor the MKC-242-induced increase in NA release. 7. The effect of MKC-242 in increasing NA release was not attenuated by repeated treatment with the drug (0.5 mg kg-1, once a day for 2 weeks).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582494

  20. Interaction of arylpiperazines with 5HT1A, 5HT1B, 5HT1C and 5HT1D receptors: do discriminatory 5HT1B receptor ligands exist?

    Microsoft Academic Search

    Philippe Schoeffter; Daniel Hoyer

    1989-01-01

    The effects of several putative 5-HT1 receptorsubtype selective ligands were investigated in biochemical models for 5-HT1A, 5-HT1B, and 5-HT1D receptors (inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus, rat and calf substantia nigra, respectively) and 5-HT1C receptors (stimulation of inositol phosphates production in pig choroid plexus). Following compounds were studied: 5-HT (5-hydroxytryptamine), TFMPP (1-(mtrifluoromethylphenyl)piperazine), mCPP (1-m-chlorophe-nyl)piperazine, 1 CGS 12066

  1. 5-Hydroxytryptamine-induced tachycardia in the pig: possible involvement of a new type of 5-hydroxytryptamine receptor.

    PubMed Central

    Bom, A. H.; Duncker, D. J.; Saxena, P. R.; Verdouw, P. D.

    1988-01-01

    1. The mechanism of 5-hydroxytryptamine (5-HT)-induced tachycardia is species-dependent and is mediated directly or indirectly either by '5-HT1-like' (cat), 5-HT2 (rat, dog) or 5-HT3 (rabbit) receptors, or by an action similar to tyramine (guinea-pig). The present investigation is devoted to the analysis of the positive chronotropic effect of 5-HT in the pentobarbitone-anaesthetized pig. 2. Intravenous bolus injections of 5-HT (3, 10 and 30 micrograms kg-1) in pigs resulted in dose-dependent increases in heart rate of 24 +/- 2, 38 +/- 3 and 51 +/- 3 beats min-1, respectively (n = 39). Topical application of a high concentration of 5-HT (150 micrograms kg-1 in 5 ml) on the right atrium was also followed by tachycardia (38 +/- 6 beats min-1, n = 4). 3. A number of drugs which antagonize responses mediated by different 5-HT receptors--phenoxybenzamine, methiothepin, metergoline, methysergide and mesulergine ('5-HT1-like' and 5-HT2 receptors), ketanserin, cyproheptadine, pizotifen and mianserin (5-HT2 receptors), and MDL 72222 and ICS 205-930 (5-HT3 receptors)--did not attenuate the chronotropic responses to 5-HT. 4. The 5-HT-induced tachycardia was also not affected by antagonists at alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors, and calcium channels. 5. Selective inhibitors of 5-HT-uptake, indalpine and fluvoxamine, themselves increased porcine heart rate and facilitated 5-HT-induced tachycardia both in magnitude and in duration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3370393

  2. Novel 5HT 2-like receptor mediates neurogenic relaxation of the guinea-pig proximal colon

    Microsoft Academic Search

    Michel R. Briejer; Louis M. A. Akkermans; Romain A. Lefebvre; Jan A. J. Schuurkes

    1995-01-01

    The aim of the current investigation was to characterize the 5-HT receptors that mediate neurogenic relaxation of the guinea-pig proximal colon. After blockade of 5-HT2A, 5-HT3 and 5-HT4 receptor-mediated contractions, 5-hydroxytryptamine (5-HT) induced relaxations yielding a biphasic concentration-response curve. Other tryptamines were also agonists with the following rank order of potency: 5-HT > 5-carboxamidotryptamine = 5-methoxytryptamine ? ?-methyl-5-HT (partial agonist)

  3. Physiological Control of Molluscan Gill Cilia by 5-Hydroxytryptamine

    PubMed Central

    Gosselin, R. E.; Moore, K. E.; Milton, A. S.

    1962-01-01

    An examination is made of the hypothesis that endogenous 5-hydroxytryptamine (5-HT) serves as a local hormone regulating ciliary activity in the lamellibranch gill. These cilia are sensitive to exogenous 5-HT and respond to it by a prompt, sustained, and reversible rise in beat frequency; at the same time the carbohydrate metabolism is stimulated, as described elsewhere. Control gill contains small but definite amounts of endogenous 5-HT according to bioassay, fluorometry, and chromatography. The amount can be increased markedly by exposing the isolated gill to the precursor substance 5-hydroxytryptophan but not l-tryptophan. As the tissue level of 5-HT rises, the spontaneous beat frequency also rises. Both remain elevated for hours and perhaps for days. The gill of Mytilus edulis is richer than the gill of Modiolus demissus in both endogenous 5-HT and effective 5-hydroxytryptophan decarboxylase activity. Modiolus gill lacks the 5-hydroxyindole oxidase by which Mytilus gill destroys 5-HT. What if any mechanism exists in Modiolus for degrading 5-HT is not known, but monoamine oxidase is not present. The 5-HT content of Mytilus and Modiolus gill cannot be modified by treatment with reserpine or ?-methyl-dopa. Which cells of the gill synthesize and destroy 5-HT has not been established, but these observations support the concept that the physiological activity of lamellibranch gill cilia is controlled by a serotonergic mechanism. PMID:13949402

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

    Microsoft Academic Search

    C P Bearcroft; D Perrett; M J G Farthing

    1998-01-01

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

  5. Release of ( sup 14 C)5-hydroxytryptamine from human platelets by red wine

    SciTech Connect

    Jarman, J.; Glover, V.; Sandler, M. (Queen Charlotte's and Chelsea Hospital, London (England))

    1991-01-01

    Red wine, at a final dilution of 1/50, caused released of ({sup 14}C)5-hydroxytryptamine (5-HT) from preloaded platelets, an effect which was not observed with any white wines or beers tested. Since 5-HT, is probably released from body stores during migraine attacks and red wine is known to provoke migraine episodes in susceptible individuals, release of 5-HT, possibly from central stores, could represent a plausible mechanism for its mode of action.

  6. Impaired uptake of 5 hydroxytryptamine platelet in essential hypertension: Clinical relevance

    Microsoft Academic Search

    Natalia Fetkovska; Alfred Pletscher; Fabrizia Ferracin; Ruth Amstein; Fritz R. Buhler

    1990-01-01

    Serotonin (5-hydroxytryptamine; 5HT) kinetics and platelet activation by 5HT were studied in patients with essential hypertension (n=45), and in matched normotensive subjects (n=45). Platelet response to 5HT and plasma beta-thromboglobulin increased with age in men, both normotensives and hypertensives. Beta-thromboglobulin and 5-hydroxyindoleacetic acid (5HIAA) excretion were higher in hyypertensive men than in wpmen. In women, no changes in platelet activity

  7. 5Hydroxytryptamine induces contraction in isolated human mammary artery: Effect of ketanserin

    Microsoft Academic Search

    Angela Monopoli; Annamaria Conti; Angelo Forlani; Ennio Ongini; Carlo Antona; Paolo Biglioli

    1990-01-01

    5-hydroxytryptamine (5HT) treatment produced dose-related contractions in the human internal mammary artery with an EC50 value of 3.4×10-7M. The 5HT2 receptor antagonist ketanserin reversed the contractions evoked by 5HT in a competitive manner at a low concentration (10-6 M), whereas a noncompetitive antagonism was apparent at higher concentrations (5× 10-8 M to 5×10-7 M). The alpha1-blocking component of ketanserin was

  8. Receptor mechanisms for 5-hydroxytryptamine in rabbit arteries

    PubMed Central

    Black, J.L.; French, R.J.; Mylecharane, E.J.

    1981-01-01

    1 Previous investigations into the vascular actions of biogenic amines implicated in migraine have shown that the contractile effects of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA) in the rabbit ear artery are mediated by a direct sympathomimetic action at ?-adrenoceptors, while in the rabbit aorta, 5-HT and NA act on pharmacologically distinct receptors. The purpose of the present investigation was to determine whether the absence of 5-HT receptors in rabbit ear arteries is characteristic of distributing arteries in general, or is confined to particular regional circulations. 2 Agonist-antagonist interactions were studied in various rabbit vascular preparations (common carotid, external carotid and femoral arterial strips, and perfused ear arteries) by determining pA2 values for pizotifen and phentolamine against 5-HT- and NA-induced contractile responses. 3 In common carotid and femoral arteries, pizotifen was a potent competitive antagonist of 5-HT, but weak against NA. The converse applied to phentolamine. In external carotid and ear arteries, pizotifen was a weak competitive antagonist of both 5-HT and NA, whereas phentolamine was a potent competitive antagonist of both. Cocaine did not influence pA2 values against NA. 4 5-HT and NA were of similar potency in common carotid and femoral arteries, but 5-HT was much less potent than NA in external carotid and ear arteries. 5 The results indicate that rabbit common carotid and femoral arteries contain both D-type 5-HT receptors and ?-adrenoceptors, as does the aorta. However, external carotid arteries, like ear arteries, do not contain specific 5-HT receptors. The action of 5-HT in the external carotid artery is mediated by ?-adrenoceptors; this is a direct sympathomimetic action since it was not inhibited by cocaine or reserpine-pretreatment. 6 The absence of 5-HT receptors in the rabbit extracranial circulation may limit the usefulness of this species as a model for research relating to migraine. PMID:6271321

  9. 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

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

    2000-01-01

    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

  10. In vivo occupancy of the 5-HT1A receptor by a novel pan 5-HT1(A/B/D) receptor antagonist, GSK588045, using positron emission tomography.

    PubMed

    Comley, Robert A; van der Aart, Jasper; Gulyás, Balázs; Garnier, Martine; Iavarone, Laura; Halldin, Christer; Rabiner, Eugenii A

    2015-05-01

    5-hydroxytryptamine 1 (5-HT1) receptor blockade in combination with serotonin reuptake inhibition may provide a more rapid elevation of synaptic 5-HT compared to serotonin reuptake alone, by blocking the inhibitory effect of 5-HT1 receptor activation on serotonin release. GSK588045 is a novel compound with antagonist activity at 5-HT1A/1B/1D receptors and nanomolar affinity for the serotonin transporter, which was in development for the treatment of depression and anxiety. Here we present the results of an in vivo assessment of the relationship between plasma exposure and 5-HT1A receptor occupancy. Six Cynomolgus monkeys (Macaca fascicularis) were scanned using the PET ligand [(11)C]WAY100635 before and after dosing with GSK588045 (0.03, 0.1 and 0.3 mg/kg 60 min i.v. infusion). Data was quantified using a simplified reference tissue model, with the cerebellar time-activity curve used as an input function. Plasma levels of GSK588045 were measured, and the EC50 of GSK588045 for 5-HT1A receptor occupancy was estimated. An Emax model described the relationship between the GSK588045 plasma concentration and 5-HT1A receptor occupancy data well. EC50 estimates (and 95% confidence intervals) for raphe nuclei and the frontal cortex were 6.99 (2.48 to 11.49) and 7.80 (2.84 to 12.76) ng/ml respectively. GSK588045 dose dependently blocked the signal of the PET ligand [(11)C]WAY100635, confirming its brain entry and occupancy of 5-HT1A receptors in the primate brain. The estimated EC50 at the post-synaptic heteroreceptors and somatodendritic autoreceptors is similar. 5-HT1 receptor blockade by compounds such as GSK588045 may provide a faster alternate mechanism of antidepressant and anxiolytic action than standard SSRI treatment. PMID:25476970

  11. 5-Hydroxytryptamine responses in neonate rat motoneurones in vitro.

    PubMed Central

    Wang, M Y; Dun, N J

    1990-01-01

    1. Current and voltage recordings were made from antidromically identified motoneurones (MNs) in transverse thoracolumbar spinal cord slices of neonatal rats. 2. Applied by superfusion (10-100 microM) or pressure ejection, 5-hydroxytryptamine (5-HT) elicited a slow depolarization (or inward current) in 81% and a hyperpolarization (or outward current) in 9% of responsive MNs; the responses persisted in a low-Ca2+, high-Mg2+ or tetrodotoxin (TTX)-containing solution. 3. 5-HT induced the occurrence in some MNs of excitatory postsynaptic potentials (EPSPs) or inhibitory postsynaptic potentials (IPSPs), which were reversibly eliminated by TTX, low-Ca2+, high-Mg2+ solution or by the 5-HT2 receptor antagonists ketanserin and spiperone. Also, kynurenic acid and strychnine abolished, respectively, the 5-HT-induced EPSPs and IPSPs. 4. The 5-HT depolarization was associated with increased membrane resistance, was reduced by hyperpolarization and nullified near -100 mV. The extrapolated reversal potential was shifted to a positive direction in elevated [K+]o. 5. The depolarizing response was mimicked by the 5-HT2 receptor agonist (+2-)-1(2,5-dimethyoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) and blocked by 5-HT antagonists methysergide and cyproheptadine and by 5-HT2 antagonists ketanserin and spiperone; methiothepin and MDL 72222 were without effect. 6. The 5-HT hyperpolarization was associated with decreased membrane resistance. The 5-HT1A agonist 8-hydroxy-2-(di-N-propylamino) tetralin hydrobromide (8-OH-DPAT) mimicked the hyperpolarizing response. 7. Single or repetitive (10-30 Hz) electrical stimuli elicited in about 30% of MNs, in addition to a fast EPSP, a slow EPSP with electrophysiological characteristics similar to that of 5-HT induced depolarization. Methysergide and spiperone abolished the slow EPSPs evoked in some of these MNs. 8. It is suggested that 5-HT, acting on 5-HT2 and 5-HT1A receptors, depolarizes and hyperpolarizes the MNs by decreasing and increasing K+ conductance. Additionally, 5-HT activates, via 5-HT2 receptors, excitatory and inhibitory interneurones, thereby indirectly affecting the activity of MNs. More importantly, 5-HT released from intraspinal nerves appears to be the mediator of a slow EPSP in a population of MNs. PMID:2150862

  12. Evidence for the differential co-localization of neurokinin-1 receptors with 5-HT receptor subtypes in rat forebrain.

    PubMed

    Hafizi, Sepehr; Serres, Florence; Pei, Qi; Totterdell, Susan; Sharp, Trevor

    2012-04-01

    Studies suggest that like selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors, antagonists at neurokinin-1 receptors (NK(1)Rs) may have antidepressant and anxiolytic properties. NK(1)Rs are present in 5-HT innervated forebrain regions which may provide a common point of interaction between these two transmitter systems. This study aimed to investigate for cellular co-localization between NK(1)Rs and 5-HT receptor subtypes in mood-related brain regions in the rat forebrain. With experiments using fluorescence immunocytochemistry, double-labelling methods demonstrated a high degree of co-localization between NK(1)Rs and 5-HT(1A) receptors in most regions examined. Co-localization was highest in the medial septum (88% NK(1)R expressing cells were 5-HT(1A) receptor-positive) and hippocampal regions (e.g. dentate gyrus, 65%), followed by the lateral/basolateral amygdala (35%) and medial prefrontal cortex (31%). In contrast, co-localization between NK(1)Rs and 5-HT(2A) receptors was infrequent (< 8%) in most areas examined except for the hippocampus (e.g. CA3, 43%). Overall co-localization between NK(1)Rs and 5-HT(1A) receptors was much greater than that between NK(1)Rs and 5-HT(2A) receptors. Thus, these experiments demonstrate a high degree of co-localization between NK(1)Rs and 5-HT(1A) receptors in cortical and limbic regions of the rat forebrain. These findings suggest a novel site of interaction between NK(1)R antagonists and the 5-HT system. PMID:22057017

  13. Pindolol increases extracellular 5HT while inhibiting serotonergic neuronal activity

    Microsoft Academic Search

    Casimir A. Fornal; Francisco J. Mart??n; Anna Mendlin; Christine W. Metzler; Bjørn Bjorvatn; Barry L. Jacobs

    1999-01-01

    The effects of pindolol, a beta-adrenoceptor blocker\\/putative 5-hydroxytryptamine (5-HT)1A\\/1B antagonist, on both the single-unit activity of serotonergic neurons in the dorsal raphe nucleus (DRN) and extracellular 5-HT levels in the caudate nucleus, were examined in freely moving cats. Administration of (±)-pindolol (1 and 10 mg\\/kg, s.c.) decreased neuronal activity and increased 5-HT levels in a dose- and time-dependent manner. The

  14. Characteristics of 5-hydroxytryptamine transport in pancreatic islets.

    PubMed Central

    Lindström, P.; Sehlin, J.; Täljedal, I. B.

    1980-01-01

    1 Transmembrane transport of 3H-labelled 5-hydroxytryptamine (5-HT) by isolated pancreatic islets of non-inbred ob/ob mice was studied. 2 5-HT was vigorously accumulated in a temperature-dependent way by the islet cells. 3 Studies of the concentration-dependence of [3H]-5-HT uptake revealed complex kinetics with one component being saturated at 1 to 3 microM 5-HT (apparent association constant 0.6 x 10(6) M(-1) and the other non-saturated up to 1 mM 5-HT. 4 The saturable uptake was inhibited by Na+-deficiency and metabolic poisoning with 2,4-dinitrophenol and antimycin A, whereas the non-saturable component was not affected. 5 Omission of K+, Ca2+ or Mg2+ did not affect the uptake rate. 6 It is concluded that 5-HT is taken up by pancreatic beta-cells by mechanisms very similar to those observed in thrombocytes and neurones. PMID:6991048

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

    PubMed

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

    2009-11-15

    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

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

    E-print Network

    Sibille, Etienne

    Antisense Inhibition of 5-Hydroxytryptamine2a Receptor Induces an Antidepressant-Like Effect Treatment with different antidepressants is invariably accom- panied by the down-regulation of the 5 of antidepressant action, we manip- ulated levels of the 5-HT2A receptor by using a nonpharmaco- logical approach

  17. The response of rat colonic mucosa to 5-hydroxytryptamine in health and following restraint stress.

    PubMed

    Goldhill, J; Porquet, M F; Angel, I

    1998-07-24

    The present study characterized the rat colonic secretory response to 5-hydroxytryptamine (5-HT) and determined alterations in this response following stress. 5-HT stimulated rat colonic short-circuit current in a concentration-dependent fashion (pD2 = 5.19). This response was subject to desensitization and was mimicked by the indolealkylamines with a rank order potency of 5-HT approximately alpha-methyl-5-HT > 5-carboxytryptamine approximately 5-methoxytryptamine. 2-Methyl-5-HT was a partial agonist. The colonic response to 5-HT was unaltered by methysergide (10 microM), ritanserin (0.1 microM), ondansetron (1 microM) or clozapine (10 microM), but was antagonized by the 5-HT4 receptor antagonists SB204070 (pD'2 = 9.32), GR113808 (pKb = 8.56), DAU6285 (pKb = 6.07) and SDZ205557 (pKb = 6.80). The response of colonic epithelial and oesophageal tunica muscularis mucosae to 5-HT is therefore mediated by a similar 5-HT4 receptor. Following wrap restraint stress, the colonic response to 5-HT became bimodal. Half of the preparations were hyper-responsive, while the rest were hypo-responsive to 5-HT. This 5-HT4 receptor may therefore be involved in stress related changes in fluid transport. PMID:9726659

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

    Microsoft Academic Search

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

    1990-01-01

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

  19. Demonstration of 5-hydroxytryptamine receptors through inhibition by methergoline in cat pial arteries in vitro.

    PubMed Central

    Edvinsson, L; Hardebo, J E

    1978-01-01

    1 In an attempt to characterize further the nature of the 5-hydroxytryptamine (5-HT)-induced contraction of intracranial vessels, cat's middle cerebral artery was exposed to this amine and the specific 5-HT receptor antagonist, methergoline, under standardized conditions in vitro. Methergoline, in increasing concentrations, produced a parallel shift of the log dose-response curve for 5-HT. 2 The Arunlakshana-Schild plot gave a straight line with a slope of -0.85. The figure corresponding to the pA2 value was 8.80. 3 The findings offer further support for the assumption that the 5-HT-induced intracranial vasoconstriction is mediated by specific 5-HT receptors. PMID:708997

  20. Vascular interaction between 5-hydroxytryptamine and 15-lipoxygenase metabolites of arachidonic acid.

    PubMed

    Van Diest, M J; Verbeuren, T J; Herman, A G

    1993-02-01

    In isolated canine saphenous veins, the contractions elicited by the 15-lipoxygenase metabolites 15-HETE and 15-HPETE were augmented by 5-hydroxytryptamine (5-HT) in a concentration-dependent way. This potentiation was not mediated by the endothelium nor was it influenced by the 5-HT2-antagonist ketanserin. Phentolamine, however, reduced both the contractions and the potentiation by 5-HT. These data provide evidence for a receptor-mediated potentiation by 5-HT which occurs independently of 5-HT2-receptors. The interaction between 5-HT or aggregating platelets and 15-HPETE was studied in isolated rabbit brachiocephalic arteries. Threshold concentrations of 5-HT and platelets markedly potentiated the contractions elicited by 15-HPETE. In brachiocephalic arteries obtained from cholesterol-fed rabbits, 15-HPETE, 5-HT and platelets caused contractions similar to those obtained in control rabbits. The potentiating effect of 5-HT and platelets on the 15-HPETE-induced contractions was also comparable to that observed in control rabbits. Moreover, no difference was found between control platelets and platelets obtained from hypercholesterolemic rabbits. Our findings demonstrate a positive interaction between 5-HT and 15-lipoxygenase metabolites of arachidonic acid in arteries and veins. This interaction persists in atherosclerotic arteries and could indicate that this mechanism is involved in the genesis of vasospasm. PMID:8453981

  1. Role of 5-hydroxytryptamine mechanisms in mediating the effects of small intestinal glucose on blood pressure and antropyloroduodenal motility in older subjects

    Microsoft Academic Search

    Diana Gentilcore; Tanya J Little; Christine Feinle-Bisset; Melvin Samsom; André JPM Smout; Michael Horowitz; Karen L Jones

    2007-01-01

    ABSTRACT Postprandial hypotension is an important clinical problem, particularly in the elderly. 5- hydroxytryptamine 3 (5-HT3) mechanisms,may,be important,in the,regulation of splanchnic blood flow, blood pressure and in mediating the effects of small intestinal nutrients on gastrointestinal motility. The aims of this study were to evaluate the effects of the 5-HT3

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

    SciTech Connect

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

    1987-03-01

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

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

    Microsoft Academic Search

    Margaret R MacLean

    1999-01-01

    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

  4. Contribution of peripheral ? 1A-adrenoceptors to pain induced by formalin or by ?-methyl-5-hydroxytryptamine plus noradrenaline

    Microsoft Academic Search

    Yanguo Hong; Frances V. Abbott

    1996-01-01

    We examined the peripheral adrenergic mechanisms involved in pain induced by ?-methyl-5-hydroxytryptamine (?-methyl-5-HT) plus (±)-noradrenaline or prostaglandin E2 and by intraplantar formalin. Agents were injected s.c. into the plantar surface of rats' paws, and the paw lifting and licking response scored. Pain produced by ?-methyl-5-HT (10 ?g) plus noradrenaline (10 ?g) was blocked by pretreatment with the ?-adrenoceptor antagonists, phentolamine

  5. Activation of human 5-hydroxytryptamine type 3 receptors via an allosteric transmembrane site.

    PubMed

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

    2015-01-01

    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

  6. 5-Hydroxytryptamine does not reduce sympathetic nerve activity or neuroeffector function in the splanchnic circulation.

    PubMed

    Darios, Emma S; Barman, Susan M; Orer, Hakan S; Morrison, Shaun F; Davis, Robert P; Seitz, Bridget M; Burnett, Robert; Watts, Stephanie W

    2015-05-01

    Infusion of 5-hydroxytryptamine (5-HT) in conscious rats results in a sustained (up to 30 days) fall in blood pressure. This is accompanied by an increase in splanchnic blood flow. Because the splanchnic circulation is regulated by the sympathetic nervous system, we hypothesized that 5-HT would: 1) directly reduce sympathetic nerve activity in the splanchnic region; and/or 2) inhibit sympathetic neuroeffector function in splanchnic blood vessels. Moreover, removal of the sympathetic innervation of the splanchnic circulation (celiac ganglionectomy) would reduce 5-HT-induced hypotension. In anaesthetized Sprague-Dawley rats, mean blood pressure was reduced from 101±4 to 63±3mm Hg during slow infusion of 5-HT (25?g/kg/min, i.v.). Pre- and postganglionic splanchnic sympathetic nerve activity were unaffected during 5-HT infusion. In superior mesenteric arterial rings prepared for electrical field stimulation, neither 5-HT (3, 10, 30nM), the 5-HT1B receptor agonist CP 93129 nor 5-HT1/7 receptor agonist 5-carboxamidotryptamine inhibited neurogenic contraction compared to vehicle. 5-HT did not inhibit neurogenic contraction in superior mesenteric venous rings. Finally, celiac ganglionectomy did not modify the magnitude of fall or time course of 5-HT-induced hypotension when compared to animals receiving sham ganglionectomy. We conclude it is unlikely 5-HT interacts with the sympathetic nervous system at the level of the splanchnic preganglionic or postganglionic nerve, as well as at the neuroeffector junction, to reduce blood pressure. These important studies allow us to rule out a direct interaction of 5-HT with the splanchnic sympathetic nervous system as a cause of the 5-HT-induced fall in blood pressure. PMID:25732865

  7. Release of endogenous 5-hydroxytryptamine from the myenteric plexus of the guinea-pig isolated small intestine.

    PubMed Central

    Holzer, P.; Skofitsch, G.

    1984-01-01

    The presence of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in, and the release of these substances from, the myenteric plexus-longitudinal muscle (MPLM) layer of the guinea-pig isolated small intestine were investigated. 5-HT and 5-HIAA were measured by high performance liquid chromatography and electrochemical detection. Freshly prepared MPLM contained measurable amounts of 5-HT and 5-HIAA. For the release experiments, the MPLM was incubated in a medium containing the 5-HT uptake inhibitor fluoxetine and the monoamine oxidase inhibitor nialamide; this led to a decrease in the 5-HIAA content of the MPLM whereas the 5-HT content remained unchanged. There was a spontaneous release of 5-HT and 5-HIAA from the MPLM. The release of 5-HT was so small that it was just detectable; it seemed equivalent to about 0.8% of the tissue stores released per min. Depolarization of the tissue by increasing the [K+] or by exposing it to veratridine enhanced the release of 5-HT in a Ca2+-dependent manner whereas the release of 5-HIAA was not increased. Tetrodotoxin inhibited the veratridine-evoked release of 5-HT but did not affect the K+-evoked release of 5-HT. The presence of 5-HT in myenteric neurones and the characteristics of the release of 5-HT from these neurones strongly support the hypothesis that 5-HT is an enteric neurotransmitter. PMID:6200171

  8. Endogenous adenosine differentially modulates 5-hydroxytryptamine release from a human enterochromaffin cell model

    Microsoft Academic Search

    Fievos L. Christofi; Minsoo Kim; Jacqueline E. Wunderlich; Jianjing Xue; Zach Suntres; Arturo Cardounel; Najma H. Javed; Jun Ge Yu; Iveta Grants; Helen J. Cooke

    2004-01-01

    Background & Aims: The aim was to determine whether adenosine receptors modulate cAMP, intracellular free calcium ([Ca2+]i), and 5-hydroxytryptamine (5-HT) release in human carcinoid BON cells.Methods: Adenosine receptor (R) mRNA, proteins, and function were identified by Western blots, immunofluorescent labeling, Fluo-4\\/AM [Ca2+]i imaging, and pharmacologic\\/physiologic techniques. Results: A1, A2, and A3Rs were present in BON cells and carcinoid tumors. Baseline

  9. 5HT 7 receptor-mediated relaxation of the oviduct in nonpregnant proestrus pigs

    Microsoft Academic Search

    Mayuko Inoue; Takio Kitazawa; Jinshan Cao; Tetsuro Taneike

    2003-01-01

    The effects of 5-hydroxytryptamine (5-HT) on the muscle tonus of the ampulla and isthmus of the oviduct isolated from nonpregnant proestrus pigs were investigated, and the 5-HT receptor subtype and mechanisms of the responses were analyzed. 5-HT (1 nM–10 ?M) caused a relaxation of longitudinal and circular muscles of the isthmus in a concentration-dependent manner. Tetrodotoxin did not change the

  10. Investigation of the 5-hydroxytryptamine receptor mediating the 'maintained' short-circuit current response in guinea-pig ileal mucosa.

    PubMed Central

    Scott, C. M.; Bunce, K. T.; Spraggs, C. F.

    1992-01-01

    1. 5-Hydroxytryptamine (5-HT) stimulated a biphasic increase in short-circuit current (SCC) in guinea-pig isolated ileal mucosa. The initial 'spike' response to 5-HT was inhibited by tetrodotoxin (0.3 microM). We have investigated the 5-HT receptor mechanism(s) controlling the second 'maintained' component of the response which remained after treatment with tetrodotoxin. 2. 5-HT stimulated concentration-related increases in SCC with an EC50 value of 5.4 microM. Isobutyl-methylxanthine (IBMX, 10 microM) produced a six fold leftward shift of this concentration-response curve, suggesting the involvement of a cyclic nucleotide(s) in these responses. 3. In the presence of IBMX, 5-HT stimulated reproducible increases in SCC with an EC50 value of 0.9 microM. The rank order of potency of indole agonists in these tests was 5-HT greater than or equal to 5-methoxytryptamine greater than 5-carboxamidotryptamine = alpha-methyl-5-HT much greater than 2-methyl-5-HT. 4. The substituted benzamides were partial agonists. Metoclopramide and cisapride produced approximately 20% of the 5-HT maximum, and renzapride and R,S-zacopride produced approximately 50% of the 5-HT maximum. Metoclopramide and cisapride inhibited the SCC responses to 5-HT with apparent pKB values of 4.8 and 7.0 respectively. 5. The SCC responses to 5-HT were not inhibited by antagonists selective for 5-HT1 (methysergide, methiothepin), 5-HT2 (ketanserin) or 5-HT3 (ondansetron, ICS205-930) receptors. 6. The SCC responses to 5-methoxytryptamine, 5-carboxamidotryptamine, alpha-methyl-5-HT and R,S-zacopride, but not 5-HT, were selectively inhibited by high concentrations of ICS205-930 with apparent pKB values of approximately 6.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1393286

  11. Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro.

    PubMed

    Doly, Stéphane; Valjent, Emmanuel; Setola, Vincent; Callebert, Jacques; Hervé, Denis; Launay, Jean-Marie; Maroteaux, Luc

    2008-03-12

    The "club drug" 3,4-methylenedioxymethamphetamine (MDMA; also known as ecstasy) binds preferentially to and reverses the activity of the serotonin transporter, causing release of serotonin [5-hydroxytryptamine (5-HT)] stores from nerve terminals. Subsequent activation of postsynaptic 5-HT receptors by released 5-HT has been shown to be critical for the unique psychostimulatory effects of MDMA. In contrast, the effects of direct activation of presynaptic and/or postsynaptic receptors by MDMA have received far less attention, despite the agonist actions of the drug itself at 5-HT(2) receptors, in particular the 5-HT(2B) receptor. Here we show that acute pharmacological inhibition or genetic ablation of the 5-HT(2B) receptor in mice completely abolishes MDMA-induced hyperlocomotion and 5-HT release in nucleus accumbens and ventral tegmental area. Furthermore, the 5-HT(2B) receptor dependence of MDMA-stimulated release of endogenous 5-HT from superfused midbrain synaptosomes suggests that 5-HT(2B) receptors act, unlike any other 5-HT receptor, presynaptically to affect MDMA-stimulated 5-HT release. Thus, our findings reveal a novel regulatory component in the actions of MDMA and represent the first demonstration that 5-HT(2B) receptors play an important role in the brain, i.e., modulation of 5-HT release. As such, 5-HT(2B) receptor antagonists may serve as promising therapeutic drugs for MDMA abuse. PMID:18337424

  12. Locally formed 5-hydroxytryptamine stimulates phosphate transport in cultured opossum kidney cells and in rat kidney.

    PubMed Central

    Hafdi, Z; Couette, S; Comoy, E; Prie, D; Amiel, C; Friedlander, G

    1996-01-01

    Renal proximal tubular cells have been shown to express aromatic L-amino acid decarboxylase (L-AAAD), which converts L-dopa into dopamine and 5-hydroxytryptophan [(OH)Trp] into 5-hydroxytryptamine (5-HT; serotonin). Because 5-HT receptors have been demonstrated in proximal cells, we hypothesized that 5-HT may act as an autocrine/paracrine modulator of proximal transport. We evaluated this possibility in opossum kidney (OK) cells, a renal epithelial cell line with a proximal phenotype expressing 5-HT1B receptors, and in intact anaesthetized rats. 5-HT synthesis by OK cells increased with incubation time and (OH)Trp concentration, and was abolished by benserazide, an L-AAAD inhibitor. 5-HT reversed parathyroid hormone (PTH)-induced cAMP accumulation in a pertussis toxin-sensitive manner and reduced the PTH inhibition of P(i) uptake without affecting the NaP(i)-4 mRNA level. The effects of 5-HT on cAMP generation and Na-P(i) co-transport were reproduced by (OH)Trp, except in the presence of benserazide, and by L-propranolol and dihydroergotamine, two 5-HT1B receptor agonists. In rats, (OH)Trp and dihydroergotamine decreased fractional P(i) excretion. Benserazide abolished the effect of (OH)Trp but not that of dihydroergotamine. In conclusion: (i) locally generated 5-HT blunts the inhibitory effect of PTH on Na-P(i) co-transport in OK cells; (ii) endogenous 5-HT decreases P(i) excretion in rats; and (iii) 5-HT is a paracrine modulator involved in the physiological regulation of renal P(i) transport. PMID:8973575

  13. Differential regulation of 5-hydroxytryptamine release by GABAA and GABAB receptors in midbrain raphe nuclei and forebrain of rats.

    PubMed Central

    Tao, R.; Ma, Z.; Auerbach, S. B.

    1996-01-01

    1. Extracellular 5-hydroxytryptamine (5-HT) was determined in dorsal raphe nucleus (DRN), median raphe nucleus (MRN) and nucleus accumbens by use of microdialysis in unanaesthetized rats. 2. Infusion of the gamma-aminobutyric acid (GABA)A receptor agonist muscimol into DRN and MRN resulted in decreased 5-HT in DRN and MRN, respectively. Muscimol infusion into nucleus accumbens had no effect on 5-HT. 3. Infusion of the GABAA receptor antagonist bicuculline into DRN resulted in increased DRN and nucleus accumbens 5-HT. Bicuculline infusion into MRN had no effect on 5-HT. This suggests that endogenous GABA had a tonic, GABAA receptor-mediated inhibitory effect on 5-HT in DRN, but not in MRN. 4. Infusion of the GABAB receptor agonist baclofen into DRN produced a decrease in DRN 5-HT. Baclofen infusion into nucleus accumbens resulted in decreased nucleus accumbens 5-HT. This suggests that GABAB receptors are present in the area of cell bodies and terminals of 5-hydroxytryptaminergic neurones. 5. Infusion of the GABAB receptor antagonists phaclofen and 2-hydroxysaclofen had no effect on midbrain raphe and forebrain 5-HT. This suggests that GABAB receptors did not contribute to tonic inhibition of 5-HT release. 6. In conclusion, 5-HT release is physiologically regulated by distinct subtypes of GABA receptors in presynaptic and postsynaptic sites. Images Figure 1 PMID:8968546

  14. Properties of 5-hydroxytryptamine3 receptor-gated currents in adult rat dorsal root ganglion neurones.

    PubMed Central

    Robertson, B.; Bevan, S.

    1991-01-01

    1. Responses to 5-hydroxytryptamine (5-HT) were examined on rat dorsal root ganglion (DRG) neurones maintained in tissue cultures, by use of whole cell recording techniques. 2. 5-HT (usually 10 microM) evoked a depolarization associated with an increase in membrane conductance in 40% of DRG neurones. There was a considerable variation in the size and persistence of this response between different batches of cells. 3. The 5-HT response was mimicked by applying the agonists 2-methyl-5-HT (10 microM) and phenylbiguanide (10 microM). Responses were blocked by ICS 205-930 (100 nM), but not by methysergide (0.1-1.0 microM). 4. 5-HT currents could be carried by sodium and caesium ions, but not by choline ions. The amplitude and duration of the 5-HT responses were dependent on the concentration of divalent cations in the extracellular solution: both became greater when calcium and magnesium concentrations were decreased. 5. Staurosporine, a putative antagonist of protein kinases, inhibited responses to 5-HT. PMID:2043929

  15. Moderate differences in circulating corticosterone alter receptor-mediated regulation of 5-hydroxytryptamine neuronal activity.

    PubMed

    Judge, Sarah J; Ingram, Colin D; Gartside, Sarah E

    2004-12-01

    Circulating glucocorticoid levels vary with stress and psychiatric illness and play a potentially important role in regulating transmitter systems that regulate mood. To determine whether chronic variation in corticosterone levels within the normal diurnal range altered the control of 5-hydroxytryptamine (5-HT) neuronal activity, male rats were adrenalectomized and implanted with either a 2% or 70% corticosterone/cholesterol pellet (100 mg). Two weeks later, the regulation of 5-HT neuronal activity in the dorsal raphe nucleus was studied by in vitro electrophysiology. At this time, serum corticosterone levels approximated the low-point (2%) and mid-point (70%) of the diurnal range. The excitatory response of 5-HT neurones to the alpha1-adrenoceptor agonist phenylephrine (1-11 microM) was significantly greater in the 2% group compared to the 70% group. By contrast, the inhibitory response to 5-HT (10-50 microM) was significantly lower in the 2% group compared to the 70% group. Thus, chronic variation in circulating corticosterone over a narrow part of the normal diurnal range causes a shift in the balance of positive and negative regulation of 5-HT neurones, with increased alpha 1-adrenoceptor-mediated excitation and reduced 5-HT-mediated autoinhibition at lower corticosterone levels. This shift would have a major impact on control of 5-HT neuronal activity. PMID:15582914

  16. Indirect action of 5-hydroxytryptamine on the isolated muscularis mucosae of the guinea-pig oesophagus

    PubMed Central

    Kamikawa, Yuichiro; Shimo, Yasuo

    1983-01-01

    1 The site of action of 5-hydroxytryptamine (5-HT) was examined on the isolated muscularis mucosae attached to the submucous plexus of the guinea-pig oesophagus. Isotonic responses of the longitudinal muscularis mucosae were recorded. 2 5-HT produced a transient contraction of the muscularis mucosae at concentrations higher than 3 ?M. The contraction was rapid in onset, reaching a peak in about 15 s or less, and was restored to the basal level after 20 to 30 s without washing out 5-HT. When the 5-HT-induced contraction faded to the basal tone, successive applications of 5-HT no longer produced any contracture. 3 Nicotine (Nic), at concentrations higher than 10 ?M, also produced a transient contraction which had a very similar pattern to that induced by 5-HT. Again, the successive application of Nic no longer produced any contracture following prior treatment with Nic itself. However, the 5-HT-induced contraction was not modified by the presence of Nic. 4 Exogenously applied acetylcholine (ACh) produced a concentration-dependent contraction of the muscularis mucoase, the 50% effective concentration (EC50) was 69 ± 5.6 nM. The contraction was sustained during incubation with ACh, and was not modified by prior treatment with 5-HT or Nic. 5 The 5-HT (100 ?M)-induced contraction was completely abolished by tetrodotoxin (0.2 ?M) and atropine (0.2 ?M). This means that the action is mediated by stimulating cholinergic nerves in the submucous plexus attached to muscularis mucosae. Moreover, the stimulating action of 5-HT does not involve nicotinic receptors, since the action was not blocked by hexamethonium (100 ?M). 6 Among several 5-MT antagonists examined, methysergide (1 ?M), ketanserin (1 ?M) and morphine (100 ?M) failed to modify the 5-HT (100 ?M)-induced contraction significantly. Cinanserin (0.1-3 ?M), cyproheptadine (3-100 nM) and phenoxybenzamine (0.1-3 ?M) inhibited the 5-HT-induced contraction, in a concentration-dependent manner, and each highest concentration abolished the response. However, none of these antagonists was specific for 5-HT, but the Nic (100 ?M) or ACh (0.1 ?M)-induced contractions were also inhibited by them. 7 The present results indicate that 5-HT contracts the muscularis mucosae of the guinea-pig oesophagus indirectly by stimulating cholinergic nerves in the submucous plexus, and has no direct action on the muscularis mucosae. In addition, the type of 5-HT receptors responsible for the stimulant action may be different from those in other parts of the gastrointestinal tract, blood vessels or brain, because of the different effects of 5-HT antagonists. PMID:6824809

  17. Characterization of the 5-hydroxytryptamine receptor type involved in inhibition of spontaneous activity of human isolated colonic circular muscle.

    PubMed Central

    Tam, F S; Hillier, K; Bunce, K T

    1994-01-01

    1. Experiments were carried out to characterize pharmacologically the 5-hydroxytryptamine (5-HT) receptor types which mediate inhibition of spontaneous contractions of the intertaenial circular muscle in human isolated colon. 2. 5-HT caused a reproducible concentration-dependent inhibition of spontaneous contractions of the circular muscle of human colon in vitro with a mean EC50 value of 0.2 microM and 95% confidence limits of 0.1-0.5 microM. No evidence for a contractile action of 5-HT was found. Tetrodotoxin (TTX, 1.5 microM) caused a rightward shift of the concentration-response curve of 5-HT with a concentration-ratio of 2.9. 3. The inhibitory response to 5-HT was mimicked by several indoles with the rank order of potency 5-HT > 5-methoxytryptamine = alpha-methyl-5-HT > 5-carboxamidotryptamine >> 2-methyl-5-HT. 5-Hydroxyindalpine was inactive. 4. The substituted benzamides were agonists with the following rank order of potency, 5-HT > renzapride > zacopride > metoclopramide > cisapride. 5. The inhibitory responses to 5-HT were not inhibited by methysergide (10 microM) or methiothepin (1 microM), which are antagonists selective for 5-HT1-like and 5-HT2 receptors, nor by ondansetron (10 microM) which is an antagonist at 5-HT3 receptors. 6. The inhibitory responses induced by 5-HT and 5-methoxytryptamine were competitively antagonized by a weak 5-HT4 receptor antagonist, tropisetron, with pKB values of approximately 6. Tropisetron had no significant effect on the inhibitory response curve produced by isoprenaline (0.01-100 microM).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7812604

  18. 5-Hydroxytryptamine stimulates the release of prostacyclin but not thromboxane A2 from isolated rat dental pulp.

    PubMed

    Hirafuji, M; Ogura, Y

    1987-04-29

    The effect of 5-hydroxytryptamine (5-HT) on the release of prostacyclin and thromboxane (TX) A2 from isolated rat dental pulp was evaluated. 5-HT (1-1,000 microM) caused a dose-dependent and marked stimulation of the release of prostacyclin but not TXA2. Of the 5-HT-related indolealkylamines tested, only tryptamine had a similar stimulatory effect while tryptophan and 5-hydroxytryptophan had no effect. Neither histamine (100 microM) nor bradykinin (100 microM) had such an effect. Our results suggest the possible involvement of 5-HT receptors in 5-HT-induced stimulation of prostacyclin production in rat dental pulp. PMID:3301370

  19. Effects of 5HT4 receptor stimulation on basal and electrically evoked release of acetylcholine from guinea-pig myenteric plexus

    Microsoft Academic Search

    H. Kilbinger; D. Wolf

    1992-01-01

    The effects of 5-methoxytryptamine and 5-hydroxytryptamine (5-HT) on both basal and electrically evoked outflow of tritium were studied in guinea-pig myenteric plexus preparations preincubated with [3H]-choline.

  20. 5-HT1A/1B Receptors as Targets for Optimizing Pigmentary Responses in C57BL/6 Mouse Skin to Stress

    PubMed Central

    Wu, Hua-Li; Pang, Si-Lin; Liu, Qiong-Zhen; Wang, Qian; Cai, Min-Xuan; Shang, Jing

    2014-01-01

    Stress has been reported to induce alterations of skin pigmentary response. Acute stress is associated with increased turnover of serotonin (5-hydroxytryptamine; 5-HT) whereas chronic stress causes a decrease. 5-HT receptors have been detected in pigment cells, indicating their role in skin pigmentation. To ascertain the precise role of 5-HT in stress-induced pigmentary responses, C57BL/6 mice were subjected to chronic restraint stress and chronic unpredictable mild stress (CRS and CUMS, two models of chronic stress) for 21 days, finally resulting in abnormal pigmentary responses. Subsequently, stressed mice were characterized by the absence of a black pigment in dorsal coat. The down-regulation of tyrosinase (TYR) and tyrosinase-related proteins (TRP1 and TRP2) expression in stressed skin was accompanied by reduced levels of 5-HT and decreased expression of 5-HT receptor (5-HTR) system. In both murine B16F10 melanoma cells and normal human melanocytes (NHMCs), 5-HT had a stimulatory effect on melanin production, dendricity and migration. When treated with 5-HT in cultured hair follicles (HFs), the increased expression of melanogenesis-related genes and the activation of 5-HT1A, 1B and 7 receptors also occurred. The serum obtained from stressed mice showed significantly decreased tyrosinase activity in NHMCs compared to that from nonstressed mice. The decrease in tyrosinase activity was further augmented in the presence of 5-HTR1A, 1B and 7 antagonists, WAY100635, SB216641 and SB269970. In vivo, stressed mice received 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), a member of the class of selective serotonin reuptake inhibitors (fluoxetine; FX) and 5-HTR1A/1B agonists (8-OH-DPAT/CP94253), finally contributing to the normalization of pigmentary responses. Taken together, these data strongly suggest that the serotoninergic system plays an important role in the regulation of stress-induced depigmentation, which can be mediated by 5-HT1A/1B receptors. 5-HT and 5-HTR1A/1B may constitute novel targets for therapy of skin hypopigmentation disorders, especially those worsened with stress. PMID:24586946

  1. An inhibitory prejunctional 5-HT1-like receptor in the isolated perfused rat kidney. Apparent distinction from the 5-HT1A, 5-HT1B and 5-HT1C subtypes.

    PubMed

    Charlton, K G; Bond, R A; Clarke, D E

    1986-01-01

    The present study has identified a receptor for 5-hydroxytryptamine (5-HT) which functions to inhibit the stimulus-induced release of [3H] noradrenaline following sympathetic periarterial nerve stimulation to the isolated perfused rat kidney. In addition to 5-HT (IC30 = 4.5 X 10(-8) mol/l), both 5-carboxamidotryptamine (IC30 = 8 X 10(-9) mol/l) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl) indole (RU-24969, IC30 = 2.5 X 10(-7) mol/l) acted as agonists whereas 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was inactive. The inhibitory effect of 5-HT on the electrically-evoked release of tritium was antagonized in a concentration-dependent manner by methiothepin (IC50 = 4 X 10(-9) mol/l), metergoline (IC50 = 4 X 10(-8) mol/l) and methysergide (IC50 = 1.3 X 10(-7) mol/l) but not by cyproheptadine, ketanserin, mesulergine, (-)-propranolol, (+/-)-pindolol, (+/-)-cyanopindolol, metoclopramide or phentolamine. It is concluded that the receptor to 5-HT conforms to general criteria defining 5-HT1-like receptors but at the present time the receptor site cannot be fitted to the designated 5-HT1A, 5-HT1B or 5-HT1C subtypes. PMID:3951568

  2. 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

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

    1995-01-01

    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

  3. Serotonin (5-HT) activation of immortalized hypothalamic neuronal cells through the 5-HT1B serotonin receptor.

    PubMed

    Tung, Stephanie; Hardy, Alexandre B; Wheeler, Michael B; Belsham, Denise D

    2012-10-01

    Serotonin [or 5-hydroxytryptamine or (5-HT)] has been implicated as a key modulator in energy homeostasis and a primary focus in the treatment of obesity. There is growing evidence that 5-HT, acting through the 5-HT 1B receptor (5-HT(1B)R) in the paraventricular nucleus of the hypothalamus (PVN), is important to this regulation. However, there is some contention as to whether 5-HT(1B)R action occurs directly on PVN neurons or indirectly via inhibitory inputs into the PVN. To address these questions, we used a novel clonal, hypothalamic neuronal cell model, adult mouse hypothalamic-2/30 (mHypoA-2/30), expressing a PVN-specific marker, single-minded homolog 1, as well as a complement of PVN neuropeptides, including TRH, vasopressin, ghrelin, nucleobindin-2, and galanin. Adult mouse hypothalamic-2/30 neurons were also found to express the 5-HT(1B)R and 5-HT 6 receptor, but not 2C, all previously linked to feeding regulation. Direct serotonergic stimulation (100 nm to 10 ?m) of these neurons resulted in dose-dependent cFos activation. 5-HT (10 ?m) suppressed forskolin-induced cAMP levels and induced a rise in intracellular Ca(2+) through ER Ca(2+) release, effects that were mimicked by the 5-HT(1B)R agonists, CGS12066B and CP93129, and that were attenuated in the presence of the 5-HT(1B)R-specific inhibitors, GR55562 and isamoltane hemifumarate. Modest transcriptional changes in ghrelin and nucleobindin-2 were also observed in response to 100 nm and 10 ?m 5-HT, respectively. These findings support the model wherein 5-HT action through the 1B receptor subtype occurs directly on PVN neurons, leading to potential modification of neuronal transcriptional and secretory machinery. PMID:22919062

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

    PubMed

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

    2015-02-11

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

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

    Microsoft Academic Search

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

    1996-01-01

    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

  6. Modulation by drugs of the release of total tritium and 3 H-5HT from rat hypothalamic slices

    Microsoft Academic Search

    Chantal Moret; Mike Briley

    1990-01-01

    The release of total tritium and 3H-5hydroxytryptamine (5-HT) evoked by electrical stimulation from prelabelled rat hypothalamic slices was studied. Lysergic acid diethylamide (LSD) decreased while methiothepin increased both total tritium and 3H-5-HT overflow. The proportion of total tritium present as 3H-5-HT was equivalent under control conditions and in the presence of methiothepin and slightly increased in the presence of LSD.

  7. Investigation of the 5-hydroxytryptamine receptor mechanism mediating the short-circuit current response in rat colon.

    PubMed Central

    Bunce, K. T.; Elswood, C. J.; Ball, M. T.

    1991-01-01

    1. 5-Hydroxytryptamine (5-HT) stimulated an increase in short-circuit current (SCC) in rat isolated colonic mucosa with an EC50 value of approximately 4 microM. The purpose of the present study was to investigate the 5-HT receptor mechanism(s) involved in this response. 2. The relatively selective 5-HT receptor agonists 5-carboxamidotryptamine (5-CT) and alpha-methyl-5-HT stimulated SCC and were 6 to 8 times less potent than 5-HT. 2-Methyl-5-HT was inactive both as an agonist and an antagonist. 3. The following compounds produced no significant inhibition of the SCC response to 5-HT: ketanserin (1 microM), methysergide (1 microM), methiothepin (0.3 microM), GR38032F (0.3 microM), tetrodotoxin (0.3 microM) and sulpiride (1 microM). 4. Both metoclopramide (3 and 10 microM) and cisapride (0.1 and 1 microM) inhibited the SCC responses to 5-HT in a concentration-related manner, and the higher doses similarly inhibited the responses to 5-CT. With both agonists the inhibitory effects of metoclopramide and cisapride were insurmountable. However, these inhibitory actions appeared to be selective since neither metoclopramide nor cisapride affected the basal SCC or the SCC response to prostaglandin E2. 5. The SCC responses to 5-HT and 5-methoxytryptamine were selectively inhibited by ICS205-930 at 3 microM, and respective pKB values of 6.0 and 6.6 were calculated. 6. It is concluded that 5-HT stimulates an SCC response in rat colon via a receptor mechanism that cannot be clearly identified as 5-HT1-like, 5-HT2 or 5-HT3. This receptor is selectively antagonized by ICS 205-930 and by the benzamides, metoclopramide and cisapride.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1855112

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

    PubMed Central

    Goto, Kei; Kawahara, Isao

    2014-01-01

    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

  9. Enhancement of 5-HT-induced anorexia: a test of the reversibility of monoamine oxidase inhibitors

    Microsoft Academic Search

    P. J. Fletcher; P. H. Yu

    1989-01-01

    Subcutaneous injection of 1 mg\\/kg 5-hydroxytryptamine (5-HT) reduced the intake of a 10% sucrose solution in rats. A single injection of the monoamine oxidase inhibitor (MAOI) clorgyline enhanced the anorectic effect of 5-HT. Such an effect persists 2, 24, 48, 72 and 96 h after injection. The clorgyline treatment almost completely inhibited type A MAO activity in the liver at

  10. 5-Hydroxytryptamine-induced Ca 2+-independent cGMP formation is mediated by nitric oxide in a nitric oxide synthase-independent manner in NG108-15 cells

    Microsoft Academic Search

    Takashi Arima; Tsuneko Mizuno; Yoshihiro Ohshima; Yoshihisa Kitamura; Tomio Segawa; Yasuyuki Nomura

    1997-01-01

    A novel pathway of 5-hydroxytryptamine (5-HT)-induced cGMP formation, which does not require Ca2+ and is distinct from the 5-HT3 receptor-mediated pathway, is reported to exist in NG108-15 cells. Although the possible involvement of undefined 5-HT receptors and membrane-bound guanylyl cyclase is suggested, the mechanism is not clarified in detail in this Ca2+-independent cGMP formation. In the present study, we investigated

  11. 5-Hydroxytryptamine and cholera secretion: a histochemical and physiological study in cats.

    PubMed Central

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

    1983-01-01

    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

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

    PubMed

    Tabor, Jami N; Cooper, Robin L

    2002-04-01

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

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

    PubMed Central

    Ireland, S. J.

    1987-01-01

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

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

    PubMed Central

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

    1996-01-01

    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

  15. The pathogenesis of endomyocardial fibrosis: the question of 5-hydroxytryptamine

    PubMed Central

    Ojo, G. O.

    1970-01-01

    Thirty Nigerians with established endomyocardial fibrosis were studied. Basal serum 5-hydroxytryptamine levels were estimated on three different occasions at one-monthly intervals. Twentyfour hours before each estimation, dietary staples containing 5-hydroxytryptamine were excluded from the diet. Subsequently the patients were fed on a plantain diet and serum levels of 5-hydroxytryptamine were estimated at one- and three-hour intervals after plantain ingestion. 5-hydroxytryptamine was assayed on the fundal strip of rat's stomach. These values were compared with those obtained in an earlier study on healthy Nigerians. It was observed that, as in healthy Nigerians, no significant increase in serum 5-hydroxytryptamine levels occurred in these patients after plantain ingestion. The difference between endomyocardial fibrosis and carcinoid heart disease is underlined and it is emphasized that no correlation exists between the incidence of endomyocardial fibrosis and the high content of 5-hydroxytryptamine in the local dietary staples. PMID:5470049

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

    PubMed Central

    Bombardi, Cristiano

    2014-01-01

    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

  17. Evidence for an inhibitory 5-HT4 receptor in urinary bladder of rhesus and Cynomolgus monkeys.

    PubMed Central

    Waikar, M. V.; Ford, A. P.; Clarke, D. E.

    1994-01-01

    1. The present study shows that 5-hydroxytryptamine (5-HT) inhibits electrically-evoked contractions of isolated urinary bladder strips from Rhesus and Cynomolgus monkeys via activation of 5-HT4 receptors. 2. 5-HT (0.1 nM-10 microM) produced concentration-dependent inhibition of the contractile response to electrical stimulation yielding a pEC50 of 7.8 (Rhesus monkey) and 7.6 (Cynomolgus monkey). This action of 5-HT was mimicked by 5-methoxytryptamine, renzapride and BIMU 8, each of which behaved as a full agonist relative to 5-HT. However, the potency estimate for BIMU 8 (pEC50 = 6.5) in Cynomolgus monkey was low, relative to 5-HT, indicating a possible heterogeneity of 5-HT4 receptors. 3. The inhibitory action of 5-HT was resistant to antagonism by methysergide (1 microM) and ondansetron (5 microM), thereby eliminating a role for 5-HT1, 5-HT2 and 5-HT3 receptors. The 5-HT4 receptor antagonists, GR 113808 (10 nM), DAU 6285 (1-10 microM) and RS 23597-190 (1 microM), produced parallel, dextral displacements of the concentration-effect curves to 5-HT and other related agonists with affinity estimates in agreement with those defined previously in other 5-HT4 receptor assay systems. 4. Experiments using direct electrical stimulation of bladder smooth muscle indicate that the 5-HT4 receptors are located post-junctionally. 5. The inhibitory action of 5-HT in isolated urinary bladder of monkey differs from the excitatory effect of 5-HT in urinary bladder of man. Species variation and its implications for the development of therapeutic agents are discussed. PMID:8012699

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

    NASA Technical Reports Server (NTRS)

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

    1986-01-01

    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.

  19. Effects of halothane on transport of 5-hydroxytryptamine by platelet membranes.

    PubMed Central

    Watkins, C A; Mylin, L M; Rannels, D E

    1986-01-01

    Na+-dependent uptake of 5-HT (5-hydroxytryptamine) into plasma membrane vesicles derived from bovine blood platelets and ATP-dependent 5-HT uptake into storage vesicles in platelet lysates were measured. Na+-dependent uptake was temperature-dependent, inhibited by imipramine and exhibited Michaelis-Menten kinetics (apparent Km, 0.12 +/- 0.02 microM; Vmax. 559 +/- 54 pmol/min per mg of protein. Halothane had no effect on Na+-dependent transport of 5-HT in plasma-membrane vesicles. ATP-dependent 5-HT transport into storage granules also exhibited Michaelis-Menten kinetics (apparent Km 0.34 +/- 0.03 microM; Vmax. 34.3 +/- 1.7 pmol/min per mg of protein) and was inhibited by noradrenaline (norepinephrine), but not by imipramine. Exposure of the granules to halothane resulted in a progressive decrease in Vmax. The results demonstrate a possible site for disruption of platelet function by anaesthetics. PMID:3741387

  20. Effect of 5-hydroxytryptamine on protein synthesis in gastrointestinal and other tissues and on serum gastrin concentrations in rats.

    PubMed Central

    Nandi Majumdar, A. P.; Nakhla, A. M.

    1979-01-01

    1 The effect of 5-hydroxytryptamine (5-HT) on protein synthesis in the gastrointestinal tissues as well as in the liver, heart and brain was studied by measuring [3H]-leucine incorporation into total tissue protein in vivo in rats. 2 A single injection of 5-HT (10 mg/kg) produced a marked inhibition (45 to 65%) in protein synthesis in the stomach (oxyntic gland area), intestine (jejunum + ileum), colon and brain, but not in the liver and heart. 3 Dose- and time-dependent studies of 5-HT-induced changes in protein synthesis in the stomach of fed rats revealed that the maximal inhibition of about 65% occurred 1 h after a dose of 12.5 mg/kg. 4 Animals deprived of food for 24 h differed from their fed counterparts only in the degree of responsiveness, in that a greater inhibition (75%) of [3H]-leucine incorporation into total protein of the stomach was observed 30 min after 5-HT injection. 5 Pretreatment of animals with methysergide (0.25 mg/kg) essentially abolished the 5-HT-mediated inhibition of protein synthesis in the stomach. 6 Serum gastrin concentration in fasted animals remained slightly elevated during the initial period of 5-HT treatment (up to 1 h). 7 The results demonstrate that in certain tissues, 5-HT markedly inhibits protein synthesis. The inhibition in protein synthesis in the gastrointestinal tract cannot be attributed to changes in the concentration of gastrin. PMID:465872

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

    PubMed Central

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

    2014-01-01

    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

  2. 5-HT is a potent relaxant in rat superior mesenteric veins

    PubMed Central

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

    2015-01-01

    Serotonin (5-HT, 5-hydroxytryptamine) reduces blood pressure of the conscious rat when administered chronically (1 week). 5-HT does not directly relax isolated arteries, and microsphere experiments in 5-HT-infused rats suggested that 5-HT increased flow to the splanchnic bed. We hypothesized that 5-HT increased splanchnic flow because of direct venous relaxation; our focus was thus on the superior mesenteric vein (SMV) as an important vein in splanchnic circulation. Real-time RT-PCR, immunohistochemistry and Western analyses supported the predominant expression of the 5-HT2B and 5-HT7 receptor in the SMV. The SMV was mounted in tissue baths for measurement of isometric contraction. 5-HT caused a concentration-dependent relaxation of the endothelin-1 (ET-1)-contracted vein. The threshold of 5-HT-induced venous relaxation was significantly lower than for 5-HT-induced venous contraction (?2 vs. 700 nmol/L, respectively). A series of serotonergic agonists established in their use of receptor characterization was tested, and the following rank order of potency found for agonist-induced relaxation (receptor selectivity): 5-CT (5-HT1/5-HT7)>5-HT = LP-44 (5-HT7)>PNU109291 (5-HT1D) = BW723C86 (5-HT2B). 8-OH-DPAT (5-HT1A/7), CP93129 (5-HT1B), mCPBG (5-HT3/4), AS19 (5-HT7) and TCB-2 (5-HT2A) did not relax the isolated vein. Consistent with these findings, two different 5-HT7 receptor antagonists SB 269970 and LY215840 but not the 5-HT2B receptor antagonist LY272015 nor the nitric oxide synthase inhibitor LNNA abolished 5-CT-induced relaxation of the isolated SMV. 5-CT (1 ?g kg?1 min?1, sc) also reduced blood pressure over 7 days. These findings suggest that 5-HT directly relaxes the SMV primarily through activation of the 5-HT7 receptor. PMID:25692021

  3. 5-HT is a potent relaxant in rat superior mesenteric veins.

    PubMed

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

    2015-02-01

    Serotonin (5-HT, 5-hydroxytryptamine) reduces blood pressure of the conscious rat when administered chronically (1 week). 5-HT does not directly relax isolated arteries, and microsphere experiments in 5-HT-infused rats suggested that 5-HT increased flow to the splanchnic bed. We hypothesized that 5-HT increased splanchnic flow because of direct venous relaxation; our focus was thus on the superior mesenteric vein (SMV) as an important vein in splanchnic circulation. Real-time RT-PCR, immunohistochemistry and Western analyses supported the predominant expression of the 5-HT2B and 5-HT7 receptor in the SMV. The SMV was mounted in tissue baths for measurement of isometric contraction. 5-HT caused a concentration-dependent relaxation of the endothelin-1 (ET-1)-contracted vein. The threshold of 5-HT-induced venous relaxation was significantly lower than for 5-HT-induced venous contraction (?2 vs. 700 nmol/L, respectively). A series of serotonergic agonists established in their use of receptor characterization was tested, and the following rank order of potency found for agonist-induced relaxation (receptor selectivity): 5-CT (5-HT1/5-HT7)>5-HT = LP-44 (5-HT7)>PNU109291 (5-HT1D) = BW723C86 (5-HT2B). 8-OH-DPAT (5-HT1A/7), CP93129 (5-HT1B), mCPBG (5-HT3/4), AS19 (5-HT7) and TCB-2 (5-HT2A) did not relax the isolated vein. Consistent with these findings, two different 5-HT7 receptor antagonists SB 269970 and LY215840 but not the 5-HT2B receptor antagonist LY272015 nor the nitric oxide synthase inhibitor LNNA abolished 5-CT-induced relaxation of the isolated SMV. 5-CT (1 ?g kg(-1) min(-1), sc) also reduced blood pressure over 7 days. These findings suggest that 5-HT directly relaxes the SMV primarily through activation of the 5-HT7 receptor. PMID:25692021

  4. Lanthanides inhibit the human noradrenaline, 5-hydroxytryptamine and dopamine transporters.

    PubMed

    Bryan-Lluka, L J; Bönisch, H

    1997-06-01

    Transporters for the monoamine neurotransmitters, including noradrenaline, 5-hydroxytryptamine [5-HT] and dopamine, have twelve transmembrane spanning regions and cotransport Na+ and Cl- ions. Another family of Na(+)-dependent transporters is that containing the Na+/glucose and Na+/proline cotransporters that are found in the epithelial cells of renal and intestinal brush border membranes. It has been shown that various trivalent lanthanides can substitute for Na+ for transport of glucose and proline. The aim of this study was to determine the effects of lanthanides on the activities of the human noradrenaline, 5-HT and dopamine transporters. Cultured cells were incubated for 2 min with 10 nM 3H-noradrenaline (SK-N-SH-SY5Y human neuroblastoma cells), 3H-5-HT (JAR human placental choriocarcinoma cells) or 3H-dopamine (COS-7 cells transfected with the cDNA of the human dopamine transporter). Specific amine uptake was determined as the difference between accumulation of the amine in the cells in the absence and presence of a corresponding uptake inhibitor. Under both isotonic (150 mM NaCl or LiCl or 90 mM lanthanide salt) and hypertonic (150 mM NaCl +100 mM LiCl, 250 mM LiCl or 150 mM lanthanide salt) conditions, replacement of Na+ by Li+, La3+, Eu3+ or Sm3+ abolished the specific uptake of noradrenaline in SK-N-SH-SY5Y cells and replacement of Na+ by Li+ or Eu3+ decreased the specific uptake of 5-HT in JAR cells by 94-100% and that of dopamine in transfected COS-7 cells by 95-99%. The direct effects of Eu3+ (with Na+ present) on the human noradrenaline transporter in SK-N-SH-SY5Y cells were also examined. Eu3+ inhibited noradrenaline uptake into the cells (IC50 2.6 mM) and nisoxetine binding to crude membranes of SK-N-SH-SY5Y cells (IC50 4.7 mM) with similar potencies. Further experiments showed that 4.5 mM EuCl3 in the presence of 150 mM Na+ caused a 3.5-fold increase in the K(m) of noradrenaline and no change in the maximal rate of noradrenaline uptake. EuCl3 (4.5 mM) also caused a pronounced inhibition of the Na(+)-dependent stimulation of noradrenaline uptake by SK-N-SH-SY5Y cells. It can be concluded from these data that, in contrast with the Na+/glucose and Na+/proline cotransporters, the lanthanides cannot substitute for Na+ in the transport of substrates by the monoamine neurotransmitter transporters and that the lanthanides inhibit the latter transporters by interacting with sites of the transporters involved in amine and Na+ binding. PMID:9205953

  5. Characterization of the 5-hydroxytryptamine receptor mediating the positive inotropic response in guinea-pig isolated left atria.

    PubMed Central

    Lattimer, N.; Gupta, P.; Rhodes, K. F.

    1993-01-01

    1. 5-Hydroxytryptamine (5-HT), in the presence of propranolol (1 microM), atropine (3 microM) and ketanserin (1 microM), induced a positive inotropic response of guinea-pig isolated electrically paced left atria (pEC50 = 7.52). The positive inotropic response was mimicked by alpha-methyl-5-HT (pEC50 = 7.26) and 5-carboxamidotryptamine (5-CT; pEC50 = 6.56) but not by sumatriptan or 1-(m-chlorophenyl) piperazine (m-CPP). 2. The 5-HT induced positive inotropic response was competitively antagonized by both mesulergine (pA2 = 7.68) and methiothepin (pA2 = 6.67). Methysergide was a surmountable antagonist at 3 nM producing a rightward shift in the 5-HT concentration-response curve giving an apparent pA2 = 9.2 with no significant reduction in the maximum. At higher concentrations, methysergide behaved as an insurmountable antagonist, significantly reducing the maximum response to 5-HT as well as producing rightward shifts in the 5-HT concentration-response curves. 3. The 5-HT-induced positive inotropic response was not antagonized by either tropisetron (10 microM) or yohimbine (10 microM). 4. The guinea-pig atrial 5-HT receptor does not satisfy the criteria for any of the currently recognised 5-HT receptor subtypes and appears to have some similarities to the atypical 5-HT receptors previously described in other peripheral tissues. PMID:8401929

  6. A pharmacological analysis of receptors mediating the excitatory response to 5-hydroxytryptamine in the guinea-pig isolated trachea.

    PubMed Central

    Lucchelli, A.; Santagostino-Barbone, M. G.; Barbieri, A.; Tonini, M.

    1994-01-01

    1. Experiments were carried out to characterize the receptors mediating the indirect excitatory response to 5-hydroxytryptamine (5-HT) in the guinea-pig isolated trachea. 2. 5-HT caused concentration-dependent contractions of tracheal strips, and the resulting concentration-response curve was biphasic in nature. The first phase was obtained with agonist concentrations in the range of 0.01-3 nM and achieved a maximum which was 30% of the total 5-HT response, while the second phase was in the range 10 nM-1 microM. 3. Atropine (0.1 microM) and tetrodotoxin (TTX: 0.3 microM) significantly reduced both phases of the 5-HT curve. Morphine (10 microM), which can act to inhibit neuronal acetylcholine release, abolished the first phase and reduced the second phase. This suggests that the first phase is mainly neurogenic (cholinergic) in nature, while the second phase is in part neurogenic and in part due to direct activation of the effector cells. 4. The 5-HT2A receptor antagonist, ketanserin (0.01, 0.1 microM) markedly depressed the first phase and shifted the second phase to the right in a parallel manner, with some depression of the 5-HT response maximum. The less selective (5-HT1/5-HT2A) antagonist, methiothepin (0.1 microM) mimicked the action of ketanserin, albeit with less potency. Concomitant administration of ketanserin and methiothepin (each at 0.1 microM) produced an antagonism similar to that caused by ketanserin (0.1 microM) alone. 5. The 5-HT3 receptor antagonists, ondansetron (0.1 microM) and granisetron (0.01 microM) slightly but significantly inhibited the first phase of the 5-HT curve without altering the second phase.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7921600

  7. Electroconvulsive shock increases the behavioural responses of rats to brain 5-hydroxytryptamine accumulation and central nervous system stimulant drugs.

    PubMed Central

    Evans, J P; Grahame-Smith, D G; Green, A R; Tordoff, A F

    1976-01-01

    1 A single electroconvulsive shock (ECS) of 150 V for 1 s increased the concentration of rat brain 5-hydroxyindoleacetic acid (5-HIAA) but did not alter brain 5-hydroxytryptamine (5-HT) or tryptophan concentrations 3 h later. 2 A single ECS decreased 5-HT synthesis 3 h and 6 h later. Synthesis was back to normal after 24 hours. The ECS-treated rats did not show greater hyperactivity produced by the increased brain 5-HT accumulation following administration of L-tryptophan and tranylcypromine at any time up to 24 h later. This suggests that a single electroshock does not alter 5-HT functional activity. 3 Twenty-four hours after the final ECS of a series of 10 shocks given once daily, the rats were given tranylcypromine and L-tryptophan. They displayed greater hyperactivity than control rats not treated with ECS, suggesting that ECS increases 5-HT functional activity. Brain concentrations of 5-HT, 5-HIAA and tryptophan were then unchanged by ECS. 5-HT synthesis and accumulation of 5-HT following tranylcypromine and L-tryptophan were not altered by ECS. 4 The hyperactivity following administration of the 5-HT agonist 5-methoxy N,N-dimethyltryptamine was enhanced by repeated (10 day) ECS, suggesting altered post-synaptic responses to 5-HT receptor stimulation. 5 Repeated ECS enhanced locomotor activity following tranylcypromine and L-DOPA. It did not alter brain noradrenaline or dopamine concentrations. 6 The latent period before a pentylenetetrazol-induced convulsion was shortened by repeated ECS. 7 Following repeated ECS there appears to be increased neuronal sensitivity to certain stimuli producing centrally mediated behavioural stimulation. This is discussed in relation to the mechanism by which electroconvulsive therapy (ECT) produces its therapeutic effect. PMID:3248

  8. 5-Hydroxytryptamine receptor-mediated phosphoinositide hydrolysis in canine cultured tracheal smooth muscle cells.

    PubMed Central

    Yang, C. M.; Yo, Y. L.; Hsieh, J. T.; Ong, R.

    1994-01-01

    1. 5-Hydroxytryptamine (5-HT) has been shown to induce contraction of tracheal smooth muscle. However, the mechanisms of action of 5-HT are not known. We therefore investigated the effects of 5-HT on phospholipase C (PLC)-mediated phosphoinositide (PI) hydrolysis and its regulation in canine cultured tracheal smooth muscle cells (TSMCs) labelled with [3H]-inositol. 5-HT-induced inositol phosphates (IPs) accumulation was time- and dose-dependent with a half-maximal response (EC50) and a maximal response at 0.38 +/- 0.05 and 10 microM, respectively. 2. Ketanserin and mianserin (10 and 100 nM), 5-HT2 receptor antagonists, were equipotent in blocking the 5-HT-induced IPs accumulation with pKB values of 8.46 and 8.21, respectively. In contrast, the dose-response curves of 5-HT-induced IPs accumulation were not shifted until the concentrations of NAN-190 and metoclopramide (5-HT1A and 5-HT3 receptor antagonists, respectively) were increased up to 10 microM. 3. Pretreatment of TSMCs with pertussis toxin or cholera toxin did not inhibit the 5-HT-induced IPs accumulation, but partially inhibited the AlF(4-)-induced IPs response. 4. Stimulation of IPs accumulation by 5-HT required the presence of external Ca2+ and was blocked by EGTA. The addition of Ca2+ (3-620 nM) to digitonin-permeabilized TSMCs directly stimulated IPs accumulation. A further Ca(2+)-dependent increase in IPs accumulation was obtained by inclusion of either guanosine 5'-O-(3-thiotriphoshate) (GTP gamma S) or 5-HT. The combination of GTP gamma S and 5-HT elicited an additive effect on IPs accumulation. 5. Treatment with phorbol 12-myristate 13-acetate (PMA, 1 microM, 30 min) abolished the 5-HT-induced IPs accumulation. The concentrations of PMA that gave a half-maximal and maximal inhibition of 5-HT-induced IPs accumulation were 2.2 +/- 0.4 nM and 1 microM, n = 3, respectively. The protein kinase C (PKC) activator, 4 alpha-phorbol 12,13-didecanoate, at 1 microM, did not influence this response. The inhibitory effect of PMA was reversed by staurosporine, a PKC inhibitor, suggesting that the inhibitory effect of PMA is mediated through the activation of PKC. 6. The site of this inhibition was further investigated by examining the effect of PMA on AlF(4-)-induced IPs accumulation in canine TSMCs. AlF(4-)-stimulated IPs accumulation was inhibited by PMA treatment, suggesting that the effect of PMA is distal to the 5-HT receptor.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:8019756

  9. Ionotrophic 5-hydroxytryptamine type 3 receptor activates the protein kinase C-dependent phospholipase D pathway in human T-cells.

    PubMed Central

    Khan, N A; Hichami, A

    1999-01-01

    The present study was undertaken to investigate the role of the 5-hydroxytryptamine (5-HT) ionotrophic receptor 5-HT(3) in the activation of human Jurkat T-cells. 5-HT and 2-methyl-5-HT (2Me-5-HT), an agonist of the 5-HT(3) receptor, induced increases in intracellular free Na(+) concentrations, [Na(+)](i), via opening of the ionotrophic receptor in these cells. These two serotonergic (5-hydroxytryptaminergic) agents potentiated phytohaemagglutinin (PHA)-induced T-cell activation. However, they failed to potentiate dioctanoglycerol-plus-ionomycin-stimulated T-cell blastogenesis. Interestingly, an inhibitor of protein kinase C (PKC), GF 109203X, curtailed significantly 5-HT and 2Me-5-HT-potentiated T-cell activation. These results demonstrate that the opening of the 5-HT(3) ionotrophic receptor is implicated in T-cell activation via the PKC pathway. Furthermore, 5-HT and 2Me-5-HT stimulated phospholipase D (PLD) activity, as measured by the production of phosphatidylethanol and phosphatidylbutanol at the expense of phosphatidic acid (PA). GF 109203X significantly curtailed the 5-HT- and 2Me-5-HT-induced PLD activity and T-cell activation. The PLD/PA pathway stimulated by these two serotonergic agents resulted in the production of 1,2-diacylglycerol (DAG) mass in Jurkat T-cells. These results altogether suggest that 5-HT and 2Me-5-HT potentiate T-cell activation via increases in [Na(+)](i) and the activation of the PKC-dependent PLD pathway. PMID:10548551

  10. Constrictor actions of acetylcholine, 5-hydroxytryptamine and histamine on bovine coronary artery inner and outer muscle

    PubMed Central

    Garland, C. J.; Keatinge, W. R.

    1982-01-01

    1. In bovine coronary arteries, cholinesterase staining showed an extensive cholinergic innervation at the adventitia—media junction, and some cholinesterase in the outer but not inner smooth muscle. 2. Acetylcholine or methacholine caused large, atropine-sensitive contractions of outer muscle but caused little contraction of inner muscle. 3. Fluorescence microscopy for monoamines and for histamine, supported by chemical assays, showed no adrenergic innervation but showed numerous fluorescent cells in the adventitia and the outer 50% of the media which stained as mast cells and contained large amounts of histamine and noradrenaline and some dopamine, but little 5-hydroxytryptamine (5-HT). 4. 5-hydroxytryptamine (acting by D receptors) and histamine (acting by H1 receptors) in high concentrations caused large contractions, of similar size, in inner and outer muscle. In given submaximal concentrations they generally caused more contraction of outer than inner muscle, particularly in the case of histamine, provided that imipramine or desipramine was present to inhibit uptake of the agents by mast cells which were present in the outer part of the artery wall. 5. Without blockade of uptake, 5-HT applied to the arteries in submaximal concentrations caused less contraction of outer than inner muscle; histamine still caused significantly more contraction of outer than inner muscle. 6. The findings indicate that the cholinergic constrictor nerves of these arteries, unlike adrenergic constrictor nerves of other systemic arteries, act almost solely on outer muscle of the vessel wall; and that mast cells give considerable protection against constriction by 5-HT, but little against histamine, reaching the vessel from its adventitial surface. ImagesPLATE 2PLATE 1 PMID:7120142

  11. Roles of serotonin receptor subtypes for the antinociception of 5HT in the spinal cord of rats

    Microsoft Academic Search

    Chang Young Jeong; Jeong Il Choi; Myung Ha Yoon

    2004-01-01

    The contribution of 5-HT (5-hydroxytryptamine) receptor subtypes to the antinociception produced by intrathecal 5-HT in the formalin test was investigated in rats. Intrathecal 5-HT suppressed both phases of behaviors produced by 5% formalin, and this was blocked by antagonists for 5-HT1B (3-[3-(Dimethylamino)propyl]-4-hy-droxy-N-[4-(4-pyridinyl)phenyl]benzamide dihydrochloride, GR 55562), 5-HT2C (N-ormethylclozapine\\/8-Chloro-11-(1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine, D-MC), 5-HT3 (1-Methyl-N-(8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-1H-indazole-3-carboxamide maleate, LY-278,584) and 5-HT4 receptors (4-Amino-5-chloro-2-metho-xy-benzoic acid 2-(diethylamino)ethyl ester hydrochloride,

  12. 5-Carboxamidotryptamine is a selective agonist at 5-hydroxytryptamine receptors mediating vasodilatation and tachycardia in anaesthetized cats.

    PubMed Central

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

    1986-01-01

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

  13. Quercetin inhibits the 5-hydroxytryptamine type 3 receptor-mediated ion current by interacting with pre-transmembrane domain I.

    PubMed

    Lee, Byung-Hwan; Jeong, Sang-Min; Jung, Sang-Min; Lee, Jun-Ho; Kim, Jong-Hoon; Yoon, In-Soo; Lee, Joon-Hee; Choi, Sun-Hye; Lee, Sang-Mok; Chang, Choon-Gon; Kim, Hyung-Chun; Han, YeSun; Paik, Hyun-Dong; Kim, Yangmee; Nah, Seung-Yeol

    2005-08-31

    The flavonoid, quercetin, is a low molecular weight substance found in apple, tomato and other fruit. Besides its antioxidative effect, quercetin, like other flavonoids, has a wide range of neuropharmacological actions including analgesia, and motility, sleep, anticonvulsant, sedative and anxiolytic effects. In the present study, we investigated its effect on mouse 5-hydroxytryptamine type 3 (5-HT3A) receptor channel activity, which is involved in pain transmission, analgesia, vomiting, and mood disorders. The 5-HT3A receptor was expressed in Xenopus oocytes, and the current was measured with the two-electrode voltage clamp technique. In oocytes injected with 5-HT3A receptor cRNA, quercetin inhibited the 5-HT-induced inward peak current (I(5-HT)) with an IC50 of 64.7 +/- 2.2 microM. Inhibition was competitive and voltage-independent. Point mutations of pre-transmembrane domain 1 (pre-TM1) such as R222T and R222A, but not R222D, R222E and R222K, abolished inhibition, indicating that quercetin interacts with the pre-TM1 of the 5-HT3A receptor. PMID:16258243

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

    PubMed Central

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

    2009-01-01

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

  15. CD4+ T cell?mediated immunological control of enterochromaffin cell hyperplasia and 5?hydroxytryptamine production in enteric infection

    PubMed Central

    Wang, Huaqing; Steeds, Justin; Motomura, Yasuaki; Deng, Yikang; Verma?Gandhu, Monica; El?Sharkawy, Rami T; McLaughlin, John T; Grencis, Richard K; Khan, Waliul I

    2007-01-01

    Background Enterochromaffin (EC) cells are dispersed throughout the gastrointestinal (GI) mucosa and are the main source of 5?hydroxytryptamine (5?HT) in the gut. 5?HT has been implicated in the pathophysiology of several GI disorders, but the mechanisms regulating 5?HT production in the gut are unknown. Aim To investigate the role of CD4+ T cells in the production of 5?HT using a model of enteric parasitic infection. Methods and results Severe combined immunodeficient (SCID) mice and their wild?type controls were infected with the nematode Trichuris muris and killed on various days after infection to study colonic EC cells and 5?HT production. The number of EC cells and the amount of 5?HT produced were significantly higher in infected wild?type mice than in non?infected mice. The number of EC cells and the amount of 5?HT after infection were significantly lower in SCID mice after infection than in wild?type mice. The number of EC cells and the amount of 5?HT was significantly increased after reconstitution of SCID mice with CD4+ T cells from infected mice and this was accompanied by an upregulation of colonic CD3 T cells and T helper 2 (Th2) cytokines. Laser capture microdissection?based molecular and immunofluorescence techniques revealed the presence of interleukin 13 receptor ?1?chain on EC cells. Conclusion These results show an important immunoendocrine axis in the gut, where secretory products from CD4+ T cells interact with EC cells to enhance the production of 5?HT in the gut via Th2?based mechanisms. These results show new insights into the mechanisms of gut function, which may ultimately lead to improved therapeutic strategies in functional and inflammatory disorders of the GI tract. PMID:17303597

  16. 5-hydroxytryptamine releases adenosine 5'-triphosphate from nerve varicosities isolated from the myenteric plexus of guinea-pig ileum.

    PubMed Central

    Al-Humayyd, M.; White, T. D.

    1985-01-01

    5-Hydroxytryptamine (5-HT)-evoked release of ATP from nerve varicosities isolated from the myenteric plexus of guinea pig ileum was investigated. 5-HT released ATP from myenteric varicosities by a Ca2+-dependent mechanism. The EC50 for release of ATP was 7 X 10(-7) M 5-HT. 5-HT-evoked release of ATP was not blocked by tetrodotoxin (TTX), indicating that release was not initiated by the opening of Na+-channels in the isolated myenteric varicosities. Release of ATP by 5-HT was diminished to 56% of control values by in vivo pretreatment of the guinea-pig with 6-hydroxydopamine (6-OHDA, 250 mg kg-1, i.p.) for 24 h. 6-OHDA pretreatment caused extensive destruction of noradrenergic varicosities as indicated by an 87% loss of noradrenaline content. Quipazine (5 X 10(-6) M) and methysergide (10(-4) M) caused a small release of ATP and blocked subsequent 5-HT-induced release of ATP. Metergoline (2.5 X 10(-5) M), (+)-tubocurarine (7 X 10(-5) M) and cocaine (10(-4) M) decreased 5-HT-induced ATP release. 5-Methoxytryptamine (10(-4) M), picrotoxin (3.5 X 10(-6) M), spiroperidol (10(-6) M), morphine (1.3 X 10(-6) M) and phenoxybenzamine (3.7 X 10(-7) M) were ineffective. The results demonstrate a 5-HT-receptor-mediated release of ATP from noradrenergic and possibly non-adrenergic varicosities in the myenteric plexus of guinea-pig ileum. The 5-HT-induced release of ATP is consistent with a possible transmitter, cotransmitter or modulatory role for ATP in the myenteric plexus. PMID:3978313

  17. Potentiation of ADP-induced aggregation in human platelet-rich plasma by 5-hydroxytryptamine and adrenaline.

    PubMed Central

    Vanags, D. M.; Rodgers, S. E.; Duncan, E. M.; Lloyd, J. V.; Bochner, F.

    1992-01-01

    1. We have used dose-response curves to quantitate the potentiation of adenosine 5'-diphosphate (ADP)-induced aggregation and thromboxane (TXA2) generation by 5-hydroxytryptamine (5-HT) and adrenaline in human citrated platelet-rich plasma. We have also quantitated the inhibition of these responses by aspirin, ketanserin and yohimbine, singly and in pairs. 2. Ketanserin (5 microM) inhibited TXA2 production and the second wave of platelet aggregation induced by a range of concentrations of ADP alone. This indicates that endogenous 5-HT, released from the platelet dense granules, contributes significantly to responses induced by ADP. 3. When 5-HT (10 microM) was added before ADP, a lower concentration of ADP was required to cause 50% aggregation and TXA2 generation. The ratio of ADP concentrations (CR) to cause 50% aggregation in the presence and absence of 5-HT was 2.1 when only added 5-HT was considered, and 5.0 when endogenous 5-HT was also taken into account. 4. Potentiation of ADP-induced aggregation by 5-HT also occurred in the presence of aspirin, resulting in a CR of 2.3. As expected, ketanserin inhibited potentiation by 5-HT in the presence and absence of aspirin. Although aspirin caused substantial inhibition of aggregation induced by ADP and 5-HT (CR 3.4), further inhibition occurred when ketanserin was also present (CR 6.5). 5. A subthreshold concentration of adrenaline (0.25 microM) caused substantial potentiation of ADP-induced aggregation in the absence (CR 4.0) and presence (CR 2.0) of aspirin. As expected, yohimbine (9 microM) inhibited this potentiation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1393289

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

    PubMed Central

    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.

    1993-01-01

    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

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

    Microsoft Academic Search

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

    2000-01-01

    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

  20. Functional Status of the Serotonin 5-HT2C Receptor (5-HT2CR) Drives Interlocked Phenotypes that Precipitate Relapse-Like Behaviors in Cocaine Dependence

    PubMed Central

    Anastasio, Noelle C; Stutz, Sonja J; Fox, Robert G; Sears, Robert M; Emeson, Ronald B; DiLeone, Ralph J; O'Neil, Richard T; Fink, Latham H; Li, Dingge; Green, Thomas A; Gerard Moeller, F; Cunningham, Kathryn A

    2014-01-01

    Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues (‘cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor (5-HT2CR) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT2CR functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT2CR macromolecular protein complex, and editing of the 5-HT2CR pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT2CR membrane protein levels concomitant with higher levels of 5-HT2CR:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT2CR mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT2CR induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT2CR tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT2CR functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors. PMID:23939424

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

    SciTech Connect

    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: knonogaki-tky@umin.ac.jp; 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)

    2006-12-29

    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.

  2. Mutations within the selectivity filter of the NMDA receptor-channel influence voltage dependent block by 5-hydroxytryptamine

    PubMed Central

    Kloda, A; Adams, D J

    2006-01-01

    Background and purpose: Voltage-dependent block by Mg2+ is a cardinal feature of NMDA receptors which acts as a coincidence detector to prevent the receptor from over-activation. Inhibition of NMDA receptor currents by 5-hydroxytryptamine (5-HT) indicated that 5-HT, similar to Mg2+, binds within the membrane electric field. In the present study, we assessed whether point mutations of critical asparagine residues located within the selectivity filter of NR1 and NR2A subunits of NMDA receptor-channel affect voltage-dependent block by 5-HT. Experimental approach: The mode of action of 5-HT and Mg2+ on wild-type and mutated NMDA receptor-channels expressed in Xenopus oocytes was investigated using the two-electrode voltage clamp recording technique. Key results: The mutation within the NR1 subunit NR1(N0S or N0Q) strongly reduced the voltage dependent block by 5-HT and increased the IC50. The corresponding mutations within the NR2 subunits NR2A(N0Q or N+1Q) reduced the block by 5-HT to a lesser extent. This is in contrast to the block produced by external Mg2+ where a substitution at the NR2A(N0) and NR2A(N+1) sites but not at the NR1(N0) site significantly reduced Mg2+ block. Conclusion and implications: The block of NMDA receptor-channels by 5-HT depends on the NR1-subunit asparagine residue and to a lesser extent on the NR2A-subunit asparagine residues. These data suggest that the interaction of 5-HT with functionally important residues in a narrow constriction of the pore of the NMDA receptor-channel provides a significant barrier to ionic fluxes through the open channel due to energetic factors governed by chemical properties of the binding site and the electric field. PMID:16894346

  3. Antagonistic properties of McNeil-A-343 at 5-HT4 and 5-HT3 receptors.

    PubMed Central

    Sagrada, A; Schiavi, G B; Cereda, E; Ladinsky, H

    1994-01-01

    1. This study describes the in vitro interaction of the muscarinic ligand McNeil-A-343 with two 5-hydroxytryptamine (5-HT) receptor subtypes, the 5-HT4 and 5-HT3 receptors, using functional as well as radioligand binding studies. 2. In the rat oesophageal muscularis mucosae, precontracted with carbachol, McNeil-A-343 was a competitive antagonist (pA2 6.2) of the 5-HT4 receptor which mediates the relaxation induced by 5-HT. The compound per se relaxed the oesophagus at high concentration only (> or = 10 microM), an effect unchanged by desensitization of the 5-HT4 receptor with 10 microM 5-methoxytryptamine. In the same preparation in the absence of tone, McNeil-A-343 displaced the carbachol concentration-response curve to the right, yielding an apparent affinity (pA2) of 4.9 for muscarinic receptors. 3. In the rat isolated superior cervical ganglion preparation, after blockade of muscarinic and nicotinic receptors, McNeil-A-343 caused a concentration-dependent depolarization that was unaffected by 100 nM ondansetron. The concentration-fast depolarization curve to 5-HT, mediated by the 5-HT3 receptor, was displaced to the right by McNeil-A-343, which showed an apparent affinity (pA2) of 4.8 for the 5-HT3 subtype. 4. In binding studies, McNeil-A-343 recognized a single population of 5-HT4 receptors in pig caudate nucleus, with a pKI of 5.9. The binding affinity of McNeil-A-343 for 5-HT3 receptors in NG 108-15 cells was approximately four times lower (pKI 5.3). Binding affinities (pKI) for muscarinic receptor subtypes in rat tissues were 5.3 (M1, cortex), 5.2 (M2, heart) and 4.9 (M3, submandibular glands), respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7532081

  4. Ca2+ as messenger of 5HT2-receptor stimulation in human blood platelets.

    PubMed

    Affolter, H; Erne, P; Bürgisser, E; Pletscher, A

    1984-04-01

    In blood platelets of man, both 5-hydroxytryptamine (5HT) and 80 nM of the Ca2+-ionophore A23187 led to rapid shape change reactions which were inhibited by prostaglandin E1 (PGE1), forskolin, 2-methyl-6-methoxy-8-nitroquinoline ( quin2 ) and chlortetracycline. The IC50-values of the inhibitors were similar in the 5HT- and the A23187-experiments. Higher amounts of A23187 abolished the inhibitory actions of PGE1 and forskolin. Furthermore, 5HT and A23187 enhanced adrenaline-induced platelet aggregation their effects showing similar time dependence. Ketanserin, an antagonist of 5HT2 -receptors, and 8-(N,N-diethyl-amino)octyl-3,4,5-trimethoxybenzoate (TMB-8), an intracellular Ca2+-antagonist, counteracted the effects of 5HT much more than those of A23187, whereas acetylsalicylate and indomethacin did not influence the actions of either 5HT or A23187. In addition, 5HT caused a concentration-dependent rise of intracellular free Ca2+ in platelets which was counteracted by ketanserin. PGE1 and forskolin reduced the resting Ca2+-levels. 5HT did not affect either the basal or the PGE1-stimulated activity of adenylate cyclase, whereas the Ca2+-ionophore A23187 slightly raised the basal activity of the enzyme. In conclusion, the functional effects of 5HT2 -receptor stimulation in human blood platelets (shape change reaction and enhancement of adrenaline aggregation) seem to be mediated by a rise of intracellular free Ca2+. PMID:6427633

  5. 6-Substituted tricyclic partial ergoline compounds are selective and potent 5-hydroxytryptamine sub 1A receptor agents

    SciTech Connect

    Slaughter, J.L.; Harrington, M.A.; Peroutka, S.J. (Stanford Univ. School of Medicine, CA (USA))

    1990-01-01

    A series of 6 tricyclic partial ergoline derivatives was analyzed using radioligand binding assays. Four agents (LY 178210, LY 254089, LY 197205, and LY 197206) display high affinity for 5-hydroxytryptamine{sub 1A} (5-HT{sub 1A}) receptor binding sites labeled by ({sup 3}H)8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and display {ge} 150 fold selectivity for the 5-HT{sub 1A} over the 5-HT{sub 1D} receptor binding site. The most potent agent investigated, LY 178210, is essentially inactive at a total of 12 other neurotransmitter receptor binding sites in the brain. Using a forskolin-stimulated adenylate cyclase assay as a model of 5-HT{sub 1A} receptor function, LY 178210 was found to display partial agonist activity which was blocked by 10{sup {minus}5} M ({minus})pindolol. These data indicate that LY 178210 is a potent and selective 5-HT{sub 1A} receptor partial agonist.

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

    PubMed Central

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

    1979-01-01

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

  7. Differences in response to 5-HT4 receptor agonists and antagonists of the 5-HT4-like receptor in human colon circular smooth muscle.

    PubMed Central

    Tam, F. S.; Hillier, K.; Bunce, K. T.; Grossman, C.

    1995-01-01

    1. In isolated circular smooth muscle strips of human colon 5-hydroxytryptamine (5-HT) produced a concentration-related inhibition of spontaneous motility. 2. The azabicycloalkyl benzimidazolones, BIMU 8 and BIMU 1, which have 5-HT4 receptor stimulant properties, inhibited motility with EC50 values of 0.76 microM and 3.19 microM respectively and their Emax values were not significantly different from 5-HT (EC50, 0.13 microM). 3. The 5-HT4 receptor antagonist, DAU 6285 (1-10 microM), displaced the 5-HT concentration-response curve to the right in a parallel concentration-dependent manner without depressing the maximum. The Schild plot was linear and the slope did not differ significantly from unity giving a pA2 value of 6.32. 4. The high affinity selective 5-HT4 receptor antagonist, GR 113808, at a concentration of 3 nM displaced the 5-HT concentration-response curve in a parallel manner giving an apparent pKB estimate of 8.9 +/- 0.24. However, higher concentrations of 10-100 nM GR 113808 did not result in a further significant displacement of the 5-HT concentration-response curve and there was no suppression of Emax. 5. GR 113808 (10 nM) also caused a parallel displacement of the concentration-response curve to the 5-HT4 receptor agonist, 5-methoxytryptamine (5-MeOT) giving apparent pKB values ranging from 8.3-9.3. 6. GR 113808 (3-100 nM) failed to displace 5-HT or 5-MeOT concentration-response curves in tissue strips from 3 patients out of a total of 10 patients studied in whom the response to 5-HT and 5-MeOT was normal.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7647972

  8. Increased defaecation caused by 5HT 4 receptor activation in the mouse

    Microsoft Academic Search

    Stephen E. Banner; Martin I. Smith; Darren Bywater; Laramie M. Gaster; Gareth J. Sanger

    1996-01-01

    The precursor to 5-hydroxytryptamine (5-HT), 5-hydroxytryptophan, (5-HTP, 5–50 mg · kg?1) administered subcutaneously (s.c.) to conscious, fed mice caused a dose dependent increase in faecal pellet and fluid output. To avoid provoking watery diarrhoea, all experiments were performed using 5-HTP at 10 mg · kg?1. This dose caused maximal increases in the fluid content (471 ± 41%) and number of

  9. Investigations of cardiovascular 5-hydroxytryptamine receptor subtypes in the rat

    Microsoft Academic Search

    James R. Docherty

    1988-01-01

    Peripheral 5-HT receptor-mediated responses were examined in pithed spontaneously hypertensive rats and normotensive wistar rats. Responses examined were: Pressor and depressor responses, tachycardia and inhibition of stimulation-evoked tachycardia. In pithed spontaneously hypertensive rats, 5-HT, but not the 5-HT1-selective agonist 5-carboxamidotryptamine, produced pressor responses, and these were potently antagonised by the 5-HT2-selective antagonists ketanserin and LY 53857. In pithed spontaneously hypertensive

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

    PubMed

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

    2015-02-01

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

  11. 5-HT7 receptor signaling: improved therapeutic strategy in gut disorders

    PubMed Central

    Kim, Janice J.; Khan, Waliul I.

    2014-01-01

    Serotonin (5-hydroxytryptamine; 5-HT) is most commonly known for its role as a neurotransmitter in the central nervous system (CNS). However, the majority of the body’s 5-HT is produced in the gut by enterochromaffin (EC) cells. Alterations in 5-HT signaling have been associated with various gut disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and enteric infections. Recently, our studies have identified a key role for 5-HT in the pathogenesis of experimental colitis. 5-HT7 receptors are expressed in the gut and very recently, we have shown evidence of 5-HT7 receptor expression on intestinal immune cells and demonstrated a key role for 5-HT7 receptors in generation of experimental colitis. This review summarizes the key findings of these studies and provides a comprehensive overview of our current knowledge of the 5-HT7 receptor in terms of its pathophysiological relevance and therapeutic potential in intestinal inflammatory conditions, such as IBD. PMID:25565996

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

    PubMed Central

    Ghatta, Srinivas; Ramarao, Poduri

    2004-01-01

    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

  13. Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes.

    PubMed

    McKenna, D J; Repke, D B; Lo, L; Peroutka, S J

    1990-03-01

    Affinities of drugs for 21 indolealkylamine derivatives, some with putative hallucinogenic activity, were determined at 5-HT1A, 5-HT2A and 5-HT2B recognition sites, using radioligand competition studies. Nearly all of the derivatives displayed greatest potency for the 5-HT2A receptor, labelled by [125I]R-(-)DOI in the cortex of the rat. Most derivatives displayed 2-10 times lower affinity at the HT2B receptor labelled by [3H]ketanserin in bovine cortex. Derivatives lacking ring substituents displayed lower affinities for all of the recognition sites, compared to derivatives substituted in the 4- or 5-position of the indole ring. The 4-hydroxylated derivatives displayed 25-380-fold selectivity for the 5-HT2A site, vs the 5-HT1A site, while the 5-substituted derivatives displayed approximately equal potency at the 5-HT1A and 5-HT2A sites. Affinity of all the compounds at the 5-HT2B site was greater than 300 nM. The 6-substituted derivatives displayed greater than micromolar affinities for all of the 5-HT recognition sites examined. The size of the N,N-dialkyl substituent was a secondary determinant of affinity, with groups larger than N,N-diisopropyl resulting in a marked reduction in affinity at both the 5-HT2A and 5-HT1A recognition sites. This study demonstrated that hallucinogenic 4-hydroxy-indolealkylamines, like psychotomimetic phenylisopropylamines, bind potently and selectively to the 5-HT2A recognition site, labelled by [125I]R-(-)DOI. This provides further evidence indicating that this recently described subtype of the 5-HT2 receptor may partially mediate the action of hallucinogenic agents. PMID:2139186

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

    PubMed

    Goyal, Rajendra N; Agrawal, Bharati

    2012-09-19

    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

  15. [ 3 H]ICS 205-930 labels 5HT 3 recognition sites in membranes of cat and rabbit vagus nerve and superior cervical ganglion

    Microsoft Academic Search

    Daniel Hoyer; Christian Waeber; Angela Karpf; Hans Neijt; Jose M. Palacios

    1989-01-01

    The binding characteristics of [3H]ICS 205-930, a 5-hydroxytryptamine 5-HT3 receptor antagonist, were investigated in membranes prepared from cat and rabbit vagus nerve (VN) and superior cervical ganglion (SCG). The autoradiographic localisation of 5-HT3 recognition sites was also assessed using [3H]ICS 205-930 in slices from cat medulla oblongata, nodose ganglion and vagus nerve.

  16. Effect of acute and prolonged tianeptine administration on the 5HT transporter: electrophysiological, biochemical and radioligand binding studies in the rat brain

    Microsoft Academic Search

    Graciela Piñeyro; Lyne Deveault; Pierre Blier; Trevor Dennis; Claude Montigny

    1995-01-01

    In the present study, in vivo extracellular unitary recordings, in vitro [3H]5-HT uptake and [3H]cyanoimipramine binding assays were used to assess the effect of acute and prolonged administration of the putative antidepressant tianeptine, on the 5-hydroxytryptamine (5-HT) transporter. Microiontophoretic application of tianeptine onto dorsal hippocampus CA3 pyramidal neurons, as well as its intravenous administration (2 mg\\/kg), increased their firing frequency.

  17. Effect of Sarpogrelate, a 5HT2A Antagonist, on Platelet Aggregation in Patients with Ischemic Stroke: Clinical-Pharmacological Dose-Response Study

    Microsoft Academic Search

    Shinichiro Uchiyama; Yukio Ozaki; Kaneo Satoh; Kazuoki Kondo; Katsuya Nishimaru

    2007-01-01

    Background and Purpose: It is widely accepted that antiplatelet therapy is effective for secondary prevention of atherosclerotic vascular diseases. We performed a double-blind, controlled clinical-pharmacological study to investigate the antiplatelet efficacy of sarpogrelate, a selective 5-hydroxytryptamine (5-HT2A) receptor antagonist, in patients with ischemic stroke, using a new assessment system employing combinations of 5-HT and epinephrine as agonists. Methods: Forty-seven patients

  18. Involvement of neurokinins in the non-cholinergic response to activation of 5-HT3 and 5-HT4 receptors in guinea-pig ileum.

    PubMed Central

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

    1994-01-01

    1. The involvement of neurokinins in the non-cholinergically-mediated contractile response induced by stimulation of 5-HT3 and 5-HT4 receptors has been examined in the longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum. 2. The 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT), showed a lower potency in this preparation than the more selective 5-HT4 receptor agonist 5-methoxytryptamine. The effect of both drugs was markedly reduced by atropine. 3. Substance P (SP) and neurokinin B (NKB) produced biphasic concentration-response curves in the preparation. Neurokinin A (NKA), the NK1 receptor agonist, [Sar9,Met(O2)11]SP and the NK3 receptor agonist, senktide yielded monophasic concentration-response curves. 4. After desensitization of the NK1 receptor with SP or [Sar9,met(O2)11]SP, in the presence of atropine, the contractile response to 2-methyl-5-HT was entirely blocked. Desensitization of NK3 receptors with NKB, also in the presence of atropine, fully suppressed the 5-HT4 receptor-mediated contraction evoked by 5-methoxytryptamine. 5. In preparations prelabelled with [3H]-choline, SP produced a concentration-dependent increase in tritium overflow, an index of [3H]-acetylcholine release, while an inverse relationship was found with NKB. At low neurokinin concentrations, the releasing effect of NKB was much more marked. 6. It is suggested that in the response to 5-HT3 receptor stimulation, there is a role for SP and acetylcholine. NKB appears to be preferentially involved in the release of acetylcholine elicited by stimulation of 5-HT4 receptors. PMID:7516254

  19. Fluorescence derivatizing procedure for 5-hydroxytryptamine and 5-hydroxyindoleacetic acid using 1,2-diphenylethylenediamine reagent and their sensitive liquid chromatographic determination.

    PubMed

    Kai, M; Iida, H; Nohta, H; Lee, M K; Ohta, K

    1998-12-11

    A pre-column derivatization method using a fluorogenic reagent, 1,2-diphenylethylenediamine (DPE) was studied for the sensitive HPLC determination of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), which are biosubstances used in the diagnosis of several diseases. For the quantitative determination, the biogenic indole compounds were converted to their corresponding fluorescent derivatives with DPE in the presence of potassium hexacyanoferrate (III) at room temperature, and then the derivatives were separated by reversed-phase liquid chromatography with fluorescence detection. The chromatographic detection limits of the fluorescent peaks at a signal-to-noise ratio of 3 were 0.3 fmol for 5-HT and 0.2 fmol for 5-HIAA. The proposed method permits the simultaneous quantification of 5-HT and 5-HIAA at concentrations higher than 2.4 nM in human urine without a clean-up procedure. PMID:9892063

  20. Discovery of 1-[3-(4-bromo-2-methyl-2h-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (nelotanserin) and related 5-hydroxytryptamine2A inverse agonists for the treatment of insomnia.

    PubMed

    Teegarden, Bradley R; Li, Hongmei; Jayakumar, Honnappa; Strah-Pleynet, Sonja; Dosa, Peter I; Selaya, Susan D; Kato, Naomi; Elwell, Katie H; Davidson, Jarrod; Cheng, Karen; Saldana, Hazel; Frazer, John M; Whelan, Kevin; Foster, Jonathan; Espitia, Stephan; Webb, Robert R; Beeley, Nigel R A; Thomsen, William; Morairty, Stephen R; Kilduff, Thomas S; Al-Shamma, Hussien A

    2010-03-11

    Insomnia affects a growing portion of the adult population in the U.S. Most current therapeutic approaches to insomnia primarily address sleep onset latency. Through the 5-hydroxytryptamine(2A) (5-HT(2A)) receptor, serotonin (5-HT) plays a role in the regulation of sleep architecture, and antagonists/inverse-agonists of 5-HT(2A) have been shown to enhance slow wave sleep (SWS). We describe here a series of 5-HT(2A) inverse-agonists that when dosed in rats, both consolidate the stages of NREM sleep, resulting in fewer awakenings, and increase a physiological measure of sleep intensity. These studies resulted in the discovery of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (Nelotanserin), a potent inverse-agonist of 5-HT(2A) that was advanced into clinical trials for the treatment of insomnia. PMID:20143782

  1. Characterization of the 5-HT4 receptor mediating tachycardia in piglet isolated right atrium.

    PubMed Central

    Medhurst, A. D.; Kaumann, A. J.

    1993-01-01

    1. In order to explore whether 5-HT4 receptor subtypes exist, we have characterized further the 5-HT4 receptor that mediates tachycardia in the piglet isolated right atrium. All experiments were carried out in the presence of propranolol (400 nM) and cocaine (6 microM). We used tryptamine derivatives, substituted benzamides and benzimidazolone derivatives as pharmacological tools. 2. Tachycardia responses to 5-hydroxytryptamine (5-HT) were mimicked by other tryptamine derivatives with the following order of potency: 5-HT > 5-methoxytryptamine alpha-methyl-5-HT = bufotenine bufotenine > 5-carboxamidotryptamine = tryptamine (after treatment with pargyline) > 5-methoxy-N,N-dimethyltryptamine > 2-methyl-5-HT. 3. The substituted benzamides were all partial agonists relative to 5-HT except (-)-zacopride which was a full agonist. The stimulant potency order was renzapride > cisapride = (-)-zacopride > metoclopramide > (+)-zacopride. 4. The benzimidazolone derivatives had contrasting effects. BIMU 8 (endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-(1-methyl(eth yl- 2-oxo-1H-benzimidazole-1-carboxamide hydrochloride) was a full agonist relative to 5-HT whilst BIMU 1 (endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-ethyl-2-oxo - 1H-benzimidazole-1-carboxamide hydrochloride) was a partial agonist with low intrinsic activity compared to 5-HT but had similar potency. We estimated a pKB of 7.9 for BIMU 1 antagonism of 5-HT-induced tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8298790

  2. Responses of the simultaneously-perfused hepatic arterial and portal venous vascular beds of the dog to histamine and 5-hydroxytryptamine.

    PubMed Central

    Richardson, P D; Withrington, P G

    1978-01-01

    1 The sympathetically-innervated hepatic arterial and portal venous vascular beds of the dog were perfused simultaneously in situ. 2 Histamine and 5-hydroxytryptamine (5-HT) were injected intra-arterially and intraportally in graded, increasing doses. 3 Intra-arterial histamine evoked decreases in hepatic arterial vascular resistance (HAVR) and increases in hepatic portal vascular resistance (HPVR). 4 Intraportal injections of histamine caused increases in HPVR and decreases in HAVR. 5 The time courses of the arterial responses to intraportal histamine and of the portal responses to intra-arterial histamine, compared with any systemic effects, showed that these effects on the liver vasculature could not be the result of recirculation of histamine. 6 Intra-arterial 5-HT evoked biphasic changes in HAVR and small falls in HPVR. Intraportal 5-HT caused falls in HPVR at low doses and rises at high doses, together, typically, with biphasic effects on HAVR. 7 It is unlikely that the arterial effects of intraportal 5-HT and the portal effects of intra-arterial 5-HT were due to recirculation of the vasoactive material. 8 Pathophysiologically, both histamine and 5-HT are released from the gastrointestinal tract into the portal vein. These experiments show that such release may affect the hepatic arterial vascular resistance (and therefore blood flow) even though vasoactive levels of the autacoids are not attained in the systemic circulation. PMID:728685

  3. Prophylaxis of Radiation-Induced Nausea and Vomiting Using 5-Hydroxytryptamine-3 Serotonin Receptor Antagonists: A Systematic Review of Randomized Trials

    SciTech Connect

    Salvo, Nadia; Doble, Brett [Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario (Canada); Khan, Luluel [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Amirthevasar, Gayathri [Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario (Canada); Dennis, Kristopher [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Pasetka, Mark; DeAngelis, Carlo [Department of Oncology Pharmacy, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Tsao, May [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada); Chow, Edward, E-mail: Edward.Chow@sunnybrook.ca [Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Canada)

    2012-01-01

    Purpose: To systematically review the effectiveness and safety of 5-hydroxytryptamine-3 receptor antagonists (5-HT3 RAs) compared with other antiemetic medication or placebo for prophylaxis of radiation-induced nausea and vomiting. Methods and Materials: We searched the following electronic databases: MEDLINE, Embase, the Cochrane Central Register of Controlled Clinical Trials, and Web of Science. We also hand-searched reference lists of included studies. Randomized, controlled trials that compared a 5-HT3 RA with another antiemetic medication or placebo for preventing radiation-induced nausea and vomiting were included. We excluded studies recruiting patients receiving concomitant chemotherapy. When appropriate, meta-analysis was conducted using Review Manager (v5) software. Relative risks were calculated using inverse variance as the statistical method under a random-effects model. We assessed the quality of evidence by outcome using the Grading of Recommendations Assessment, Development, and Evaluation approach. Results: Eligibility screening of 47 articles resulted in 9 included in the review. The overall methodologic quality was moderate. Meta-analysis of 5-HT3 RAs vs. placebo showed significant benefit for 5-HT3 RAs (relative risk [RR] 0.70; 95% confidence interval [CI] 0.57-0.86 for emesis; RR 0.84, 95% CI 0.73-0.96 for nausea). Meta-analysis comparing 5-HT3 RAs vs. metoclopramide showed a significant benefit of the 5-HT3 RAs for emetic control (RR 0.27, 95% CI 0.15-0.47). Conclusion: 5-Hydroxytryptamine-3 RAs are superior to placebo and other antiemetics for prevention of emesis, but little benefit was identified for nausea prevention. 5-Hydroxytryptamine-3 RAs are suggested for prevention of emesis. Limited evidence was found regarding delayed emesis, adverse events, quality of life, or need for rescue medication. Future randomized, controlled trials should evaluate different 5-HT3 antiemetics and new agents with novel mechanisms of action such at the NK{sub 1} receptor antagonists to determine the most effective drug. Delayed nausea and vomiting should be a focus of future study, perhaps concentrating on the palliative cancer population.

  4. Structure-activity relations for the inhibition of 5-hydroxytryptamine uptake by tricyclic antidepressants into synaptosomes from serotoninergic neurones in rat brain homogenates

    PubMed Central

    Horn, A.S.; Trace, R.C.A.M.

    1974-01-01

    1 The inhibitory effects of various analogues of imipramine on [3H]-5-hydroxytryptamine (5-HT) uptake into homogenates of rat hypothalamus were examined. 2 For structures with a three carbon side chain the tertiary amine derivative was more potent than the compound with a secondary amine function. 3 Potency was reduced by increasing or decreasing the length of the three carbon side chain by one carbon atom. 4 Substitution of a methyl group in the ? or ? position in the side chain reduced potency. 5 Replacement of the dimethylene bridge in imipramine by a sulphur atom or substitution of a C=C double bond for the exocyclic N-C bond of imipramine both led to a fall in potency. 6 3-Chlorimipramine was the most potent inhibitor of [3H]-5-hydroxytryptamine uptake of the compounds tested. PMID:4451753

  5. Serotonin (5-hydroxytryptamine; 5-HT) is known to have a modulatory action on synaptic transmission in the central

    E-print Network

    Nagayama, Toshiki

    giant (LG)-mediated escape in the crayfish (Glanzman and Krasne, 1983; Yeh et al., 1996, 1997; Teshiba responses of crayfish including the abdominal postural system (for a review, see Kravitz, 1988). Direct injection of serotonin into the systemic circulation of crayfish and lobster results in long-lasting tonic

  6. Interaction between 5-HTTLPR and 5-HT1B genotype status enhances cerebral 5-HT1A receptor binding.

    PubMed

    Baldinger, Pia; Kraus, Christoph; Rami-Mark, Christina; Gryglewski, Gregor; Kranz, Georg S; Haeusler, Daniela; Hahn, Andreas; Spies, Marie; Wadsak, Wolfgang; Mitterhauser, Markus; Rujescu, Dan; Kasper, Siegfried; Lanzenberger, Rupert

    2015-05-01

    Serotonergic neurotransmission is thought to underlie a dynamic interrelation between different key structures of the serotonin system. The serotonin transporter (SERT), which is responsible for the reuptake of serotonin from the synaptic cleft into the neuron, as well as the serotonin-1A (5-HT1A) and -1B (5-HT1B) receptors, inhibitory auto-receptors in the raphe region and projection areas, respectively, are likely to determine serotonin release. Thereby, they are involved in the regulation of extracellular serotonin concentrations and the extent of serotonergic effects in respective projection areas. Complex receptor interactions can be assessed in vivo with positron emission tomography (PET) and single-nucleotide-polymorphisms, which are thought to alter protein expression levels. Due to the complexity of the serotonergic system, gene×gene interactions are likely to regulate transporter and receptor expression and therefore subsequently serotonergic transmission. In this context, we measured 51 healthy subjects (mean age 45.5±12.9, 38 female) with PET using [carbonyl-(11)C]WAY-100635 to determine 5-HT1A receptor binding potential (5-HT1A BPND). Genotyping for rs6296 (HTR1B) and 5-HTTLPR (SERT gene promoter polymorphism) was performed using DNA isolated from whole blood. Voxel-wise whole-brain ANOVA revealed a positive interaction effect of genotype groups (5-HTTLPR: LL, LS+SS and HTR1B: rs6296: CC, GC+GG) on 5-HT1A BPND with peak t-values in the bilateral parahippocampal gyrus. More specifically, highest 5-HT1A BPND was identified for individuals homozygous for both the L-allele of 5-HTTLPR and the C-allele of rs6296. This finding suggests that the interaction between two major serotonergic structures involved in serotonin release, specifically the SERT and 5-HT1B receptor, results in a modification of the inhibitory serotonergic tone mediated via 5-HT1A receptors. PMID:25652393

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

    PubMed Central

    Green, A R

    2008-01-01

    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

  8. Mitochondrial monoamine oxidase-A-mediated hydrogen peroxide generation enhances 5-hydroxytryptamine-induced contraction of rat basilar artery

    PubMed Central

    Poon, Christina Chui Wa; Seto, Sai Wang; Au, Alice Lai Shan; Zhang, Qian; Li, Rachel Wai Sum; Lee, Wayne Yuk Wai; Leung, George Pak Heng; Kong, Siu Kai; Yeung, John Hok Keung; Ngai, Sai Ming; Ho, Ho Pui; Lee, Simon Ming Yuen; Chan, Shun Wan; Kwan, Yiu Wa

    2010-01-01

    BACKGROUND AND PURPOSE We evaluated the role(s) of monoamine oxidase (MAO)-mediated H2O2 generation on 5-hydroxytryptamine (5-HT)-induced tension development of isolated basilar artery of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. EXPERIMENTAL APPROACH Basilar artery (endothelium-denuded) was isolated for tension measurement and Western blots. Enzymically dissociated single myocytes from basilar arteries were used for patch-clamp electrophysiological and confocal microscopic studies. KEY RESULTS Under resting tension, 5-HT elicited a concentration-dependent tension development with a greater sensitivity (with unchanged maximum tension development) in SHR compared with WKY (EC50: 28.4 ± 4.1 nM vs. 98.2 ± 9.4 nM). The exaggerated component of 5-HT-induced tension development in SHR was eradicated by polyethylene glycol-catalase, clorgyline and citalopram whereas exogenously applied H2O2 enhanced the 5-HT-elicited tension development in WKY. A greater protein expression of MAO-A was detected in basilar arteries from SHR than in those from WKY. In single myocytes and the entire basilar artery, 5-HT generated (clorgyline-sensitive) a greater amount of H2O2 in SHR compared with WKY. Whole-cell iberiotoxin-sensitive Ca2+-activated K+ (BKCa) amplitude measured in myocytes of SHR was approximately threefold greater than that in WKY (at +60 mV: 7.61 ± 0.89 pA·pF?1 vs. 2.61 ± 0.66 pA·pF?1). In SHR myocytes, 5-HT caused a greater inhibition (clorgyline-, polyethylene glycol-catalase- and reduced glutathione-sensitive) of BKCa amplitude than in those from WKY. CONCLUSIONS AND IMPLICATIONS 5-HT caused an increased generation of mitochondrial H2O2 via MAO-A-mediated 5-HT metabolism, which caused a greater inhibition of BKCa gating in basilar artery myocytes, leading to exaggerated basilar artery tension development in SHR. PMID:20977458

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

    PubMed

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

    2012-07-01

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

  10. [11C]WAY100635 PET demonstrates marked 5HT1A receptor changes in sporadic ALS

    Microsoft Academic Search

    M. R. Turner; E. A. Rabiner; A. Hammers; A. Al-Chalabi; P. M. Grasby; C. E. Shaw; D. J. Brooks; P. N. Leigh

    2005-01-01

    Summary The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involve- ment in vivo remains elusive. WAY100635 binds select- ively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the

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

    PubMed Central

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

    1991-01-01

    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

  12. Long-term fluoxetine treatment decreases 5HT 1A receptor responsivity in obsessive-compulsive disorder

    Microsoft Academic Search

    K. P. Lesch; A. Hoh; H. M. Schulte; M. Osterheider; T. Müller

    1991-01-01

    Fluoxetine (FLX) is a selective serotonin (5-HT) reuptake inhibitor with therapeutic benefit in patients with obsessive-compulsive disorder (OCD). To evaluate the effect of chronic FLX treatment on 5-HT1A receptor responsivity, hypothermic, neuroendocrine, and behavioral responses to the selective 5-HT1A receptor ligand ipsapirone (IPS) were examined in patients with primary OCD. A single dose of 0.3 mg\\/kg of IPS or placebo

  13. Selective Recognition of 5-Hydroxytryptamine and Dopamine on a Multi-Walled Carbon Nanotube-Chitosan Hybrid Film-Modified Microelectrode Array

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    1998-01-01

    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

  15. Voltammetric Detection of 5-Hydroxytryptamine Release in the Rat Brain

    PubMed Central

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

    2009-01-01

    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 sub-second 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-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

  16. Diaz et al. 1 5-HT2B receptors are required for serotonin-selective antidepressant actions

    E-print Network

    Paris-Sud XI, Université de

    Diaz et al. 1 5-HT2B receptors are required for serotonin-selective antidepressant actions Running title: 5-HT2B receptors in antidepressant responses Silvina Laura Diaz, Stéphane Doly, Nicolas Narboux Abstract The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepressants

  17. Effects of venlafaxine on extracellular concentrations of 5HT and noradrenaline in the rat frontal cortex: augmentation via 5HT 1A receptor antagonism

    Microsoft Academic Search

    L. A Dawson; H. Q Nguyen; A Geiger

    1999-01-01

    Venlafaxine is a novel serotonin\\/noradrenaline reuptake inhibitor (SNRI) which has been shown clinically to be an effective antidepressant (AD) with a faster onset of action than serotonin specific reuptake inhibitors (SSRI). Preclinically, venlafaxine has been shown to potently inhibit dorsal raphe neuronal (DRN) firing through a 5-HT1A mediated mechanism, in a similar manner to SSRIs. Here we demonstrate the acute

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

    PubMed

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

    2015-01-15

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

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

    PubMed

    Wang, Qi; He, Maoxian

    2014-08-01

    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

  20. Mapping of CBV changes in 5-HT(1A) terminal fields by functional MRI in the mouse brain.

    PubMed

    Mueggler, Thomas; Razoux, Florence; Russig, Holger; Buehler, Anna; Franklin, Tamara B; Baltes, Christof; Mansuy, Isabelle M; Rudin, Markus

    2011-04-01

    Visualization of brain activity in humans and animals using functional magnetic resonance imaging (fMRI) is an established method for translational neuropsychopharmacology. It is useful to study the activity of defined brain structures, however it requires further refinement to allow more specific cellular analyses, like for instance, the activity of selected pools of brain cells. Here, we investigated brain activity in serotonergic pathways in the adult mouse brain by using acute pharmacological challenge of 5-hydroxytryptamine (5-HT) 1A receptors. We show that administration of the 5-HT(1A) receptor agonist 8-OH-DPAT prompts a dose-dependent reduction in local cerebral blood volume (CBV) in brain areas rich in neurons expressing post-synaptic 5-HT(1A) receptor, including the prefrontal cortex, hippocampus and amygdalar nuclei. Region-specific inhibition of the response by co-injection of 8-OH-DPAT with the selective 5-HT(1A) receptor antagonist WAY-100635, or in 5-HT(1A) knock-out mice, suggests that 5-HT(1A) receptors are the primary targets of the agonist. Overall, the data demonstrate the feasibility of mapping region-specific serotonergic transmission in the adult mouse brain in vivo by non-invasive fMRI. The method opens novel perspectives for investigating 5-HT(1A) receptor functions in mouse models of human pathologies resulting from a dysfunction of the 5-HT(1A) receptor or the serotonergic system, including depression and anxiety. PMID:20656461

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

    PubMed Central

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

    2009-01-01

    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

  2. Comparison of contractile responses to 5-hydroxytryptamine and sumatriptan in human isolated coronary artery: synergy with the thromboxane A2-receptor agonist, U46619.

    PubMed

    Cocks, T M; Kemp, B K; Pruneau, D; Angus, J A

    1993-09-01

    1. The interaction between the thromboxane A2 receptor agonist, U46619 and two 5-hydroxytryptamine (5-HT) receptor agonists, the non-selective, naturally occurring agonist, 5-HT and the selective 5-HT1-like agonist, sumatriptan were studied in human epicardial coronary arteries in vitro. 2. Coronary artery rings (2-4 mm in diameter) were prepared from epicardial arteries from explant hearts of patients undergoing heart transplant (cardiomyopathy, n = 13; ischaemic heart disease, n = 10) and unused donor hearts (n = 5). Each ring of artery was set at optimal resting conditions to record changes in isometric force. 3. The majority of artery rings developed phasic, rhythmic contractions either spontaneously or in response to all vasoconstrictor agonists tested. Both the spontaneous and agonist-induced phasic contractions were abolished by nifedipine (0.1 microM). 4. Concentration-contraction curves to 5-HT-receptor agonists and noradrenaline (NA), were first constructed in artery rings that did not develop phasic activity. 5-HT and ergometrine were the most potent agonists with EC50 values of 6.8 +/- 0.2 and 7.7 +/- 0.2 (-log M) respectively. Potencies (EC50's) to sumatriptan, methysergide and noradrenaline could not be determined due to their poor ability to contract the coronary artery. Maximum contractions (Emax; normalized as a percentage of the contraction to a maximum-depolarizing concentration of K+ in physiological salt solution (KPSS)) for 5-HT, ergometrine, sumatriptan, methysergide and noradrenaline were 40 +/- 10, 9 +/- 3, < 5, < 5 and < 5% respectively. 5. In arteries without phasic activity, U46619 (1 nM) caused an increase in force of 3.8 +/- 1% KPSS. With U46619 present, the Emax values for 5-HT, ergometrine, sumatriptan and methysergide were all markedly increased. For 5-HT and sumatriptan, E., values were 92+/- 4% and 49 +/- 14% KPSSrespectively. The presence of U46619 did not significantly change the sensitivity (EC50) to 5-HT.6. In a separate series of arteries, nifedipine (0.1 microM) was used to block phasic, contractile activity. The synergy observed between U46619 and 5-HT or sumatriptan still occurred although the Emax values for each agonist were depressed but the EC50 values were again unaffected.7. In conclusion, these in vitro studies indicate that the normally poor contractions to sumatriptan, inhuman coronary arteries are significantly enhanced when active force is induced with a thromboxane A2-receptor agonist, U46619. The enhanced response is not specific for either sumatriptan or 5-HT,-like receptors since contractions to 5-HT, ergometrine and methysergide were also potentiated by U46619. PMID:8220898

  3. Implication of acidic lipids in 5-hydroxytryptamine receptor mechanisms

    SciTech Connect

    Yoshikawa, S.; Ishitani, R.

    1985-02-04

    To establish the possible involvement of acidic lipids in 5-HT receptor mechanisms, the authors subjected whole rat brain synaptic plasma membranes to treatment with several kinds of lipid-modifying reagents and examined the (/sup 3/H)5-HT and (/sup 3/H)spiperone binding properties of the membranes. (/sup 3/H)5-HT binding was decreased by treatment with Azure A, while (/sup 3/H)spiperone binding was not altered. Similarly, prior treatment with arylsulphatase reduced the former binding, but had no effect on the latter binding. On the other hand, neither (/sup 3/H)ligand binding was sensitive to phospholipases C and D. In contrast, prior treatment with phospholipase A/sub 2/ (unheated) drastically decreased the (/sup 3/H)5-HT binding and also affected the (/sup 3/H)spiperone binding to some extent. Chelation of Ca/sup 2 +/ by EGTA (5 mM) prior to incubation of membranes with the unheated phospholipase A/sub 2/ did not completely prevent the inhibitory effect of this enzyme on (/sup 3/H)5-HT binding, while in the heated enzyme (at 100/sup 0/C for 10 min) EGTA exhibited this preventive effect perfectly. Furthermore, it was an interesting find that at least a low concentration of the heated phospholipase A/sub 2/ (0.01 U) had no effect on the (/sup 3/H)spiperone binding, as contrasted with the case of (/sup 3/H)5-HT binding. In addition, the reduction of (/sup 3/H)5-HT binding capacity in membranes treated with phospholipase A/sub 2/ (heated and unheated) was restored only slightly by treatment with BSA (1%). 17 references, 4 tables.

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

    PubMed Central

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

    1997-01-01

    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

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

    PubMed

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

    2013-01-01

    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

  6. Stimulating healthy tissue regeneration by targeting the 5-HT2B receptor in chronic liver disease

    PubMed Central

    Ebrahimkhani, Mohammad R; Oakley, Fiona; Murphy, Lindsay B; Mann, Jelena; Moles, Anna; Perugorria, Maria J; Ellis, Elizabeth; Lakey, Anne F; Burt, Alastair D; Douglass, Angela; Wright, Matthew C; White, Steven A; Jaffré, Fabrice; Maroteaux, Luc; Mann, Derek A

    2012-01-01

    Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood1. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT2B) on HSCs by serotonin, which activates expression of transforming growth factor ?1 (TGF-?1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT2B enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT2B or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT2B attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT2B is clinically safe in humans and may be therapeutic in chronic liver disease. PMID:22120177

  7. 5-HT Radioligands for Human Brain Imaging With PET and SPECT

    PubMed Central

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

    2014-01-01

    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

  8. Application of Quantitative Structure–Activity Relationship Models of 5-HT1A Receptor Binding to Virtual Screening Identifies Novel and Potent 5-HT1A Ligands

    PubMed Central

    2015-01-01

    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

  9. 3H-5-hydroxytryptamine accumulation by rat brain synaptic vesicles in a membrane-impermeant medium, and selective reduction by 5,7-dihydroxytryptamine.

    PubMed

    Ruth, J A; Cuizon, J V; Park, S H; Ullman, E A; Wilson, W R

    1986-03-31

    In order to examine possible selectivity of amine uptake by synaptic vesicles, the ATP-stimulated accumulation of 3H-5-hydroxytryptamine (5HT) by synaptic vesicles from rat whole brain was examined in a medium comprised largely of membrane-impermeant anions (d-tartrate). Such media have previously been shown to stabilize vesicular accumulation of several neurotransmitters. Accumulation of 3H-5HT did not occur in tartrate medium alone, but was increased biphasically with increasing concentrations of both potassium phosphate and potassium bicarbonate. At optimal concentrations of each anion (10 mM), stable accumulation of 3H-5HT was observed at 37 degrees (26.1 +/- 1.2 pmol/mg protein; Km 6 X 10(-7) M), which was reduced by greater than 95% in the absence of K2ATP, at 4 degrees C, in the presence of 10(-6) M reserpine, or in the presence of the proton ionophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP). Uptake was significantly antagonized by millimolar concentrations of Na+, Mg++ or Cl-, but was unaffected by ouabain (10(-5) M). Pretreatment of animals with 5,7-dihydroxytryptamine (5,7-DHT) (200 micrograms, intraventricular) 10 days prior to sacrifice reduced endogenous 5HT levels by 70%, while levels of endogenous norepinephrine (NE) and dopamine (DA) were unaffected. Accumulation of 3H-5HT, examined in the presence of 10(-6) M NE to block 3H-5HT accumulation by vesicles from noradrenergic nerve endings, was reduced by 40% in vesicles from treated animals. Vesicular accumulation of 3H-(-)-NE and 3H-DA was unaffected by 5,7-DHT treatment. The data suggest the possibility of preferential accumulation of 3H-5HT by vesicles arising from serotonergic nerve endings. PMID:3959750

  10. Cocaine inhibits GABA release in the VTA through endogenous 5-HT.

    PubMed

    Cameron, D L; Williams, J T

    1994-11-01

    The ventral tegmental area (VTA) is thought to be involved in the addictive properties of many drugs, including cocaine. It has been hypothesized that cocaine exerts its actions in the VTA by blocking the reuptake of dopamine released from the dendrites of the A10 dopamine neurons, thus prolonging the actions of dopamine at D2 autoreceptors. However, cocaine also blocks the reuptake of the other monoamines, including serotonin (5-HT). Using intracellular recordings from midbrain dopamine neurons in a brain slice preparation, we have found that cocaine (0.1-10 microM) inhibited the GABAB IPSP in a dose-dependent manner. This effect was observed in the presence of the D2 dopamine receptor antagonists sulpiride (1 microM) and eticlopride (0.1 microM). 5-HT mimicked this effect, as did the selective 5-HT1D receptor agonist sumatriptan and the 5-HT-releasing agent fenfluramine. The actions of both 5-HT and cocaine were attenuated by the 5-HT1C/D antagonist metergoline. Pretreatment of slices with the 5-HT-depleting agent p-chloroamphetamine (pCA; 10 microM) abolished the inhibition of the GABAB IPSP by cocaine but failed to affect the actions of sumatriptan. We conclude that cocaine acts to modulate the GABA input to A10 dopamine neurons via inhibition of the 5-HT transporter, increasing the concentration of 5-HT at presynaptic 5-HT1D receptors. These actions of cocaine were apparent at lower concentrations than those required to act via inhibition of the dopamine transporter. This reduction of inhibitory synaptic input into the VTA would be expected to attenuate the GABA-mediated feedback inhibition from the nucleus accumbens, thus leading to increased activation of dopamine neurons. PMID:7965077

  11. Influence of Altered Hormonal Status on Platelet 5-HT and MAO-B Activity in Cigarette Smokers.

    PubMed

    Padmavathi, Pannuru; Reddy, Vaddi Damodara; Swarnalatha, Kodidela; Hymavathi, Reddyvari; Varadacharyulu, N Ch

    2015-04-01

    The present study was designed to understand the cigarette smoking-induced alterations in hormones and the resulting changes in platelet serotonin (5-hydroxytryptamine, 5-HT) and monoamine oxidase (MAO-B) activity in chronic smokers. Human male volunteers aged 35 ± 8 years, were divided into two groups, namely controls and smokers (12 ± 2 cigarettes per day for 7-10 years). Results showed that cigarette smoking significantly (p < 0.05) elevated plasma triiodothyronine (T3), cortisol and testosterone levels with significant (p < 0.05) reduction in plasma tryptophan and thyroxin (T4). Moreover, smokers showed reduced platelet 5-HT levels and MAO-B activity. In smokers, plasma cortisol was negatively correlated with tryptophan (r = -0.386), platelet MAO-B (r = -0.264), and 5-HT (r = -0.671), and positively correlated with testosterone (r = 0.428). However, testosterone was negatively correlated with platelet MAO-B (r = -0.315), and 5-HT (r = -.419) in smokers. Further, smokers plasma T3 levels were negatively correlated with platelet MAO-B (r = -0.398), and 5-HT (r = -0.541), whereas T4 levels were positively correlated with platelet MAO-B (r = 0.369), and 5-HT (r = 0.454). In conclusion, our study showed that altered testosterone and cortisol levels may aggravate behavior, mood disturbances and symptoms of depression by decreasing platelet 5-HT and MAO-B activity in smokers. PMID:25883430

  12. Modulation by drugs of the release of total tritium and 3H-5-HT from rat hypothalamic slices.

    PubMed

    Moret, C; Briley, M

    1990-05-01

    The release of total tritium and 3H-5-hydroxytryptamine (5-HT) evoked by electrical stimulation from prelabelled rat hypothalamic slices was studied. Lysergic acid diethylamide (LSD) decreased white methiothepin increased both total tritium and 3H-5-HT overflow. The proportion of total tritium present as 3H-5-HT was equivalent under control conditions and in the presence of methiothepin and slightly increased in the presence of LSD. Whereas the addition of the 5-HT uptake blocker, citalopram, did not modify the evoked release of total tritium, the monoamine oxidase inhibitor, pargyline, decreased it. In the presence of either of these drugs the proportion of 3H-5-HT was increased. In the presence of citalopram, the inhibition by LSD was reduced on both the release of total tritium and of 3H-5-HT. It thus appears that changes in electrically evoked total tritium overflow in general reflect changes in 3H-5-HT release. When uptake inhibitors or monoamine oxidase inhibitors are present in the medium, the situation is, however, more complex and results from experiments measuring only the release of total tritium should be interpreted with caution. PMID:2366876

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

    PubMed Central

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

    1994-01-01

    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

  14. Evidence concerning the involvement of 5-hydroxytryptamine in the locomotor activity produced by amphetamine or tranylcypromine plus L-DOPA.

    PubMed Central

    Green, A R; Kelly, P H

    1976-01-01

    1 Pretreatment of rats with p-chlorophenylalanine (PCPA; 2 X 200 mg/kg) decreased the concentration of 5-hydroxytryptamine (5-HT) in the brain. It also decreased the locomotor activity produced by tranylcypromine plus L-DOPA administration 24 h after the second dose of PCPA. 2 Pretreatment with p-chloroamphetamine, which produced a similar decrease in brain 5-HT concentrations did not decrease the locomotor response to tranylcypromine and L-DOPA. 3 PCPA pretreatment decreased the rise in the concentration of DOPA and dopamine in the brain following tranylcypromine and L-DOPA, suggesting its effect on the dopamine-induced locomotor activity was the result of this drug diminishing dopamine formation in the brain, probably by inhibiting L-DOPA uptake. 4 The locomotor activity produced by tranylcypromine and L-DOPA was not decreased by pretreatment 6 h earlier with disulfiram (400 mg/kg). This argues against the locomotor activity being due to noradrenergic stimulation. 5 PCPA pretreatment did not alter amphetamine-induced stereotypy or the circling behaviour in unilateral nigro-striatal lesioned rats. PMID:1276533

  15. Effects of 5-HT receptor agonists on depolarization-induced [3H]-noradrenaline release in rabbit hippocampus and human neocortex.

    PubMed

    Allgaier, C; Warnke, P; Stangl, A P; Feuerstein, T J

    1995-09-01

    1. The present study attempted to determine whether noradrenaline (NA) release in rabbit hippocampus and human neocortex is modulated by presynaptic 5-hydroxytryptamine (5-HT) receptors. 2. Slices of rabbit hippocampus and human neocortex, loaded with [3H]-noradrenaline ([3H]-NA) were superfused and the effects of 5-hydroxytryptamine (5-HT) receptor ligands on electrically evoked [3H]-NA release were investigated. 3. In rabbit hippocampus, 5-HT, 5-carboxamidotryptamine (5-CT; 32 microM) and 2-CH3-5-HT (32 microM) increased [3H]-NA release elicited with 360 pulses/3 Hz. Facilitation of transmitter release was not influenced by the 5-HT3 receptor antagonist, tropisetron but was prevented by the alpha 2-adrenoceptor antagonist, rauwolscine. When autoinhibition was avoided by stimulating the tissue with 4 pulses/100 Hz (pseudo-one pulse-(POP) stimulation), 2-CH3-5-HT decreased evoked transmitter release, whereas 5-HT and 5-CT had no effect. Inhibition caused by 2-CH3-5-HT was not affected by tropisetron but counteracted by the alpha 2-adrenoceptor ligands, clonidine and rauwolscine. Inhibition caused by clonidine was diminished in the presence of 5-CT or 2-CH3-5-HT. 4. In human neocortex, [3H]-NA release elicited with 360 pulses/3 Hz was increased by 10 microM 5-HT and 32 microM 5-CT, whereas 2-CH3-5-HT was ineffective. [3H]-NA release evoked with a modified POP stimulation (2 bursts of 4 pulses/100 Hz, 3.5 min apart) was not affected by 2-CH3-5-HT or 5-CT. 5. The present results indicate that 5-HT, 2-CH3-5-HT and 5-CT can act on presynaptic alpha 2-autoreceptors as partial agonists (2-CH3-5-HT; in rabbit hippocampal tissue) or antagonists (5-HT and 5-CT; in tissue of rabbit hippocampus and human neocortex). Furthermore the existence of autoinhibition dictates whether these drugs cause facilitation of release, inhibition or have no effect. PMID:8528558

  16. Further characterization, by use of tryptamine and benzamide derivatives, of the putative 5-HT4 receptor mediating tachycardia in the pig.

    PubMed Central

    Villalón, C. M.; den Boer, M. O.; Heiligers, J. P.; Saxena, P. R.

    1991-01-01

    1. It has recently been shown that the tachycardic response to 5-hydroxytryptamine (5-HT) in the anaesthetized pig, being mimicked by 5-methoxytryptamine and renzapride and blocked by high doses of ICS 205-930, is mediated by the putative 5-HT4 receptor. In the present investigation we have further characterized this receptor. 2. Intravenous bolus injections of the tryptamine derivatives, 5-HT (3, 10 and 30 micrograms kg-1), 5-methoxytryptamine (3, 10 and 30 micrograms kg-1) and alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT; 3, 10, 30 and 100 micrograms kg-1), resulted in dose-dependent increases in heart rate of, respectively, 25 +/- 2, 48 +/- 3 and 68 +/- 3 beats min-1 (5-HT; n = 35); 15 +/- 1, 32 +/- 2 and 57 +/- 3 beats min-1 (5-methoxytryptamine; n = 30); 6 +/- 4, 18 +/- 6, 34 +/- 6 and 64 +/- 11 beats min-1 (alpha-methyl-5-HT; n = 3).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2043916

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

    PubMed

    McDonald, M Danielle; Walsh, Patrick J

    2004-05-01

    When injected arterially, serotonin (5-hydroxytryptamine; 5-HT) has been shown to elicit naturally sized urea pulse events in the gulf toadfish, Opsanus beta. The goal of the present study was to determine which 5-HT receptor(s) was involved in mediating this serotonergic stimulation of the pulsatile excretion mechanism. Toadfish were surgically implanted with caudal arterial catheters and intraperitoneal catheters and injected with either 8-OH-DPAT (1 micro mol kg(-1)), a selective 5-HT(1A) receptor agonist, alpha-methyl-5-HT (1 micro mol kg(-1)), a 5-HT(2) receptor agonist, or ketanserin, a 5-HT(2) receptor antagonist (0.01, 0.1, 1 and 10 micro mol kg(-1)) plus alpha-methyl-5-HT. 8-OH-DPAT injection did not mediate an increase in urea excretion, ruling out the involvement of 5-HT(1A) receptors in pulsatile excretion. However, within 5 min, alpha-methyl-5-HT injection caused an increase in the excretion of urea in >95% (N=27) of the fish injected, with an average pulse size of 652+/-102 micro mol N kg(-1) (N=26). With alpha-methyl-5-HT injection there was no corresponding increase in ammonia or [(3)H]PEG 4000 permeability. Urea pulses elicited by alpha-methyl-5-HT were inhibited in a dose-dependent fashion by the 5-HT(2) receptor antagonist ketanserin, which at low doses caused a significant inhibition of pulse size and at higher doses significantly inhibited the occurrence of pulsatile excretion altogether. However, neither 8-OH-DPAT nor alpha-methyl 5-HT injection had an effect on plasma cortisol or plasma urea concentrations. These findings suggest the involvement of a 5-HT(2)-like receptor in the regulation of pulsatile urea excretion. PMID:15143134

  18. Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors.

    PubMed

    Lam, Daniel D; Przydzial, Magdalena J; Ridley, Simon H; Yeo, Giles S H; Rochford, Justin J; O'Rahilly, Stephen; Heisler, Lora K

    2008-03-01

    The neurotransmitter serotonin (5-hydroxytryptamine) is a well-established modulator of energy balance. Both pharmacological and genetic evidence implicate the serotonin 2C receptor (5-HT(2C)R) as a critical receptor mediator of serotonin's effects on ingestive behavior. Here we characterized the effect of the novel and selective 5-HT(2C)R agonist BVT.X on energy balance in obese and lean mice and report that BVT.X significantly reduces acute food intake without altering locomotor activity or oxygen consumption. In an effort to elucidate the mechanism of this effect, we examined the chemical phenotype of 5-HT(2C)R-expressing neurons in a critical brain region affecting feeding behavior, the arcuate nucleus of the hypothalamus. We show that 5-HT(2C)Rs are coexpressed with neurons containing proopiomelanocortin, known to potently affect appetite, in the arcuate nucleus of the hypothalamus of the mouse. We then demonstrate that prolonged infusion with BVT.X in obese mice significantly increases Pomc mRNA and reduces body weight, percent body fat, and initial food intake. To evaluate the functional importance of melanocortin circuitry in the effect of BVT.X on ingestive behavior, we assessed mice with disrupted melanocortin pathways. We report that mice lacking the melanocortin 4 receptor are not responsive to BVT.X-induced hypophagia, demonstrating that melanocortins acting on melanocortin 4 receptor are a requisite downstream pathway for 5-HT(2C)R agonists to exert effects on food intake. The data presented here not only indicate that the novel 5-HT(2C)R agonist BVT.X warrants further investigation as a treatment for obesity but also elucidate specific neuronal pathways potently affecting energy balance through which 5-HT(2C)R agonists regulate ingestive behavior. PMID:18039773

  19. 5-HT Obesity Medication Efficacy via POMC Activation is Maintained During Aging

    PubMed Central

    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

    2014-01-01

    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

  20. Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens

    PubMed Central

    Jean, Alexandra; Conductier, Grégory; Manrique, Christine; Bouras, Constantin; Berta, Philippe; Hen, René; Charnay, Yves; Bockaert, Joël; Compan, Valérie

    2007-01-01

    Anorexia nervosa is a growing concern in mental health, often inducing death. The potential neuronal deficits that may underlie abnormal inhibitions of food intake, however, remain largely unexplored. We hypothesized that anorexia may involve altered signaling events within the nucleus accumbens (NAc), a brain structure involved in reward. We show here that direct stimulation of serotonin (5-hydroxytryptamine, 5-HT) 4 receptors (5-HT4R) in the NAc reduces the physiological drive to eat and increases CART (cocaine- and amphetamine-regulated transcript) mRNA levels in fed and food-deprived mice. It further shows that injecting 5-HT4R antagonist or siRNA-mediated 5-HT4R knockdown into the NAc induced hyperphagia only in fed mice. This hyperphagia was not associated with changes in CART mRNA expression in the NAc in fed and food-deprived mice. Results include that 5-HT4R control CART mRNA expression into the NAc via a cAMP/PKA signaling pathway. Considering that CART may interfere with food- and drug-related rewards, we tested whether the appetite suppressant properties of 3,4-N-methylenedioxymethamphetamine (MDMA, ecstasy) involve the 5-HT4R. Using 5-HT4R knockout mice, we demonstrate that 5-HT4R are required for the anorectic effect of MDMA as well as for the MDMA-induced enhancement of CART mRNA expression in the NAc. Directly injecting CART peptide or CART siRNA into the NAc reduces or increases food consumption, respectively. Finally, stimulating 5-HT4R- and MDMA-induced anorexia were both reduced by injecting CART siRNA into the NAc. Collectively, these results demonstrate that 5-HT4R-mediated up-regulation of CART in the NAc triggers the appetite-suppressant effects of ecstasy. PMID:17913892

  1. 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

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

    2012-01-01

    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 (http://www.broad.mit.edu/cmap/) 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

  2. Potentiation of P2X1 ATP-gated currents by 5-hydroxytryptamine 2A receptors involves diacylglycerol-dependent kinases and intracellular calcium.

    PubMed

    Ase, Ariel R; Raouf, Ramin; Bélanger, Danny; Hamel, Edith; Séguéla, Philippe

    2005-10-01

    Postsynaptic P2X1 ATP-gated channels are expressed in smooth muscle cells of the vascular and genitourinary systems, where they mediate desensitizing neurogenic contractions. Using the model of the isolated rat tail artery, we show that the vasoactive mediator 5-hydroxytryptamine (5-HT), via the 5-HT2A metabotropic receptor, regulates the desensitization kinetics of P2X1 responses by increasing their rate of recovery. Reconstituting the potentiation of P2X1 ATP-gated currents by 5-HT2A receptors in the Xenopus oocyte expression system, we provide evidence that this modulation depends on the activation of novel protein kinase C isoforms and protein kinase D (also named PKCmu) downstream of phospholipase Cbeta. Other major kinases like Ca2+/calmodulin kinase II, protein kinase A, mitogen-activated protein kinases, and tyrosine kinases were found not to be involved. Moreover, we report that buffering intracellular Ca2+ ions with the chelator 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) decreases the rate of recovery of P2X1 responses and increases their sensitivity to potentiation by 5-HT2A receptors or by the diacylglycerol analog phorbol ester 12-myristate 13-acetate. We conclude that intracellular Ca2+ and a subset of diacylglycerol-dependent protein kinases regulate the activity of P2X1 receptor channels by modulating their recovery from desensitization. PMID:15958718

  3. Tong Xie Yao Fang relieves irritable bowel syndrome in rats via mechanisms involving regulation of 5-hydroxytryptamine and substance P

    PubMed Central

    Yin, Yue; Zhong, Lei; Wang, Jian-Wei; Zhao, Xue-Ying; Zhao, Wen-Jing; Kuang, Hai-Xue

    2015-01-01

    AIM: To investigate whether the Chinese medicine Tong Xie Yao Fang (TXYF) improves dysfunction in an irritable bowel syndrome (IBS) rat model. METHODS: Thirty baby rats for IBS modeling were separated from mother rats (1 h per day) from days 8 to 21, and the rectum was expanded by angioplasty from days 8 to 12. Ten normal rats were used as normal controls. We examined the effects of TXYF on defection frequency, colonic transit function and smooth muscle contraction, and the expression of 5-hydroxytryptamine (5-HT) and substance P (SP) in colonic and hypothalamus tissues by Western blot and RT-PCT techniques in both normal rats and IBS model rats with characterized visceral hypersensitivity. RESULTS: Defecation frequency was 1.8 ± 1.03 in normal rats and 4.5 ± 1.58 in IBS model rats (P < 0.001). However, the defecation frequency was significantly decreased (3.0 ± 1.25 vs 4.5 ± 1.58, P < 0.05), while the time (in seconds) of colon transit function was significantly increased (256.88 ± 20.32 vs 93.36 ± 17.28, P < 0.001) in IBS + TXYF group rats than in IBS group rats. Increased colonic smooth muscle tension and contract frequency in IBS model rats were significantly decreased by administration of TXYF. Exogenous agonist stimulants increased spontaneous activity and elicited contractions of colon smooth muscle in IBS model rats, and all of these actions were significantly reduced by TXYF involving 5-HT and SP down-regulation. CONCLUSION: TXYF can modulate the activity of the enteric nervous system and alter 5-HT and SP activities, which may contribute to the symptoms of IBS.

  4. Neuroprotective effect of N-acyl 5-hydroxytryptamines on glutamate-induced cytotoxicity in HT-22 cells.

    PubMed

    Jin, Mei Chen; Yoo, Jae-Myung; Sok, Dai-Eun; Kim, Mee Ree

    2014-12-01

    Some endocannabinoids have been known to express anti-inflammatory and antioxidant actions independent of cannabinoid receptors. In this respect, we investigated whether N-acyl 5-hydroxytryptamines (5-HTs) might prevent against glutamate-induced oxidative cytotoxicity in HT-22 cells, and attempted to elucidate the mechanism for their cytoprotective action. N-acyl 5-HTs with palmitoyl, stearoyl, arachidonoyl or docosahexaenoyl chain expressed a remarkable protective effect on glutamate-induced cytotoxicity. Additionally, glutamate-induced oxidative stress, represented by the increase of reactive oxygen species level and the reduction of glutathione level, was prevented markedly by N-acyl 5-HTs at submicromolar levels. Further, N-palmitoyl 5-HT, the most cytoprotective, enhanced antioxidant defense by up-regulating the expression of antioxidant enzymes such as heme oxygenase-1, glutamate-cysteine ligase catalytic subunit or NAD(P)H quinine oxidoreductase-1 in the presence or absence of glutamate. Consistent with this, N-palmitoyl 5-HT stimulated nuclear translocation of Nrf2 in early phase (2 h), and this effect was remarkably suppressed by inhibitors of PI3K, PDK-1, Akt or p38 MAPK. Additionally, N-palmitoyl 5-HT suppressed glutamate-induced activation of ERK in late phase (12 h), but not in early phase (2 h), presumably supporting the implication of MEK/ERK pathway in glutamate-induced cytotoxicity. Collectively, it is suggested that N-acyl 5-HTs may attenuate glutamate-induced cytotoxicity via the activation of PI3K/PDK-1/Akt- and p38 MAPK-dependent Nrf2 signaling in early phase as well as the suppression of MEK/ERK pathway in late phase. PMID:25307111

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

    PubMed

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

    2014-03-01

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

  6. Reduced signal transduction by 5-HT4 receptors after long-term venlafaxine treatment in rats

    PubMed Central

    Vidal, R; Valdizan, EM; Vilaró, MT; Pazos, A; Castro, E

    2010-01-01

    BACKGROUND AND PURPOSE The 5-HT4 receptor may be a target for antidepressant drugs. Here we have examined the effects of the dual antidepressant, venlafaxine, on 5-HT4 receptor-mediated signalling events. EXPERIMENTAL APPROACH The effects of 21 days treatment (p.o.) with high (40 mg·kg?1) and low (10 mg·kg?1) doses of venlafaxine, were evaluated at different levels of 5-HT4 receptor-mediated neurotransmission by using in situ hybridization, receptor autoradiography, adenylate cyclase assays and electrophysiological recordings in rat brain. The selective noradrenaline reuptake inhibitor, reboxetine (10 mg·kg?1, 21 days) was also evaluated on 5-HT4 receptor density. KEY RESULTS Treatment with a high dose (40 mg·kg?1) of venlafaxine did not alter 5-HT4 mRNA expression, but decreased the density of 5-HT4 receptors in caudate-putamen (% reduction = 26 ± 6), hippocampus (% reduction = 39 ± 7 and 39 ± 8 for CA1 and CA3 respectively) and substantia nigra (% reduction = 49 ± 5). Zacopride-stimulated adenylate cyclase activation was unaltered following low-dose treatment (10 mg·kg?1) while it was attenuated in rats treated with 40 mg·kg?1 of venlafaxine (% reduction = 51 ± 2). Furthermore, the amplitude of population spike in pyramidal cells of CA1 of hippocampus induced by zacopride was significantly attenuated in rats receiving either dose of venlafaxine. Chronic reboxetine did not modify 5-HT4 receptor density. CONCLUSIONS AND IMPLICATIONS Our data indicate a functional desensitization of 5-HT4 receptors after chronic venlafaxine, similar to that observed after treatment with the classical selective inhibitors of 5-HT reuptake. PMID:20880406

  7. Role of 5-Hydroxytryptamine2C Receptors in Ca2+-Dependent Ethanol Potentiation of GABA Release onto Ventral Tegmental Area Dopamine Neurons

    PubMed Central

    Theile, Jonathan W.; Morikawa, Hitoshi; Gonzales, Rueben A.; Morrisett, Richard A.

    2009-01-01

    Activation of ventral tegmental area (VTA)-dopaminergic (DA) neurons by ethanol has been implicated in the rewarding and reinforcing actions of ethanol. GABAergic transmission is thought to play an important role in regulating the activity of DA neurons. We have reported previously that ethanol enhances GABA release onto VTA-DA neurons in a brain slice preparation. Because intraterminal Ca2+ levels regulate neurotransmitter release, we investigated the roles of Ca2+-dependent mechanisms in ethanol-induced enhancement of GABA release. Acute ethanol enhanced miniature inhibitory postsynaptic current (mIPSC) frequency in the presence of the nonspecific voltage-gated Ca2+ channel inhibitor, cadmium chloride, even though basal mIPSC frequency was reduced by cadmium. Conversely, the inositol-1,4,5-triphosphate receptor inhibitor, 2-aminoethoxydiphenylborane, and the sarco/endoplasmic reticulum Ca2+ ATPase pump inhibitor, cyclopiazonic acid, eliminated the ethanol enhancement of mIPSC frequency. Recent studies suggest that the G protein-coupled receptor, 5-hydroxytryptamine (5-HT) 2C, may modulate GABA release in the VTA. Thus, we also investigated the role of 5-HT2C receptors in ethanol enhancement of GABAergic transmission. Application of 5-HT and the 5-HT2C receptor agonist, Ro-60-0175 [(?S)-6-chloro-5-fluoro-?-methyl-1H-indole-1-ethanamine fumarate], alone enhanced mIPSC frequency of which the latter was abolished by the 5-HT2C receptor antagonist, SB200646 [N-(1-methyl-5-indoyl)-N-(3-pyridyl)urea hydrochloride], and substantially diminished by cyclopiazonic acid. Furthermore, SB200646 abolished the ethanol-induced increase in mIPSC frequency and had no effect on basal mIPSC frequency. These observations suggest that an increase in Ca2+ release from intracellular stores via 5-HT2C receptor activation is involved in the ethanol-induced enhancement of GABA release onto VTA-DA neurons. PMID:19225162

  8. Comparison of contractile responses to 5-hydroxytryptamine and sumatriptan in human isolated coronary artery: synergy with the thromboxane A2-receptor agonist, U46619.

    PubMed Central

    Cocks, T. M.; Kemp, B. K.; Pruneau, D.; Angus, J. A.

    1993-01-01

    1. The interaction between the thromboxane A2 receptor agonist, U46619 and two 5-hydroxytryptamine (5-HT) receptor agonists, the non-selective, naturally occurring agonist, 5-HT and the selective 5-HT1-like agonist, sumatriptan were studied in human epicardial coronary arteries in vitro. 2. Coronary artery rings (2-4 mm in diameter) were prepared from epicardial arteries from explant hearts of patients undergoing heart transplant (cardiomyopathy, n = 13; ischaemic heart disease, n = 10) and unused donor hearts (n = 5). Each ring of artery was set at optimal resting conditions to record changes in isometric force. 3. The majority of artery rings developed phasic, rhythmic contractions either spontaneously or in response to all vasoconstrictor agonists tested. Both the spontaneous and agonist-induced phasic contractions were abolished by nifedipine (0.1 microM). 4. Concentration-contraction curves to 5-HT-receptor agonists and noradrenaline (NA), were first constructed in artery rings that did not develop phasic activity. 5-HT and ergometrine were the most potent agonists with EC50 values of 6.8 +/- 0.2 and 7.7 +/- 0.2 (-log M) respectively. Potencies (EC50's) to sumatriptan, methysergide and noradrenaline could not be determined due to their poor ability to contract the coronary artery. Maximum contractions (Emax; normalized as a percentage of the contraction to a maximum-depolarizing concentration of K+ in physiological salt solution (KPSS)) for 5-HT, ergometrine, sumatriptan, methysergide and noradrenaline were 40 +/- 10, 9 +/- 3, < 5, < 5 and < 5% respectively. 5. In arteries without phasic activity, U46619 (1 nM) caused an increase in force of 3.8 +/- 1% KPSS.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8220898

  9. Involvement of 5-HT? receptors in vortioxetine's modulation of circadian rhythms and episodic memory in rodents.

    PubMed

    Westrich, Ligia; Haddjeri, Nasser; Dkhissi-Benyahya, Ouria; Sánchez, Connie

    2015-02-01

    Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders, antidepressants that target key 5-HT (serotonin) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility. Vortioxetine is a multimodal antidepressant that inhibits 5-HT1D, 5-HT3, 5-HT7 receptor activity, 5-HT reuptake, and enhances the activity of 5-HT1A and 5-HT1B receptors. In this study, we investigated the effects of vortioxetine on the period length of PER2::LUC expression, circadian behavior, and episodic memory, using tissue explants from genetically modified PER2::LUC mice, locomotor activity rhythm monitoring, and the object recognition test, respectively. Incubation of tissue explants from the suprachiasmatic nucleus of PER2::LUC mice with 0.1 ?M vortioxetine increased the period length of PER2 bioluminescence. Monitoring of daily wheel-running activity of Sprague-Dawley rats treated with vortioxetine (10 mg/kg, s.c.), alone or in combination with the 5-HT1A receptor agonist flesinoxan (2.5 mg/kg, s.c.) or the 5-HT7 receptor antagonist SB269970 (30 mg/kg, s.c.), just prior to activity onset revealed significant delays in wheel-running behavior. The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the 5-HT7 receptor partial agonist AS19. Finally, in the object recognition test, vortioxetine (10 mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 (5 mg/kg, i.p.). In conclusion, the present study shows that vortioxetine, partly via its 5-HT7 receptor antagonism, induced a significant effect on circadian rhythm and presented promnesic properties in rodents. PMID:25446573

  10. 5HT2 Receptor Activation Facilitates P2X Receptor Mediated Excitatory Neurotransmission to Cardiac Vagal Neurons in the Nucleus Ambiguus

    PubMed Central

    Dergacheva, Olga; Wang, Xin; Kamendi, Harriet; Cheng, Qi; Pinol, Ramon Manchon; Jameson, Heather; Gorini, Christopher; Mendelowitz, David

    2008-01-01

    Summary Parasympathetic preganglionic cardiac vagal neurons (CVNs) which dominate the control of heart rate are located within the nucleus ambiguus (NA). Serotonin (5HT), and in particular 5HT2 receptors, play an important role in cardiovascular function in the brainstem. However, there is a lack of information on the mechanisms of action of 5HT2 receptors in modulating parasympathetic cardiac activity. This study tests whether activation of 5HT2 receptors alters excitatory glutamatergic and purinergic neurotransmission to CVNs. Application of ?-methyl-5-hydroxytryptamine (?-Me-5HT), a 5HT2 agonist, reversibly increased both the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in CVNs. Similar responses were obtained with alpha-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine hydrochloride (BW723C86), and m-chlorophenylpiperazine (m-CPP), 5HT2B and 5HT2B/C receptor agonists, respectively. The facilitation evoked by ?-Me-5HT was prevented by the 5HT2B/C receptor antagonist SB206553 hydrochloride (SB206553). Interestingly, the blockage of both NMDA and non-NMDA glutamatergic receptors did not prevent ?-Me-5HT-evoked facilitation of mEPSCs, however, the responses were blocked by the P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). The responses evoked by ?-Me-5HT were mimicked by application of ?,?-methylene ATP (?,?-Me-ATP), a P2X receptor agonist, which were also blocked by PPADS. In summary, these results indicate activation of 5HT2 receptors facilitates excitatory purinergic, but not glutamatergic, neurotransmission to CVNs. PMID:18396300

  11. Insights into the complex influence of 5-HT signaling on thalamocortical axonal system development

    PubMed Central

    van Kleef, Esmee SB; Gaspar, Patricia; Bonnin, Alexandre

    2012-01-01

    The topographic organization of the thalamocortical axons (TCAs) in the barrel field (BF) in the rodent primary somatosensory cortex (S1) results from a succession of temporally and spatially precise developmental events. Prenatally, growth and guidance mechanisms enable TCAs to navigate through the forebrain and reach the cortex. Postnatally, TCAs grow into the cortex and the refinement of their terminal arborization pattern in layer IV creates barrel-like structures. The combined results of studies performed over the past 20 years clearly show that serotonin (5-hydroxytryptamine; 5-HT) signaling modulates these pre- and early postnatal developmental processes. In this context, 5-HT signaling can purposely be described as ‘modulating’ rather than ‘controlling’ because developmental alterations of 5-HT synthesis, uptake or degradation either have a dramatic, moderate or no effect at all on TCA pathway and BF formation. In this review we summarize and compare the outcomes of diverse pharmacological and genetic manipulations of 5-HT signaling on TCA pathway and BF formation, in an attempt to understand these discrepancies. PMID:22607002

  12. Repeated administration of lead decreases brain 5-HT metabolism and produces memory deficits in rats.

    PubMed

    Haider, Saida; Shameem, Saima; Ahmed, Shahida P; Perveen, Tahira; Haleem, Darakhshan J

    2005-01-01

    Long-term exposure to low levels of lead (Pb2+) has been shown to produce learning and memory deficits in rodents and humans. These deficits are thought to be associated with altered brain monoamine neurotransmission. Increased brain 5-HT (5-hydroxytryptamine; serotonin) activity is thought to be a prerequisite for maintaining control over the cognitive information process, and is said to have a role in learning and memory. This study was designed to investigate the effects of Pb2+ administration on brain 5-HT metabolism and memory function in rats. Rats were injected daily for three weeks with Pb2+-acetate at a dose of 100 mg/kg body weight. The assessment of memory was done using the Radial arm maze (RAM) and Passive avoidance tests. The results showed spatial working memory (SWM) deficits as well as decreased brain 5-HT metabolism. Increased serotonin activity is considered to be an indication of improved cognitive performance. The results are discussed in the context of lead-induced decreases in 5-HT metabolism playing a role in the impairment of memory. PMID:16341275

  13. Activation of serotonin 5-HT? receptor induces coronary flow increase in isolated rat heart.

    PubMed

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

    2015-02-01

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

  14. Mutagenic analysis of the intracellular portals of the human 5-HT3A receptor.

    PubMed

    Carland, Jane E; Cooper, Michelle A; Livesey, Matthew R; Hales, Tim G; Peters, John A; Lambert, Jeremy J

    2013-11-01

    Structural models of Cys-loop receptors based on homology with the Torpedo marmorata nicotinic acetylcholine receptor infer the existence of cytoplasmic portals within the conduction pathway framed by helical amphipathic regions (termed membrane-associated (MA) helices) of adjacent intracellular M3-M4 loops. Consistent with these models, two arginine residues (Arg(436) and Arg(440)) within the MA helix of 5-hydroxytryptamine type 3A (5-HT3A) receptors act singularly as rate-limiting determinants of single-channel conductance (?). However, there is little conservation in primary amino acid sequences across the cytoplasmic loops of Cys-loop receptors, limiting confidence in the fidelity of this particular aspect of the 5-HT3A receptor model. We probed the majority of residues within the MA helix of the human 5-HT3A subunit using alanine- and arginine-scanning mutagenesis and the substituted cysteine accessibility method to determine their relative influences upon ?. Numerous residues, prominently those at the 435, 436, 439, and 440 positions, were found to markedly influence ?. This approach yielded a functional map of the 5-HT3A receptor portals, which agrees well with the homology model. PMID:24030822

  15. Pharmacometric Analyses to Support Early Development Decisions for LY2878735: A Novel Serotonin Norepinephrine Reuptake Inhibitor.

    PubMed

    Raddad, E; Melhem, M R; Sloan-Lancaster, J S; Miller, J W; Van Wart, S A; Rubino, C M

    2013-01-01

    LY2878735 is a novel dual serotonin (5-hydroxytryptamine (5-HT)) and norepinephrine (NE) reuptake inhibitor (SNRI) in development for chronic pain indications. In vitro profile suggests a more balanced profile as compared with other SNRI's, which is expected to confer superior clinical efficacy. LY2878735 is metabolized partly by the genetically polymorphic cytochrome P450 (CYP) 2D6 pathway, raising pharmacokinetic (PK) variability concerns. Phase 1 PK and biomarker data were analyzed by pharmacometric methods to characterize the balance between dual-target engagement and adverse effects on heart rate (HR) and blood pressure (BP). A narrow range of plasma LY2878735 levels was associated with an acceptable balance. As compared with poor metabolizers (PM), CYP2D6 extensive metabolizers (EM) have 21- and threefold higher clearance and distribution volume, respectively. Even with a CYP2D6-based dosing paradigm, a superior therapeutic index comparable to duloxetine, a widely used SNRI, was not achievable and LY2878735 development was thus terminated. Model-based approach effectively synthesizes PK-pharmacodynamic (PD) relationships, enabling efficient early development decisions.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e66; doi:10.1038/psp.2013.43; published online 21 August 2013. PMID:23965782

  16. The effect of MDMA (3,4-methylenedioxymethamphetamine) on the 5HT synthesis rate in the rat brain: an autoradiographic study

    Microsoft Academic Search

    Dorotea Mück-Šeler; Sho Takahashi; Mirko Diksic

    1998-01-01

    The effect of MDMA (3,4-methylenedioxymethamphetamine), a psychotropic amphetamine derivative, treatment on the rate of serotonin (5-hydroxytryptamine; 5-HT) synthesis in the rat brain was studied by autoradiography using ?-[14C]-methyl-l-tryptophan method. Three different treatment protocols were compared to the control (saline) treated rats: (1) rats treated twice with 10 mg\\/kg every 12 h (20 mg\\/kg total) and injected tracer for the synthesis

  17. AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels

    SciTech Connect

    Barrett, R.J.; Appell, K.C.; Kilpatrick, B.F.; Proakis, A.G.; Nolan, J.C.; Walsh, D.A. (A. H. Robins Research Labs., Richmond, VA (USA))

    1991-01-01

    In vivo and in vitro methods were used to characterize AHR-16303B, a novel compound with antagonistic action at 5-HT2 receptors and voltage-sensitive calcium channels. The 5-HT2 receptor-antagonistic properties of AHR-16303B were demonstrated by inhibition of (a) (3H)ketanserin binding to rat cerebral cortical membranes (IC50 = 165 nM); (b) 5-hydroxytryptamine (5-HT)-induced foot edema in rats (minimum effective dose, (MED) = 0.32 mg/kg orally, p.o.); (c) 5-HT-induced vasopressor responses in spontaneously hypertensive rats (SHR) (ID50 = 0.18 mg/kg intravenously (i.v.), 1.8 mg/kg p.o.), (d) 5-HT-induced antidiuresis in rats (MED = 1 mg/kg p.o.), and (e) platelet aggregation induced by 5-HT + ADP (IC50 = 1.5 mM). The calcium antagonist properties of AHR-16303B were demonstrated by inhibition of (a) (3H)nimodipine binding to voltage-sensitive calcium channels on rabbit skeletal muscle membranes (IC50 = 15 nM), (b) KCl-stimulated calcium flux into cultured PC12 cells (IC50 = 81 nM), and (c) CaCl2-induced contractions of rabbit thoracic aortic strips (pA2 = 8.84). AHR-16303B had little or no effect on binding of radioligands to dopamine2 (DA2) alpha 1, alpha 2, H1, 5-HT1 alpha, beta 2, muscarinic M1, or sigma opioid receptors; had no effect on 5-HT3 receptor-mediated vagal bradycardia; and had only minor negative inotropic, chronotropic, and dromotropic effects on isolated guinea pig atria. In conscious SHR, 30 mg/kg p.o. AHR-16303B completely prevented the vasopressor responses to i.v. 5-HT, and decreased blood pressure (BP) by 24% 3 h after dosing.

  18. Synergy between 5-HT4 receptor activation and acetylcholinesterase inhibition in human colon and rat forestomach.

    PubMed

    Cellek, S; Thangiah, R; Jarvie, E M; Vivekanandan, S; Lalude, O; Sanger, G J

    2008-05-01

    5-Hydroxytryptamine (5-HT4) receptor agonists increase gastrointestinal (GI) motility by enhancing enteric acetylcholine release which is then metabolized by acetylcholinesterase (AChE) to inactive metabolites. As both AChE inhibitors and, more usually, 5-HT4 receptor agonists are used to increase GI motility, an understanding of how these two different types of drugs might interact becomes of great importance. Our aim was to investigate the hypothesis that the effect of AChE inhibition will synergise with the ability of 5-HT4 receptor agonism to increase cholinergic activity, leading to an effect greater than that evoked by each action alone. We tested the activity of the 5-HT4 receptor agonist, prucalopride (10 nmol L(-1)-30 micromol L(-1)) and an AChE inhibitor, neostigmine (1 nmol L(-1)-10 micromol L(-1)) on cholinergically mediated contractions elicited by electrical field stimulation of human isolated colon circular muscle and rat isolated forestomach longitudinal strips. The experiments with human colon were performed in the presence of an inhibitor of nitric oxide synthase (N(omega)-nitro-l-arginine methyl ester, 300 micromol L(-1)). Prucalopride and neostigmine both enhanced cholinergic contractions in both tissues. The effect of prucalopride was inhibited in both tissues by SB-204070, a 5-HT4 receptor antagonist. In the presence of a minimum effective concentration of neostigmine (30 nmol L(-1)) and a submaximum concentration of prucalopride (3 micromol L(-1)) the enhancement of contractions was greater than either compound alone in both tissues. These data demonstrate that the combination of prucalopride and neostigmine potentiate cholinergic contractions more than their arithmetic sum of their individual values. The results suggest that a synergy between 5-HT4 receptor agonism and AChE inhibition could be established pharmacologically which could be utilized as a novel prokinetic approach to functional GI disorders. PMID:18194150

  19. Role of 5-HT3 Receptor on Food Intake in Fed and Fasted Mice

    PubMed Central

    Li, Bingjin; Shao, Dongyuan; Luo, Yungang; Wang, Pu; Liu, Changhong; Zhang, Xingyi; Cui, Ranji

    2015-01-01

    Background Many studies have shown that 5-hydroxytryptamine (5-HT) receptor subtypes are involved in the regulation of feeding behavior. However, the relative contribution of 5-HT3 receptor remains unclear. The present study was aimed to investigate the role of 5-HT3 receptor in control of feeding behavior in fed and fasted mice. Methodology/Principal Findings Food intake and expression of c-Fos, tyrosine hydroxylase (TH), proopiomelanocortin (POMC) and 5-HT in the brain were examined after acute treatment with 5-HT3 receptor agonist SR-57227 alone or in combination with 5-HT3 receptor antagonist ondansetron. Food intake was significantly inhibited within 3 h after acute treatment with SR 57227 in fasted mice but not fed mice, and this inhibition was blocked by ondansetron. Immunohistochemical study revealed that fasting-induced c-Fos expression was further enhanced by SR 57227 in the brainstem and the hypothalamus, and this enhancement was also blocked by ondansetron. Furthermore, the fasting-induced downregulation of POMC expression in the hypothalamus and the TH expression in the brain stem was blocked by SR 57227 in the fasted mice, and this effect of SR 57227 was also antagonized by ondansetron. Conclusion/Significance Taken together, our findings suggest that the effect of SR 57227 on the control of feeding behavior in fasted mice may be, at least partially, related to the c-Fos expression in hypothalamus and brain stem, as well as POMC system in the hypothalamus and the TH system in the brain stem. PMID:25789930

  20. Preclinical characterization of WAY-211612: a dual 5-HT uptake inhibitor and 5-HT1A receptor antagonist and potential novel antidepressant

    PubMed Central

    Beyer, CE; Lin, Q; Platt, B; Malberg, J; Hornby, G; Sullivan, KM; Smith, DL; Lock, T; Mitchell, PJ; Hatzenbuhler, NT; Evrard, DA; Harrison, BL; Magolda, R; Pangalos, MN; Schechter, LE; Rosenzweig-Lipson, S; Andree, TH

    2009-01-01

    Background and purpose As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT1A receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT1A receptor antagonist activities, was evaluated in preclinical models. Experimental approach Occupancy studies confirmed the mechanism of action of WAY-211612, while its in vivo profile was characterized in microdialysis and behavioural models. Key results WAY-211612 inhibited 5-HT reuptake (Ki = 1.5 nmol·L?1; KB = 17.7 nmol·L?1) and exhibited full 5-HT1A receptor antagonist activity (Ki = 1.2 nmol·L?1; KB = 6.3 nmol·L?1; Imax 100% in adenyl cyclase assays; KB = 19.8 nmol·L?1; Imax 100% in GTP?S). WAY-211612 (3 and 30 mg·kg?1, po) occupied 5-HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5-HT1A receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY-211612 (3–30 mg·kg?1, po) raised levels of cortical 5-HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg?1, s.c.) and a 5-HT1A antagonist (WAY-100635; 0.3 mg·kg?1, s.c). WAY-211612 (3.3–30 mg·kg?1, s.c.) decreased aggressive behaviour in the resident-intruder model, while increasing the number of punished crossings (3–30 mg·kg?1, i.p. and 10–56 mg·kg?1, po) in the mouse four-plate model and decreased adjunctive drinking behaviour (56 mg·kg?1, i.p.) in the rat scheduled-induced polydipsia model. Conclusions and implications These findings suggest that WAY-211612 may represent a novel antidepressant. PMID:19338583

  1. Effect of fluvoxamine on platelet 5HT2A receptors as studied by [3H]lysergic acid diethylamide ([3H]LSD) binding in healthy volunteers

    Microsoft Academic Search

    O. Spigset; Tom Mjörndal

    1997-01-01

    Alterations in platelet 5-HT2A receptor characteristics have been reported in major depression as well as in other psychiatric diseases, and some effort\\u000a has been made to utilize platelet 5-HT2A receptor status as a biological correlate to antidepressant drug response. In order to investigate whether treatment with\\u000a a selective serotonin reuptake inhibitor affects platelet 5-HT2A receptors, we have studied platelet [3H]lysergic

  2. Analysis of the 5-HT receptors mediating contractions in the rabbit isolated renal artery.

    PubMed Central

    Tadipatri, S.; van Heuven-Nolsen, D.; Feniuk, W.; Saxena, P. R.

    1991-01-01

    1. Using a number of agonist and antagonist compounds, we have attempted to characterize the responses and receptors involved in the effects of 5-hydroxytryptamine (5-HT) in the rabbit isolated renal artery. 2. In vessel segments precontracted with the thromboxane-mimetic agent, U46619 (100 nM), neither 5-HT (10(-8) to 10(-4) M) nor 5-carboxamidotryptamine (5-CT; 10(-8) to 3 x 10(-4) M) caused relaxations like those observed with methacholine. Both 5-HT and 5-CT further increased the tone of the vessels, with pD2 values of 7.1 and 7.9, respectively. 3. In the absence of U46619, both 5-HT (10(-7) to 3 x 10(-3) M) and 5-CT (10(-7) to 10(-3) M) contracted the rabbit renal artery, but with reduced potencies. The contractions to 5-HT were reproducible and the rank order of potency (pD2) of the agonists was: alpha-methyl-5-HT (5.7), sumatriptan (5.3), 5-HT (5.1), 8-hydroxy-2(di-n-propylamino)tetralin (5.0), 5-CT (4.7) and 5-methoxytryptamine (4.3). 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane, flesinoxan and RU 24969 elicited either only small contractions or none at all. 4. The contractile effect of 5-HT was unaffected by MDL 72222 (10(-6) M) and metergoline (10(-8) and 10(-7) M), was weakly antagonized by ketanserin and phentolamine (pKB: 6.6 and 6.8, respectively), but was effectively antagonized by methiothepin (pKB: 8.6). Responses to 5-CT and sumatriptan were affected by ketanserin, phentolamine and methiothepin similarly to 5-HT-induced responses. 5. Ketanserin was ineffective against noradrenaline-induced contractions, which were antagonized by phentolamine with a pKB of 7.3.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1667289

  3. Effects of calcium entry blocking agents on 5-hydroxytryptamine- and noradrenaline-induced contractions of rat isolated jugular vein and aorta.

    PubMed

    Gouw, M A; Wilffert, B; van Zwieten, P A

    1989-05-01

    We calculated the contribution of the intracellular releasable calcium pool to the contractile responses induced by 5-hydroxytryptamine (5-HT) and noradrenaline (NA) by constructing time-response curves to the agonists in Ca2+-deficient medium in the isolated rat jugular vein and aorta. Biexponential curves were obtained compatible with a two compartment model. In the aorta the intracellular calcium pools are likely to be different for both 5-HT and NA. Moreover, we investigated the effect of maximally effective concentrations of calcium entry blocking agents (CEB's) on K+, 5-HT- and NA-induced contractions in Ca2+-containing medium. Only a moderate inhibiting effect of nifedipine, diltiazem, flunarizine and gallopamil on 5-HT- and NA-induced Ca2+ influx could be observed; in contrast, K+-induced Ca2+ influx could be antagonized completely. The calculated contribution of intracellular Ca2+ to 5-HT- and NA-induced contractions, obtained from the experiments in Ca2+-"free" medium was much lower than that obtained after pretreatment with CEB's, leading to the conclusion that after CEB-pretreatment a Ca2+ influx component persists. This hypothesis was supported by the observation that contractions in Ca2+-"free" medium consist of a monophasic, fast response only, whereas after CEB-pretreatment a response similar to the control, including a slow, sustained component, was obtained. The Ca2+ influx component not affected by maximally effective concentrations of CEB's seems to represent an inflow of extracellular Ca2+ directly into the cytosol and not into an intracellular calcium store. PMID:2505089

  4. Identification of 5-HT3A and 5-HT3B receptor subunits in human hippocampus.

    PubMed

    Brady, Catherine A; Dover, Terri J; Massoura, Andrew N; Princivalle, Alesandra P; Hope, Anthony G; Barnes, Nicholas M

    2007-04-01

    The pentameric 5-HT(3) receptor complex is a ligand-gated ion channel that mediates fast synaptic transmission in the brain. Expression of two subunits (5-HT(3A) and 5-HT(3B) subunits) gives rise to at least two receptor isoforms (homomeric 5-HT(3A) and heteromeric 5-HT(3A/3B) receptors), which differ in their biophysical characteristics, although expression of these proteins has not been investigated in human brain. The expression of h5-HT(3A) and 5-HT(3B) subunits in the human hippocampus was investigated using selective polyclonal antibodies (SDS-PAGE/Western blotting, immunohistochemistry), with expression of each subunit verified by PCR detection of subunit transcripts. 5-HT(3A) and 5-HT(3B) subunit immunoreactivity was identified within the human hippocampus. The cellular pattern of expression for each subunit was similar, with predominant immunoreactivity associated with pyramidal neurones in CA fields 2 and 3, and also the relatively large neurones within the hilus (CA4 field). Transcripts for each subunit were also identified in human hippocampal tissue. These findings indicate that human hippocampal neurones are capable of forming at least two, functionally different, isoforms of the 5-HT(3) receptor. Furthermore the expression pattern of 5-HT(3A) and 5-HT(3B) subunits in human hippocampus appears to differ with the rodent counterpart, which may underlie the differences in some of the behavioural effects of 5-HT(3) receptor antagonists between these species. PMID:17327132

  5. Type 1 diabetes-induced hyper-responsiveness to 5-hydroxytryptamine in rat pulmonary arteries via oxidative stress and induction of cyclooxygenase-2.

    PubMed

    Lopez-Lopez, Jose G; Moral-Sanz, Javier; Frazziano, Giovanna; Gomez-Villalobos, Maria J; Moreno, Laura; Menendez, Carmen; Flores-Hernandez, Jorge; Lorente, Jose A; Cogolludo, Angel; Perez-Vizcaino, Francisco

    2011-07-01

    Recent epidemiological data suggest that diabetes is a risk factor for pulmonary arterial hypertension. The aim of the present study was to analyze the link between type 1 diabetes and pulmonary arterial dysfunction in rats. Male Sprague-Dawley rats were randomly divided into a control group (saline) and a diabetic group (70 mg/kg streptozotocin). After 6 weeks, diabetic animals showed a down-regulation of the lung bone morphogenetic protein receptor type 2, up-regulation of 5-hydroxytryptamine (5-HT) 2A receptors and cyclooxygenase-2 (COX-2) proteins as measured by Western blot analysis, and increased contractile responses to 5-HT in isolated intrapulmonary arteries. The hyper-responsiveness to 5-HT was endothelium-independent and unaffected by inhibition of nitric-oxide synthase but prevented by indomethacin, the selective COX-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398), superoxide dismutase, and the NADPH oxidase inhibitor apocynin or chronic treatment with insulin. However, diabetic rats at 6 weeks did not develop elevated right ventricular pressure or pulmonary artery muscularization, whereas a longer exposure (4 months) to diabetes induced a modest, but significant, increase in right ventricular systolic pressure. In conclusion, type 1 diabetes mellitus in rats induces a number of changes in lung protein expression and pulmonary vascular reactivity characteristic of clinical and experimental pulmonary arterial hypertension but insufficient to elevate pulmonary pressure. Our results further strengthen the link between diabetes and pulmonary arterial hypertension. PMID:21521772

  6. Effects of nitric oxide in 5-hydroxytryptamine-, cholera toxin-, enterotoxigenic Escherichia coli- and Salmonella Typhimurium-induced secretion in the porcine small intestine.

    PubMed

    Grøndahl, Marie Louise; Unmack, Martin Andreas; Ragnarsdóttir, Helga Berglind; Hansen, Mark Berner; Olsen, John Elmerdahl; Skadhauge, Erik

    2005-08-01

    The effects of nitric oxide (NO) in the secretory response to the endogenous secretagogue 5-hydroxytryptamine (5-HT), the enterotoxins heat-labile enterotoxigenic Escherichia coli (ETEC) toxin (LT) and cholera toxin (CT), and various cultures of ETEC and Salmonella serotype Typhimurium in the porcine small intestine (Sus scrofa) were investigated. In anaesthetized pigs, jejunal tied-off loops were instilled with 5-HT, LT, CT, various cultures of ETEC or S. Typhimurium. Pigs were given intravenously isotonic saline or isotonic saline containing the NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME). L-NAME significantly induced an increased fluid accumulation in loops induced by 5-HT, ETEC and stn-mutated S. Typhimurium. Fluid accumulation in loops instilled with wild-type S. Typhimurium was increased by L-NAME, although not significantly, while there was no effect on fluid accumulation induced by an invH-mutated isogenic strain. No significant effect of L-NAME was observed on the fluid accumulation induced by the purified enterotoxins LT and CT. The results also demonstrated a relatively large difference in the ability to induce fluid accumulation between the bacteria strains. Diastolic, systolic and mean blood pressures were significantly increased and the body temperature was significantly decreased in groups of pigs treated with L-NAME. In conclusion, the results suggest that NO has a proabsorptive effect in the intact porcine jejunum and is involved in the systemic vascular tone. PMID:16098780

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2014-12-01

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

  9. Postnatal Day 2 to 11 Constitutes a 5-HT-Sensitive Period Impacting Adult mPFC Function

    PubMed Central

    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.; Ansorge, Mark S.

    2014-01-01

    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

  10. Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress.

    PubMed

    Sachs, Benjamin D; Ni, Jason R; Caron, Marc G

    2015-02-24

    Brain serotonin (5-HT) deficiency and exposure to psychosocial stress have both been implicated in the etiology of depression and anxiety disorders, but whether 5-HT deficiency influences susceptibility to depression- and anxiety-like phenotypes induced by psychosocial stress has not been formally established. Most clinically effective antidepressants increase the extracellular levels of 5-HT, and thus it has been hypothesized that antidepressant responses result from the reversal of endogenous 5-HT deficiency, but this hypothesis remains highly controversial. Here we evaluated the impact of brain 5-HT deficiency on stress susceptibility and antidepressant-like responses using tryptophan hydroxylase 2 knockin (Tph2KI) mice, which display 60-80% reductions in brain 5-HT. Our results demonstrate that 5-HT deficiency leads to increased susceptibility to social defeat stress (SDS), a model of psychosocial stress, and prevents the fluoxetine (FLX)-induced reversal of SDS-induced social avoidance, suggesting that 5-HT deficiency may impair antidepressant responses. In light of recent clinical and preclinical studies highlighting the potential of inhibiting the lateral habenula (LHb) to achieve antidepressant and antidepressant-like responses, we also examined whether LHb inhibition could achieve antidepressant-like responses in FLX-insensitive Tph2KI mice subjected to SDS. Our data reveal that using designer receptors exclusively activated by designer drugs (DREADDs) to inhibit LHb activity leads to reduced SDS-induced social avoidance behavior in both WT and Tph2KI mice. This observation provides additional preclinical evidence that inhibiting the LHb might represent a promising alternative therapeutic approach under conditions in which selective 5-HT reuptake inhibitors are ineffective. PMID:25675490

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

    PubMed

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

    2015-01-01

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

  12. Blockade of 5-hydroxytryptamine(3) receptors prevents cisplatin-induced but not motion- or xylazine-induced emesis in the cat

    NASA Technical Reports Server (NTRS)

    Lucot, James B.

    1989-01-01

    The effects of the 5-hydroxytryptamine(3) (5-HT-3) antagonists ICS 205-930 and MDL 72222 on the emesis induced by motion or by emetic doses of xylazine (0.66 mg/kg administered SC) or cisplatin (7.5 mg/kg infused over a period of 4-5 min) were investigated in cats. It was found that neither the low (0.1 mg/kg) or the high (1.0 mg.kg) doses of ICS 205-930 or MDL 72222 prevented emesis elicited by screening motion challenges or xylazine. On the other hand, treatment cats by 1.0 mg/kg of ICS 205-930 was effective against cisplatin-induced motion sickness, in agreement with earlier results obtained on other mammals.

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

    PubMed

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

    2007-01-01

    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

  14. Human 5HT4 and 5HT7 Receptor Splice Variants: Are they Important?

    PubMed Central

    Coupar, Ian M; Desmond, Paul V; Irving, Helen R

    2007-01-01

    G-protein-coupled receptors (GPCRs), which are encoded by >300 genes in the human genome, are by far the largest class of targets for modern drugs. These macromolecules display inherent adaptability of function, which is partly due to the production of different forms of the receptor protein. These are commonly called ‘isoforms’ or ‘splice variants’ denoting the molecular process of their production/assembly. Not all GPCRs are expressed as splice variants, but certain subclasses of 5HT receptors are for example, the 5HT4 and 5HT7 receptors. There are at least 11 human 5HT4 and three h5HT7 receptor splice variants. This review describestheir discoveries, nomenclature and structures. The discovery that particular splice variants are tissue specific (or prominent) has highlighted their potential as future drug targets. In particular, this review examines the functional relevance of different 5HT4 and 5HT7 receptor splice variants. Examples are given to illustrate that splice variants have differential modulatory influences on signalling processes. Differences in agonist potency and efficacies and also differences in desensitisation rates to 5HT occur with both 5HT4 and 5HT7 receptor splice variants. The known and candidate signalling systems that allow for splice variant specific responses include GPCR interacting proteins (GIPs) and GPCR receptor kinases (GRKs) which are examined.Finally, the relevance of 5HT receptor splice variants to clinical medicine and to the pharmaceutical industry is discussed. PMID:19305739

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

    PubMed Central

    Kaida, Kei; Yamashita, Hiromi; Toda, Kazuo

    2014-01-01

    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

  16. Further characterization, by use of tryptamine and benzamide derivatives, of the putative 5-HT4 receptor mediating tachycardia in the pig.

    PubMed

    Villalón, C M; den Boer, M O; Heiligers, J P; Saxena, P R

    1991-01-01

    1. It has recently been shown that the tachycardic response to 5-hydroxytryptamine (5-HT) in the anaesthetized pig, being mimicked by 5-methoxytryptamine and renzapride and blocked by high doses of ICS 205-930, is mediated by the putative 5-HT4 receptor. In the present investigation we have further characterized this receptor. 2. Intravenous bolus injections of the tryptamine derivatives, 5-HT (3, 10 and 30 micrograms kg-1), 5-methoxytryptamine (3, 10 and 30 micrograms kg-1) and alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT; 3, 10, 30 and 100 micrograms kg-1), resulted in dose-dependent increases in heart rate of, respectively, 25 +/- 2, 48 +/- 3 and 68 +/- 3 beats min-1 (5-HT; n = 35); 15 +/- 1, 32 +/- 2 and 57 +/- 3 beats min-1 (5-methoxytryptamine; n = 30); 6 +/- 4, 18 +/- 6, 34 +/- 6 and 64 +/- 11 beats min-1 (alpha-methyl-5-HT; n = 3). 3. The increases in heart rate following i.v. administration of certain substituted benzamide derivatives were genereally less marked and not dose-dependent: 1 + 5, 11 + 3 and 10 + 5 beats min1- after 300, 1000 and 3000,jgkg' of metoclopramide, respectively, (n = 8); 21 + 4, 19 + 2 and 2 + 2 beats min'- after 100, 300 and lOOOIpgkg1- of cisapride, respectively, (n = 5); 6 + 2, 14 + 2, 37 + 6, 43 + 8 and 34 + 10 beats min- after 10, 30, 100, 300 and lOOOjigkg' of zacopride, respectively, (n = 6); and 1 + 1, 2 + 1 and 5 + 2 beats min- 1 after 300, 1000 and 3000 pg kg' of dazopride, respectively, (n = 4). These drugs behaved as partial agonists, antagonizing the responses to 5-HT and 5-methoxytryptamine dosedependently. 4. The 5-HT3 receptor agonist 1-phenyl-biguanide (100, 300 and lOOOpgkg-1) induced only slight increases in heart rate of 1 + 1, 6 + 2 and 11 + 1 beats min 1, respectively, (n = 3). These effects were not antagonized by the selective 5-HT3 receptor antagonist granisetron (3mgkg-1). In addition, 1-phenylbiguanide (1000,pg kg- 1) did not modify the tachycardia induced by either 5-HT- or 5- methoxytryptamine. 5. High doses (3mg kg- 1) of ICS 205-930, a 5-HT3 receptor antagonist with an indole group and devoid of effects on porcine heart rate per se, antagonized the stimulatory effects of 5-HT, 5-methoxytryptamine, alpha-Me-5-HT, metoclopramide, cisapride, zacopride, dazopride and 1-phenyl-biguanide. However, the 5-HT2 receptor antagonist ketanserin (0.5 mg kg- 1), the 5-HT3 receptor antagonists granisetron (3mg kg- 1) and MDL 72222 (3mg kg- ') and the dopamine D2 receptor antagonist domperidone (3 mg kg- 1) had no antagonist activity. 6. The above results support our contention that 5-HT, 5-methoxytryptamine, alpha-Me-5-HT and the substituted benzamide derivatives increase porcine heart rate by a direct action on the cardiac pacemaker, via the activation of a putative 5-HT4 receptor. The pharmacological profile of this novel 5-HT receptor is similar (neurones from mouse brain colliculi and human heart) or, perhaps, even identical (guinea-pig cholinergic neurones) to other putative 5-HT4 receptors. PMID:2043916

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

    PubMed Central

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

    2014-01-01

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

  18. Characterization of the 5-hydroxytryptamine receptors mediating contraction in the intestine of Suncus murinus

    PubMed Central

    Javid, Farideh A; Naylor, Robert J

    1999-01-01

    The effects of 5-HT and 5-HT agonists to induce contraction and the 5-HT receptors mediating these effects were investigated in the proximal, central and terminal intestinal segments of Suncus murinus.The contraction curves to 5-HT (3?nM–30??M) were shifted to the right by methysergide (1??M) and ritanserin (0.1??M), without affecting the maximum response.In the central and terminal segments (but not the proximal segments) ondansetron (1??M) and atropine (1??M) significantly attenuated the contractions to higher concentrations of 5-HT. The selective 5-HT4 receptor antagonist SB204070 (1?nM), failed to modify 5-HT induced contractions in any segment examined.5-carboxamidotryptamine, ?-methyl-5-HT and 5-methoxytryptamine (0.003–3.0??M) induced contractions but unlike 5-HT, higher concentrations of these three agents failed to increase the response or were associated with a decrease in response. 2-methyl-5-HT (0.03–1.0??M) was ten times less potent than 5-HT to induce contraction but achieved the same maximum response.The contractions induced by the lower concentrations of 2-methyl-5-HT (0.03–1.0??M) in all segments were markedly reduced or abolished by methysergide (1.0??M); the response to the higher concentrations of 2-methyl-5-HT (3–30.0??M) were markedly reduced by atropine (1.0??M) and ondansetron (1.0??M).In all segments examined, tetrodotoxin (1??M) significantly reduced the 5-HT-induced contraction.It is concluded that the 5-HT-induced contraction was mediated via 5-HT2 (ritanserin sensitive) receptors in all regions of the intestine, with 5-HT3 (ondansetron sensitive) receptors mediating an additional major component in the central and terminal regions. PMID:10482918

  19. The guinea-pig distal colon--a sensitive preparation for the investigation of 5-HT4 receptor-mediated contractions.

    PubMed Central

    Wardle, K. A.; Sanger, G. J.

    1993-01-01

    1. Experiments were designed to characterize pharmacologically the contractile responses to 5-hydroxytryptamine (5-HT) in the guinea-pig isolated distal colon longitudinal muscle-myenteric plexus preparation (LMMP). 2. In the presence of methiothepin (100 nM) and granisetron (1 microM), 5-HT (10 pM-10 nM) produced concentration-dependent contractile responses of the guinea-pig distal colon LMMP, with a pEC50 of 9.2 +/- 0.08. 3. Responses to 5-HT were mimicked by a series of tryptamine analogues, with the following rank order of potency; 5-HT > 5-MeOT >> 5-CT > tryptamine > 2-Me-5-HT. All were found to be full agonists. 4. Responses to 5-HT were also mimicked by a series of substituted benzamide analogues. Their rank order of potency was 5-HT > renzapride > cisapride > (S)-zacopride > (R)-zacopride > metoclopramide. All were full agonists relative to 5-HT. 5. The benzimidazolone derivatives, BIMU 1 and BIMU 8 were approximately equipotent partial agonists (intrinsic activities of 0.8 +/- 0.07 and 0.5 +/- 0.08 respectively) in the guinea-pig distal colon. 6. Tropisetron produced a rightward displacement of the 5-HT concentration-effect curve, yielding an apparent pA2 of 6.4 +/- 0.1. The slope of the Schild plot (1.3 +/- 0.1) was significantly greater than unity. 7. SDZ 205,557 produced a concentration-dependent shift to the right of the 5-HT concentration-response curve, yielding an estimated pA2 of 7.8 +/- 0.1 and a slope which did not significantly deviate from unity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8306106

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

    PubMed

    Haberzettl, Robert; Fink, Heidrun; Bert, Bettina

    2015-01-15

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

  1. Synergistic effect of 5-HT1A and ?1 receptor activation on prefrontal dopaminergic transmission under circulating steroid deficiency.

    PubMed

    Hiramatsu, Naoki; Ago, Yukio; Hasebe, Shigeru; Nishimura, Akira; Mori, Kazuya; Takuma, Kazuhiro; Matsuda, Toshio

    2013-12-01

    Serotonin (5-HT)1A and ?1 receptors have been implicated in psychiatric disorders. We previously found that combined 5-HT reuptake inhibition and ?1 receptor activation has a synergistic effect on prefrontal dopaminergic transmission in adrenalectomized/castrated mice lacking circulating steroid hormones. In the present study, we examined the mechanisms underlying this neurochemical synergism. Systemic administration of fluvoxamine, a selective 5-HT reuptake inhibitor with agonistic activity towards the ?1 receptor, increased prefrontal dopamine (DA) levels, and adrenalectomy/castration potentiated this fluvoxamine-induced increase in DA. This enhancement of DA release was blocked by WAY100635 (a 5-HT1A receptor antagonist), but not by ritanserin (a 5-HT2 receptor antagonist), azasetron (a 5-HT3 receptor antagonist) or SB269970 (a 5-HT7 receptor antagonist). Individually, osemozotan (a 5-HT1A receptor agonist) and (+)-SKF-10,047 (a ?1 receptor agonist) did not alter prefrontal monoamine levels in adrenalectomized/castrated and sham-operated mice differentially. In contrast, co-administration of these drugs increased prefrontal DA levels to a greater extent in adrenalectomized/castrated mice than in sham-operated animals. Furthermore, co-administration of osemozotan and (+)-SKF-10,047 increased expression of the neuronal activity marker c-Fos in the ventral tegmental area of adrenalectomized/castrated mice, but not in sham-operated animals. These findings suggest that combined activation of 5-HT1A and ?1 receptors has a synergistic effect on prefrontal dopaminergic transmission under circulating steroid deficiency, and that this interaction may play an important role in the regulation of the prefrontal DA system. PMID:23851260

  2. Effects of 5HT uptake inhibitors on the pressor response to 5HT in the pithed rat. The significance of the 5HT blocking property.

    PubMed

    Petersen, E N; Olsson, S O; Squires, R F

    1977-06-01

    A study was made of the effects of several serotonin (5HT) uptake inhibitors on 5HT-induced pressor responses in pithed rats, 5HT uptake into rat brain synaptosomes and 5HT-induced contractions of rat ileum in vitro. All drugs except desimipramine were potent uptake inhibitors (IC50 less than 10(-7) M), Femoxetine, chlorimipramine, imipramine and desimipramine all inhibited 5HY-induced contractions of the rat ileum in vitro and the pressor response to 5HT in vivo. FG 7051, FG 7052 and dexchlorpheniramine were weak 5HT antagonists on the rat ileum but potentiated the pressor responses to 5HT; the most potent uptake inhibitor, FG 7051, was the strongest potentiator. These results suggest that uptake inhibition is important for this potentiation. It is concluded that 5HT uptake inhibitors with potent 5HT receptor blocking properties antagonize the pressor response to 5HT and mask the potentiation due to uptake inhibition. PMID:872876

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

    Microsoft Academic Search

    SuJean Choi; Elizabeth Jonak; John D. Fernstrom

    2004-01-01

    Although the selective toxicity of 5,7-dihydroxytryptamine (5,7-DHT) is thought to depend on the drug's transport into serotonin (5HT) neurons via the 5HT transporter, few studies have critically examined this postulation. We therefore evaluated if 5,7-DHT-induced reductions in 5HT concentrations and synthesis rate in rat brain are blocked by pretreatment with 5HT-selective reuptake inhibitors. Rats pretreated with desipramine (DMI) (to prevent

  4. The effect of adrenalectomy on 5-hydroxytryptamine and corticosteroid receptor subtype messenger RNA expression in rat hippocampus.

    PubMed

    Holmes, M C; Yau, J L; French, K L; Seckl, J R

    1995-01-01

    Both central serotonergic dysfunction and glucocorticoid hypersecretion have been separately implicated in the aetiology of affective disorders. The hippocampus highly expresses receptors for 5-hydroxytryptamine and glucocorticoids, and adrenalectomy alters the responsivity of hippocampal neurons to 5-hydroxytryptamine. The hippocampus thus represents a prime locus for interactions between the two systems. In this study we examined the effects of glucocorticoid manipulations on neuronal expression of messenger RNA encoding corticosteroid receptor and 5-hydroxytryptamine receptor subtypes in the hippocampus and 5-hydroxytryptamine1A messenger RNA expression in the dorsal raphe, in the rat. Interestingly, there was no effect of adrenalectomy on 5-hydroxytryptamine1A or 5-hydroxytryptamine2A receptor messenger RNA expression in the dorsal or ventral hippocampus at any time point measured. Furthermore, no changes in 5-hydroxytryptamine1A receptor gene expression were seen in the dorsal raphe (encoding autoreceptors) after adrenalectomy. However, 5-hydroxytryptamine2C (5-hydroxytryptamine1C) receptor messenger RNA expression was increased specifically in posterior CA1 and CA3 neurons following adrenalectomy, an effect that was reversed by glucocorticoid replacement. Following adrenalectomy, glucocorticoid and mineralocorticoid receptor messenger RNA expression increased in the dentate gyrus, CA1 and CA3 subfields of the hippocampus. These increases were apparent 6 h after adrenalectomy, were maintained at two days, but 14 days after adrenalectomy hippocampal glucocorticoid receptor and mineralocorticoid receptor gene expression had returned to control levels. These effects of adrenalectomy were abolished by dexamethasone, but not aldosterone administration, suggesting mediation by autoregulatory glucocorticoid receptors. Our results show that adrenalectomy only transiently increases corticosteroid receptor gene expression in the hippocampus, and selectively increases hippocampal 5-hydroxytryptamine2C receptor messenger RNA expression. The resulting change in 5-hydroxytryptamine2C receptor-mediated responses may produce the alterations in hippocampal neuronal activity in response to 5-hydroxytryptamine observed after adrenalectomy. PMID:7700524

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

    PubMed

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

    2006-09-01

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

  6. Effect of Mimosa pudica (Linn.) extract on anxiety behaviour and GABAergic regulation of 5-HT neuronal activity in the mouse.

    PubMed

    Ayissi Mbomo, Rigobert; Gartside, Sasha; Ngo Bum, Elizabeth; Njikam, Njifutie; Okello, Ed; McQuade, Richard

    2012-04-01

    Mimosa pudica (Linn.) (M. pudica L.) is a plant used in some countries to treat anxiety and depression. In the present study we investigated the effects of an aqueous extract of M. pudica L. on mouse anxiety-like behaviour using the elevated T maze, and on regulation of dorsal raphe nucleus (DRN) 5-hydroxytryptamine (5-HT) neuronal activity using an in-vitro mouse brain slice preparation. Acute treatment with M. pudica L. extract had an anxiolytic effect on behaviour in the elevated T maze, specifically on inhibitory avoidance behaviour. Acute application of the extract alone had no effect on the activity of DRN 5-HT neurones. However, when co-applied with the GABA(A) receptor agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), the extract enhanced the inhibitory effect of the THIP on DRN 5-HT neurones. These observed effects of M. pudica L. on both behaviour and GABA modulation of 5-HT neuronal activity are similar to the effects of diazepam, the established anxiolytic and positive modulator of the GABA(A) receptor. This study suggests that the aqueous extract of M. pudica L. contains a positive modulator of GABA(A) receptor function and provides impetus for further investigation of the neuropharmacologically active constituents of the extract. PMID:21427203

  7. Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study

    PubMed Central

    2012-01-01

    Background 1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions. Methods Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics’ (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6?months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. Results Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p?5-HT3 RA group (p?5-HT3 RAs. Further studies on impact of step therapy policy are warranted in order to minimize the clinical and economic burden of CINV. PMID:22823909

  8. Characterization of a ( sub 3 H)-5-hydroxtyryptamine binding site in rabbit caudate nucleus that differs from the 5-HT sub 1A , 5-HT sub 1B , 5-HT sub 1C and 5-HT sub 1D subtypes

    SciTech Connect

    Xiong, Wencheng; Nelson, D.L. (Univ. of Arizona, Tucson (USA))

    1989-01-01

    ({sup 3}H)5-HT binding sites were analyzed in membranes prepared from the rabbit caudate nucleus (CN). ({sup 3}H)5-HT labeled both 5-HT{sub 1A} and 5-HT{sub 1C} recognition sites, defined by nanomolar affinity for 8-OH-DPAT and mesulergine respectively; however, these represented only a fraction of total specific ({sup 3}H)5-HT binding. Saturation experiments of ({sup 3}H)5-HT binding in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine to block 5-HT{sub 1A} and 5-HT{sub 1C} sites revealed that non-5-HT{sub 1A}/non-5-HT{sub 1C} sites represented about 60% of the total 5-HT{sub 1} sites and that they exhibited saturable, high affinity, and homogeneous binding. The pharmacological profile of the non-5-HT{sub 1A}/non-5-HT{sub 1C} sites (designated 5-HT{sub 1R}) also differed from that of 5-HT{sub 1B} and 5-HT{sub 2} sites, but was similar to that of the 5-HT{sub 1D} site. However, significant differences existed between the 5-HT{sub 1D} and 5-HT{sub 1B} sites for their K{sub i} values for spiperone, spirilene, metergoline, and methiothepin. The study of modulatory agents also showed differences between the 5-HT{sub 1R} and 5-HT{sub 1D} sites. In addition, calcium enhanced the effects of GTP on the 5-HT{sub 1R} sites, whereas calcium inhibited the GTP effect on the 5-HT{sub 1D} sites.

  9. Neonatal Citalopram Treatment Inhibits the 5-HT Depleting Effects of MDMA Exposure in Rats

    PubMed Central

    2011-01-01

    Neonatal exposure to 3,4-methylenedioxymethamphetamine (MDMA) produces long-term learning and memory deficits and increased anxiety-like behavior. The mechanism underlying these behavioral changes is unknown, but we hypothesized that it involves perturbations to the serotonergic system as this is the principal mode of action of MDMA in the adult brain. During development, 5-HT is a neurotrophic factor involved in neurogenesis, synaptogenesis, migration, and target region specification. We have previously shown that MDMA exposure (4 × 10 mg/kg/day) from postnatal day (P)11–20 (analogous to human third trimester exposure) induces ?50% decreases in hippocampal 5-HT throughout treatment. To determine whether MDMA-induced 5-HT changes are determinative, we tested if these changes could be prevented by treatment with a selective serotonin reuptake inhibitor (citalopram: CIT). In a series of experiments, we evaluated the effects of different doses and dose regimens of CIT on MDMA-induced 5-HT depletions in three brain regions (hippocampus, entorhinal cortex, and neostriatum) at three time points (P12, P16, P21) during the treatment interval (P11–20) known to induce behavioral alterations when animals are tested as adults. We found that 5 mg/kg CIT administered twice daily significantly attenuated MDMA-induced 5-HT depletions in all three regions at all three ages but that the protection was not complete at all ages. Striatal dopamine was unaffected. We also found increases in hippocampal NGF and plasma corticosterone following MDMA treatment on P16 and P21, respectively. No changes in BDNF were observed. CIT treatment may be a useful means of interfering with MDMA-induced 5-HT reductions and thus permit tests of the hypothesis that the drug’s cognitive and/or anxiety effects are mediated through early disruptions to 5-HT dependent developmental processes. PMID:22582138

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

    PubMed Central

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

    2014-01-01

    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

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

    PubMed

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

    2013-06-01

    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 this 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: (i) (±)-3,4-methylenedioxymethamphetamine (MDMA); (ii) a combination of the monoamine oxidase inhibitor clorgyline with the 5HT precursor 5-hydroxytryptophan; (iii) 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

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

    PubMed Central

    ISLAM, Md. Zahorul; WATANABE, Yutaka; NGUYEN, Ha Thi Thanh; YAMAZAKI-HIMENO, Emi; OBI, Takeshi; SHIRAISHI, Mitsuya; MIYAMOTO, Atsushi

    2014-01-01

    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

  13. [Ondansetron: a specific 5-HT3 serotonin receptor inhibitor, a new antiemetic in oncology].

    PubMed

    d'Allens, H; Aubert, B; Bons, J; Pappo, M

    1991-01-01

    Serotonin (5-Hydroxytryptamine) seems to play a dominant role in triggering vomiting induced by cytotoxic agents through the stimulation of 5-HT3 receptors. They have been observed in the GI tract as well as in the brain (area postrema). Ondansetron is a specific antagonist of 5-HT3 serotonin receptors. Its anti-emetic activity is very powerful in the ferret. The availability of an injectable or oral form of this product allows the overall treatment of acute and delayed emesis and its administration is in accordance with different schedules: single IV injection or a continuous 24 hour infusion or repeated IV injection followed by oral treatment. The pharmacokinetics of the drug are as follows: absorption begins about 30 minutes after the administration per os, its biodisponibility is about 60%, its clearance: 20 ml/minute and its elimination half life about 3 hours. Different double blind studies, carried out in parallel groups or in cross over, demonstrated the superiority of ondansetron over metoclopramide in the control of nausea and vomiting, whether or not the chemotherapy contained cisplatin; a more recent study shows also that ondansetron was superior to alizapride and methylprednisolone in combination. Side effects of ondansetron do not include extrapyramidal symptoms but only headaches and constipation. The use of ondansetron improves the well-being of patients receiving chemotherapy and increases protocol compliance. PMID:1838490

  14. A 5-HT3 receptor antagonist potentiates the behavioral, neurochemical and electrophysiological actions of an SSRI antidepressant.

    PubMed

    Bétry, C; Overstreet, D; Haddjeri, N; Pehrson, A L; Bundgaard, C; Sanchez, C; Mørk, A

    2015-04-01

    More effective treatments for major depression are needed. We studied if the selective 5-HT3 receptor antagonist ondansetron can potentiate the antidepressant potential of the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine using behavioral, neurochemical and electrophysiological methods. Flinders Sensitive Line (FSL) rats, treated with ondansetron, and/or a sub-effective dose of paroxetine, were assessed in the forced swim test. The effects of an acute intravenous administration of each compound alone and in combination were evaluated with respect to 5-HT neuronal firing rate in the dorsal raphe nucleus (DRN). Effects of s.c. administration of the compounds alone and in combination on extracellular levels of 5-HT were assessed in the ventral hippocampus of freely moving rats by microdialysis. The results showed that ondansetron enhanced the antidepressant activity of paroxetine in the forced swim test. It partially prevented the suppressant effect of paroxetine on DRN 5-HT neuronal firing and enhanced the paroxetine-induced increase of hippocampal extracellular 5-HT release. These findings indicate that 5-HT3 receptor blockade potentiates the antidepressant effects of SSRIs. Since both paroxetine and ondansetron are used clinically, it might be possible to validate this augmentation strategy in depressed patients. PMID:25697477

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

    PubMed

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

    2004-05-01

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

  16. Inhibition of excitatory non-adrenergic non-cholinergic bronchoconstriction in guinea-pig airways in vitro by activation of an atypical 5-HT receptor.

    PubMed Central

    Ward, J. K.; Fox, A. J.; Barnes, P. J.; Belvisi, M. G.

    1994-01-01

    1. The effect of 5-hydroxytryptamine (5-HT) was studied on excitatory neurally mediated non-adrenergic non-cholinergic (NANC) contractions evoked by electrical field stimulation (EFS) in guinea-pig isolated bronchi. 2. 5-HT (0.1-100 microM) produced a concentration-dependent inhibition of the excitatory NANC response with 50.9 +/- 5.0% (n = 5, P < 0.01) inhibition at 100 microM. This inhibition was not significantly affected by the 5-HT2 antagonist, ketanserin (1 microM) when inhibitions (+/- ketanserin) at each concentration of 5-HT were compared by unpaired t tests; however, this concentration appeared to produce a leftward shift (approximately 10 fold) of the 5-HT concentration-inhibition curve. Ketanserin (1 microM) was effective in blocking bronchoconstriction evoked by activation of 5-HT2A receptors on airway smooth muscle. In the presence of ketanserin (1 microM) 5-HT (100 microM) evoked an inhibition of 57.4 +/- 5.9% (n = 5, P < 0.01) with an EC50 of 0.57 microM. 3. Inhibition evoked by 5-HT (0.1-100 microM) was unaffected by the alpha-adrenoceptor antagonist phentolamine (1 microM), the beta 2-adrenoceptor antagonist, ICI 118551 (0.1 microM), the 5-HT1A/B antagonist, cyanopindolol (1 microM) or the 5-HT3/4 antagonist, ICS 205-930 (1 microM). 4. Methiothepin (0.1 microM) produced an insurmountable inhibition of the effect of 5-HT (0.1-100 microM), reducing the maximum inhibition produced by 5-HT (100 microM) to 30.2 +/- 5.0% (n = 5, P < 0.001) and suggesting a non-competitive antagonism. Methiothepin inhibited the effect of 5-HT (10 microM) in a concentration-dependent manner with an IC50 of 81 nM.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7518294

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

    PubMed Central

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

    1995-01-01

    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.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7647983

  18. Regulation of 5HT release from enterochromaffin cells

    Microsoft Academic Search

    K. Racké; A. Reimann; H. Schwörer; H. Kilbinger

    1995-01-01

    Large amounts of 5-HT are present in the mammalian intestine where the amine is concentrated in the enterochromaffin cells (ECs) of the mucosa. ECs have the enzymes to synthesize 5-HT, are endowed with a specific, imipramine-sensitive 5-HT uptake mechanism and can store 5-HT in specific secretory vesicles. ECs can secrete 5-HT in a calcium-dependent manner. In particular, calcium influx through

  19. Thyroxine Replacement Increases Central 5Hydroxytryptamine Activity and Reduces Depressive Symptoms in Hypothyroidism

    Microsoft Academic Search

    Anthony J. Cleare; Alan McGregor; Susan M. Chambers; Sheila Dawling; Veronica O’Keane

    1996-01-01

    Hypothyroidism is associated with both reduced central 5-HT function and an increased incidence of depression. This study tested the hypothesis that the reduced 5-HT function returns to normal with thyroxine replacement therapy. Seven hypothyroid patients were tested before and after adequate thyroxine replacement. Cortisol and prolactin responses to d-fenfluramine, a centrally acting 5-HT-releasing agent, were used as an index of

  20. Partial purification and characterization of the sodium-ion-coupled 5-hydroxytryptamine transporter of rat cerebral cortex.

    PubMed Central

    Graham, D; Esnaud, H; Langer, S Z

    1992-01-01

    A procedure for the extensive purification of the Na(+)-coupled 5-hydroxytryptamine transporter of rat cerebral cortex has been developed. The 5-hydroxytryptamine transporter was solubilized with the non-ionic detergent digitonin, and the detergent extracts were subjected to sequential affinity chromatography on a citalopram-based agarose support and wheat-germ-agglutinin-Sepharose. 5-Hydroxytryptamine transporters in the affinity-purified preparation were identified by using the selective 5-hydroxytryptamine-uptake inhibitor [3H]paroxetine, and were shown to display a similar pharmacological profile to those present in particulate preparations. An overall transporter purification of around 2000-fold was achieved with a 9% recovery. SDS/PAGE of affinity-chromatographed material starting from detergent extracts incubated in the presence or absence of 1 mM-citalopram indicated that a polypeptide of M(r) 73,000 corresponded to the 5-hydroxytryptamine-transporter protein. Images Fig. 3. PMID:1417739

  1. Effects of Experimental Hypothyroidism on 5HT1A, 5HT2A Receptors, 5HT Uptake Sites and Tryptophan Hydroxylase Activity in Mature Rat Brain

    Microsoft Academic Search

    Alexander Kulikov; Xavier Moreau; Régine Jeanningros

    1999-01-01

    The study was aimed at investigating the repercussions of deficiency in thyroid function with and without thyroid hormone (TH) replacement on the neurochemical entities which underly serotonin (5-HT) neutrotransmission, namely 5-HT1A, 5-HT2A receptors, 5-HT transporter and tryptophan hydroxylase (TPH) in the mature brain. Surgically thyroidectomized male Wistar rats received: (1) an iodine-free diet to produce severe hypothyroidism; (2) hormonal replacement

  2. Modular Design of Cys-loop Ligand-gated Ion Channels: Functional 5-HT3 and GABA ?1 Receptors Lacking the Large Cytoplasmic M3M4 Loop

    PubMed Central

    Jansen, Michaela; Bali, Moez; Akabas, Myles H.

    2008-01-01

    Cys-loop receptor neurotransmitter-gated ion channels are pentameric assemblies of subunits that contain three domains: extracellular, transmembrane, and intracellular. The extracellular domain forms the agonist binding site. The transmembrane domain forms the ion channel. The cytoplasmic domain is involved in trafficking, localization, and modulation by cytoplasmic second messenger systems but its role in channel assembly and function is poorly understood and little is known about its structure. The intracellular domain is formed by the large (>100 residues) loop between the ?-helical M3 and M4 transmembrane segments. Putative prokaryotic Cys-loop homologues lack a large M3M4 loop. We replaced the complete M3M4 loop (115 amino acids) in the 5-hydroxytryptamine type 3A (5-HT3A) subunit with a heptapeptide from the prokaryotic homologue from Gloeobacter violaceus. The macroscopic electrophysiological and pharmacological characteristics of the homomeric 5-HT3A-glvM3M4 receptors were comparable to 5-HT3A wild type. The channels remained cation-selective but the 5-HT3A-glvM3M4 single channel conductance was 43.5 pS as compared with the subpicosiemens wild-type conductance. Coexpression of hRIC-3, a protein that modulates expression of 5-HT3 and acetylcholine receptors, significantly attenuated 5-HT–induced currents with wild-type 5-HT3A but not 5-HT3A-glvM3M4 receptors. A similar deletion of the M3M4 loop in the anion-selective GABA-?1 receptor yielded functional, GABA-activated, anion-selective channels. These results imply that the M3M4 loop is not essential for receptor assembly and function and suggest that the cytoplasmic domain may fold as an independent module from the transmembrane and extracellular domains. PMID:18227272

  3. Effect of mefenorex on 5-HT release: studies in vitro on rat hypothalamic slices and in vivo by microdialysis.

    PubMed

    Orosco, M; Moret, C; Briley, M; Nicolaidis, S

    1995-04-01

    Mefenorex, used for 20 years as an anorexic drug, has not been studied so far with regard to its central mechanism of action, although its chemical structure suggests a serotonergic mechanism. In the present study, the effect of mefenorex on serotonin (5-HT) release was investigated both in vitro, on rat hypothalamic slices and in vivo, using microdialysis in the paraventricular (PVN)-ventromedian (VMH) hypothalamic area while mefenorex was applied locally by means of counterdialysis. In vitro, mefenorex increased the spontaneous release of 3H 5-HT from hypothalamic slices but not the electrically evoked release. This suggests a 5-HT releasing action of mefenorex not mediated through the terminal autoreceptor. The in vivo study confirmed the enhanced release and provided additional information. The delayed and modest increase of the 5-HT intracellular metabolite 5-HIAA may be indicative of an inhibition of reuptake. The dopaminergic system was also, but more modestly, activated by mefenorex. The increase in 5-HT release together with the inhibition of its reuptake may represent the main mechanism of action of mefenorex, and the secondary activation of the dopaminergic system may contribute in its anorexigenic effect at the level of the PVN-VMH area. PMID:7617691

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

    PubMed

    Kloda, Anna; Adams, David J

    2005-02-01

    The effect of 5-HT and related indolealkylamines on heteromeric recombinant NMDA receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp recording technique. In the absence of external Mg(2+) ions, 5-HT inhibited NMDA receptor-mediated currents in a concentration-dependent manner. The inhibitory effect of 5-HT was independent of the NR1a and NR2 subunit combination. The inhibition of glutamate-evoked currents by 5-HT was use- and voltage-dependent. The voltage sensitivity of inhibition for NR1a+NR2 subunit combinations by 5-HT was similar, exhibiting an e-fold change per approximately 20 mV, indicating that 5-HT binds to a site deep within the membrane electric field. The inhibition of the open NMDA receptor by external Mg(2+) and 5-HT was not additive, suggesting competition between Mg(2+) and 5-HT for a binding site in the NMDA receptor channel. The concentration-dependence curves for 5-HT and 5-methoxytryptamine (5-MeOT) inhibition of NMDA receptor-mediated currents are shifted to the right in the presence of external Mg(2+). The related indolealkylamines inhibited glutamate-evoked currents with the following order of inhibitory potency: 5-MeOT=5-methyltryptamine>tryptamine>7-methyltryptamine>5-HT>tryptophan=melatonin. Taken together, these data suggest that 5-HT and related compounds can attenuate glutamate-mediated excitatory synaptic responses and may provide a basis for drug treatment of excitoxic neurodegeneration. PMID:15655527

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

    PubMed Central

    Kloda, Anna; Adams, David J

    2005-01-01

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

  6. Prostacyclin biosynthesis and reduced 5-HT uptake after complement-induced endothelial injury in the dog isolated lung.

    PubMed Central

    Bult, H.; Heiremans, J. J.; Herman, A. G.; Malcorps, C. M.; Peeters, F. A.

    1988-01-01

    1. Pulmonary prostacyclin (PGI2) biosynthesis was evaluated in relation to endothelial integrity before and after complement activation in isolated plasma-perfused lung lobes of the dog. 2. The plasma was activated with zymosan (ZAP, n = 4), yeast cells (YAP, n = 4) or yeast with 3 microM indomethacin (Indo + YAP, n = 3). Immunoreactive 6-oxo-prostaglandin F1 alpha (i-6-oxo-PGF1 alpha) and thromboxane B2 (iTXB2) were measured to monitor PGI2 and TXA2 biosynthesis. 3. The kinetic parameters Km and Vmax of 5-hydroxytryptamine (5-HT) uptake were calculated on the basis of multiple indicator diffusion data to evaluate endothelial integrity. 4. YAP and ZAP induced a biphasic increase of the arterial perfusion pressure. The immediate pressure peak was partly mediated by TXA2 and the TXB2 was subsequently cleared by the lung. 5. The apparent Vmax of 5-HT uptake remained constant throughout the experiment. Thus, complement activation did not affect the number of endothelial 5-HT carrier sites available to the perfusate. 6. The apparent Km of 5-HT uptake was enhanced in 9 lungs exposed to activated plasma complement for 20 min. This decreased affinity for 5-HT probably reflects endothelial injury. It was transient as the apparent Km had returned to the baseline value after 60 min. 7. PGI2 clearance and biosynthesis were virtually absent in the control period. PGI2 formation increased drastically after infusion of ZAP or YAP and was proportional to the endothelial injury expressed as elevated Km or pulmonary oedema. Thus, PGI2 biosynthesis might be a marker of severe endothelial distress. PMID:3291998

  7. Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

    PubMed Central

    Bos, Rémi; Sadlaoud, Karina; Boulenguez, Pascale; Buttigieg, Dorothée; Liabeuf, Sylvie; Brocard, Cécile; Haase, Georg; Bras, Hélène; Vinay, Laurent

    2013-01-01

    In healthy adults, activation of ?-aminobutyric acid (GABA)A and glycine receptors inhibits neurons as a result of low intracellular chloride concentration ([Cl–]i), which is maintained by the potassium-chloride cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of several neurological disorders, including spasticity and chronic pain following spinal cord injury (SCI). Given the critical role of KCC2 in regulating the strength and robustness of inhibition, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance. We show that activation of 5-hydroxytryptamine (5-HT) type 2A receptors to serotonin hyperpolarizes the reversal potential of inhibitory postsynaptic potentials (IPSPs), EIPSP, in spinal motoneurons, increases the cell membrane expression of KCC2 and both restores endogenous inhibition and reduces spasticity after SCI in rats. Up-regulation of KCC2 function by targeting 5-HT2A receptors, therefore, has therapeutic potential in the treatment of neurological disorders involving altered chloride homeostasis. However, these receptors have been implicated in several psychiatric disorders, and their effects on pain processing are controversial, highlighting the need to further investigate the potential systemic effects of specific 5-HT2AR agonists, such as (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2). PMID:23248270

  8. Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link?

    PubMed Central

    2015-01-01

    5-Hydroxytryptamine 2A receptors (5-HT2A-Rs) are G-protein coupled receptors. In agreement with their location in the brain, they have been implicated not only in various central physiological functions including memory, sleep, nociception, eating and reward behaviors, but also in many neuropsychiatric disorders. Interestingly, a bidirectional link between depression and epilepsy is suspected since patients with depression and especially suicide attempters have an increased seizure risk, while a significant percentage of epileptic patients suffer from depression. Such epidemiological data led us to hypothesize that both pathologies may share common anatomical and neurobiological alteration of the 5-HT2A signaling. After a brief presentation of the pharmacological properties of the 5-HT2A-Rs, this review illustrates how these receptors may directly or indirectly control neuronal excitability in most networks involved in depression and epilepsy through interactions with the monoaminergic, GABAergic and glutamatergic neurotransmissions. It also synthetizes the preclinical and clinical evidence demonstrating the role of these receptors in antidepressant and antiepileptic responses. PMID:25852551

  9. Action of 5-hydroxytryptamine on intestinal ion transport in the rat.

    PubMed Central

    Hardcastle, J; Hardcastle, P T; Redfern, J S

    1981-01-01

    1. 5-HT increased the electrical activity of rat jejunum both in vivo and in vitro. The increased potential difference and short-circuit current resulted from a stimulation of electrogenic chloride secretion. NaCl absorption may also have been inhibited. 2. 5-HT did not alter cyclic AMP levels in isolated enterocytes. 3. The 5-HT response in vivo was unaffected by atropine, cyproheptadine, propranolol and hexamethonium. Phenoxybenzamine reduced the maximum response without affecting the dose required to produce a 50% maximum response. Methysergide, at a dose of 40 mg/kg, had a similar effect while a lower dose of 2 mg/kg produced no change. Mianserin competitively antagonized the response to 5-HT, a dose of 2 mg/kg producing a fourfold increase in the amount of 5-HT required to produce a 50% maximum response. 4. Acetylcholine and 5-HT seem to act independently in inducing intestinal secretion since atropine did not block the response to 5-HT and Mianserin did not alter the response to acetylcholine. 5. Experiments in which the intestinal villi or crypts were subjected to preferential damage suggested that 5-HT primarily produced its response at the crypt cell level. PMID:6275078

  10. Stimulation of 5HT2A receptors on astrocytes in primary culture opens voltage-independent Ca fn2 fn2 influx factor; CRAC, Ca 2-release-activated Ca 2 channel; DOCC, depletion-operated Ca 2 channel; DAG, diacylglycerol; DMSO, dimethyl sulphoxide; DMEM, Dulbecco’s modified Eagle’s medium; EGTA, ethylene glycol-bis ( ?-aminoethyl ether) N,N,N?N?tetraacetic acid; FPPO, 4-(4-fluorobenzoyl)-1-(4-phenylbutyl) piperidine oxalate; GFAP, glial fibrillary acidic protein; HHBSS, Hepes-buffered Hank’s balanced salt solution; 5HT, 5-hydroxytryptamine; IP 3, inositol 1,4,5-trisphosphate; IP 4, inositol (1,3,4,5)-tetraphosphate; PEST, penicillin\\\\streptomycin; PTX, pertussis toxin; PLC, phospholipase C; PI, polyphosphoinositides; PKC, protein kinase C; ROCC, receptor-operated Ca 2 channel; SMOCC, second-messenger-operated Ca 2 channel; VICC, voltage-independent Ca 2 channel; VOCC, voltage-operated Ca 2 channel; ?-CgTx, ?-conotoxin GVIA. channels

    Microsoft Academic Search

    Gull-Britt Hagberg; Fredrik Blomstrand; Michael Nilsson; Hadassah Tamir; Elisabeth Hansson

    1997-01-01

    Mechanisms underlying the 5-HT2A receptor induction of intracellular Ca2 mobilization and Ca2 influx in type I astroglial cells in primary culture from newborn rat cerebral cortex were evaluated. The 5-HT-evoked Ca2-transients, inhibited by the 5-HT2A antagonists ketanserin or 4-(4-fluorobenzoyl)-1-(4-phenylbutyl) piperidine oxalate, consisted of an initial peak caused by inositol 1,4,5-trisphosphate (IP3)-mediated Ca2 release from internal stores, and a second sustained

  11. Reversal of sibutramine-induced anorexia with a selective 5HT 2C receptor antagonist

    Microsoft Academic Search

    Suzanne Higgs; Alison J. Cooper; Nicholas M. Barnes

    2011-01-01

    Rationale  The monoamine reuptake inhibitor sibutramine reduces food intake but the receptor subtypes mediating the effects of sibutramine\\u000a on feeding remain to be clearly identified.\\u000a \\u000a \\u000a \\u000a \\u000a Objectives  The involvement of the 5-HT2C receptor subtype in the satiety-enhancing effects of sibutramine was investigated by examining the effects of co-administration\\u000a of sibutramine with the selective 5-HT2C receptor antagonist SB 242084\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Microstructural analyses of licking for

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

    Microsoft Academic Search

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

    1997-01-01

    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

  13. Differential staining of catecholamines, 5-hydroxytryptamine and related compounds in aldehyde-fixed tissues

    Microsoft Academic Search

    E. Solcia; R. Sampietro; C. Capella

    1969-01-01

    Factors influencing the fixation of biogenic amines by solutions of glutaraldehyde, formaldehyde, acrolein and glyoxal as well as the influences of these aldehydes on the histochemical reactivity of biogenic amines, have been extensively investigated. Selective stainings of 5-hydroxytryptamine, noradrenaline, dopamine and related substances in many aldehyde-fixed tissues have been achieved by systematically applying some “phenol” methods such as argentaffin, ferric-ferricyanide,

  14. Behavioural changes induced in conscious mice by intracerebroventricular injection of catecholamines, acetylcholine and 5-hydroxytryptamine.

    PubMed Central

    Herman, Z S

    1975-01-01

    1 A simple method of injecting soluble substances into the lateral ventricle of the brain of the conscious mouse is described. 2 The effect of various doses of noradrenaline, dopamine, acetylcholine, 5-hydroxytryptamine given into the right lateral brain ventricle were tested on locomotor and exploratory activities of mice. 3 Noradrenaline in a dose of 0.1 mug increased locomotor activity. This effect was prevented by phenoxybensamine but not by propranolol. 4 Higher doses of noradrenaline (1 or 10 mug) decreased locomotor and exploratory activities. Propranolol but not phenoxybenzamine abolished these effects. 5 Dopamine (0.1 or 1 mug) increased locomotor activity. The higher doses also induced tremor. 6 The highese dose of dopamine tested (10 mug) elicited stereotypical behaviour. 7 All the behavioural phenomena induced by 0.1 mug and 10 mug of dopamine were blocked by pimozide. 8 Acetylcholine (1 and 10 mug) and 5-hydroxytryptamine (1 mug) inhibited locomotor and exploratory activity. 9 The effects of 1 and 10 mug of acetylcholine were abolished by atropine (5 mg/kg i.p. Methysergide (5 mg/kg i.p.) had no influence on the effects of 5-hydroxytryptamine (1 mug). PMID:1203622

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

    PubMed Central

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

    1994-01-01

    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

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

    PubMed Central

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

    1995-01-01

    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

  17. Conservation of 5-HT1A receptor-mediated autoinhibition of serotonin (5-HT) neurons in mice with altered 5-HT homeostasis

    PubMed Central

    Araragi, Naozumi; Mlinar, Boris; Baccini, Gilda; Gutknecht, Lise; Lesch, Klaus-Peter; Corradetti, Renato

    2013-01-01

    Firing activity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is controlled by inhibitory somatodendritic 5-HT1A autoreceptors. This autoinhibitory mechanism is implicated in the etiology of disorders of emotion regulation, such as anxiety disorders and depression, as well as in the mechanism of antidepressant action. Here, we investigated how persistent alterations in brain 5-HT availability affect autoinhibition in two genetically modified mouse models lacking critical mediators of serotonergic transmission: 5-HT transporter knockout (Sert-/-) and tryptophan hydroxylase-2 knockout (Tph2-/-) mice. The degree of autoinhibition was assessed by loose-seal cell-attached recording in DRN slices. First, application of the 5-HT1A-selective agonist R(+)-8-hydroxy-2-(di-n-propylamino)tetralin showed mild sensitization and marked desensitization of 5-HT1A receptors in Tph2-/- mice and Sert-/- mice, respectively. While 5-HT neurons from Tph2-/- mice did not display autoinhibition in response to L-tryptophan, autoinhibition of these neurons was unaltered in Sert-/- mice despite marked desensitization of their 5-HT1A autoreceptors. When the Tph2-dependent 5-HT synthesis step was bypassed by application of 5-hydroxy-L-tryptophan (5-HTP), neurons from both Tph2-/- and Sert-/- mice decreased their firing rates at significantly lower concentrations of 5-HTP compared to wildtype controls. Our findings demonstrate that, as opposed to the prevalent view, sensitivity of somatodendritic 5-HT1A receptors does not predict the magnitude of 5-HT neuron autoinhibition. Changes in 5-HT1A receptor sensitivity may rather be seen as an adaptive mechanism to keep autoinhibition functioning in response to extremely altered levels of extracellular 5-HT resulting from targeted inactivation of mediators of serotonergic signaling. PMID:23935583

  18. Serotonin 5HT 3 receptors in the central nervous system

    Microsoft Academic Search

    Pascal Chameau; Johannes A. van Hooft

    2006-01-01

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

  19. Effects of drugs acting on cerebral 5-hydroxytryptamine mechanisms on dopamine-dependent turning behaviour in mice.

    PubMed Central

    Milson, J A; Pycock, C J

    1976-01-01

    1. The effects of drugs acting on cerebral 5-hydroxytryptaminergic mechanisms on drug-induced turning behaviour in mice with unilateral destruction of nigro-striatal dopaminergic nerve terminals have been studied. 2. Administration of L-tryptophan (400 mg/kg) or 5-hydroxytryptophan (200 mg/kg) increased brain 5-hydroxytryptamine and decreased the turning induced by both apomorphine (2 mg/kg) and amphetamine (5 mg/kg). 3. Parachlorophenylalanine (3 X 500 mg/kg) decreased brain 5-hydroxytryptamine and increased both apomorphine and amphetamine-induced circling behaviour. 4. Varying the protein content of dietary intake significantly altered brain 5-hydroxytryptamine and tryptophan levels, spontaneous locomotor activity and amphetamine-induced circling behaviour in these mice. 5. Systemic administration of methysergide (0.5-4 mg/kg), lysergic acid diethylamide (0.025-0.2 mg/kg), cyproheptadine (2.5-20 mg/kg) or clomipramine (0.6-20 mg/kg) produced no consistent effect on drug-induced turning behaviour. 6. The results suggest that circling behaviour due to striatal dopamine receptor stimulation is depressed by an elevation of brain 5-hydroxytryptamine and enhanced by a reduction in brain 5-hydroxytryptamine. 7. The possible physiological relationship between dopamine and 5-hydroxytryptamine neurones in the basal ganglia is discussed. PMID:130178

  20. Cholinergic modulation of the release of 5-hydroxytryptamine from the guinea pig ileum

    Microsoft Academic Search

    H. Schwörer; K. Racké; H. Kilbinger

    1987-01-01

    Isolated segements of the guinea pig ileum were vascularly perfused and the release of 5-HT and its metabolite 5-HIAA into the portal venous effluent determined by HPLC with electrochemical detection. Test substances were applied via the arterial perfusion medium. Oxotremorine inhibited concentration-dependently the release of 5-HT and 5-HIAA (by 47% at 1 µmol\\/l). Scopolamine (0.1 µmol\\/1) did not affect the

  1. 5-HT2 receptor subtypes: a family re-united?

    PubMed

    Baxter, G; Kennett, G; Blaney, F; Blackburn, T

    1995-03-01

    The current classification for 5-HT2 receptors accommodates three subtypes. In addition to the originally defined 5-HT2 receptor, sanctuary is now provided for the structurally related 5-HT1c receptor (now 5-HT2c) and at least one atypical 5-HT receptor subtype. The strong functional union of this family is reflected in the paucity of ligands that will discriminate between its subtypes and prompts some re-evaluation of the activities of compounds which may now be regarded as nonselective for the receptor subtypes in this class. In this article, Gordon Baxter and colleagues examine the pharmacology of both officially recognized and atypical 5-HT2 receptor subtypes. A number of novel selective agents are highlighted, some of which may prove useful for 5-HT2 receptor classification and, ultimately, clarify the mechanistic basis for current and future therapeutic strategies which target this receptor family. PMID:7792930

  2. Potentiating action of MKC-242, a selective 5-HT1A receptor agonist, on the photic entrainment of the circadian activity rhythm in hamsters

    PubMed Central

    Moriya, T; Yoshinobu, Y; Ikeda, M; Yokota, S; Akiyama, M; Shibata, S

    1998-01-01

    Serotonergic projections from the midbrain raphe nuclei to the suprachiasmatic nuclei (SCN) are known to regulate the photic entrainment of circadian clocks. However, it is not known which 5-hydroxytryptamine (5-HT) receptor subtypes are involved in the circadian regulation. In order to verify the role of 5-HT1A receptors, we examined the effects of 5-{3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole HCl (MKC-242), a selective 5-HT1A receptor agonist, on photic entrainment of wheel-running circadian rhythms of hamsters.MKC-242 (3?mg?kg?1, i.p.) significantly accelerated the re-entrainment of wheel-running rhythms to a new 8?h delayed or advanced light-dark cycle.MKC-242 (3?mg?kg?1, i.p.) also potentiated the phase advance of the wheel-running rhythm produced by low (5 lux) or high (60 lux) intensity light pulses. In contrast, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT)(5?mg?kg?1, i.p.), a well known 5-HT1A/5-HT7 receptor agonist, only suppressed low intensity (5 lux) light-induced phase advances.The potentiating actions of MKC-242 on light pulse-induced phase advances were observed even when injected 20 or 60?min after the light exposure.The potentiating action of MKC-242 was antagonized by WAY100635, a selective 5-HT1A receptor blocker, but not by ritanserin, a 5-HT2/5-HT7 receptor blocker, indicating that MKC-242 is activating 5-HT1A receptors.Light pulse-induced c-fos expression in the SCN and the intergeniculate leaflet (IGL) were unaffected by MKC-242 (3?mg?kg?1, i.p.).HPLC analysis demonstrated that MKC-242 (3?mg?kg?1, i.p.) decreased the 5-HIAA content in the SCN.The present results suggest that presynaptic 5-HT1A receptor activation may be involved in the potentiation of photic entrainment by MKC-242 in hamsters. PMID:9863658

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

    PubMed

    Kemp, B K; Cocks, T M

    1995-10-01

    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. 6. Pretreatment of the saphenous vein with sodium nitroprusside (SNP; 10 microM) caused a small sustained relaxation and significantly depressed the maximal contraction to 5-HT without affecting sensitivity and abolished the contraction curve to sumatriptan and methysergide. When the relaxation response to SNP was reversed with U46619 (1-4 nM), the contraction curves to 5-HT, sumatriptan and methysergide were similar to those obtained prior to relaxation with SNP. In contrast, the same treatment with SNP had little affect on the contraction curve to noradrenaline.7 In conclusion, the pattern of U46619-enhanced reactivity of 5-HT, sumatriptan and methysergide in SNP-treated dog saphenous vein, highlights the importance of functional antagonism when assessing reactivity to contractile agonists in isolated blood vessels. PMID:8564247

  4. Long-term modulation of presynaptic 5-HT-output: experimentally induced changes in cortical 5-HT-transporter density, tryptophan hydroxylase content and 5-HT innervation density.

    PubMed

    Huether, G; Zhou, D; Rüther, E

    1997-01-01

    Whereas experimentally induced long-term changes of postsynaptic mechanisms of 5-HT neurotransmission have been studied in great detail, much less is currently known about the effects of certain treatments on the presynaptic components governing the output of 5-HT in individual brain regions. This contribution summarizes the results of a series of experiments on the influence of different physiologic and pharmacologic manipulations on three different parameters of 5-HT presynapses, 5-HT transporter density, tryptophan hydroxylase content, and serotonin level in the rat frontal cortex. The combined measurement of several parameters of 5-HT presynapses allows to differentiate between treatments which exclusively affect the density of 5-HT transporters (long-term food restriction), which exclusively affect the level of tryptophan hydroxylase apoenzyme (imipramine treatment of olfactory bulbectomized rats) or which cause a parallel increase (bulbectomy, chronic administration of tranylcypramine to rats with chemical lesions of their cortical 5-HT innervation) or a parallel decrease (administration of p-chloroamphetamine) of both parameters, indicating treatment-induced changes in the density of 5-HT presynapses in the frontal cortex. Each of these changes may lead to an altered output of serotonergic afferences, and may therefore act to either potentiate or to attenuate the impact of serotonin-mediated effects on the activity of local networks located in a certain brain region. PMID:9503252

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

    PubMed

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

    2013-09-01

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

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

    PubMed

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

    2014-01-01

    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

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

    PubMed

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

    2000-02-01

    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

  8. GABA and 5-HT systems are implicated in the anxiolytic-like effect of spinosin in mice.

    PubMed

    Liu, Jie; Zhai, Wei-Min; Yang, Yuan-Xiao; Shi, Jin-Li; Liu, Qian-Tong; Liu, Guo-Lin; Fang, Nan; Li, Jian; Guo, Jian-You

    2015-01-01

    The present study investigated the anxiolytic-like effects of spinosin, one of the major flavonoids in Ziziphi Spinosae Semen (ZSS), in experimental models of anxiety compared with a known anxiolytic, diazepam. Repeated treatment with spinosin (2.5 and 5mg/kg/day, p.o.) significantly increased the percentage of entries into and time spent on the open arms of the elevated plus maze compared with the control group. In the light/dark box test, spinosin exerted an anxiolytic-like effect at 5mg/kg. In the open-field test, 5mg/kg spinosin increased the number of central entries. Spinosin did not affect spontaneous activity. The anxiolytic-like effects of spinosin in the elevated plus maze, light/dark box test, and open field test were blocked by the ?-aminobutyric acid-A (GABAA) receptor antagonist flumazenil (3mg/kg, i.p.) and 5-hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635 (1mg/kg, i.p.). These results suggest that spinosin exerts anxiolytic-like effects, and its mechanism of action appears to be modulated by GABAA and 5-HT1A receptors. PMID:25449359

  9. Agonists and antagonists induce different palonosetron dissociation rates in 5-HT?A and 5-HT?AB receptors.

    PubMed

    Lummis, Sarah C R; Thompson, Andrew J

    2013-10-01

    Palonosetron is a potent 5-HT? receptor antagonist with a unique structure and some unusual properties. Here we explore the properties of palonosetron at heterologously expressed 5-HT?A and 5-HT?AB receptors. We used receptors expressed in HEK293 cells, and functionally analysed them using a membrane potential sensitive dye in a Flexstation, which revealed IC??s of 0.24 nM and 0.18 nM for 5-HT?A and 5-HT?AB receptors respectively. Radioligand binding studies with [(3)H]palonosetron revealed similar Kds: 0.34 nM for 5-HT3A and 0.15 nM for 5-HT?AB receptors. Kinetic studies showed palonosetron association and dissociation rates were slightly faster in 5-HT?AB than 5-HT?A receptors, and for both subtypes dissociation rates were ligand-dependent, with antagonists causing more rapid dissociation than agonists. Similar ligand effects were not observed for [(3)H]granisetron dissociation studies. These data support previous studies which show palonosetron has actions distinct to other 5-HT3 receptor antagonists, and the slow rates observed for agonist induced dissociation (t?/? > 10 h) could at least partly explain the long duration of palonosetron effects in vivo. PMID:23747573

  10. Heat stress, plasma concentrations of adrenaline, noradrenaline, 5-hydroxytryptamine and cortisol, mood state and cognitive performance.

    PubMed

    McMorris, Terry; Swain, Jon; Smith, Marcus; Corbett, Jo; Delves, Simon; Sale, Craig; Harris, Roger C; Potter, Julia

    2006-08-01

    The primary aims of this paper were to examine the effect of heat stress on working memory, choice reaction time and mood state, and to investigate the relationship between heat induced changes in plasma concentrations of selected neurotransmitters and hormones, and cognition. Heat stress resulted in a deterioration of performance on a central executive task (random movement generation) but not on verbal and spatial recall, and choice reaction time tasks. Perceptions of vigour decreased and fatigue increased following exposure to heat stress. Plasma concentrations of cortisol and 5-hydroxytryptamine significantly increased following exposure to heat. Regression analyses showed that percent body mass loss and change from baseline (Delta) concentrations of cortisol, post-exposure to heat, were significant predictors of Delta random movement generation and Delta fatigue. A secondary purpose was to examine the effect of recovery on cognition and mood. Following recovery, the performance of the central executive task was poorer than pre-treatment. Mood states, catecholamines and 5-hydroxytryptamine concentrations returned to pre-treatment values, but cortisol fell to a level significantly lower. Regression correlations showed that Delta adrenaline and Delta scores, post-recovery, on the central executive task were significantly correlated. Delta noradrenaline correlated significantly with Delta fatigue. It was concluded that heat stress results in deterioration in the performance of central executive tasks and perceptions of mood state, and that this can be predicted by changes in body mass loss and plasma concentrations of the hormones cortisol and adrenaline. PMID:16309771

  11. Epiminocyclohepta[b]indole analogs as 5-HT6 antagonists.

    PubMed

    Henderson, Alan J; Guzzo, Peter R; Ghosh, Animesh; Kaur, Jagjit; Koo, Jia-Man; Nacro, Kassoum; Panduga, Shailaja; Pathak, Rashmi; Shimpukade, Bharat; Tan, Valentina; Xiang, Kai; Wierschke, Jonathan D; Isherwood, Matthew L

    2012-02-15

    A new series of epiminocyclohepta[b]indoles with potent 5-HT(6) antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT(6) receptor occupancy studies. The compound was found to have excellent oral absorption, a highly favorable PK profile and demonstrated pharmacodynamic interaction with the 5-HT(6) receptor as shown by ex vivo autoradiography. PMID:22290076

  12. Carrier-dependent and Ca2+-dependent 5-HT and dopamine release induced by (+)-amphetamine, 3,4-methylendioxy-methamphetamine, p-chloroamphetamine and (+)-fenfluramine

    PubMed Central

    Crespi, Daniela; Mennini, Tiziana; Gobbi, Marco

    1997-01-01

    The mechanism underlying 5-hydroxytryptamine (5-HT) and/or dopamine release induced by (+)-amphetamine ((+)-Amph), 3,4-methylendioxymethamphetamine (MDMA), p-chloroamphetamine (pCA) and (+)-fenfluramine ((+)-Fen) was investigated in rat brain superfused synaptosomes preloaded with the 3H neurotransmitters. Their rank order of potency for [3H]-5-HT-releasing activity was the same as for inhibition of 5-HT uptake (pCA?MDMA?(+)-Fen>>(+)-Amph). Similarly, their rank order as [3H]-dopamine releasers and dopamine uptake inhibitors was the same ((+)-Amph>>pCA=MDMA>>(+)-Fen). We also confirmed that the release induced by these compounds was prevented by selective transporter inhibitors (indalpine or nomifensine). [3H]-5-HT and/or [3H]-dopamine release induced by all these compounds was partially (31–80%), but significantly Ca2+-dependent. Lack of extracellular Ca2+ did not alter uptake mechanisms nor did it modify the carrier-dependent dopamine-induced [3H]-dopamine release. (+)-Amph-induced [3H]-dopamine release and pCA- and MDMA-induced [3H]-5-HT release were significantly inhibited by ?-agatoxin-IVA, a specific blocker of P-type voltage-operated Ca2+-channels, similar to the previous results on (+)-Fen-induced [3H]-5-HT release. Methiothepin inhibited the Ca2+-dependent component of (+)-Amph-induced [3H]-dopamine release with high potency (70?nM), as previously found with (+)-Fen-induced [3H]-5-HT release. The inhibitory effect of methiothepin was not due to its effects as a transporter inhibitor or Ca2+-channel blocker and is unlikely to be due to its antagonist properties on 5-HT1/2, dopamine or any other extracellular receptor. These results indicate that the release induced by these compounds is both ‘carrier-mediated' and Ca2+-dependent (possibly exocytotic-like), with the specific carrier allowing the amphetamines to enter the synaptosome. The Ca2+-dependent release is mediated by Ca2+-influx (mainly through P-type Ca2+-channels), possibly triggered by the drug interacting with an unknown intracellular target, affected by methiothepin, common to both 5-HT and dopamine synaptosomes. PMID:9283711

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

    PubMed Central

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

    2014-01-01

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

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

    Microsoft Academic Search

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

    1998-01-01

    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

  15. 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)

    Lucot, James B.

    1990-01-01

    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.

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

    PubMed

    Lucot, J B

    1990-05-16

    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 non-specific 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. PMID:2142095

  17. Kinetics of 5-HT2B receptor signaling: profound agonist-dependent effects on signaling onset and duration.

    PubMed

    Unett, David J; Gatlin, Joel; Anthony, Todd L; Buzard, Daniel J; Chang, Steve; Chen, Chuan; Chen, Xiaohua; Dang, Huong T-M; Frazer, John; Le, Minh K; Sadeque, Abu J M; Xing, Charles; Gaidarov, Ibragim

    2013-12-01

    The kinetics of drug-receptor interactions can profoundly influence in vivo and in vitro pharmacology. In vitro, the potencies of slowly associating agonists may be underestimated in assays capturing transient signaling events. When divergent receptor-mediated signaling pathways are evaluated using combinations of equilibrium and transient assays, potency differences driven by kinetics may be erroneously interpreted as biased signaling. In vivo, drugs with slow dissociation rates may display prolonged physiologic effects inconsistent with their pharmacokinetic profiles. We evaluated a panel of 5-hydroxytryptamine2B (5-HT2B) receptor agonists in kinetic radioligand binding assays and in transient, calcium flux assays, and inositol phosphate accumulation assays; two functional readouts emanating from G?q-mediated activation of phospholipase C. In binding studies, ergot derivatives demonstrated slow receptor association and dissociation rates, resulting in significantly reduced potency in calcium assays relative to inositol phosphate accumulation assays. Ergot potencies for activation of extracellular signal-regulated kinases 1 and 2 were also highly time-dependent. A number of ergots produced wash-resistant 5-HT2B signaling that persisted for many hours without appreciable loss of potency, which was not explained simply by slow receptor-dissociation kinetics. Mechanistic studies indicated that persistent signaling originated from internalized or sequestered receptors. This study provides a mechanistic basis for the long durations of action in vivo and wash-resistant effects in ex vivo tissue models often observed for ergots. The 5-HT2B agonist activity of a number of ergot-derived therapeutics has been implicated in development of cardiac valvulopathy in man. The novel, sustained nature of ergot signaling reported here may represent an additional mechanism contributing to the valvulopathic potential of these compounds. PMID:24049061

  18. Selective and functional 5-hydroxytryptamine4 receptor antagonism by SB 207266.

    PubMed Central

    Wardle, K. A.; Bingham, S.; Ellis, E. S.; Gaster, L. M.; Rushant, B.; Smith, M. I.; Sanger, G. J.

    1996-01-01

    1. The pharmacology of a novel 5-HT4 receptor antagonist, SB 207266 has been evaluated in vitro in the guinea-pig distal colon longitudinal muscle myenteric plexus (LMMP) and in vivo in the dog Heidenhain pouch. 2. SB 207266 is a highly potent antagonist of 5-HT-evoked, cholinergically-mediated contractions in the guinea-pig distal colon. Low concentrations (0.1-10 nM) produced a parallel shift to the right of the concentration-effect curve (apparent pA2 10.6 +/- 0.1) with no significant effect on the maximum response. With higher concentrations of SB 207266 (30 nM and above) the maximum response to 5-HT was reduced. 3. The antagonism seen with SB 207266 cannot be attributed to a non-selective effect since high concentrations (1 microM) had no effect on cholinergically-mediated contractions evoked by the nicotinic receptor agonist DMPP in the same preparation. 4. SB 207266 is not an irreversible antagonist since the effects of the compound were reversible upon washing of the tissue. 5. In the dog Heidenhain pouch, oral (0.1-100 micrograms kg-1) and intravenous (0.1-100 micrograms kg-1) administration of SB 207266 produced a dose-dependent antagonism of the contractions evoked by a bolus intravenous injection of 5-HT. An ID50 for SB 207266 of 1.3 micrograms kg-1 was obtained following i.v. administration and 9.6 micrograms kg-1 following oral administration. 6. The antagonistic effects of SB 207266 (0.1-100 micrograms kg-1) in the dog Heidenhain pouch were long lasting since, following oral administration, the response to 5-HT was reduced for at least 135 min. 7. SB 207266 is a highly potent, highly selective and orally active 5-HT4 receptor antagonist. This compound is the first orally active amide to be identified in this class of antagonists and as such is an important new tool in the evaluation of 5-HT4 receptor function both in vitro and in vivo. PMID:8762092

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

    PubMed

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

    2015-02-01

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

  20. The arylpiperazine derivatives N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide and N-benzyl-4-(2-diphenyl)-1-piperazinehexanamide exert a long-lasting inhibition of human serotonin 5-HT7 receptor binding and cAMP signaling

    PubMed Central

    Atanes, Patricio; Lacivita, Enza; Rodríguez, Javier; Brea, José; Burgueño, Javier; Vela, José Miguel; Cadavid, María Isabel; Loza, María Isabel; Leopoldo, Marcello; Castro, Marián

    2013-01-01

    We performed a detailed in vitro pharmacological characterization of two arylpiperazine derivatives, compound N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211) previously identified as a high-affinity brain penetrant ligand for 5-hydroxytryptamine (serotonin) type 7 (5-HT7) receptors, and its analog N-benzyl-4-(2-diphenyl)-1-piperazinehexanamide (MEL-9). Both ligands exhibited competitive displacement of [3H]-(2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine ([3H]-SB-269970) radioligand binding and insurmountable antagonism of 5-carboxamidotryptamine (5-CT)-stimulated cyclic adenosine monophosphate (cAMP) signaling in human embryonic kidney (HEK293) cells stably expressing human 5-HT7 receptors. They also inhibited forskolin-stimulated adenylate cyclase activity in 5-HT7-expressing HEK293 cells but not in the parental cell line. The compounds elicited long-lasting (at least 24 h) concentration-dependent inhibition of radioligand binding at 5-HT7-binding sites in whole-cell radioligand binding assays, after pretreatment of the cells with the compounds and subsequent compound removal. In cAMP assays, pretreatment of cells with the compounds rendered 5-HT7 receptors unresponsive to 5-CT and also rendered 5-HT7-expressing HEK293 cells unresponsive to forskolin. Compound 1-(2-biphenyl)piperazine (RA-7), a known active metabolite of LP-211 present in vivo, was able to partially inhibit 5-HT7 radioligand binding in a long-lasting irreversible manner. Hence, LP-211 and MEL-9 were identified as high-affinity long-acting inhibitors of human 5-HT7 receptor binding and function in cell lines. The detailed in vitro characterization of these two pharmacological tools targeting 5-HT7 receptors may benefit the study of 5-HT7 receptor function and it may lead to the development of novel selective pharmacological tools with defined functional properties at 5-HT7 receptors. PMID:25505568

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

    PubMed

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

    2015-02-01

    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

  2. ECT AND PLATELET 5HT UPTAKE IN MAJOR DEPRESSION

    PubMed Central

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

    1997-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  4. 6-Hydroxybuspirone is a major active metabolite of buspirone: assessment of pharmacokinetics and 5-hydroxytryptamine1A receptor occupancy in rats.

    PubMed

    Wong, Harvey; Dockens, Randy C; Pajor, Lori; Yeola, Suresh; Grace, James E; Stark, Arlene D; Taub, Rebecca A; Yocca, Frank D; Zaczek, Robert C; Li, Yu-Wen

    2007-08-01

    The pharmacokinetics and in vivo potency of 6-hydroxybuspirone (6-OH-buspirone), a major metabolite of buspirone, were investigated. The plasma clearance (47.3 +/- 3.5 ml/min/kg), volume of distribution (2.6 +/- 0.3 l/kg), and half-life (1.2 +/- 0.2 h) of 6-OH-buspirone in rats were similar to those for buspirone. Bioavailability was higher for 6-OH-buspirone (19%) compared with that for buspirone (1.4%). After intravenous infusions to steady-state levels in plasma, 6-OH-buspirone and buspirone increased 5-hydroxytryptamine (HT)(1A) receptor occupancy in a concentration-dependent manner with EC(50) values of 1.0 +/- 0.3 and 0.38 +/- 0.06 microM in the dorsal raphe and 4.0 +/- 0.6 and 1.5 +/- 0.3 microM in the hippocampus, respectively. Both compounds appeared to be approximately 4-fold more potent in occupying presynaptic 5-HT(1A) receptors in the dorsal raphe than the postsynaptic receptors in the hippocampus. Oral dosing of buspirone in rats resulted in exposures (area under the concentration-time profile) of 6-OH-buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP), another major metabolite of buspirone, that were approximately 12 (6-OH-buspirone)- and 49 (1-PP)-fold higher than the exposure of the parent compound. As a whole, these preclinical data suggest that 6-OH-buspirone probably contributes to the clinical efficacy of buspirone as an anxiolytic agent. PMID:17494642

  5. Postnatal Development of Serotonergic Innervation, 5HT1A Receptor Expression, and 5HT Responses in Rat Motoneurons

    Microsoft Academic Search

    Edmund M. Talley; Negar N. Sadr; Douglas A. Bayliss

    We compared the electrophysiological responses to serotonin (5-HT) of neonatal and juvenile rat hypoglossal motoneurons (HMs) by using intracellular recording techniques in a brainstem slice preparation. In neonatal HMs (#P8), 5-HT caused a sub- stantial decrease in the amplitude of spike afterhyperpolariza- tion (AHP) that was associated with an increase in the minimal repetitive firing frequency (Fmin). Previous work has

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

    PubMed Central

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

    2013-01-01

    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

  7. Venlafaxine and its interaction with WAY 100635: effects on serotonergic unit activity and behavior in cats

    Microsoft Academic Search

    Bjørn Bjorvatn; Casimir A Fornal; Francisco J Mart??n; Christine W Metzler; Barry L Jacobs

    2000-01-01

    The therapeutic efficacy of antidepressant drugs that inhibit the reuptake of serotonin (5-hydroxytryptamine, 5-HT) may be enhanced by blocking their indirect activation of 5-HT1A autoreceptors, which mediate feedback inhibition of serotonergic neuronal activity. In this study, we examined the effects of venlafaxine, a dual 5-HT\\/noradrenaline reuptake inhibitor, alone and in combination with the selective 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY

  8. Antipsychotic-like effect by combined treatment with citalopram and WAY 100635: involvement of the 5-HT2C receptor.

    PubMed

    Eltayb, Amani; Wadenberg, Marie-Louise G; Schilström, Björn; Svensson, Torgny H

    2007-06-01

    Catalepsy occurs following high dopamine (DA) D2 blockade by typical antipsychotic drugs (APDs). We showed that a combination of a high dose of citalopram, a selective serotonin reuptake inhibitor (SSRI) and the selective 5-HT1A receptor antagonist WAY 100635 produces significant catalepsy in rats, similar to APDs. Here, we investigated the potential antipsychotic activity of lower doses of citalopram+WAY 100635, using the conditioned avoidance response (CAR) test. Cataleptogenic liability of the combination was evaluated with the catalepsy test. Citalopram and WAY 100635 in combination, but not when given alone, produced a significant antipsychotic action in CAR without significant catalepsy, similar to the effect of a low dose of the typical APD haloperidol. Pretreatment with a selective 5-HT2C receptor antagonist, SB 242084, completely prevented the citalopram/WAY 100635-induced suppression of CAR indicating an involvement of the 5-HT2C receptor. In summary, treatment with an SSRI/5-HT1A antagonist combination might prove beneficial in psychiatric disorders with psychotic/depressive symptoms. PMID:16879758

  9. 5HT1A-mediated stimulation of cortisol release in major depression: use of non-invasive cortisol measurements to predict clinical response.

    PubMed

    Papakostas, George I; Chuzi, Sarah E; Sousa, Jessica L; Fava, Maurizio

    2010-03-01

    The purpose of the present study was to explore 5HT1A-mediated cortisol release in major depressive disorder (MDD) patients in order to determine whether the degree of 5HT1A-receptor sensitivity can predict response to treatment with selective serotonin reuptake inhibitors (SSRIs). We examined whether the sensitivity of the 5HT1A receptor, as measured by the difference in salivary cortisol levels immediately before and 90 min following the administration of a single dose of the 5HT1A-selective agonist buspirone, predicted treatment outcome following an 8-week, fixed-dose, open trial of the SSRI escitalopram in 17 outpatients with MDD. Change in cortisol levels before and 90 min after the administration of buspirone were not found to predict treatment outcome, whether defined as clinical response (50% or greater reduction in symptom severity), or remission of symptoms. In conclusion, in the present study, we did not find that the change in salivary cortisol levels following the administration of a 5HT1A-selective agonist predicted treatment outcome following an 8-week, fixed-dose, open-label trial of the SSRI escitalopram among outpatients with MDD. Although the 5HT1A-desensitization hypothesis is still a valid one, the results of the present study could not provide any evidence in support. PMID:19641981

  10. Molecular cloning of a serotonin receptor from human brain (5HT1E): a fifth 5HT1-like subtype.

    PubMed Central

    McAllister, G; Charlesworth, A; Snodin, C; Beer, M S; Noble, A J; Middlemiss, D N; Iversen, L L; Whiting, P

    1992-01-01

    Degenerate primers, suitable for polymerase chain reaction studies and based on the conserved structure of G protein-coupled receptors, were used to isolate cDNA clones encoding putative G protein-coupled receptors from a human hippocampal cDNA library. One clone isolated by this approach (AC1) encoded a putative receptor with 39% amino acid sequence identity to the serotonin 5HT1A receptor and 47% identity to the 5HT1D receptor. When expressed transiently in the human embryonic kidney cell line 293, AC1 cDNA-encoded receptor displayed high affinity (Kd = 15 nM) and saturability for [3H]serotonin, suggesting that AC1 encodes a 5HT1-like receptor. However, 5-carboxamidotryptamine demonstrated low affinity (pKi = 5.15) compared with serotonin (pKi = 8.14), consistent with the observed binding of the putative 5HT1E receptor. The excellent correlation observed between the pharmacology of the expressed receptor encoded by AC1 and the human brain 5HT1E binding site confirms that AC1 encodes a 5HT1E receptor and establishes a fifth 5HT1-like receptor subtype. Images PMID:1608964

  11. Role of 5HT in stress, anxiety, and depression

    Microsoft Academic Search

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

    1996-01-01

    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

  12. Serotonin 5HT 2 receptor availability in chronic cocaine abusers

    Microsoft Academic Search

    Gene-Jack Wang; Nora D Volkow; Jean Logon; Joanna S Fowler; David Schlyer; Robert R MacGregor; Robert J Hitzemann; Albert Gjedde; Alfred P Wolf

    1995-01-01

    Serotonin 5-HT2 receptor availability was evaluated in chronic cocaine abusers (n = 19) using positron emission tomography and F-18 N-methylspiperone and was compared to control subjects (n = 19). 5-HT2 Receptor availability was measured in frontal, occipital, cingulate and orbitofrontal cortices using the ratio of the distribution volume in the region of interest to that in the cerebellum which is

  13. 5-HT7 receptor efficacy distribution throughout the canine stomach

    PubMed Central

    Janssen, Pieter; Prins, Nicolaas H; Peeters, Pieter J; Zuideveld, Klaas P; Lefebvre, Romain A

    2004-01-01

    This study aimed to determine, quantify and explain regional differences in the relaxant response to the selective 5-HT1 and 5-HT7 receptor agonist 5-carboxamidotryptamine (5-CT) throughout the canine stomach. Longitudinal muscle strips from eight gastric corpus regions and six antrum regions were mounted for isotonic measurement. The 5-CT-induced relaxation was examined on a prostaglandin F2?-induced submaximal response, expressed as percentage of this response and fitted to the operational model of agonism (OMOA). 5-HT7 receptor messenger RNA (mRNA) expression was compared by means of quantitative PCR. 5-CT inhibited PGF2?-induced tonic contraction (corpus) and increase of phasic contraction amplitude (antrum). The consistent antagonism produced by the selective 5-HT7 receptor antagonist SB-269970 (10 nM, pA2 estimates 8.2–8.9) confirmed that in every region, the inhibition by 5-CT was 5-HT7 receptor mediated. However, variation in the maximum effect (61–108%) and pEC50 (6.4–8.6) was observed throughout the different regions. The OMOA explained these differences as differences in the efficacy parameter ? (ratio of receptor density and coupling efficiency; log ? estimates ranging from 0.1 to 2.1). The log ? gradient decreases going from the lesser to the greater curvature. A proportional difference (68%) in the relative expression of 5-HT7 receptor mRNA between the lesser and the greater curvature indicates that differences in receptor density contribute to the observed functional differences. This study illustrates that 5-HT7 receptors are present throughout the ventral wall of the canine stomach, but the efficacy (expressed as log ?) is clearly greater close to the lesser curvature. Differences in 5-HT7 receptor expression at least partially explain the functional differences. PMID:15339857

  14. Social interactions determine postural network sensitivity to 5-HT.

    PubMed

    Cattaert, Daniel; Delbecque, Jean-Paul; Edwards, Donald H; Issa, Fadi A

    2010-04-21

    The excitability of the leg postural circuit and its response to serotonin (5-HT) were studied in vitro in thoracic nervous system preparations of dominant and subordinate male crayfishes. We demonstrate that the level of spontaneous tonic activity of depressor and levator motoneurons (MNs) (which control downward and upward movements of the leg, respectively) and the amplitude of their resistance reflex are larger in dominants than in subordinates. Moreover, we show that serotonergic neuromodulation of the postural circuit also depends on social status. Depressor and levator MN tonic firing rates and resistance reflex amplitudes were significantly modified in the presence of 10 mum 5-HT in dominants but not in subordinates. Using intracellular recording from depressor MNs, we show that their input resistance was not significantly different in dominants and subordinates in control conditions. However, 5-HT produced a marked depolarization in dominants and a significantly weaker depolarization in subordinates. Moreover, in the presence of 5-HT, the amplitude of the resistance reflex and the input resistance of MNs increased in dominants and decreased in subordinates. The peak amplitude and the decay phase of unitary EPSPs triggered by sensory spikes were significantly increased by 5-HT in dominants but not in subordinates. These observations suggest that neural networks are more reactive in dominants than in subordinates, and this divergence is even reinforced by 5-HT modulation. PMID:20410113

  15. The 5-HT3 receptor as a therapeutic target

    PubMed Central

    Thompson, Andrew J; Lummis, Sarah CR

    2007-01-01

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

  16. Role of 5-ht2c receptor density on behaviour in mice 

    E-print Network

    Stevenson, Paula Louise

    2011-07-05

    The neurotransmitters serotonin (5-HT) and dopamine (DA) play roles in eating disorders, mood disorders, such as depression and anxiety, and in the regulation of locomotion. The 5-HT2C receptor is one of fourteen 5-HT receptor subtypes...

  17. Effect of ethanol on thrombin-induced platelet phospholipid breakdown and release of (TH)-5-hydroxytryptamine

    SciTech Connect

    Fenn, G.C.; Caberos, L.P.; Littleton, J.M.

    1985-01-01

    Ethanol has been reported previously to inhibit chemically-induced platelet aggregation and the release of platelet contents. In platelet suspensions the mechanical stimulus of stirring can induce slow aggregation and the loss of endogenous arachidonic acid from phospholipids by activation of platelet phospholipases. These changes are prevented by the presence of ethanol 20-100 mM, whereas, in unstirred suspensions, ethanol alone has no effect on platelet phospholipids. Under similar conditions of reduced platelet: platelet contact, chemical stimuli, such as thrombi, although unable to produce visible aggregation, still cause the release of (TH)-5-hydroxytryptamine from platelets and also initiate the breakdown of platelet phospholipids. Ethanol does not now inhibit the thrombin-induced release of platelet contents and has little effect on phosphatidylinositol breakdown, though it inhibits phosphatidylcholine breakdown. Ethanol may therefore inhibit platelet aggregation by reducing the effect of mechanical and chemical stimuli on the activation of phospholipase A2. In contrast ethanol has rather little effect on the receptor-mediated breakdown of phosphatidylinositol which is apparently sufficient to trigger the release of platelet contents.

  18. Radioimmunoassay of serotonin (5-hydroxytryptamine) in cerebrospinal fluid, plasma, and serum

    SciTech Connect

    Engbaek, F.; Voldby, B

    1982-04-01

    A direct radioimmunoassay is described for serotonin (5-hydroxytryptamine) in cerebrospinal fluid, platelet-poor plasma, and serum. Antisera in rabbits was raised against serotonin diazotized to a conjugate of bovine albumin and D,L-p-aminophenylalanine. Polyethylene glycol, alone or in combination with anti-rabbit immunoglobulins, is used to separate bound and unbound tritiated serotonin. The minimum concentration of serotonin detectable is 2 nmol/L in a 200-..mu..L sample. Within-day precision (CV) is 4.3% between-day precision 7.7%. Analytical recoveries of serotonin are 109% and 101% for cerebrospinal fluid and plasma, respectively. Tryptophan, 5-hydroxytryptophan, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophol do not interfere with the assay. However, 5-methoxytryptamine and tryptamine cross react. Of samples of cerebrospinal fluid from patients with disc herniations (n=21) or low-pressure hydrocephalus (n=10), one-third had concentrations of 2-4 nmol/L and two-thirds were below the minimum detectable concentration. The observed range for the concentration of serotonin in plasma of 14 normal subjects was 5-14 nmol/L (mean +/- SD, 9 +/- 3 nmol/L). The observed ranges for serotonin in serum were: for 10 women 520-900 (mean +/- SD: 695 +/- 110) nmol/L and for 10 men 380-680 (520 +/- 94) nmol/L.

  19. Prostate Cancer in Elderly Croatian Men: 5-HT Genetic Polymorphisms and the Influence of Androgen Deprivation Therapy on Osteopenia—A Pilot Study

    PubMed Central

    Paukovi?, Paulina; Cvijeti?, Selma; Pizent, Alica; Jurasovi?, Jasna; Milkovi?-Kraus, Sanja; Dodig, Slavica; Mück-Šeler, Dorotea; Mustapi?, Maja; Pivac, Nela; Lana-Feher-Turkovi?; Pavlovi?, Mladen

    2012-01-01

    Background: The aim of this study was to determine the relationship between body mass index, biochemical parameters, and 5-hydroxytryptamine (5-HT) genetic polymorphisms and prostate dysfunction in an elderly general male population. Results: One hundred and seventeen elderly male subjects [60 men without symptoms of prostate hyperplasia, 42 men with untreated benign prostatic hyperplasia (BPH), and 15 men with prostate cancer (PCa)] treated with finasteride or flutamide were included. Multiple comparisons showed significant difference in age, T-score, concentration of phosphorus, calcium, C-reactive protein, and prostate-specific antigen (PSA) between the groups. T-score was the lowest and phosphorus concentration was the highest in the PCa group. Highest PSA, proteins, calcium, and Hekal's formula score were found in the BPH group. Patients with PCa were more frequent GG+GA carriers of 5-HT1B 1997A/G gene polymorphism (p=0.035). Univariate regression analysis showed association of PCa-treated subjects with age (p=0.010) and 5-HT1B genetic polymorphism (p=0.018). Antiandrogen therapy affects T-score (p=0.017), serum phosphorus (p=0.008), glucose (p=0.036), and total proteins (p=0.050). Multivariate-stepwise logistic regression analysis showed the significant association of treated PCa with age (p=0.028) and inorganic phosphorus (p=0.005), and a marginal association with ultrasonographic T-score (p=0.052). Conclusions: Antiandrogen therapy might induce bone mineral loss in elderly PCa patients. Preliminary data imply that the genetic variants of the 5-HT1B receptor might be associated with PCa. PMID:22420486

  20. Effect of chronic Albizzia julibrissin treatment on 5-hydroxytryptamine1A receptors in rat brain.

    PubMed

    Jung, Ji Wook; Cho, Jae-Han; Ahn, Nam Yoon; Oh, Hye Rim; Kim, Sun Yeou; Jang, Choon-Gon; Ryu, Jong Hoon

    2005-05-01

    Quantitative receptor autoradiography and behavioral studies were employed to investigate whether the aqueous extract of Albizzia julibrissin (AEAJ) specifically targets serotonergic systems in rat brain. AEAJ was orally administered at 50 and 200 mg/kg to adult male SD rats for 7 days. Treatment with AEAJ (200 mg/kg) significantly increased time-spent in open arms and the number of open arm entries in an elevated plus-maze (EPM) versus saline controls (P<0.05). Moreover, those effects of AEAJ were blocked by WAY 100635, a 5-HT1A receptor antagonist. Following behavioral evaluation, the binding of [3H]8-hyroxy-2-(di-n-propylamino) tertalin ([3H]8-OH-DPAT) to 5-HT1A receptors in rat brain was investigated. [3H]8-OH-DPAT binding after AEAJ (200 mg/kg) treatment showed a marked increase in the frontal cortex, hippocampus (CA2 and CA3 regions) and in the lateral septum versus vehicle-treated controls. No changes of [3H]8-OH-DPAT binding were observed in the caudate putamen, dentate gyrus and CA1 areas of the hippocampus or in the hypothalamus. In the dorsal raphe region, [3H]8-OH-DPAT binding was significantly reduced by AEAJ (50 mg/kg) treatment but was unchanged by AEAJ (200 mg/kg). These results suggest that the anxiolytic-like effect of A. julibrissin is mediated by the changes of serotonergic nervous system, especially 5-HT1A receptors. PMID:15894080

  1. Behavioral/Systems/Cognitive Contribution of 5-HT2 Receptor Subtypes to

    E-print Network

    Paris-Sud XI, Université de

    ,whichspontaneouslyexpressedlessNREMS than wild-type animals. In 5-HT2A / mice, 5-HT2B receptor blockade produced a reduction of NREMS-selective ligands in wild-type (5-HT2A / ) and knock-out (5-HT2A / ) mice that do not express 5-HT2A receptors-spectrum antagonist at 5-HT2 receptors, ritanserin (Leysen et al., 1985), substantially increases NREMS in humans

  2. The determination of 5-hydroxytryptamine, related indolealkylamines and 5-hydroxyindoleacetic acid in the bovine eye by gas chromatography-negative ion chemical ionization mass spectrometry.

    PubMed

    Best, S A; Midgley, J M; Huang, W; Watson, D G

    1993-01-01

    Methods were developed for the analysis of 5-hydroxytryptamine, related indolealkylamines (tryptamine, melatonin, 5-methoxytryptamine, N-acetyl-5-hydroxytryptamine and 6-hydroxymelatonin) and 5-hydroxyindole-3-acetic acid (5HIAA) in bovine retina, aqueous and vitreous humours. 5-Hydroxytryptamine and related indolealkylamines were extracted and derivatized to form their corresponding pentafluoropropionyl spirocyclic derivatives. 5HIAA was extracted and derivatized to the corresponding pentafluoropropionamide-trifluoroethyl derivative. Identification and quantitation by gas chromatography-negative ion chemical ionization mass spectrometry was made with reference to deuteriated internal standards. 5-Hydroxytryptamine was present in all (n = 34) retinal samples analysed (20.53 +/- 1.64 ng) while N-acetyl-5-hydroxytryptamine was detected in half of the samples of retina (0.06 +/- 0.02 ng). Melatonin (0.15 +/- 0.06 ng) and tryptamine (0.78 +/- 0.34 ng) were detected in only a small number of retinas. 5-Methoxytryptamine was not present in retina. 5-Hydroxytryptamine was also present in aqueous (0.76 +/- 0.17 ng ml-1 and vitreous (0.35 +/- 0.05 ng ml-1' humours from bovine eye. Tryptamine, melatonin, 5-methoxytryptamine and N-acetyl-5-hydroxytryptamine were not detected in bovine aqueous and vitreous humours. 5HIAA was found in both bovine aqueous (2.03 +/- 0.38 ng ml-1) and vitreous (0.65 +/- 0.06 ng ml-1) humours, but its consistent determination in retina was obviated by interference from spurious peaks. PMID:7689343

  3. Cyclic AMP facilitates the electrically evoked release of radiolabelled noradrenaline, dopamine and 5-hydroxytryptamine from rat brain slices.

    PubMed

    Schoffelmeer, A N; Wardeh, G; Mulder, A H

    1985-07-01

    The adenylate cyclase activator forskolin as well as 8-bromo-cyclic AMP enhanced the electrically evoked release of 3H-noradrenaline and 3H-5-hydroxytryptamine from superfused rat neocortical slices and that of 3H-dopamine from neostriatal slices with comparable EC50's of about 0.5 and 50 microM, respectively, without affecting spontaneous tritium efflux. The phosphodiesterase inhibitor ZK 62771 (3-100 microM) also enhanced 3H-noradrenaline and 3H-dopamine release but slightly reduced 3H-5-hydroxytryptamine release. However, this drug profoundly enhanced spontaneous tritium release in the latter case. The facilitatory effect of forskolin (0.3 microM) on the release of the amine neurotransmitters was potentiated in the presence of ZK 62771 (30 microM). Therefore, cyclic AMP appears to exert a general facilitatory effect on the release of these biogenic amines from central nerve terminals. PMID:2995841

  4. The 5-hydroxytryptamine2A receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol (M100907) attenuates impulsivity after both drug-induced disruption (dizocilpine) and enhancement (antidepressant drugs) of differential-reinforcement-of-low-rate 72-s behavior in the rat.

    PubMed

    Ardayfio, Paul A; Benvenga, Mark J; Chaney, Stephen F; Love, Patrick L; Catlow, John; Swanson, Steven P; Marek, Gerard J

    2008-12-01

    Previous work has suggested that N-methyl-d-aspartate (NMDA) receptor antagonism and 5-hydroxytryptamine (5-HT)(2A) receptor blockade may enhance and attenuate, respectively, certain types of impulsivity mediated by corticothalamostriatal circuits. More specifically, past demonstrations of synergistic "antidepressant-like" effects of a 5-HT(2A) receptor antagonist and fluoxetine on differential-reinforcement-of-low-rate (DRL) 72-s schedule of operant reinforcement may speak to the role of 5-HT(2A) receptor blockade with respect to response inhibition as an important prefrontal cortical executive function relating to motor impulsivity. To examine the dynamic range over which 5-HT(2A) receptor blockade may exert effects on impulsivity, [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol] (M100907) was examined both alone and in combination with the psychotomimetic NMDA receptor antagonist dizocilpine [e.g., (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; MK-801] and two different antidepressants, the tricyclic antidepressant desmethylimipramine (DMI) and the monoamine oxidase inhibitor tranylcypromine in rats performing under a DRL 72-s schedule. MK-801 increased the response rate, decreased the number of reinforcers obtained, and exerted a leftward shift in the inter-response time (IRT) distribution as expected. A dose of M100907 that exerted minimal effect on DRL behavior by itself attenuated the psychotomimetic effects of MK-801. Extending previous M100907-fluoxetine observations, addition of a minimally active dose of M100907 to low doses of DMI and tranylcypromine enhanced the antidepressant-like effect of the antidepressants. Therefore, it may be that a tonic excitation of 5-HT(2A) receptors modulates impulsivity and function of corticothalamostriatal circuits over an extensive dynamic range. PMID:18772320

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

    Chernoloz, Olga; El Mansari, Mostafa; Blier, Pierre

    2012-01-01

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

  7. Influence of 5-HT1A and 5-HTTLPR genetic variants on the schizophrenia symptoms and occurrence of treatment-resistant schizophrenia

    PubMed Central

    Terzi?, Tea; Kastelic, Matej; Dolžan, Vita; Plesni?ar, Blanka Kores

    2015-01-01

    This study aimed to explore the influence of two genetic polymorphisms of the 5-hydroxytryptamine 1A receptor (5-HT1A) and solute carrier family 6, member 4 (SLC6A4) genes on the clinical symptoms and treatment resistance in Slovenian patients with schizophrenia. A total of 138 patients with schizophrenia were evaluated using the Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Clinical Global Impression, and Global Assessment of Functioning. Based on the selected criteria, 94 patients were included in the treatment-responsive and 44 in the treatment-resistant group. All subjects and 94 controls were genotyped for the 5-HT1A rs6295 and 5-HTTLPR polymorphisms. There were no statistically significant differences in the frequencies of these polymorphisms between the patients with schizophrenia and the control group and between the treatment-resistant and treatment-responsive group of schizophrenia patients. Polymorphisms rs6295 and 5-HTTLPR had an influence on the Global Assessment of Functioning scale score, while 5-HTTLPR also had an influence on the total score of the negative subscale within the Positive and Negative Syndrome Scale. Although we found no effect on progression toward the treatment-resistant schizophrenia, our data suggest that the rs6295 and 5-HTTLPR polymorphisms can influence some clinical symptoms in schizophrenia.

  8. The effect on motion sickness and oculomotor function of GR 38032F, a 5-HT3-receptor antagonist with anti-emetic properties.

    PubMed Central

    Stott, J R; Barnes, G R; Wright, R J; Ruddock, C J

    1989-01-01

    1. The 5-hydroxytryptamine (5-HT3) receptor antagonist, GR 38032F, which possesses potent anti-emetic properties in vomiting induced by cancer chemotherapeutic drugs, has been tested to determine its value in the prophylaxis of motion sickness induced by cross-coupled stimulation. The double-blind trial compared GR 38032F with both a placebo (lactose) and with hyoscine. In addition, studies of ocular pursuit and saccadic eye movements were carried out following the administration of each drug. 2. The prophylactic effect of GR 38032F on motion-induced nausea was indistinguishable from that of placebo, whereas following hyoscine subjects showed a highly significant (P less than 0.001) increase in tolerance to cross-coupled stimulation. Tests of oculomotor function showed no effect on saccadic eye movement from either drug. However, both drugs produced a significant (P less than 0.05) though small reduction in eye velocity gain during pursuit eye movement. 3. These findings suggest that the 5-HT3 receptor is not involved in the neural pathways that bring about motion sickness, but that it may have a role in the control of ocular pursuit. The absence of an anti-motion sickness effect from a drug that is effective in the treatment of vomiting induced by cancer chemotherapy serves to emphasize that different neural mechanisms are involved in the generation of motion sickness. PMID:2523720

  9. Regulating prefrontal cortex activation: an emerging role for the 5-HT?A serotonin receptor in the modulation of emotion-based actions?

    PubMed

    Aznar, Susana; Klein, Anders B

    2013-12-01

    The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala and the striatal circuitry, areas involved in emotion and reward processing. The PFC, however, is able to modulate amygdala reactivity via a feedback loop to this area. A role for serotonin in adjusting for this circuitry of cognitive regulation of emotion has long been suggested based primarily on the positive pharmacological effect of elevating serotonin levels in anxiety regulation. Recent animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-hydroxytryptamine (5-HT)2A serotonin receptor in the PFC feedback regulatory projection onto the amygdala. This receptor is highly expressed in the prefrontal cortex areas, playing an important role in modulating cortical activity and neural oscillations (brain waves). This makes it an interesting potential pharmacological target for the treatment of neuropsychiatric modes characterized by lack of inhibitory control of emotion-based actions, such as addiction and other impulse-related behaviors. In this review, we give an overview of the 5-HT2A receptor distribution (neuronal, intracellular, and anatomical) along with its functional and physiological effect on PFC activation, and how that relates to more recent findings of a regulatory effect of the PFC on the emotional control of our actions. PMID:23696058

  10. Selectivity of 3H-MADAM binding to 5-hydroxytryptamine transporters in vitro and in vivo in mice; correlation with behavioural effects

    PubMed Central

    Larsen, A K; Brennum, L T; Egebjerg, J; Sánchez, C; Halldin, C; Andersen, P H

    2004-01-01

    Binding of the novel radioligand 3H-2-(2-dimethylaminomethyl-phenylsulphanyl)-5-methyl-phenylamine (3H-MADAM) to the serotonin transporter (SERT) was used to characterise a range of selective serotonin re-uptake inhibitors (SSRIs) in vitro and in vivo. 3H-MADAM bound with high affinity in a saturable manner to both human SERT expressed in CHO cells (Kd=0.20 nM (pKd=9.74±0.12), Bmax=35±4 fmol mg?1 protein) and mouse cerebral cortex membranes (Kd=0.21 nM (pKd=9.66±0.10), Bmax=50±24 fmol mg?1 protein). Binding of 3H-MADAM was highly selective for SERT in vitro as demonstrated by the in vitro profile of MADAM tested at 75 different receptors, ion channels and transporters. This was further substantiated by the pharmacological profile of the binding. Hence, the binding of 3H-MADAM was potently inhibited by SSRIs but not by selective inhibitors of noradrenaline transport and dopamine transport. Likewise, a 5-HT2A/2C receptor antagonist did not inhibit 3H-MADAM binding. 3H-MADAM binding in vivo was inhibited only by compounds which also inhibited the binding of 3H-MADAM in vitro (the SSRIs, mixed SERT/noradrenaline transport inhibitors and clomipramine), confirming the selectivity of 3H-MADAM for SERT also in vivo. Moreover, compounds effective in inhibiting 3H-MADAM binding were the only ones found to be active in the mouse 5-HTP potentiation test confirming the model as a behavioural correlate to in vivo 5-HT uptake. Finally, it was found that a SERT occupancy of 85–95% was necessary to produce 50% of the maximum behavioural response (ED50). PMID:14993096

  11. Modulatory effects of achatin-I, an Achatina endogenous neuroactive peptide, on responses to 5-hydroxytryptamine.

    PubMed

    Liu, G J; Takeuchi, H

    1993-02-01

    Achatin-I (Gly-D-Phe-L-Ala-L-Asp) was found in the ganglia of an African giant snail (Achatina fulica Férussac), and proposed as an excitatory neurotransmitter of Achatina neurones. At 3 x 10(-6) the peptide markedly enhanced the fast inward current (Iin) of an Achatina neurone type, TAN (tonically autoactive neurone), produced by the pneumatic pressure ejection of 5-HT. This Iin was facilitated immediately by the achatin-I perfusion, and the facilitation decreased gradually even with the peptide present. The dose (duration)-response curves of the TAN fast Iin on pressure ejection in the absence (control) and presence of achatin-I at 3 x 10(-6) M (n = 8) were analyzed as follows. The ED50 (95% confidence limit) were 59.3 ms (13.9-95.3 ms) for the control, and 36.5 ms (19.5-52.6 ms) for achatin-I. The Emax were 1.06 +/- 0.11 nA for the control, and 1.74 +/- 0.26 nA for achatin-I (P < 0.01 for paired data). Among achatin-I derivatives, achatin-II (Gly-L-Phe-L-Ala-L-Asp) enhanced the TAN fast response to 5-HT, but was ten times weaker than achatin-I. [L-Glu4]achatin-I (Gly-D-Phe-L-Ala-L-Glu) and achatin-I amide (Gly-D-Phe-Ala-L-Asp-NH2) had no facilitatory effect. We propose that achatin-I is a neuromodulator as well as a neurotransmitter for Achatina giant neurones. PMID:8095899

  12. 5-Hydroxytryptamine (serotonin) 2A receptor gene polymorphism is associated with schizophrenia

    PubMed Central

    Sujitha, Subash Padmajeya; Nair, Asha; Banerjee, Moinak; Lakshmanan, Srinivasan; Harshavaradhan, Sampth; Gunasekaran, Soosiah; Gopinathan, Anilkumar

    2014-01-01

    Background & objectives: Schizophrenia, the debilitating neuropsychiatric disorder, is known to be heritable, involving complex genetic mechanisms. Several chromosomal regions associated with schizophrenia have been identified during the past; putative gene (s) in question, to be called the global signature for the pathophysiology of the disease, however, seems to evade us. The results obtained from the several population-wise association-non association studies have been diverse. We therefore, undertook the present study on Tamil speaking population in south India to examine the association between the single nucleotide polymorphisms (SNPs) at the serotonin receptor gene (5HT2A) and the occurrence of the disease. Methods: Blood samples collected from 266 cases and 272 controls were subjected to genotyping (PCR amplification of candidate SNPs, RFLP and sequencing). The data on the SNPs were subjected to statistical analysis for assessing the gene frequencies in both the cases and the controls. Results: The study revealed significant association between the genotypic frequencies of the serotonin receptor polymorphism and schizophrenia. SNP analysis revealed that the frequencies of GG (30%, rs6311) and CC genotypes (32%, rs6313), were higher in patients (P<0.05) than in controls. The study also showed presence of G and C alleles in patients. Significant levels of linkage disequilibrium (LD) were found to exist between the genotype frequencies of rs6311 and rs6313. Interpretation & conclusions: This study indicated an association between the SNPs (rs6311 and rs6313) of the serotonin receptor 5HT2A and schizophrenia. HapMap analysis revealed that in its genotype distribution, the Tamil speaking population was different from several other populations across the world, signifying the importance of such ethnicity-based studies to improve our understanding of this complex disease. PMID:25758572

  13. The 5-HT[subscript 3A] Receptor Is Essential for Fear Extinction

    ERIC Educational Resources Information Center

    Kondo, Makoto; Nakamura, Yukiko; Ishida, Yusuke; Yamada, Takahiro; Shimada, Shoichi

    2014-01-01

    The 5-HT [subscript 3] receptor, the only ionotropic 5-HT receptor, is expressed in limbic regions, including the hippocampus, amygdala, and cortex. However, it is not known whether it has a role in fear memory processes. Analysis of 5-HT [subscript 3A] receptor knockout mice in fear conditioning paradigms revealed that the 5-HT [subscript 3A]…

  14. Centrally acting hypotensive agents with affinity for 5-HT1A binding sites inhibit forskolin-stimulated adenylate cyclase activity in calf hippocampus.

    PubMed Central

    Schoeffter, P.; Hoyer, D.

    1988-01-01

    1. A number of centrally acting hypotensive agents and other ligands with high affinity for 5-hydroxytryptamine1A (5-HT1A) recognition sites have been tested on forskolin-stimulated adenylate cyclase activity in calf hippocampus, a functional model for 5-HT1A-receptors. 2. Concentration-dependent inhibition of forskolin-stimulated adenylate cyclase activity was elicited by the reference 5-HT1-receptor agonists (mean EC50 value, nM): 5-HT (22), 5-carboxamidotryptamine (5-CT, 3.2), 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, 8.6), N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT, 2.3), 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine (PAPP or LY 165163, 20), 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole (RU 24969, 20), buspirone (65) and ipsapirone (56). Emax amounted to 18-20% inhibition for all but the latter two agonists (14%). 3. The following hypotensive agents with high affinity for 5-HT1A sites were potent agonists in this system (mean EC50 value, nM): flesinoxan (24), indorenate (99), erythro-1-(1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-piperidyl )- 2-benzimidazolinone (R 28935, 2.5), urapidil (390) and 5-methyl-urapidil (3.5). The first two agents were full agonists, whereas the latter three acted as partial agonists with 60-80% efficacy. 4. Metergoline and methysergide behaved as full agonists and cyanopindolol as a partial agonist with low efficacy. Spiroxatrine and 2-(2,6-dimethoxyphenoxyethyl)aminomethyl- 1,4-benzodioxane (WB 4101) which bind to 5-HT1A sites with nanomolar affinity, were agonists and inhibited potently forskolin-stimulated adenylate cyclase in calf hippocampus, showing mean EC50 values of 23 and 15 nM, respectively. Spiroxatrine and WB 4101 yielded 90% and 50% efficacy, respectively. 5. Spiperone and methiothepin (each 1 microM) caused rightward shifts of the concentration-effect curve to 8-OH-DPAT, without loss of the maximal effect, as did the partial agonist cyanopindolol (0.1 microM) and the (-)- and (+)-enantiomers of pindolol (1 microM and 0.1 mM, respectively). 6. There was an excellent correlation (r = 0.90, P = 0.0001) between the pEC50 values (ranging from 6.4 to 8.7) of the 19 agonists tested at adenylate cyclase and their pKD for 5-HT1A recognition sites. Apparent pKB values of antagonists at adenylate cyclase and their pKD values for 5-HT1A binding sites were also significantly correlated. 7. This study further indicates that the 5-HT1A recognition site and the 5-HT receptor mediating inhibition of adenylate cyclase in hippocampus are the same.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:3207999

  15. 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.

    PubMed

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

    2002-11-01

    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

  16. [11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS.

    PubMed

    Turner, M R; Rabiner, E A; Hammers, A; Al-Chalabi, A; Grasby, P M; Shaw, C E; Brooks, D J; Leigh, P N

    2005-04-01

    The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involvement in vivo remains elusive. WAY100635 binds selectively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the cortex. [11C]-WAY100635 PET is, therefore, a potential marker of cerebral neuronal loss or dysfunction in ALS. Twenty-one ALS subjects and 19 healthy volunteers underwent [11C]-WAY100635 PET of the brain. A cortical template consisting of multiple volumes of interest (VOI) was applied to each individual's [11C]-WAY100635 binding potential (BP) image to determine the regional reduction in binding in ALS patients compared to controls. There was a marked reduction (21%) in both the global cortical and raphe BP of [11C]-WAY100635 in ALS patients (P < 0.001), with regional variations in the VOI analysis that ranged from 16% to 29% decrease compared with the control group, and trends to greater reductions in those with bulbar involvement. To clarify the significance of the global cortical reductions, statistical parametric mapping was used as an alternative method to identify the cortical regions with the most significant decreases in [11C]-WAY100635 binding. SPM analysis revealed the greatest differences between ALS cases and controls in frontotemporal regions, cingulate and lateral precentral gyri. The reductions in cortical [11C]-WAY100635 binding were not related to depression, riluzole or other drug use. We postulate that the reduction of 5-HT1A binding represents loss of, or damage to, neurones bearing these receptors although we cannot exclude the possibility that these reductions reflect alterations in receptor expression or function. Further investigation into the role of the 5-HT1A receptor and the potential of [11C]-WAY100635 PET as a marker of cortical dysfunction in ALS is warranted. PMID:15689356

  17. Serotonin acts through 5-HT1 and 5-HT2 receptors to exert biphasic actions on GnRH neuron excitability in the mouse.

    PubMed

    Bhattarai, Janardhan P; Roa, Juan; Herbison, Allan E; Han, Seong Kyu

    2014-02-01

    The effect of serotonin (5-HT) on the electrical excitability of GnRH neurons was examined using gramicidin perforated-patch electrophysiology in transgenic GnRH-green fluorescent protein mice. In diestrous female, the predominant effect of 5-HT was inhibition (70%) with 50% of these cells also exhibiting a late-onset excitation. Responses were dose dependent (EC(50) = 1.2?M) and persisted in the presence of amino acid receptor antagonists and tetrodotoxin, indicating a predominant postsynaptic action of 5-HT. Studies in neonatal, juvenile, peripubertal, and adult mice revealed that 5-HT exerted less potent responses from GnRH neurons with advancing postnatal age in both sexes. In adult male mice, 5-HT exerted less potent hyperpolarizing responses with more excitations compared with females. In addition, adult proestrous female GnRH neurons exhibited reduced inhibition and a complete absence of biphasic hyperpolarization-excitation responses. Studies using 5-HT receptor antagonists demonstrated that the activation of 5-HT(1A) receptors mediated the inhibitory responses, whereas the excitation was mediated by the activation of 5-HT(2A) receptors. The 5-HT-mediated hyperpolarization involved both potassium channels and adenylate cyclase activation, whereas the 5-HT excitation was dependent on protein kinase C. The effects of exogenous 5-HT were replicated using fluoxetine, which enhances endogenous 5-HT levels. These studies demonstrate that 5-HT exerts a biphasic action on most GnRH neurons whereby a fast 5HT(1A)-mediated inhibition occurs alongside a slow 5-HT(2A) excitation. The balance of 5-HT-evoked inhibition vs excitation is developmentally regulated, sexually differentiated, and variable across the estrous cycle and may play a role in regulation of hypothalamic-pituitary-gonadal axis throughout postnatal development. PMID:24265447

  18. Importance of h5HT 1B Receptor Selectivity for 5HT Terminal Autoreceptor Activity: an In Vivo Microdialysis Study in the Freely-moving Guineapig

    Microsoft Academic Search

    C ROBERTS; G. W PRICE; L GASTER; B. J JONES; D. N MIDDLEMISS; C ROUTLEDGE

    1997-01-01

    The importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity was investigated with the selective h5-HT1B receptor ligands SB 219085, SB 220272, SB 224289 and SB 216641. The studies employed measurement of compound affinity and efficacy in vitro and the measurement of extracellular 5-HT in the frontal cortex of the freely-moving guinea-pig using in vivo microdialysis. All compounds had

  19. The antiemetic drug trimethobenzamide prevents hypophagia due to acetyl salicylate, but not to 5HT 1B or 5HT 1C agonists

    Microsoft Academic Search

    G. A. Kennett; G. Curzon

    1988-01-01

    Pretreatment with the antiemetic agent trimethobenzamide (TMB) prevented the hypophagic response of rats to acetyl salicylate\\u000a (a known emetic in man and dogs). However, it did not affect the hypophagic responses to the 5-HT1B agonist RU 24969, or to the 5-HT1C\\/5-HT1B agonistsmCPP and TFMPP. The results therefore suggest that the hypophagic effects of the 5-HT agonists do not involve a

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

    PubMed Central

    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

    2014-01-01

    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

  1. A novel class of 5HT 2a receptor antagonists: Aryl aminoguanidines

    Microsoft Academic Search

    Henry U. Bryant; David L. Nelson; Donald Button; Harlan W. Cole; Melvyn B. Baez; Virginia L. Lucaites; David B. Wainscott; Cecilia Whitesitt; Jon Reel; Richard Simon; Gary A. Koppel

    1996-01-01

    Local delivery of serotonin (5-HT) produces a rapid edematous response in soft tissues via increased fluid extravasation which is prevented by 5-HT2 antagonists such as ketanserin or mianserin. Here we report the effects of a new class of aminoguanidine 5-HT2 antagonists, with relative selectivity for 5-HT2A receptors which are potent inhibitors of 5-HT-induced paw edema in the rat. Radioligand binding

  2. Agonist-directed trafficking of signalling at serotonin 5-HT2A, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells.

    PubMed

    Cussac, Didier; Boutet-Robinet, Elisa; Ailhaud, Marie-Christine; Newman-Tancredi, Adrian; Martel, Jean-Claude; Danty, Nathalie; Rauly-Lestienne, Isabelle

    2008-10-10

    Several examples of agonist-directed trafficking of receptor signalling at 5-HT2A and 5-HT2C receptors have been reported that involve independent downstream transduction pathways. We now report the functional selectivity of a series of chemically diverse agonists at human (h)5-HT2A, h5-HT2B and h5-HT2C-VSV by examining two related responses, the upstream activation of Gq/11 proteins in comparison with its associated cascade of calcium mobilisation. At the h5-HT2A receptor, d-lysergic acid diethylamide (LSD) and the antiparkinsonian agents lisuride, bromocriptine and pergolide exhibit a higher potency for Gq/11 activation than calcium release in contrast with all the other tested ligands such as 5-HT, mCPP and BW723C86, that show an opposite preference of signalling pathway. Comparable observations are made at h5-HT2B and h5-HT2C-VSV receptors, suggesting a similar mechanism of functional selectivity for the three serotonin receptors. Interestingly, the non-hallucinogenic compound lisuride behaves as a partial agonist for both Gq/11 activation and calcium release at the three 5-HT2 receptors, in contrast with DOI, LSD, pergolide and bromocriptine, which are known to provoke hallucinations, and behave as more efficacious agonists. Hence, a functional selectivity for Gq/11 activation together with a threshold of efficacy at h5-HT2A (and possibly h5-HT2B and/or h5-HT2C-VSV) may contribute to hallucinogenic liability. Thus, our results extend the notion of agonist-directed trafficking of receptor signalling to all the 5-HT2-receptor family and indicate that measures of Gq/11 activation versus calcium release may be useful to identify more effective therapeutic drugs with limited side effects. PMID:18703043

  3. Serotonin (5HT) in Veins: Not All in Vain

    Microsoft Academic Search

    A. Elizabeth Linder; Wei Ni; Jessica L. Diaz; Theodora Szasz; Robert Burnett; Stephanie W. Watts

    2007-01-01

    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

  4. Activation of 5HT neuronal activity during motor behavior

    Microsoft Academic Search

    Barry L. Jacobs; Casimir A. Fornal

    1995-01-01

    Brain serotonin (5-HT) neuronal activity is activated preferentially in association with motor activity. This is especially clear during changes in tonic motor output and during repetitive responses mediated by central pattern generators, such as locomotion, respiration and chewing. These and other data support the hypothesis that the primary function of the brain serotonin system is to facilitate motor output. Concurrently,

  5. p-Chloroamphetamine, a serotonin-releasing drug, elicited in rats a hyperglycemia mediated by the 5HT 1A and 5HT 2B\\/2C receptors

    Microsoft Academic Search

    Jun Yamada; Yumi Sugimoto; Tomoko Yoshikawa

    1998-01-01

    The effects of a serotonin (5-HT) releasing drug, p-chloroamphetamine, on plasma glucose levels were investigated in rats. p-Chloroamphetamine elicited a significant hyperglycemia. The hyperglycemic effects of p-chloroamphetamine were completely prevented by the 5-HT synthesis inhibitor, p-chlorophenylalanine. Prior adrenodemedullation abolished the hyperglycemia elicited by p-chloroamphetamine. p-Chloroamphetamine-induced hyperglycemia was prevented by methysergide, which blocks the 5-HT1 and 5-HT2 receptor, the 5-HT1A\\/1B\\/2C receptor

  6. Using Cerebral White Matter for Estimation of Nondisplaceable Binding of 5-HT1A Receptors in Temporal Lobe Epilepsy

    PubMed Central

    Giovacchini, Giampiero; Conant, Shielah; Herscovitch, Peter; Theodore, William H.

    2011-01-01

    The estimation of nondisplaceable binding from cerebellar white matter, rather than from whole cerebellum, was proposed for the PET tracer carbonyl-11C-WAY-100635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridyl)cyclohexane-carboxamidel]) because of the heterogeneity of total ligand binding in this region. For the 5-hydroxytryptamine receptor 1A (5-HT1A) antagonist 18F-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-2-pyridyl)trans-4-fluorocyclohexanecarboxamide (18F-FCWAY), the estimation of nondisplaceable binding from cerebellum (VND) may be additionally biased by spillover of 18F-fluoride activity from skull. We aimed to assess the effect of using cerebral white matter as reference region on detection of group differences in 5-HT1A binding with PET and 18F-FCWAY. Methods In 22 temporal lobe epilepsy patients (TLE) and 10 healthy controls, 18F-FCWAY distribution volume in cerebral white matter (VWM) was computed using an extrapolation method as part of a partial-volume correction (PVC) algorithm. To assess the feasibility of applying this method to clinical studies in which PVC is not performed, VWM was also calculated by placing circular, 6-mm-diameter regions of interest (ROIs) in the centrum semiovalis on parametric images. Binding potentials were BPF = (VT ? VND)/fP and BPF-WM = (VT ? VWM)/fP, where VT is total distribution volume and fP = 18F-FCWAY plasma free fraction. Statistical analysis was performed using t tests and linear regression. Results In the whole group, VWM was 14% ± 19% lower than VND (P < 0.05). VWM/fP was significantly (P < 0.05) lower in patients than in controls. All significant (P < 0.05) reductions of 5-HT1A receptor availability in TLE patients detected by BPF were also detected using BPF-WM. Significant (P < 0.05) reductions of 5-HT1A specific binding were detected by BPF-WM, but not BPF, in ipsilateral inferior temporal cortex, contralateral fusiform gyrus, and contralateral amygdala. However, effect sizes were similar for BPF-WM and BPF. The value of VWM calculated with the ROI approach did not significantly (P > 0.05) differ from that calculated with the extrapolation approach (0.67 ± 0.32 mL/mL and 0.72 ± 0.34 mL/mL, respectively). Conclusion Cerebral white matter can be used for the quantification of nondisplaceable binding of 5-HT1A without loss of statistical power for detection of regional group differences. The ROI approach is a good compromise between computational complexity and sensitivity to spillover of activity, and it appears suitable to studies in which PVC is not performed. For 18F-FCWAY, this approach has the advantage of avoiding spillover of 18F-fluoride activity onto the reference region. PMID:19837769

  7. A study of the mechanism of MDMA ('ecstasy')-induced neurotoxicity of 5-HT neurones using chlormethiazole, dizocilpine and other protective compounds.

    PubMed Central

    Colado, M. I.; Green, A. R.

    1994-01-01

    1. An investigation has been made in rats into the neurotoxic effect of the relatively selective 5-hydroxytryptamine (5-HT) neurotoxin, 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') using chlormethiazole and dizocilpine, both known neuroprotective compounds and also gamma-butyrolactone, ondansetron and pentobarbitone. 2. Administration of MDMA (20 mg kg-1, i.p.) resulted in a 50% loss of cortical and hippocampal 5-HT and 5-hydroxyindole acetic acid (5-HIAA) 4 days later. This reflects the long term neurotoxic loss of 5-HT that occurs. Injection of gamma-butyrolactone (GBL; 400 mg kg-1, i.p.) 5 min before and 55 min after the MDMA provided substantial protection. Pentobarbitone (25 mg kg-1, i.p.) using the same dose regime was also protective, but ondansetron (0.5 mg kg-1 or 0.1 mg kg-1, i.p.) was without effect. 3. MDMA (20 mg kg-1) had no significant effect on striatal dopamine concentration 4 days later but did produce a small decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) content. There were few significant changes in rats given MDMA plus GBL, ondansetron or pentobarbitone. 4. A single injection of MDMA (20 mg kg-1, i.p.) resulted in a greater than 80% depletion of 5-HT in hippocampus and cortex 4 h later, reflecting the initial rapid release that had occurred. None of the neuroprotective compounds (chlormethiazole, 50 mg kg-1; dizocilpine, 1 mg kg-1; GBL, 400 mg kg-1; pentobarbitone, 25 mg kg-1) given 5 min before and 55 min after the MDMA injection, altered the degree of 5-HT loss. 5. Acute MDMA injection increased striatal dopamine content (28%) and decreased the DOPAC content. In general, administration of the drugs under investigation did not significantly alter these MDMA-induced changes. Both chlormethiazole and GBL produced a greater increase in dopamine than MDMA alone, but this was apparently an additive effect to the action of either drug alone.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1 PMID:7516800

  8. Antidepressant drug development: Focus on triple monoamine reuptake inhibition.

    PubMed

    Lane, Roger M

    2014-10-14

    Many patients with major depressive disorder (MDD) only partially respond, and some have no clinically meaningful response, to current widely used antidepressant drugs. Due to the purported role of dopamine in the pathophysiology of depression, triple-reuptake inhibitors (TRIs) that simultaneously inhibit serotonin (5-HT), norepinephrine (NE) and dopamine reuptake could be a useful addition to the armamentarium of treatments for MDD. A TRI should more effectively activate mesolimbic dopamine-related reward-networks, restore positive mood and reduce potent 5-HT reuptake blockade associated "hypodopaminergic" adverse effects of decreased libido, weight gain and "blunting" of emotions. On the other hand, dopaminergic effects raise concern over abuse liability and TRIs may have many of the cardiovascular effects associated with NET inhibition. Several clinical development programs for potential TRI antidepressants have failed to demonstrate significantly greater efficacy than placebo or standard of care. Successful late-stage clinical development of a TRI is more likely if experimental research studies in the target population of depressed patients have demonstrated target engagement that differentially and dose-dependently improves assessments of reward-network dysfunction relative to existing antidepressants. TRI treatment could be individualized on the basis of predictive markers such as the burden of decreased positive mood symptoms and/or neuroimaging evidence of reward network dysfunction. This review focuses on how the next generation of monoamine-based treatments could be efficiently developed to address unmet medical need in MDD. PMID:25315829

  9. High and low affinity 5-HT2 and 5-HT1C binding sites: responses to neonatal 5,7-DHT lesions in rat brain.

    PubMed

    Pranzatelli, M R; Gregory, C M

    1993-01-01

    5-HT receptor denervation supersensitivity has been proposed to explain behavioural supersensitivity to L-5-HTP in rats with 5,7-dihydroxytryptamine (5,7-DHT) lesions. No upregulation of 5-HT2 binding sites was found despite supersensitivity to putative 5-HT2,1C drugs. To test the hypothesis that the 5-HT1C properties of these drugs are involved instead, dose-response and time-course studies of 5-HT1C and 5-HT2 receptors were performed using several different radioligands in rat brain after making neonatal 5,7-DHT lesions by intraperitoneal injection. 5-HT1C sites labelled with [3H]-mesulergine showed a distinct regional distribution: brainstem > diencephalon > cortex > hippocampus > cerebellum, constituting 65, 70, 31, 70, and 73% of total sites labelled by [3H]-mesulergine in the absence of 20 nM spiperone to block 5-HT2 sites, respectively. 5,7-DHT lesions did not significantly alter BMAX, KD, or nH of [3H]-mesulergine-labelled 5-HT1C sites in cortex or other regions but did reduce the density of cortical [3H]-paroxetine sites (-55%). Cortical 5-HT1C sites labelled by [3H]-5-HT or [3H]-mianserin, and cortical 5-HT2 sites labelled by [3H]-DOB or [3H]-ketanserin, were also unaffected. These data suggest that although denervation supersensitivity of 5-HT1C or 5-HT2 receptors may occur at the level of the receptor transducer-effector, there is no evidence it occurs at the receptor recognition site. PMID:8243108

  10. Modulation of noradrenergic neuronal firing by selective serotonin reuptake blockers

    PubMed Central

    Szabo, Steven T; Montigny, Claude de; Blier, Pierre

    1999-01-01

    Using in vivo extracellular unitary recording, the effect of short term (2-day) and long-term (21-day) administration of the selective 5-HT reuptake inhibitor (SSRI) paroxetine (10?mg?kg?1 day?1, s.c. using osmotic minipumps) was examined on the spontaneous firing activity of locus coeruleus noradrenergic neurons. Long-term but not short-term treatment significantly decreased firing activity. Thus, it appears that enhancing 5-HT neurotransmission by sustained SSRI administration leads to a reduction of the firing rate of noradrenergic neurons. The SSRI paroxetine therefore alters the activity of noradrenergic neurons with a delay that is consistent with its therapeutic action in depression and panic disorder. PMID:10188964

  11. Evidence that d -fenfluramine anorexia is mediated by 5HT 1 receptors

    Microsoft Academic Search

    J. C. Neill; S. J. Cooper

    1989-01-01

    The effects of eight serotonin (5-HT) receptor antagonists on the anorectic effect of d-fenfluramine (3.0 mg\\/kg, IP) were examined in a test of sweet mash consumption, using non-deprived male rats. d-Fenfluramine's effect was attenuated by the mixed 5-HT1\\/5-HT2 receptor antagonists, methiothepin and metergoline; by the 5-HT2 receptor antagonist ritanserin; and by (±)cyanopindolol, a mixed 5-HT1A\\/5-HT1B receptor antagonist. In contrast, d-fenfluramine's

  12. Evidence for the existence of FGFR1-5-HT1A heteroreceptor complexes in the midbrain raphe 5-HT system.

    PubMed

    Borroto-Escuela, Dasiel O; Narvaez, Manuel; Pérez-Alea, Mileidys; Tarakanov, Alexander O; Jiménez-Beristain, Antonio; Mudó, Giuseppa; Agnati, Luigi F; Ciruela, Francisco; Belluardo, Natale; Fuxe, Kjell

    2015-01-01

    The ascending midbrain 5-HT neurons known to contain 5-HT1A autoreceptors may be dysregulated in depression due to a reduced trophic support. With in situ proximity ligation assay (PLA) and supported by co-location of the FGFR1 and 5-HT1A immunoreactivities in midbrain raphe 5-HT cells, evidence for the existence of FGFR1-5-HT1A heteroreceptor complexes were obtained in the dorsal and median raphe nuclei of the Sprague-Dawley rat. Their existence in the rat medullary raphe RN33B cell cultures was also established. After combined FGF-2 and 8-OH-DPAT treatment, a marked and significant increase in PLA positive clusters was found in the RN33B cells. Similar results were reached upon coactivation by agonists in HEK293T cells using the Fluorescent Resonance Energy Transfer (FRET) technique resulting in increased FRETmax and reduced FRET50 values. The heteroreceptor complex formation was dependent on TMV of the 5-HT1A receptor since it was blocked by incubation with TMV but not with TMII. Taken together, the 5-HT1A autoreceptors by being recruited into a FGFR1-5-HT1A heteroreceptor complex in the midbrain raphe 5-HT nerve cells may develop a novel function, namely a trophic role in many midbrain 5-HT neuron systems originating from the dorsal and medianus raphe nuclei. PMID:25485703

  13. The opposite effect of a 5-HT1B receptor agonist on 5-HT synthesis, as well as its resistant counterpart, in an animal model of depression

    PubMed Central

    Skelin, Ivan; Kova?evi?, Tomislav; Sato, Hiroki; Diksic, Mirko

    2013-01-01

    Flinders Sensitive Line (FSL) rat is as an animal model of depression with altered parameters of the serotonergic (5-HT) system function (5-HT synthesis rates, tissue concentrations, release, receptor density and affinity), as well as an altered sensitivity of these parameters to different 5-HT based antidepressants. The effects of acute and chronic treatments with the 5-HT1B agonist, CP-94253 on 5-HT synthesis, in the FSL rats and the Flinders Resistant Line (FRL) controls were measured using ?-[14C]methyl-L-tryptophan (?-MTrp) autoradiography. CP-94253 (5 mg/kg), or an adequate volume of saline, was injected i.p. as a single dose in the acute experiment or delivered via the subcutaneously implanted osmotic minipump (5 mg/kg/day for 14 days) in the chronic experiment. The acute treatment with CP-94253 significantly decreased the 5-HT synthesis in both the FRL and FSL rats, with a more widespread effect in the FRL rats. Chronic treatment with CP-94253 significantly decreased 5-HT synthesis in the FRL rats, while 5-HT synthesis in the FSL rats was significantly increased throughout the brain. In both the acute and chronic experiment, the FRL rats had higher brain 5-HT synthesis rates, relative to the FSL rats. The shift in the direction of the treatment effect from acute to chronic, using the 5-HT1B agonist, CP-94253, on 5-HT synthesis in the FSL model of depression, with an opposite effect on the control FRL rats, suggests the differential adaptation of the 5-HT system in the FSL and FRL rats to chronic stimulation of 5-HT1B receptors. PMID:22542420

  14. Alcohol drinking in rats is attenuated by the mixed 5-HT1 agonist/5-HT2 antagonist FG 5893.

    PubMed

    Singh, G K; Kalmus, G W; Björk, A K; Myers, R D

    1993-01-01

    Over the last three decades, the neurotransmitter serotonin (5-HT) has been implicated in the etiological mechanisms underlying the excessive drinking of ethyl alcohol. Recently, the 5-HT2 antagonist amperozide was found to reduce selectively the high intake of alcohol in the cyanamide-induced drinking rat without any adverse side effects. The purpose of the present study was to determine the action on alcohol drinking of the novel second-generation amperozide-like drug, which is a mixed 5-HT1 agonist/5-HT2 antagonist, FG 5893 (2-[4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl]-3-pyridinecarb oxylic acid methyl ester). To induce preference for alcohol in Sprague-Dawley rats, the enzyme aldehyde dehydrogenase was inhibited by cyanamide administered in the absence of alcohol in a dose of 10 mg/kg twice a day over three days. A standard three-bottle preference test was used in which water and a maximally preferred concentration of alcohol were offered to each animal. Following control tests of alcohol preference for 3 days, either a saline control vehicle or FG 5893 in a dose of 0.5, 1.0, or 2.5 mg/kg was administered subcutaneously at 1600 and 2200 for 3 consecutive days. Whereas control injections of saline were without effect on alcohol consumption, all doses of FG 5893 significantly reduced the 24-h intake of alcohol in terms of both absolute g/kg and proportion of alcohol to total fluid intake. Further, the 1.0 and 2.5 mg/kg doses of FG 5893 continued to suppress alcohol consumption over two 4-day tests immediately following the injection sequence and after a 40-day interval.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8507395

  15. Effects of Acute MDMA Intoxication on Mood and Impulsivity: Role of the 5-HT2 and 5-HT1 Receptors

    PubMed Central

    van Wel, Janelle H. P.; Kuypers, Kim P. C.; Theunissen, Eef L.; Bosker, Wendy M.; Bakker, Katja; Ramaekers, Johannes G.

    2012-01-01

    MDMA induces positive mood and increases impulse control during intoxication, but only a few studies on the neuropharmacological mechanisms underlying these processes have been conducted. It was hypothesized that pretreatment with 5-HT1 and 5-HT2 receptor blockers would prevent MDMA effects on mood and impulsivity. Subjects (N?=?17) participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. T1–T2 combinations were: placebo-placebo, 20 mg pindolol-placebo, 50 mg ketanserin-placebo, placebo-75 mg MDMA, 20 mg pindolol-75 mg MDMA and 50 mg ketanserin-75 g MDMA. Subjects completed a Profile of Mood States (POMS) questionnaire and several impulsivity tasks (Stop signal task, Matching familiar figures task, Cue dependent reversal learning task) at 1.5 hrs post-treatment. MDMA alone increased both positive (vigor, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. MDMA also increased stop reaction time in the Stop signal task and reaction time in the Matching familiar figures task. Pretreatment with ketanserin blocked MDMA effects on positive affect, but not negative affect. Ketanserin did not influence the effects of MDMA on impulsivity. Pindolol did not interact with MDMA on any of the measures. In conclusion, 5-HT2 receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. 5-HT1 receptors do not appear to be involved in MDMA effects on mood and impulse control. Trial Registration Nederlands Trial Register NTR2352 PMID:22808116

  16. Rational Drug Design Leading to the Identification of a Potent 5-HT2C Agonist Lacking 5-HT2B Activity

    PubMed Central

    2011-01-01

    The 5-HT2C receptor is an attractive drug target in the quest for new therapeutics to treat a variety of human disorders. We have previously undertaken a structural optimization campaign that has led to some potent and moderately selective 5-HT2C receptor agonists. After expanding our structure–function library, we were able to combine our data sets so as to allow the design of compounds of improved selectivity and potency. We disclose herein the structural optimization of our previously reported 5-HT2B/5-HT2C agonists, which has led to the identification of a highly selective 5-HT2C agonist, (+)-trans-[2-(2-cyclopropylmethoxyphenyl)cyclopropyl]methylamine hydrochloride, with an EC50 of 55 nM and no detectable agonism at the 5-HT2B receptor. PMID:22778800

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

    PubMed Central

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

    2014-01-01

    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

  18. Treatment of severe, drug resistant obsessive compulsive disorder with the 5HT 1D agonist sumatriptan

    Microsoft Academic Search

    Liat Stern; Joseph Zohar; Rivka Cohen; Yehuda Sasson

    1998-01-01

    The serotonergic system has been implicated in both the aetiology and pharmacological treatment of obsessive compulsive disorder. In pharmacological challenge tests, mCPP, a 5-HT agonist, with an affinity for 5HT2C as well as 5HT1A and 5HT1D, receptors, was associated with a transient exacerbation of obsessive compulsive symptoms. Chronic administration of mCPP was found to bring about some relief of these

  19. Decreased 5HT2a Receptor Binding in Patients with Anorexia Nervosa

    Microsoft Academic Search

    Kurt Audenaert; Koen Van Laere; Filip Dumont; Miriam Vervaet; Ingeborg Goethals; Guido Slegers; John Mertens; Cees van Heeringen; Rudi A. Dierckx

    Indirect estimations of brain neurotransmitters in patients with anorexia nervosa (AN) and low weight have demonstrated a reduction in brain serotonin (5-HT) turnover in general and led to hypotheses about dysfunction in the 5-HT2a receptor system. It was our aim to investigate the central 5-HT2a receptor binding index using SPECT brain imaging. Methods: The 5-HT2a recep- tors of low-weight patients

  20. Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity.

    PubMed

    Weber, Tillmann; Vogt, Miriam A; Gartside, Sarah E; Berger, Stefan M; Lujan, Rafael; Lau, Thorsten; Herrmann, Elke; Sprengel, Rolf; Bartsch, Dusan; Gass, Peter

    2015-05-01

    Both the glutamatergic and serotonergic (5-HT) systems are implicated in the modulation of mood and anxiety. Descending cortical glutamatergic neurons regulate 5-HT neuronal activity in the midbrain raphe nuclei through ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. To analyze the functional role of GLUA1-containing AMPA receptors in serotonergic neurons, we used the Cre-ERT2/loxP-system for the conditional inactivation of the GLUA1-encoding Gria1 gene selectively in 5-HT neurons of adult mice. These Gria1(5-HT-/-) mice exhibited a distinct anxiety phenotype but showed no alterations in locomotion, depression-like behavior, or learning and memory. Increased anxiety-related behavior was associated with significant decreases in tryptophan hydroxylase 2 (TPH2) expression and activity, and subsequent reductions in tissue levels of 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine in the raphe nuclei. However, TPH2 expression and activity as well as monoamine levels were unchanged in the projection areas of 5-HT neurons. Extracellular electrophysiological recordings of 5-HT neurons revealed that, while ?1-adrenoceptor-mediated excitation was unchanged, excitatory responses to AMPA were enhanced and the 5-HT1A autoreceptor-mediated inhibitory response to 5-HT was attenuated in Gria1(5-HT-/-) mice. Our data show that a loss of GLUA1 protein in 5-HT neurons enhances AMPA receptor function and leads to multiple local molecular and neurochemical changes in the raphe nuclei that dysregulate 5-HT neuronal activity and induce anxiety-like behavior. PMID:25547714

  1. Immunohistological localization of 5-HT in the CNS and feeding system of the Stable Fly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    5-HT immunoreactive neurons were detected in the CNS of the stable fly. The finding of strong innervations of the cibarial pump muscles and the foregut by 5-HT IR neurons in the feeding-related systems suggests that 5-HT may play a crucial role in the control of the feeding behavior in both the larv...

  2. 5-HT1B and other related serotonergic proteins are altered in APPswe mutation.

    PubMed

    Tajeddinn, Walid; Persson, Torbjörn; Maioli, Silvia; Calvo-Garrido, Javier; Parrado-Fernandez, Cristina; Yoshitake, Takashi; Kehr, Jan; Francis, Paul; Winblad, Bengt; Höglund, Kina; Cedazo-Minguez, Angel; Aarsland, Dag

    2015-05-01

    Serotonergic dysfunction is implicated in Alzheimer's disease (AD). In addition, reductions in brain of both monoamine synthesis and release have been reported. Serotonin 1B receptors (5-HT1B), along with serotonin transporter (SERT) are among the regulators of extracellular 5-HT levels. We investigated the effect of the familial AD APP (Amyloid precursor protein) K670N/M671L double mutation, APP Swedish mutation (APPswe), on the expression of 5-HT1B, SERT, MAOA, p11 and 5-HT and its metabolite 5-HIAA in SH-SY5Y human neuroblastoma cell line stably transfected with APPswe mutation. In addition, hippocampal expressions of 5-HT1B and SERT were assessed in wild type and transgenic mice expressing APPswe mutation (Tg2576) at different age groups. We found a reduction of 5-HT1B as well as SERT in both APPswe in vitro and ex vivo. P11 and 5HT were also reduced, whereas 5HT turnover and MAOA were increased. Our results indicate that APPswe induced decreased 5-HT1B expression and 5-HT release, as well as increased MAOA activity and 5-HT breakdown. Further studies to explore the detailed mechanism behind reduced 5-HT1B and SERT in AD and their clinical implications are needed. PMID:25841787

  3. Localization of 5-HT1A and 5-HT2A positive cells in the brainstems of control age-matched and Alzheimer individuals

    PubMed Central

    Yeung, L. Y.; Kung, H. F.

    2010-01-01

    Serotonin receptor 1A and 2A positive cells in postmortem brainstems were demonstrated via immunohistochemistry in eight control age-matched elderly individuals and eight Alzheimer patients. The 5-HT1A positive cells were found in substantia nigra, pontile nucleus, and vagal as well as dorsal raphe nucleus, while 5-HT2A receptor positive cells were found in motor, sensory and spinal trigeminal nuclei, pontile nucleus, substantia nigra, and nucleus solitarius. A comparison in density of positive cells per unit area was made between control age-matched and Alzheimer individuals. Statistically significant differences (p???0.01) in density were observed in 5-HT1A cells in pontile, dorsal raphe, and vagal nuclei between control age-matched and Alzheimer, and in 5-HT2A positive cells in the sensory trigeminal nucleus, between control and Alzheimer. This de novo study indicated the presence of 5-HT1A and 5-HT2A receptor positive cells in the above nuclei of human brainstem and revealed differences in density between control age-matched and Alzheimer, indicating possible functional derangements in Alzheimer patients in these areas. In addition, colocalization studies indicated that 5-HT1A receptors were in cholinergic cells and gamma-aminobutyric acid positive fibers were linked to 5-HT2A receptor positive cells. It is hoped that understanding these two important 5-HT receptors and their localization might lead to advances in future therapeutic development. PMID:20508993

  4. The antiemetic drug trimethobenzamide prevents hypophagia due to acetyl salicylate, but not to 5-HT1B or 5-HT1C agonists.

    PubMed

    Kennett, G A; Curzon, G

    1988-01-01

    Pretreatment with the antiemetic agent trimethobenzamide (TMB) prevented the hypophagic response of rats to acetyl salicylate (a known emetic in man and dogs). However, it did not affect the hypophagic responses to the 5-HT1B agonist RU24969, or to the 5-HT1C/5-HT1B agonists mCPP and TFMPP. The results therefore suggest that the hypophagic effects of the 5-HT agonists do not involve a malaise-dependent mechanism similar to that mediating the effect of acetyl salicylate. PMID:3147468

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

    PubMed Central

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

    2010-01-01

    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

  6. Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes.

    PubMed

    Borroto-Escuela, Dasiel O; Romero-Fernandez, Wilber; Narvaez, Manuel; Oflijan, Julia; Agnati, Luigi F; Fuxe, Kjell

    2014-01-01

    Dopamine D2LR-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor-receptor interactions. In the current study the existence of D2L-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist (3)H-raclopride binding sites and significantly reduced the pKiH values of the high affinity D2R agonist binding sites in (3)H-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2LR agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DOI and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists. PMID:24309097

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

    SciTech Connect

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

    1985-12-01

    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.

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

    PubMed Central

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

    2014-01-01

    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

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

    E-print Network

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

    2014-04-28

    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...

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

    SciTech Connect

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

    1990-01-01

    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.

  11. Selective Serotonin Reuptake Inhibitors: A Review of its Effects on Intraocular Pressure

    PubMed Central

    Costagliola, Ciro; Parmeggiani, Francesco; Semeraro, Francesco; Sebastiani, Adolfo

    2008-01-01

    The increase in serotonin (5-HT) neurotransmission is considered to be one of the most efficacious medical approach to depression and its related disorders. The selective serotonin reuptake inhibitors (SSRIs) represent the most widely antidepressive drugs utilized in the medical treatment of depressed patients. Currently available SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram. The primary SSRIs pharmacological action’s mechanism consists in the presynaptic inhibition on the serotonin reuptake, with an increased availability of this amine into the synaptic cleft. Serotonin produces its effects as a consequence of interactions with appropriate receptors. Seven distinct families of 5-HT receptors have been identified (5-HT1 to 5-HT7), and subpopulations have been described for several of these. The interaction between serotonin and post-synaptic receptors mediates a wide range of functions. The SSRIs have a very favorable safety profile, although clinical signs of several unexpected pathologic events are often misdiagnosed, in particular, those regarding the eye. In all cases reported in the literature the angle-closure glaucoma represents the most important SSRIs-related ocular adverse event. Thus, it is not quite hazardous to hypothesize that also the other reported and unspecified visual disturbances could be attributed - at least in some cases - to IOP modifications. The knowledge of SSRIs individual tolerability, angle-closure predisposition and critical IOP could be important goals able to avoid further and more dangerous ocular side effects. PMID:19587851

  12. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells.

    PubMed

    Gurbuz, Nilgun; Ashour, Ahmed A; Alpay, S Neslihan; Ozpolat, Bulent

    2014-01-01

    Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B- and 5-HT1D-mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new therapeutic targets for managing pancreatic cancer. PMID:25170871

  13. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells.

    PubMed

    Gurbuz, Nilgun; Ashour, Ahmed A; Alpay, S Neslihan; Ozpolat, Bulent

    2014-01-01

    Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B- and 5-HT1D- mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new therapeutic targets for managing pancreatic cancer. PMID:25268648

  14. Down-Regulation of 5-HT1B and 5-HT1D Receptors Inhibits Proliferation, Clonogenicity and Invasion of Human Pancreatic Cancer Cells

    PubMed Central

    Alpay, S. Neslihan; Ozpolat, Bulent

    2014-01-01

    Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B– and 5-HT1D–mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new therapeutic targets for managing pancreatic cancer. PMID:25170871

  15. Effects of 8-OHDPAT and 5-HT1A antagonists WAY100135 and WAY100635, on guinea-pig behaviour and dorsal raphe 5-HT neurone firing.

    PubMed Central

    Mundey, M. K.; Fletcher, A.; Marsden, C. A.

    1996-01-01

    1. The effects of 5-HT1A antagonists on guinea-pig behaviour and dorsal raphe neuronal activity were investigated. 2. WAY100135 (10 mg kg-1, s.c.) and WAY100635 (1 mg kg-1, s.c.) significantly reduced the behaviours induced by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (1 mg kg-1, s.c.) indicative of post-synaptic 5-HT1A receptor antagonism. WAY100635 (10 mg kg-1, s.c.) alone induced ear twitches, which were antagonized by ketanserin (1 mg kg-1, s.c.), but no other overt behaviours. 3. WAY100635 (0.125 mg kg-1, i.v.) produced a right-ward shift in the dose-related inhibition of neuronal firing by 8-OHDPAT (5-100 micrograms kg-1, i.v.) but did not affect the maximum inhibition induced by 8-OHDPAT indicating competitive antagonism between 8-OHDPAT and WAY100635 at the 5-HT1A somato-dendritic autoreceptor in the dorsal raphe nucleus of the guinea-pig. WAY100635 also produced a dose-related increase in the basal firing of 5-HT neurones in the dorsal raphe nucleus and restored the firing of dorsal raphe neurones previously inhibited by 8-OHDPAT (10 micrograms kg-1, i.v.). 4. The results indicate that WAY100635 is a competitive 5-HT1A antagonist in the guinea-pig. Furthermore WAY100635 can increase 5-HT neuronal firing, suggesting that it blocks a 5-HT1A receptor-mediated inhibitory tone acting on guinea-pig 5-HT neurones resulting in increased 5-HT release and 5-HT2 receptor-mediated behaviours. PMID:8646424

  16. The interaction of trichloroethanol with murine recombinant 5-HT3 receptors.

    PubMed Central

    Downie, D L; Hope, A G; Belelli, D; Lambert, J J; Peters, J A; Bentley, K R; Steward, L J; Chen, C Y; Barnes, N M

    1995-01-01

    1. The effects of ethanol, chloral hydrate and trichloroethanol upon the 5-HT3 receptor have been investigated by use of electrophysiological techniques applied to recombinant 5-HT3 receptor subunits (5-HT3R-A or 5-HT3R-As) expressed in Xenopus laevis oocytes. Additionally, the influence of trichloroethanol upon the specific binding of [3H]-granisetron to membrane preparations of HEK 293 cells stably transfected with the murine 5-HT3R-As subunit and 5-HT3 receptors endogenous to NG 108-15 cell membranes was assessed. 2. Ethanol (30-300 mM), chloral hydrate (1-30 mM) and trichloroethanol (0.3-10 mM), produced a reversible, concentration-dependent, enhancement of 5-HT-mediated currents recorded from oocytes expressing either the 5-HT3R-A, or the 5-HT3R-As subunit. 3. Trichloroethanol (5 mM) produced a parallel leftward shift of the 5-HT concentration-response curve, reducing the EC50 for 5-HT from 1 +/- 0.04 microM (n = 4) to 0.5 +/- 0.01 microM (n = 4) for oocytes expressing the 5-HT3R-A. A similar shift, from 2.1 +/- 0.05 microM (n = 11) to 1.3 +/- 0.1 microM (n = 4), was observed in oocytes expressing the 5-HT3R-As subunit. Trichloroethanol (5 mM) had little or no effect upon the maximum current produced by 5-HT for either recombinant receptor. 4. Trichloroethanol (5 mM) similarly reduced the EC50 for 2-methyl-5-HT from 13 +/- 0.4 microM (n = 4) to 4.6 +/- 0.2 microM (n = 4) and from 15 +/- 2 microM (n = 4) to 5 +/- 0.4 microM (n = 4) for oocytes expressing the 5-HT3R-A and 5-HT3R-As subunit respectively. Additionally, trichloroethanol (5 mM) produced a clear enhancement of the maximal current to 2-methyl-5-HT (expressed as a percentage of the maximal current to 5-HT) from 63 +/- 0.7% (n = 4) to 101 +/- 1.6% (n = 4) and from 9 +/- 0.2% (n = 4) to 74 +/- 2% (n = 4) for oocytes expressing the 5-HT3R-A and 5-HT3R-As subunit respectively. 5. Trichloroethanol (2.5 mM) had no effect upon the Kd, or Bmax, of specific [3H]-granisetron binding to membrane homogenates of NG 108-15 cells or HEK 293 cells. Similarly, competition for [3H]-granisetron binding by the 5-HT3 receptor antagonists ondansetron and tropisetron was unaffected. However, competition for [3H]-granisetron binding by the 5-HT3 receptor agonists, 5-HT, 2-methyl-5-HT and phenylbiguanide was enhanced by trichloroethanol (2.5 mM).(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7541281

  17. Cocaine potentiates multiple 5-HT2A receptor signaling pathways and is associated with decreased phosphorylation of 5-HT2A receptors in vivo.

    PubMed

    Franklin, Jade M; Carrasco, Gonzalo A

    2015-03-01

    Cocaine addiction is a chronic relapsing disorder in which the underlying mechanisms are not well understood. Here, we used Sprague-Dawley rats injected with either saline (1 ml/kg) or cocaine (15 mg/kg) for 7 days (b.i.d, i.p) to study the effect of cocaine on several components of 5-HT2A receptor signaling in prefrontal cortex (PFCx). We detected enhanced activation of 5-HT2A receptor-mediated phospholipase C beta (PLC?) and extracellular regulated kinase 1/2 activity in PFCx of cocaine-treated rats. Although we were unable to detect changes in the protein levels of several proteins associated with 5-HT2A receptor signaling such as caveolin-1, postsynaptic density protein 95, ?-arrestin 2, etc., we found a significant reduction in the phosphorylation status of cortical 5-HT2A receptors. This phenomenon was associated with reduced levels of G-protein receptor kinase 5 (GRK5), but not GRK2 or RSK2, proteins. Our results suggest that decreased phosphorylation of 5-HT2A receptors could mediate, at least in part, the cocaine-induced potentiation of multiple 5-HT2A receptor signaling pathways in rat PFCx. As discussed in this manuscript, we hypothesize that preventing these neuroadaptations in 5-HT2A receptor signaling may alleviate some of the aversive withdrawal-associated symptoms that contribute to relapse to cocaine abuse. PMID:25213649

  18. Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5-HT(1A)), dopamine (D(2)) and benzodiazepine receptors.

    PubMed

    Glennon, R A; Dukat, M; Grella, B; Hong, S; Costantino, L; Teitler, M; Smith, C; Egan, C; Davis, K; Mattson, M V

    2000-08-01

    A large series of beta-carbolines was examined for their ability to bind at [3H]agonist-labeled 5-HT(2A) serotonin receptors. Selected beta-carbolines were also examined at 5-HT(2C) serotonin receptors, 5-HT(1A) serotonin receptors, dopamine D(2) receptors, and benzodiazepine receptors. Indolealkylamines and phenylisopropylamines were also evaluated in some of these binding assays. The beta-carbolines were found to bind with modest affinity at 5-HT(2A) receptors, and affinity was highly dependent upon the presence of ring substituents and ring saturation. The beta-carbolines displayed little to no affinity for 5-HT(1A) serotonin receptors, dopamine D(2) receptors and, with the exception of beta-CCM, for benzodiazepine receptors. Examples of beta-carbolines, indolealkylamines (i.e. N,N-dimethyltryptamine analogs), and phenylisopropylamines have been previously shown to produce common stimulus effects in animals trained to discriminate the phenylisopropylamine hallucinogen DOM (i.e. 1-(2, 5-dimethoxy-4-methylphenyl)-2-aminopropane) from vehicle. Although the only common receptor population that might account for this action is 5-HT(2A), on the basis of a lack of enhanced affinity for agonist-labeled 5-HT(2A) receptors, as well as on their lack of agonist action in the PI hydrolysis assay, it is difficult to conclude that the beta-carbolines behave in a manner consistent with that of other classical hallucinogens. PMID:10940539

  19. The anabolic-androgenic steroid nandrolone induces alterations in the density of serotonergic 5HT1B and 5HT2 receptors in the male rat brain.

    PubMed

    Kindlundh, A M S; Lindblom, J; Bergström, L; Nyberg, F

    2003-01-01

    Anabolic-androgenic steroids (AAS) are partly misused by males in order to become brave and intoxicated and these agents are highly associated with psychosis, disinhibition, aggression and acts of violence. Since such behavioral states have been related to an imbalanced serotonergic system and the involvement of the serotonergic 5HT(1B) and the 5HT(2) receptors, it was important to discern the impact of AAS on these receptors. The objective of our study was to investigate the effects of 2 weeks of treatment with the AAS nandrolone decanoate at three different doses (1, 5, 15 mg/kg/day) on the total specific binding of the radioligands [(125)I]-(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (5HT(2) receptors) by autoradiography. All doses caused a significant down-regulation of the 5HT(1B) receptor density in the hippocampal CA(1) and in the medial globus pallidus and a significant up-regulation of the 5HT(2) receptor density in the nucleus accumbens shell. Alterations in receptor density were also observed in the lateral globus pallidus, ventromedial hypothalamus, the amygdala and in the intermediate layers of various cortex regions. In conclusion, serotonergic 5HT(1B) or 5HT(2) receptors are likely to play important roles in mediating observed emotional states and behavioral changes among AAS abusers. PMID:12763073

  20. Phosphotidylinositol turnover in vascular, uterine, fundal, and tracheal smooth muscle: effect of serotonin (5HT)

    SciTech Connect

    Cohen, M.L.; Wittenauer, L.A.

    1986-03-01

    In brain, platelets, and aorta, 5HT has been reported to increase phosphotidylinositol turnover, an effect linked to 5HT/sub 2/ receptors. The authors examined the effect of 5HT on /sup 3/H-inositol-1-phosphate (/sup 3/H-I-P) in tissues possessing 5HT/sub 2/ receptors that mediate contraction to 5HT (rat jugular vein, aorta, uterus and guinea pig trachea) and in a tissue in which contraction to 5HT is not mediated by 5HT/sub 2/ receptors (rat stomach fundus). Tissues were incubated (37/sup 0/C, 95% O/sub 2/, 5% CO/sub 2/) with /sup 3/H-inositol (90 min), washed, LiCl/sub 2/ (10 mM) and 5HT added for 90 min, extracted, and /sup 3/H-I-P eluted from a Dowex-1 column. Basal /sup 3/H-I-P was 10-fold higher in the uterus than in the other tissues. 5HT (10/sup -6/-10/sup -4/M) increased /sup 3/H-I-P in the jugular vein, aorta, and uterus but not in the trachea or fundus. Maximum increase was greatest in the jugular vein (8-fold) with an ED/sub 50/ of 0.4 ..mu..M 5HT. The selective 5HT/sub 2/ receptor blocker, LY53857 (10/sup -8/M) antagonized the increase in /sup 3/H-I-P by 5HT in the jugular vein, aorta and uterus. Pargyline (10/sup -5/M) added to the trachea and fundus did not unmask an effect of 5HT (10/sup -4/M). These data suggest that (1) the jugular vein produced the most sensitive response to 5HT-induced increases in /sup 3/H-I-P, (2) increases in /sup 3/H-I-P by 5HT in smooth muscle may be linked to 5HT/sub 2/ receptors and (3) activation of 5HT/sub 2/ receptors as occurred in the trachea will not always increase /sup 3/H-I-P.

  1. Evidence for involvement of 5HT 1C and 5HT 2 receptors in the food intake suppressant effects of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)

    Microsoft Academic Search

    Charanjit S. Aulakh; James L. Hill; Hakan T. Yoney; Dennis L. Murphy

    1992-01-01

    Administration of various doses of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) to rats produced dose-related decreases in 1-h food intake in the food-deprived paradigm. Pretreatment with spiperone (5-HT1A\\/5-HT2\\/D2 antagonist), propranolol or CGP361A (?-adrenoceptor antagonists that also have binding affinities for 5-HT1A and 5-HT1B sites) and MDL-72222 (5-HT3 antagonist) did not attenuate DOI-induced suppression of food intake. In contrast, pretreatment with metergoline (5-HT1\\/5-HT2 antagonist) completely

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

    PubMed Central

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

    2014-01-01

    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

  3. Antagonist Functional Selectivity: 5-HT2A Serotonin Receptor Antagonists Differentially Regulate 5-HT2A Receptor Protein Level In Vivo

    PubMed Central

    Yadav, Prem N.; Kroeze, Wesley K.; Farrell, Martilias S.

    2011-01-01

    Dysregulation of the 5-HT2A receptor is implicated in both the etiology and treatment of schizophrenia. Although the essential role of 5-HT2A receptors in atypical antipsychotic drug actions is widely accepted, the contribution of 5-HT2A down-regulation to their efficacy is not known. We hypothesized that down-regulation of cortical 5-HT2A receptors contributes to the therapeutic action of atypical antipsychotic drugs. To test this hypothesis, we assessed the effect of chronically administered antipsychotics (clozapine, olanzapine, and haloperidol) and several 5-HT2A antagonists [ketanserin, altanserin, ?-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (M100907), ?-phenyl-1-(2-phenylethyl)-4-piperidinemethano (M11939), 4-[(2Z)-3-{[2-(dimethylamino)ethoxy]amino}-3-(2-fluorophenyl)prop-2-en-1-ylidene]cyclohexa-2,5-dien-1-one (SR46349B), and pimavanserin], on the phencyclidine (PCP)-induced hyperlocomotor response and cortical 5-HT2A receptor levels in C57BL/6J mice. Clozapine and olanzapine, but not haloperidol, induced receptor down-regulation and attenuated PCP-induced locomotor responses. Of the selective 5-HT2A antagonists tested, only ketanserin caused significant receptor protein down-regulation, whereas SR46349B up-regulated 5-HT2A receptors and potentiated PCP-hyperlocomotion; the other 5-HT2A receptor antagonists were without effect. The significance of these findings with respect to atypical antipsychotic drug action is discussed. PMID:21737536

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

    PubMed

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

    2013-10-11

    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

  5. Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT(2A) receptors.

    PubMed

    Blaazer, Antoni R; Smid, Pieter; Kruse, Chris G

    2008-09-01

    Agonist activation of central 5-HT(2A) receptors results in diverse effects, such as hallucinations and changes of consciousness. Recent findings indicate that activation of the 5-HT(2A) receptor also leads to interesting physiological responses, possibly holding therapeutic value. Selective agonists are needed to study the full therapeutic potential of this receptor. 5-HT(2A) ligands with agonist profiles are primarily derived from phenylalkylamines, indolealkylamines, and certain piperazines. Of these, phenylalkylamines, most notably substituted phenylisopropylamines, are considered the most selective agonists for 5-HT(2) receptors. This review summarizes the structure-activity relationships (SAR) of phenylalkylamines as agonist ligands for 5-HT(2A) receptors. Selectivity is a central theme, as is selectivity for the 5-HT(2A) receptor and for its specific signaling pathways. SAR data from receptor affinity studies, functional assays, behavioral drug discrimination as well as human studies are discussed. PMID:18666267

  6. SB216641 and BRL-15572 – compounds to pharmacologically discriminate h5HT1B and h5HT1D receptors

    Microsoft Academic Search

    G. W. Price; M. J. Burton; L. J. Collin; M. Duckworth; L. Gaster; M. Göthert; B. J. Jones; C. Roberts; J. M. Watson; D. N. Middlemiss

    1997-01-01

    Despite only modest homology between h5-HT1B and h5-HT1D receptor amino acid sequences, these receptors display a remarkably similar pharmacology. To date there are few compounds\\u000a which discriminate between these receptor subtypes and those with some degree of selectivity, such as ketanserin, have greater\\u000a affinity for other 5-HT receptor subtypes. We now report on two compounds, SB-216641 (N-[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2’-methyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1’-biphenyl)-4-carboxamide)\\u000a and BRL-15572

  7. Inter-relationship between different platelet measures of 5-HT and their relationship to aggression in human subjects.

    PubMed

    Marseille, Robert; Lee, Royce; Coccaro, Emil F

    2012-03-30

    The objective of this study was to explore the inter-relationship of three platelet measures of serotonergic function (5-HT): 5-HT Transporter Binding, 5-HT-2 Receptor Binding and 5-HT Content and to explore their inter-relationship with measures of aggression and impulsivity. 58 male subjects with personality disorder were studied. Numbers of platelet 5-HT Transporter and 5-HT-2 Receptor sites were assessed by examining the Bmax of ³H-Paroxetine Binding and the Bmax of ¹²?I-LSD Binding to the blood platelet; 5-HT Content was assessed by measuring the amount of 5-HT in the platelet material. Life history of aggression was assessed by Life History of Aggression. Impulsivity was assessed by the Impulsivity Scale of the Eysenck Personality Questionnaire-II. Platelet 5-HT Transporter Binding correlated with both 5-HT-2 Receptor Binding and 5-HT Content; the latter two variables did not correlate with each other. Only Platelet 5-HT Transporter binding correlated significantly with LHA Aggression. These data suggest that while Platelet 5-HT Transporter binding correlates with both 5-HT-2 Receptor Binding and with 5-HT Content, that only 5-HT Transporter Binding represents a correlate of aggression in male personality disordered subjects. PMID:22019855

  8. Discovery of 2-substituted benzoxazole carboxamides as 5HT 3 receptor antagonists

    Microsoft Academic Search

    Zhicai Yang; David J. Fairfax; Jun-Ho Maeng; Liaqat Masih; Alexander Usyatinsky; Carla Hassler; Soshanna Isaacson; Kevin Fitzpatrick; Russell J. DeOrazio; Jianqing Chen; James P. Harding; Matthew Isherwood; Svetlana Dobritsa; Kevin L. Christensen; Jonathan D. Wierschke; Brian I. Bliss; Lisa H. Peterson; Cathy M. Beer; Christopher Cioffi; Michael Lynch; W. Martin Rennells; Justin J. Richards; Timothy Rust; Yuri L. Khmelnitsky; Marlene L. Cohen; David D. Manning

    2010-01-01

    A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT3 receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT3A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT3 receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of

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

    NASA Astrophysics Data System (ADS)

    Ivachtchenko, A. V.

    2014-05-01

    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.

  10. RS 23597-190: a potent and selective 5-HT4 receptor antagonist.

    PubMed Central

    Eglen, R. M.; Bley, K.; Bonhaus, D. W.; Clark, R. D.; Hegde, S. S.; Johnson, L. G.; Leung, E.; Wong, E. H.

    1993-01-01

    1. The pharmacological properties of RS 23597-190 (3-(piperdine-1-yl)-propyl-4-amino-5-chloro-2-methoxy benzoate hydrochloride) have been studied in vitro and in vivo. 2. RS 23597-190 competitively antagonized 5-HT4 receptor-mediated relaxations of rat, carbachol precontracted oesophageal muscularis mucosae, (pA2 = 7.8 +/- 0.1; Schild slope = 1.2 +/- 0.2). Affinity estimates (-log KB) at 5-HT4 receptors using either renzapride or SC-53116 as agonists yielded a -log KB value of 8.0 +/- 0.01. In contrast, RS 23597-190 failed to antagonize contractile responses to 5-HT of guinea-pig ileal 5-HT3 receptors, even at concentrations up to 10 microM. 3. Increases in short-circuit current, induced by 5-HT, were studied in guinea-pig ileal mucosal sheets. Concentration-response curves to 5-HT were biphasic, with the high potency phase to 5-HT inhibited by RS 23597-190 and mimicked by 5-methoxytryptamine. The -log KB value for RS 23597-190 at the high potency phase was 7.3 confirming that 5-HT4 receptors mediated the high potency phase. 4. In rat isolated vagus nerve, 5-HT elicited a slow, maintained depolarization at low concentrations and a rapid, transient depolarization at higher concentrations. The high potency, slow depolarizing phase to 5-HT was abolished selectively in the presence of 1 microM RS 23597-190 and the low potency phase was abolished selectively in the presence of 1 microM ondansetron. These data confirm that 5-HT4 and 5-HT3 receptors mediated slow and fast depolarization responses, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8220871

  11. Presynaptic modulation of 5HT release in the rat septal region

    Microsoft Academic Search

    S. Rutz; C. Riegert; A. K. Rothmaier; R. Jackisch

    2007-01-01

    5-HT released from serotonergic axon terminals in the septal nuclei modulates the activity of septal output neurons (e.g. septohippocampal cholinergic neurons) bearing somatodendritic 5-HT receptors. Therefore, we studied the mechanisms involved in the presynaptic modulation of 5-HT release in the lateral (LS) and medial septum (MS), and the diagonal band of Broca (DB). HPLC analysis showed that tissue concentrations of

  12. 5HT 2A receptor gene polymorphisms in anorexia nervosa and bulimia nervosa

    Microsoft Academic Search

    Benedetta Nacmias; Valdo Ricca; Andrea Tedde; Barbara Mezzani; Carlo Maria Rotella; Sandro Sorbi

    1999-01-01

    To examine the distribution of different polymorphisms in genes of the 5-HT system in patients with anorexia nervosa (AN) and bulimia nervosa (BN), we analyzed the distribution of a polymorphism (?1438G\\/A) and the presence of known mutations in 5-HT2A and 5-HT2C receptor genes in 168 Italian female patients affected by AN and BN. Patients with AN restricting type (ANr) only,

  13. Serotonergic Regulation of the Orexin\\/Hypocretin Neurons through the 5HT1A Receptor

    Microsoft Academic Search

    Yo Muraki; Akihiro Yamanaka; Natsuko Tsujino; Thomas S. Kilduff; Katsutoshi Goto; Takeshi Sakurai

    2004-01-01

    Both orexin and serotonin (5-HT) have important roles in the regulation of sleep-wakefulness, as well as in feeding behavior. We examined the effects of 5-HT on orexin\\/hypocretin neurons, using hypothalamic slices prepared from orexin\\/enhanced green fluorescent protein (EGFP) transgenic mice in which EGFP is expressed exclusively in orexin neurons. Patch-clamp recording from EGFP-expressing cells showed that 5-HT hyperpolarized all orexin

  14. Fawn hooded rats are subsensitive to the food intake suppressant effects of 5HT agonists

    Microsoft Academic Search

    Philip Wang; Charanjit S. Aulakh; James L. Hill; Dennis L. Murphy

    1988-01-01

    The food intake suppressant effects of three serotonin agonists, m-CPP (a selective 5-HT1B agonist), 8-OHDPAT (a selective 5-HT1A agonist) and fenfluramine (a 5-HT releasing agent) were compared in three different rat strains: Wistar, Sprague-Dawley (SD) and Fawn-Hooded (FH) rats. Administration of all three serotonin agonists produced dose-dependent decreases in 1 h food intake in all three strains. FH animals were

  15. 5HT 1A receptor agonists: recent developments and controversial issues

    Microsoft Academic Search

    J. De Vry

    1995-01-01

    During the last decade, serotonin (5-HT)1A receptors have been a major target for neurobiological research and drug development. 5-HT1A receptors have been cloned and a variety of selective agonists, such as the aminotetraline 8-OH-DPAT and the pyrimidinylpiperazine ipsapirone, have become available. Demonstrations of apparent intrinsic activity of these ligands at 5-HT1A receptors, however, depend highly on the particular assay system.

  16. Sex Differences in the Regulation of Serotonergic Transmission and Behavior in 5HT Receptor Knockout Mice

    Microsoft Academic Search

    Michelle D Jones; Irwin Lucki

    2005-01-01

    Few studies have examined the relationship between genetics, stress, and sex-linked differences in neurotransmitter systems. Examining serotonin (5-HT) receptor knockout mice on stress-induced behavioral depression, female 5-HT1B receptor knockout mice demonstrated significantly reduced immobility than either male 5-HT1B receptor knockout mice or male and female wild-type mice on the tail suspension test (TST) and forced swimming test. The behavioral phenotype

  17. Optimization of 5-hydroxytryptamines as dual function inhibitors targeting phospholipase A2 and leukotriene A4 hydrolase.

    PubMed

    Meng, Hu; Liu, Ying; Zhai, Yujing; Lai, Luhua

    2013-01-01

    Dual function inhibitors targeting phospholipase A(2) (PLA(2)) and leukotriene A(4) hydrolase (LTA(4)H) may balance the arachidonic acid (AA) metabolic network and be used as new anti-inflammatory drugs. In previous study, we discovered multi-target drugs towards the AA metabolic network, among which a dual-target inhibitor (JMC08-4) for human nonpancreatic secretory phospholipase A(2) (hnps-PLA(2)) and human leukotriene A(4) hydrolase (LTA(4)H-h) was found. Based on the structure of compound JMC08-4, new dual-target inhibitors were designed assisted by molecular docking. In this report, a series of 5-hydroxytryptamine compounds were synthesized; and most of these title compounds showed more potent inhibitory activity than compound JMC08-4 in the in vitro bioassay against these two enzymes. The best one inhibited hnps-PLA(2) and LTA(4)H-h with IC(50) values of 9.2 ± 0.5 ?M and 2.4 ± 1.4 ?M, respectively. PMID:23220644

  18. Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists.

    PubMed

    Yang, Zhicai; Fairfax, David J; Maeng, Jun-Ho; Masih, Liaqat; Usyatinsky, Alexander; Hassler, Carla; Isaacson, Soshanna; Fitzpatrick, Kevin; DeOrazio, Russell J; Chen, Jianqing; Harding, James P; Isherwood, Matthew; Dobritsa, Svetlana; Christensen, Kevin L; Wierschke, Jonathan D; Bliss, Brian I; Peterson, Lisa H; Beer, Cathy M; Cioffi, Christopher; Lynch, Michael; Rennells, W Martin; Richards, Justin J; Rust, Timothy; Khmelnitsky, Yuri L; Cohen, Marlene L; Manning, David D

    2010-11-15

    A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D). PMID:20889341

  19. Synthesis and binding properties of new long-chain 4-substituted piperazine derivatives as 5-HT1A and 5-HT7 receptor ligands.

    PubMed

    Modica, Maria N; Intagliata, Sebastiano; Pittalà, Valeria; Salerno, Loredana; Siracusa, Maria A; Cagnotto, Alfredo; Salmona, Mario; Romeo, Giuseppe

    2015-04-01

    New long-chain 4-substituted piperazines linked to a thienopyrimidine or a quinazoline system were synthesized and tested for their binding properties on human cloned 5-HT1A and 5-HT7 serotonin receptors. Some structural modifications, concerning tree main portions, that is, terminal fragment, chain length, and aryl substituents, were examined. The 2- and 3-substituted thienopyrimidinone and quinazolinone systems were selected as terminal fragment and a chain length of four or five methylene units was set. Explored aryl substituents were phenyl, phenylmethyl, 3- or 4-chlorophenyl, and 2-ethoxyphenyl. Title compounds showed affinity for 5-HT1A and 5-HT7 receptors. In particular, 2-ethoxyphenyl derivatives 40 and 45 displayed Ki values in the nanomolar range on both receptors, acting as dual ligands. PMID:25759032

  20. Social instigation and aggressive behavior in mice: role of 5HT 1A and 5HT 1B receptors in the prefrontal cortex

    Microsoft Academic Search

    Lígia Aline Centenaro; Karin Vieira; Nicolle Zimmermann; Klaus A. Miczek; Aldo Bolten Lucion; Rosa Maria Martins de Almeida

    2008-01-01

    Rationale  Social instigation is used in rodents to induce high levels of aggression, a pattern of behavior with certain parallels to\\u000a that of violent individuals. This procedure consists of a brief exposure to a provocative stimulus male, before direct confrontation\\u000a with an intruder. Studies using 5-HT1A and 5-HT1B receptor agonists show an effective reduction in aggressive behavior. An important site of

  1. Evidence for a role for central 5-HT2B as well as 5-HT2A receptors in cardiovascular regulation in anaesthetized rats

    PubMed Central

    Knowles, Ian D; Ramage, Andrew G

    1999-01-01

    The effects of injections i.c.v. of quipazine, (2??mol?kg?1) and 1-(2,5-di-methoxy-4-iodophenyl)-2-aminopropane (DOI; 2??mol?kg?1) on renal sympathetic and phrenic nerve activity, mean arterial blood pressure (MAP) and heart rate were investigated in ?-chloralose anaesthetized rats pretreated with a peripherally acting 5-HT2 receptor antagonist.Quipazine or DOI caused a rise in MAP which was associated with a tachycardia and renal sympathoinhibition in rats pretreated (i.c.v.) with the antagonist vehicle 10% PEG. These effects of quipazine were completely blocked by pretreatment with cinanserin (a 5-HT2 receptor antagonist) and attenuated by spiperone (a 5-HT2A receptor antagonist). However, pretreatment with SB200646A (a 5-HT2B/2C receptor antagonist) only blocked the sympathoinhibition, while pretreatment with SB204741 (a 5-HT2B receptor antagonist) reversed the sympathoinhibition to excitation as it also did for DOI. Quipazine also caused renal sympathoexcitation in the presence (i.v.) of a vasopressin V1 receptor antagonist.Injection (i.v.) of the V1 receptor antagonist at the peak pressor response evoked by quipazine alone and in the presence of SB204741 caused an immediate fall in MAP. For quipazine alone the renal sympathoinhibition was slowly reversed to an excitation, while the renal sympathoexcitation observed in the presence of SB204741 was potentiated. In both, the quipazine-evoked tachycardia was unaffected.The data indicate that cardiovascular responses caused by i.c.v. quipazine and DOI are primarily due to activation of central 5-HT2A receptors, which causes the release of vasopressin and a tachycardia. This released vasopressin appears to suppress a 5-HT2A receptor-evoked central increase in sympathetic outflow, which involves the activation of central 5-HT2B receptors indirectly by the released vasopressin. PMID:10516629

  2. 5HT 1A agonists induce hippocampal theta activity in freely moving cats: role of presynaptic 5HT 1A receptors

    Microsoft Academic Search

    Franco Marrosu; Casimir A. Fornal; Christine W. Metzler; Barry L. Jacobs

    1996-01-01

    Electrical activity in the dorsal hippocampus was recorded in freely moving cats in response to intravenous administration of 5-HT1A agonist and antagonist drugs. Administration of low doses of the selective 5-HT1A agonists 8-OH-DPAT (5–20 ?g\\/kg) and ipsapirone (20–100 ?g\\/kg) produced rhythmic slow activity (theta) in the hippocampal EEG within 30 s. Similar effects were observed with BMY 7378 (20 and

  3. Overexpression of 5-HT2C receptors in forebrain leads to elevated anxiety and hypoactivity

    PubMed Central

    Kimura, Atsuko; Stevenson, Paula L; Carter, Roderick N; MacColl, Gavin; French, Karen L; Paul Simons, J; Al-Shawi, Raya; Kelly, Valerie; Chapman, Karen E; Holmes, Megan C

    2009-01-01

    The 5-HT2C receptor has been implicated in mood and eating disorders. In general, it is accepted that 5-HT2C receptor agonists increase anxiety behaviours and induce hypophagia. However, pharmacological analysis of the roles of these receptors is hampered by the lack of selective ligands and the complex regulation of receptor isoforms and expression levels. Therefore, the exact role of 5-HT2C receptors in mood disorders remain controversial, some suggesting agonists and others suggesting antagonists may be efficacious antidepressants, while there is general agreement that antagonists are beneficial anxiolytics. In order to test the hypothesis that increased 5-HT2C receptor expression, and thus increased 5-HT2C receptor signalling, is causative in mood disorders, we have undertaken a transgenic approach, directly altering the 5-HT2C receptor number in the forebrain and evaluating the consequences on behaviour. Transgenic mice overexpressing 5-HT2C receptors under the control of the CaMKII? promoter (C2CR mice) have elevated 5-HT2C receptor mRNA levels in cerebral cortex and limbic areas (including the hippocampus and amygdala), but normal levels in the hypothalamus, resulting in > 100% increase in the number of 5-HT2C ligand binding sites in the forebrain. The C2CR mice show increased anxiety-like behaviour in the elevated plus-maze, decreased wheel-running behaviour and reduced activity in a novel environment. These behaviours were observed in the C2CR mice without stimulation by exogenous ligands. Our findings support a role for 5-HT2C receptor signalling in anxiety disorders. The C2CR mouse model offers a novel and effective approach for studying disorders associated with 5-HT2C receptors. PMID:19614978

  4. Expression of serotonin (5-HT) during CNS development of the cephalopod mollusk, Idiosepius notoides.

    PubMed

    Wollesen, Tim; Degnan, Bernard M; Wanninger, Andreas

    2010-11-01

    Cephalopods are unique among mollusks in exhibiting an elaborate central nervous system (CNS) and remarkable cognitive abilities. Despite a profound knowledge of the neuroanatomy and neurotransmitter distribution in their adult CNS, little is known about the expression of neurotransmitters during cephalopod development. Here, we identify the first serotonin-immunoreactive (5-HT-ir) neurons during ontogeny and describe the establishment of the 5-HT system in the pygmy squid, Idiosepius notoides. Neurons that are located dorsally to each optic lobe are the first to express 5-HT, albeit only when the lobular neuropils are already quite elaborated. Later, 5-HT is expressed in almost all lobes, with most 5-HT-ir cell somata appearing in the subesophageal mass. Further lobes with numerous 5-HT-ir cell somata are the subvertical and posterior basal lobes and the optic and superior buccal lobes. Hatching squids possess more 5-HT-ir neurons, although the proportions between the individual brain lobes remain the same. The majority of 5-HT-ir cell somata appears to be retained in the adult CNS. The overall distribution of 5-HT-ir elements within the CNS of adult I. notoides resembles that of adult Octopus vulgaris and Sepia officinalis. The superior frontal lobe of all three species possesses few or no 5-HT-ir cell somata, whereas the superior buccal lobe comprises many cell somata. The absence of 5-HT-ir cell somata in the inferior buccal lobes of cephalopods and the buccal ganglia of gastropods may constitute immunochemical evidence of their homology. This integrative work forms the basis for future studies comparing molluscan, lophotrochozoan, ecdysozoan, and vertebrate brains. PMID:20976473

  5. Allosteric modulation of 5-HT(1A) receptors by zinc: Binding studies.

    PubMed

    Barrondo, Sergio; Sallés, Joan

    2009-02-01

    5-HT(1A) receptors were studied via [(3)H]WAY-100635 and [(3)H]8-OH-DPAT binding to rat brain cortical membranes. We characterized the effect of zinc (Zn(2+)) on the binding properties of the 5-HT(1A) receptor. The allosteric ternary complex model was applied to determine the dissociation constant (K(A)) of Zn(2+) and their cooperativity factors (alpha) affecting the dissociation constants (K(D), K(i)) of [(3)H]WAY-100635, [(3)H]8-OH-DPAT, and serotonin (5-HT), the endogenous neurotransmitter. Zn(2+) (5microM-1mM) inhibited the binding of agonist/antagonist to 5-HT1A receptors, mostly by decreasing both the ligands' affinity and the maximal number of sites. In [(35)S]GTPgammaS binding assays Zn(2+) behaved as insourmountable antagonist of 5-HT1A receptors, in agreement with radioligand binding assays. The residues involved in the formation of the inhibitory binding site on the 5-HT1A receptor were assessed by using N-ethyl-maleimide (NEM) or diethylpyrocarbonate (DEPC) which modify preferentially cysteine and histidine residues, respectively. Exposure to both agents did not block the negative allosteric effects of Zn(2+) on agonist and antagonist binding. Our findings represent the first quantitative analysis of allosteric binding interactions for 5-HT(1A) receptors. The physiological significance of Zn(2+) modulation of 5-HT(1A) receptors is unclear, but the colocalization of 5-HT(1A) receptors and Zn(2+) in the nervous system (e.g. in the hippocampus and cerebral cortex) suggests that Zn(2+) released at nerve terminals may modulate signals generated by the 5-HT(1A) receptors in vivo. Finally, these findings suggest that synaptic Zn(2+) may be a factor influencing the effectiveness of therapies that rely on 5-HT(1A) receptor activity. PMID:18951909

  6. Effects of general anaesthetics on 5-HT neuronal activity in the dorsal raphe nucleus.

    PubMed

    McCardle, Caroline E; Gartside, Sarah E

    2012-03-01

    The ascending 5-HT system has been and continues to be the subject of much research. The majority of in vivo electrophysiological and neurochemical studies of 5-HT function in rodents have been conducted in animals under anaesthesia - usually chloral hydrate or urethane. However, the effects of anaesthetics, on 5-HT function have not been systematically investigated. Here we used in vitro electrophysiology in dorsal raphe slices, to determine the effects of anaesthetically relevant concentrations of chloral hydrate (100 ?M and 1 mM), urethane (10 and 30 mM), pentobarbitone (10 and 100 ?M) and ketamine (10, 100 and 300 ?M) on regulators of 5-HT firing activity. We examined i) basal firing (driven by ?(1) adrenoceptors), ii) the excitatory response to N-methyl-d-aspartate (NMDA), iii) the 5-HT(1A) autoreceptor-mediated inhibitory response to 5-HT and iv) the GABA(A) receptor-mediated inhibitory response to 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridinyl-3-ol (THIP, gaboxadol). Pentobarbitone selectively enhanced the response to THIP. Ketamine decreased basal firing, attenuated the response to NMDA, and enhanced responses to both 5-HT and THIP. Chloral hydrate had marginal effects on basal firing, slightly attenuated the NMDA response, and enhanced both the 5-HT and THIP responses. Urethane increased basal firing, decreased the NMDA response, increased the response to THIP, but had no effect on the 5-HT response. Our data indicate that all anaesthetics tested significantly affect the regulators of 5-HT neuronal function. These findings will aid in the interpretation of previous reports of in vivo studies of the 5-HT system and will allow researchers to make a rational selection of anaesthetic for future studies. PMID:22197516

  7. Social instigation and aggressive behavior in mice: role of 5-HT1A and 5-HT1B receptors in the prefrontal cortex

    PubMed Central

    Centenaro, Lígia Aline; Vieira, Karin; Zimmermann, Nicolle; Miczek, Klaus A.; Lucion, Aldo Bolten

    2015-01-01

    Rationale Social instigation is used in rodents to induce high levels of aggression, a pattern of behavior with certain parallels to that of violent individuals. This procedure consists of a brief exposure to a provocative stimulus male, before direct confrontation with an intruder. Studies using 5-HT1A and 5-HT1B receptor agonists show an effective reduction in aggressive behavior. An important site of action for these drugs is the ventral orbitofrontal cortex (VO PFC), an area of the brain which is particularly relevant in the inhibitory control of aggressive and impulsive behavior. Objectives The objectives of the study are to assess the anti-aggressive effects of 5-HT1A and 5-HT1B agonist receptors [8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT) and CP-93,129] in the VO PFC of socially provoked male mice. To confirm the specificity of the receptor, 5-HT1A and 5-HT1B antagonist receptors (WAY-100,635 and SB-224,289) were microinjected into the same area, in order to reverse the agonist effects. Results 8-OH-DPAT (0.56 and 1.0 ?g) reduced the frequency of attack bites. The lowest dose of CP-93,129 (0.1 ?g) also decreased the number of attack bites and lateral threats. 5-HT1A and 5-HT1B receptor agonists differed in their effects on non-aggressive activities, the former decreasing rearing and grooming, and the latter, increasing these acts. Specific participation of the 1A and 1B receptors was verified by reversal of anti-aggressive effects using selective antagonists WAY-100,635 (10.0 ?g) and SB-224,289 (1.0 ?g). Conclusions The decrease in aggressiveness observed with microinjections of 5-HT1A and 5-HT1B receptor agonists into the VO PFC of socially provoked mice, supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner. PMID:18688602

  8. Role of 5-HT2C receptors in modulating spinal nociceptive processing in neuropathic pain 

    E-print Network

    Patel, Anisha

    2010-01-01

    of the neurotransmitters that may be involved. A long-circuited spinal-brainstem-spinal loop can act through 5-HT3 receptors on presynaptic terminals to facilitate afferent nociceptive inputs, especially in models of neuropathic pain. We show that 5-HT2C receptors may also...

  9. Serotonin decreases aggression via 5HT 1A receptors in the fighting fish Betta splendens

    Microsoft Academic Search

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

    2007-01-01

    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

  10. N-Oxide analogs of WAY-100635: new high affinity 5-HT1A receptor antagonists

    E-print Network

    Shen, Jun

    N-Oxide analogs of WAY-100635: new high affinity 5-HT1A receptor antagonists Sandrine Marchais 2 are well-known high affinity 5-HT1A receptor antagonists, which when labeled with carbon-11 (b and metabolic properties, the pyridinyl N-oxide moiety was incorporated into analogs of 1 and 2. NOWAY 3

  11. Exploring a potential palonosetron allosteric binding site in the 5-HT3 receptor?

    PubMed Central

    Del Cadia, Marta; De Rienzo, Francesca; Weston, David A.; Thompson, Andrew J.; Menziani, Maria Cristina; Lummis, Sarah C.R.

    2013-01-01

    Palonosetron (Aloxi) is a potent second generation 5-HT3 receptor antagonist whose mechanism of action is not yet fully understood. Palonosetron acts at the 5-HT3 receptor binding site but recent computational studies indicated other possible sites of action in the extracellular domain. To test this hypothesis we mutated a series of residues in the 5-HT3A receptor subunit (Tyr73, Phe130, Ser163, and Asp165) and in the 5-HT3B receptor subunit (His73, Phe130, Glu170, and Tyr143) that were previously predicted by in silico docking studies to interact with palonosetron. Homomeric (5-HT3A) and heteromeric (5-HT3AB) receptors were then expressed in HEK293 cells to determine the potency of palonosetron using both fluorimetric and radioligand methods to test function and ligand binding, respectively. The data show that the substitutions have little or no effect on palonosetron inhibition of 5-HT-evoked responses or binding. In contrast, substitutions in the orthosteric binding site abolish palonosetron binding. Overall, the data support a binding site for palonosetron at the classic orthosteric binding pocket between two 5-HT3A receptor subunits but not at allosteric sites previously identified by in silico modelling and docking. PMID:24128813

  12. Antidepressant and anti-anxiety like effects of 4i (N-(3-chloro-2-methylphenyl) quinoxalin-2-carboxamide), a novel 5-HT3 receptor antagonist in acute and chronic neurobehavioral rodent models.

    PubMed

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

    2014-07-15

    Depression and anxiety are the most debilitating mood disorders with poor therapeutic recovery rates. In the last decades, 5-HT3 receptor antagonists have been identified as potential agents for mood disorders. The current investigation focuses on evaluating the, antidepressant and anti-anxiety like effects of a novel 5-HT3 antagonist, 4i (N-(3-chloro-2-methylphenyl) quinoxalin-2-carboxamide). Preliminary, in vitro 5-HT3 receptor binding affinity was performed in isolated longitudinal muscle-myenteric plexus from the guinea pig ileum. Consequently, neurobehavioral effects of 4i in acute and chronic rodent models were evaluated. In addition, involvement of serotonergic system in the postulated effects of the compound was analyzed by in vivo assay. in vitro, 4i demonstrated high 5-HT3 receptor antagonistic activity (pA2, 7.6). in vivo acute study, 4i exhibited decreased duration of immobility in forced swim and tail suspension tests, and increased exploratory parameters as number and duration of nose-poking in hole board test and latency and time spent in aversive brightly illuminated light chamber in light-dark model. Moreover, in chronic model of depression, i.e., olfactory bulbectomy with behavioral deficits, 4i reversed depressive anhedonia in sucrose preference test and anxious hyperactive behavior in open field test in rats. Furthermore, synergistic effect of 4i with fluoxetine (a selective serotonin reuptake inhibitor) and inhibitory effect of 1-(m-chlorophenyl)-biguanide (a 5-HT3 receptor agonist) revealed serotonergic modulation by 4i mediated 5-HT3 receptor antagonism, which was further confirmed by potentiation of 5-hydroxytryptophan (a serotonin synthesis precursor) induced head twitch response. These findings suggest the potential antidepressant and anti-anxiety like effects of 4i, which may be related to the modulation of serotonergic system. PMID:24747753

  13. Stress-Induced Depression Is Alleviated by Aerobic Exercise Through Up-Regulation of 5-Hydroxytryptamine 1A Receptors in Rats

    PubMed Central

    Kim, Tae Woon; Lim, Baek Vin; Baek, Dongjin; Ryu, Dong-Soo; Seo, Jin Hee

    2015-01-01

    Purpose: Stress is associated with depression, which induces many psychiatric disorders. Serotonin, also known as 5-hydroxy-tryptamine (5-HT), acts as a biochemical messenger and regulator in the brain. It also mediates several important physiological functions. Depression is closely associated with an overactive bladder. In the present study, we investigated the effect of treadmill exercise on stress-induced depression while focusing on the expression of 5-HT 1A (5-H1A) receptors in the dorsal raphe. Methods: Stress was induced by applying a 0.2-mA electric foot shock to rats. Each set of electric foot shocks comprised a 6-second shock duration that was repeated 10 times with a 30-second interval. Three sets of electric foot shocks were applied each day for 7 days. For the confirmation of depressive state, a forced swimming test was performed. To visualize the expression of 5-HT and tryptophan hydroxylase (TPH), immunohistochemistry for 5-HT and TPH in the dorsal raphe was performed. Expression of 5-H1A receptors was determined by western blot analysis. Results: A depressive state was induced by stress, and treadmill exercise alleviated the depression symptoms in the stress-induced rats. Expressions of 5-HT, TPH, and HT 1A in the dorsal raphe were reduced by the induction of stress. Treadmill exercise increased 5-HT, TPH, and HT 1A expressions in the stress-induced rats. Conclusions: Treadmill exercise enhanced 5-HT synthesis through the up-regulation of 5-HT1A receptors, and improved the stress-induced depression. In the present study, treadmill exercise improved depression symptoms by enhancing 5-HT1A receptor expression. The present results suggest that treadmill exercise might be helpful for the alleviation of overactive bladder and improve sexual function. PMID:25833478

  14. 3,4-Methylenedioxyamphetamine (MDA) analogues exhibit differential effects on synaptosomal release of 3H-dopamine and 3H-5-hydroxytryptamine

    SciTech Connect

    McKenna, D.J.; Guan, X.M.; Shulgin, A.T. (Department of Neurology Neurological Sciences, Stanford University Medical Center, CA (USA))

    1991-03-01

    The effect of various analogues of the neurotoxic amphetamine derivative, MDA (3,4-methylenedioxyamphetamine) on carrier-mediated, calcium-independent release of 3H-5-HT and 3H-DA from rat brain synaptosomes was investigated. Both enantiomers of the neurotoxic analogues MDA and MDMA (3,4-methylenedioxymethamphetamine) induce synaptosomal release of 3H-5-HT and 3H-DA in vitro. The release of 3H-5-HT induced by MDMA is partially blocked by 10(-6) M fluoxetine. The (+) enantiomers of both MDA and MDMA are more potent than the (-) enantiomers as releasers of both 3H-5-HT and 3H-DA. Eleven analogues, differing from MDA with respect to the nature and number of ring and/or side chain substituents, also show some activity in the release experiments, and are more potent as releasers of 3H-5-HT than of 3H-DA. The amphetamine derivatives {plus minus}fenfluramine, {plus minus}norfenfluramine, {plus minus}MDE, {plus minus}PCA, and d-methamphetamine are all potent releasers of 3H-5-HT and show varying degrees of activity as 3H-DA releasers. The hallucinogen DOM does not cause significant release of either 3H-monoamine. Possible long-term serotonergic neurotoxicity was assessed by quantifying the density of 5-HT uptake sites in rats treated with multiple doses of selected analogues using 3H-paroxetine to label 5-HT uptake sites. In the neurotoxicity study of the compounds investigated, only (+)MDA caused a significant loss of 5-HT uptake sites in comparison to saline-treated controls. These results are discussed in terms of the apparent structure-activity properties affecting 3H-monoamine release and their possible relevance to neurotoxicity in this series of MDA congeners.

  15. 5-HT(3)-receptor subunits A and B are co-expressed in neurons of the dorsal root ganglion.

    PubMed

    Morales, M; McCollum, N; Kirkness, E F

    2001-09-17

    The type 3 serotonin (5-HT(3)) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT). Many pharmacological, behavioral, and electrophysiological studies indicate heterogeneous properties for this receptor. Although the basis for this heterogeneity is unknown, one possible explanation for these findings resides in the subunit composition of the receptor. Two 5-HT(3)-receptor subunits have been cloned: the 5-HT(3)-receptor subunit A (5-HT(3A)) and the 5-HT(3)-receptor subunit B (5-HT(3B)). Recombinant co-expression of 5-HT(3A) and 5-HT(3B) subunits produces a functional heteromeric 5-HT(3A/3B) receptor with pharmacological and electrophysiological properties different from those displayed by the 5-HT(3A) homomeric receptor. In the present report, we used in situ hybridization histochemistry to demonstrate that the 5-HT(3B) subunit is expressed in rat dorsal root ganglion (DRG) neurons. We determined with cellular resolution that 5-HT(3B) subunit mRNA was expressed in 43.2 +/- 2.8% of the total population of DRG neurons. By comparison, the 5-HT(3A) subunit was more widely expressed, with 70.0 +/- 2.8% of the total population of DRG neurons expressing this subunit. Further analyses showed that most of the neurons containing mRNA for the 5-HT(3B) subunit (91.5 +/- 3.4%) also expressed the 5-HT(3A) subunit. In contrast, nearly half the population of neurons expressing 5-HT(3A) subunit lacked (52.8 +/- 5.9%) transcripts for the 5-HT(3B) subunit. These results provide the first evidence indicating that the 5-HT(3B) subunit of the 5-HT(3) receptor is expressed in DRG and suggest that sensory neurons have the capacity to synthesize at least two structurally different 5-HT(3) receptors: a heteromeric 5-HT(3A/3B) receptor and a homomeric 5-HT(3A) receptor. Consequently, 5-HT(3) receptors with different properties might be present in peripheral and central axons of the DRG. These findings open the possibility that distinct types of 5-HT(3) receptors may be involved in perception and/or processing of sensory information. J. Comp. Neurol. 438:163-172, 2001. Published 2001 Wiley-Liss, Inc. PMID:11536186

  16. Involvement of 5-HT2 receptors in the behaviours produced by intrathecal administration of selected 5-HT agonists and the TRH analogue (CG 3509) to rats.

    PubMed Central

    Fone, K. C.; Johnson, J. V.; Bennett, G. W.; Marsden, C. A.

    1989-01-01

    1. The behavioural effects of the intrathecal injection of a thyrotrophin-releasing hormone (TRH) analogue L-orotyl-L-histidyl-prolineamide (CG 3509, 0.5 micrograms), the non-selective 5-HT1 and 5-HT2 receptor agonist 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT, 2-100 micrograms) and the selective 5-HT2 receptor agonist 2,5-dimethoxy-alpha,4-dimethyl-benzene ethamine hydrochloride (DOM, 2-25 micrograms) were compared with the response of systemically administered 5-MeODMT (2 mg kg-1, i.p.) in rats, to establish whether the agonist-induced behaviours were mediated by bulbospinal 5-HT1 or 5-HT2 receptors. 2. Intrathecal injection of 5-MeODMT or DOM produced dose-related back muscle contractions (a previously undocumented behaviour) and wet-dog shakes which were both markedly attenuated by ritanserin pretreatment (1 mg kg-1, i.p.) indicating the involvement of 5-HT2 receptors. In contrast, reciprocal forepaw treading, flat body posture and Straub-tail were evoked by 5-MeODMT but not by DOM indicating that these behaviours were not produced by 5-HT2 receptor activation alone. However, as ritanserin pretreatment reduced the reciprocal forepaw treading induced by intrathecal 5-MeODMT, this behaviour may be facilitated by 5-HT2 receptor activation. 3. Intrathecal 5,7-dihydroxytryptamine (5,7-DHT, 2 x 150 micrograms) treatment decreased thoraco-lumbar spinal cord 5-HT (-95%) and potentiated the back muscle contractions produced by intrathecal DOM injection without altering the wet-dog shake behaviour. None of the components of the 5-HT syndrome produced by 5-MeODMT (2 mg kg-1, i.p.), with the exception of a small increase in wet-dog shakes, was significantly altered by intrathecal 5,7-DHT (which reduced thoraco-lumbar spinal cord 5-HT by 84%). Taken together these data suggest that the only 5-HT agonist-induced behaviour mediated by the activation of 5-HT2 receptors located postsynaptic to bulbospinal 5-hydroxytryptaminergic (5-HTergic) neurones was back muscle contractions. 4. The wet-dog shake and forepaw licking behaviors produced by intrathecal CG 3509 (0.5 micrograms) were attenuated when ritanserin was administered intrathecally 30 min before, but not when it was given at the same time as CG 3509 and neither behaviour was altered by intrathecal 5,7-DHT. This suggests that bulbospinal 5-HTergic neurones are not involved in the production of these TRH analogue-induced behaviours and that the 5-HT2 receptors which mediate these behaviours are not located in the spinal cord. Images Figure 2 Figure 4 PMID:2470455

  17. Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5-HT3 Receptor Ligands

    PubMed Central

    2012-01-01

    The 5-HT3 receptor, a pentameric ligand-gated ion channel (pLGIC), is an important therapeutic target. During a recent fragment screen, 6-chloro-N-methyl-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine (1) was identified as a 5-HT3R hit fragment. Here we describe the synthesis and structure–activity relationships (SAR) of a series of (iso)quinoline and quinazoline compounds that were synthesized and screened for 5-HT3R affinity using a [3H]granisetron displacement assay. These studies resulted in the discovery of several high affinity ligands of which compound 22 showed the highest affinity (pKi > 10) for the 5-HT3 receptor. The observed SAR is in agreement with established pharmacophore models for 5-HT3 ligands and is used for ligand–receptor binding mode prediction using homology modeling and in silico docking approaches. PMID:23006041

  18. 5-HT2 and 5-HT7 receptor agonists facilitate plantar stepping in chronic spinal rats through actions on different populations of spinal neurons

    PubMed Central

    S?awi?ska, Urszula; Miazga, Krzysztof; Jordan, Larry M.

    2014-01-01

    There is considerable evidence from research in neonatal and adult rat and mouse preparations to warrant the conclusion that activation of 5-HT2 and 5-HT1A/7 receptors leads to activation of the spinal cord circuitry for locomotion. These receptors are involved in control of locomotor movements, but it is not clear how they are implicated in the responses to 5-HT agonists observed after spinal cord injury. Here we used agonists that are efficient in promoting locomotor recovery in paraplegic rats, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OHDPAT) (acting on 5-HT1A/7 receptors) and quipazine (acting on 5-HT2 receptors), to examine this issue. Analysis of intra- and interlimb coordination confirmed that the locomotor performance was significantly improved by either drug, but the data revealed marked differences in their mode of action. Interlimb coordination was significantly better after 8-OHDPAT application, and the activity of the extensor soleus muscle was significantly longer during the stance phase of locomotor movements enhanced by quipazine. Our results show that activation of both receptors facilitates locomotion, but their effects are likely exerted on different populations of spinal neurons. Activation of 5-HT2 receptors facilitates the output stage of the locomotor system, in part by directly activating motoneurons, and also through activation of interneurons of the locomotor central pattern generator (CPG). Activation of 5-HT7/1A receptors facilitates the activity of the locomotor CPG, without direct actions on the output components of the locomotor system, including motoneurons. Although our findings show that the combined use of these two drugs results in production of well-coordinated weight supported locomotion with a reduced need for exteroceptive stimulation, they also indicate that there might be some limitations to the utility of combined treatment. Sensory feedback and some intraspinal circuitry recruited by the drugs can conflict with the locomotor activation. PMID:25191231

  19. Effects of age of serotonin 5-HT2 receptors in cocaine abusers and normal subjects

    SciTech Connect

    Wang, G.J.; Volkow, N.D.; Logan, J. [Brookhaven National Laboratory, Upton, NY (United States)] [and others

    1995-05-01

    We measured the effect of age on serotonin 5-HT2 receptor availability and compared it with the effects on dopamine D2 receptors on 19 chronic cocaine abusers (35.2{plus_minus}9.8 years, range 18-54 years old) and 19 age matched normal controls using positron emission tomography (PET) and F-18 N-methylspiperone (NMS). 5-HT2 Receptor availability was measure din frontal (FR), occipital (OC), cingulate (CI) and orbitofrontal (OF) cortices using the ratio of the distribution volume in the region of interest to that in the cerebelium (CB) which is a function of Bmax/Kd. D2 receptor availability in the basal ganglia was measured using the {open_quotes}ratio index{close_quotes} (slope of striatum/CB versus time over 180 min of the scan) which is a function of Bmax. 5-HT2 Receptor availability differed among regions and were as follows: CI>OF>OC>FC.5-HT2 Receptor availability decreased significantly with age. This effect was more accentuated for 5-HT2 receptor availability in FR than in OC(df=1, p<0.025). Striatal dopamine D2 receptors were also found to decrease significantly with age (r=0.63, p<0.007). In a given subject, D2 receptor availability was significantly correlated with 5-HT2 receptor availability in FR (r=0.51, p<0.035) but not in OC. The values for 5-HT2 receptor availability were not different in normal subjects and cocaine abusers. These results document a decline in 5-HT2 and D2 receptors with age and document an association between frontal 5-HT2 and striatal D2 receptor availability. These results did not show any changes in 5-HT2 receptor availability in cocaine abusers as compared to control subjects.

  20. Characterization, solubilization and partial purification of serotonin 5-HT1C receptors

    SciTech Connect

    Yagaloff, K.A.

    1986-01-01

    /sup 125/I-Lysergic acid diethylamide (/sup 125/I-LSD) binds with high affinity to a unique serotonergic site on rat choroid plexus. These sites were localized to choroid plexus epithelial cells using a novel high resolution autoradiographic technique. In membrane preparations, the serotonergic site density was 3100 fmol/mg protein, which is 10 fold higher than the density of any other serotonergic site in brain homogenates. The pharmacology of this site, termed the 5-HT1c site, does not match that of 5-Ht1a, 5-HT1b or 5HT2 serotonergic sites. 5-Ht1c sites were solubilized from pig choroid plexus using the zwitterionic detergent, CHAPS. High affinity labelling of the solubilized site was obtained using the serotonergic radioligand, N1-methyl-2-(/sup 125/I)lysergic acid diethylamide (/sup 125/I-MIL). Choroid plexus tumors obtained from transgenic mice were examined for the presence of serotonin 5-HT1c receptors. /sup 125/I-LSD binding to choroid plexus tumors displays a pharmacological profile that matches the properties of 5-HT1c receptors in normal choroid plexus. The tumor exhibits the highest site density of serotonin receptors (6600 fmol/mg protein) found in any tissue. /sup 125/I-LSD autoradiography of brain sections from transgenic mice shows high levels of specific labelling over the tumor. The affinities of various indolealkyl, phenlakyl and beta-carboline derivatives for the serotonin 5-HT1c receptor were measured in pig choroid plexus using /sup 125/I-MIL. Serotonin precursors and metabolites were all very weak inhibitors of specific /sup 125/I-MIL binding. Structure-affinity relationships were determined for a number of indolealkylamine analogues. Only serotonin is present in cerebrospinal fluid at concentrations near its 5-HT1c inhibition constant, suggesting that serotonin is the natural 5-HT1c agonist.

  1. Effect of Peripheral 5-HT on Glucose and Lipid Metabolism in Wether Sheep

    PubMed Central

    Watanabe, Hitoshi; Saito, Ryo; Nakano, Tatsuya; Takahashi, Hideyuki; Takahashi, Yu; Sumiyoshi, Keisuke; Sato, Katsuyoshi; Chen, Xiangning; Okada, Natsumi; Iwasaki, Shunsuke; Harjanti, Dian W.; Sekiguchi, Natsumi; Sano, Hiroaki; Kitazawa, Haruki; Rose, Michael T.; Ohwada, Shyuichi; Watanabe, Kouichi; Aso, Hisashi

    2014-01-01

    In mice, peripheral 5-HT induces an increase in the plasma concentrations of glucose, insulin and bile acids, and a decrease in plasma triglyceride, NEFA and cholesterol concentrations. However, given the unique characteristics of the metabolism of ruminants relative to monogastric animals, the physiological role of peripheral 5-HT on glucose and lipid metabolism in sheep remains to be established. Therefore, in this study, we investigated the effect of 5-HT on the circulating concentrations of metabolites and insulin using five 5-HT receptor (5HTR) antagonists in sheep. After fasting for 24 h, sheep were intravenously injected with 5-HT, following which-, plasma glucose, insulin, triglyceride and NEFA concentrations were significantly elevated. In contrast, 5-HT did not affect the plasma cholesterol concentration, and it induced a decrease in bile acid concentrations. Increases in plasma glucose and insulin concentrations induced by 5-HT were attenuated by pre-treatment with Methysergide, a 5HTR 1, 2 and 7 antagonist. Additionally, decreased plasma bile acid concentrations induced by 5-HT were blocked by pre-treatment with Ketanserin, a 5HTR 2A antagonist. However, none of the 5HTR antagonists inhibited the increase in plasma triglyceride and NEFA levels induced by 5-HT. On the other hand, mRNA expressions of 5HTR1D and 1E were observed in the liver, pancreas and skeletal muscle. These results suggest that there are a number of differences in the physiological functions of peripheral 5-HT with respect to lipid metabolism between mice and sheep, though its effect on glucose metabolism appears to be similar between these species. PMID:24505376

  2. Allelic variation in the serotonin transporter promoter affects neuromodulatory effects of a selective serotonin transporter reuptake inhibitor (SSRI)

    Microsoft Academic Search

    Peter Eichhammer; Berthold Langguth; Rainer Wiegand; Alexander Kharraz; Ulrich Frick; Göran Hajak

    2003-01-01

      \\u000a \\u000a Rationale. Antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) has been shown to depend on functional polymorphisms\\u000a within the promoter region of the serotonin transporter gene (5-HTTLPR). This gene gives rise to a biallelic polymorphism\\u000a designated long (l) and short (s). Homozygosity for the long variant (ll-genotype) is associated with a two times more efficient\\u000a 5-HT uptake compared to

  3. Estradiol and brain serotonin reuptake transporter in long-term ovariectomized parkinsonian monkeys.

    PubMed

    Sánchez, Maria Gabriela; Morissette, Marc; Di Paolo, Thérèse

    2013-08-01

    This study evaluated the effect of a one month 17?-estradiol treatment on brain serotonin (5-HT) reuptake transporter (SERT) in long-term ovariectomized (OVX) female monkeys (Macaca fascicularis) bearing a unilateral lesion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injected directly into the left substantia nigra modeling Parkinson disease (PD). Ovariectomy and MPTP lesion were performed four years before the estrogen treatment to model postmenopausal PD patients. SERT was measured by autoradiography using the radioligand [(3)H]Citalopram. Specific binding to SERT decreased in anterior cerebral cortex, nucleus accumbens, caudate nucleus and putamen on the lesioned side of 17?-estradiol and vehicle-treated monkeys compared to the intact side. In caudate nucleus and putamen the lesioned-induced decrease of [(3)H]Citalopram specific binding was more extensive in anterior and middle than posterior parts. [(3)H]Citalopram specific binding was increased in the cortex anterior cingulate gyrus of monkeys treated with 17?-estradiol in both brain hemispheres and was unchanged in the other brain regions investigated including the raphe nucleus. Positive correlations between [(3)H]Citalopram specific binding and 5-HT as well as 5-HIAA concentrations (reported previously) were obtained in the caudate nucleus and putamen and a negative correlation between SERT binding and 5-HIAA/5-HT concentration ratio suggesting MPTP lesion-induced 5-HT neuronal loss and lower 5-HT neurotransmission controlling and decreasing SERT for homeostasis. 17?-estradiol treatment initiated four years after ovariectomy of monkeys modeling hormonal conditions of post-menopause shows that SERT still displays some responsiveness to estrogens as observed in the anterior cingulate cortex. These results support a role of estrogens in 5-HT activity in PD. PMID:23719069

  4. Combinatorial QSAR modeling of specificity and subtype selectivity of ligands binding to serotonin receptors 5HT1E and 5HT1F.

    PubMed

    Wang, Xiang S; Tang, Hao; Golbraikh, Alexander; Tropsha, Alexander

    2008-05-01

    The Quantitative Structure-Activity Relationship (QSAR) approach has been applied to model binding affinity and receptor subtype selectivity of human 5HT1E and 5HT1F receptor-ligands. The experimental data were obtained from the PDSP Ki Database. Several descriptor types and data-mining approaches have been used in the context of combinatorial QSAR modeling. Data mining approaches included k Nearest Neighbor, Automated Lazy Learning (ALL), and PLS; descriptor types included MolConnZ, MOE, DRAGON, Frequent Subgraphs (FSG), and Molecular Hologram Fingerprints (MHFs). Highly predictive QSAR models were generated for all three data sets (i.e., for ligands of both receptor subtypes and for subtype selectivity), and different individual techniques were proved best in each case. For real value activity data available for 5HT1E and 5HT1F ligand binding, models were characterized by leave-one-out cross-validated R(2) (q(2)) for the training sets and predictive R(2) values for the test sets. The best models for 5HT1E ligands were obtained with the kNN approach combined with MolConnZ descriptors (q(2)=0.69, R(2)=0.92); for 5HT1F ligands ALL QSAR method using MolConnZ descriptors gave the best results (R(2)=0.92). Rigorously validated classification models were also developed for the 5HT1E/5HT1F subtype selectivity data set with high correct classification accuracy for both training (CCRtrain=0.88) and test (CCRtest=1.00) sets using kNN with MolConnZ descriptors. The external predictive power of QSAR models was further validated by virtual screening of The Scripps Research Institute (TSRI) screening library to recover 5HT1E agonists and antagonists (not present in the original PDSP data set) with high enrichment factors. The successful development of externally predictive and interpretative QSAR models affords further design and discovery of novel subtype specific GPCR agents. PMID:18470978

  5. Effects of 5-hydroxytryptamine 2C receptor agonist MK212 and 2A receptor antagonist MDL100907 on maternal behavior in postpartum female rats.

    PubMed

    Chen, Weihai; Zhang, Qi; Su, Wenxin; Zhang, Haorong; Yang, Yu; Qiao, Jing; Sui, Nan; Li, Ming

    2014-02-01

    Maternal behavior in rats is a highly motivated and well-organized social behavior. Given the known roles of serotonin (5-HT) in emotion, motivation, social behavior, and major depression - and its known interaction with dopamine - it is likely that serotonin also plays a crucial role in this behavior. So far, there are surprisingly few studies focusing on 5-HT in maternal behavior, except for maternal aggression. In the present study, we examined the effects of 5-HT2C receptor agonism and 5-HT2A receptor antagonism on maternal behavior in postpartum female rats. We hypothesized that activation of 5-HT2C receptors and blockade of 5-HT2A receptors would produce a functionally equivalent disruption of maternal behavior because these two receptor subtypes often exert opposite effects on various brain functions and psychological processes relevant to rat maternal behavior. On postpartum Days 5, 7, and 9, Sprague-Dawley mother rats were given a single injection of 0.9% NaCl solution, the 5-HT2C agonist MK212 (0.5, 1.0 or 2.0 mg/kg, ip), or the 5-HT2A antagonist MDL100907 (0.05, 0.5 or 2.0 mg/kg, ip). Maternal behavior was tested 30 min before and 30 min, 120 min, 240 min after injection. Acute injection of MK212 significantly disrupted pup retrieval, pup licking, pup nursing, and nest building in a dose-dependent fashion. At the tested doses, MDL100907 had little effect on various components of rat maternal behavior. Across the 3 days of testing, no apparent sensitization or tolerance associated with repeated administration of MK212 and MDL100907 was found. We concluded that rat maternal performance is critically dependent on 5-HT2C receptors, while the role of 5-HT2A receptors is still inconclusive. Possible behavioral mechanisms of actions of 5-HT2C receptor in maternal behavior are discussed. PMID:24321440

  6. The 5-HT4 receptor levels in hippocampus correlates inversely with memory test performance in humans.

    PubMed

    Haahr, Mette Ewers; Fisher, Patrick; Holst, Klaus; Madsen, Karine; Jensen, Christian Gaden; Marner, Lisbeth; Lehel, Szabols; Baaré, William; Knudsen, Gitte; Hasselbalch, Steen

    2013-11-01

    The cerebral serotonin (5-HT) system is involved in cognitive functions such as memory and learning and animal studies have repeatedly shown that stimulation of the 5-HT type 4 receptor (5-HT4 R) facilitates memory and learning and further that the 5-HT4 R modulates cellular memory processes in hippocampus. However, any associations between memory functions and the expression of the 5-HT4 R in the human hippocampus have not been investigated. Using positron emission tomography with the tracer [(11) C]SB207145 and Reys Auditory Verbal Learning Test we aimed to examine the individual variation of the 5-HT4R binding in hippocampus in relation to memory acquisition and consolidation in healthy young volunteers. We found significant, negative associations between the immediate recall scores and left and right hippocampal BPND , (p = 0.009 and p = 0.010 respectively) and between the right hippocampal BPND and delayed recall (p = 0.014). These findings provide evidence that the 5-HT4 R is associated with memory functions in the human hippocampus and potentially pharmacological stimulation of the receptor may improve episodic memory. PMID:22736538

  7. Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth.

    PubMed

    Duhr, Fanny; Déléris, Paul; Raynaud, Fabrice; Séveno, Martial; Morisset-Lopez, Séverine; Mannoury la Cour, Clotilde; Millan, Mark J; Bockaert, Joël; Marin, Philippe; Chaumont-Dubel, Séverine

    2014-07-01

    The serotonin6 receptor (5-HT6R) is a promising target for treating cognitive deficits of schizophrenia often linked to alterations of neuronal development. This receptor controls neurodevelopmental processes, but the signaling mechanisms involved remain poorly understood. Using a proteomic strategy, we show that 5-HT6Rs constitutively interact with cyclin-dependent kinase 5 (Cdk5). Expression of 5-HT6Rs in NG108-15 cells induced neurite growth and expression of voltage-gated Ca(2+) channels, two hallmarks of neuronal differentiation. 5-HT6R-elicited neurite growth was agonist independent and prevented by the 5-HT6R antagonist SB258585, which behaved as an inverse agonist. Moreover, it required receptor phosphorylation at Ser350 by Cdk5 and Cdc42 activity. Supporting a role of native 5-HT6Rs in neuronal differentiation, neurite growth of primary neurons was reduced by SB258585, by silencing 5-HT6R expression or by mutating Ser350 into alanine. These results reveal a functional interplay between Cdk5 and a G protein-coupled receptor to control neuronal differentiation. PMID:24880860

  8. Interaction between 5-HT1B receptors and nitric oxide in zebrafish responses to novelty.

    PubMed

    Maximino, Caio; Lima, Monica Gomes; Batista, Evander de Jesus Oliveira; Oliveira, Karen Renata Herculano Matos; Herculano, Anderson Manoel

    2015-02-19

    Nitric oxide (NO) and serotonin (5-HT) interact at the molecular and systems levels to control behavioral variables, including agression, fear, and reactions to novelty. In zebrafish, the 5-HT1B receptor has been implicated in anxiety and reactions to novelty, while the 5-HT1A receptor is associated with anxiety-like behavior; this role of the 5-HT1A receptor is mediated by NO. This work investigated whether NO also participates in the mediation of novelty responses by the 5-HT1B receptor. The 5-HT1B receptor inverse agonist SB 224,289 decreased bottom-dwelling and erratic swimming in zebrafish; the effects on bottom-dwelling, but not on erratic swimming, were blocked by pre-treatment with the nitric oxide synthase inhibitor L-NAME. These effects underline a novel mechanism by which 5-HT controls zebrafish reactivity to novel environments, with implications for the study of neotic reactions, exploratory behavior, and anxiety-like states. PMID:25545556

  9. Luciferase Reporter Gene Assay on Human 5-HT Receptor: Which Response Element Should Be Chosen?

    PubMed Central

    Chen, Yiming; Xu, Zhongyu; Wu, Dang; Li, Jian; Song, Cheng; Lu, Weiqiang; Huang, Jin

    2015-01-01

    Serotonin (5-HT) receptors are valuable molecular targets for antipsychotic drug discovery. Current reported methods for detecting 5-HT receptors, such as cAMP accumulation and calcium influx assay, are often demanding specialized instruments and inconvenient. The luciferase reporter gene assay, based on the responsible-element-regulated expression of luciferase, has been widely applied in the high-throughput functional assay for many targets because of its high sensitivity and reliability. However, 5-HT receptors couple to multiple G-proteins regulate respective downstream signalling pathways and are usually detected using different response elements. Hence, finding a suitable response element to fulfil the detection of different 5-HT receptors and make the results of luciferase reporter gene assays generalizable is very useful for active compounds screening. Here, we conducted three luciferase reporter assays using CRE, NFAT, and SRE response elements attached to 5-HT to detect the activation of different 5-HT receptors in CHO-K1 cells. The potencies and efficacies of the reported ligands (agonists and antagonists) were determined and compared. Our results indicate that CRE-luciferase reporter gene is sensitive and reliable to detect the activities of G protein-coupled 5-HT receptors. PMID:25622827

  10. 5-HT2C Receptors Localize to Dopamine and GABA Neurons in the Rat Mesoaccumbens Pathway

    PubMed Central

    Bubar, Marcy J.; Stutz, Sonja J.; Cunningham, Kathryn A.

    2011-01-01

    The serotonin 5-HT2C receptor (5-HT2CR) is localized to the limbic-corticostriatal circuit, which plays an integral role in mediating attention, motivation, cognition, and reward processes. The 5-HT2CR is linked to modulation of mesoaccumbens dopamine neurotransmission via an activation of ?-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA). However, we recently demonstrated the expression of the 5-HT2CR within dopamine VTA neurons suggesting the possibility of a direct influence of the 5-HT2CR upon mesoaccumbens dopamine output. Here, we employed double-label fluorescence immunochemistry with the synthetic enzymes for dopamine (tyrosine hydroxylase; TH) and GABA (glutamic acid decarboxylase isoform 67; GAD-67) and retrograde tract tracing with FluoroGold (FG) to uncover whether dopamine and GABA VTA neurons that possess 5-HT2CR innervate the nucleus accumbens (NAc). The highest numbers of FG-labeled cells were detected in the middle versus rostral and caudal levels of the VTA, and included a subset of TH- and GAD-67 immunoreactive cells, of which >50% also contained 5-HT2CR immunoreactivity. Thus, we demonstrate for the first time that the 5-HT2CR colocalizes in DA and GABA VTA neurons which project to the NAc, describe in detail the distribution of NAc-projecting GABA VTA neurons, and identify the colocalization of TH and GAD-67 in the same NAc-projecting VTA neurons. These data suggest that the 5-HT2CR may exert direct influence upon both dopamine and GABA VTA output to the NAc. Further, the indication that a proportion of NAc-projecting VTA neurons synthesize and potentially release both dopamine and GABA adds intriguing complexity to the framework of the VTA and its postulated neuroanatomical roles. PMID:21687728