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Effects of metformin on intestinal 5-hydroxytryptamine (5HT) release and on 5HT 3 receptors  

Microsoft Academic Search

Nearly 30% of patients treated with metformin experience gastrointestinal side effects. Since release of 5-hydroxytryptamine (5-HT) from the intestine is associated with nausea, vomiting, and diarrhea, we examined whether metformin induces 5-HT release from the intestinal mucosa. In 40% of tissue biopsy specimens of human duodenal mucosa, metformin (1, 10, and 30 µM) caused an increase in 5-HT outflow by

L. X. Cubeddu; H. Bönisch; M. Göthert; G. Molderings; K. Racké; G. Ramadori; K. J. Miller; H. Schwörer



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

Microsoft Academic Search

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).

Philippe Schoeffter; Daniel Hoyer



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

PubMed Central

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

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



Stimulation of Growth Hormone Release by 5Hydroxytryptamine (5HT) in Cultured Rat Anterior Pituitary Cell Aggregates: Evidence for Mediation by 5HT2B, 5HT7, 5HT1B, and Ketanserin-Sensitive Receptors  

Microsoft Academic Search

5-Hydroxytryptamine (5-HT) promotes the release of GH by a hypothalamic site of action. The present study explores a pu- tative pituitary action in a perifused rat anterior pituitary aggregate cell culture system. In aggregates cultured with 1 nMestradiolforexpressionofthe5-HT4,-5,and-6receptor(R), 5-HT promptly stimulated GH secretion with a dose depen- dency between 1 and 10 nM. The effect of 5-HT was partially blocked

A. Papageorgiou; C. Denef



Electron Microscopic Cytochemistry of 5-Hydroxytryptamine (5-HT) in the Beta Cells of Guinea Pig Endocrine Pancreas.  

National Technical Information Service (NTIS)

In order to localize 5-hydroxytryptamine (5-HT) stores in the islet of Langerhans of guinea pig pancreas, a cytochemical procedure for the ultrastructural differentiation between catecholamines and indoleamines was used. Islet tissue of animals receiving ...

G. Jaim-Etcheverry L. M. Zieher



5Hydroxytryptamine receptors with a 5HT 6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes  

Microsoft Academic Search

This study deals with the characterization of 5-hydroxytryptamine (5-HT, serotonin) receptors positively linked to adenylyl cyclase in membranes from pig brain caudate. 5-HT and related agonists induced a concentration-dependent stimulation of adenylyl cyclase activity in pig caudate membranes, with the following rank order of potency (mean pEC50 values): 5-HT (7.1) = 5-methoxytryptamine (6.9) > 5-carboxamidotryptamine (5.6) > sumatriptan (50 values

Philippe Schoeffter; Christian Waeber



Roles of 5-hydroxytryptamine (5-HT) receptor subtypes in the inhibitory effects of 5-HT on C-fiber responses of spinal wide dynamic range neurons in rats.  


5-Hydroxytryptamine (5-HT; serotonin) plays an important role in the descending control of nociception. 5-HT and its receptors have been extensively studied in the modulation of nociceptive transmission at the spinal level using behavioral tests that may be affected by the effects of 5-HT on motor performance and skin temperature. Using electrophysiological methods, the present study aimed to systematically investigate the roles of 5-HT receptor subtypes on the inhibitory effects of 5-HT on responses of the spinal wide dynamic range (WDR) neurons to C-fiber inputs in rats. Under basal conditions, topical application of 5-HT to the spinal cord inhibited the C-fiber responses of WDR neurons dose-dependently, whereas antagonists of 5-HT(1A) [WAY 100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate salt

Liu, Feng-Yu; Xing, Guo-Gang; Qu, Xiao-Xiu; Xu, Isabella S; Han, Ji-Sheng; Wan, You



Mechanism of block by fluoxetine of 5-hydroxytryptamine 3 (5HT 3)-mediated currents in NCB20 neuroblastoma cells  

Microsoft Academic Search

The effect of fluoxetine (Prozac) on 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells was examined using the whole-cell patch-clamp technique. Fluoxetine produced a significant reduction of peak amplitude without altering the activation time course of 5-HT3-mediated currents. These effects were concentration-dependent, with an ic50 value of 4.15?M. No voltage dependence was evident in fluoxetine’s block of 5-HT3-mediated currents over the

Jin-Sung Choi; Bok Hee Choi; Hye Sook Ahn; Myung-Jun Kim; Duck-Joo Rhie; Shin Hee Yoon; Do Sik Min; Yang-Hyeok Jo; Myung-Suk Kim; Ki-Wug Sung; Sang June Hahn



The action of SDZ 205,557 at 5-hydroxytryptamine (5-HT3 and 5-HT4) receptors.  

PubMed Central

1. The interaction of the novel antagonist, SDZ 205,557 (2-methoxy-4-amino-5-chloro benzoic acid 2-(diethylamino) ethyl ester), at 5-HT3 and 5-HT4 receptors has been assessed in vitro and in vivo. 2. In guinea-pig hippocampus and in the presence of 0.4 microM 5-carboxamidotryptamine, 5-HT4-mediated stimulation of adenylyl cyclase was competitively antagonized by SDZ 205,557, with a pA2 value of 7.5, and a Schild slope of 0.81. In rat carbachol-contracted oesophagus, 5-HT4-receptor mediated relaxations were surmountably antagonized by SDZ 205,557 with a similar pA2 value (7.3). This value was agonist-independent with the exception of (R)-zacopride, against which a significantly lower value (6.4) was observed. 3. In functional studies of 5-HT3 receptors, SDZ 205,557 exhibited an affinity of 6.2 in guinea-pig ileum compared with 6.9 at binding sites labelled by [3H]-quipazine in NG108-15 cells. In the anaesthetized, vagotomized micropig, SDZ 205,557 produced only a transient blockade of 5-HT4-mediated tachycardia. This contrasted with tropisetron, which was active for over 60 min after administration. The half-lives for the inhibitory responses of SDZ 205,557 and tropisetron were 23 and 116 min, respectively. 4. In conclusion, SDZ 205,557 has similar affinity for 5-HT3 and 5-HT4 receptors. The apparent selectivity observed in guinea-pig is due to the atypical nature of the 5-HT3 receptor in this species. The short duration of action of this novel antagonist may complicate its use in vivo. SDZ 205,557 should, therefore, be used with appropriate caution in studies defining the 5-HT4 receptor.

Eglen, R. M.; Alvarez, R.; Johnson, L. G.; Leung, E.; Wong, E. H.



5-HT1-like receptors mediate 5-hydroxytryptamine-induced contraction of guinea-pig isolated iliac artery.  

PubMed Central

1. The effects of 5-hydroxytryptamine (5-HT) and of the 5-HT1-like receptor agonists, 5-carboxamidotryptamine (5-CT) and sumatriptan (GR43175) were investigated in isolated ring preparations of guinea-pig common iliac artery. 2. The three agonists induced very weak, if any, contractions of unstimulated preparations, whereas they elicited concentration-dependent contractions in preparations given a moderate tone by a threshold concentration of prostaglandin F2 alpha (PGF2 alpha). 3. Under the latter conditions, Emax values for 5-HT and 5-CT reached about 45% of PGF2 alpha maximal effect, whereas the Emax value of sumatriptan was significantly lower (about 35%). The rank order of potency (mean EC50 value, nM) was 5-CT (6.6) greater than 5-HT (22.9) greater than sumatriptan (155). Pargyline, cocaine or deoxycorticosterone were without significant effect on the contractions induced by 5-HT. 4. The 5-HT3 receptor antagonist, (1 alpha H, 3 alpha,5 alpha H-tropan-3-yl) 1-H-indole-3-carboxylic acid ester (ICS 205-930; 1 microM), had no effect on 5-HT-, 5-CT- and sumatriptan-induced contractions. 5. The 5-HT2 receptor antagonist, ketanserin (1 microM) caused only small rightward shifts (concentration-ratios, about 2) in the concentration-response curves to 5-HT, 5-CT and sumatriptan without significantly depressing the maximum effects. 6. In the presence of ketanserin (1 microM), the non-selective 5-HT receptor antagonist, methiothepin (0.1 microM), shifted the concentration-response curves to 5-HT and 5-CT to the right in a parallel manner and to a similar extent for both agonists (respective mean pKB values, 8.07 and 8.27).(ABSTRACT TRUNCATED AT 250 WORDS)

Sahin-Erdemli, I.; Hoyer, D.; Stoll, A.; Seiler, M. P.; Schoeffter, P.



Mediation of 5-hydroxytryptamine-induced tachycardia in the pig by the putative 5-HT4 receptor.  

PubMed Central

Intravenous bolus injections of 5-hydroxytryptamine (5-HT; 3, 10 and 30 micrograms kg-1), 5-methoxytryptamine (5-MeO-T; 3, 10 and 30 micrograms kg-1), renzapride (BRL 24924; 3, 10, 30 and 100 micrograms kg-1) and isoprenaline (0.03, 0.1 and 0.3 micrograms kg-1) to anaesthetized pigs increased heart rate by, respectively, 22 +/- 3, 44 +/- 3 and 65 +/- 4 beats min-1 (5-HT; n = 17); 12 +/- 1, 26 +/- 2 and 44 +/- 4 beats min-1 (5-MeO-T; n = 15), 5 +/- 2, 11 +/- 2, 18 +/- 4 and 37 +/- 5 beats min-1 (renzapride; n = 8) and 17 +/- 2, 46 +/- 3 and 75 +/- 3 beats min-1 (isoprenaline; n = 13). The responses to 5-HT, 5-MeO-T and renzapride were antagonized by ICS 205-930 (1 and 3 mg kg-1, i.v.), which did not modify the increases in heart rate by isoprenaline. Renzapride showed tachyphylaxis and attenuated the responses to 5-HT. These findings indicate that 5-HT elicits tachycardia in the pig by acting on a novel receptor, either similar or identical to the 5-HT4 receptor identified in mouse brain colliculi.

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



Cisapride and structural analogs selectively enhance 5-hydroxytryptamine (5-HT)-induced purinergic neurotransmission in the guinea pig proximal colon.  


In the guinea pig proximal colon, 5-hydroxytryptamine (5-HT) stimulates neuronal 5-HT1-like receptors to induce relaxations that are mediated by nitric oxide and ATP. In the current study, the effects of cisapride and structural analogs on these 5-HT-induced relaxations were investigated. In the continuous presence of ketanserin (0.3 microM) and tropisetron (3 microM) to block contractions via 5-HT2A, 5-HT3 and 5-HT4 receptors, 5-HT induced relaxations that yielded a biphasic concentration-response curve. Cisapride (0.1-1 microM) enhanced the second phase of the concentration-response curve to 5-HT by about 20% to 40%, whereas from 0.3 microM onwards, it inhibited the first phase. Also in the presence of cisapride (0.3 microM), tetrodotoxin (0.3 microM) abolished the relaxations to 5-HT. Cisapride (0.3 microM) did not affect the concentration-response curves to isoprenaline, nitroglycerin, nitroprusside or exogenous ATP, which demonstrated its specificity. The 5-HT relaxation-enhancing effects of cisapride were not mimicked by phentolamine (1 microM), NAN-190 (0.03 microM), spiperone (1 microM), citalopram (0.3 microM), paroxetine (0.3 microM), pargyline (100 microM) or SDZ 205-557 (0.3 microM). In the presence of the inhibitor of nitric oxide synthesis, NG-nitro-L-arginine (100 microM), cisapride (0.3 microM) still enhanced the remaining relaxations to 5-HT (2-3-fold). However, in the presence of the P2-purinoceptor antagonist suramin (300 microM), cisapride did not enhance the relaxations to 5-HT. In the presence of NG-nitro-L-arginine, the cisapride-enhanced relaxations to 5-HT were inhibited by about 90% by suramin. We conclude that in the guinea pig colon, cisapride selectively facilitates the suramin-sensitive, ATP-mediated part of the relaxation to 5-HT via an unidentified effect on intramural nerves. PMID:7636723

Briejer, M R; Veen, G J; Akkermans, L M; Lefebvre, R A; Schuurkes, J A



Molecular cloning and functional expression of 5-HT1E-like rat and human 5-hydroxytryptamine receptor genes.  

PubMed Central

Sequential polymerase chain reaction experiments were performed to amplify a unique sequence representing a guanine nucleotide-binding protein (G-protein)-coupled receptor from rat hypothalamic cDNA. Degenerate oligonucleotides corresponding to conserved amino acids from transmembrane domains III, V, and VI of known receptors [5-HT1A, 5-HT1C, and 5-HT2; 5-HT is serotonin (5-hydroxytryptamine)] were used as primers for the sequential reactions. The resulting product was subcloned and used to screen a rat genomic library to identify a full-length clone (MR77) containing an intronless open reading frame encoding a 366-amino acid seven-transmembrane domain protein. The human homolog was isolated, and its encoded protein had 93% overall amino acid identity with the rat sequence. Within the conserved transmembrane domains, the sequences exhibit approximately 52%, 59%, 65%, and 68% amino acid identity with the known rat 5-HT1A, rat 5-HT1B, rat 5-HT1D, and human 5-HT1E receptors, respectively. MR77 was subcloned into a eukaryotic expression vector system and expressed in CosM6 cells. Studies on broken cell preparations indicate that the expressed receptor exhibits 125I-labeled d-lysergic acid diethylamide (LSD) binding that can be displaced by serotonin but not by other biogenic amines. The specific binding is displaced by the selective 5-HT1D agonist sumatriptan but not by the mixed 5-HT1A/1D agonist 5-carboxyamidotryptamine. 125I-labeled LSD binding was competitively antagonized by the ergot alkaloids methysergide and ergotamine. HeLa cells transfected with the MR77 gene exhibited inhibition of adenylate cyclase in response to serotonin. MR77 is expressed at low levels throughout the brain, with the greatest expression in the cortex, hippocampus, and striatum. MR77 thus represents a 5-HT receptor of the 5-HT1 class, and we propose that, based on the pharmacological characterization, MR77 represents an additional 5-HT1E-like receptor. Images Fig. 3

Lovenberg, T W; Erlander, M G; Baron, B M; Racke, M; Slone, A L; Siegel, B W; Craft, C M; Burns, J E; Danielson, P E; Sutcliffe, J G



Stimulation of growth hormone release by 5-hydroxytryptamine (5-HT) in cultured rat anterior pituitary cell aggregates: evidence for mediation by 5-HT2B, 5-HT7, 5-HT1B, and ketanserin-sensitive receptors.  


5-Hydroxytryptamine (5-HT) promotes the release of GH by a hypothalamic site of action. The present study explores a putative pituitary action in a perifused rat anterior pituitary aggregate cell culture system. In aggregates cultured with 1 nM estradiol for expression of the 5-HT4, -5, and -6 receptor (R), 5-HT promptly stimulated GH secretion with a dose dependency between 1 and 10 nM. The effect of 5-HT was partially blocked by methiothepin and methysergide; by SB-206553, a 5-HTR2B/C antagonist; SB-269970, a 5-HTR7/5A antagonist; and SB-224289, a 5-HTR1B antagonist. The GH response was fully blocked by combined administration of SB-206553+SB-269970 and SB-206553+ketanserin but not by SB-206553+spiperone. Culturing the aggregates without estradiol diminished the magnitude of the GH response to 5-HT as well as the impact of 5-HTR7/5 blockade on the response. Basal GH release was stimulated by the 5-HTR2 agonists 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, m-chlorophenyl piperazine, and alpha-methyl 5-HT; 5-carboxytryptamine (agonist at 5-HTR1, -5, and -7); tryptamine (preferential 5-HTR7 agonist); and the selective 5-HTR1B agonist CP93129 but not the 5-HTR1A agonists 7-(dipropylamino)tetralin-1-ol-8-hydroxy-2-(di-n-propylamino)tetralin and the 5-HTR1B/D agonist sumatriptan. The selective 5-HTR2B agonist BW 723C86 stimulated GH release, and the selective 5-HTR2B antagonist SB-204741 attenuated the GH response to 5-HT. The present data suggest that 5-HT may release GH through a pituitary site of action, and that the 5-HTR2B, 5-HTR7 and 5-HTR1B mediate this response, with possibly an inhibitory component of the 5-HTR1D. The relative contribution of these receptors may be modulated by estrogen. PMID:17584957

Papageorgiou, A; Denef, C



Endogenous activation of spinal 5-hydroxytryptamine (5-HT) receptors contributes to the thermoregulatory activation of brown adipose tissue.  


Neurons in the rostral raphe pallidus (RPa) play an essential role in the regulation of sympathetically mediated metabolism and thermogenesis in brown adipose tissue (BAT). The presence of serotonergic neurons in the RPa that are retrogradely labeled following pseudorabies virus injections into BAT suggests that these neurons play a role in the regulation of BAT. In urethane/chloralose-anesthetized rats, whole body cooling decreased skin (-5.7 +/- 2.3 degrees C) and core (-1.3 +/- 0.2 degrees C) temperatures and resulted in an increase in BAT sympathetic nerve activity (SNA; +1,026 +/- 344% of baseline activity). Serial microinjections of the 5-hydroxytryptamine (5-HT) receptor antagonist, methysergide (1.2 nmol/site), but not saline vehicle, into the intermediolateral cell column (IML) in spinal segments T2-T5 markedly attenuated the cooling-evoked increase in BAT SNA (remaining area under the curve, AUC: 36 +/- 9% of naive cooling response). Microinjections of the 5-HT(1A) receptor antagonist, WAY-100635 (1.2 nmol/site), or the 5-HT(7) receptor antagonist, SB-269970 (1.2 nmol/site), into the T2-T5 IML also attenuated the cold-evoked increase in BAT SNA (remaining activity at peak inhibition: 47 +/- 8% and 39 +/- 12% of the initial cold-evoked response, respectively). The increases in BAT SNA evoked by microinjection of N-methyl-d-aspartate (NMDA) (12 pmol) or bicuculline (30 pmol) into the RPa were attenuated following microinjections of methysergide, but not saline vehicle, into the T2-T5 IML (NMDA remaining AUC, 64 +/- 13% of naive response; bicuculline remaining AUC, 52 +/- 5% of naive response). These results are consistent with our earlier demonstration of a potentiating effect of 5-HT within the IML on BAT SNA and indicate that activation of 5-HT(1A) and 5-HT(7) receptors in the spinal cord contributes to increases in BAT SNA and thermogenesis. PMID:20071609

Madden, Christopher J; Morrison, Shaun F



Endogenous activation of spinal 5-hydroxytryptamine (5-HT) receptors contributes to the thermoregulatory activation of brown adipose tissue  

PubMed Central

Neurons in the rostral raphe pallidus (RPa) play an essential role in the regulation of sympathetically mediated metabolism and thermogenesis in brown adipose tissue (BAT). The presence of serotonergic neurons in the RPa that are retrogradely labeled following pseudorabies virus injections into BAT suggests that these neurons play a role in the regulation of BAT. In urethane/chloralose-anesthetized rats, whole body cooling decreased skin (?5.7 ± 2.3°C) and core (?1.3 ± 0.2°C) temperatures and resulted in an increase in BAT sympathetic nerve activity (SNA; +1,026 ± 344% of baseline activity). Serial microinjections of the 5-hydroxytryptamine (5-HT) receptor antagonist, methysergide (1.2 nmol/site), but not saline vehicle, into the intermediolateral cell column (IML) in spinal segments T2–T5 markedly attenuated the cooling-evoked increase in BAT SNA (remaining area under the curve, AUC: 36 ± 9% of naive cooling response). Microinjections of the 5-HT1A receptor antagonist, WAY-100635 (1.2 nmol/site), or the 5-HT7 receptor antagonist, SB-269970 (1.2 nmol/site), into the T2–T5 IML also attenuated the cold-evoked increase in BAT SNA (remaining activity at peak inhibition: 47 ± 8% and 39 ± 12% of the initial cold-evoked response, respectively). The increases in BAT SNA evoked by microinjection of N-methyl-d-aspartate (NMDA) (12 pmol) or bicuculline (30 pmol) into the RPa were attenuated following microinjections of methysergide, but not saline vehicle, into the T2–T5 IML (NMDA remaining AUC, 64 ± 13% of naive response; bicuculline remaining AUC, 52 ± 5% of naive response). These results are consistent with our earlier demonstration of a potentiating effect of 5-HT within the IML on BAT SNA and indicate that activation of 5-HT1A and 5-HT7 receptors in the spinal cord contributes to increases in BAT SNA and thermogenesis.

Morrison, Shaun F.



Yohimbine and rauwolscine inhibit 5-hydroxytryptamine-induced contraction of large coronary arteries of calf through blockade of 5 HT 2 receptors  

Microsoft Academic Search

5-Hydroxytryptamine (5 HT)-induced contractions were investigated on cocaine-treated strips of bovine large coronary arteries.1.The a2-adrenoceptor blockers rauwolscine and yohimbine antagonized competitively 5 HT-induced contractions. The estimated equilibrium dissociation constantsKB (-log mol\\/l) were 7.1 for rauwolscine and 7.3 for yohimbine. The affinity of yohimbine for the receptors mediating the response to 5HT appears to be 10 times higher than for postsynaptic

A. J. Kaumann



5-hydroxytryptamine level and 5-HT2A receptor mRNA expression in the guinea pigs eyes with spectacle lens-induced myopia  

PubMed Central

AIM To investigate 5-hydroxytryptamine (5-HT) function and 5-HT receptor 2A (5-HT2A) mRNA expression in the formation of lens-induced myopia (LIM). METHODS Lens-induced myopia construction method was applied to generate myopia on guinea pig right eye (LIM eye). RESULTS LIM eyes formed significant myopia with longer axial length. 5-HT level in retina, choroids and sclera from LIM eyes was significantly higher than that in control group. 5-HT2A mRNA expression was also significantly up-regulated. CONCLUSION Refraction lens could induce myopia in guinea pig and 5-HT may play an important role in the formation of myopia by binding with 5-HT2A receptor.

Yang, Ji-Wen; Xu, Yan-Chun; Sun, Lin; Tian, Xiao-Dan



Roles of 5Hydroxytryptamine (5HT) Receptor Subtypes in the Inhibitory Effects of 5HT on C-Fiber Responses of Spinal Wide Dynamic Range Neurons in Rats  

Microsoft Academic Search

Hydroxytryptamine (5-HT; serotonin) plays an important role in the descending control of nociception. 5-HT and its receptors have been extensively studied in the modulation of nociceptive transmission at the spinal level using behavioral tests that may be affected by the effects of 5-HT on motor performance and skin temperature. Using electrophysiological methods, the present study aimed to systematically investigate the

Feng-Yu Liu; Guo-Gang Xing; Xiao-Xiu Qu; Isabella S. Xu; Ji-Sheng Han; You Wan



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

Microsoft Academic Search

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

Anders Pettersson; Bengt Persson; Matts Henning; Thomas Hedner



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


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

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



Oligomer Size of the Serotonin 5-Hydroxytryptamine 2C (5-HT2C) Receptor Revealed by Fluorescence Correlation Spectroscopy with Photon Counting Histogram Analysis  

PubMed Central

Fluorescence correlation spectroscopy (FCS) and photon counting histogram (PCH) are techniques with single molecule sensitivity that are well suited for examining the biophysical properties of protein complexes in living cells. In the present study, FCS and PCH were applied to determine the diffusion coefficient and oligomeric size of G-protein-coupled receptors. FCS was used to record fluctuations in fluorescence intensity arising from fluorescence-tagged 5-hydroxytryptamine 2C (5-HT2C) receptors diffusing within the plasma membrane of HEK293 cells and rat hippocampal neurons. Autocorrelation analysis yielded diffusion coefficients ranging from 0.8 to 1.2 ?m2/s for fluorescence-tagged receptors. Because the molecular brightness of a fluorescent protein is directly proportional to the number of fluorescent proteins traveling together within a protein complex, it can be used to determine the oligomeric size of the protein complex. FCS and PCH analysis of fluorescence-tagged 5-HT2C receptors provided molecular brightness values that were twice that of GFP and YFP monomeric controls, similar to a dimeric GFP control, and unaltered by 5-HT. Bimolecular fluorescence complementation of the N- and C-terminal halves of YFP attached to 5-HT2C receptors was observed in endoplasmic reticulum/Golgi and plasma membranes with a brightness equal to monomeric YFP. When GFP-tagged 5-HT2C receptors were co-expressed with a large excess of untagged, non-fluorescent 5-HT2C receptors, the molecular brightness was reduced by half. PCH analysis of the FCS data were best described by a one-component dimer model without monomers or tetramers. Therefore, it is concluded that 5-HT2C receptors freely diffusing within the plasma membrane are dimeric.

Herrick-Davis, Katharine; Grinde, Ellinor; Lindsley, Tara; Cowan, Ann; Mazurkiewicz, Joseph E.



5-Hydroxytryptamine 6 receptor (5-HT(6)) receptor and apolipoprotein E (ApoE) polymorphisms in patients with Alzheimer's disease in the Basque Country.  


Although there is considerable evidence implicating apolipoprotein E (ApoE) epsilon4 in the development of the Alzheimer's disease (AD), additional factors are also known to be involved. Thus, an association has been described between C267T polymorphism of the 5-hydroxytryptamine 6 receptor (5-HT(6)) receptor gene and AD. This case-control study analyzes the ApoE and 5-HT(6) receptor polymorphisms in 173 cases and 102 age and sex matched controls from Araba and Bizkaia (The Basque Country, Spain). The analysis of ApoE showed the frequencies of epsilon4 allele to be significantly higher in AD patients (0.292) than in the controls (0.083). When 5-HT(6) receptor polymorphism was analyzed, a greater frequency of 267C allele was observed in AD patients than in controls, though the difference was not statistically significant. Likewise regarding ApoE epsilon4 status, no statistically significant difference was observed. In conclusion, the association of ApoE epsilon4 to AD in a sample of patients from the Basque Country is confirmed, though the association to C267T polymorphism of the 5-HT(6) receptor has not been observed. PMID:12618306

Alvarez-Alvarez, Maite; Galdos, Luis; Fernández-Martínez, Manuel; Gómez-Busto, Fernando; García-Centeno, Victoria; Arias-Arias, Caridad; Sánchez-Salazar, Carmen; Rodríguez-Martínez, Ana Belén; Zarranz, Juan José; de Pancorbo, Marian M



5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases.  

PubMed Central

1. The distribution, pharmacology and effects of neurodegenerative diseases on 5-HT4 receptors in human brain have been characterized in vitro. 2. The 5-HT4 receptor in post mortem human brain tissue was specifically labelled with [3H]-GR 113808. In human putamen, this ligand labelled a homogeneous population of sites, with an apparent affinity (-log Kd) of 10.1 and a density (Bmax) of 5.73 fmol mg-1 tissue. The pharmacology of this site was characterized by use of a series of displacing ligands, and the following rank order of apparent affinities (with mean +/- s.d. -log Ki values in parentheses) was generated: GR113808 (10.05 +/- 0.04) > SDZ 205,557 (8.65 +/- 0.08) > DAU 6285 (7.95 +/- 0.04) > BIMU-1 (7.81 +/- 0.06) > DAU 6215 (7.42 +/- 0.23) > tropisetron (7.39 +/- 0.23) > 5-HT (7.32 +/- 1.00) > BIMU-8 (7.25 +/- 0.04) > (R)-zacopride (5.82 +/- 0.04). The Hill coefficients were not significantly different from unity, consistent with an interaction at a single site. A comparison of the affinities of these compounds with those obtained from guinea-pig striatum indicated no evidence of species differences. 3. The regional distribution of 5-HT4 receptors was assessed by determining the density of binding sites for [3H]-GR 113808.(ABSTRACT TRUNCATED AT 250 WORDS)

Reynolds, G P; Mason, S L; Meldrum, A; De Keczer, S; Parnes, H; Eglen, R M; Wong, E H



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

NASA Astrophysics Data System (ADS)

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

Yang, Yue; Gao, Hongwei



Pharmacological studies on YM992, a novel antidepressant with selective serotonin re-uptake inhibitory and 5-HT2A receptor antagonistic activity.  


YM992 ((S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride) is a novel compound that has selective serotonin (5-hydroxytryptamine, 5-HT) re-uptake inhibition and 5-HT2A receptor antagonistic activity in vivo. YM992, fluoxetine and citalopram showed 5-HT uptake inhibition activity in l-5-hydroxy-tryptophan (l-5-HTP)-treated mice. YM992 and trazodone attenuated 5-HT2A/2C receptor agonist-induced head-twitches in mice, indicating that these drugs had 5-HT2A receptor antagonistic activity. YM992 and amitriptyline were highly active in the mouse tail suspension test. In contrast, fluoxetine and citalopram showed only a tendency to reduce the immobility time. Single treatment with YM992 as well as trazodone and fluoxetine ameliorated the learning deficit of olfactory-bulbectomized rats, whereas citalopram and amitriptyline showed an ameliorative effect only after chronic treatment. Although YM992 has moderate affinity for alpha1-adrenoceptors, alpha1-adrenoceptor antagonism of YM992 in vivo was 10 times weaker than that of trazodone. These results demonstrate that YM992 has 5-HT uptake inhibition and 5-HT2A receptor antagonistic activity in vivo, and suggest that YM992 may be a novel antidepressant with high efficacy in clinical use. PMID:9218680

Takeuchi, H; Yatsugi, S; Hatanaka, K; Nakato, K; Hattori, H; Sonoda, R; Koshiya, K; Fujii, M; Yamaguchi, T



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

Microsoft Academic Search

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 (\\




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

Microsoft Academic Search

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

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



5-HT1A and 5-HT7 receptor crosstalk in the regulation of emotional memory: implications for effects of selective serotonin reuptake inhibitors.  


This study utilized pharmacological manipulations to analyze the role of direct and indirect activation of 5-HT(7) receptors (5-HT(7)Rs) in passive avoidance learning by assessing emotional memory in male C57BL/6J mice. Additionally, 5-HT(7)R binding affinity and 5-HT(7)R-mediated protein phosphorylation of downstream signaling targets were determined. Elevation of 5-HT by the selective serotonin reuptake inhibitor (SSRI) fluoxetine had no effect by itself, but facilitated emotional memory performance when combined with the 5-HT(1A)R antagonist NAD-299. This facilitation was blocked by the selective 5-HT(7)R antagonist SB269970, revealing excitatory effects of the SSRI via 5-HT(7)Rs. The enhanced memory retention by NAD-299 was blocked by SB269970, indicating that reduced activation of 5-HT(1A)Rs results in enhanced 5-HT stimulation of 5-HT(7)Rs. The putative 5-HT(7)R agonists LP-44 when administered systemically and AS19 when administered both systemically and into the dorsal hippocampus failed to facilitate memory. This finding is consistent with the low efficacy of LP-44 and AS19 to stimulate protein phosphorylation of 5-HT(7)R-activated signaling cascades. In contrast, increasing doses of the dual 5-HT(1A)R/5-HT(7)R agonist 8-OH-DPAT impaired memory, while co-administration with NAD-299 facilitated of emotional memory in a dose-dependent manner. This facilitation was blocked by SB269970 indicating 5-HT(7)R activation by 8-OH-DPAT. Dorsohippocampal infusion of 8-OH-DPAT impaired passive avoidance retention through hippocampal 5-HT(1A)R activation, while 5-HT(7)Rs appear to facilitate memory processes in a broader cortico-limbic network and not the hippocampus alone. PMID:22801295

Eriksson, Therese M; Holst, Sarah; Stan, Tiberiu L; Hager, Torben; Sjögren, Benita; Ogren, Sven Öve; Svenningsson, Per; Stiedl, Oliver



N-{[2-(4-Phenyl-piperazin-1-yl)-ethyl]-phenyl}-arylamides with Dopamine D2 and 5-Hydroxytryptamine 5HT1 A Activity: Synthesis, Testing, and Molecular Modeling.  


The ratio of affinities toward the dopamine D2 and the 5-hydroxytryptamine 5-HT1A receptors is one of the important parameters that determine the efficiency of antipsychotic drugs. Here, we present the synthesis of ortho-, meta-, and para-N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-arylamides and their structure-activity relationship studies on dopamine D2 and 5-hydroxytryptamine 5-HT1A receptors. It was shown that the biological activity of the described ligands strongly depends on their topology as well as on the nature of the heteroaryl group in the head of the molecules. Docking simulations together with conformational analysis revealed a rational explanation for the ligands' behavior. The molecular model of receptor-ligand interactions described herein provided us with a tool for the rational design of new compounds with a favorable D2 /5-HT1A profile. PMID:24105736

Sukalovic, Vladimir; Bogdan, Anca Elena; Tovilovic, Gordana; Ignjatovic, Djurdjica; Andric, Deana; Kostic-Rajacic, Sladjana; Soskic, Vukic



Effect of YM992, a novel antidepressant with selective serotonin re-uptake inhibitory and 5-HT 2A receptor antagonistic activity, on a marble-burying behavior test as an obsessive-compulsive disorder model.  


YM992 ((S)-2-[[(7-fluoroindan-4-yl)oxy]methyl]morpholine) monohydrochloride is a novel antidepressant with selective serotonin (5-hydroxytryptamine, 5-HT) re-uptake inhibition and 5-HT(2A) receptor antagonistic activity. The effects of YM992 and two selective 5-HT re-uptake inhibitors (SSRIs) were studied in a marble-burying behavior test as a model of an obsessive-compulsive disorder (OCD) in mice at doses of 5, 10 and 15 mg/kg, i.p. YM992 and fluoxetine significantly inhibited marble-burying behavior at a dose of 15 mg/kg (i.p.) without affecting spontaneous locomotor activities. Citalopram also significantly inhibited the behavior at doses of 5, 10 and 15 mg/kg (i.p.) without affecting spontaneous locomotor activities. These results suggest that YM992, as well as SSRIs, may exhibit anti-OCD activity in addition to an antidepressive effect in clinical use. PMID:12419892

Takeuchi, Hiromi; Yatsugi, Shin-ichi; Yamaguchi, Tokio



4-( sup 125 I)iodo-(2,5-dimethoxy)phenylisopropylamine and ( sup 3 H)ketanserin labeling of 5-hydroxytryptamine2 (5HT2) receptors in mammalian cells transfected with a rat 5HT2 cDNA: Evidence for multiple states and not multiple 5HT2 receptor subtypes  

SciTech Connect

Evidence has accumulated indicating that the radioactive hallucinogens 4-bromo-(3H)(2,5-dimethoxy)phenylisopropylamine ((3H)DOB) and 4-(125I)iodo-(2,5-dimethoxy)phenylisopropylamine ((125I)DOI) label an agonist high affinity state of the 5-hydroxytryptamine2 (5HT2) receptor and (3H)ketanserin labels both agonist high and low affinity states. Recently, an alternative hypothesis has been put forward proposing that the radioactive hallucinogens are labeling a 5HT2 receptor subtype distinct from the receptor labeled by (3H)ketanserin. In order to provide definitive evidence as to which of these hypotheses is correct, the rat 5HT2 receptor gene was transfected into NIH-3T3 cells and COS cells. Neither nontransfected cell type expresses 5HT2 receptors; the transfected cells expressed high affinity binding sites for both (125I) DOI (KD = 0.8 nM and Bmax = 363 fmol/mg in NIH-3T3 cells; KD = 0.2 nM and Bmax = 26 fmol/mg in COS cells) and (3H)ketanserin (KD = 0.4 nM and Bmax = 5034 fmol/mg in NIH-3T3 cells; KD = 1.0 nM and Bmax = 432 fmol/mg in COS cells). The affinities of agonists and antagonists for the (125I)DOI-labeled receptor were significantly higher than for the (3H)ketanserin-labeled receptor. The affinities of agonists and antagonists for these binding sites were essentially identical to their affinities for the sites radiolabeled by these radioligands in mammalian brain homogenates. The (125I)DOI binding was guanyl nucleotide sensitive, indicating a coupling to a GTP-binding protein. These data indicate that the 5HT2 receptor gene product contains both the guanyl nucleotide-sensitive (125I)DOI binding site and the (3H)ketanserin binding site. Therefore, these data indicate that the 5HT2 receptor gene product can produce a high affinity binding site for the phenylisopropylamine hallucinogen agonists as well as for the 5HT2 receptor antagonists.

Teitler, M.; Leonhardt, S.; Weisberg, E.L.; Hoffman, B.J. (Albany Medical College, NY (USA))



Cisapride and a structural analogue, R 76,186, are 5-hydroxytryptamine4 (5-HT4) receptor agonists on the guinea-pig colon ascendens.  


The purpose of this study was to investigate whether the effects of cisapride and its close structural analogue R 76,186 on the isolated guinea-pig colon ascendens, are mediated through 5-HT4 receptors. Both cisapride and R 76,186 induced contractions in a concentration-dependent fashion, giving monophasic concentration-response curves (cisapride: EC50 = 1.1 x 10(-7) M, maximum effect = 40.3% of methacholine-induced (3 x 10(-7) M) contractions; R 76,186: EC50 = 2.4 x 10(-8) M, maximum effect = 52.1%). Blockade of either 5-HT2 or 5-HT3 receptors did not affect the responses to cisapride. However, tropisetron (in 5-HT4 receptor-blocking concentrations), and DAU 6285 and SDZ 205-557, two novel selective 5-HT4 receptor antagonists, depressed the concentration-response curve to cisapride (to about 50%), and the curve to R 76,186 was shifted to the right. The apparent pA2 values were 6.6 (tropisetron), 6.3 (DAU 6285), and 7.5 (SDZ 205-557). However, none of these antagonisms was purely competitive as higher concentrations of these antagonists depressed the curve to R 76,186. Desensitization of the 5-HT4 receptor with 5-methoxytryptamine (5-MeOT) inhibited the responses to cisapride, and abolished those to R 76,186. The contractions to cisapride and R 76,186 were sensitive to mutual antagonism, depressing their concentration-response curves. Conclusions: Both cisapride and R 76,186 mediate their contractile effects in the guinea-pig colon ascendens through agonism at the 5-HT4 receptor, though cisapride also uses a non-5-HT mechanism. R 76,186 is a selective and potent 5-HT4 receptor agonist. PMID:8321323

Briejer, M R; Akkermans, L M; Meulemans, A L; Lefebvre, R A; Schuurkes, J A



Oligomer size of the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor revealed by fluorescence correlation spectroscopy with photon counting histogram analysis: evidence for homodimers without monomers or tetramers.  


Fluorescence correlation spectroscopy (FCS) and photon counting histogram (PCH) are techniques with single molecule sensitivity that are well suited for examining the biophysical properties of protein complexes in living cells. In the present study, FCS and PCH were applied to determine the diffusion coefficient and oligomeric size of G-protein-coupled receptors. FCS was used to record fluctuations in fluorescence intensity arising from fluorescence-tagged 5-hydroxytryptamine 2C (5-HT(2C)) receptors diffusing within the plasma membrane of HEK293 cells and rat hippocampal neurons. Autocorrelation analysis yielded diffusion coefficients ranging from 0.8 to 1.2 ?m(2)/s for fluorescence-tagged receptors. Because the molecular brightness of a fluorescent protein is directly proportional to the number of fluorescent proteins traveling together within a protein complex, it can be used to determine the oligomeric size of the protein complex. FCS and PCH analysis of fluorescence-tagged 5-HT(2C) receptors provided molecular brightness values that were twice that of GFP and YFP monomeric controls, similar to a dimeric GFP control, and unaltered by 5-HT. Bimolecular fluorescence complementation of the N- and C-terminal halves of YFP attached to 5-HT(2C) receptors was observed in endoplasmic reticulum/Golgi and plasma membranes with a brightness equal to monomeric YFP. When GFP-tagged 5-HT(2C) receptors were co-expressed with a large excess of untagged, non-fluorescent 5-HT(2C) receptors, the molecular brightness was reduced by half. PCH analysis of the FCS data were best described by a one-component dimer model without monomers or tetramers. Therefore, it is concluded that 5-HT(2C) receptors freely diffusing within the plasma membrane are dimeric. PMID:22593582

Herrick-Davis, Katharine; Grinde, Ellinor; Lindsley, Tara; Cowan, Ann; Mazurkiewicz, Joseph E



The loop C region of the murine 5-HT3A receptor contributes to the differential actions of 5-hydroxytryptamine and m-chlorophenylbiguanide.  


Sequence and predicted structural similarities between members of the Cys loop superfamily of ligand-gated ion channel receptors and the acetylcholine binding protein (AChBP) suggest that the ligand-binding site is formed by six loops that intersect at subunit interfaces. We employed site-directed mutagenesis to investigate the role of amino acids from the loop C region of the murine 5-HT(3AS)R in interacting with two structurally different agonists, serotonin (5-HT) and m-chlorophenylbiguanide (mCPBG). Mutant receptors were evaluated using radioligand binding, two-electrode voltage clamp, and immunofluorescence studies. Electrophysiological assays were employed to identify changes in response characteristics and relative efficacies of mCPBG and the partial agonist, 2-methyl 5-HT (2-Me5-HT). We have also constructed novel 5-HT and mCPBG docked models of the receptor binding site based on homology models of the AChBP. Both ligand-docked models correlate well with results from mutagenesis and electrophysiological assays. Four key amino acids were identified as being important to ligand binding and/or gating of the receptor. Among these, I228 and D229 are specific for effects mediated by 5-HT compared to mCPBG, indicating a differential interaction of these ligands with loop C. Residues F226 and Y234 are important for both 5-HT and mCPBG interactions. Mutations at F226, I228, and Y234 also altered the relative efficacies of agonists, suggesting a role in the gating mechanism. PMID:15966738

Suryanarayanan, Asha; Joshi, Prasad R; Bikádi, Zsolt; Mani, Muthalagi; Kulkarni, Trupti R; Gaines, Chandra; Schulte, Marvin K



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

SciTech Connect

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

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



Differential inhibition of serotonin release by 5HT and NA reuptake blockers after systemic administration  

Microsoft Academic Search

The inhibition of serotonin (5-HT) release produced by antidepressants varying in relative selectivity for blocking uptake of 5-HT and noradrenaline (NA) was compared. Release was measured by microdialysis in anesthetized rats with nerve terminal 5-HT uptake inhibited by local infusion of citalopram (1 ?M) through a dialysis probe in hippocampus. With 5-HT uptake first blocked in hippocampus, systemic injection of

S. B. Auerbach; J. F. Lundberg; S. Hjorth



Exercise performance is not influenced by a 5-HT reuptake inhibitor.  


The purpose of the present study was to examine the effect of a selective serotonin (5-HT) reuptake inhibitor (SSRI) on exercise performance during a 90 min time trial. Eight well trained male cyclists (VO2max 68.1 +/- 9.5 ml/kg/min) performed three 90 min time trials at 65% Wattmax. Blood samples were collected via an indwelling venous catheter for adrenocorticotropin hormone (ACTH), prolactin (PRL), cortisol, catecholamines, growth hormone (GH) and beta-endorphins. The evening before and the morning of the time trials, the subjects ingested a capsule containing either placebo (lactose) or 20 mg Fluoxetine-HCI (Prozac, Ely Lilly Belgium). A double blind, randomized, placebo controlled, cross-over design was performed. Performance was not influenced by the SSRI. As expected, all blood parameters increased significantly during exercise (p < 0.05). During the SSRI trial most parameters were slightly lower but only significantly for endorphins and PRL (p < 0.05). The results demonstrate that performance is not influenced by an SSRI, although some plasma hormones indicate a central effect of the drug. Surprisingly, the increases in PRL and endorphins were lower during the SSRI trial, meaning that the hormonal modulation during exercise might be regulated by the interaction between neurotransmitters rather than by serotonin alone. PMID:11510868

Meeusen, R; Piacentini, M F; Van Den Eynde, S; Magnus, L; De Meirleir, K



Reversal of learned helplessness by selective serotonin reuptake inhibitors in rats is not dependent on 5-HT availability.  


Serotonin (5-HT) and 5-HT(1A) receptors have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, particularly in the case of selective serotonin reuptake inhibitors (SSRIs). In the rat learned helplessness (LH) paradigm, a valid animal model of human depression, repeated treatment with the 5-HT(1A) receptor agonist 8-OH-DPAT (0.125 and 0.5mg/kg) and several classes of antidepressants such as the tricyclic agent desipramine (30 and 60mg/kg), the monoamine oxidase inhibitor (MAOI) pargyline (60mg/kg) and the SSRIs fluoxetine (15 and 30mg/kg), paroxetine (15 and 30mg/kg) and sertraline (30mg/kg) improved behavioural deficit in helpless rats. The involvement of serotonergic mechanisms in the antidepressant-like effect of these agents was investigated using the selective 5-HT(1A) receptor antagonist WAY 100,635 and the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA). Pretreatment with WAY 100,635 blocked the 8-OH-DPAT-induced reduction in escape failures, but did not counteract the antidepressant effect of fluoxetine and paroxetine. PCPA given alone did not modify helpless behaviour nor did it affect the behavioural effect of 8-OH-DPAT, fluoxetine and paroxetine. Adaptive changes in 5-HT(1A) receptor function were studied by measuring 8-OH-DPAT-mediated hypothermia and lower lip retraction (LLR) in the animals 24h after LH test session. Fluoxetine and paroxetine treatments caused a marked reduction in agonist-induced responses, an effect completely prevented by WAY 100,635 and PCPA. In conclusion, whereas direct agonist activity at postsynaptic 5-HT(1A) receptors attenuated helpless behaviour, the antidepressant-like effect of SSRIs was found to be independent of their actions on either 5-HT(1A) receptor function or extracellular 5-HT. PMID:17141811

Zazpe, Arturo; Artaiz, Inés; Labeaga, Luis; Lucero, María Luisa; Orjales, Aurelio



Comparison of effects of a selective 5-HT reuptake inhibitor versus a 5-HT4 receptor agonist on in vivo neurogenesis at the rectal anastomosis in rats.  


It was recently reported that activation of enteric neural 5-HT(4) receptors (SR4) promotes reconstruction of enteric neural circuit injury in distal gut of guinea pigs and that this reconstruction involves neural stem cells. We aimed to explore a novel approach using a selective serotonin reuptake inhibitor (SSRI), which increases endogenous 5-HT, to repair enteric nerve fiber injury in the rat distal gut. Enteric nerve fiber injury was performed by rectal transection and subsequent end-to-end one-layer anastomosis. The SSRI fluvoxamine maleate (100 ?mol/l) was applied locally at the anastomotic site to compare with the 5-HT(4) agonist mosapride citrate (100 ?mol/l) (applied for patent) applied locally and orally. Unlike mosapride, fluvoxamine failed to promote the regeneration of the nerve fiber tract across the anastomosis. Furthermore, fluvoxamine did not generate anti-distal-less homeobox 2 (DLX2)- and anti-SR4-positive cells (neural stem cells) and/or anti-neurofilament (NF)-positive cells (neural cells) in newly formed granulation tissue at the anastomosis, whereas these cell types were observed in mosapride-treated preparations. In contrast to its effects in guinea pigs, mosapride generated 5-bromo-2'-deoxyuridine (BrdU)-positive neural cells in ganglia sites 3 mm oral and anal from the anastomosis 2 wk after nerve fiber injury. All actions of mosapride were observed after local and or oral applications. These findings indicate that local SSRI treatment does not induce in vivo nerve fiber tract growth across the anastomosis in the rat distal gut. Mosapride induces nerve fiber tract growth across the anastomosis, mediated through enteric neural stem cells possibly from neural crest-derived stem cells or mesenchymal stem cells in the bone marrow. PMID:22194416

Kawahara, Isao; Kuniyasu, Hiroki; Matsuyoshi, Hiroko; Goto, Kei; Obata, Koji; Misawa, Hiromi; Fujii, Hisao; Takaki, Miyako



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

Microsoft Academic Search

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

R. Schreiber; C. Melon; Jean De Vry



Blockade of serotonin 5HT 1B and 5HT 2A receptors suppresses the induction of locomotor activity by 5HT reuptake inhibitors, citalopram and fluvoxamine, in NMRI mice exposed to a novel environment: a comparison to other 5HT receptor subtypes  

Microsoft Academic Search

Rationale  Though 5-HT plays an important role in the modulation of motor function, which is perturbed in depressive states, little is\\u000a known concerning the influence of serotonin reuptake inhibitors (SSRIs) on locomotor activity (LA). Recently, we demonstrated\\u000a that SSRIs, such as citalopram, enhance LA in mice exposed to a novel environment.\\u000a \\u000a \\u000a \\u000a Objectives  This study examined the role of multiple classes of 5-HT

Mark J. Millan; Sylvie Veiga; Sylvie Girardon; Mauricette Brocco



Polymorphisms in the 5Hydroxytryptamine 2A Receptor and CytochromeP4502D6 Genes Synergistically Predict Fluvoxamine-Induced Side Effects in Japanese Depressed Patients  

Microsoft Academic Search

5-Hydroxytryptamine (5-HT) receptors are thought to be associated with the gastrointestinal side effects induced by selective serotonin reuptake inhibitors. CytochromeP450 (CYP) 2D6 may also be associated with the side effects induced by fluvoxamine, since the plasma fluvoxamine concentration depends on a CYP2D6 gene polymorphism. This study investigated whether 5-HT receptor and CYP2D6 gene polymorphisms could predict the occurrence of the

Yutaro Suzuki; Kazushi Sawamura; Toshiyuki Someya



2,5-Disubstituted tetrahydrofurans as selective serotonin re-uptake inhibitors  

Microsoft Academic Search

Enhancement of 5-hydroxytryptamine (5-HT, serotonin) neurotransmission is a viable means of treating depression. On the basis of this observation, agents that inhibit re-uptake of 5-HT were prepared based on (?)-cocaine and aryltropanes as lead compounds because they are reasonably potent 5-HT re-uptake inhibitors. Molecular dissection of an aryltropane provided a series of 5- and 6-membered ring compounds. From among this

Troy Voelker; Haiji Xia; Keith Fandrick; Robert Johnson; Aaron Janowsky; John R. Cashman



Inactivation of 5HT2C Receptors Potentiates Consequences of Serotonin Reuptake Blockade  

Microsoft Academic Search

The enhancement of central serotonin system function underlies the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs), which have become the most commonly used class of antidepressant agents. However, many individuals experience depressive episodes that are resistant to SSRI treatment. Homeostatic mechanisms that limit the extent to which SSRIs enhance serotonergic neurotransmission have been implicated in this phenomenon. Here, we

Thomas I F H Cremers; Marco Giorgetti; Fokko J Bosker; Sandra Hogg; Jørn Arnt; Arne Mørk; Gerard Honig; Klaus-Peter Bøgesø; Ben H C Westerink; Hans den Boer; Håkan V Wikstrom; Laurence H Tecott; TIFH Cremers



Cortical 5-hydroxytryptamine2A-receptor mediated excitatory synaptic currents in the rat following repeated daily fluoxetine administration.  


Down-regulation of 5-hydroxytryptamine(2A) (5-HT(2A)) receptors has been a consistent effect induced by most antidepressant drugs. The evidence for down-regulation of 5-HT(2A) receptor binding following subchronic treatment with fluoxetine and other selective serotonin reuptake inhibitors (SSRIs) is mixed. The question of 5-HT(2A) receptor sensitivity during chronic administration of antidepressants is important since activation of 5-HT(2A) receptors is associated with impulsivity. Continued activation of 5-HT(2A) receptors may functionally oppose activation of other non-5-HT(2A) receptors in the prefrontal cortex associated with the clinical efficacy of SSRI treatment. Therefore, the effects of repeated daily administration of fluoxetine (10 mg/kg, i.p. x 3 weeks) on pharmacologically characterized electrophysiological response mediated by 5-HT(2A) receptor activation, 5-HT-induced excitatory postsynaptic currents (EPSCs), in rat prefrontal cortical slices was examined. The concentration-response curve for 5-HT-induced EPSCs was unchanged following subchronic fluoxetine treatment. This subchronic fluoxetine treatment failed to modify electrophysiological responses to AMPA in layer V pyramidal cells as well. These findings would be consistent with the hypothesis that blockade of 5-HT(2A) receptors may enhance the effects of SSRIs or serotonin/norepinephrine reuptake inhibitors (SNRIs). PMID:18486339

Marek, Gerard J



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

Microsoft Academic Search

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

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



Ultrastructural Cytochemistry and Pharmacology of 5-Hydroxytryptamine in Adrenergic Nerve Endings. I. Localization of Exogenous 5-Hydroxytryptamine in the Autonomic Nerves of the Rat Vas Deferens.  

National Technical Information Service (NTIS)

Pharmacologic and electron microscopic cytochemical procedures were performed in the rat vas deferens in order to study the localization of exogenously administered 5-hydroxytryptamine (5-HT) in adrenergic nerve endings. Exogenous 5-HT accumulated in the ...

G. Jaim-Etcheverry L. M. Zieher



5Hydroxytryptamine receptors in the human cardiovascular system  

Microsoft Academic Search

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

Alberto J. Kaumann; Finn Olav Levy



S41744, a dual neurokinin (NK)1 receptor antagonist and serotonin (5-HT) reuptake inhibitor with potential antidepressant properties: a comparison to aprepitant (MK869) and paroxetine.  


Though neurokinin(1) (NK(1)) receptors are implicated in depressed states and their treatment, selective antagonists have disappointed in clinical trials. Accordingly, we designed a novel ligand, S41744 (2-piperazin-1-yl-indan-2-carboxylic-acid-(3-chloro-5-fluoro-benzyl)-methyl-amide), which both blocks NK(1) receptors and interferes with serotonin (5-HT) reuptake. S41744 mimicked the selective antagonist aprepitant in binding human (h)NK(1) receptors and in antagonising Substance-P-mediated Extracellular-Regulated-Kinase phosphorylation (pK(B), 7.7). Further, it dose-dependently (0.63-40.0 mg/kg, i.p.) displaced ex vivo [(3)H]-[Sar(9),Met(O(2))(11)]-Substance P binding to gerbil striatum, attenuated formalin-induced hind-paw licking in gerbils, and antagonised locomotion induced by i.c.v. administration of the NK(1) agonist GR73632 to guinea pigs. Like paroxetine, S41744 recognised h5-HT transporters, reduced synaptosomal uptake of 5-HT (pK(B), 7.9), and dose-dependently (0.63-10.0 mg/kg) elevated dialysis levels of 5-HT in the hippocampus and frontal cortex of freely-moving guinea pigs. Further, S41744 increased extracellular levels of 5-HT in frontal cortex and hippocampus of rats to a greater extent than paroxetine, and its inhibitory influence upon serotonergic perikarya was blunted relative to its affinity for 5-HT transporters. S41744 more potently blocked stress-induced vocalizations in guinea pigs than aprepitant and paroxetine, and it was active in forced-swim and marble-burying procedures of putative antidepressant properties in mice. While aprepitant displayed anxiolytic actions in stress-induced foot-tapping and social interaction tests in gerbils, paroxetine was anxiogenic and S41744 "neutral", reflecting balanced NK(1) antagonism and suppression of 5-HT reuptake. Moreover, S41744 shared anxiolytic actions of aprepitant in the rat Vogel Conflict Test. In conclusion, S41744 is an innovative NK(1) antagonist/5-HT reuptake inhibitor justifying further evaluation for treatment of stress-related disorders. PMID:20483567

Millan, Mark J; Dekeyne, Anne; Gobert, Alain; Mannoury la Cour, Clotilde; Brocco, Mauricette; Rivet, Jean-Michel; Di Cara, Benjamin; Lejeune, Françoise; Cremers, Thomas I; Flik, Gunnar; de Jong, Trynke R; Olivier, Berend; de Nanteuil, Guillaume



In vitro neuronal and vascular responses to 5-HT in rats chronically exposed to MDMA  

PubMed Central

This study examined the effects of chronic exposure of rats to 3,4-methylenedioxymethamphetamine (MDMA) on [3H]5-hydroxytryptamine ([3H]5-HT) re-uptake into purified rat brain synaptosomes, 5-HT-induced isometric contraction of aortic rings and [3H]5-HT re-uptake into rat aorta.Rats were administered MDMA (20?mg?kg?1 i.p.) twice daily over 4 days. One, 7, 14 or 21 days post treatment, whole brain synaptosomes and descending thoracic aortic rings were prepared for investigation.Chronic MDMA treatment significantly reduced the maximum rate (Vmax) of specific high-affinity [3H]5-HT re-uptake 1 day after treatment and for up to 21 days post-final administration of MDMA. Direct application of MDMA (100??M) abolished synaptosomal re-uptake of [3H]5-HT in vitro.Chronic MDMA administration significantly reduced the maximum contraction (Emax) to 5-HT at 1 and 7 days after treatment, but not at 14 or 21 days.Chronic MDMA administration had no effect on sodium-dependent [3H]5-HT re-uptake into aorta 1 day after treatment, nor did 100??M MDMA have any direct effect on [3H]5-HT uptake into aortic rings in vitro.These results show, for the first time, an altered responsiveness of vascular tissue to MDMA after chronic administration. In addition, they demonstrate a difference in the sensitivity of central and peripheral 5-HT uptake systems to chronic MDMA exposure, and suggest that the action of MDMA in the cardiovascular system does not arise from a direct effect of MDMA on peripheral 5-HT transport.

Cannon, Dara M; Keenan, Alan K; Guiry, Patrick J; Buon, Christophe; Baird, Alan W; McBean, Gethin J



5-HT3 Receptors*  

PubMed Central

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

Lummis, Sarah C. R.



5-Hydroxytryptamine (serotonin) in the gastrointestinal tract  

PubMed Central

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.

Gershon, Michael D.



5-hydroxytryptamine receptors in the hypothalamus mediate thermoregulatory responses in rabbits  

Microsoft Academic Search

1. The effects of microinjection of 5-hydroxytryptamine (5-HT) or its antagonists methysergide (a 5-HT1 receptor antagonist), cyproheptadine (a mixed 5-HT1\\/5-HT2 receptor antagonist), or ketanserin (a 5-HT2 receptor antagonist) into the preoptic anterior hypothalamus on thermoregulatory responses were assessed in conscious rabbits at different ambient temperatures (Ta). 2. Intrahypothalamic injection of 5-HT caused dose-dependent hypothermia in rabbits when the Ta was

S. J. Won; M. T. Lin



Effect of the SSRI, Escitalopram, and Non-selective 5HT Reuptake Inhibitors in an Animal Model of Pain  

Microsoft Academic Search

Antidepressants are frequently used as adjuvants for analgesic treatment of pain (Sindrupt and Jensen, 1999). Furthermore the somatic complaints accompanying depression are often relieved by antidepressan ts. However, the pharmacological mechanisms by which such pain relief is mediated remain unclear. In the present study we investigated the analgesic potential of selective serotonin reuptake inhibitors (SSRIs) including the most selective serotonin

Connie Sánchez; Michael Owens



Evidence for involvement of 5-hydroxytryptamine(1B) autoreceptors in the enhancement of serotonin turnover in the mouse brain following repeated treatment with fluoxetine.  


The effect of repeated treatment with the selective serotonin reuptake inhibitor fluoxetine on synthesis and turnover of 5-hydroxytryptamine (5-HT) was studied in the mouse brain in vivo. The concentration of 5-hydroxytryptophan (5-HTP), 5-hydroxyindoleacetic acid (5-HIAA) and 5-HT was measured in hypothalamus, hippocampus and frontal cortex after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD 1015). Fluoxetine 6.9 mg/kg s.c. was injected once daily for three weeks. Three days after the final daily injection of fluoxetine 5-HT synthesis (5-HTP accumulation) and turnover (5-HIAA/5-HT ratio) were significantly enhanced compared with saline-treated mice. The 5-HIAA/5-HT ratio was already significantly elevated after 3 days of fluoxetine treatment and continued to increase during treatment for 2-3 weeks. The increase in 5-HIAA/5-HT ratio was considerably larger (150-200% of controls) than the increase in 5-HTP accumulation (110-120%), which reached significance only after 3 weeks of treatment. The increase in 5-HT synthesis may be secondary to that of the turnover. The 5-HIAA/5-HT ratio returned to control values after a 14 days washout period. Simultaneous treatment with the long-acting 5-HT(1B)-receptor antagonist, SB 224289 for 14 days counteracted the fluoxetine-induced increase in 5-HIAA/5-HT ratio that indicates involvement of 5-HT(1B) autoreceptors in the development of this increase. It is proposed that the fluoxetine-induced enhancement of 5-HT turnover was evoked by the long-lasting stimulation of 5-HT(1B) autoreceptors that resulted in an intraneuronal compensatory adaptation of the basal 5-HT release. PMID:12377268

Stenfors, Carina; Ross, Svante B



5HT Receptor-Associated Proteins (FRAPs)  

Microsoft Academic Search

Dysfunction in the serotonergic system contributes to the etiology and pathophysiology of a variety of neuropsychiatric and\\u000a systemic disorders, and 5-hydroxytryptamine(5-HT) receptors as a group represent important therapeutic targets for many of\\u000a these debilitating diseases. Encompassing a diverse group of proteins that interact with 5-HT receptors, 5-HT receptor-associated\\u000a proteins (FRAPs) coordinate receptor targeting to the appropriate subcellular compartments, organization of

Zongqi Xia; Douglas J. Sheffler; Bryan L. Roth


Effects of tramadol and O-demethyl-tramadol on human 5HT reuptake carriers and human 5HT 3A receptors: A possible mechanism for tramadol-induced early emesis  

Microsoft Academic Search

([3H]5-HT)-uptake and patch-clamp techniques were used to study the actions of (+) and (?) tramadol and the active metabolites of tramadol, (+) and (?) O-demethyl-tramadol on the human serotonin (5-HT) transporter and the human 5-HT3A receptor, stably expressed in HEK-293 cells. The (+) and (?) enantiomers of tramadol suppressed the human 5-HT transporter concentration-dependently (IC50=1.0 and 0.8 ?M, respectively), resulting

Martin Barann; Bernd Urban; Ulrike Stamer; Zita Dorner; Heinz Bönisch; Michael Brüss



A 5-hydroxytryptamine receptor in human atrium.  

PubMed Central

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

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



The Inhibitory Effects of Tramadol on 5Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes  

Microsoft Academic Search

Although tramadol is widely available as an analgesic, its mechanism of antinociception remains unresolved. Serotonin (5-hydroxytryptamine, 5-HT) is a monoam- inergic neurotransmitter that modulates numerous sensory, motor, and behavioral processes. The 5-HT type 2C receptor (5-HT2CR) is one of the major 5-HT receptor subtypes and is implicated in many important effects of 5-HT, including pain, feeding, and locomo- tion. In

Junichi Ogata; Kouichiro Minami; Yasuhito Uezono; Takashi Okamoto; Munehiro Shiraishi; Akio Shigematsu; Yoichi Ueta



Putative serotonin reuptake inhibitor-induced spawning and parturition in freshwater bivalves is inhibited by mammalian 5-HT2 receptor antagonists.  


Selective serotonin reuptake inhibitors (SSRIs) can mimic the physiological actions of serotonin, and in bivalve molluscs they induce zebra mussel spawning and fingernail clam parturition. We have elucidated further the pharmacology of SSRI-induced spawning and part-urition by blocking these reproductive processes with two mammalian 5-HT(2) receptor antagonists, cyproheptadine and mianserin. These two antagonists were potent inhibitors of both spawning and parturition induced by the SSRIs fluvoxamine, fluoxetine, and zimelidine. In zebra mussels, both cyproheptadine and mianserin significantly blocked spawning induced by fluvoxamine and by zimelidine. In the fingernail clams Sphaerium spp., both cyproheptadine and mianserin blocked fluvoxamine-induced parturition. A possible mechanism of action for SSRI-induced spawning and parturition in bivalves is suggested. PMID:12840841

Fong, Peter P; Philbert, Caroline M; Roberts, Brian J



Concentration and Uptake of 5Hydroxytryptamine in Platelets from Cluster Headache and Migraine Patients  

Microsoft Academic Search

Concentrations of 5-hydroxytryptamine (5-HT) in platelets were determined in 33 cluster headache patients (17 males) and in 34 migraine patients (16 males) outside attacks. The 5-HT uptake into platelets was measured and the kinetic constants Vmax and Km determined in 26 cluster patients (14 males) and in 30 migraine patients (13 males). Significantly lower 5-HT concentrations in whole blood were

Elisabet Waldenlind; Svante B Ross; Jan Sääf; Karl Ekbom; Lennart Wetterberg



Autoradiographic visualization on the role of central (sup 3)H-5-hydroxytryptamine in acupuncture analgesia.  

National Technical Information Service (NTIS)

The role played by central 5-hydroxytryptamine (5-HT) in electroacupuncture analgesia has been studied in rats by means of autoradiography with isotopic tracers (sup 3)H-5-HT. The purpose of the study is to determine the localization of (sup 3)H-5-HT in t...

S. Zhu F. Shi Z. Liu J. Jiang



Anti-emetic effect of mosapride citrate hydrate, a 5-HT4 receptor agonist, on selective serotonin reuptake inhibitors (SSRIs)-induced emesis in experimental animals.  


Although selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, they frequently cause gastrointestinal adverse effects, such as nausea and emesis. In the present study, we investigated the anti-emetic effect of mosapride, a 5-HT(4) receptor agonist, on SSRIs-induced emesis in Suncus murinus and dogs. We also examined the effect of mosapride on SSRIs-induced delay in gastric emptying and increase in gastric vagal afferent activity in rats. Oral administration of paroxetine, but not its subcutaneous administration, dose-dependently caused emesis in both animals. Mosapride inhibited paroxetine-induced emesis in Suncus murinus and dogs with ID(50) values of 7.9 and 1.1 mg/kg, respectively. The anti-emetic effect of mosapride was partially inhibited by SB207266, a selective 5-HT(4) antagonist. Intragastric administration of paroxetine increased gastric vagal afferent discharge in anesthetized rats. Mosapride failed to suppress this increase. On the other hands, mosapride improved the delay in gastric emptying caused by paroxetine in rats. We have shown in this study that oral administration of SSRIs causes emesis and activates gastric vagal afferent activity in experimental animals and that mosapride inhibits SSRIs-induced emesis, probably via improvement of SSRIs-induced delay in gastric emptying. These findings highlight the promising potential of mosapride as an anti-emetic agent. PMID:23257657

Mine, Yukiko; Oku, Seiko; Yoshida, Naoyuki



Characterization of the contraction to 5-HT in the canine colon longitudinal muscle.  


1. Although conscious dogs have often been used for colonic motility studies with 5-hydroxytryptamine (5-HT), the effects of 5-HT on the isolated colon have not been thoroughly characterized yet. The current study was undertaken to characterize the response to 5-HT of the canine isolated colon longitudinal muscle. 2. Longitudinal strips of canine midcolon deprived of (sub)mucosa were prepared for isotonic measurement. 5-HT induced contractions from 3 nM onwards, which were not affected by selective inhibition of 5-HT re-uptake, monoamine oxidase or blockade of alpha-adrenoceptors. Tetrodotoxin (0.3 microM) did not affect the responses to 5-HT, suggesting that smooth muscle 5-HT receptors are involved. The selective 5-HT4 receptor antagonist SB 204070 (10 nM) slightly enhanced contractions to 5-HT and therefore it was included in the organ bath solution in all further experiments. The 5-HT1 and 5-HT2 receptor antagonist methysergide (0.1 microM) depressed the curve to 5-HT, but the selective 5-HT3 receptor antagonist granisetron (0.3 microM) had no effect. 3. Besides 5-HT, alpha-methyl-5-HT (alpha-Me-5-HT), 5-methoxytryptamine (5-MeOT), 2-methyl-5-HT (2-Me-5-HT) and 5-carboxamidotryptamine (5-CT) also induced contractions, with the following rank order of potency (pEC50 values in parentheses): 5-HT (6.9) = alpha-methyl-5-HT (6.9) > 2-Me-5-HT (5.8) = 5-MeOT (5.7) = 5-CT (5.6), indicative of 5-HT2 receptor involvement, alpha-Me-5-HT produced a bell-shaped curve, which was not affected by alpha-adrenoceptor blockade. 5-HT, 5-MeOT, 2-Me-5-HT and 5-CT produced a monophasic concentration-response curve, consistent with an interaction with a single receptor site. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and tryptamine only induced contractions at a concentration exceeding 1 microM. 4. The selective 5-HT2B receptor antagonist SB 204741 (0.3 microM) did not affect the curve to 5-HT. Ketanserin, cisapride and spiroxatrine behaved as competitive antagonists with pKb values of, respectively, 8.4, 8.1 and 6.7. Spiroxatrine (1 microM) shifted the curve to 5-MeOT rightward yielding an apparent pA2 of 7.1. Other antagonists at 5-HT2A receptors also surmountably inhibited the contractions to 5-HT (apparent pA2 value in parentheses): mesulergine (8.2), cinanserin (8.2), yohimbine (6.2) and mianserin (8.6). However, as well as a rightward shift, methiothepin (8.3), pizotifen (8.6) and spiperone (8.8) also caused a depression of the curve, indicative of "pseudo-irreversible' antagonism. Taken together, the above mentioned affinity estimates most closely corresponded to literature affinity values for 5-HT2A receptors. 5. It was concluded that 5-HT induces contractions of the canine midcolon longitudinal muscle primarily by stimulation of smooth muscle 5-HT2A receptors. The presence of inhibitory 5-HT4 receptors cannot be ruled out. PMID:9051313

Prins, N H; Briejer, M R; Schuurkes, J A



Characterization of the contraction to 5-HT in the canine colon longitudinal muscle  

PubMed Central

Although conscious dogs have often been used for colonic motility studies with 5-hydroxytryptamine (5-HT), the effects of 5-HT on the isolated colon have not been thoroughly characterized yet. The current study was undertaken to characterize the response to 5-HT of the canine isolated colon longitudinal muscle.Longitudinal strips of canine midcolon deprived of (sub)mucosa were prepared for isotonic measurement. 5-HT induced contractions from 3?nM onwards, which were not affected by selective inhibition of 5-HT re-uptake, monoamine oxidase or blockade of ?-adrenoceptors. Tetrodotoxin (0.3??M) did not affect the responses to 5-HT, suggesting that smooth muscle 5-HT receptors are involved. The selective 5-HT4 receptor antagonist SB 204070 (10?nM) slightly enhanced contractions to 5-HT and therefore it was included in the organ bath solution in all further experiments. The 5-HT1 and 5-HT2 receptor antagonist methysergide (0.1??M) depressed the curve to 5-HT, but the selective 5-HT3 receptor antagonist granisetron (0.3??M) had no effect.Besides 5-HT, ?-methyl-5-HT (?-Me-5-HT), 5-methoxytryptamine (5-MeOT), 2-methyl-5-HT (2-Me-5-HT) and 5-carboxamidotryptamine (5-CT) also induced contractions, with the following rank order of potency (pEC50 values in parentheses): 5-HT (6.9)=?-methyl-5-HT (6.9)>2-Me-5-HT (5.8)=5-MeOT (5.7)=5-CT (5.6), indicative of 5-HT2 receptor involvement. ?-Me-5-HT produced a bell-shaped curve, which was not affected by ?-adrenoceptor blockade. 5-HT, 5-MeOT, 2-Me-5-HT and 5-CT produced a monophasic concentration-response curve, consistent with an interaction with a single receptor site. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and tryptamine only induced contractions at a concentration exceeding 1??M.The selective 5-HT2B receptor antagonist SB 204741 (0.3??M) did not affect the curve to 5-HT. Ketanserin, cisapride and spiroxatrine behaved as competitive antagonists with pKb values of, respectively, 8.4, 8.1 and 6.7. Spiroxatrine (1??M) shifted the curve to 5-MeOT rightward yielding an apparent pA2 of 7.1. Other antagonists at 5-HT2A receptors also surmountably inhibited the contractions to 5-HT (apparent pA2 value in parentheses): mesulergine (8.2), cinanserin (8.2), yohimbine (6.2) and mianserin (8.6). However, as well as a rightward shift, methiothepin (8.3), pizotifen (8.6) and spiperone (8.8) also caused a depression of the curve, indicative of ‘pseudo-irreversible' antagonism. Taken together, the above mentioned affinity estimates most closely corresponded to literature affinity values for 5-HT2A receptors.It was concluded that 5-HT induces contractions of the canine midcolon longitudinal muscle primarily by stimulation of smooth muscle 5-HT2A receptors. The presence of inhibitory 5-HT4 receptors cannot be ruled out.

Prins, Nicolaas H; Briejer, Michel R; Schuurkes, Jan A J



Mediation of 5HT-induced internal carotid vasodilatation in GR127935- and ritanserin-pretreated dogs by 5HT 7 receptors  

Microsoft Academic Search

The vasoconstrictor effects of 5-hydroxytryptamine (5-HT) in the internal carotid bed of anaesthetised dogs with bilateral vagosympathectomy are mainly mediated by both 5-HT1B and 5-HT2 receptors. The blockade of this vasoconstrictor effect of 5-HT by the combined use of the antagonists, GR127935 (5-HT1B\\/1D) and ritanserin (5-HT2), unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present

David Centurión; Araceli Sánchez-López; Mario I. Ortiz; Peter De Vries; Pramod R. Saxena; Carlos M. Villalón



Disrupting 5-HT(2A) receptor/PDZ protein interactions reduces hyperalgesia and enhances SSRI efficacy in neuropathic pain.  


Antidepressants are one of the first-line treatments for neuropathic pain. Despite the influence of serotonin (5-hydroxytryptamine, 5-HT) in pain modulation, selective serotonin reuptake inhibitors (SSRIs) are less effective than tricyclic antidepressants. Here, we show, in diabetic neuropathic rats, an alteration of the antihyperalgesic effect induced by stimulation of 5-HT(2A) receptors, which are known to mediate SSRI-induced analgesia. 5-HT(2A) receptor density was not changed in the spinal cord of diabetic rats, whereas postsynaptic density protein-95 (PSD-95), one of the PSD-95/disc large suppressor/zonula occludens-1 (PDZ) domain containing proteins interacting with these receptors, was upregulated. Intrathecal injection of a cell-penetrating peptidyl mimetic of the 5-HT(2A) receptor C-terminus, which disrupts 5-HT(2A) receptor-PDZ protein interactions, induced an antihyperalgesic effect in diabetic rats, which results from activation of 5-HT(2A) receptors by endogenous 5-HT. The peptide also enhanced antihyperalgesia induced by the SSRI fluoxetine. Its effects likely resulted from an increase in receptor responsiveness, because it revealed functional 5-HT(2A) receptor-operated Ca(2+) responses in neurons, an effect mimicked by knockdown of PSD-95. Hence, 5-HT(2A) receptor/PDZ protein interactions might contribute to the resistance to SSRI-induced analgesia in painful diabetic neuropathy. Disruption of these interactions might be a valuable strategy to design novel treatments for neuropathic pain and to increase the effectiveness of SSRIs. PMID:20531396

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



Effects of milnacipran, a 5-HT and noradrenaline reuptake inhibitor, on C-fibre-evoked field potentials in spinal long-term potentiation and neuropathic pain  

PubMed Central

BACKGROUND AND PURPOSE The analgesic action of 5-HT and noradrenaline reuptake inhibitors (SNRIs) on nociceptive synaptic transmission in the spinal cord is poorly understood. We investigated the effects of milnacipran, an SNRI, on C-fibre-evoked field potentials (FPs) in spinal long-term potentiation (LTP), a proposed synaptic mechanism of hypersensitivity, and on the FPs in a neuropathic pain model. EXPERIMENTAL APPROACH C-fibre-evoked FPs by electrical stimulation of the sciatic nerve fibres were recorded in the spinal dorsal horn of anaesthetized adult rats, and LTP was induced by high-frequency stimulation of the sciatic nerve fibres. A rat model of neuropathic pain was produced by L5 spinal nerve ligation and transection. KEY RESULTS Milnacipran produced prolonged inhibition of C-fibre-evoked FPs when applied spinally after the establishment of LTP of C-fibre-evoked FPs in naïve animals. In the neuropathic pain model, spinal administration of milnacipran clearly reduced the basal C-fibre-evoked FPs. These inhibitory effects of milnacipran were blocked by spinal administration of methysergide, a 5-HT1/2 receptor antagonist, and yohimbine or idazoxan, ?2-adrenoceptor antagonists. However, spinal administration of milnacipran in naïve animals did not affect the basal C-fibre-evoked FPs and the induction of spinal LTP. CONCLUSION AND IMPLICATIONS Milnacipran inhibited C-fibre-mediated nociceptive synaptic transmission in the spinal dorsal horn after the establishment of spinal LTP and in the neuropathic pain model, by activating both spinal 5-hydroxytryptaminergic and noradrenergic systems. The condition-dependent inhibition of the C-fibre-mediated transmission by milnacipran could provide novel evidence regarding the analgesic mechanisms of SNRIs in chronic pain.

Ohnami, S; Kato, A; Ogawa, K; Shinohara, S; Ono, H; Tanabe, M



Antagonism of 5-hydroxytryptamine2A Receptor Results in Decreased Contractile Response of Bovine Lateral Saphenous Vein to Tall Fescue Alkaloids  

Technology Transfer Automated Retrieval System (TEKTRAN)

Pharmacologic profiling of 5-hydroxytryptamine (5HT) receptors of bovine lateral saphenous vein has shown that cattle grazing endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) have altered responses to ergovaline (ERV), 5HT, 5HT2A and 5HT7 agonists. To determine if 5HT...


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

Microsoft Academic Search

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

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



Identification of a novel 5HT 4 receptor splice variant (r5HT 4c1) and preliminary characterisation of specific 5HT 4a and 5HT 4b receptor antibodies  

Microsoft Academic Search

The human 5-hydroxytryptamine (5-HT4) receptor is encoded by a highly complex gene which gives rise to at least 10 distinct splice variants. However, the functional relevance of these variants is unknown. In rat, only three such variants have been identified, 5-HT4a (r5-HT4a), 5-HT4b (r5-HT4b) and 5-HT4e (r5-HT4e). In the current study we identify and characterise the pharmacology of a novel

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



Naftopidil inhibits 5-hydroxytryptamine-induced bladder contraction in rats.  


Naftopidil is an ?(1D) and ?(1A) subtype-selective ?(1)-adrenoceptor antagonist that has been used to treat lower urinary tract symptoms of benign prostatic hyperplasia. In this study, we investigated the effects of naftopidil on 5-hydroxytryptamine (5-HT)-induced rat bladder contraction (10(-8)-10(-4) M). Naftopidil (0.3, 1, and 3 ?M) inhibited 5-HT-induced bladder contraction in a concentration-dependent manner. On the other hand, other ?(1)-adrenoceptor antagonists, tamsulosin, silodosin or prazosin, did not inhibit 5-HT-induced bladder contraction. The 5-HT-induced bladder contraction was inhibited by both ketanserin and 4-(4-fluoronaphthalen-1-yl)-6-propan-2-ylpyrimidin-2-amine (RS127445), serotonin 5-HT(2A) and 5-HT(2B) receptor antagonists, respectively. In addition, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and ?-methyl-5-HT, 5-HT(2A) and 5-HT(2) receptor agonists, respectively, induced bladder contraction. The 5-HT-induced bladder contraction was not inhibited by N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-yl-cyclohexanecarboxamide (WAY-100635), [1-[2[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate (GR113808) or (R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulphonyl]phenol (SB269970), 5-HT(1A), 5-HT(4) and 5-HT(7) receptor antagonists, respectively. Naftopidil inhibited both the 5-HT(2A) and 5-HT(2) receptor agonists-induced bladder contractions. Naftopidil binds to the human 5-HT(2A) and 5-HT(2B) receptors with pKi values of 6.55 and 7.82, respectively. These results suggest that naftopidil inhibits 5-HT-induced bladder contraction via blockade of the 5-HT(2A) and 5-HT(2B) receptors in rats. Furthermore, 5-HT-induced bladder contraction was enhanced in bladder strips obtained from bladder outlet obstructed rats, with this contraction inhibited by naftopidil. The beneficial effects of naftopidil on storage symptoms such as urinary frequency and nocturia in patients with benign prostatic hyperplasia may be due, in part, to the blockade of the 5-HT(2A) and 5-HT(2B) receptors in the bladder. PMID:23274492

Sakai, Takumi; Kasahara, Ken-ichi; Tomita, Ken-ichi; Ikegaki, Ichiro; Kuriyama, Hiroshi



Effect of selective serotonin reuptake inhibitors via 5-HT1A receptors on L-DOPA-induced rotational behavior in a hemiparkinsonian rat model.  


L-Dihydroxyphenylalanine (L-DOPA) is considered the gold standard for the treatment of Parkinson's disease (PD). However, long-term administration of L-DOPA can induce abnormal side effects. On the other hand, selective serotonin reuptake inhibitors (SSRIs) including fluoxetine have gained tremendous popularity in the treatment of depression in PD. SSRIs are thought to influence motor function in PD via pharmacological modification of interactions between serotonergic and dopaminergic networks, which are complex and not yet fully understand. In this study, intranigral injection of 6-hydroxydopamine (6-OHDA) in rats caused a significant loss of tyrosine hydroxylase immunoreactivity in the striatum and substantia nigra. However, tryptophan hydroxylase immunoreactivity of the striatum and raphe nucleus was unaffected by 6-OHDA. Immunohistochemical analysis reveal that the serotonergic system was unaffected by the injection of 6-OHDA. We demonstrated also that pre-treatment with fluoxetine significantly suppressed L-DOPA-induced rotational behavior. Additionally, fluoxetine suppressed L-DOPA-induced ERK1/2 and histone H3 phosphorylation. These effects of fluoxetine were abolished by pre-treatment with WAY 100135, a 5-HT(1A) antagonist. These results suggest that fluoxetine may influence motor function in PD via pharmacological modification of interactions between serotonergic and dopaminergic neuronal networks. PMID:22510520

Inden, Masatoshi; Abe, Mari; Minamino, Hideaki; Takata, Kazuyuki; Yoshimoto, Kanji; Tooyama, Ikuo; Kitamura, Yoshihisa



Peristalsis evoked by 5-HT and renzapride: evidence for putative 5-HT4 receptor activation.  

PubMed Central

The effect of 5-hydroxytryptamine and renzapride was studied on the peristaltic reflex elicited in vitro in the guinea-pig ileum. Both agents evoked the reflex at subthreshold intraluminal pressures (50% of threshold) and were blocked by ICS 205-930 (3 microM), but not ondansetron (5 microM). This novel finding suggests strongly that the prokinetic action of renzapride and gut motility stimulating action of 5-hydroxytryptamine are mediated via agonism at the putative 5-HT4 receptor.

Craig, D. A.; Clarke, D. E.



Differential inhibitory effects of drugs acting at the noradrenaline and 5-hydroxytryptamine transporters in rat and human neocortical synaptosomes*  

PubMed Central

Background and purpose: Although the amino acid sequences of rat and human 5-hydroxytryptamine (5-HT) and noradrenaline (NA) transporters (i.e. SERT and NET) are highly homologous, species differences exist in the inhibitory effects of drugs acting at these transporters. Therefore, comparison of the potencies of drugs acting at SERT and NET in native human and rat neocortex may serve to more accurately predict their clinical profile. Experimental approach: Synaptosomes prepared from fresh human and rat neocortical tissues were used for [3H]-5-HT and [3H]-NA saturation and competition uptake experiments. The drugs tested included NA reuptake inhibitors (desipramine, atomoxetine and (S,S)-reboxetine), 5-HT reuptake blockers (citalopram, fluoxetine and fluvoxamine) and dual 5-HT/NA reuptake inhibitors (duloxetine and milnacipran). Key results: In saturation experiments on synaptosomal [3H]-5-HT and [3H]-NA uptake, the dissociation constants did not indicate species differences although a smaller density of both SERT and NET was observed in human tissues. In competition experiments with the various drugs, marked species differences in their potencies were observed, especially at SERT. The rank order of selectivity ratios (SERT/NET) in human neocortex was as follows: citalopram ? duloxetine = fluvoxamine ? fluoxetine > milnacipran > desipramine = atomoxetine > (S,S)-reboxetine. Significant species differences in these ratios were observed for duloxetine, atomoxetine and desipramine. Conclusions and implications: This study provides the first compilation of drug potency at native human neocortical SERT and NET. The significant species differences (viz., human vs. rat) in drug potency suggest that the general use of rodent data should be limited to predict clinical efficacy or profile.

Mantovani, M; Dooley, DJ; Weyerbrock, A; Jackisch, R; Feuerstein, TJ



Pharmacology of 5-hydroxytryptamine receptors in frog skin epithelium.  

PubMed Central

1. 5-Hydroxytryptamine (5-HT) stimulates active sodium transport and decreases the passive mucosal to serosal chloride permeability across frog skin. The relative importance of the different regions of the 5-HT molecule in the mediation of these responses has been studied using a range of structurally related compounds. 2. Substitution in the ethyl amine side chain of 5-HT (5-hydroxytryptophan) results in decreased receptor affinity and intrinsic activity; removal of the side chain (5-hydroxyindole) abolishes activity. Methoxy substitution of the 5-OH moiety of 5-HT has no effect on intrinsic activity but reduces affinity; displacement of the hydroxyl group to position 6 diminishes intrinsic activity and affinity. 3. It is concluded that both of the 5-HT-induced physiological effects are mediated via a single receptor which is distinct from alpha- and beta-adrenoceptors.

Dalton, T



Circadian variation in sensitivity of suprachiasmatic and lateral geniculate neurones to 5-hydroxytryptamine in the rat.  

PubMed Central

Extracellular single-unit recordings were obtained from neurones in the suprachiasmatic nuclei (s.c.n.) of the rat (a putative circadian pace-maker), the ventral lateral geniculate nucleus (v.l.g.n.) and the hippocampus. These areas receive a 5-hydroxytryptamine (5-HT) innervation from the raphe nuclei. Recording of neuronal activity in the s.c.n., v.l.g.n. and the hippocampus revealed a diurnal variation in the response to the ionophoresis of 5-HT. This variation was manifest as a 2-3-fold increase in post-synaptic sensitivity to 5-HT during the subjective dark (active) phase of the circadian cycle. In contrast there was no apparent circadian variation in the sensitivity of s.c.n., v.l.g.n. or hippocampal neurones to ionophoresed gamma-aminobutyric acid (GABA). Neuronal activity recorded in the s.c.n., v.l.g.n. and hippocampus also exhibited a circadian variation in the recovery from 5-HT-induced suppression of firing. This may reflect reuptake processes as recovery can be prolonged by ionophoresis of uptake blockers (imipramine or fluoxetine). Rats (n = 15) expressing circadian arrhythmicity in their rest-activity behaviour induced by long-term continuous illumination (150-200 lx) showed no apparent circadian variation in 5-HT sensitivity. This loss was accompanied by either the development of a 5-6-fold subsensitivity to ionophoresed 5-HT (eleven out of fifteen rats) or a 2-3-fold supersensitivity to ionophoresed 5-HT (four out of fifteen rats). A similar loss of circadian variation and the development of a subsensitivity to ionophoresed 5-HT was also found in three rats sustaining complete electrolytic lesions of the s.c.n. These changes were not found in rats (n = 4) with partial s.c.n. lesions. These results implicate the s.c.n., or fibres passing through it, in the circadian modulation of 5-HT sensitivity in neurones both intrinsic to the s.c.n. circadian pace-maker itself and in the hippocampus and lateral geniculate nucleus (regions remote from the s.c.n.).

Mason, R



Ocular Hypotension: Involvement of Serotonergic 5HT 2 Receptors  

Microsoft Academic Search

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

Najam A. Sharif


Detection of Microwave Heating in 5-Hydroxytryptamine-Induced Hypothermic Mice.  

National Technical Information Service (NTIS)

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

R. J. Smialowicz M. M. Riddle P. L. Brugnolotti R. R. Rogers K. L. Compton



The effects of tianeptine on wet-dog shakes, fore-paw treading and a flexor reflex in rats are consistent with enhancement of 5-hydroxytryptamine uptake.  


Tianeptine is a novel antidepressant which uniquely facilitates 5-hydroxytryptamine (5-HT) uptake. When given in a dose of 10 mg/kg to rats pretreated with either carbidopa or phenelzine, it markedly reduced the frequency of wet-dog shakes, fore-paw treading, tremor and hind-limb abduction evoked by L-5-hydroxytryptophan (L-5-HTP) given 30 or 60 min later. This effect of tianeptine was opposite to that of paroxetine, a selective 5-HT uptake inhibitor, which greatly increased the 5-HTP-induced behavioural syndrome. In contrast, tianeptine did not affect behaviours elicited by the 5-HT receptor agonists, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) or (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), which are not substrates for the 5-HT uptake process. In spinal animals, tianeptine attenuated an ipsilateral flexor reflex, an effect opposite to that of citalopram, a selective 5-HT uptake inhibitor. These effects of tianeptine are consistent with its ability to increase 5-HT reuptake. PMID:1915578

Koshikawa, N; Mocaër, E; Stephenson, J D



Comparison of stimulus properties of fluoxetine and 5-HT receptor agonists in a conditioned taste aversion procedure.  


Pre-exposure to 5-hydroxytryptamine (5-HT) receptor agonists in conditioned taste aversion experiments was used to characterize the stimulus properties of fluoxetine. The taste aversion induced by fluoxetine (10 mg/kg) was completely prevented when mice were pre-exposed to fluoxetine or when they were pre-exposed to the preferential 5-HT1C receptor agonist MK 212. Pre-exposure to MK 212 also prevented the conditioned taste aversion induced by another serotonin uptake inhibitor, paroxetine. A partial attenuation of fluoxetine-induced conditioned taste aversion was seen after pre-exposure to a high dose of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 1 mg/kg), but not to lower doses. No familiarization for the fluoxetine stimulus was obtained by pre-exposure to treatments with the mixed 5-HT1C/2 receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). With the reversed sequence, pre-exposure to fluoxetine prevented the conditioned taste aversion induced by MK 212 or 8-OH-DPAT and reduced that induced by DOI. It is concluded that the acute stimulus properties of fluoxetine mostly resemble those of a 5-HT1C receptor agonist. This supports the suggestion that the 5-HT1C receptor can play an important role in the therapeutic effect of 5-HT reuptake inhibitors. PMID:8013551

Berendsen, H H; Broekkamp, C L



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

Microsoft Academic Search

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



The emerging role of serotonin (5-hydroxytryptamine) in the skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5)  

PubMed Central

Novel molecular pathways obligatory for bone health are being rapidly identified. One pathway recently revealed involves gut-derived 5-hydroxytryptamine (5-HT) mediation of the complete skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5). Mounting evidence supports 5-HT as an important regulatory compound in bone with previous evidence demonstrating that bone cells possess functional pathways for responding to 5-HT. In addition, there is growing evidence that potentiation of 5-HT signaling via inhibition of the 5-HT transporter (5-HTT) has significant skeletal effects. The later is clinically significant as the 5-HTT is a popular target of pharmaceutical agents, such as selective serotonin reuptake inhibitors (SSRIs), used for the management of major depressive disorder and other affective conditions. The observation that 5-HT mediates the complete skeletal effects of LRP5 represents a significant paradigm shift from the traditional view that LRP5 located on the cell surface membrane of osteoblasts exerts direct skeletal effects via Wnt/beta-catenin signaling. This paper discusses the mounting evidence for skeletal effects of 5-HT and the ability of gut-derived 5-HT to satisfactorily explain the skeletal effects of LRP5.

Warden, Stuart J.; Robling, Alexander G.; Haney, Elizabeth M.; Turner, Charles H.; Bliziotes, Michael M.



Receptor mechanisms for 5-hydroxytryptamine in rabbit arteries  

PubMed Central

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.

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



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

Microsoft Academic Search

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

C P Bearcroft; D Perrett; M J G Farthing



Unique Allosteric Regulation of 5-hydroxytryptamine Receptor-Mediated Signal Transduction by Oleamide  

Microsoft Academic Search

The effects of oleamide, an amidated lipid isolated from the cerebrospinal fluid of sleep-deprived cats, on serotonin receptor-mediated responses were investigated in cultured mammalian cells. In rat P11 cells, which endogenously express the 5-hydroxytryptamine2A (5HT2A) receptor, oleamide significantly potentiated 5HT-induced phosphoinositide hydrolysis. In HeLa cells expressing the 5HT7 receptor subtype, oleamide caused a concentration-dependent increase in cAMP accumulation but with

Elizabeth A. Thomas; Monica J. Carson; Michael J. Neal; J. Gregor Sutcliffe



Effect of 5-hydroxytryptamine and its antagonists on colonic smooth muscle of the rabbit  

Microsoft Academic Search

The effect of 5-hydroxytryptamine (5HT) was studied in circular and longitudinal muscle from the proximal and distal colon of New Zealand white rabbits. 5HT stimulated a dose-dependent isometric contraction of distal and proximal circular muscle that was greater than in distal longitudinal muscle (P50 for 5HT stimulation of distal circular muscle (-7.0±0.1), distal longitudinal muscle, and proximal circular muscle was

W. W. Ng; J. Jing; P. E. Hyman; W. J. Snape



Characteristics of 5-Hydroxytryptamine Receptors Involved in Contraction of Feline Ileal Longitudinal Smooth Muscle  

PubMed Central

A number of studies have demonstrated that 5-hydroxytryptamine (5-HT) can induce muscle contraction or relaxation response and enhance secretion in the gastrointestinal tract via a multiplicity of 5-HT receptor subtypes. In the present study, we investigated the pharmacological characterization of the 5-HT-induced contractile response in longitudinal smooth muscle isolated from the feline ileum. Addition of 5-HT into muscle chambers enhanced the basal tone and spontaneous activity in a concentration-dependent manner. The neurotoxin tetrodotoxin did not alter the 5-HT-induced contraction of the longitudinal muscles. Neither atropine nor guanethidine affected the contraction. The 5-HT agonists, 5-methylserotonin hydrochloride and mosapride, also evoked concentration-dependent contractions. The 5-HT-induced contraction was enhanced by the 5HT2 receptor antagonist ketanserin and the 5-HT3 receptor antagonist ondansetron but was inhibited by the 5-HT1 receptor antagonist methysergide and 5-HT4 receptor antagonist GR113808. These results indicate that 5-HT1 and 5-HT4 receptors may mediate the contraction of the 5-HT-induced response and 5-HT2 and 5-HT3 receptors may mediate 5-HT-induced relaxation in feline ileal longitudinal smooth muscles.

Wang, YiYi; Park, Sun Young; Oh, Kyung Hoon; Min, Youngsil; Lee, Yun-Jeong; Lee, Seok-Yong



Characteristics of 5-hydroxytryptamine receptors involved in contraction of feline ileal longitudinal smooth muscle.  


A number of studies have demonstrated that 5-hydroxytryptamine (5-HT) can induce muscle contraction or relaxation response and enhance secretion in the gastrointestinal tract via a multiplicity of 5-HT receptor subtypes. In the present study, we investigated the pharmacological characterization of the 5-HT-induced contractile response in longitudinal smooth muscle isolated from the feline ileum. Addition of 5-HT into muscle chambers enhanced the basal tone and spontaneous activity in a concentration-dependent manner. The neurotoxin tetrodotoxin did not alter the 5-HT-induced contraction of the longitudinal muscles. Neither atropine nor guanethidine affected the contraction. The 5-HT agonists, 5-methylserotonin hydrochloride and mosapride, also evoked concentration-dependent contractions. The 5-HT-induced contraction was enhanced by the 5HT(2) receptor antagonist ketanserin and the 5-HT(3) receptor antagonist ondansetron but was inhibited by the 5-HT(1) receptor antagonist methysergide and 5-HT(4) receptor antagonist GR113808. These results indicate that 5-HT(1) and 5-HT(4) receptors may mediate the contraction of the 5-HT-induced response and 5-HT(2) and 5-HT(3) receptors may mediate 5-HT-induced relaxation in feline ileal longitudinal smooth muscles. PMID:22128258

Wang, Yiyi; Park, Sun Young; Oh, Kyung Hoon; Min, Youngsil; Lee, Yun-Jeong; Lee, Seok-Yong; Sohn, Uy Dong



Effects of 5-hydroxytryptamine on canine isolated coronary arteries.  

PubMed Central

The effects of 5-hydroxytryptamine (5-HT) were studied in vitro on proximal and distal portions of canine interventricular and circumflex coronary arterial strips. 5-HT produced concentration-related contractions in the proximal portion whether contracted previously with KCl or not. These responses were still present after either chemical sympathetic denervation or release of noradrenaline induced by K+-free salt solution. In contrast, the distal portions of coronary arteries did not respond to 5-HT. Concentration-response curves to 5-HT exhibited a classical hyperbolic shape with a calculated Hill-coefficient of approximately 1. Methysergide and phentolamine but not morphine shifted to the right and depressed the maximum of the dose-response curves to 5-HT. It is concluded that the contractions produced by 5-HT in the proximal portion of the interventricular and circumflex coronary arteries are not due to the release of endogenous noradrenaline. The vessels appear to possess separate receptors for 5-HT and noradrenaline and the 5-HT responses belong to neither the M nor the D type.

Porquet, M. F.; Pourrias, B.; Santamaria, R.



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

Microsoft Academic Search

Ionic currents induced by 5-hydroxytryptamine (5-HT) in cultured neuroblastoma N18 cells were studied using whole-ceU voltage clamp. The re- sponse was blocked by 1-10 nM 5-HTs receptor-specific antagonists MDL 7222 or ICS 205-930, but not by 1 #M 5-HT1\\/5-HT ~ receptor antagonist spiperone or 5-HT 2 receptor-specific antagonist ketanserin. These 5-HT 3 receptors seem to be ligand-gated channels because the




A 5HT 4 -like receptor in human left atrium  

Microsoft Academic Search

The effects of 5-hydroxytryptamine (5-HT) on left atrial preparations obtained from 5 patients with terminal heart failure who were undergoing heart transplant surgery were investigated. The preparations were paced under isometric conditions. In the presence of (-)-pindolol I pmol\\/l (to block ß-adrenoceptors) and cocaine 6 gmol\\/l (to block tissue uptake of 5-HT) 5-HT increased contractile force with a pEC50 of

Louise Sanders; Alberto J. Kaumann



Evidence for 5HT 2B and 5HT 7 receptor-mediated relaxation in pulmonary arteries of weaned pigs  

Microsoft Academic Search

This study characterizes the relaxant response to 5-hydroxytryptamine (5-HT) in prostaglandin F 2? (PGF 2?)-precontracted pulmonary arteries of weaned pigs. In arterial rings with intact endothelium, the relaxation to 5-HT was biphasic. The high affinity component of relaxation to 5-HT (0.1–10 nM) was abolished by mechanical removal of the endothelium or after the addition of l-NAME (200 ?M), and was

S. Jähnichen; E. Glusa; H. H. Pertz



5-HT1A receptor as a key player in the brain 5-HT system.  


Among an impressive variety of identified serotonin receptors, 5-HT1A attracts particular attention due to its central role in the regulation of 5-HT-ergic neurotransmission and the data on its involvement in the mechanisms of stress response, aggressive behavior, anxiety, and depression. This review concentrates on the cross-regulation between 5-HT receptors and the implication of the 5-HT1A receptor in the genetic control of 5-HT-related behavior. Specifically, it describes the (1) functional interactions between 5-HT1A, 5-HT2A, 5-HT3, and 5-HT7 receptors; (2) cross-talk between 5-HT1A receptor and genes encoding key members of the brain 5-HT system; (3) implication of the 5-HT1A receptor in natural hibernation and genetic predisposition to different kinds of defensive behavior; and (4) role of 5-HT1A autoreceptors and heteroreceptors in anxiety, depression, and suicide, and in the antidepressant effect of serotonin reuptake inhibitors. This review provides converging lines of evidence that the 5-HT1A receptor contributes to the action of other 5-HT receptors, modulating their effect on behavior, and describes new data on the unique role of the 5-HT1A receptor in the indirect regulation of gene expression and in the autoregulation of the brain 5-HT system. PMID:23492554

Popova, Nina K; Naumenko, Vladimir S



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

NASA Astrophysics Data System (ADS)

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

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



5-Hydroxytryptamine-induced calcium-channel gating in rainbow trout (Oncorhynchus mykiss) peripheral blood lymphocytes.  

PubMed Central

The present study was conducted on peripheral blood lympho-cytes of rainbow trout (Oncorhynchus mykiss) to assess the role of 5-hydroxytryptamine (5-HT; 'serotonin') in calcium signalling. 5-HT-induced increases in intracellular free calcium concentrations, [Ca2+]i, and its action was mediated by 5-HT receptor subtype 3 (5-HT3), but not by 5-HT receptor subtype 1A (5-HT1A) or subtype 2 (5-HT2) in these cells. In Ca2+-containing medium (1 mM CaCl2), 5-HT and 2-methyl-5-HT (5-HT3 receptor agonist) induced increases in [Ca2+]i, whereas in Ca2+-free medium (0 Ca2+, 1 mM EGTA), these two agents failed to evoke increases in [Ca2+]i in these cells, demonstrating that 5-HT mobilizes Ca2+ from the extracellular environment. Furthermore, 5-HT-induced increases in [Ca2+]i are not contributed to by the intracellular endoplasmic reticulum (ER) pool, as thapsigargin, an agent that recruits Ca2+ from ER stores, had additive effects on 5-HT-induced [Ca2+]i responses in fish peripheral lymphocytes. 5-HT-induced increases in [Ca2+]i were mediated by 5-HT3 receptors via gating the calcium through L-type, but not N-type, calcium channels in trout lymphocytes.

Ferriere, F; Khan, N A; Meyniel, J P; Deschaux, P



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

Microsoft Academic Search

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

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



5-HT receptor types in the rat ileum longitudinal muscle: focus on 5-HT2 receptors mediating contraction.  


The 5-hydroxytryptamine (5-HT) receptor(s) that mediate(s) contraction of the rat ileum longitudinal muscle was studied. 5-HT and alpha-methyl-5-HT equipotently induced contractions, whereas 5-methoxytryptamine and 2-methyl-5-HT (partial agonist) were less potent; this rank order of potency suggests involvement of a 5-HT2 receptor. Neither tetrodotoxin nor atropine affected the contraction to 5-HT, suggesting a smooth muscle localization of these 5-HT2 receptors. The presence of either a selective 5-HT2B (SB 204741), 5-HT3 (granisetron) or 5-HT4 (SB 204070) antagonist, slightly affected the contractions to 5-HT. Thus, they were also included in the organ bath solution in all subsequent experiments in order to pharmacologically isolate the main contractile component. Using (if possible) 5-HT2A receptor-selective concentrations, ketanserin, ritanserin, metergoline, spiperone, mianserin, methiothepin, mesulergine, methysergide and cisapride all inhibited the contractions to 5-HT, causing a depression of the curve to 5-HT (i.e. surmountable antagonism was not observed with any of the above agents). Comparison of the affinities of these compounds for the various 5-HT2 receptor subtypes revealed that the receptor involved in the contractions to 5-HT most closely resembles the 5-HT2A receptor. However, cinanserin at a concentration expected to inhibit 5-HT2A receptor-mediated effects, failed to affect the contractions to 5-HT. It is thus concluded that on the longitudinal smooth muscle of the rat ileum, at least a part of the contraction to 5-HT is mediated by 5-HT receptors resembling the 5-HT2A receptor subtype. PMID:9430791

Briejer, M R; Mathis, C; Schuurkes, J A



[5-hydroxytryptamine and 5-methoxytryptamine increase tolerance to global cerebral ischemia].  


In the global cerebral ischemia, 5-hydroxytryptamine (serotonin, 5-HT) and 5-methoxytryptamine (5-MT) produce a significant neuroprotector effect closely correlated with their hypothermic action. This expands the spectrum of cerebral functions controlled by 5-HT. At the same time, melatonin and 2-iodmelatonin, which are chemically (but not pharmacologically) close to 5-HT and 5-MT, do not exhibit such protective effects. Probably, an important role in the interaction with 5-HT receptors belongs to the NH2 group of the indole ring. PMID:18318189

Gavrilov, S S; Kulinski?, V I


Contractile effects of 5-hydroxytryptamine and 5-carboxamidotryptamine in the equine jejunum  

PubMed Central

The use of human prokinetic drugs in colic horses leads to inconsistent results. This might be related to differences in gastrointestinal receptor populations. The motor effects of 5-hydroxytryptamine (5-HT; serotonin) on the equine mid-jejunum were therefore studied. Longitudinal muscle preparations were set up for isotonic measurement. 5-HT induced tonic contractions with superimposed phasic activity; these responses were not influenced by tetrodotoxin and atropine, suggesting a non-neurogenic, non-cholinergic pathway. The 5-HT receptor antagonists GR 127935 (5-HT1B,D), ketanserin (5-HT2A), SB 204741 (5-HT2B), RS 102221 (5-HT2C), granisetron (5-HT3), GR 113808 (5-HT4) and SB 269970 (5-HT7) had no influence on the 5-HT-induced response; the 5-HT1A receptor antagonists NAN 190 (pKb=8.13±0.06) and WAY 100635 (pKb=8.69±0.07), and the 5-HT1,2,5,6,7 receptor antagonist methysergide concentration-dependently inhibited the 5-HT-induced contractile response. The 5-HT1,7 receptor agonist 5-carboxamidotryptamine (5-CT) induced a contractile response similar to that of 5-HT; its effect was not influenced by tetrodotoxin and atropine, and SB 269970, but antagonised by WAY 100635. 8-OHDPAT, buspiron and flesinoxan, which are active at rat and human 5-HT1A receptors, had no contractile influence. These results suggest that the contractile effect of 5-HT in equine jejunal longitudinal muscle is due to interaction with muscular 5-HT receptors, which cannot be characterised between the actually known classes of 5-HT receptors.

Delesalle, Catherine; Deprez, Piet; Schuurkes, Jan A J; Lefebvre, Romain A



Contractile effects of 5-hydroxytryptamine and 5-carboxamidotryptamine in the equine jejunum.  


The use of human prokinetic drugs in colic horses leads to inconsistent results. This might be related to differences in gastrointestinal receptor populations. The motor effects of 5-hydroxytryptamine (5-HT; serotonin) on the equine mid-jejunum were therefore studied. Longitudinal muscle preparations were set up for isotonic measurement. 5-HT induced tonic contractions with superimposed phasic activity; these responses were not influenced by tetrodotoxin and atropine, suggesting a non-neurogenic, non-cholinergic pathway. The 5-HT receptor antagonists GR 127935 (5-HT(1B,D)), ketanserin (5-HT(2A)), SB 204741 (5-HT(2B)), RS 102221 (5-HT(2C)), granisetron (5-HT(3)), GR 113808 (5-HT(4)) and SB 269970 (5-HT(7)) had no influence on the 5-HT-induced response; the 5-HT(1A) receptor antagonists NAN 190 (pK(b)=8.13+/-0.06) and WAY 100635 (pK(b)=8.69+/-0.07), and the 5-HT(1,2,5,6,7) receptor antagonist methysergide concentration-dependently inhibited the 5-HT-induced contractile response. The 5-HT(1,7) receptor agonist 5-carboxamidotryptamine (5-CT) induced a contractile response similar to that of 5-HT; its effect was not influenced by tetrodotoxin and atropine, and SB 269970, but antagonised by WAY 100635. 8-OHDPAT, buspiron and flesinoxan, which are active at rat and human 5-HT(1A) receptors, had no contractile influence. These results suggest that the contractile effect of 5-HT in equine jejunal longitudinal muscle is due to interaction with muscular 5-HT receptors, which cannot be characterised between the actually known classes of 5-HT receptors. PMID:16230998

Delesalle, Cathérine; Deprez, Piet; Schuurkes, Jan A J; Lefebvre, Romain A



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

PubMed Central

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

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



Interactions between 5-hydroxytryptamine receptor subtypes: Is a disturbed receptor balance contributing to the symptomatology of depression in humans?  

Microsoft Academic Search

The purpose of this review is to describe the consequences of antidepressant treatment on the behaviour of rodents after activation of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes. In a summary table, the involvement of 5-HT receptors in inducing behavioural changes are described. It is emphasized that these effects are not always only exclusively linked to serotonergic functions nor that they are

H. H. G. Berendsen



5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders: More than 30 years of research  

Microsoft Academic Search

An overview of the behavioral data arising from the vast literature concerning the involvement of 5-hydroxytryptamine (5-HT) neurotransmission in the regulation of anxiety is presented. More than 1300 experiments were carried out in this area and they provide evidence that: (1) results obtained in ethologically based animal models of anxiety with drugs stimulating 5-HT transmission are most consistent with the

Guy Griebel



Peripheral 5-HT1D and 5-HT7 serotonergic receptors modulate sympathetic neurotransmission in chronic sarpogrelate treated rats.  


5-HT2 receptor activation induces vasoconstriction, hypertension and platelet aggregation; therefore, its blocking may be useful in cardiovascular diseases, probably due to alterations in the modulation of serotonergic system. The aim of this study was to evaluate whether 5-HT2 receptor blockade changes serotonergic modulation of sympathetic neurotransmission in pithed rats. Serotonergic modulation of sympathetic neurotransmission was investigated in Wistar rats treated with sarpogrelate, a 5-HT2 receptor antagonist, during 14 days (30mg/kg/day). After central nervous system destruction, we conducted electrical stimulation throughout the spinal cord flow to study the 5-HT-related products action on adrenergic system. 5-Hydroxytryptamine exerted inhibition of sympathetic outflow in sarpogrelate-treated pithed rats. This effect was mimicked and enhanced by 5-CT (5-HT1/7 receptor agonist). L-694,247 and AS-19, 5-HT1D and 5-HT7 receptor agonists respectively, reproduced this action. Pretreatment with LY310762+SB258719 (5-HT1D and 5-HT7 receptor antagonists, respectively) completely abolished 5-CT inhibitory action. The nature of this action was prejunctional since these agonists did not modify the pressor responses induced by exogenous noradrenaline. Western Blot analysis confirmed a higher expression of 5-HT1D receptors in sarpogrelate-treated rats. Experimental 5-HT2 receptor blockade induces changes in the 5-HT receptors involved in the serotonergic inhibition of sympathetic-induced pressor responses. Prejunctional activation of 5-HT1D and 5-HT7 receptors induces a significantly higher serotonergic inhibition on adrenergic neurotransmission in sarpogrelate-treated pithed rats. The antagonism of 5-HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect, which may explain the beneficial effects of this blockade in cardiovascular disorders where 5-hydroxytryptamine plays a crucial role. PMID:23769743

García-Pedraza, José Ángel; García, Mónica; Martín, María Luisa; Gómez-Escudero, Jesús; Rodríguez-Barbero, Alicia; San Román, Luis; Morán, Asunción



The effect of mosapride (5HT4 receptor agonist) on insulin sensitivity and GLUT4 translocation  

Microsoft Academic Search

AimsWe investigated the effect of mosapride, 5HT-4 (5-hydroxytryptamine) agonist, on blood glucose level and insulin sensitivity in subjects with impaired glucose tolerance (IGT) and conducted an in vitro study to evaluate the action mechanism.

J. S. Nam; J. Y. Nam; J. S. Yoo; M. Cho; J. S. Park; C. W. Ahn; B. S. Cha; E. J. Lee; S. K. Lim; K. R. Kim; H. C. Lee



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


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

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



Dopamine and 5-hydroxytryptamine actions on the cardiac ganglion of the lobster Homarus americanus  

Microsoft Academic Search

The cardioexcitor monoamines dopamine (DA) and 5-hydroxytryptamine (5HT) accelerate bursting by isolated cardiac ganglia\\u000a of the lobster Homarusamericanus most effectively when they act on a region of the ganglionic trunk anterior to the small cells which have been considered\\u000a the pacemakers of the system. 5HT may exert its acceleratory action by depolarizing cell processes. Neither the somata nor\\u000a the spike-initiating

A. Berlind



Receptors for 5-hydroxytryptamine on the sympathetic nerves of the rabbit heart  

Microsoft Academic Search

1.The Langendorff perfused rabbit heart has been used to investigate the effects of 5-hydroxytryptamine (5-HT) and several closely related analogues as stimulants and inhibitors of transmitter release from the terminal cardiac sympathetic nerves.2.Sympathomimetic responses to 5-HT were unaffected by perfusion of hearts with hexamethonium at a concentration which abolished responses to DMPP and by perfusion with morphine or methysergide unless

J. R. Fozard; A. T. M. Mobarok Ali



Role of peripheral 5-HT(4), 5-HT(6), and 5-HT(7) receptors in development and maintenance of secondary mechanical allodynia and hyperalgesia.  


The role of 5-hydroxytryptamine (5-HT)(4), 5-HT(6), and 5-HT(7) receptors in formalin-induced secondary allodynia and hyperalgesia in rats was assessed. Formalin produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term secondary mechanical allodynia and hyperalgesia. Pretreatment (-10min) with cromoglycate (195-1950nmol/paw) partially inhibited acute nociceptive behaviors and completely prevented secondary allodynia and hyperalgesia on day 6 after injection. Ipsilateral peripheral pretreatment with the selective 5-HT(4) (ML-10302, 1-100nmol/paw), 5-HT(6) (EMD-386088, 0.001-0.01nmol/paw), and 5-HT(7) (LP-12, 0.01-100nmol/paw) receptor agonists significantly increased secondary allodynia and hyperalgesia in both paws. In contrast, ipsilateral peripheral pretreatment with the selective 5-HT(4) (GR-125487, 1-100nmol/paw), 5-HT(6) (SB-258585, 0.00001-0.001nmol/paw), and 5-HT(7) (SB-269970, 0.1-10nmol/paw) receptor antagonists significantly prevented formalin-induced secondary allodynia and hyperalgesia in both paws. The pronociceptive effect of ML-10302 (100nmol/paw), EMD-386088 (0.01nmol/paw), and LP-12 (100nmol/paw) were completely prevented by GR-125487 (5-HT(4) antagonist, 1nmol/paw), SB-258585 (5-HT(6) antagonist, 0.00001nmol/paw), and SB-269970 (5-HT(7), antagonist, 0.01nmol/paw), respectively. Ipsilateral peripheral posttreatment with cromoglycate or GR-125487 (1-100nmol/paw), SB-258585 (0.001-0.1nmol/paw), and SB-269970 (0.1-10nmol/paw) reversed formalin-induced secondary allodynia and hyperalgesia in both paws. Results suggest that a barrage of afferent input induced by 5-HT at peripheral 5-HT(4), 5-HT(6), and 5-HT(7) receptors participate in the development and maintenance of formalin-induced long-term secondary allodynia and hyperalgesia in the rat. 5-hydroxytryptamine (5-HT) released in peripheral tissues after formalin injection sensitized primary afferent neurons via 5-HT(4), 5-HT(6), and 5-HT(7) receptors, leading to development and maintenance of secondary allodynia and hyperalgesia. PMID:21239110

Godínez-Chaparro, Beatriz; Barragán-Iglesias, Paulino; Castañeda-Corral, Gabriela; Rocha-González, Héctor I; Granados-Soto, Vinicio



Enhanced Aggressive Behavior in Mice Lacking 5HT1B Receptor  

Microsoft Academic Search

The neuromodulator serotonin (5-hydroxytryptamine, 5-HT) has been associated with mood disorders such as depression, anxiety, and impulsive violence. To define the contribution of 5-HT receptor subtypes to behavior, mutant mice lacking the 5-HT1B receptor were generated by homologous recombination. These mice did not exhibit any obvious developmental or behavioral defects. However, the hyperlocomotor effect of the 5-HT1A\\/1B agonist RU24969 was

Frederic Saudou; Djamel Ait Amara; Andree Dierich; Marianne Lemeur; Sylvie Ramboz; Louis Segu; Marie-Christine Buhot; Rene Hen



5HT1C receptor-mediated stimulation of inositol phosphate production in pig choroid plexus  

Microsoft Academic Search

1) 5-HT (5-hydroxytryptamine, serotonin) induces inositol phosphate production in a pig choroid plexus preparation. This effect has been pharmacologically characterized and the data compared to those obtained from radioligand binding studies performed with [3H]mesulergine to 5-HT1C sites in pig choroid plexus membranes. 2) The rank order of potency of agonists stimulating inositol phosphate production was: a-methyl-5-HT > 1-methyl-5-HT > DOI

Daniel Hoyer; Christian Waeber; Philippe Schoeffter; Jose Maria Palacios; Anant Dravid



5HT1B Receptor Subtype and Aging in Rat Resistance Vessels  

Microsoft Academic Search

The effects of 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine, and sumatriptan on rat caudal arteries were examined, with the goal of finding experimental conditions useful in enhancing the ‘silent’ 5-HT1B receptor subtype. It was shown that both reserpine treatment and K+ depolarizationincreased the vasoconstriction by 5-HT receptor agonists. The role of the 5-HT2A receptor in vasoconstriction was examined using ritanserin (50 nmol\\/l), a

Guglielmina Froldi; Monica Montopoli; Miriam Zanetti; Paola Dorigo; Laura Caparrotta



Neuropharmacological Profile of Novel and Selective 5HT6 Receptor Agonists: WAY181187 and WAY208466  

Microsoft Academic Search

One of the most recently identified serotonin (5-hydroxytryptamine (5-HT)) receptor subtypes is the 5-HT6 receptor. Although in-depth localization studies reveal an exclusive distribution of 5-HT6 mRNA in the central nervous system, the precise biological role of this receptor still remains unknown. In the present series of experiments, we report the pharmacological and neurochemical characterization of two novel and selective 5-HT6

Lee E Schechter; Qian Lin; Deborah L Smith; Guoming Zhang; Qin Shan; Brian Platt; Michael R Brandt; Lee A Dawson; Derek Cole; Ron Bernotas; Albert Robichaud; Sharon Rosenzweig-Lipson; Chad E Beyer; LE Schechter



5-Hydroxytryptamine-Induced Phosphoinositide Hydrolysis and Ca 2+ Mobilisation in Canine Cultured Aorta Smooth Muscle Cells  

Microsoft Academic Search

The effect of 5-hydroxytryptamine (5-HT) on phospholipase C (PLC)-mediated phosphoinositide (PI) hydrolysis and intracellular Ca2+ ([Ca2+]i) changes was investigated in canine cultured aorta smooth muscle cells (ASMCs). 5-HT-stimulated inositol phosphate (IP) accumulation was time and concentration dependent with a half-maximal response (pEC50) and a maximal response at 6.4 and 10 ?M, n = 6, respectively. Stimulation of ASMCs by 5-HT

Chi-Tso Chiu; Hui-Liang Tsao; Lir-Wan Fan; Chuan-Chwan Wang; Chin-Sung Chien; Chuen-Mao Yang



Forskolin Inhibits 5-Hydroxytryptamine-Induced Phosphoinositide Hydrolysis and Ca 2+ Mobilisation in Canine Cultured Aorta Smooth Muscle Cells  

Microsoft Academic Search

The effect of forskolin on 5-hydroxytryptamine (5-HT)-induced inositol phosphate (IP) and Ca2+ mobilisation was investigated in canine cultured aorta smooth muscle cells (ASMCs). Pretreatment of ASMCs with forskolin attenuated 5-HT-induced IP accumulation and Ca2+ mobilisation in a time- and concentration-dependent manner. The half-maximal effects (pEC50) of forskolin to attenuate IP and Ca2+ responses to 5-HT occurred at concentrations of 6.28

Chuen-Mao Yang; Chi-Tso Chiu; Chuan-Chwan Wang; Hui-Liang Tsao; Lir-Wan Fan



Role of 5-hydroxytryptamine and mast cells in the tachykinin-induced contraction of rat trachea in vitro  

Microsoft Academic Search

The in vivo bronchoconstrictor effect of tachykinins in Fisher 344 rats is accompanied by release into the airways of 5-hydroxytryptamine (5-HT). 5-HT is possibly derived from mast cells. In the present study the presumed mast cell–tachykinin interaction was studied in isolated trachea from Fisher 344 rats. Contractions induced by neurokinin A were largely reduced by the 5-HT antagonist methysergide, partially

Guy F Joos; Romain A Lefebvre; Gillian R Bullock; Romain A Pauwels



Excitation and depression of cortical neurones by 5-hydroxytryptamine  

PubMed Central

1. 5-Hydroxytryptamine (5-HT) and various 5-HT antagonists have been applied micro-electrophoretically from multibarrelled micropipettes into the environment of single neurones in the post-sigmoid and suprasylvian gyri of the cat cerebral cortex. 2. In unanaesthetized animals (encéphale isolé) a high proportion of neurones (30%) were excited by 5-HT. This excitation usually had a rapid onset and was seen both in spontaneously active neurones and in otherwise quiescent neurones in which firing was induced by L-glutamate. Some neurones were so sensitive that the uncontrolled diffusion from micropipettes was sufficient to excite them. More cells were excited by 5-HT applied as a cation from solutions of the bimaleate salt than when solutions of the creatinine sulphate salt were used. 3. In a high proportion of cells (33%) spontaneous firing or amino acid excitation was depressed by 5-HT. 4. A mixed effect was seen in a small proportion (6%) of the cells tested; usually 5-HT caused an excitation initially which was followed by a depression. In other cells, desensitization occurred, and the excitatory effect of 5-HT was diminished or lost. 5. When glutamate was used to excite otherwise quiescent cells, there was a significant increase in the number of cells excited by 5-HT and a significant decrease in the number of cells unaffected compared with spontaneously active cells. 6. The micro-electrophoretic application of D-lysergic diethylamide (LSD 25), 2-brom LSD (BOL 148), methysergide (UML 491), or 2?- (3-dimethylaminopropylthio)cinnamanilide (SQ 10643) temporarily prevented excitation by 5-HT in half the cells tested. LSD and SQ 10643 were particularly potent in this respect. This antagonism of 5-HT excitation could still be seen when excitation of the cell by L-glutamate or acetylcholine (ACh) was unaffected. 7. The depression induced by 5-HT was not prevented by the application of known 5-HT antagonists in the majority of the cells tested (93%). In two cells, however, the depression was reversibly prevented by these antagonists. 8. Some cells tested with 5-HT were also tested with ACh or (—)-noradrenaline. The response of a cell to ACh was not significantly related to its response to 5-HT. The degree of correlation between the responses to noradrenaline and 5-HT was large, but not statistically significant with the small number of cells studied. 9. The effects of 5-HT on cells in animals anaesthetized with ?-chloralose did not differ significantly from its effects in unanaesthetized preparations. It is suggested that the use of this anaesthetic may prove a useful alternative to unanaesthetized preparations. 10. The systemic injection of small quantities of thiopentone sodium selectively and reversibly reduced the sensitivity of some units to excitation by 5-HT at a time when the response to glutamate was unaffected. On other occasions, the 5-HT excitation was unaffected, though the response to glutamate was reduced. 11. These results are discussed in relation to the possible nature of the 5-HT receptors in the cerebral cortex, and the interfering effects of anaesthesia on the response of brain cells to potential transmitter substances.

Roberts, M. H. T.; Straughan, D. W.



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

PubMed Central

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

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



Important messages in the 'post': recent discoveries in 5-HT neurone feedback control.  


The neurotransmitter 5-hydroxytryptamine (5-HT, serotonin) mediates important brain functions and contributes to the pathophysiology and successful drug treatment of many common psychiatric disorders, especially depression. It is established that a key mechanism involved in the control of 5-HT neurones is feedback inhibition by presynaptic 5-HT autoreceptors, which are located on 5-HT cell bodies and nerve terminals. However, recent experiments have discovered an unexpected complexity of 5-HT neurone control, specifically in the form of postsynaptic 5-HT feedback mechanisms. These mechanisms have the physiological effects of 5-HT autoreceptors but use additional 5-HT receptor subtypes and operate through neural inputs to 5-HT neurones. A postsynaptic feedback system that excites 5-HT neurones has also been reported. This article discusses current knowledge of the pharmacology and physiology of these new found 5-HT feedback mechanisms and considers their possible contribution to depression pathophysiology and utility as a resource of novel antidepressant drug strategies. PMID:17996955

Sharp, Trevor; Boothman, Laura; Raley, Josie; Quérée, Philip



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

Microsoft Academic Search

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

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



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

Microsoft Academic Search

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

Margaret R MacLean



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

PubMed Central

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

Hamel, E.; Bouchard, D.



Identification of serotonin 5HT3 recognition sites by radioligand binding in NG108-15 neuroblastoma-glioma cells  

Microsoft Academic Search

The 5-HT (5-hydroxytryptamine, serotonin) receptors\\u000ahave been subdivided into 3 main classes\\u000atermed 5-HT?, 5-HT? and 5-HT?. Although well characterized in various isolated\\u000atissue models, 5-HT? receptors, in contrast\\u000ato 5-HT? and 5-HT? receptors,\\u000ahave not yet been identified by means of radioligand\\u000abinding techniques.\\u000aWe now report on the identification of 5-HT?\\u000arecognition sites in NG 108-15 neuroblastomaglioma\\u000acells

D. Hoyer; H. C. Neijt



Pharmacological characteristics and regulation of 5HT receptor-stimulated phosphoinositide hydrolysis in the rat spinal cord  

Microsoft Academic Search

In slices from immature rat spinal cord, both 5-hydroxytryptamine (5-HT) and the 5-HT2A\\/C receptor agonists (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and ?-methyl-5-HT (?-Me-5-HT) stimulate phosphoinositide (PI) hydrolysis. PI breakdown is also increased by the 5-HT3 receptor agonist 2-Me-5-HT but not by phenylbiguanide. The effect of either 5-HT or DOI is blocked by selective 5-HT2A receptor antagonists such as spiperone and ketanserin and more

E. Toscano; G. Romero; C. Oset; J. Del R??o



Pharmacological characterization of 5-hydroxytryptamine-induced excitation of afferent cervical vagus nerve in anaesthetized rats.  

PubMed Central

1. An excitatory response to 5-hydroxytryptamine (5-HT) was measured from the afferent vagus nerve of anaesthetized rats. Measurements were determined by an extracellular recording from the whole nerve. 2. Intravenous bolus injection of 5-HT (1.56-100 micrograms kg-1) evoked a dose-dependent excitation of afferent vagus nerve activity. This response was blocked not only by a selective 5-HT3 receptor antagonist, GR38032F (10 and 100 micrograms kg-1), but also by a 5-HT2 receptor antagonist, ketanserin (10 and 100 micrograms kg-1). 3. Both a 5-HT3 receptor agonist, 2-methyl-5-HT (3.12-100 micrograms kg-1), and a 5-HT2 receptor agonist, alpha-methyl-5-HT (3.12-50 micrograms kg-1), produced a dose-dependent excitation of afferent vagus nerve activity. These excitatory effects were antagonized by GR38032F (10 micrograms kg-1) and ketanserin (10 micrograms kg-1), respectively. 4. A 5-HT1 like receptor agonist, 5-carboxamidotryptamine (50 micrograms kg-1), and a putative 5-HT4 receptor agonist, 5-methoxytryptamine (100 micrograms kg-1), failed to produce excitatory effects on the afferent vagus nerve. 5. These results suggest that the 5-HT-induced excitatory response of the afferent vagus nerve might be mediated not only via 5-HT3 receptors but also via 5-HT2 receptors in anaesthetized rats. It is unlikely, however, that either 5-HT1-like or putative 5-HT4 receptors are involved in the excitatory response of the afferent vagus nerve to 5-HT.

Yoshioka, M.; Ikeda, T.; Abe, M.; Togashi, H.; Minami, M.; Saito, H.



On the nature of the receptor mediating the action of 5-hydroxytryptamine in potentiating responses of the mouse urinary bladder strip to electrical stimulation  

Microsoft Academic Search

1.Superfused mouse bladder strip responded to electrical stimulation (ES) by twitch contractions. These contractions were potentiated by 5-hydroxytryptamine (5-HT;0.03–3.0 µM).2.Three tryptamine analogues were tested for their ability to potentiate the responses to ES and their relative activities were compared with values in the literature. 5-Carboxamidotryptamine was more potent than 5-HT, N-?-methyl 5-HT was about equipotent, anda-methyl 5-HT was much less

Susan E. Holt; Marie Cooper; J. H. Wyllie



Modulation of crayfish retinal sensitivity by 5-hydroxytryptamine.  


The responsiveness of crayfish retinal photoreceptors to light was enhanced by exposure to 5-hydroxytryptamine (5-HT), either following injection into whole animals or following topical application to isolated eyestalks or retinas. The effect was measured as an increment in the amplitude of the receptor potential, and was dose-dependent in the range 10(-6)-10(-3) mol l-1 (injected as a 0.1 microliter dose in intact animals). It was more pronounced at low levels of illumination and was reversibly blocked by methysergide. The enhancement was a consequence of a dual effect: (a) retraction of the proximal pigment granules within the photoreceptors, with a corresponding increase in the light-admittance function of the retina; and (b) a direct effect, facilitating a membrane conductance increase which mediated the generation of the receptor potential. A set of axons in the lamina ganglionaris with a 5-HT-like immunoreactivity was found in the vicinity of the photoreceptor axons. 5-HT antagonists were capable of blocking the physiological retraction of pigment granules in photoreceptors at night, suggesting that 5-HT acts as a modulator during the nocturnal phase of the circadian cycle in the crayfish retina. PMID:2355208

Aréchiga, H; Bañuelos, E; Frixione, E; Picones, A; Rodríguez-Sosa, L



The psychopharmacology of 5-HT3 receptors.  


The review presents evidence that 5-HT3 receptors within the brain may contribute to the control of behavior. 5-HT3 receptor antagonists GR38032F, zacopride, ICS 205-930 and other agents are very potent in reducing mesolimbic dopamine hyperactivity caused by the injection of amphetamine or infusion of dopamine into the rat nucleus accumbens and amygdala, and the ventral striatum of the marmoset. Such actions are distinguished from those of neuroleptic agents by a failure to reduce normal levels of activity or to induce a rebound hyperactivity after discontinuation of treatment. Indeed, the 5-HT3 receptor antagonists can prevent the neuroleptic-induced rebound hyperactivity. Further evidence that 5-HT3 receptors moderate limbic dopamine function is shown by their ability to reduce both the behavioral hyperactivity and changes in limbic dopamine metabolism caused by DiMe-C7 injection into the ventral tegmental area. The 5-HT3 receptor antagonists also have an anxiolytic profile in the social interaction test in the rat, the light/dark exploration test in the mouse, the marmoset human threat test and behavioral observations in the cynomolgus monkey. They differ from the benzodiazepines by an absence of effect in the rat water lick conflict test and a withdrawal syndrome. Importantly, the 5-HT3 receptor antagonists are highly effective to prevent the behavioral syndrome following withdrawal from treatment with diazepam, nicotine, cocaine and alcohol. Intracerebral injection techniques in the mouse indicate that the dorsal raphe nucleus and amygdala may be important sites of 5-HT3 receptor antagonist action to inhibit aversive behavior. Studies with GR38032F indicate an additional effect in reducing alcohol consumption in the marmoset. The identification and distribution of 5-HT3 receptors in the brain using a number of 5-HT3 receptor ligands, [3H]65630, [3H]zacopride and [3H]ICS 205-930 correlates between studies, and the 5-HT3 recognition sites in cortical, limbic and other areas meet the criteria for 5-HT3 receptors to mediate the above behavioral effects. Thus the use of 5-HT3 receptor antagonists reveals an important role for 5-hydroxytryptamine in the control of disturbed behavior in the absence of effect on normal behavior. The profile of action of the 5-HT3 receptor antagonists has generated a major clinical interest in their potential use for schizophrenia, anxiety and in the control of drug abuse. PMID:2203069

Costall, B; Naylor, R J; Tyers, M B



Pharmacological analysis of 5-hydroxytryptamine effects on electrically stimulated human isolated urinary bladder.  

PubMed Central

1. 5-Hydroxytryptamine (5-HT) is able to potentiate the contractions induced by electrical field stimulation of pieces of human isolated urinary bladder. On the basis of available selective 5-HT agonists and antagonists, we have further investigated the receptors involved and their site of action. 2. 5-HT produced a concentration-dependent increase of the contractile response to electrical field stimulation from 0.1 nM to 1 microM. At higher concentrations (up to 100 microM) the effect decreased. These activities were mimicked by a variety of 5-HT agonists, for which the following rank order of potency was found: 5-HT greater than alpha-methyl 5-HT greater than 5-methoxytryptamine greater than 5-carboxamidotryptamine greater than 2-methyl 5-HT much greater than GR 43175. In addition the gastro-prokinetics agents metoclopramide, cisapride and the 5-HT3 antagonist ICS 205-930 behaved as 5-HT agonists, their EC50 values being 2.3, 0.3, and 0.5 (microM) respectively. 3. The 5-HT potentiating effect was resistant to antagonism by ondansetron (1 microM) and cyanopindolol (1 microM), selective 5-HT3 and 5-HT1A/1B antagonists respectively. The 5-HT2 antagonists ketanserin (1 microM), spiperone (1 microM) and methysergide (1 microM) also showed a weak inhibitory activity. Methiothepin (0.1-1 microM) antagonized only the inhibitory effect of 5-HT. Metoclopramide (0.1-1 microM), cisapride (0.01-0.1 microM) and ICS 205-930 (0.3-3 microM) all produced a rightward displacement of the 5-HT response curve with concomitant reduction of the maximum response.(ABSTRACT TRUNCATED AT 250 WORDS)

Corsi, M.; Pietra, C.; Toson, G.; Trist, D.; Tuccitto, G.; Artibani, W.




Microsoft Academic Search

Binding properties of gastrointestinal prokinetic benzamides for both cloned human 5-hydroxytryptamine (5-HT)3receptors and cloned human 5-HT4receptors were examined and pharmacological properties of YM-53389{(+)-(S)-2-chloro-5-methoxy-4-[5-(2-piperidylmethyl)-1,2,4-oxadiazol-3-yl]aniline monohydrochloride} were characterised in animals. Cisapride, renzapride and zacopride inhibited specific binding of [3H]ramosetron to cloned human 5-HT3receptors, withKivalues of 684, 7.64 and 0.38 nm, respectively. YM-53389, however, slightly replaced that (Ki>10,000 nm). YM-53389, cisapride, renzapride and




Two members of a distinct subfamily of 5-hydroxytryptamine receptors differentially expressed in rat brain.  

PubMed Central

We report two serotonin (5-hydroxytryptamine, 5-HT) receptors, MR22 and REC17, that belong to the G-protein-associated receptor superfamily. MR22 and REC17 are 371 and 357 amino acids long, respectively, as deduced from nucleotide sequence and share 68% mutual amino acid identity and 30-35% identity with known catecholamine and 5-HT receptors. Saturable binding of 125I-labeled (+)-lysergic acid diethylamide to transiently expressed MR22 in COS-M6 cells was inhibited by ergotamine > methiothepin > 5-carboxamidotryptamine > 5-HT. For REC17, the rank of potency was ergotamine > 5-carboxamidotryptamine > methiothepin > methysergide > 5-HT. Both were insensitive to 5-HT1A, 5-HT1D or 5-HT2 serotonergic ligands [8-hydroxy-2-(di-n-propylamino)tetralin, sumatriptan, and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]. The mRNAs encoding MR22 were detected in the CA1 region of hippocampus, the medial habenula, and raphe nuclei. In contrast, mRNAs encoding REC17 were found throughout the rat central nervous system. We propose that REC17 and MR22, designated as 5-HT5 alpha and 5-HT5 beta, represent a distinct subfamily of 5-HT receptors. Images Fig. 3 Fig. 4

Erlander, M G; Lovenberg, T W; Baron, B M; de Lecea, L; Danielson, P E; Racke, M; Slone, A L; Siegel, B W; Foye, P E; Cannon, K



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

PubMed Central

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.

Edvinsson, L; Hardebo, J E



Heterogeneity of 5-hydroxytryptamine receptors in the rat uterus and stomach strip.  

PubMed Central

Experiments were performed using the rat isolated uterus and the rat stomach strip to investigate the effects of 5-hydroxytryptamine (5-HT) on 5-HT receptors in the presence of different antagonists. Amitriptyline, methysergide and trazodone were used to antagonize the response to 5-HT in these tissues. The pA2 value for amitriptyline with 5-HT as the agonist was estimated from the Schild plot analysis and found to differ significantly (P less than 0.05) in the stomach strip (6.36) from that in the isolated uterus (9.06). A similar difference was found using trazodone; here the pA2 value was 6.74 in the stomach strip and 8.49 in the isolated uterus. These results indicate a difference between the two tissues. This difference is discussed in terms of heterogeneity of 5-HT receptors.

Wrigglesworth, S. J.



Inhibitory 5-hydroxytryptamine receptors involved in pressor effects obtained by stimulation of sympathetic outflow from spinal cord in pithed rats.  

PubMed Central

1. A study was made of the effects of 5-hydroxytryptamine (5-HT) on pressor response induced in vivo by electrical stimulation of the sympathetic outflow from the spinal cord of pithed rats. All animals had been pretreated with atropine. Intravenous infusion of 5-hydroxytryptamine at doses of 10 and 20 micrograms kg-1 min-1 reduced the pressor effects obtained by electrical stimulation at intervals of 10 min over the 1 h of infusion. 2. This inhibitory action of 5-HT was depressed by cyproheptadine and methiothepin but was not modified by ketanserin or MDL-72222. By contrast, the inhibitory action of 5-HT was lost in pithed rats that had been pretreated with exogenous noradrenaline. 3. The 5-HT1 receptor agonist 5-carboxamidotryptamine (5-CT) caused an inhibition of the pressor response, whereas the 5-HT3 receptor agonist, 1-phenylbiguanide, produced a variable but significant increase in the pressor response. The 5-HT2 receptor agonist, m-CPP, did not modify the pressor sympathetic response. 4. Our results suggest that 5-hydroxytryptamine interferes with sympathetic neurotransmission by inhibiting pressor effects as a result of stimulation of the complete sympathetic outflow, and that this inhibition is mainly through a presynaptic 5-HT1 mechanism.

Moran, A; Velasco, C; Salvador, T; Martin, M L; San Roman, L



Ionic mechanism of a hyperpolarizing 5-hydroxytryptamine effect on leech neuropile glial cells.  


The ionic mechanism of a membrane effect of 5-hydroxytryptamine (5-HT) on neuropile glial (NG) cells in ganglia of the medicinal leech was investigated with conventional single-barrelled microelectrodes. Control experiments were made with double-barrelled ion-selective microelectrodes. 5-Hydroxytryptamine hyperpolarized the NG-cell membrane and increased the conductance considerably. Methysergide, a potent 5-HT antagonist, blocked the 5-HT-induced hyperpolarization completely. When leech ganglia were superfused with physiological bathing media free of 5-HT, the NG-cell membrane conductance returned to the original value, but the membrane potential recovered only partially from the hyperpolarization in most experiments. In glial membranes artificially depolarized by means of constant-current injection, the amplitude of the 5-HT response increased. The amplitude decreased with membrane hyperpolarization and reversed at - 73 mV, close to the potassium equilibrium potential. The reversal potential changed by 52 mV when the extracellular potassium concentration was altered by a factor of 10. We conclude that 5-HT increases the potassium conductance of NG-cell membranes. PMID:7139311

Walz, W; Schlue, W R



Immunohistochemical localization of 5HT 2A receptors in peripheral sensory axons in rat glabrous skin  

Microsoft Academic Search

Serotonin (5-hydroxytryptamine, 5-HT) is a well known inflammatory mediator and algesic substance. It has been hypothesized that 5-HT can have a direct action on peripheral sensory axons, but there has been no anatomical demonstration of 5-HT receptors on peripheral primary afferent processes. The present study shows that 32% of unmyelinated axons at the dermal-epidermal junction are immunohistochemically stained with antibodies

Susan M Carlton; Richard E Coggeshall



Platelet 5-hydroxytryptamine increases with platelet age in dogs.  


Thrombocytopenia was induced in mongrel dogs by two mechanisms: immunologically, by intravenous injection of heterologous antiplatelet antibody, and non-immunologically, by circulating the blood through glass beads in anesthetized animals. The platelet content of 5-HT was monitored before and during the recovery of the blood platelet counts. This period is associated with the normalization of the mean platelet survival time and with a progressive increase in the mean age of the circulating platelet population. A continuous increment in platelet 5-HT closely followed the increase in platelet counts in both models of thrombocytopenia, and a strong correlation was found between the platelet age and 5-HT content. These findings support the concept that platelets accumulate 5-HT during their physiological aging process, contradicting the notion that a negative balance in 5-HT content results at the end of their physiological lifespan in circulation. These results are not in conflict with the concept that circulating platelets release and re-uptake 5-HT. PMID:1771619

Mezzano, D; del Pino, G E; Montesinos, M; García, M E; Aranda, E; Foradori, A



Characterization of 5-HT3 and 'atypical' 5-HT receptors mediating guinea-pig ileal contractions in vitro.  

PubMed Central

1. Neuronal 5-hydroxytryptamine (5-HT) receptors mediating contraction of guinea-pig ileal segments have been characterized in vitro by the use of methysergide to block 5-HT1-like and 5-HT2 receptors. Concentration-response curves to 5-HT were biphasic (first phase, defined as those responses occurring between 1 nM and 0.32 microM 5-HT, -log EC50 = 7.15 +/- 0.08; second phase, defined as these responses occurring between 0.32 microM and 32 microM 5-HT, -log EC50 = 5.32 +/- 0.03) but monophasic to 5-methoxytryptamine (-log EC50 = 7.0 +/- 0.08) and 2 methyl 5-HT (-log EC50 = 5.2 +/- 0.13). The maximal response of the first phase to 5-HT and the maximal response to 5-methoxytryptamine were 30 +/- 4% and 35 +/- 5% respectively of the maximum response to the second phase of the 5-HT concentration-effect curve (set at 100%). In contrast, the maximal response to 2-methyl-5-HT equalled that obtained with 5-HT (second phase). 2. The responses comprising the second phase of the concentration-effect curve to 5-HT were antagonized by 1 microM ICS 205-930, ondansetron, granisetron, quipazine, N-methyl-quipazine and (R,S)-zacopride and the following pKB values, with 5-HT as the agonist, were obtained at the 5-HT3 receptor: ICS 205-930 7.61 +/- 0.05, ondansetron 6.90 +/- 0.04, granisetron 7.90 +/- 0.04, (S)-zacopride 8.11 +/- 0.06, (R,S)-zacopride 7.64 +/- 0.11, and (R)-zacopride 7.27 +/- 0.06.(ABSTRACT TRUNCATED AT 250 WORDS)

Eglen, R. M.; Swank, S. R.; Walsh, L. K.; Whiting, R. L.



Toward Selective Drug Development for the Human 5-Hydroxytryptamine 1E Receptor: A Comparison of 5-Hydroxytryptamine 1E and 1F Receptor Structure-Affinity RelationshipsS?  

PubMed Central

The 5-hydroxytryptamine (5-HT) 1E receptor is highly expressed in the human frontal cortex and hippocampus, and this distribution suggests the function of 5-HT1E receptors might be linked to memory. To test this hypothesis, behavioral experiments are needed. Because rats and mice lack a 5-HT1E receptor gene, knockout strategies cannot be used to elucidate this receptor's functions. Thus, selective pharmacological tools must be developed. The tryptamine-related agonist BRL54443 [5-hydroxy-3-(1-methylpiperidin-4-yl)-1H-indole] is one of the few agents that binds 5-HT1E receptors with high affinity and some selectively; unfortunately, it binds equally well to 5-HT1F receptors (Ki ? 1 nM). The differences between tryptamine binding requirements of these two receptor populations have never been extensively explored; this must be done to guide the design of analogs with greater selectivity for 5-HT1E receptors versus 5-HT1F receptors. Previously, we determined the receptor binding affinities of a large series of tryptamine analogs at the 5-HT1E receptor; we now examine the affinities of this same series of compounds at 5-HT1F receptors. The affinities of these compounds at 5-HT1E and 5-HT1F receptors were found to be highly correlated (r = 0.81). All high-affinity compounds were full agonists at both receptor populations. We identified 5-N-butyryloxy-N,N-dimethyltryptamine as a novel 5-HT1F receptor agonist with >60-fold selectivity versus 5-HT1E receptors. There is significant overlap between 5-HT1E and 5-HT1F receptor orthosteric binding properties; thus, identification of 5-HT1E-selective orthosteric ligands will be difficult. The insights generated from this study will inform future drug development and molecular modeling studies for both 5-HT1E and 5-HT1F receptors.

Klein, Michael T.; Dukat, Malgorzata; Glennon, Richard A.



The Tramadol Metabolite, O-Desmethyl Tramadol, Inhibits 5Hydroxytryptamine Type 2C Receptors Expressed in Xenopus Oocytes  

Microsoft Academic Search

Purpose: Tramadol is widely used clinically as an analgesic, yet the mechanism by which it produces antinociception remains unclear. O-Desmethyl tramadol, the main metabolite of tramadol, is a more potent analgesic than tramadol. We reported previously that tramadol inhibits the 5-hydroxytryptamine (5-HT) type 2C receptor (5-HT2CR), a G-protein-coupled receptor that is expressed widely within brain and that mediates several effects

Takafumi Horishita; Kouichiro Minami; Yasuhito Uezono; Munehiro Shiraishi; Junichi Ogata; Takashi Okamoto; Akio Shigematsu



Identification of 5-hydroxytryptamine 1A receptor agents using a composite pharmacophore analysis and chemical database screening  

Microsoft Academic Search

A composite pharmacophore analysis and computer-assisted chemical database screening were used to identify a previously unrecognized class of 5-hydroxytryptamine1A (5-HT1A) receptor active agents. An analysis of published data led to the identification of 20 different chemical structures which share nanomolar affinity for the 5-HT1A receptor. From a composite pharmacophore analysis of all 20 potent agents, we hypothesized that compounds containing

Andrew J. Sleight; Stephen J. Peroutka



Regional differences in the effects of forced swimming on extracellular levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid  

Microsoft Academic Search

The effects of forced swimming for 30 min on extracellular 5-hydroxytryptamine (5-HT) levels were examined in five brain regions in rats using in vivo microdialysis. A single dialysis probe was implanted under surgical anesthesia into either the striatum, ventral hippocampus, frontal cortex, amygdala, or lateral septum on the day before the study. Dialysate content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA)

Lynn G. Kirby; Angela R. Allen; Irwin Lucki



The serotonin 5-HT3 receptor: a novel neurodevelopmental target  

PubMed Central

Serotonin (5-hydroxytryptamine, 5-HT), next to being an important neurotransmitter, recently gained attention as a key-regulator of pre- and postnatal development in the mammalian central nervous system (CNS). Several receptors for 5-HT are expressed in the developing brain including a ligand-gated ion channel, the 5-HT3 receptor. Over the past years, evidence has been accumulating that 5-HT3 receptors are involved in the regulation of neurodevelopment by serotonin. Here, we review the spatial and temporal expression patterns of 5-HT3 receptors in the pre- and early postnatal rodent brain and its functional implications. First, 5-HT3 receptors are expressed on GABAergic interneurons in neocortex and limbic structures derived from the caudal ganglionic eminence. Mature inhibitory GABAergic interneurons fine-tune neuronal excitability and thus are crucial for the physiological function of the brain. Second, 5-HT3 receptors are expressed on specific glutamatergic neurons, Cajal–Retzius cells in the cortex and granule cells in the cerebellum, where they regulate morphology, positioning, and connectivity of the local microcircuitry. Taken together, the 5-HT3 receptor emerges as a potential key-regulator of network formation and function in the CNS, which could have a major impact on our understanding of neurodevelopmental disorders in which 5-HT plays a role.

Engel, Mareen; Smidt, Marten P.; van Hooft, Johannes A.



Role of Serotonin 5-HT3 Receptors in Intestinal Inflammation.  


Serotonin (5-hydroxytryptamine; 5-HT), a well-characterized neurotransmitter in the central nervous system, plays a crucial role in regulating mood, body temperature, sleep, appetite, and metabolism. Serotonin is synthesized in the serotonergic neuron of the central nervous system; however, approximately 90% of serotonin is synthesized and localized in the gastrointestinal (GI) tract, especially in the enterochromaffin (EC) cells. In the GI tract, serotonin mediates control over a variety of physiological functions such as contraction/relaxation of smooth muscle, and peristaltic and secretory reflexes, directly or indirectly through intrinsic primary afferent neurons. The receptors mediating the action of serotonin are mainly classified into 7 major groups known as the 5-HT1 to 5-HT7 receptors. The 5-HT3 receptor is distinguished from among the other 5-HT receptor subtypes because it is only a ligand-gated ion channel, whereas the other subtypes serve as G protein-coupled receptors. The 5-HT3 receptor, which is generally considered to be localized in the central and peripheral nervous systems, is involved in processes associated with emotion, cognition, memory, pain perception, and GI functions including secretion and motility. Recently, an increasing number of findings have provided evidence of the important role of the 5-HT3 receptor in the regulation of inflammatory and immune responses. In fact, several 5-HT3 receptor antagonists have been reported to ameliorate intestinal inflammation. Therefore, this review focuses on the role of 5-HT3 receptors in the pathogenesis of intestinal inflammation. PMID:23995650

Kato, Shinichi



Activation of 5HT1B receptors in the nucleus accumbens reduces amphetamine-induced enhancement of responding for conditioned reward  

Microsoft Academic Search

Previously, we have demonstrated that 5-hydroxytryptamine (5-HT) injected into the nucleus accumbens attenuates the potentiating\\u000a effects of d-amphetamine on responding for conditioned reward (CR). The present studies examined the 5-HT receptor involved in this effect\\u000a by investigating the effects of 5-HT agonists with differing affinities for 5-HT1 and 5-HT2 receptors on d-amphetamine-induced potentiation of responding for CR. Rats were trained

Paul J. Fletcher; Karin M. Korth



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

Microsoft Academic Search

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

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



The therapeutic role of 5-HT1A and 5-HT2A receptors in depression  

PubMed Central

The selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressant drugs, because they are well tolerated and have no severe side effects. They rapidly block serotonin (5-HT) reuptake, yet the onset of their therapeutic action requires weeks of treatment. This delay is the result of presynaptic and postsynaptic adaptive mechanisms secondary to reuptake inhibition. The prevention of a negative feedback mechanism operating at the 5-HT autoreceptor level enhances the neurochemical and clinical effects of SSRIs. The blockade of 5-HT2A receptors also seems to improve the clinical effects of SSRIs. These receptors are located postsynaptically to 5-HT axons, mainly in the neocortex. Pyramidal neurons in the prefrontal cortex are particularly enriched in 5-HT2A receptors. Their blockade may affect the function of prefrontal–subcortical circuits, an effect that probably underlies the beneficial effects of the addition of atypical antipsychotic drugs, which are 5-HT2A receptor antagonists, to SSRIs in treatment-resistant patients.

Celada, Pau; Puig, M. Victoria; Amargos-Bosch, Merce; Adell, Albert; Artigas, Francesc



Palonosetron: a second-generation 5-hydroxytryptamine receptor antagonist.  


Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles and patient risk factors (female gender, younger age, alcohol consumption, history of motion sickness) are the major risk factors for CINV. The use of 5-hydroxytryptamine (5-HT)3 receptor antagonists plus dexamethasone has significantly improved the control of acute CINV, but delayed nausea and vomiting remains a clinical problem. A new agent, palonosetron, has recently been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. Palonosetron is a 5-HT3 receptor antagonist with a longer half-life and a higher binding affinity than first-generation 5-HT3 receptor antagonists. In a single dosing study, palonosetron was highly effective in controlling CINV compared with a single dose of dolasetron or ondansetron in patients receiving moderately emetogenic chemotherapy. Palonosetron in combination with dexamethasone demonstrated control of CINV in patients receiving highly emetogenic chemotherapy. Palonosetron appeared to be as effective in subsequent courses of chemotherapy compared with the initial course of chemotherapy. There were no clinically relevant differences seen among palonosetron, ondansetron or dolasetron in laboratory, electrocardiographic or vital-sign changes, and adverse reactions reported in the clinical trials were the most common reactions reported for the 5-HT3 receptor antagonist class. Recent studies using palonosetron-based anti-emetic combinations in moderately and highly emetogenic chemotherapy, as well as in the clinical setting of multiple-day chemotherapy, have been reported. Future studies may consider the use of palonosetron with current and other new agents and in other clinical settings, such as bone marrow transplantation and radiation therapy. PMID:17026451

Navari, Rudolph M



Changes in Gastroduodenal 5-Hydroxytryptamine-Containing Cells Induced by Dehydroleucodine  

Microsoft Academic Search

In previous work, we demonstrated that dehydroleucodine (DhL), a lactone isolated from Artemisia douglasiana Besser, prevents gastroduodenal damage induced by absolute ethanol (EtOH). The present study examined the effects of DhL – applied alone or before EtOH – on gastroduodenal cells containing 5-hydroxytryptamine (5-HT), to clarify the mechanism of action of the drug. Mice were divided into four groups: (I)

Alicia Penissi; Laura Mariani; Marta Souto; Jorge Guzmán; Ramón Piezzi



Biochemical and immunohistochemical determination of 5-hydroxytryptamine located in mast cells in the trigeminal ganglion of the rat and guinea pig  

Microsoft Academic Search

The presence of 5-hydroxytryptamine (5-HT), as well as its precursor (5-HTP) and metabolite (5-HIAA), were biochemically determinated in the trigeminal ganglion of the guinea pig and rat. The distribution of 5-HT in the ganglion and in its posterior root was studied using both indirect immunofluorescence and the peroxidase-antiperoxidase method. In order to increase the possible 5-HT content of primary sensory

J. I. Lehtosalo; H. Uusitalo; J. Laakso; A. Palkama; M. Härkönen



Cyclic GMP Elevation by 5Hydroxytryptamine Is Due to Nitric Oxide Derived from Endogenous Nitrosothiol in NG108-15 Cells  

Microsoft Academic Search

To clarify the involvement of nitric oxide (NO) derived from nitrosothiols (RSNO) in 5-hydroxytryptamine (5-HT)-induced Ca2+-independent cGMP formation (CIGF) in NG108-15 cells, we investigated the effects of 5-HT on intracellular contents of RSNO as well as of NO metabolites. 5-HT stimulation resulted in an increase in the intracellular contents of nitrate and cGMP. RSNO was detected in NG108-15 cells and

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



Chronic tryptophan deprivation attenuates gating deficits induced by 5-HT1A, but not 5-HT2 receptor activation.  


The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts a multifaceted function in the modulation of information processing, through the activation of multiple receptor families. In particular, stimulation of 5-HT1A and 5-HT2A receptors leads to sensorimotor gating impairments and perceptual perturbations. Previous evidence has shown that chronic deprivation of l-tryptophan (TRP), the precursor of 5-HT, results in marked reductions of 5-HT brain levels, as well as neuroplastic alterations in 5-HT1A and 5-HT2A expression and/or signaling. Building on these premises, in the present study we tested whether a prolonged TRP deprivation may differentially impact the roles of these receptors in the regulation of the prepulse inhibition (PPI) of the acoustic startle reflex, a dependable index of gating. Male Sprague-Dawley rats were fed for 14 days with either a regimen with negligible TRP content (TR-) or the same diet supplemented of TRP (TR+). At the end of this schedule, rats were treated with the prototypical 5-HT1A receptor agonist 8-OH-DPAT (62.5-250?g/kg, subcutaneous, s.c.) or the 5-HT2 receptor agonist DOI (0.25-1mg/kg, s.c.). Notably, the PPI deficits induced by 8-OH-DPAT in TR- rats were significantly milder than those observed in their TR+ counterparts; these effects were fully prevented by the 5-HT1A antagonist WAY-100135 (10mg/kg, intraperitoneal). Conversely, TRP deprivation did not affect the PPI-disrupting properties of DOI. These findings suggest that prolonged 5-HT depletion attenuates the influence of 5-HT1A, but not 5-HT2 receptors on sensorimotor gating, confirming the distinct mechanisms of these two targets in PPI regulation. PMID:23141373

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



Cisapride and 5-hydroxytryptamine enhance motility in the canine antrum via separate pathways, not involving 5-hydroxytryptamine1,2,3,4 receptors.  


Prokinetic benzamides (e.g., cisapride) enhance gastrointestinal motility and transit. In vitro studies on the guinea pig ileum suggest that their effect is mediated via serotonergic 5-hydroxytryptamine (5-HT4) receptors, resulting in a facilitation of cholinergic neurotransmission. However, most in vivo studies have been performed on the canine stomach. Therefore, our aim was to determine whether the findings obtained on the guinea pig ileum can be extrapolated to another species and another organ. Does a benzamide facilitate cholinergic neutrotransmission on strips of the canine stomach in vitro? If so, does the benzamide exert its effect via a serotonergic 5-HT4 mechanism? Longitudinal muscle strips with adhering myenteric plexus were isolated from the canine stomach and were electrically stimulated at submaximal frequencies resulting in a mean contractile response of 16 +/- 7% of the response to methacholine (10(-6) M). Atropine and tetrodotoxin (both 3 x 10(-7) M) abolished the contractile responses, whereas hexamethonium (10(-4) M) had no effect. Cisapride (3 x 10(-7) M) enhanced the contractile responses from 14 to 70% (59 +/- 5% increase). 5-HT (3 x 10(-7) M) similarly enhanced the responses from 12 to 72% (58 +/- 5% increase). Cisapride induced a sustained enhancement throughout the duration of the experiment; in contrast, the effect of 5-HT subsided in about 90 min. Single-concentration administration of cisapride (10(-8)-10(-6) M) and 5-HT (10(-9)-3 x 10(-7) M) resulted in EC50 values of 1.0 (0.8-1.4) x 10(-7) M for cisapride and 1.3 (0.8-2.1) x 10(-8) M for 5-HT. Methiothepin and methysergide (both 3 x 10(-7) M; 5-HT1-receptor antagonists), ketanserin and LY 53857 (both 3 x 10(-7) M; 5-HT2-receptor antagonists), granisetron (3 x 10(-7) M; 5-HT3-receptor antagonist) or ICS 205-930 (3 x 10(-7) M; 5-HT3-receptor antagonist and in addition 5-HT4-receptor antagonist at 3 x 10(-6) M) did not reduce the responses to both cisapride and 5-HT. 1-(1-Naphthalenyl)piperazine (10(-6) M; 5-HT-receptor antagonist in the rat gastric fundus) significantly reduced the increase by 5-HT (24 +/- 7%; 7-31%) but had no effect on the cisapride (3 x 10(-7) M)-induced increase (69 +/- 4%; 8-77%).(ABSTRACT TRUNCATED AT 400 WORDS) PMID:8093733

de Ridder, W J; Schuurkes, J A



Menthol Inhibits 5-HT3 Receptor-Mediated Currents.  


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

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



The GR127935-sensitive 5-HT1 receptors mediating canine internal carotid vasoconstriction: resemblance to the 5-HT1B, but not to the 5-HT1D or 5-ht1F, receptor subtype  

PubMed Central

This study has further investigated the pharmacological profile of the GR127935-sensitive 5-HT1 receptors mediating vasoconstriction in the internal carotid bed of anaesthetized vagosympathectomized dogs. One-minute intracarotid infusions of the agonists 5-hydroxytryptamine (5-HT; 0.1–10??g?min?1; endogenous ligand) and sumatriptan (0.3–10??g?min?1; 5-HT1B/1D), but not PNU-142633 (1–1000??g?min?1; 5-HT1D) or LY344864 (1–1000??g?min?1; 5-ht1F), produced dose-dependent decreases in internal carotid blood flow without changing blood pressure or heart rate. The responses to 5-HT were apparently resistant to blockade by i.v. administration of the antagonists SB224289 (300??g?kg?1; 5-HT1B), BRL15572 (300??g?kg?1; 5-HT1D) or ritanserin (100??g?kg?1; 5-HT2). In contrast, the responses to sumatriptan were antagonized by SB224289, but not by BRL15572. In the animals receiving SB224289, but not those receiving BRL15572, the subsequent administration of ritanserin abolished the 5-HT-induced vasoconstriction and unmasked a vasodilator component. Similarly, in ritanserin-treated animals, the subsequent administration of SB224289, but not BRL15572, completely blocked the 5-HT-induced vasoconstriction, revealing vasodilatation. In animals receiving initially BRL15572, the subsequent administration of SB224289 did not affect (except at 10??g?min?1) the vasoconstrictor responses to 5-HT. Notably, in animals pretreated with 1000??g?kg?1 of mesulergine, a 5-HT2/7 receptor antagonist, 5-HT produced a dose-dependent vasoconstriction, which was practically abolished by SB224289. After BRL15572, no further blockade was produced and the subsequent administration of ritanserin was similarly inactive. These results suggest that the GR127935-sensitive 5-HT1 receptors mediating canine internal carotid vasoconstriction resemble the 5-HT1B but not the 5-HT1D or 5-ht1F, receptor subtype.

Centurion, David; Sanchez-Lopez, Araceli; De Vries, Peter; Saxena, Pramod R; Villalon, Carlos M



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

PubMed Central

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.

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



5-HT3 Receptors  

PubMed Central

The 5-HT3 receptor is a member of the Cys-loop family of ligand-gated ion channels. These receptors are located in both the peripheral and central nervous systems, where functional receptors are constructed from five subunits. These subunits may be the same (homopentameric 5-HT3A receptors) or different (heteropentameric receptors, usually comprising of 5-HT3A and 5-HT3B receptor subunits), with the latter having a number of distinct properties. The 5-HT3 receptor binding site is comprised of six loops from two adjacent subunits, and critical ligand binding amino acids in these loops have been largely identified. There are a range of selective agonists and antagonists for these receptors and the pharmacophore is reasonably well understood. There are also a wide range of compounds that can modulate receptor activity. Studies have suggested many diverse potential disease targets that might be amenable to alleviation by 5-HT3 receptor selective compounds but to date only two applications have been fully realised in the clinic: the treatment of emesis and irritable-bowel syndrome.

Thompson, A. J.; Lummis, S. C. R.



Stimulation of the lateral hypothalamus produces antinociception mediated by 5HT 1A, 5HT 1B and 5HT 3 receptors in the rat spinal cord dorsal horn  

Microsoft Academic Search

The lateral hypothalamus is part of an efferent system that modifies pain at the spinal cord dorsal horn, but the mechanisms by which lateral hypothalamus-induced antinociception occur are not fully understood. Previous work has shown that antinociception produced from electrical stimulation of the lateral hypothalamus is mediated in part by spinally projecting 5-hydroxytryptamine (5-HT) neurons in the ventromedial medulla. To

J. E. Holden; E. Naleway Farah; Y. Jeong



Usefulness of 5Ht 2a Receptor Antagonists for The Treatment of Cardiovascular Complications in Diabetes  

Microsoft Academic Search

\\u000a The elevated level of 5-hydroxytryptamine (5-HT) has been reported to be asso-ciated with cardiovascular complications in\\u000a diabetes. Using different 5-HT receptor agonists and antagonists, 5-HT receptors were found to be involved in glycemic control.\\u000a Sarpogre-late, 5-HT2A receptor antagonist, was shown to produce beneficial effects in type 1 and type 2 diabetic rats. It not only reduced serum\\u000a glucose and lipid

Ramesh K. Goyal; Dhananjay N. Umrani; Dipali N. Bodiwala; Naranjan S. Dhalla


Gramine: a vasorelaxing alkaloid acting on 5-HT(2A) receptors.  


The vascular effects of gramine on resistance vessels were evaluated, in particular as regards the 5-hydroxytryptamine (5-HT) system. We compared the action of gramine with that of ketanserin, a 5-HT (2A) antagonist; both compounds induced concentration-dependent relaxation in precontracted arterial rings. Also, the 5-HT concentration-effect curve shifted to the right in the presence of gramine, like ketanserin. These results suggest that gramine is a vasorelaxing agent acting mainly by antagonism at 5-HT (2A) receptors. PMID:15095157

Froldi, Guglielmina; Silvestrin, Barbara; Dorigo, Paola; Caparrotta, Laura



Sleep and Sleep Homeostasis in Mice Lacking the 5-HT2c Receptor  

PubMed Central

Studies in humans and rats indicate that serotonin (5-hydroxytryptamine, 5-HT) receptors are involved in mammalian sleep expression. We investigated the contribution of the 5-HT2c receptor to sleep expression by examining sleep patterns in mice bearing a targeted null mutation of this receptor. 5-HT2c receptor knock-out mice had more wakefulness, several abnormalities in rapid eye movement sleep expression and an enhanced response to sleep deprivation compared with wild-type control mice. These findings suggest that 5HT2c receptors may mediate several effects on sleep that have been ascribed to serotonin.

Frank, Marcos G.; Stryker, Michael P.; Tecott, Laurence H.



The action of 5-hydroxytryptamine on chemoreceptor discharges of the cat's carotid body.  

PubMed Central

1 Chemoreceptor discharges were recorded in vivo from fine filaments of the carotid sinus nerve containing a single or several active units; their frequency was used as an index of receptor activity. The effects of 5-hydroxytryptamine (5-HT) on chemoreceptors were studied in 26 adult cats. At times, sinus baroreceptor discharges were recorded from the carotid nerve and the effect of 5-HT on the discharges was examined. 2 Intra-carotid injections of 5-HT (2-20 mug) induced a sharp and brief increase in chemoreceptor discharges, followed by depression or block which lasted for several seconds. Repeated injections at short intervals, and a small dose after a large dose of 5-HT resulted in depressed or blocked response to 5-HT. 3 5-HT in high doses (10-20 mug, i.a.) slightly depressed the chemoreceptor discharges induced by either acetylcholine (ACh) or NaCN, when these substances were applied within 20 s after 5-HT. 5-HT (5-20 mug, i.a.) applied during asphyxia induced a further increase in chemoreceptor discharges, soon followed by block of the discharges lasting for several seconds. 4 Atropine or hexamethonium in high doses did not change the chemoreceptor response to 5-HT, while that to ACh was markedly depressed. 5 (+)-Lysergic diethylamide (LSD), methysergide or gramine did not alter the response to 5-HT, while LSD in low doses produced a marked increase in chemoreceptor discharges. 6 Acute and chronic treatment with reserpine (5-10 mg/kg, i.v.) of the animals did not change the sensitivity and the reactivity of the chemoreceptor to ACh and NaCN, while the chemoreceptor response to 5-HT was augmented, indicating an increase in the sensitivity of chemoreceptors to 5-HT. 7 5-HT in small doses (2-10 mug, i.a.) induced a marked increase in sinus baroreceptor discharges; subsequently discharges were depressed or blocked for several seconds. 8 The results are discussed in relation to possible mechanism of action of 5-HT on the chemoreceptors. It is concluded that the exogenous 5-HT probably acts directly on the chemosensory nerve endings and depolarizes them, but 5-HT contained in the carotid body does not play a significant role in the generation of chemoreceptor discharges.

Nishi, K



The action of 5-hydroxytryptamine on chemoreceptor discharges of the cat's carotid body.  


1 Chemoreceptor discharges were recorded in vivo from fine filaments of the carotid sinus nerve containing a single or several active units; their frequency was used as an index of receptor activity. The effects of 5-hydroxytryptamine (5-HT) on chemoreceptors were studied in 26 adult cats. At times, sinus baroreceptor discharges were recorded from the carotid nerve and the effect of 5-HT on the discharges was examined. 2 Intra-carotid injections of 5-HT (2-20 mug) induced a sharp and brief increase in chemoreceptor discharges, followed by depression or block which lasted for several seconds. Repeated injections at short intervals, and a small dose after a large dose of 5-HT resulted in depressed or blocked response to 5-HT. 3 5-HT in high doses (10-20 mug, i.a.) slightly depressed the chemoreceptor discharges induced by either acetylcholine (ACh) or NaCN, when these substances were applied within 20 s after 5-HT. 5-HT (5-20 mug, i.a.) applied during asphyxia induced a further increase in chemoreceptor discharges, soon followed by block of the discharges lasting for several seconds. 4 Atropine or hexamethonium in high doses did not change the chemoreceptor response to 5-HT, while that to ACh was markedly depressed. 5 (+)-Lysergic diethylamide (LSD), methysergide or gramine did not alter the response to 5-HT, while LSD in low doses produced a marked increase in chemoreceptor discharges. 6 Acute and chronic treatment with reserpine (5-10 mg/kg, i.v.) of the animals did not change the sensitivity and the reactivity of the chemoreceptor to ACh and NaCN, while the chemoreceptor response to 5-HT was augmented, indicating an increase in the sensitivity of chemoreceptors to 5-HT. 7 5-HT in small doses (2-10 mug, i.a.) induced a marked increase in sinus baroreceptor discharges; subsequently discharges were depressed or blocked for several seconds. 8 The results are discussed in relation to possible mechanism of action of 5-HT on the chemoreceptors. It is concluded that the exogenous 5-HT probably acts directly on the chemosensory nerve endings and depolarizes them, but 5-HT contained in the carotid body does not play a significant role in the generation of chemoreceptor discharges. PMID:1182345

Nishi, K



Dual effects of 5-hydroxytryptamine on the release of gamma-aminobutyric acid from myenteric neurones of the guinea-pig ileum.  

PubMed Central

The effects of 5-hydroxytryptamine (5-HT) on the release of gamma-aminobutyric acid (GABA) were examined in the longitudinal muscle-myenteric plexus (LM-MP) preparation of guinea-pig ileum. 5-HT increased the spontaneous release and inhibited the electrically-evoked release of [3H]-GABA. The 5-HT-evoked release was Ca2+-dependent and tetrodotoxin-sensitive, and was antagonized by (3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester (ICS 205-930), but not by methysergide and ketanserin. The inhibitory effect of 5-HT was antagonized by methysergide, but not by ketanserin and ICS 205-930. 8-Hydroxy-2-(di-n-propylamino)tetralin mimicked the inhibitory effect of 5-HT. Thus, 5-HT may exert an excitatory effect on the enteric GABAergic neurone via the 5-HT3 receptor and an inhibitory effect via the 5-HT1A receptor.

Shirakawa, J.; Takeda, K.; Taniyama, K.; Tanaka, C.



Effects of prior 5-hydroxytryptamine exposure on rat islet insulin secretory and phospholipase C responses.  


Glucose-induced insulin secretion is inhibited by 5-hydroxytryptamine (5HT). In the present studies the specificity of 5HT inhibition of release and the potential biochemical mechanisms involved were investigated. Dose-dependent inhibition of 15 mM glucose-induced secretion was induced by a prior 3 h incubation with 5HT. At the highest 5HT concentration (500 microM) employed, both first and second phase responses to 15 mM glucose were reduced 50-60%. In addition, this level (500 microM) of 5HT virtually abolished 10 mM glucose-induced secretion. In contrast, secretion in response to the protein kinase C activator phorbol 12-myristate 13-acetate (500 nM) was immune to 500 microM 5HT pre-treatment. Glucose usage rates were comparable in both control and 500 microM 5HT-pretreated islets. However, the generation of inositol phosphates and the efflux of 3H-inositol from 3H-inositol-prelabeled islets in response to stimulatory glucose were impaired in parallel with insulin secretion. Based on these observations the following conclusions were reached: (1) 5HT impairs glucose-induced insulin release by altering glucose-induced activation of phospholipase C. (2) Biochemical events distal to phospholipase C remain intact despite this proximal biochemical lesion. (3) Amperometric analysis of 5HT release from 5HT-pretreated islets must take into consideration its profound adverse impact on glucose-induced insulin secretion. PMID:15034191

Zawalich, Walter S; Tesz, Gregory J; Zawalich, Kathleen C



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

PubMed Central

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

Bulbring, Edith; Gershon, M. D.



Molecular basis for cis-urocanic acid as a 5-HT(2A) receptor agonist.  


The underlying mechanisms of urocanic acid (UA) to induce immune suppression remain elusive until the recent finding that cis-UA acts via the serotonin, 5-hydroxytryptamine (5-HT) receptor subtype 5-HT(2A). In the present study, the interactions of cis-UA to 5-HT(2A) receptor were explored and compared with those of 5-HT to the same receptor using computational docking. Similar binding modes were observed for cis-UA and 5-HT with 5-HT(2A) receptor and the former possessed relatively higher binding affinity, which may account for cis-UA being a serotonin receptor agonist. Moreover, the molecular basis for the distinct binding affinities between the trans- and cis-UA with 5-HT(2A) receptor was also provided. PMID:19683920

Shen, Liang; Ji, Hong-Fang



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

PubMed Central

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)

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



Regulation of extrasynaptic 5-HT by SERT function in 5-HT-absorbing neurons underscores adaptation behavior in C. elegans  

PubMed Central

Serotonin (5-HT)-absorbing neurons use serotonin reuptake transporter (SERT) to uptake serotonin (5-HT) from extracellular space but do not synthesize it. While 5-HT-absorbing neurons have been identified in diverse organisms from C. elegans to humans, their function has not been elucidated. Here, we show that SERT in 5-HT-absorbing neurons controls behavioral response to food deprivation in C. elegans. The AIM and RIH interneurons uptake 5-HT released from chemosensory neurons and secretory neurons. Genetic analyses suggest that 5-HT secreted by both synaptic vesicles and dense core vesicles diffuse readily to the extrasynaptic space adjacent to the AIM and RIH neurons. Loss of mod-5/SERT function blocks the 5-HT absorption. mod-5/SERT mutants have been shown to exhibit exaggerated locomotor response to food deprivation. We found that transgenic expression of MOD-5/SERT in the 5-HT-absorbing neurons fully corrected the exaggerated behavior. Experiments of cell-specific inhibition of synaptic transmission suggest that the synaptic release of 5-HT from the 5-HT-absorbing neurons is not required for this behavioral modulation. Our data point to the role of 5-HT-absorbing neurons as temporal-spatial regulators of extrasynaptic 5-HT. Regulation of extrasynaptic 5-HT levels by 5-HT-absorbing neurons may represent a fundamental mechanism of 5-HT homeostasis, integrating the activity of 5-HT-producing neurons with distant targets in the neural circuits, and could be relevant to some actions of SSRIs in human.

Jafarau, Gholamali; Xie, Yusu; Kullyev, Andrey; Liang, Bin; Sze, Ji Ying



Activation of Colonic Mucosal 5-HT4 Receptors Accelerates Propulsive Motility and Inhibits Visceral Hypersensitivity  

PubMed Central

BACKGROUND & AIMS 5-hydroxytryptamine receptor (5-HT4R) agonists promote gastrointestinal motility and attenuate visceral pain, but concerns about adverse reactions have restricted their availability. We tested the hypotheses that 5-HT4 receptors are expressed in the colonic epithelium and that 5-HT4R agonists can act intraluminally to increase motility and reduce visceral hypersensitivity. METHODS Mucosal expression of the 5-HT4R was evaluated by reverse-transcriptase polymerase chain reaction and immunohistochemical analysis of tissues from 5-HT4R(BAC)-enhanced green fluorescent protein mice. Amperometry, histology, and short-circuit current measurements were used to study 5-HT, mucus, and Cl? secretion, respectively. Propulsive motility was measured in guinea pig distal colon, and visceromotor responses were recorded in a rat model of colonic hypersensitivity. 5-HT4R compounds included cisapride, tegaserod, naronapride, SB204070, and GR113808. RESULTS Mucosal 5-HT4 receptors were present in the small and large intestines. In the distal colon, 5-HT4 receptors were expressed by most epithelial cells, including enterochromaffin and goblet cells. Stimulation of 5-HT4Rs evoked mucosal 5-HT release, goblet cell degranulation, and Cl? secretion. Luminal administration of 5-HT4R agonists accelerated propulsive motility; a 5-HT4R antagonist blocked this effect. Bath application of 5-HT4R agonists did not affect motility. Oral or intracolonic administration of 5-HT4R agonists attenuated visceral hypersensitivity. Intracolonic administration was more potent than oral administration, and was inhibited by a 5-HT4R antagonist. CONCLUSIONS Mucosal 5-HT4 receptor activation can mediate the prokinetic and antinociceptive actions of 5-HT4R agonists. Colon-targeted, intraluminal delivery of 5-HT4R agonists might be used to promote motility and alleviate visceral pain, while restricting systemic bioavailability and resulting adverse side effects.




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

Microsoft Academic Search

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

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



The spin trap reagent alpha-phenyl-N-tert-butyl nitrone prevents 'ecstasy'-induced neurodegeneration of 5-hydroxytryptamine neurones.  


Administration of a single dose (10 mg/kg i.p.) of 3,4-methylenedioxy-methamphetamine (MDMA or 'ecstasy') produced a 40% loss of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cortex and hippocampus of Dark Agouti rats 7 days later. Binding of [3H]paroxetine to the presynaptic 5-HT nerve terminals in cortex was decreased by approximately 30%. Injection of the spin trap reagent alpha-phenyl-N-tert-butyl nitrone (PBN; 150 mg/kg i.p.) 10 min prior and 120 min post MDMA administration totally prevented the loss in [3H]paroxetine binding in the cortex and attenuated the loss of 5-HT and 5-HIAA in both brain regions. PBN alone had no effect on [3H]paroxetine binding or brain 5-HT content. These data suggest that MDMA produces neurodegeneration of 5-HT neurones because of reactive free radical formation. PMID:8566105

Colado, M I; Green, A R



Differential influence of selective 5-HT5A vs 5-HT1A, 5-HT1B, or 5-HT2C receptor blockade upon light-induced phase shifts in circadian activity rhythms: interaction studies with citalopram.  


Though serotonergic mechanisms modulate circadian rhythms, roles of individual serotonin (5-HT) receptors remain uncertain since data are lacking for antagonists. Herein, both the 5-HT(5A) receptor antagonist, A843277 (10 mg/kg), and the 5-HT(1B) antagonist, SB224289 (1 mg/kg), inhibited light-induced phase advances in hamster circadian wheel-running rhythms. Conversely, though 5-HT(1A) and 5-HT(7) receptors are likewise implicated in circadian scheduling, their blockade by WAY100635 (0.5 mg/kg) and SB269970 (1 mg/kg), respectively, was ineffective. Since actions of 5-HT reuptake inhibitors are modified by antagonists, we evaluated their influence on suppression of phase advances by citalopram (10 mg/kg). Its action was potentiated by WAY100635 and the 5-HT(2C) antagonist, SB242084 (1 mg/kg), but not by A842377, SB224289, SB269970, and antagonists at 5-HT(2A) (MDL100907) and 5-HT(6) (SB399885) receptors. In conclusion, this is the first in vivo evidence for an influence of 5-HT(5A) receptors upon circadian rhythms, but no single class of 5-HT receptor mediates their control by citalopram. PMID:19604677

Gannon, Robert L; Peglion, Jean-Louis; Millan, Mark J



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

PubMed Central

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

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



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


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

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



5HT2A Receptor Gene Promoter Polymorphism in Relation to Abdominal Obesity and Cortisol  

Microsoft Academic Search

Objective: There is considerable evidence that cortisol secretion is associated with obesity. The regulation of the 5-hydroxytryptamine receptor 2A (5-HT2A) gene might play an essential role because it is involved in the control of cortisol secretion. Therefore, we examined the potential impact of the 5-HT2A ?1438G\\/A promoter polymorphism on obesity and estimates of insulin, glucose, and lipid metabolism as well

Roland Rosmond; Claude Bouchard; Per Björntorp



Pharmacological characterisation of 5HT receptors positively coupled to adenylyl cyclase in the rat hippocampus  

Microsoft Academic Search

The pharmacological properties of 5-hydroxytryptamine (5-HT) receptors positively coupled to adenylyl cyclase in the rat hippocampus\\u000a were investigated using selective agonists and antagonists. 5-HT (0.008–125 ?M) stimulated cyclic AMP formation in homogenates\\u000a of rat hippocampus in a concentration-dependent manner. The maximal increase in cyclic AMP formation occurred at 1 ?M (141\\u000a ? 6%) and the half-maximal effect (EC50) at 50

Rudolf Markstein; Machiko Matsumoto; Christian Kohler; Hiroko Togashi; Mitsuhiro Yoshioka; Daniel Hoyer



Rabbit isolated renal artery contractions by some tryptamine derivatives, including 2-methyl-5-HT, are mediated by a 5-HT1-like receptor.  

PubMed Central

1. Despite the fact that 5-hydroxytryptamine (5-HT)-induced contractions of the rabbit isolated renal artery are mediated by a receptor belonging to the heterogeneous 5-HT1-like category, we observed that the so-called selective 5-HT3 receptor agonist, 2-methyl-5-HT, caused a concentration-dependent contraction of this vessel. This study was therefore undertaken to analyze the effects of 2-methyl-5-HT in the renal artery segments, either quiescent or precontracted with U46619 (10(-7) M). alpha-Methyl-5-HT and 5-methoxytryptamine, which have high affinities for 5-HT2 and 5-HT4 receptors, respectively, were used for comparison. 2. In the precontracted vessel segments, the maximum contractile responses obtained with 2-methyl-5-HT, alpha-methyl-5-HT, 5-methoxytryptamine and 5-HT were similar to those in the quiescent segments. However the pD2 values were higher in the precontracted segments, making them about 4-100 fold more sensitive. 3. Neither MDL 72222 (10(-6) M) nor tropisetron (3 x 10(-6) M) suppressed renal artery contractions elicited by 5-HT, 2-methyl-5-HT, alpha-methyl-5-HT or 5-methoxytryptamine, thus ruling out the involvement of 5-HT3 as well as 5-HT4 receptors. 4. On the other hand, both methiothepin (10(-8) and 10(-7) M) and ketanserin (10(-7) and 10(-6) M) caused a rightward shift of agonist concentration-effect curves.(ABSTRACT TRUNCATED AT 250 WORDS)

Tadipatri, S.; Feniuk, W.; Saxena, P. R.



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

PubMed Central

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

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



Effects of N-ethylmaleimide on 5-hydroxytryptamine transport and sodium content in rabbit platelets.  

PubMed Central

1. The present study analysed the mechanism underlying the inhibitory action of N-ethylmaleimide (NEM) on the 5-hydroxytryptamine (5-HT) uptake by blood platelets. 2. Rabbit platelets suspended in protein-free buffer were first preincubated for 45 min in the absence and presence of NEM (20 to 160 microM) or ouabain (0.5-2.0 microM) and then either analysed for their Na+ and K+ content or incubated (15s) with various concentrations of [3H]-5-HT (0.13-4.03 microM) to determine Km and Vmax for 5-HT uptake. 3. Both NEM and ouabain produced concentration-dependent decreases in Vmax with IC50 values of 52 and 0.58 microM, respectively. Neither drug changed Km significantly. 4. Both NEM and ouabain increased the Na+ and decreased the K+ content of platelets in a concentration-dependent manner. 5. There was a linear correlation between Vmax (expressed in % of control) and the reciprocal cellular Na+ content, with the results for both drugs falling onto one and the same regression line (r = 0.992; n = 8). This regression showed that an increase in Na+ content by 69% sufficed to reduce Vmax by 50%. 6. At concentrations that reduced 5-HT uptake by about 60%, neither NEM nor ouabain altered the potency of imipramine for inhibition of 5-HT uptake. 7. Hence, NEM inhibits 5-HT transport by inhibiting the Na+/K+-ATPase and not by a direct interaction with the 5-HT carrier. The consequential increase in the intracellular Na+ concentration reduces the transmembrane Na+ gradient and, therefore, hinders 5-HT inward transport. This action of the drug does not affect the ability of the carrier to bind 5-HT or imipramine.

Wolfel, R.; Halbrugge, T.; Graefe, K. H.



Smooth muscle layer-dependent distribution of 5-hydroxytryptamine7 receptor in the porcine myometrium  

PubMed Central

To analyse the mechanisms of muscle layer-dependent inhibition of porcine myometrial contractility by 5-hydroxytryptamine (5-HT), the effects of 5-HT, 5-carboxamidotryptamine(5-CT), 5-methoxytryptamine (5-MeOT), forskolin and cyclic adenosine 3?, 5?-monophosphate (cyclic AMP) analogues on spontaneous and stimulant-induced contractions were examined in longitudinal (LM) and circular muscles (CM). In addition, accumulation of cyclic AMP by 5-HT and distribution of 5-HT7 receptors in LM and CM layers were compared using biochemical and molecular approaches.5-HT receptor agonists inhibited the spontaneous contractions of LM and CM (5-CT>5-HT>5-MeOT), but CM was more sensitive than was LM. The inhibition by the agonists was antagonized by methiothepin (100?nM).Carbachol-, high-K+-, histamine- and Ca2+-induced contractions were inhibited by 5-HT with different responsivenesses (CM>LM). Even in the presence of 3-isobutyl-1-methylxanthine (IBMX), the inhibition by 5-HT in the CM was still more conspicuous than that in the LM.Compared with the CM, the inhibition of spontaneous contraction by forskolin, dibutyryl-cyclic AMP and 8-bromo-cyclic AMP was marked in the LM.5-HT (1?nM–1??M) increased the cyclic AMP in both muscle layers, but the increment in the CM was higher than that in the LM whether IBMX was present or not.LM and CM layers contained a single class of [3H]-5-CT binding sites with a similar Kd value (0.21–0.24?nM). However, Bmax (5-HT7 receptor concentration) in the CM (120.6?fmol?mg?1 protein) was higher than that in the LM (30.4?fmol?mg?1 protein).The molecular study (reverse transcription polymerase chain reaction) demonstrated the expression of 5-HT7 receptor mRNA in the CM was higher than that in the LM.These results suggest that the muscle layer-dependent difference in inhibition by 5-HT is not restricted to spontaneous contraction but applies to various contractions in the porcine myometrium. Different inhibition of the contractility by 5-HT is caused by muscle layer-related accumulation of cyclic AMP (CM>LM), due to smooth muscle-layer dependent distribution (CM>LM) of 5-HT7 receptors.

Kitazawa, Takio; Yamada, Yuko; Iwano, Hidetomo; Yokota, Hiroshi; Yuasa, Akira; Taneike, Tetsuro



Evaluation of the ocular hypotensive response of serotonin 5-HT1A and 5-HT2 receptor ligands in conscious ocular hypertensive cynomolgus monkeys.  


Published investigations of serotonin-1A (5-hydroxytryptamine1A; 5-HT1A) receptor agonists and serotonin-2A (5-hydroxytryptamine2A; 5-HT2A) receptor antagonists in nonprimate species provide conflicting results with regard to their intraocular pressure-lowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. We evaluated the effect of selected 5-HT1A agonists and 5-HT2A receptor antagonists on intraocular pressure in a nonhuman primate model, the conscious cynomolgus monkey with laser-induced ocular hypertension. Neither selective 5-HT1A agonists [e.g., R-8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan] nor selective 5-HT2 receptor antagonists [e.g., R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M-100907) and 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxamide (SB-242084)] lowered intraocular pressure in the primate model following topical ocular administration. However, compounds that function as agonists at both the 5-HT1A and 5-HT2 receptors were found to effectively lower intraocular pressure in the model: 5-hydroxy-alpha-methyltryptamine, 5-methoxy-alpha-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-methoxy-N,N-dimethyltryptamine. Furthermore, the selective 5-HT2 receptor agonist R-(-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane lowered intraocular pressure in the primate model, demonstrating a pharmacological response associated with activation of the 5-HT2 receptor. These observations suggest that compounds that function as efficient agonists at 5-HT2 receptors should be considered as potential agents for the control of intraocular pressure in the treatment of ocular hypertension and glaucoma in humans. PMID:12676887

May, Jesse A; McLaughlin, Marsha A; Sharif, Najam A; Hellberg, Mark R; Dean, Thomas R



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

Microsoft Academic Search

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

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



Functional properties of a cloned 5-hydroxytryptamine ionotropic receptor subunit: comparison with native mouse receptors.  

PubMed Central

1. A comparative study of the whole-cell and single-channel properties of cloned and native mouse 5-hydroxytryptamine ionotropic receptors (5-HT3) was undertaken using mammalian cell lines expressing the cloned 5-HT3 receptor subunit A (5-HT3R-A), superior cervical ganglia (SCG) neurones and N1E-115 cells. 2. No pharmacological difference was found in the sensitivity to the agonists 5-HT and 2-methyl-5-HT, or to the antagonists d-tubocurare and 3-tropanyl-3,5-dichlorobenzoate (MDL-72222). 3. Current-voltage (I-V) relationships of whole-cell currents showed inward rectification in the three preparations. Rectification was stronger both in cells expressing the 5-HT3R-A subunit and in N1E-115 cells when compared with SCG neurones. 4. No clear openings could be resolved in 5-HT-activated currents in patches excised from cells expressing the 5-HT3R-A subunit or N1E-115 cells. Current fluctuation analysis of whole-cell and excised-patch records revealed a slope conductance of 0.4-0.6 pS in both preparations. Current-voltage relationships of these channels showed strong rectification that fully accounted for the whole-cell voltage dependence. 5. In contrast, single channels of about 10 pS were activated by 5-HT in patches excised from SCG neurones. The weak voltage dependence of their conductance did not account completely for the rectification of whole-cell currents. A lower unitary conductance (3.4 pS) was inferred from whole-cell noise analysis. 6. We conclude that the receptor expressed from the cloned cDNA is indistinguishable from the 5-HT3 receptor of N1E-115 cells, suggesting an identical structure for these two receptors. The higher conductance and different voltage dependence of the 5-HT3 receptor in SCG neurones might indicate the participation of an additional subunit in the structure of native ganglionic 5-HT3 receptors. Homo-oligomeric 5-HT3R-A channels may also be present as suggested by the lower conductance estimated by whole-cell noise analysis.

Hussy, N; Lukas, W; Jones, K A



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


A decreased level of brain 5-hydroxytryptamine (5-HT) has been theorized to be a core pathogenic factor in depression for half a century. The theory arose from clinical observations that drugs enhancing extracellular levels of 5-HT (5-HT(Ext)) have antidepressant effects in many patients. However, whether such drugs indeed correct a primary deficit remains unresolved. Still, a number of anomalies in putative biomarkers of central 5-HT function have been repeatedly reported in depression patients over the past 40 years, collectively indicating that 5-HT deficiency could be present in depression, particularly in severely ill and/or suicidal patients. This body of literature on putative 5-HT biomarker anomalies and depression has recently been corroborated by data demonstrating that such anomalies indeed occur consequent to severely reduced 5-HT(Ext) levels in a mouse model of naturalistic 5-HT deficiency, the tryptophan hydroxylase 2 His(439) knockin (Tph2KI) mouse. In this review, we will critically assess the evidence for 5-HT deficiency in depression and the possible role of polymorphisms in the Tph2 gene as a causal factor in 5-HT deficiency, the latter investigated from a clinical as well as preclinical angle. PMID:22826344

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



Evidence for 5-HT1B/1D and 5-HT2A receptors mediating constriction of the canine internal carotid circulation  

PubMed Central

The present study has investigated the preliminary pharmacological profile of the receptors mediating vasoconstriction to 5-hydroxytryptamine (5-HT) in the internal carotid bed of vagosympathectomised dogs. One minute intracarotid infusions of the agonists 5-HT (0.1–10??g?min?1), sumatriptan (0.3–10??g?min?1; 5-HT1B/1D), 5-methoxytryptamine (1–100??g?min?1; 5-HT1, 5-HT2, 5-HT4, 5-ht6 and 5-HT7) or DOI (0.31–10??g?min?1; 5-HT2), but not 5-carboxamidotryptamine (0.01–0.3??g?min?1; 5-HT1, 5-ht5A and 5-HT7), 1-(m-chlorophenyl)-biguanide (mCPBG; 1–1000??g?min?1; 5-HT3) or cisapride (1–1000??g?min?1; 5-HT4), resulted in dose-dependent decreases in internal carotid blood flow, without changing blood pressure or heart rate. The vasoconstrictor responses to 5-HT, which remained unaffected after saline, were resistant to blockade by i.v. administration of the antagonists ritanserin (100??g?kg?1; 5-HT2A/2B/2C) in combination with tropisetron (3000??g?kg?1; 5-HT3/4) or the cyclo-oxygenase inhibitor, indomethacin (5000??g?kg?1), but were abolished by the 5-HT1B/1D receptor antagonist, GR127935 (30??g?kg?1). Interestingly, after administration of GR127935, the subsequent administration of ritanserin unmasked a dose-dependent vasodilator component. GR127935 or saline did not practically modify the vasoconstrictor effects of 5-MeO-T. In animals receiving GR127935, the subsequent administration of ritanserin abolished the vasoconstrictor responses to 5-MeO-T unmasking a dose-dependent vasodilator component. The vasoconstriction induced by sumatriptan was antagonized by GR127935, but not by ritanserin. Furthermore, ritanserin (100??g?kg?1) or ketanserin (100??g?kg?1; 5-HT2A), but not GR127935, abolished DOI-induced vasoconstrictor responses. The above results suggest that 5-HT-induced internal carotid vasoconstriction is predominantly mediated by 5-HT1B/1D and 5-HT2A receptors.

Centurion, David; Ortiz, Mario I; Sanchez-Lopez, Araceli; De Vries, Peter; Saxena, Pramod R; Villalon, Carlos M



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

PubMed Central

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

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



Evidence of 5-HT components in human sperm: implications for protein tyrosine phosphorylation and the physiology of motility.  


Serotonin (5-hydroxytryptamine; C(10)H(12)N(2)O (5-HT)) is produced in the CNS and in some cells of peripheral tissues. In the mammalian male reproductive system, both 5-HT and tryptophan hydroxylase (TPH) have been described in Leydig cells of the testis and in principal cells of the caput epididymis. In capacitated hamster sperm, it has been shown that 5-HT promotes the acrosomal reaction. The aim of this work was to explore the existence of components of the serotoninergic system and their relevance in human sperm physiology. We used both immunocytochemistry and western blot to detect serotoninergic markers such as 5-HT, TPH1, MAO(A), 5-HT(1B), 5-HT(3), and 5HT(T); HPLC for TPH enzymatic activity; Computer Assisted Semen Analysis assays to measure sperm motility parameters and pharmacological approaches to show the effect of 5-HT in sperm motility and tyrosine phosphorylation was assessed by western blot. We found the presence of serotoninergic markers (5-HT, TPH1, MAO(A), 5-HT(1B), 5-HT(2A), 5-HT(3), 5-HT(T), and TPH enzymatic activity) in human sperm. In addition, we observed a significant increase in tyrosine phosphorylation and changes in sperm motility after 5-HT treatment. In conclusion, our data demonstrate the existence of components of a serotoninergic system in human sperm and support the notion for a functional role of 5-HT in mammalian sperm physiology, which can be modulated pharmacologically. PMID:23028123

Jiménez-Trejo, Francisco; Tapia-Rodríguez, Miguel; Cerbón, Marco; Kuhn, Donald M; Manjarrez-Gutiérrez, Gabriel; Mendoza-Rodríguez, C Adriana; Picazo, Ofir



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

PubMed Central

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

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



Caenorhabditis elegans avoids staphylococcal superantigenic toxins via 5-hydroxytryptamine-dependent pathway.  


Avoidance behavior of Caenorhabditis elegans, a nematode, towards Staphylococcus aureus, a pathogenic bacterium, was studied. Caenorhabditis elegans avoided S. aureus cultures and also their culture supernatants, suggesting that secretory molecules are involved in the repellent activity. We demonstrated that toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxin C (SEC), the superantigenic toxins produced by S. aureus, are responsible for the nematode avoidance. By using TSST-1 and SEC mutants, the results indicated that the repellent activity of these toxins is independent of their superantigenic activity. The TSST-1 and SEC were found to locate at chemosensory neurons that are responsible for the recognition of repellents and avoidance of pathogenic bacteria. When mutants of C. elegans deficient in Toll/interleukin-1 receptor (TIR-1) and 5-hydroxytryptamine (5-HT) biosynthesis were used, avoidance behavior was attenuated. In the 5-HT biosynthesis deficient mutant nematodes, the avoidance activity was recovered when exogenous 5-HT was added. tph-1 expression and 5-HT production were upregulated when the nematodes were treated with TSST-1 or SEC. These results suggest that C. elegans avoids S. aureus by recognizing secretory molecules including TSST-1 and SEC and this avoidance is dependent on TIR and production of 5-HT. PMID:23145824

Osanai, Arihiro; Hu, Dong-Liang; Nakane, Akio



Antidepressant-like activity of 5HT 1A agonists measured with the forced swim test  

Microsoft Academic Search

This study examined the abilities of 5-hydroxytryptamine (5-HT) agonists with varying selectivity for different subtypes of 5-HT receptors to produce antidepressant-like behavioral effects in the forced swim test in rats. The 5-HT1A agonists 8-OH-DPAT (0.125–1.0 mg\\/kg, SC) and tandospirone (SM-3997) (5–20 mg\\/kg, SC) both produced dose-related decreases in immobility time following subchronic treatment in rats. These effects were similar to

Scott Wieland; Irwin Lucki



VRX-03011, a novel 5HT 4 agonist, enhances memory and hippocampal acetylcholine efflux  

Microsoft Academic Search

Recent evidence suggests that 5-hydroxytryptamine (5-HT)4 receptor activity enhances cognition and provides neuroprotection. Here we report the effects of VRX-03011, a novel partial 5-HT4 agonist, that is both potent (Ki?30nM) and highly selective (Ki>5?M for all other 5-HT receptors tested). In separate experiments, rats received VRX-03011 (0.1–10mg\\/kg i.p.) 30min prior to spontaneous alternation testing in a no-delay or a 30-s

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



Characterization of the receptor mediating contraction of human umbilical artery by 5-hydroxytryptamine.  

PubMed Central

The 5-hydroxytryptamine (5-HT) receptor in human umbilical artery was found to be similar to that in rabbit aorta. The pD2 was 7.45, pA2 for methysergide 8.63 and pA2 for phentolamine 6.21. Noradrenaline gave only very weak contractions at non-physiological concentrations. Amidephrine and xylazine did not contract human umbilical artery. It is concluded that there is no significant population of functional alpha-adrenoceptors in this vessel. The implications of these findings are discussed in relation to the control of the umbilical circulation.

McGrath, J. C.; MacLennan, S. J.; Stuart-Smith, K.



Expression of serotonin and its 5-HT1A receptor in canine cutaneous mast cell tumours.  


Mast cells of a number of different animal species have been reported to contain serotonin (5-hydroxytryptamine; 5-HT), a monoamine capable of numerous and complex actions, which may include an impact on tumour growth. Limited previous studies have suggested that normal or neoplastic canine mast cells do not express 5-HT. In the present study, canine cutaneous mast cell tumours (MCTs) of Patnaik histological grades I-III were investigated immunohistochemically for expression of 5-HT and its receptor (R) 5-HT1A. The proportion of positively labelled cells and the intensity of labelling of individual cells were determined. Both 5-HT and the 5-HT1A receptor were expressed by non-neoplastic dermal mast cells and neoplastic mast cells. More neoplastic mast cells expressed 5-HT than the 5-HT1AR. Poorly differentiated tumours expressed fewer of both molecules, but the better differentiated mast cells at the periphery of such lesions had more consistent 5-HT expression. 5-HT and the 5-HT1A receptor may be involved in the differentiation of canine MCTs and in the microvascular complications associated with these neoplasms. PMID:19446835

Fröberg, G Kastengren; Lindberg, R; Ritter, M; Nordlind, K



5-HT1A/1B, 5-HT6, and 5-HT7 serotonergic receptors recruitment in tonic-clonic seizure-induced antinociception: role of dorsal raphe nucleus.  


Pharmacological studies have been focused on the involvement of different neural pathways in the organization of antinociception that follows tonic-clonic seizures, including 5-hydroxytryptamine (5-HT)-, norepinephrine-, acetylcholine- and endogenous opioid peptide-mediated mechanisms, giving rise to more in-depth comprehension of this interesting post-ictal antinociceptive phenomenon. The present work investigated the involvement of 5-HT(1A/1B), 5-HT(6), and 5-HT(7) serotonergic receptors through peripheral pretreatment with methiothepin at doses of 0.5, 1.0, 2.0 and 3.0 mg/kg in the organization of the post-ictal antinociception elicited by pharmacologically (with pentylenetetrazole at 64 mg/kg)-induced tonic-clonic seizures. Methiothepin at 1.0 mg/kg blocked the post-ictal antinociception recorded after the end of seizures, whereas doses of 2.0 and 3.0 mg/kg potentiated the post-ictal antinociception. The nociceptive thresholds were kept higher than those of the control group. However, when the same 5-hydroxytryptamine receptors antagonist was microinjected (at 1.0, 3.0 and 5.0 microg/0.2 microL) in the dorsal raphe nucleus, a mesencephalic structure rich in serotonergic neurons and 5-HT receptors, the post-ictal hypo-analgesia was consistently antagonized. The present findings suggest a dual effect of methiothepin, characterized by a disinhibitory effect on the post-ictal antinociception when peripherally administered (possibly due to an antagonism of pre-synaptic 5-HT(1A) serotonergic autoreceptors in the pain endogenous inhibitory system) and an inhibitory effect (possibly due to a DRN post-synaptic 5-HT(1B), 5-HT(6), and 5-HT(7) serotonergic receptors blockade) when centrally administered. The present data also suggest that serotonin-mediated mechanisms of the dorsal raphe nucleus exert a key-role in the modulation of the post-ictal antinociception. PMID:19416688

Freitas, Renato Leonardo; Ferreira, Célio Marcos dos Reis; Urbina, Maria Angélica Castiblanco; Mariño, Andrés Uribe; Carvalho, Andressa Daiane; Butera, Giuseppe; de Oliveira, Ana Maria; Coimbra, Norberto Cysne



Simultaneous measurement of adenosine, dopamine, acetylcholine and 5-hydroxytryptamine in cerebral mice microdialysis samples by LC-ESI-MS/MS.  


A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method has been developed for the simultaneous measurement of adenosine (ADE), dopamine (DA), acetylcholine (ACh) and 5-hydroxytryptamine (5-HT) in mouse brain microdialysates. High method sensitivity (LLOQ of 0.05nM) was achieved by optimization of chromatographic and mass spectrometric parameters. The method was fully validated for its sensitivity, selectivity, matrix effect and stability. The LC-MS/MS method was successfully applied to evaluate the effect of the systemic administration of cocaine or amphetamine on the extracellular levels of ADE, DA, ACh and 5-HT in the mouse nucleus accumbens by microdialysis. PMID:22921776

Cannazza, Giuseppe; Carrozzo, Marina M; Cazzato, Addolorata S; Bretis, Irina M; Troisi, Luigino; Parenti, Carlo; Braghiroli, Daniela; Guiducci, Stefania; Zoli, Michele



Interaction of tryptamine and ergoline compounds with threonine 196 in the ligand binding site of the 5-hydroxytryptamine6 receptor.  


We examined the ligand-binding site of the 5-hydroxytryptamine6 (5-HT6) receptor using site-directed mutagenesis. Interactions with residues in two characteristic positions of trans-membrane region V are important for ligand binding in several bioamine receptors. In the 5-HT6 receptor, one of these residues is a threonine (Thr196), whereas in most other mammalian 5-HT receptors, the corresponding residue is alanine. After transient expression in human embryonic kidney 293 cells, we determined the effects of the mutation T196A on [3H]d-lysergic acid diethylamide (LSD) binding and adenylyl cyclase stimulation. This mutation produced a receptor with a 10-fold reduced affinity for [3H]LSD and a 6-fold reduced affinity for 5-HT. The potency of both LSD and 5-HT for stimulation of adenylyl cyclase was also reduced by 18- and 7-fold, respectively. The affinity of other N1-unsubstituted ergolines (e.g., ergotamine, lisuride) was reduced 10-30 fold, whereas the affinity of N1-methylated ergolines (e.g., metergoline, methysergide, mesulergine) and other ligands, such as methiothepine, clozapine, ritanserin, amitriptyline, and mainserin, changed very little or increased. This indicates that in wild-type 5-HT6 receptor, Thr196 interacts with the N1 of N1-unsubstituted ergolines and tryptamines, probably forming a hydrogen bond. Based on molecular modeling, a serine residue in transmembrane region IV of the 5-HT2A receptor has previously been proposed to interact with the N1-position of 5-HT. When the corresponding residue of the 5-HT6 receptor (Ala154) was converted to serine, no change in the affinity of twelve 5-HT6 receptor ligands or in the potency of 5-HT and LSD could be detected, suggesting that this position does not contribute to the ligand binding site of the 5-HT6 receptor. PMID:9284367

Boess, F G; Monsma, F J; Meyer, V; Zwingelstein, C; Sleight, A J



Regulation of 5-Hydroxytryptamine-Induced Signal Transduction in Canine Cultured Aorta Smooth Muscle Cells by Phorbol Ester  

Microsoft Academic Search

Regulation of the increase in inositol phosphates (IPs) production and intracellular Ca2+ concentration ([Ca2+]i) by protein kinase C (PKC) was investigated in cultured canine aorta smooth muscle cells (ASMCs). Stimulation of ASMCs by 5-hydroxytryptamine (5-HT) led to IPs formation and caused an initial transient [Ca2+]i peak followed by a sustained elevation of [Ca2+]i in a concentration-dependent manner. Pretreatment of ASMCs

Chuen-Mao Yang; Chi-Tso Chiu; Lir-Wan Fan; Hui-Liang Tsao; Chuan-Chwan Wang



Antispasmodic Activity of Persea cordata Vell. Mez. (Lauraceae) Fractions on Guinea Pig Ileum Induced by 5Hydroxytryptamine and Bradykinin  

Microsoft Academic Search

Problem statement: Persea cordata previously demonstrated antispasmodic action against two neurotransmitters. It is important confirm such action against other neurotransmitters. Approach: Present study described the antispasmodic activity of polar (EtOAc; n-BuOH) and non polar (n- hexane; dichloromethane) fractions from the bark of Persea cordata, against guinea pig ileum contracted by 5-hydroxytryptamine (5-HT) and bradykinin (BK). Results: The results indicated that

Julio A. Zampirolo; Hellen K. Stulzer; Monika Piazzon Tagliari; Valfredo Schlemper; Valdir Cechinel-Filho



Effect of Acanthopanax senticosus on 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe of exercised rats  

Microsoft Academic Search

Acanthopanax senticosus Harms (AS) is classified into the family of Araliaceae. The plant has been used as an analeptic aid, which improves weakened physical status and strength. Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter and tryptophan hydroxylase (TPH) catalyzes the rate-f the raphe nuclei. These are associated with “central fatigue hypotheses” in the brain.In the present study, the effects of

Yong-Taek Rhim; Hong Kim; Sung-Jin Yoon; Sung-Soo Kim; Hyun-Kyung Chang; Taeck-Hyun Lee; Hee-Hyuk Lee; Min-Chul Shin; Mal-Soon Shin; Chang-Ju Kim



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


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

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



Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex.  


Classic hallucinogens such as lysergic acid diethylamide are thought to elicit their psychotropic actions via serotonin receptors of the 5-hydroxytryptamine 2A subtype (5-HT(2A)R). One likely site for these effects is the prefrontal cortex (PFC). Previous studies have shown that activation of 5-HT(2A)Rs in this region results in a robust increase in spontaneous glutamatergic synaptic activity, and these results have led to the widely held idea that hallucinogens elicit their effect by modulating synaptic transmission within the PFC. Here, we combine cellular and molecular biological approaches, including single-cell 5-HT(2A)Rs inactivation and 5-HT(2A)R rescue over a 5-HT(2A)R knockout genetic background, to distinguish between competing hypotheses accounting for these effects. The results from these experiments do not support the idea that 5-HT(2A)Rs elicit the release of an excitatory retrograde messenger nor that they activate thalamocortical afferents, the two dominant hypotheses. Rather, they suggest that 5-HT(2A)Rs facilitate intrinsic networks within the PFC. Consistent with this idea, we locate a discrete subpopulation of pyramidal cells that is strongly excited by 5-HT(2A)R activation. PMID:17535909

Béïque, Jean-Claude; Imad, Mays; Mladenovic, Ljiljana; Gingrich, Jay A; Andrade, Rodrigo



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

Microsoft Academic Search

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

M. Danielle McDonald; Patrick J. Walsh



Translating 5-HT receptor pharmacology.  


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

Sanger, G J



Interaction between picrotoxin and 5-hydroxytryptamine in the superior cervical ganglion of the cat  

PubMed Central

1. Electrophysiological techniques were utilized to study the actions of 5-hydroxytryptamine (5-HT) and picrotoxin on the superior cervical ganglion of the cat. 2. The intra-arterial administration of 5-HT to the ganglion elicited both depressant and excitatory actions. In low doses (0·01-0·5 ?g) the amine produced a depression of ganglionic transmission. In larger doses (2-50 ?g) it produced an excitation of ganglion cells (early discharge) and an initial enhancement of transmission, which was followed by depression. Picrotoxin (25-500 ?g, i.a.) blocked the initial excitatory effects of 5-HT but did not block the depression. Picrotoxin did not antagonize the excitatory actions of injected cholinomimetic agents or potassium chloride. 3. In ganglia conditioned by repetitive stimulation of the preganglionic nerve (30 Hz for 30 s) 5-HT also elicited a late-occurring and very prolonged discharge on certain postganglionic nerves (`spinal') but not on others (external carotid). The late discharge was only partially depressed by picrotoxin. 4. Recordings from the surface of the superior cervical ganglion revealed that 5-HT produced three types of ganglionic potentials: (1) an initial transient depolarization which coincided with the early discharge, (2) a late-occurring, prolonged depolarization which coincided with the late discharge, and (3) a hyperpolarization which in some experiments accompanied the depression of transmission. The late depolarization and hyperpolarization were not observed in every experiment. Picrotoxin (25-500 ?g) blocked the initial depolarization, but did not block the late depolarization or the hyperpolarization. 5. It is concluded the 5-HT can produce three distinct responses in the superior cervical ganglion: a depressant effect and two types of excitation. It seems likely that depression and excitation occur via the activation of different receptors, since picrotoxin selectively blocks the latter. The finding that picrotoxin is a 5-HT antagonist in peripheral ganglia raises the possibility that picrotoxin might also influence tryptaminergic mechanisms in the central nervous system.

de Groat, W. C.; Lalley, P. M.



Molecular pharmacology of 5HT1D recognition sites: Radioligand binding studies in human, pig and calf brain membranes  

Microsoft Academic Search

1)The binding characteristics of [3H]5-HT (5-hydroxytryptamine, serotonin) were investigated in membrane preparations of several regions from calf, pig and human brain in the presence of 100 nmol\\/l 8-OH-DPAT (8-hydroxy-2[di-n-dipropylamino]tetralin) and 100 nmol\\/l mesulergine in order to mask 5-HT1A and 5-HT1C sites.2)[3H]5-HT bound rapidly, reversibly and stereo-selectively to a population of high affinity recognition sites in membranes from pig caudate, calf

C. Waeber; P. Schoeffter; J. M. Palacios; D. Hoyer



Effects of a selective 5-HT2 agonist, DOI, on 5-HT neuronal firing in the dorsal raphe nucleus and 5-HT release and metabolism in the frontal cortex.  

PubMed Central

Systemic administration of the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (50 and 100 micrograms kg-1, i.v.) inhibited dorsal raphe neuronal firing. DOI (100 micrograms kg-1, i.v.) also produced a decrease in extracellular 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex measured by microdialysis. However, local administration of DOI into the frontal cortex produced no change in extracellular 5-HT and 5-HIAA at any dose given (1, 10 and 100ng). The results demonstrate that DOI is a potent inhibitor of 5-HT neuronal firing and terminal release and that the effects on release are not mediated by an action within the terminal region. The site of action and the receptor involved in the inhibition remains to be determined.

Wright, I. K.; Garratt, J. C.; Marsden, C. A.



Investigation into the 5-hydroxytryptamine-induced atropine-resistant neurogenic contraction of guinea-pig proximal colon.  

PubMed Central

1. The aim of this study was to characterize the receptors mediating the atropine-resistant neurogenic contraction to 5-hydroxytryptamine (5-HT) in the longitudinal muscle of the guinea-pig proximal colon and to determine the type of tachykinin receptors involved in the contractile response to 5-HT by the use of selective antagonists. 2. In the presence of atropine (0.3 microM), guanethidine (5 microM), hexamethonium (100 microM), ketanserin (0.1 microM) and indomethacin (3 microM), 5-HT (0.01-3 microM) produced concentration-dependent neurogenic contractions of colonic strips and at 0.3 microM produced a maximal effect (pEC50 = 7.39 +/- 0.09, n = 18). The 5-HT4 receptor stimulant, 5-methoxytryptamine (5-MeOT, 0.03-10 microM) also produced neurogenic contractions with similar maximum effect to those of 5-HT (pEC50 = 6.89 +/- 0.16). 3. The 5-HT4 receptor antagonist, DAU 6285 (3 microM) shifted the concentration-response curves to both 5-HT and 5-MeOT to the right without significant depression of the maximum, but the 5-HT1/5-HT2 receptor antagonist, metitepine (0.1 microM) and the 5-HT3 receptor antagonist, ondansetron (0.3 microM) had no effect on the control curves to 5-HT and 5-MeOT. 4. The selective NK1 receptor antagonist, FK 888 (1 microM) markedly attenuated the contractions to 5-HT and 5-MeOT. In contrast, the selective NK2 receptor antagonist, SR 48968 (10 nM) and the selective NK3 receptor antagonist, SR 142801 (10 nM) had no effect on the contractions to 5-HT and 5-MeOT. 5. These results indicate that the 5-HT-induced atropine-resistant neurogenic contraction of guinea-pig proximal colon is due to activation of 5-HT4 receptors, presumably located on excitatory motor neurones, innervating the longitudinal muscle. The contraction evoked by activation of the 5-HT4 receptors is mediated primarily via NK1 receptors but not NK2 or NK3, suggesting that the 5-HT4 receptor-mediated contraction is evoked indirectly via tachykinin release from tachykinin-releasing excitatory neurones.

Kojima, S.; Shimo, Y.



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

PubMed Central

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)

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



Rhodnius prolixus Malpighian tubule's aquaporin expression is modulated by 5-hydroxytryptamine.  


The purpose of the present study was to detect the presence of an aquaporin-like water channel, a member of the major intrinsic protein (MIP) family, in the Malpighian tubule (MT) of the hematophagous insect Rhodnius prolixus, which excrete a large bulk of fluid after a massive blood meal, and its possible regulation by 5-hydroxytryptamine (5-HT). Reverse transcription polymerase chain reaction (RT-PCR) and Southern blots of cDNA was obtained from adult R. prolixus MT poly (A)+ RNA. Employing degenerate primers corresponding to the NPA (amino acid sequence motifs repeats Asn-Pro-Ala) highly conserved domain of amino acids sequences of all members of the MIP gene family, we were able to identify a 365-base pair PCR product. The R. prolixus MT mRNA expression of this water transporter is increased in the animal after blood meal and in tubules treated with 5-hydroxytryptamine or cAMP. The up-regulated expression of MT MIP mRNA after a blood meal is probably due to the action of 5-hydroxytryptamine via a cyclic AMP dependent pathway. PMID:15484262

Martini, Sabrina V; Goldenberg, Regina C; Fortes, Fabio S A; Campos-de-Carvalho, Antônio C; Falkenstein, Dóris; Morales, Marcelo M



Contributions of 5-HT Neurons to Respiratory Control: Neuromodulatory and Trophic Effects  

PubMed Central

Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter produced by a small number of neurons in the midbrain, pons and medulla. These neurons project widely throughout the neuraxis, where they release 5-HT and co-localized neuropeptides such as substance P (SP) and thyrotropin-releasing hormone (TRH). Each of these chemicals produce effects largely through G protein-coupled receptors, second messenger systems and subsequent neuromodulatory effects on target neurons. Emerging evidence suggests that 5-HT has additional modes of action during development and in adult mammals, including trophic effects (neurogenesis, cell differentiation, proliferation, migration and maturation) and influences on synaptic plasticity. Here, we discuss some of the neuromodulatory and trophic roles of 5-HT in general and in the context of respiratory control, as well as the regulation of release of modulatory neurotransmitters from 5-HT neurons. Future directions of study are also discussed.

Hodges, Matthew R.; Richerson, George B.



Methylenedioxymethamphetamine induces opposite changes in central pre- and postsynaptic 5-HT1A receptors in rats.  


The present study examined the short- and long-term effects of single and repeated administration of 3,4-methylenedioxy-methamphetamine (MDMA, 'ecstasy') on somatodendritic and postsynaptic 5-HT1A receptors of the rat brain. [3H]8-Hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) was used to label 5-HT1A receptors in the brain stem region containing the dorsal raphe nucleus and in the frontal cortex. As expected, both schedules of treatment reduced the serotonin (5-hydroxytryptamine, 5-HT) content and [3H]paroxetine binding in the frontal cortex but not in the brain stem. Multiple but not single MDMA administration significantly reduced 5-HT1A receptor density in the selected brain stem region. In the frontal cortex, both MDMA treatments increased or tended to increase 5-HT1A receptor number, the effect being more marked after repeated drug administration. PMID:8566108

Aguirre, N; Galbete, J L; Lasheras, B; Del Río, J



Nelumbinis Semen reverses a decrease in 5HT 1A receptor binding induced by chronic mild stress, a depression-like symptom  

Microsoft Academic Search

Depression is associated with a dysfunctional serotonin (5-hydroxytryptamine; 5-HT) system. More recently, several lines of\\u000a evidence suggest that an important factor in the development of depression may be a deficit in the function and expression\\u000a of 5-HT1A receptors. The present study assessed ifNelumbinis Semen (N. s.) had an anti-depression effect through reversing a decrease in 5-HT1A receptor binding in rats

Choon-Gon Jang; Moonkyu Kang; Jae-Han Cho; Sun-Bok Lee; Hyuntaek Kim; Seong-Kyu Park; Jinwoo Lee; Moochang Hong; Min Kyu Shin; In-Sup Shim; Hyunsu Bae



Effects of the antidepressant trazodone, a 5HT 2A\\/2C receptor antagonist, on dopamine-dependent behaviors in rats  

Microsoft Academic Search

Rationale: 5-Hydroxytryptamine, via stimula- tion of 5-HT2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT2A receptors enhances stimulated DAergic neuro- transmission. The antidepressant trazodone is a 5-HT2A\\/2C receptor antagonist. Objectives: To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system. Methods: The effect of pretreatment with

Jehangir J. Balsara; Sujata A. Jadhav; Rajani K. Gaonkar; Ramona V. Gaikwad; Jagdish H. Jadhav



Serotonin (5HT), Fluoxetine, Imipramine and Dopamine Target Distinct 5HT Receptor Signaling to Modulate Caenorhabditis elegans Egg-Laying Behavior  

Microsoft Academic Search

Drugs that target the serotonergic system are the most commonly prescribed therapeutic agents and are used for treatment of a wide range of behavioral and neurological disorders. However, the mechanism of the drug action remain a conjecture. Here, we dissect the genetic targets of serotonin (5HT), the selective 5HT reuptake inhibitor (SSRI) fluoxetine (Prozac), the tricyclic antidepressant imipramine, and dopamine.

Catherine M. Dempsey; Scott M. Mackenzie; Andrew Gargus; Gabriela Blanco; Ji Ying Sze



Blockade of motion- and cisplatin-induced emesis by a 5-HT2 receptor agonist in Suncus murinus.  

PubMed Central

1. The effects of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOl), a 5-hydroxytryptamine 5-HT2A/5-HT2C receptor agonist, on motion- and cisplatin-induced emesis were studied in Suncus murinus. Subcutaneous injection of DOl, 30 min prior to the emetic stimuli, dose-dependently blocked the emesis induced by motion sickness and cisplatin (20 mg kg-1, i.p.) with estimated ID50 values of 640 and 780 micrograms kg-1, respectively. 2. alpha-Methyl-5-hydroxytryptamine (alpha-Me-5-HT), a peripheral 5-HT2A/5-HT2C receptor agonist, had no effect on motion- and cisplatin-induced emesis. 3. The antiemetic effects of DOl on motion- and cisplatin-induced emesis were attenuated by preadministration of ketanserin, a selective 5-HT2A receptor antagonist. 4. The present results suggest an inhibitory role for central 5-HT2 receptors in the emetic reflex mechanism and that a 5-HT2 receptor agonist may be a useful tool to investigate the involvement of 5-HT receptors in the emetic reflex.

Okada, F; Saito, H; Matsuki, N



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

PubMed Central

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

Henderson, L P



Characterization of the 5-HT receptor subtypes involved in the motor behaviours produced by intrathecal administration of 5-HT agonists in rats.  

PubMed Central

1. The motor behavioural effects of intrathecal injections of 5-hydroxytryptamine (5-HT) and a variety of 5-HT receptor agonists were examined in adult Wistar rats to establish; (a) which 5-HT receptor subtype/s elicit each behaviour and (b) whether these receptors are located within the spinal cord. 2. Intrathecal injection of 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT), (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) or 2,5-dimethoxy-alpha,4-dimethylbenzene ethamine hydrochloride (DOM) produced dose-related back muscle contractions (BMC) and wet dog shakes (WDS) which were both markedly attenuated by intraperitoneal pretreatment with either ritanserin (1 mg kg-1), ketanserin (0.16 mg kg-1) or mianserin (0.6 mg kg-1) indicating the involvement of 5-HT2 receptors in both these motor behaviours. Both fluoxetine (1-20 mg kg-1, i.p.) and high doses of 5-HT (50 micrograms) following fluoxetine (5 mg kg-1, i.p.) also elicited BMC, further confirming the involvement of 5-HT in this behaviour. 3. Intrathecal 5-carboxamidotryptamine (5-CT) evoked a marked wet-dog shake response without producing any BMC. Intrathecal pretreatment with 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) enhanced, while in contrast 2-methyl-5-HT pretreatment attenuated, 5-HT agonist-induced BMC without affecting WDS. These data suggest that the spinal 5-HT2 receptors mediating BMC are positively modulated by 5-HT1A but negatively influenced by 5-HT3 receptor activation and may be of a different subtype to the supra-spinal 5-HT2 receptors which elicit WDS.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1 Figure 5

Fone, K. C.; Robinson, A. J.; Marsden, C. A.



Effects of the antagonists MDL 72222 and ketanserin on responses of cat carotid body chemoreceptors to 5-hydroxytryptamine.  

PubMed Central

The effects of intracarotid (i.c.) injections of 5-hydroxytryptamine (5-HT; 1-50 micrograms) on carotid chemoreceptor activity recorded from the carotid sinus nerve have been studied in anaesthetized cats. Three separate components in the complex response of the chemoreceptors to injected 5-HT were identified. Firstly, a transient burst of activity was obtained during the injection period in 56% of the recordings. Secondly, in all the recordings a period of chemodepression commenced a few seconds after completing the injection and was usually dose-related. Thirdly, a delayed longer-lasting chemoexcitation occurred in many experiments, concomitant with a fall in systemic blood pressure. The neuronal 5-HT receptor antagonist MDL 72222 (10-100 micrograms kg-1, i.c.) virtually abolished the transient chemoexcitation evoked during 5-HT injections and also significantly increased the mean ID50 for 5-HT-induced chemodepression; in 37% of recordings 5-HT caused a dose-related chemoexcitation after the high dose of MDL 72222. Neither the delayed chemoexcitation nor the hypotension caused by 5-HT were much affected by the antagonist. MDL 72222 itself had a biphasic effect on chemosensory discharge, causing depression followed by a delayed excitation. The 5-HT2-receptor antagonist ketanserin (100 micrograms kg-1, i.c.) had no appreciable effect on the transient chemoexcitation evoked during 5-HT injections and caused a slight but significant increase in the mean ID50 for 5-HT-induced chemodepression. The delayed chemoexcitation and accompanying hypotension associated with 5-HT were both substantially reduced or abolished by the antagonist. Ketanserin itself caused a short-lasting period of chemoexcitation. All the effects of injected 5-HT on chemosensory discharge could be abolished by the combination of MDL 72222 and ketanserin (100 micrograms kg-1, i.c.). Neither MDL 72222 nor ketanserin had any significant effect upon the response of the carotid chemoreceptors to hypoxia. The rate at which discharge increased, and also the steady-state discharge before and during hypoxia, were unaffected by the antagonists, alone or in combination. At least two types of 5-HT receptor appeared to be involved in the response of carotid body chemoreceptors to 5-HT. Transient excitation and chemodepression were mediated via MDL 72222-sensitive (peripheral neuronal) receptors whereas the delayed chemoexcitation and associated hypotension involved a ketanserin-sensitive, presumably 5-HT2-, receptor. It appears unlikely that 5-HT plays a crucial role in chemoreception.

Kirby, G. C.; McQueen, D. S.



The Emergence of 5HT 2B Receptors as Targets to Avoid in Designing and Refining Pharmaceuticals  

Microsoft Academic Search

The long-term use of certain drugs, such as fenfluramine, dihydroergotamine, and pergolide, has been associated with an increased\\u000a risk for valvular heart disease (VHD) and pulmonary hypertension (PH). Recent investigations have implicated the 5-hydroxytryptamine2B (5-HT2B) receptor in the pathogenesis of VHD and PH. Specifically, the activation of 5-HT2B receptors by VHD- and PH-associated drugs leads to proliferative lesions in the

Vincent Setola; Bryan L. Roth


Loss of 5-hydroxytryptamine from mammalian circulating labelled platelets  

PubMed Central

1. Platelets were obtained from three species of animal: rats, rabbits and dogs. They were labelled with 111In oxine to tag individual platelets and with 14C-labelled 5-hydroxytryptamine (5-HT). Doubly labelled platelets from rabbits and dogs were returned to their donors; in the case of rats the platelets were injected intravenously into other, identical rats. At time intervals from 2 to 64 hr, blood samples were drawn and platelets were collected. 111In and 14C were separately counted. In some experiments animals received the 5-HT precursor, 5-hydroxytryptophan (5-HTP) I.P. (for rats and rabbits) or subcutaneously (for dogs) in a dose of 20 mg/kg daily to accelerate synthesis of 5-HT. 2. 111In disappeared in approximately an exponential fashion in all experiments and the rate of disappearance was not affected by treatment with 5-HTP. The half-life for 111In in four control rats was 18·7 hr and in five rats treated with 5-HTP was 17·8 hr. In rabbits the half-life was 20·4 hr for eight control and 21·2 hr for seven treated with 5-HTP. In the dogs the half-life was 21·0 hr for control and 27·7 hr for experiments with 5-HTP. In control rats, the 14C behaved like the 111In. However, in control rabbits the half-life for 14C was 38·0 hr which is significantly longer than for 111In (P < 0·005). 14C also disappeared more slowly than the 111In in the dogs. 3. In all species treatment with 5-HTP accelerated the disappearance of the 14C approximately three-fold. This was not a reserpine-like effect because the platelets contained more, not less 5-HT than usual. 4. In an attempt to discover the fate of 5-HT disappearing from circulating platelets, experiments were made in which platelets from one rat were doubly labelled, and were then injected into two other rats from the identical strain; one of the recipients received daily I.P. injections of 20 mg/kg of 5-HTP. The other rat in each pair acted as a control. 5. Results from twelve control rats showed that the 14C/111In ratio in several tissues deviated from that found in platelets. Deviations occurred in both directions; in the spleen, liver and kidney the ratio was significantly lower than in the platelets (P < 0·01), whereas in the adrenals, thyroid, bladder and gut the ratio was significantly higher (P < 0·05 for thyroid, < 0·01 for others). In the gut, however, the ratio was significantly raised (P < 0·01) only at 5 hr. 6. Administration of unlabelled 5-HTP to another twelve rats greatly reduced the 14C in platelets. Under these conditions many tissues in addition to those above had a higher ratio of 14C/111In than platelets. These tissues included muscle, skin, salivary gland, kidney, heart, aorta, testis and seminal vesicle. As with platelets, the absolute counts of 14C/g of tissue decreased significantly after 5-HTP administration (platelets by 67%, brain by 56%, pancreas by 49%, lungs by 39%, liver by 37%, kidney by 29%, testis by 23% and seminal vesicle by 22%). On the other hand, there were significant rises of 93% in the skin and 21% in the muscle. Paper chromatography showed that 73-86% of the 14C in tissues still behaved like 5-HT, except in the bladder and adrenals which contained unidentified material. 7. It is concluded that under normal conditions platelets deposit 5-HT in specific tissues, notably gut, adrenals and thyroid. When unlabelled 5-HTP is administered, the labelled 5-HT is deposited in a variety of tissues, and especially in the skin.

Osim, E. E.; Wyllie, J. H.



Vascular 5-HT1-like receptors that mediate contraction of the dog isolated saphenous vein and carotid arterial vasoconstriction in anaesthetized dogs are not of the 5-HT1A or 5-HT1D subtype.  

PubMed Central

1. There is controversy about whether 5-HT1A receptors mediate contraction of isolated cerebral blood vessels. We have therefore compared the vascular actions of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT) with those of the 5-HT1-like receptor agonist, sumatriptan, on the dog isolated saphenous vein, which contains a 5-HT1-like receptor similar to those on cerebral blood vessels, and in the carotid circulation of the anaesthetized dog. 2. 5-Hydroxytryptamine (5-HT), sumatriptan and 8-OH-DPAT each caused contraction of dog isolated saphenous vein with a rank order of agonist potency of 5-HT greater than sumatriptan greater than 8-OH-DPAT and EC50 values (95% confidence limits) of 0.06 (0.04-0.08), 0.3 (0.1-0.8) and 3.9 (2.0-7.5) microM respectively. The maximum contractile effect produced by each agonist was similar. 3. The contractile effects of 5-HT, sumatriptan and 8-OH-DPAT in the dog isolated saphenous vein were resistant to antagonism by the 5-HT1A receptor antagonists spiperone, spiroxatrine and pindolol (all 1 microM). The 5-HT1D receptor ligands, metergoline (0.1 microM) rauwolscine (1 microM) and yohimbine (1 microM) had little or no antagonist activity. In contrast, the non-selective 5-HT1-like receptor blocking drug, methiothepin (0.03-0.3 microM) potently antagonized the contractile effects of 5-HT, sumatriptan and 8-OH-DPAT to a similar degree, suggesting that all three agonists act at the same receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

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



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

PubMed Central

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)

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



Nitric oxide is involved in 5-HT-induced relaxations of the guinea-pig colon ascendens in vitro.  


1. In the guinea-pig colon ascendens, 5-hydroxytryptamine (5-HT) induces contractions, mediated by 5-HT2, 5-HT3 and 5-HT4 receptors, and relaxations, through a 5-HT1 receptor subtype, that triggers the release of an inhibitory neurotransmitter. Nitric oxide (NO) is one of the main candidates of NANC inhibitory neurotransmission in the gut. The aim of this study was to establish whether NO is involved in 5-HT-induced relaxations of the guinea-pig colon ascendens. 2. Antagonists to block the contractile responses to 5-HT via 5-HT2, 5-HT3 and 5-HT4 receptors were present throughout the experiments and methacholine was administered to precontract the strips. Under these conditions, 5-HT concentration-dependently induced relaxations from 10 nM onwards (EC50 = 258 (172-387) nM). The relaxations were inhibited by metergoline (10 nM) and methiothepine (100 nM) and abolished by tetrodotoxin (TTX, 320 nM). Guanethidine (3.2 microM) did not affect them. 3. NG-nitro-L-arginine (L-NNA) inhibited the responses to 5-HT (IC50 = 18.7 (13.3-26.3) microM); at the highest 5-HT concentration a maximum inhibition of about 75% was observed with 320 microM L-NNA. This inhibition was reversed with L-arginine. Relaxations to glyceryl trinitrate (GTN) were not inhibited by L-NNA. 4. Haemoglobin (32 microM) inhibited the relaxations to 5-HT and GTN, but not those to isoprenaline (Iso). Methylene blue (10 microM) inhibited the relaxations to 5-HT but did not affect those caused by GTN or Iso. 5. It is concluded that 5-HT induces relaxations that involve NO.We also confirmed that 5-HT induces these relaxations via (a) 5-HT, receptor subtype(s), located on neurones. PMID:1472972

Briejer, M R; Akkermans, L M; Meulemans, A L; Lefebvre, R A; Schuurkes, J A



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

PubMed Central

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

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



The actions of 5-hydroxytryptamine and histamine on the isolated ileum of the tree shrew (Tupaia glis).  

PubMed Central

1. Contractions to 5-hydroxytryptamine (5-HT) and histamine of longitudinal muscle from the isolated ileum of the tree shrew (Tupaia), guinea-pig and rat were investigated by constructing dose-response curves and studying the effects of various antagonists. 2 In the Tupaia and rat ileum the contraction to 5-HT was reduced by methysergide but not affected by tetrodotoxin (TTX), morphine, hexamethonium (C6) or atropine. The response of guinea-pig ileum to 5-HT was not significantly inhibited by methysergide or C6, but was blocked by TTX, morphine and atropine. 3 Histamine-induced contraction of Tupaia and guinea-pig ileum was antagonized by diphenhydramine but not by TTX, morphine, C6 or atropine. Histamine was almost without effect on the rat ileum.

Sakai, K.; Shiraki, Y.; Tatsumi, T.; Tsuji, K.



Site-directed mutagenesis of the 5-HT1B receptor increases the affinity of 5-HT for the agonist low-affinity conformation and reduces the intrinsic activity of 5-HT.  


The antagonist radioligand [3H]GR125743 and the agonist radioligand [3H]5-HT were used to investigate the pharmacological characteristics of the G protein uncoupled agonist low-affinity and G protein coupled agonist high-affinity conformations of the wild-type and mutant human 5-hydroxytryptamine 1B (5-HT1B) receptors. We found that substitution of phenylalanine 185 in transmembrane region IV by alanine or methionine resulted in a reduced number of receptors in the coupled conformation, as well as a reduced affinity of 5-HT for the uncoupled conformation. In contrast, substitution of phenylalanine 331 in transmembrane region VI by alanine increased the affinity of 5-HT for the uncoupled conformation 11-fold thus reducing the agonist low-affinity to agonist high-affinity (K(il)/K(ih)) ratio 5-fold. This reduced ratio was correlated with a significantly reduced intrinsic activity of 5-HT previously determined by its ability to inhibit forskolin-stimulated cAMP production. In conclusion, these results show that single amino acid substitutions can selectively change the affinity of 5-HT for the G protein uncoupled conformation of the 5-HT1B receptor and alter the intrinsic activity of the ligand. PMID:11399261

Grånäs, C; Nordquist, J; Mohell, N; Larhammar, D



Approaching the 5-HT? receptor heterogeneity by computational studies of the transmembrane and intracellular domains.  


5-hydroxytryptamine type-3 receptor (5-HT?), an important target of many neuroactive drugs, is a cation selective transmembrane pentamer whose functional stoichiometries and subunit arrangements are still debated, due to the extreme complexity of the system. The three dimensional structure of the 5-HT?R subunits has not been solved so far. Moreover, most of the available structural and functional data is related to the extracellular ligand-binding domain, whereas the transmembrane and the intracellular receptor domains are far less characterised, although they are crucial for receptor function. Here, for the first time, 3D homology models of the transmembrane and the intracellular receptor domains of all the known human 5-HT? subunits have been built and assembled into homopentameric (5-HT(3A)R, 5-HT(3B)R, 5-HT(3C)R, 5-HT(3D)R and 5-HT(3E)R) and heteropentameric receptors (5-HT(3AB), 5-HT(3AC), 5-HT(3AD) and 5-HT(3AE)), on the basis of the known three-dimensional structures of the nicotinic-acetylcholine receptor and of the ligand gated channel from Erwinia chrysanthemi. The comparative analyses of sequences, modelled structures, and computed electrostatic properties of the single subunits and of the assembled pentamers shed new light both on the stoichiometric composition and on the physicochemical requirements of the functional receptors. In particular, it emerges that a favourable environment for the crossing of the pore at the transmembrane and intracellular C terminus domain levels by Ca²? ions is granted by the maximum presence of two B subunits in the 5-HT? pentamer. PMID:23771549

Del Cadia, Marta; De Rienzo, Francesca; Menziani, Maria Cristina



Quantitative autoradiographic localization of [3H]imipramine binding sites in the brain of the rat: relationship to ascending 5-hydroxytryptamine neuron systems.  

PubMed Central

Quantitative autoradiography shows that there is a close relationship between [3H]imipramine binding sites and the distribution of 5-hydroxytryptamine (5-HT) neurons in the rat brain. High labeling is observed in the midbrain raphe nuclei, the areas of the dopamine cell groups of the substantia nigra and of the ventral tegmental area of Tsai, the ventral amygdaloid nucleus, the midline thalamic area, and parts of the hypothalmus. Thus, antidepressant drugs that have high affinity for [3H]imipramine binding sites can exert an influence at the 5-HT cell body as well as at the 5-HT nerve terminal level. The present results underline the possibility that the 5-HT and dopamine hypotheses for the mechanism of action of antidepressant drugs are not mutually exclusive, because both 5-HT and dopamine neurons can be regulated by large numbers of [3H]imipramine binding sites. Images

Fuxe, K; Calza, L; Benfenati, F; Zini, I; Agnati, L F



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

PubMed Central

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

Endo, Y.



Long-lasting neuroprotective effect of sildenafil against 3,4-methylenedioxymethamphetamine- induced 5-hydroxytryptamine deficits in the rat brain.  


Sildenafil, given shortly before 3,4-methylenedioxymethamphetamine (MDMA), affords protection against 5-hydroxytryptamine (5-HT) depletions caused by this amphetamine derivative by an acute preconditioning-like mechanism. Because acute and delayed preconditionings do not share the same mechanisms, we investigated whether sildenafil would also protect the 5-HT system of the rat if given 24 hr before MDMA. For this, MDMA (3 × 5 mg/kg i.p., every 2 hr) was administered to rats previously treated with sildenafil (8 mg/kg p.o.). One week later, 5-HT content and 5-HT transporter density were measured in the striatum, frontal cortex, and hippocampus of the rats. Our findings indicate that sildenafil afforded significant protection against MDMA-induced 5-HT deficits without altering the acute hyperthermic response to MDMA or its metabolic disposition. Sildenafil promoted ERK1/2 activation an effect that was paralleled by an increase in MnSOD expression that persisted 24 hr later. In addition, superoxide and superoxide-derived oxidants, shown by ethidium fluorescence, increased after the last MDMA injection, an effect that was prevented by sildenafil pretreatment. Similarly, MDMA increased nitrotyrosine concentration in the hippocampus, an effect not shown by sildenafil-pretreated rats. In conclusion, our data demonstrate that sildenafil produces a significant, long-lasting neuroprotective effect against MDMA-induced 5-HT deficits. This effect is apparently mediated by an increased expression of MnSOD and a subsequent reduced susceptibility to the oxidative stress caused by MDMA. PMID:21948520

Puerta, Elena; Barros-Miñones, Lucia; Hervias, Isabel; Gomez-Rodriguez, Violeta; Orejana, Lourdes; Pizarro, Neus; de la Torre, Rafael; Jordán, Joaquín; Aguirre, Norberto



The recombinant 5-HT1A receptor: G protein coupling and signalling pathways  

PubMed Central

The 5-hydroxytryptamine 5-HT1A receptor was one of the first G protein coupled receptors whose cDNA and gene were isolated by molecular cloning methods. Transfection of the cDNA of this receptor into cells previously bearing no 5-HT receptors has resulted in the acquisition of large amounts of information regarding potential signal transduction pathways linked to the receptor, correlations of receptor structure to its various functions, and pharmacological properties of the receptor. Transfection studies with the 5-HT1A receptor have generated critical new information that might otherwise have been elusive. This information notably includes the discovery of unsuspected novel signalling linkages, the elucidation of the mechanisms of receptor desensitization, the refinement of models of the receptor pharmacophore, and the development of silent receptor antagonists, among others. The current review summarizes the most important studies of the recombinant 5-HT1A receptor in the decade since the identificiation of its cDNA.

Raymond, John R; Mukhin, Yurii V; Gettys, Thomas W; Garnovskaya, Maria N



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

PubMed Central

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



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

Microsoft Academic Search

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

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



5HT 6 Receptors as Targets for the Treatment of Cognitive Deficits in Schizophrenia  

Microsoft Academic Search

Cloned in the human in 1996 and localized to human chromosome 1p35–p36 (1), the 5-hydroxytryptamine6 5-ht6 receptor was initially discovered in the rat central nervous system (CNS) using methods from molecular biology (2,3). A 440-amino-acid polypeptide, the human receptor exhibits 89% homology to that of the resequenced rat receptor (1). The almost exclusive distribution of the receptor in the rat

Rudy Schreiber; Andrew Sleight; Marie Woolley


5HT 2 receptor regulation of acetylcholine release induced by dopaminergic stimulation in rat striatal slices  

Microsoft Academic Search

The role of 5-hydroxytryptamine (5-HT) receptor subtypes in acetylcholine (ACh) release induced by dopamine or neurokinin receptor stimulation was studied in rat striatal slices. The dopamine D1 receptor agonist SKF 38393 potentiated in a tetrodotoxin-sensitive manner the K+-evoked [3H]ACh release while SCH 23390, a dopamine D1 receptor antagonist, had no effect. [3H]ACh release was decreased by the dopamine D2 receptor

M. J Ram??rez; E Cenarruzabeitia; B Lasheras; J Del Rio



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

PubMed Central

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

Fukui, K; Vogt, M



The anti-emetic potential of the 5-hydroxytryptamine3 receptor antagonist BRL 43694.  

PubMed Central

In ferrets, the selective 5-hydroxytryptamine (5-HT) 5-HT3 receptor antagonist BRL 43694 given as a single injection (0.05-0.5 mg kg-1 i.v.) before cisplatin, or by divided dose (2 x 0.005-2 x 0.5 mg kg-1 i.v.) before and after cisplatin dramatically reduced or abolished the severe cisplatin-induced vomiting. BRL 43694 also substantially reduced the vomiting induced by cyclophosphamide:doxorubicin, and prevented the trimelamol-induced emesis. The severe emesis caused by whole body exposure to X-irradiation was prevented by intravenous or oral BRL 43694. A single i.v. dose of BRL 43694 given during an emetic episode or within the peak emetic period, abolished the vomiting induced by the cytotoxic drugs and by X-irradiation, usually within 30 s. Where the induction of emesis was prevented or subsequently abolished by BRL 43694, the associated behaviour (subjectively assessed as nausea) was also absent or greatly attenuated. BRL 43694 (0.1 mg kg-1 i.v.) did not affect the emesis evoked in dogs by the dopamine agonist apomorphine. The potent anti-emetic activity of BRL 43694 is discussed in terms of potential clinical use, and of the fundamental role that 5-HT3 receptors may play in the mechanisms of nausea and vomiting.

Bermudez, J.; Boyle, E. A.; Miner, W. D.; Sanger, G. J.



The 5-HT1A receptor and 5-HT transporter in temporal lobe epilepsy  

PubMed Central

Objective: To study 5-HT transport and 5-HT1A receptors in temporal lobe epilepsy (TLE) and depression. Methods: Thirteen patients had PET with [11C]DASB for 5-HTT and [18F]FCWAY for 5-HT1A receptor binding, MRI, and psychiatric assessment. Sixteen healthy volunteers had [11C]DASB, 19 had [18F]FCWAY, and 6 had both PET studies. We used a reference tissue model to estimate [11C]DASB binding. [18F]FCWAY volume of distribution was corrected for plasma-free fraction. Images were normalized to common space. The main outcome was the regional asymmetry index. Positive asymmetry indicates relative reduced binding (reflecting transporter activity) ipsilateral to epileptic foci. Results: Mean regional [11C]DASB binding and asymmetry did not differ between patients and controls. [18F]FCWAY asymmetry was significantly greater for patients than controls in hippocampus, amygdala, and fusiform gyrus. On analysis of variance with region as a repeated measure, depression diagnosis had a significant effect on [11C]DASB asymmetry, with significantly higher [11C]DASB asymmetry in insular cortex (trend for fusiform gyrus). In insular cortex, patients had a significant correlation between [18F]FCWAY asymmetry and [11C]DASB asymmetry. Conclusions: Our study showed increased [11C]DASB asymmetry in insula and fusiform gyrus, and relatively reduced transporter activity, in subjects with both TLE and depression, as compared to subjects with TLE alone, implying reduced reuptake and thus increased synaptic 5-HT availability. This finding may represent a compensatory mechanism for 5-HT1A receptor loss. Altered serotonergic mechanisms have an important role in TLE and concomitant depression.

Martinez, Ashley; Finegersh, Andrey; Cannon, Dara M.; Dustin, Irene; Nugent, Alison; Herscovitch, Peter



Nitric oxide is involved in 5-HT-induced relaxations of the guinea-pig colon ascendens in vitro.  

PubMed Central

1. In the guinea-pig colon ascendens, 5-hydroxytryptamine (5-HT) induces contractions, mediated by 5-HT2, 5-HT3 and 5-HT4 receptors, and relaxations, through a 5-HT1 receptor subtype, that triggers the release of an inhibitory neurotransmitter. Nitric oxide (NO) is one of the main candidates of NANC inhibitory neurotransmission in the gut. The aim of this study was to establish whether NO is involved in 5-HT-induced relaxations of the guinea-pig colon ascendens. 2. Antagonists to block the contractile responses to 5-HT via 5-HT2, 5-HT3 and 5-HT4 receptors were present throughout the experiments and methacholine was administered to precontract the strips. Under these conditions, 5-HT concentration-dependently induced relaxations from 10 nM onwards (EC50 = 258 (172-387) nM). The relaxations were inhibited by metergoline (10 nM) and methiothepine (100 nM) and abolished by tetrodotoxin (TTX, 320 nM). Guanethidine (3.2 microM) did not affect them. 3. NG-nitro-L-arginine (L-NNA) inhibited the responses to 5-HT (IC50 = 18.7 (13.3-26.3) microM); at the highest 5-HT concentration a maximum inhibition of about 75% was observed with 320 microM L-NNA. This inhibition was reversed with L-arginine. Relaxations to glyceryl trinitrate (GTN) were not inhibited by L-NNA. 4. Haemoglobin (32 microM) inhibited the relaxations to 5-HT and GTN, but not those to isoprenaline (Iso). Methylene blue (10 microM) inhibited the relaxations to 5-HT but did not affect those caused by GTN or Iso. 5. It is concluded that 5-HT induces relaxations that involve NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Briejer, M. R.; Akkermans, L. M.; Meulemans, A. L.; Lefebvre, R. A.; Schuurkes, J. A.



5-HT is present in nerves of guinea pig sphincter of Oddi and depolarizes sphincter of Oddi neurons.  


This study involved immunohistochemistry and intracellular electrophysiology to investigate serotonergic neurotransmission in the sphincter of Oddi (SO). 5-Hydroxytryptamine (HT)-positive neurons (14 cells/preparation) and nerve fibers were observed in the ganglionated plexus. Serotonergic nerve fibers, which persisted under 2- to 6-day organ culture, were densely distributed, with varicose endings encircling some SO neurons. When 5-HT was applied to SO neurons, it elicited three different responses: 1) a fast depolarization to 5-HT in 31 of 62 cells was mimicked by 2-methyl-5-HT and blocked by LY-278584 (1 microM); 2) a prolonged depolarization to 5-HT in 21 of 62 cells evoked an increase in input resistance and was attenuated by the 5-HT1P antagonist renzapride (1 microM) but not by the 5-HT4 antagonist SDZ-205557 (0.1-10 microM); and 3) an indirect depolarization blocked by TTX or atropine was observed in 32 of 62 cells. 5-HT superfusion elicited a dose-dependent monophasic depolarization (EC50 = 2 microM, n=14). In conclusion, 5-HT is present in nerves of the SO and elicits both 5-HT3 and 5-HT1P receptor-mediated depolarizations, supporting the concept that 5-HT plays a role in SO regulation. PMID:9815032

Hillsley, K; Mawe, G M



The modulatory action of 5-hydroxytryptamine on sodium efflux: the barnacle muscle fibre as a model system.  


A study has been made of the action of 5-hydroxytryptamine (5-HT) on the radio-sodium efflux from single barnacle muscle fibres. (i) Stimulation of the Na efflux by external application of 5-HT is seen in both unpoisoned and ouabain-poisoned fibres. (ii) Concentrations of 5-HT as low as 10(-9)M are effective. (iii) Characteristically, the response to 5-HT is prompt in onset, reaches a peak within 20 min and then decays rather rapidly. Fibres from certain barnacle specimens are sometimes unresponsive to 5-HT. Such fibres, however, can be rendered responsive by preinjecting into them the non-hydrolysable GTP analogue, Gpp(NH)p. The response of the ouabain-insensitive Na efflux to 5-HT depends on external Ca2+ and, to a certain extent, on external Na+. (i) The response to 5-HT is unaffected by prior external application of Ca2+ antagonists, viz. verapamil, Cd2+ and WB-4101. (ii) The calmodulin antagonist, trifluoperazine (10(-5)M), completely abolishes the response to 5-HT, even in fibres preinjected with Gpp(NH)p. (iii) Diphenylhydantoin is less effective than trifluoperazine (TFP). Whereas the receptor antagonist methysergide is ineffective, cyproheptadine is very effective. (i) Prior application of the phosphodiesterase inhibitor 1-propyl-3-methyl-7-(5-hydroxyhexyl)-xanthine (PMX) or the inhibitor 1-isoamyl-3-isobutyl-xanthine (IAX) augments the size of the response to 5-HT, but fails to stop the response from decaying. (ii) Augmentation of the response to 5-HT by IAX is seen despite the presence of 10(-5) M-TFP. Prior injection of Mg2+ or protein kinase inhibitor (PKI) leads to abolition or reduction of the response to 5-HT. These results demonstrate that barnacle fibres are a useful preparation for investigation the natriferic action of 5-HT. They also support the view that the response to 5-HT involves a receptor-adenylate cyclase complex and is the result of activation by newly formed cAMP of cAMP-dependent protein kinase. PMID:2861030

Bittar, E E; Chambers, G



Effects of chronic treatment with escitalopram or citalopram on extracellular 5-HT in the prefrontal cortex of rats: role of 5-HT1A receptors  

PubMed Central

Microdialysis was used to study the acute and chronic effects of escitalopram (S-citalopram; ESCIT) and chronic citalopram (CIT), together with the 5-HT1A receptor antagonist WAY100,635 (N-[2-[methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide trihydrochloride) and the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on extracellular 5-hydroxytryptamine (5-HT) levels in the rat prefrontal cortex. Extracellular 5-HT rose to 234 and 298% of basal values after subcutaneous (s.c.) acute doses of 0.15 and 0.63 mg kg?1 ESCIT. No further increase was observed at 2.5 mg kg?1 ESCIT (290%). The effect of 13-day s.c. infusion of 10 mg kg?1day?1 ESCIT on extracellular 5-HT (422% of baseline) was greater than after 2 days (257% of baseline), whereas exposure to ESCIT was similar. In contrast, the increase in extracellular 5-HT induced by the infusion of CIT for 2 (306%) and 13 days (302%) was similar. However, brain and plasma levels of S-citalopram in rats infused with CIT for 13 days were lower than after 2 days. Acute treatment with 2.5 mg kg?1 ESCIT or 5 mg kg?1 CIT raised extracellular 5-HT by 243 and 276%, respectively, in rats given chronic vehicle but had no effect in rats given ESCIT (10 mg kg?1 day?1) or CIT (20 mg kg?1 day?1) for 2 or 13 days, suggesting that the infused doses had maximally increased extracellular 5-HT. WAY100,635 (0.1 mg kg?1 s.c.) increased extracellular 5-HT levels by 168, 174 and 169% of prechallenge values in rats infused with vehicle or ESCIT for 2 or 13 days, respectively. WAY100,635 enhanced extracellular 5-HT levels to 226, 153 and 164% of prechallenge values in rats infused with vehicle or CIT for 2 and 13 days, respectively. 8-OH-DPAT (0.025 mg kg?1) reduced extracellular 5-HT by 54% in control rats, but had no effect in those given ESCIT and CIT for 13 days. This series of experiments led to the conclusion that chronic treatment with ESCIT desensitizes the 5-HT1A receptors, regulating the release of 5-HT in the prefrontal cortex and enhances the effect of the drug on extracellular 5-HT. They also indicate that chronic treatment with ESCIT and CIT did not prevent WAY100,635 from raising extracellular 5-HT.

Ceglia, I; Acconcia, S; Fracasso, C; Colovic, M; Caccia, S; Invernizzi, R W



Vascular 5-HT1-like receptors mediating vasoconstriction and vasodilatation: their characterization and distribution in the intact canine cardiovascular system.  

PubMed Central

1. In anaesthetized dogs, intra-left atrial administration of 5-hydroxytryptamine (5-HT) and selected tryptamine analogues (5-carboxamidotryptamine, 5-CT; 5-methyl tryptamine, 5-MT; alpha-methyl 5-hydroxytryptamine, alpha-HT; sumatriptan, Sum) in the presence of ketanserin and MDL72222 (5-HT2 and 5-HT3 receptor antagonists, respectively), produced dose-related changes in carotid, coronary and renal vascular conductance mediated by vascular 5-HT1-like receptors. 2. In the carotid vascular bed, 5-HT, 5-MT, alpha-HT and Sum were vasoconstrictors with a rank order of potency (comparing ED50 values) of 5-HT = Sum > 5-MT > alpha-HT. By contrast in this vascular bed, 5-CT was a potent vasodilator. 3. In the coronary vascular bed, 5-HT, 5-CT, 5-MT and alpha-HT were vasodilators with a rank order of potency (comparing ED50 values) of 5-CT > 5-HT > 5-MT > alpha-HT. In this vascular bed, Sum was without effect. 4. In the renal vascular bed, 5-HT, 5-CT, 5-MT, alpha-HT and Sum were vasoconstrictors with a rank order of potency (comparing ED50 values) of 5-CT > 5-HT > Sum > 5-MT > alpha-HT. 5. The coronary (and carotid) vasodilator responses to 5-CT were antagonized by the 5-HT1-like receptor antagonists, spiperone (1 mg kg-1) and methiothepin (0.1 mg kg-1), whereas the renal vasoconstrictor responses to this tryptamine analogue were antagonized only by methiothepin.(ABSTRACT TRUNCATED AT 250 WORDS)

Cambridge, D; Whiting, M V; Butterfield, L J; Marston, C



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

NASA Astrophysics Data System (ADS)

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

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



Y25130 hydrochloride, a selective 5HT3 receptor antagonist has potent antimitogenic and apoptotic effect on HT29 colorectal cancer cell line.  


Serotonin (5-hydroxytryptamine, 5-HT) is known to be a mitogenic factor in several malignancies. It elicits its mitogenic effect through a wide range of 5-HT receptor subtypes and several internal cellular transcription pathways. According to wide distribution of 5-HT3 and 5-HT4 receptors in the gastrointestinal tract, the main aim of this study was to investigate the effect of these receptor agonists and antagonists in a colorectal cell line. In cell culture, we investigated the effects of 5-HT, 5-HT3 and 5-HT4 receptor agonists and antagonists on proliferation of HT29 cells. We also tested apoptosis for the receptor antagonists with TUNEL apoptosis test. In addition, we assayed effects of 5-HT receptor antagonists on cell cycle kinetics with flow cytometery. Proliferation assay revealed that phenylbiguanide (a 5-HT3 receptor selective agonist) increased proliferation of HT29 cells significantly and Y25130 hydrochloride (a 5-HT3 receptor antagonist) had the opposite effect; but for 5-HT4 receptor antagonist, these effects were not significant. In addition, potent apoptotic and cell cycle arresting effect was found for a selective 5-HT3 receptor antagonist but we have not seen any significant effect for the 5-HT4 receptor antagonist. The findings of this study provide strong evidence for the potential role of 5-HT3 receptors in colorectal cancer. PMID:20010428

Ataee, Ramin; Ajdary, Soheila; Zarrindast, Mohammadreza; Rezayat, Mehdi; Shokrgozar, Mohammad Ali; Ataee, Amin



Inverse agonist and neutral antagonist actions of synthetic compounds at an insect 5-HT1 receptor  

PubMed Central

Background and purpose: 5-Hydroxytryptamine (5-HT) has been shown to control and modulate many physiological and behavioural functions in insects. In this study, we report the cloning and pharmacological properties of a 5-HT1 receptor of an insect model for neurobiology, physiology and pharmacology. Experimental approach: A cDNA encoding for the Periplaneta americana 5-HT1 receptor was amplified from brain cDNA. The receptor was stably expressed in HEK 293 cells, and the functional and pharmacological properties were determined in cAMP assays. Receptor distribution was investigated by RT-PCR and by immunocytochemistry using an affinity-purified polyclonal antiserum. Key results: The P. americana 5-HT1 receptor (Pea5-HT1) shares pronounced sequence and functional similarity with mammalian 5-HT1 receptors. Activation with 5-HT reduced adenylyl cyclase activity in a dose-dependent manner. Pea5-HT1 was expressed as a constitutively active receptor with methiothepin acting as a neutral antagonist, and WAY 100635 as an inverse agonist. Receptor mRNA was present in various tissues including brain, salivary glands and midgut. Receptor-specific antibodies showed that the native protein was expressed in a glycosylated form in membrane samples of brain and salivary glands. Conclusions and implications: This study marks the first pharmacological identification of an inverse agonist and a neutral antagonist at an insect 5-HT1 receptor. The results presented here should facilitate further analyses of 5-HT1 receptors in mediating central and peripheral effects of 5-HT in insects.

Troppmann, B; Balfanz, S; Baumann, A; Blenau, W



5-HT1A Receptor Null Mutant Mice Responding Under a Differential-Reinforcement-of-Low-Rate 72-Second Schedule of Reinforcement  

PubMed Central

Over the last two decades, our ever-increasing ability to manipulate the mouse genome has resulted in a variety of genetically defined mouse models of depression and other psychiatric and neurological disorders. However, it is still the case that some relevant rodent models for depression and antidepressant action have been validated experimentally in rats only and not in mice. An important example of such models is the operant model of antidepressant action known as differential-reinforcement-of-low-rates 72-second (DRL 72-s). A specific set of drug-induced changes on the performance of rats responding under a DRL 72-s schedule of reinforcement has been shown to be a highly reliable predictor of antidepressant activity in human depressive disorders. The aim of this study is to validate the use of the DRL 72-s schedule in mice by both genetic and pharmacological means. We have analyzed the actions of the specific serotonin reuptake inhibitor (SSRI) fluoxetine and the tricyclic agent desipramine (DMI) on wild-type and 5-hydroxytryptamine 1A receptor-null mutant (5-HT1AR KO) mice. In agreement with the literature on rats, we found that fluoxetine produced an acute antidepressant-like effect in 5-HT1AR KO mice but not in wild-type (Wt) mice. Additionally, an antidepressant-like effect was observed when DMI was administered to both 5-HT1AR KO and Wt mice. In conclusion: through the use of both genetic and pharmacological strategies, this study validates the extension of a protocol involving the DRL 72-s operant schedule of reinforcement as a behavioral model for the action of antidepressants in mice.

Scott-McKean, Jonah J.; Wenger, Galen R.; Tecott, Laurence H.; Costa, Alberto C.S.



5-Hydroxytryptamine levels in the pulmonary arterioles of broilers with induced pulmonary hypertension and its relationship to pulmonary vascular remodelling.  


This experiment was performed to explore the relationship between 5-hydroxytryptamine (5-HT) levels in pulmonary arterioles and in pulmonary vascular remodelling in broilers. Pulmonary arterial hypertension was induced by injecting cellulose microparticles intravenously. Pulmonary hypertension syndrome (PHS) morbidity, right ventricle/total ventricle weight ratio (RV/TV), packed cell volume (PCV), haemoglobin concentration (HB), vessel wall area to vessel total area ratio (WA/TA) and mean tunica media thickness in pulmonary arterioles (mMTPA) were measured. Proliferating cell nuclear antigen (PCNA), argyrophilic nucleolar organizer region proteins (Ag-NORs) and 5-HT content in pulmonary arterioles were determined. The results showed that injecting cellulose microparticles intravenously in broilers could successfully increase the PHS morbidity, significantly elevate RV/TV, PCV and HB, significantly increase mMTPA and WA/TA, and significantly increase the argyrophilic particles in smooth muscle cell nucleoli, PCNA-positive cells in the medial layer, and the 5-HT content in pulmonary arterioles. Correlation analysis showed that the level of 5-HT was strongly positively correlated with PCNA and Ag-NORs. The results indicated that the increase of 5-HT in the tunica media could possibly promote the proliferation of smooth muscle cells in pulmonary arterioles and thus the occurrence of pulmonary vascular remodelling. PMID:23782167

Li, Ying; Zeng, Jian-Ying; Tang, Zhao-Xin; Li, Yu-Gu; Guo, Jian-Ying; Pan, Jia-Qiang



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

SciTech Connect

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.

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



Release of 5-hydroxytryptamine by pentagastrin and its role in the 'fade' of stimulated gastric secretion in cats.  

PubMed Central

1. The release of 5-hydroxytryptamine (5-HT) by pentagastrin and the 'fade' phenomenon seen in acid gastric secretion during a continuous intravenous infusion of pentagastrin have been studied in anaesthetized cats. 2. During an intravenous infusion of pentagastrin, acid secretion rose steeply to a maximum at 45 min. It was maintained at this rate for only 15-30 min, after which it decreased gradually. Meanwhile there was a marked increase in the 5-HT content of the plasma which reached a peak at 120 min and remained just below the peak concentration for the rest of the experiment. 3. Acid secretion due to an intravenous infusion of histamine on the other hand, steadily increased over the 3 h collection period. Meanwhile there was only a gradual small increase in the 5-HT content of the plasma. 4. Whereas there was a continuous steady increase in acid secretion in response to an intravenous infusion of pentagastrin in cats pre-treated with reserpine, acid secretion rose to a sharp peak and then decreased gradually when reserpinized cats were given a simultaneous infusion of 5-HT along with the pentagastrin. 5. It is concluded that 5-HT is released by pentagastrin and that it is responsible for the 'fade' phenomenon seen in acid secretion during infusions of pentagastrin, first of all augmenting acid secretion and then inhibiting it.

Izzat, A; Waton, N G



Prostaglandin E2 is a mediator of 5-hydroxytryptamine induced water and electrolyte secretion in the human jejunum.  

PubMed Central

Studies in the rat jejunum in vivo have shown that 5-hydroxytryptamine (5-HT) causes secretion of fluid and luminal release of prostaglandin (PG) E2. These effects can be blocked by indomethacin and ketanserin, which suggests that PGE2 may be an important intermediate in the transduction mechanism leading to 5-HT induced fluid secretion. To test this hypothesis in man 'steady state' perfusions (9 ml/min) were done in eight healthy volunteers using the triple lumen technique. The proximal jejunum was perfused with Ringer's solution which contained 51Cr-EDTA as a non-absorbable marker. Before and after the administration of indomethacin (1.0 mg/kg iv) the effects of exogenous 5-HT (10 micrograms/kg/min iv) on jejunal net transport of fluid and electrolytes and jejunal flow rate (JFR) of PGE2 were measured in 15-min periods for 2 x 60 minutes after a 60 minute control period. 5-HT reversed fluid and electrolyte absorption into profuse secretion (p less than 0.01, Duncan's multiple range test) and significantly increased JFR of PGE2 (p less than 0.01). Indomethacin partly restored fluid and electrolyte absorption (p less than 0.01) and inhibited JFR of PGE2 (p less than 0.05). These results provide further evidence in favour of the theory that PGs are involved in 5-HT induced intestinal fluid secretion.

Munck, L K; Mertz-Nielsen, A; Westh, H; Bukhave, K; Beubler, E; Rask-Madsen, J



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

PubMed Central

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.

Ramirez, M. J.; Cenarruzabeitia, E.; Del Rio, J.; Lasheras, B.



5-HT1A Receptor Function in Major Depressive Disorder  

PubMed Central

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

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



Ovarian hormone modulates 5-hydroxytryptamine 3 receptors mRNA expression in rat colon with restraint stress-induced bowel dysfunction  

Microsoft Academic Search

AIM: To examine the effects of ovarian hormone on the expression of 5-hydroxytryptamine 3 receptors (5-HT3R) in rat colon of restraint stress-induced bowel dysfunction. METHODS: Twenty-four female Sprague-Dawley rats were randomly divided into three groups of 8 each: sham operation, ovariectomy (OVX) and ovariectomy with estrogen (E2) and progesterone (P) replacement therapy (OVX+E2+P). The rats were subjected to 1-h restraint

Tian-Jin Li; Bao-Ping Yu; Wei-Guo Dong; He-Sheng Luo; Long Xu; Mu-Qi Li



Separate 5-hydroxytryptamine receptors on the salivary gland of the blowfly are linked to the generation of either cyclic adenosine 3',5'-monophosphate or calcium signals.  

PubMed Central

1 5'-Hydroxytryptamine (5-HT) stimulates the formation of two separate second messengers in the salivary gland of the blowfly. Activation of adenylate cyclase raises adenosine 3',5'-monophosphate (cyclic AMP) whereas the hydrolysis of phosphatidylinositol (PI) is associated with an increase in calcium permeability. The possibility that these two signal pathways might be controlled by separate 5-HT receptors was studied by testing the specificity of 5-HT analogues and antagonists. 2 The parent compound 5-HT was found to stimulate both cyclic AMP formation and the related parameters of PI hydrolysis and calcium transport with similar dose-response relationships. 3 Certain analogues such as 4- and 5-fluoro-alpha-methyltryptamine were capable of raising cyclic AMP levels and stimulating fluid secretion but did not stimulate the hydrolysis of PI or the entry of calcium. 4 Other analogues, which had chloro or methyl substituents at the 5-position, were found to stimulate the hydrolysis of PI and the transport of calcium at much lower doses than those required to stimulate the formation of cyclic AMP. 5 Antagonists were also found to exert selective effects. Methysergide was a potent inhibitor of PI hydrolysis whereas cinanserin was far more selective in blocking the stimulatory effect of 5-HT on cyclic AMP formation. 6 It is concluded that 5-HT acts on two separate receptors, a 5-HT1 receptor acting through calcium and a 5-HT2 receptor which mediates its effects through cyclic AMP.

Berridge, M. J.; Heslop, J. P.



5-Hydroxytryptamine Modulates Migration, Cytokine and Chemokine Release and T-Cell Priming Capacity of Dendritic Cells In Vitro and In Vivo  

PubMed Central

Beside its well described role in the central and peripheral nervous system 5-hydroxytryptamine (5-HT), commonly known as serotonin, is also a potent immuno-modulator. Serotoninergic receptors (5-HTR) are expressed by a broad range of inflammatory cell types, including dendritic cells (DCs). In this study, we aimed to further characterize the immuno-biological properties of serotoninergic receptors on human monocyte-derived DCs. 5-HT was able to induce oriented migration in immature but not in LPS-matured DCs via activation of 5-HTR1 and 5-HTR2 receptor subtypes. Accordingly, 5-HT also increased migration of pulmonary DCs to draining lymph nodes in vivo. By binding to 5-HTR3, 5-HTR4 and 5-HTR7 receptors, 5-HT up-regulated production of the pro-inflammatory cytokine IL-6. Additionally, 5-HT influenced chemokine release by human monocyte-derived DCs: production of the potent Th1 chemoattractant IP-10/CXCL10 was inhibited in mature DCs, whereas CCL22/MDC secretion was up-regulated in both immature and mature DCs. Furthermore, DCs matured in the presence of 5-HT switched to a high IL-10 and low IL-12p70 secreting phenotype. Consistently, 5-HT favoured the outcome of a Th2 immune response both in vitro and in vivo. In summary, our study shows that 5-HT is a potent regulator of human dendritic cell function, and that targeting serotoninergic receptors might be a promising approach for the treatment of inflammatory disorders.

Blumenthal, Britta; Grimm, Melanie; Cicko, Sanja; Panther, Elisabeth; Sorichter, Stephan; Herouy, Yared; Di Virgilio, Francesco; Ferrari, Davide; Norgauer, Johannes; Idzko, Marco



Rapid desensitization and resensitization of 5-HT sub 2 receptor mediated phosphatidyl inositol hydrolysis by serotonin agonists in quiescent calf aortic smooth muscle cells  

SciTech Connect

Agonist regulation of 5-hydroxytryptamine{sub 2} (5-HT{sub 2}) receptors was studied in calf aortic smooth muscle cultures incubated in a quiescent, defined synthetic medium that does not stimulate cell proliferation, but that provides cells with supplements that maintain cell viability. In these cells, 5-hydroxytryptamine (5-HT)-induced ({sup 3}H)inositol phosphates accumulation showed the characteristics of a 5-HT{sub 2} receptor coupled transducing system according to the inhibition of the response by 5-HT{sub 2} antagonists at nanomolar concentrations. The 5-HT{sub 2} receptor coupled response became rapidly desensitized during continued incubation with 5-HT and 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM); nearly full desensitization was obtained in two hours with 10 {mu}M 5-HT and DOM pretreatment. The recovery of the response had a half-live of 5 hours after 2 hours pretreatment and of 9.5 to 12.5 hours after 24 to 96 hours agonist pretreatment. The DOM-induced desensitization of the 5-HT{sub 2} receptor coupled response was fully blocked by 0.1 {mu}M cinanserin. Cinanserin alone did not induce desensitization or up-regulation of the 5-HT{sub 2} receptor coupled response at 0.1 {mu}M.

Pauwels, P.J.; Van Gompel, P.; Leysen, J.E. (Janssen Research Foundation, Beerse (Belgium))



Glucose-dependent trafficking of 5-HT3 receptors in rat gastrointestinal vagal afferent neurons  

PubMed Central

Background Intestinal glucose induces gastric relaxation via vagally mediated sensory-motor reflexes. Glucose can alter the activity of gastrointestinal (GI) vagal afferent (sensory) neurons directly, via closure of ATP-sensitive potassium channels, as well as indirectly, via the release of 5-hydroxytryptamine (5-HT) from mucosal enteroendocrine cells. We hypothesized that glucose may also be able to modulate the ability of GI vagal afferent neurons to respond to the released 5-HT, via regulation of neuronal 5-HT3 receptors. Methods Whole cell patch clamp recordings were made from acutely dissociated GI-projecting vagal afferent neurons exposed to equiosmolar Krebs’ solution containing different concentrations of D-glucose (1.25–20mM) and the response to picospritz application of 5-HT assessed. The distribution of 5-HT3 receptors in neurons exposed to different glucose concentrations was also assessed immunohistochemically. Key Results Increasing or decreasing extracellular D-glucose concentration increased or decreased, respectively, the 5-HT-induced inward current as well as the proportion of 5-HT3 receptors associated with the neuronal membrane. These responses were blocked by the Golgi-disrupting agent Brefeldin-A (5µM) suggesting involvement of a protein trafficking pathway. Furthermore, L-glucose did not mimic the response of D-glucose implying that metabolic events downstream of neuronal glucose uptake are required in order to observe the modulation of 5-HT3 receptor mediated responses. Conclusions & Inferences These results suggest that, in addition to inducing the release of 5-HT from enterochromaffin cells, glucose may also increase the ability of GI vagal sensory neurons to respond to the released 5-HT, providing a means by which the vagal afferent signal can be amplified or prolonged.

Babic, Tanja; Troy, Amanda E; Fortna, Samuel R; Browning, Kirsteen N



Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2B Receptor Agonists: Implications for Drug Safety Assessment  

PubMed Central

Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine2B (5-HT2B) receptor agonists. We have shown that activation of 5-HT2B receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT2B receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT2B receptor agonists (hits); 14 of these had previously been identified as 5-HT2B receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then “functionally profiled” (i.e., assayed in parallel for 5-HT2B receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC50 data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT2B receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease.

Huang, Xi-Ping; Setola, Vincent; Yadav, Prem N.; Allen, John A.; Rogan, Sarah C.; Hanson, Bonnie J.; Revankar, Chetana; Robers, Matt; Doucette, Chris



Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment.  


Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine(2B) (5-HT(2B)) receptor agonists. We have shown that activation of 5-HT(2B) receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT(2B) receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT(2B) receptor agonists (hits); 14 of these had previously been identified as 5-HT(2B) receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then "functionally profiled" (i.e., assayed in parallel for 5-HT(2B) receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC(50) data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT(2B) receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease. PMID:19570945

Huang, Xi-Ping; Setola, Vincent; Yadav, Prem N; Allen, John A; Rogan, Sarah C; Hanson, Bonnie J; Revankar, Chetana; Robers, Matt; Doucette, Chris; Roth, Bryan L



Responsiveness of C neurons in rat dorsal root ganglion to 5-hydroxytryptamine-induced pruritic stimuli in vivo.  


Itching is a common symptom in dermatologic diseases and causes restless scratching of the skin, which aggravates the condition. The mechanism of the itch sensation, however, is enigmatic. The present study included behavioral tests and electrophysiological recordings from rat dorsal root ganglion (DRG) neurons in vivo to analyze the response to pruritic stimuli induced by topical application of 5-hydroxytryptamine (5-HT) to the skin. Topically applied 5-HT to the rostral back evoked scratching, whereas application of the vehicle did not. Following subcutaneous injection of the opioid receptor antagonist naloxone, the number of scratches decreased, suggesting that the scratching was preferentially mediated by itch but not pain sensation. To elucidate the firing properties of DRG neurons in response to topically applied 5-HT, intracellular recordings were made from DRG neurons in vivo. None of the Abeta and Adelta neurons responded to 5-HT; in contrast, 25 of 91 C neurons (27%) exhibited repetitive firing in response to 5-HT, which could be classified into two firing patterns: one was a transient type, characterized by low firing frequency that decreased within 5 min; the other was a long-lasting type, having high firing frequency that continued increasing after 5 min. The time course of the firing pattern of long-lasting C neurons was comparable to the scratching behavior. Intriguingly, the long-lasting-type neurons had a significantly smaller fast afterhyperpolarization than that of the 5-HT-insensitive neurons. These observations suggest that the long-lasting-firing C neurons in rat DRG sensitive to 5-HT are responsible for conveying pruritic information to the spinal cord. PMID:20484528

Hachisuka, Junichi; Furue, Hidemasa; Furue, Masutaka; Yoshimura, Megumu




Microsoft Academic Search

Numerous neurotransmitter systems (e.g. dopamine, y-aminobutyric acid (GABA), the endogenous opioids, and serotonin (5-hydroxytryptamine, 5-HT)) are involved in the regulation of alcohol consumption. Because 5-HT reuptalce inhibitors and opioid antagonists modify the activity of neurotransmitters, it has been hypothesized that they may also mediate the desire to drink alcohol by acting on specific receptors in the brain. Animal studies have




A 5HT7 Receptor-Mediated Depolarization in the Anterodorsal Thalamus. II. Involvement of the Hyperpolarization-Activated Current Ih  

Microsoft Academic Search

Previous studies have shown that 5-hydroxytryptamine (5-HT) can modulate the hyperpolarization-activated nonselective cat- ion current (Ih) to elicit a membrane depolarization in neurons. However, the receptor subtype involved in this response re- mains controversial. In the accompanying study, we have iden- tified a 5-HT7 receptor-mediated depolarization in the an- terodorsal nucleus of the thalamus (ADn). In the present study, we



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

Microsoft Academic Search

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

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



ERK1\\/2 inhibition attenuates cerebral blood flow reduction and abolishes ETB and 5HT1B receptor upregulation after subarachnoid hemorrhage in rat  

Microsoft Academic Search

Upregulation of endothelin B (ETB) and 5-hydroxytryptamine 1B (5-HT1B) receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK1\\/2). In the present study, we hypothesized that inhibition of ERK1\\/2 alters the ETB and 5-HT1B receptor upregulation and at the same time prevents

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



5HT2 and 3 receptor antagonists suppress the response of rat type I slowly adapting mechanoreceptor: an in vitro study  

Microsoft Academic Search

Previous experiments have shown an increase in rat type I mechanoreceptor responsiveness during arterial serotonin (5-hydroxytryptamine) infusion and the presence of serotonin immunostaining in Merkel cells. The current findings demonstrate that the 5-HT2 antagonists ritanserin and ketanserin, as well as the 5-HT3 antagonist MDL 72222, reduce type I response to a standardized mechanical stimulus in an in vitro skin preparation.

Liang He; Robert P. Tuckett; Kathleen B. English



5HT 2C receptor RNA editing in the amygdala of C57BL\\/6J, DBA\\/2J, and BALB\\/cJ mice  

Microsoft Academic Search

Post-transcriptional RNA editing of the G-protein coupled 5-hydroxytryptamine-2C (5-HT2C) receptor predicts an array of 24 receptor isoforms, some of which are characterized by reduced constitutive activity and potency to initiate intracellular signaling. The amygdala is integral to anxiety, fear, and related psychiatric diseases. Activation of 5-HT2C receptors within the amygdala is anxiogenic. Here, we describe the RNA editing profiles from

Elizabeth A. Hackler; David C. Airey; Caitlin C. Shannon; Monsheel S. Sodhi; Elaine Sanders-Bush



The nature of the binding between LSD and a 5-HT receptor  

PubMed Central

1 (+)-Lysergic acid diethylamide (LSD) mimicked 5-hydroxytryptamine (5-HT) in its ability to stimulate fluid secretion, to change transepithelial and intracellular potentials as well as to increase the cyclic 3?,5?-adenosine monophosphate (cyclic AMP) concentrations of isolated salivary glands of Calliphora. 2 Unlike 5-HT, LSD disengages slowly from the receptor and fluid secretion continues despite repeated washing. 3 Both 5-HT and tryptamine prevented LSD from acting on the glands. 4 LSD bound to the receptor was slowly displaced when glands were treated with agonists (tryptamine) or antagonists (gramine). 5 The property of LSD which permits it to function as an agonist despite remaining tightly bound to the receptor is discussed as a possible basis for its profound effects within the central nervous system.

Berridge, M.J.; Prince, W.T.



Emesis and Defecations Induced by the 5-Hydroxytryptamine (5-HT3) Receptor Anatagonist Zacopride in the Ferret.  

National Technical Information Service (NTIS)

Three antiemetic compounds (zacopride, batanopride, granisetron 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 clin...

G. L. King



Pharmacological profile of the receptors that mediate external carotid vasoconstriction by 5-HT in vagosympathectomized dogs.  

PubMed Central

1. 5-Hydroxytryptamine (5-HT) can produce vasodilatation or vasoconstriction of the canine external carotid bed depending upon the degree of carotid sympathetic tone. Hence, external carotid vasodilatation to 5-HT in dogs with intact sympathetic tone is primarily mediated by prejunctional 5-HT1-like receptors similar to the 5-HT1D subtype, which inhibit the carotid sympathetic outflow. The present investigation is devoted to the pharmacological analysis of the receptors mediating external carotid vasoconstriction by 5-HT in vagosympathectomized dogs. 2. Intracarotid (i.c.) infusions for 1 min of 5-HT (0.3, 1, 3, 10, 30 and 100 micrograms) resulted in dose-dependent decreases in both external carotid blood flow and the corresponding conductance; both mean arterial blood pressure and heart rate remained unchanged during the infusions of 5-HT. These responses to 5-HT were resistant to blockade by antagonists at 5-HT2 (ritanserin) and 5-HT3/5-HT4 (tropisetron) receptors, but were partly blocked by the 5-HT1-like and 5-HT2 receptor antagonist, methiothepin (0.3 mg kg-1); higher doses of methiothepin (1 and 3 mg kg-1) caused little, if any, further blockade. These methiothepin (3 mg kg-1)-resistant responses to 5-HT were not significantly antagonized by MDL 72222 (0.3 mg kg-1) or tropisetron (3 mg kg-1). 3. The external carotid vasoconstrictor effects of 5-HT were mimicked by the selective 5-HT1-like receptor agonist, sumatriptan (3, 10, 30 and 100 micrograms during 1 min, i.c.), which produced dose-dependent decreases in external carotid blood flow and the corresponding conductance; these effects of sumatriptan were dose-dependently antagonized by methiothepin (0.3, 1 and 3 mg kg-1), but not by 5-HT1D-like receptor blocking doses of metergoline (0.1 mg kg-1). 4. The above vasoconstrictor effects of 5-HT remained unaltered after administration of phentolamine, propranolol, atropine, hexamethonium, brompheniramine, cimetidine and haloperidol, thus excluding the involvement of alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors. Likewise, inhibition of either 5-HT-uptake (with fluoxetine) or cyclo-oxygenase (with indomethacin), depletion of biogenic amines (with reserpine) or blockade of calcium channels (with verapamil) did not modify the effects of 5-HT. 5. Taken together, the above results support our contention that the external carotid vasoconstrictor responses to 5-HT in vagosympathectomized dogs are mainly mediated by activation of sumatriptan-sensitive 5-HT1-like receptors. It must be emphasized, notwithstanding, that other mechanisms of 5-HT, including an interaction with a novel 5-HT receptor (sub)type and/or an indirect action that may lead to the release of a known (or even unknown) neurotransmitter substance cannot be categorically excluded.

Villalon, C. M.; Ramirez-San Juan, E.; Castillo, C.; Castillo, E.; Lopez-Munoz, F. J.; Terron, J. A.



Increases in aggregation by and uptake of 5-hydroxytryptamine with platelets from rabbits treated with chlorpromazine.  

PubMed Central

1 Citrated platelet-rich plasma was prepared from New Zealand white rabbits before, during and after administration of chlorpromazine (2 mg/kg) intramuscularly once daily for 3 to 4 weeks. 2 In these plasmas, the velocity of platelet aggregation by 5-hydroxytryptamine (5-HT) added at 1, 3 and 10 microM increased greatly, beginning 3 to 4 days after the start of chlorpromazine injections and lasting for a similar period after they were terminated. The increase had two maxima, the first after 6 to 10 days and the second after 17 to 24 days. Chlorpromazine treatment did not affect aggregation by adenosine diphosphate (ADP). 3 The uptake of 5-HT by rabbit platelets was very fast and linear for less than 10 s. In platelets from untreated rabbits the uptake had a Km of 0.35 +/- 0.08 microM and a Vmax of 39.8 +/- 6.1 pmol 10(-8) platelets 10(-1) (n = 5). 4 In platelets from rabbits injected with chlorpromazine (see (2) above) both kinetic constants increased significantly, the Km to 0.88 +/- 0.08 microM and the Vmax to 67.8 +/- 5.5 pmol. 10(-8) platelets. 10(-1) s (n = 9).

Baldacci, M.; Baldacci, M.; Bergel, T. D.; Born, G. V.; Hickman, M.



5-hydroxytryptamine uptake blockers attenuate the 5-hydroxytryptamine-releasing effect of 3,4-methylenedioxymethamphetamine and related agents.  


This study examined the [3H]5-HT-releasing properties of 3,4-methylenedioxymethamphetamine (MDMA) and related agents, all of which cause significant release of [3H]5-HT from rat brain synaptosomes. 5-HT uptake blockers dose dependently block MDMA-induced [3H]5-HT release. The EC50s of the uptake drugs in blocking MDMA-induced release correlate with their affinity for the 5-HT uptake site labeled by [3H]paroxetine (r = 0.98; P less than 0.01). These data demonstrate that the 5-HT uptake carrier plays a significant role in the release of 5-HT induced by MDMA and related agents. PMID:1971219

Hekmatpanah, C R; Peroutka, S J



Is the action of cisapride on the guinea-pig ileum mediated via 5-HT4 receptors?  


It has been suggested that benzamides, like cisapride, exert their effects on the guinea-pig ileum via activation of a 5-HT receptor (5-HT4 receptor?) mechanism. The aim of this study was to determine whether an how the 5-HT4 receptor (previously described in mouse colliculi neurones) is involved in the cisapride-induced effect. The effects induced by cisapride were compared with those of 5-hydroxytryptamine (5-HT) and 5-methoxytryptamine (5-MeOT) either alone or in the presence of a 5-HT4 antagonist (micromolar concentration of ICS 205-930) or a benzamide antagonist (R 50 595). As a model we used the electrically stimulated longitudinal muscle myenteric plexus preparation from the guinea-pig ileum. Cisapride (3.10(-7) M), 5-HT and a 5-HT4 receptor agonist 5-MeOT (3.10(-10)-10(-6) M) induced similar effects, i.e. enhancement of the twitch responses. After rinsing the organ baths, a second addition of the agonists resulted in a similar response. The studied agonists showed mutual desensitization. Cisapride desensitized the response induced by 5-HT or 5-MeOT, and 5-MeOT or 5-HT desensitized the effect induced by cisapride. In preparations preincubated with a 5-HT4 receptor antagonist, ICS 205-930- (3.10(-6) M) or R 50 595 (3.10(-7) M), a benzamide with a specific antagonistic action on the effect induced by 5-HT and benzamides on the guinea-pig ileum, the effects induced by cisapride, 5-HT and 5-MeOT were abolished. These results indicate that cisapride indeed exerts its effect via an agonistic action on a serotonin receptor, probably the previously described 5-HT4 receptor. PMID:1555639

Meulemans, A L; Schuurkes, J A



Does cyclic 3' ,5'-adenosine monophosphate act as second messenger in a voltage-dependent response to 5-hydroxytryptamine in Aplysia?  

PubMed Central

1 The possibility that cyclic adenosine 3',5'-monophosphate (cyclic AMP) mediates a voltage-dependent inward current elicited by 5-hydroxytryptamine (5-HT) in RB and LB cells of the abdominal ganglion of Aplysia was tested. 2 Intracellular injection of cyclic AMP elicited an inward current with a similar time course, potential dependence and ionic sensitivity as the response to 5-HT. 3 Intracellular injection of guanylyl imidodiphosphate (GMP-PNP), which activated adenylate cyclase, neither mimicked nor enhanced the 5-HT-evoked current. On the contrary, it reduced the current. 4 The phosphodiesterase inhibitors, Ro20-1724, isobutyl methylxanthine (IBMX) and theophylline, each antagonized the voltage-dependent response to 5-HT. To varying degrees they each induced an inward current. 5 The adenylate cyclase antagonist, dithiobisnitrobenzoic acic (DTNB), had no effect on the response to 5-HT when applied either intracellularly or extracellularly. Intracellular injection of the phosphodiesterase activator imidazole also had no effect. 6 Tubocurarine and neostigmine did not reduce the voltage-dependent inward current evoked by 5-HT; methysergide elicited an inward current. 7 Although the observations that cyclic AMP and 5-HT can evoke similar voltage-dependent inward currents in RB and LB neurones of Aplysia might suggest a second messenger role for the cyclic nucleotide, the pharmacological data are inconsistent with this hypothesis.

Pellmar, T. C.



Platelet met-enkephalin immunoreactivity and 5-hydroxytryptamine concentrations in migraine patients: effects of 5-hydroxytryptophan, amitriptyline and chlorimipramine treatment.  


In thirty patients with common migraine the platelet concentrations of met-enkephalin immunoreactivity (ME) (76 +/- 9 pg/mg protein) were similar to those in 23 healthy volunteers (77 +/- 5), suggesting that there is no alteration in the ME pool in this biochemical compartment in migraine. Chronic treatment (4 weeks) with drugs that interfere with 5-hydroxytryptamine (5-HT) synthesis or uptake induced the expected changes in platelet 5-HT levels, i.e. a rise following administration of the 5-HT precursor 5-hydroxytryptophan (daily dose: 300-500 mg, n = 9) and a decrease after amine uptake inhibition by amitryptyline (30-75 mg, n = 7) and even more by chlorimipramine (30-50 mg, n = 9). Platelet ME concentrations rose by up to approximately 90% over the basal values after either 5-hydroxytryptophan (significantly from week 2) or amitriptyline (at week 2) and were unchanged after chlorimipramine, indicating that 5-HT and ME concentrations in platelets can vary independently. The high platelet ME levels following 5-hydroxytryptophan and amitriptyline cannot be explained at present. They might be due either to increased ME synthesis, possibly in the megakaryocyte, or to decreased utilization by platelets or both. PMID:6610476

Boiardi, A; Picotti, G B; Di Giulio, A M; Bussone, G; Galva, M D; La Mantia, L; Mantegazza, P



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


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

Goyal, Rajendra N; Agrawal, Bharati



Octopamine and 5-hydroxytryptamine mediate hemocytic phagocytosis and nodule formation via eicosanoids in the beet armyworm, Spodoptera exigua.  


Octopamine and 5-hydroxytryptamine (5-HT) have been known to mediate cellular immune responses, such as hemocytic phagocytosis and nodule formation, during bacterial invasion in some insects. In addition, eicosanoids also mediate these cellular immune reactions in various insects, resulting in clearing the bacteria circulating in the hemolymph. This study investigated a hypothesis on signal cross-talk between both types of immune mediators in the beet armyworm, Spodoptera exigua, which had been observed in the effect of eicosanoids on mediating the cellular immune responses. In response to bacterial infection, octopamine or 5-HT markedly enhanced both hemocytic phagocytosis and nodule formation in S. exigua larvae. Their specific antagonists, phentolamine (an octopamine antagonist) or ketanserin (a 5-HT antagonist) suppressed both cellular immune responses of S. exigua. These effects of biogenic monoamines on the immune mediation were expressed through eicosanoids because the inhibitory effects of both antagonists were rescued by the addition of arachidonic acid (a precursor of eicosanoid biosynthesis). Furthermore, the stimulatory effects of both monoamines on the cellular immune responses were significantly suppressed by different inhibitors acting at their specific levels of eicosanoid biosynthesis. Taken together, this study suggests that octopamine and 5-HT can mediate hemocytic phagocytosis and nodule formation through a downstream signal pathway relayed by eicosanoids in S. exigua. PMID:19140126

Kim, Geun Seob; Nalini, Madanagopal; Kim, Yonggyun; Lee, Dae-Weon



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


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

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



Role of prucalopride, a serotonin (5-HT4) receptor agonist, for the treatment of chronic constipation  

PubMed Central

Constipation affects up to a quarter of the population in developed countries and is associated with poor quality of life and significant economic burden. Many patients with chronic constipation are dissatisfied with current therapy due to lack of long-term efficacy or side effects. Previous nonselective 5-hydroxytryptamine receptor 4 (5-HT4) agonists have been associated with significant interactions with other receptors (5-HT1B, 5-HT1D, and 5-HT2B for tegaserod; hERG for cisapride), leading to adverse cardiovascular events resulting in withdrawal of these drugs from the market. Prucalopride is a novel gastrointestinal prokinetic agent. It acts as a high affinity, highly-selective 5-HT4 agonist. Its efficacy in patients with chronic constipation has been demonstrated in several phase II and phase III clinical trials showing significant improvements in bowel transit, bowel function, gastrointestinal symptoms, and quality of life, with benefit maintained for up to 24 months in open label, multicenter, follow-up studies. Prucalopride’s high selectivity for the 5-HT4 receptor may explain its favorable safety and tolerability profiles, even in elderly subjects with stable cardiovascular disease. Prucalopride is a well tolerated and efficacious prokinetic medication that should enhance the treatment of chronic constipation unresponsive to first-line treatments.

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



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


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

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



Novel 5-HT2-like receptor mediates neurogenic relaxation of the guinea-pig proximal colon.  


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 > or = alpha-methyl-5-HT (partial agonist) > tryptamine (partial agonist). 5-Hydroxytryptophan, 2-methyl-5-HT and N-methyltryptamine were virtually inactive as agonists. The curve to 5-HT was not affected by pargyline, citalopram, phentolamine, or by the 5-HT4 receptor antagonists 2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205-557) and (1-butyl-4-piperidinylmethyl)-8-amino-7-chloro-1,4-benzodioxan+ ++-5-carboxylate (SB 204070). 8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), 5-methoxy-3[1,2,3,6-tetrahydroxypyridin-4-yl]-1H-indole (RU 24969), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), 1-(3-chlorophenyl)piperazine (mCPP), 1-(m-trifluoromethylphenyl)-piperazine (TFMPP), flesinoxan, sumatriptan and 6-chloro-2-(piperazinyl)-pyrazine (MK212) were inactive as 5-HT receptor agonists. The first phase of the curve to 5-HT was inhibited by: metergoline (pA2 = 8.8 +/- 0.3, against 5-methoxytryptamine 9.3 +/- 0.3), methysergide (non-surmountable), methiothepin (non-surmountable), spiroxatrine (non-surmountable), MK212 (non-surmountable), mesulergine (7.8 +/- 0.3), mCPP (7.1 +/- 0.1), mianserin (7.0 +/- 0.4), ritanserin (8.9 +/- 0.2), rauwolscine (7.0 +/- 0.2), yohimbine (6.2 +/- 0.2), 1-(1-naphthyl)-piperazine (7.7 +/- 0.2) and RU 24969 (6.4 +/- 0.1), but not by 1-(2-methoxyphenyl)4-[4-(2-phthalimidobtyl]-piperazine (NAN-190), spiperone, sumatriptan, 8-OH-DPAT and flesinoxan. It is suggested that the 5-HT receptor under study could be considered an unknown 5-HT2-like receptor. PMID:7556392

Briejer, M R; Akkermans, L M; Lefebvre, R A; Schuurkes, J A



Actions of the 5-hydroxytryptamine 1 receptor agonist sumatriptan on interdigestive gastrointestinal motility in man  

PubMed Central

Background—Pharmacological studies of the enteric nervous system have shown the presence of several subtypes of 5-hydroxytryptamine (5HT) receptor, which might be involved in control of the migrating motor complex. ?Aims—To study the effect of sumatriptan, an agonist of enteric neuronal 5HT1P receptors, on interdigestive motility in man. ?Subjects and methods—In 12 healthy subjects, interdigestive motility was recorded manometrically in the upper gastrointestinal tract. In seven subjects blood samples were drawn every 15 minutes for radioimmunoassay of motilin and somatostatin. After two phase 3s of the migrating motor complex, 6 mg of sumatriptan was administered subcutaneously. Recording continued until two more phase 3s had occurred. ?Results—Sumatriptan induced a premature phase 3 in the jejunum after a median of 10 (8) minutes. The duration of the migrating motor complex cycle was shortened at the expense of phase 2. After sumatriptan, plasma somatostatin concentrations were reduced and gastric phase 3s were suppressed, although median motilin concentrations and the occurrence of plasma motilin peaks were not affected. Phase 3s of the migrating motor complex preceding sumatriptan were associated with motilin peaks, while phase 3s after sumatriptan were not. Furthermore, pretreatment with sumatriptan prevented the induction of a gastric phase 3 by the motilin agonist erythromycin. ?Conclusions—Administration of the 5HT1P receptor agonist sumatriptan induces a premature intestinal phase 3, suppresses gastric phase 3s, prevents induct- ion of a gastric phase 3 by erythromycin, and reduces plasma somatostatin concentrations. ?? Keywords: migrating motor complex; motilin; somatostatin; erythromycin; enteric nervous system

Tack, J; Coulie, B; Wilmer, A; Peeters, T; Janssens, J



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

PubMed Central

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

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



The role of noradrenaline and 5-hydroxytryptamine in yohimbine-induced increases in alcohol-seeking in rats  

PubMed Central

Rationale and objectives We previously showed that systemic administration of the prototypical alpha-2 noradrenaline (NA) receptor antagonist yohimbine increases alcohol self-administration and reinstatement. Yohimbine also acts as an agonist of 5-hydroxytryptamine (5-HT) 5-HT1A receptors, which have been shown to be involved in alcohol seeking. Here, we determined the contributions of the alpha-2 and 5-HT1A properties of yohimbine to its effects on alcohol seeking. Methods The effects of lesions of the dorsal or ventral NA bundles with 6-OHDA on yohimbine-induced alcohol self-administration were first determined in male Wistar rats trained to self-administer alcohol (12% w/v, 0.19 ml per alcohol delivery), and then on reinstatement induced by yohimbine after extinction of the operant response. It was then determined whether the selective alpha-2 antagonist RS-79948 (0.1, 0.2, 0.4 mg/kg) would mimic the effects of yohimbine on self-administration and reinstatement. The effects of the alpha-2 receptor agonist clonidine, or the 5-HT1A antagonist WAY 100,635 were then determined on yohimbine-induced self-administration and reinstatement. Results Lesions of the NA systems did not affect yohimbine-induced alcohol self-administration or reinstatement, and RS-79948 did not mimic the effects of yohimbine. Clonidine did not significantly affect increased alcohol self-administration induced by yohimbine, but did attenuate its effects on reinstatement. Blockade of 5-HT1A receptors reduced both yohimbine-induced self-administration and reinstatement. Conclusions These results suggest that alpha-2 antagonist properties of yohimbine may play a role in the reinstatement of alcohol-seeking, but not self-administration. On the other hand, yohimbine's actions on 5-HT1A receptors contribute to its effects on both alcohol self-administration and reinstatement.

Le, Anh Dzung; Funk, Douglas; Harding, Stephen; Juzytsch, Walter; Fletcher, Paul J.



In the rat forced swimming test, chronic but not subacute administration of dual 5HT\\/NA antidepressant treatments may produce greater effects than selective drugs  

Microsoft Academic Search

The rat forced swimming test (FST) distinguishes selective serotonin (5-HT) and selective noradrenaline (NA) reuptake-inhibitors, which respectively increase swimming and climbing behaviours. However, NA-system-mediated inhibition of 5-HT-induced swimming prevents dual 5-HT\\/NA reuptake-inhibition to produce concurrently climbing with swimming. Since adaptative neurochemical processes occur in the treatment of depression, we examined the influence of long-term antidepressant treatment on these interactions. Methods:

Jean-Philippe Rénéric; Manuel Bouvard; Luis Stinus



Facilitation of acetylcholine release in rat frontal cortex by indeloxazine hydrochloride: involvement of endogenous serotonin and 5HT4 receptors  

Microsoft Academic Search

Effects of indeloxazine hydrochloride, an inhibitor of serotonin (5-HT) and norepinephrine (NE) reuptake with a facilitatory\\u000a effect on 5-HT release, on acetylcholine (ACh) output in frontal cortex of conscious rats were characterized using an in vivo\\u000a microdialysis technique. Systemic administration of indeloxazine (3 and 10 mg\\/kg, i.p.) increased ACh and 5-HT output in a\\u000a dose-dependent manner. Depletion of endogenous monoamines

Takashi Yamaguchi; Masanori Suzuki; Minoru Yamamoto



Implication of 5HT 2 receptor subtypes in the mechanism of action of antidepressants in the four plates test  

Microsoft Academic Search

Rationale: Theselectiveserotoninreuptakeinhib- itors (SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs) increase synaptic levels of serotonin, leading to an increased activation of a multitude of specific postsynaptic 5-HT receptors. However, it is not yet known which 5-HT receptor subtypes mediate the therapeutic ef- fects ofantidepressants. Methods: Theeffectsof the SSRI, paroxetine and the SNRI, venlafaxine were evaluated in the mouse

Bríd Áine Nic Dhonnchadha; Nadège Ripoll; Florence Clénet; Martine Hascoët; Michel Bourin



The role of nitric oxide (NO) in 5-HT-induced relaxations of the guinea-pig stomach.  


In a previous study we showed that the relaxations induced after vagal stimulation of the guinea-pig stomach are mediated via nitric oxide (NO) or a NO-related substance. Intra-arterial injection (i.a.) of 5-hydroxytryptamine (5-HT) also induced relaxations in the guinea-pig stomach. Since it has been shown that in the guinea-pig colon 5-HT-induced relaxations are mediated via NO the aim of this study was to establish whether NO is involved in the 5-HT-induced relaxations in the guinea-pig stomach. Intra-arterial injection of 5-HT induced dose-dependent relaxations of the stomach. Since atropine and alpha- and beta-adrenoceptor blocking agents did not influence the relaxation and since tetrodotoxin (TTX) blocked the relaxations, this effect is mediated via NANC-neurons. Administration of a NO-synthase-inhibitor NG-nitro-L-arginine (L-NNA) concentration-dependently reduced the 5-HT-induced relaxations. Haemoglobin (a NO-scavanger) did not affect the relaxations to 5-HT, while addition of methylene blue, an inhibitor of soluble guanylate cyclase, reduced the relaxations by 50%. Addition of an opioid receptor agonist (loperamide), a 5-HT1 antagonist (methiothepin or metergoline) or a 5-HT4 receptor agonist (cisapride) or -antagonist (tropisetron in micromolar concentrations) inhibited the 5-HT-induced relaxations. Neither the 5-HT4 receptor agonist renzapride, nor the novel 5-HT4 receptor antagonist SDZ 205-557, affected the relaxations to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7506394

Meulemans, A L; Helsen, L F; Schuurkes, J A



A conserved cysteine residue in the third transmembrane domain is essential for homomeric 5-HT3 receptor function  

PubMed Central

The cysteine (Cys) residue at position 312 in the third transmembrane domain (M3) is conserved among 5-hydroxytryptamine type 3 (5-HT3) receptor subunits and many other subunits of the nicotinic acetylcholine (nACh) related Cys-loop receptor family, including most of the ?-aminobutyric acid type A (GABAA) and glycine receptor subunits. To elucidate a possible role for the Cys-312 in human 5-HT3A receptors, we replaced it with alanine and expressed the 5-HT3A(C312A) mutant in HEK293 cells. The mutation resulted in an absence of 5-HT-induced whole-cell current without reducing homopentamer formation, surface expression or 5-HT binding. The 5-HT3A(C312A) mutant, when co-expressed with the wild-type 5-HT3A subunit, did not affect functional expression of receptors, suggesting that the mutant is not dominant negative. Interestingly, co-expression of 5-HT3A(C312A) with 5-HT3B led to surface expression of heteropentamers that mediated small 5-HT responses. This suggests that the Cys-312 is essential for homomeric but not heteromeric receptor gating. To further investigate the relationship between residue 312 and gating we replaced it with amino acids located at the equivalent position within other Cys-loop subunits that are either capable or incapable of forming functional homopentamers. Replacement of 5-HT3A Cys-312 by Gly or Leu (equivalent residues in the nACh receptor ? and ? subunits) abolished and severely attenuated function, respectively, whereas replacement by Thr or Ser (equivalent residues in nACh receptor ?7 and GABAA? subunits) supported robust function. Thus, 5-HT3A residue 312 and equivalent polar residues in the M3 of other Cys-loop subunits are essential determinants of homopentameric gating.

Wu, Dai-Fei; Othman, Nidaa A; Sharp, Douglas; Mahendra, Arjun; Deeb, Tarek Z; Hales, Tim G



Protective effects of 5HT 1A receptor agonists against neuronal damage demonstrated in vivo and in vitro  

Microsoft Academic Search

Summary  The aim of the present study was to evaluate the neuroprotective effect of the 5-hydroxytryptamine1A (5-HT1A) agnists, CM 57493 and urapidil, in vivo and in vitro, respectively. In vivo permanent occlusion of the middle cerebral artery (MCA) was performed in male Wistar rats. Forty-eight hours after electrocoagulation of the MCA and infarct volume was determined. Pretreatment of the rat with

B. Peruche; C. Backhauß; J. H. M. Prehn; J. Krieglstein



5-hydroxytryptamine1A-like receptor activation in the bed nucleus of the stria terminalis: electrophysiological and behavioral studies.  


The anteriorlateral bed nucleus of the stria terminalis (BNST AL) and the serotonergic system are believed to modulate behavioral responses to stressful and/or anxiogenic stimuli. However, although the BNST AL receives heavy serotonergic innervation, the functional significance of this input is not known. Data obtained from in vitro whole-cell patch clamp recording in the rat BNST slice show that exogenous application of 5-hydroxytryptamine (5-HT) evoked a heterogeneous response in BNST AL neurons. The principal action of 5-HT in this region was inhibitory, evoking a membrane hyperpolarization (5-HTHyp) and a concomitant reduction in input resistance in the majority of neurons tested. The broad-spectrum 5-HT1 agonist, 5-carboxamindotryptamine (5-CT), but not R(+/-)8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT), mimicked the 5-HTHyp response in the BNST. Moreover, the outward current mediating 5-HTHyp was inwardly rectifying and sensitive to the G protein activated inwardly rectifying K+ (G IRK) channel blocker, tertiapin-Q. In the CNS 5-HT1A receptors are thought to couple to GIRK channels, suggesting that 5-HTHyp in BNST AL neurons was mediated by activation of 5-HT1A-like receptors. This was confirmed by the blockade of both 5-HTHyp and 5-CTHyp by the specific 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY100635 200nM). Furthermore, an in vivo examination of the functional consequences of 5-HT1A-like induced inhibition of BNST neurons revealed that infusion of 5-CT into the BNST significantly reduced the acoustic startle response, without affecting the general motor activity of the animals. These data point to the possibility that 5-HT1A mediated inhibition of the BNST AL could contribute to an anxiolytic action. Hence, we propose that in response to stressful stimuli, enhanced levels of 5-HT in the BNST AL plays a critical homeostatic role in feedback inhibition of the anxiogenic response to these stimuli. PMID:15381287

Levita, L; Hammack, S E; Mania, I; Li, X-Y; Davis, M; Rainnie, D G



The role of 5-hydroxytryptamine 7 receptors in the phencyclidine-induced novel object recognition deficit in rats.  


The role of 5-hydroxytryptamine (serotonin) (5-HT)(7) receptor antagonism in the actions of atypical antipsychotic drugs (APDs), e.g., amisulpride, clozapine, and lurasidone, if any, is uncertain. We examined the ability of 5-HT(7) receptor antagonism alone and as a component of amisulpride and lurasidone to reverse deficits in rat novel object recognition (NOR) produced by subchronic treatment with the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP), and we examined the ability of supplemental 5-HT(7) antagonism to augment the inability of sulpiride, haloperidol, and (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), a metabotropic glutamate receptor (mGluR) 2/3 agonist, which lack 5-HT(7) antagonism, to reverse the NOR deficit. The 5-HT(7) receptor antagonist, (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine (SB269970) (0.1-1 mg/kg) dose-dependently reversed PCP-induced NOR deficits. In addition, the ability of lurasidone (0.1 mg/kg) and amisulpride (3 mg/kg) to reverse this deficit was blocked by cotreatment with the 5-HT(7) receptor agonist (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS19) (5-10 mg/kg), which did not affect NOR in naive rats. Sulpiride, a less potent 5-HT(7) antagonist than amisulpride, did not itself improve the PCP-induced NOR deficit. However, a subeffective dose of SB269970 (0.1 mg/kg) in combination with subeffective doses of lurasidone (0.03 mg/kg), amisulpride (1 mg/kg), or sulpiride (20 mg/kg), also reversed the PCP-induced NOR deficit. Pimavanserin, a 5-HT(2A) inverse agonist, LY379268, and haloperidol did not potentiate the ability of subeffective SB269970 to improve the NOR deficit. Furthermore, the mGluR2/3 antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid (LY341495), which blocks the effect of clozapine to reverse the NOR deficit, did not block the SB269970-induced amelioration of the NOR deficit. These results suggest 5-HT(7) antagonism may contribute to the efficacy of some atypical APDs in the treatment of cognitive impairment in schizophrenia and may itself have some benefit in this regard. PMID:21558435

Horiguchi, M; Huang, M; Meltzer, H Y



Evidence for an involvement of 5HT1B receptors in the inhibition of male rat ejaculatory behavior produced by 5HTP  

Microsoft Academic Search

The administration of the 5-hydroxytryptamine (5-HT) precursor 5hydroxytryptophan (5-HTP) (25mg\\/kg IP), in combination with\\u000a an inhibitor of peripheral 5-HTP decarboxylase, produced a dose-dependent increase in the ejaculation latency of male rats,\\u000a and this effect was enhanced by additional treatment with the 5-HT1 receptor antagonist (?)-pindolol (2mg\\/kg SC). The 5-HT2A\\/C receptor agonist ()1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125–0.5mg\\/kg SC) did not by itself affect

S. Ahlenius; Knut Larsson



The behavioural responses to 8-OH-DPAT, ipsapirone and the novel 5HT1A receptor agonist Bay Vq 7813 in the pig  

Microsoft Academic Search

In pigs, behavioural responses were examined after administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a full agonist at 5-hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype, and the pyrimidinylpiperazine derivatives ipsapirone and Bay Vq 7813 (2-[4-(2-pyrimidinyl)-1-piperazinylpropyl]-1,2-benzisothiazol-3(2H)one-1,1-dioxide), which act as partial agonists at 5-HT1A receptors. The most prominent behavioural response examined after 8-OH-DPAT, 0.5 mg\\/kg i. m., ipsapirone, 2–5 mg\\/kg i.m., and Bay Vq 7813,

Wolfgang Löscher; Ulrike Witte; Gabriele Fredow; Jörg Traber; Thomas Glaser



Time trial performance in normal and high ambient temperature: is there a role for 5HT?  

Microsoft Academic Search

The original central fatigue hypothesis suggested that fatigue during prolonged exercise might be due to higher 5-HT activity.\\u000a Therefore, we examined the effects of acute administration of a selective 5-HT reuptake inhibitor (SSRI) on performance and\\u000a thermoregulation. Eleven healthy trained male cyclists completed four experimental trials (two in 18°C, two in 30°C) in a\\u000a double-blind randomised crossover design. Subjects ingested

Bart Roelands; Maaike Goekint; Luk Buyse; Frank Pauwels; Guy De Schutter; Francesca Piacentini; Hiroshi Hasegawa; Phil Watson; Romain Meeusen



Activation of 5-HT3 receptors leads to altered responses 6 months after MDMA treatment.  


The recreational drug "Ecstasy" [3,4-methylenedioxymethamphetamine (MDMA)] has a well-characterised neurotoxic effect on the 5-hydroxytryptamine (5-HT) neurons in animals. Despite intensive studies, the long-term functional consequencies of the 5-HT neurodegeneration remains elusive. The aim of this study was to investigate whether any alteration of 5-hydroxytryptamine-3 (5-HT(3)) receptor functions on the sleep-wake cycle, motor activity, and quantitative EEG could be detected 6 months after a single dose of 15 mg/kg of MDMA. The selective 5-HT(3) receptor agonist m-chlorophenylbiguanide (mCPBG; 1 mg/kg, i.p.) or vehicle was administered to freely moving rats pre-treated with MDMA (15 mg/kg, i.p.) or vehicle 6 months earlier. Polysomnographic and motor activity recordings were performed. Active wake (AW), passive wake (PW), light slow wave sleep (SWS-1), deep slow wave sleep (SWS-2), and paradoxical sleep were classified. In addition, EEG power spectra were calculated for the second hour after mCPBG treatment for each stage. AW increased and SWS-1 decreased in the second hour after mCPBG treatment in control animals. mCPBG caused significant changes in the EEG power in states with cortical activation (AW, PW, paradoxical sleep). In addition, mCPBG had a biphasic effect on hippocampal theta power in AW with a decrease in 7 Hz and a stage-selective increase in the upper range (8-9 Hz). Effects of mCPBG on the time spent in AW and SWS-1 were eliminated or reduced in MDMA-treated animals. In addition, mCPBG did not increase the upper theta power of AW in rats pre-treated with MDMA. These data suggest long-term changes in 5-HT(3) receptor function after MDMA. PMID:20052506

Gyongyosi, Norbert; Balogh, Brigitta; Katai, Zita; Molnar, Eszter; Laufer, Rudolf; Tekes, Kornelia; Bagdy, Gyorgy



Evidence that the accumulation of 5-hydroxytryptamine in the liver but not in the brain may cause the hypoglycaemia induced by 5-hydroxytryptophan.  

PubMed Central

Experiments were undertaken to determine whether the site of the hypoglycaemic action of 5-hydroxytryptophan (5-HTP), a direct precursor of 5-hydroxytryptamine (5-HT), was in the central nervous system or in the liver. The fall in blood glucose followed the rapid increase in the amount of 5-HT both in the brain and liver after 5-HTP injection into pargyline-treated and non-treated mice. Carbidopa, an inhibitor of peripheral aromatic amino acid decarboxylase, prevented the elevation of 5-HT levels in the liver of both pargyline-treated and non-treated mice. In contrast, carbidopa did not prevent but rather enhanced the elevation of 5-HT levels in the brain of both groups of mice. Corresponding to the prevention of 5-HT elevation in the liver, the fall in blood glucose was prevented by carbidopa. These results support the idea that the accumulation of 5-HT in the liver but not in the brain causes the hypoglycaemia induced by 5-HTP.

Endo, Y.



A comparison of 5-hydroxytryptamine receptors mediating contraction in rabbit aorta and dog saphenous vein: evidence for different receptor types obtained by use of selective agonists and antagonists.  

PubMed Central

Using recently available selective agonists and antagonists we have examined further our postulate (Apperley et al., 1980) that 5-hydroxytryptamine (5-HT) mediates contraction of dog saphenous vein via a different 5-HT receptor type from that in the rabbit aorta. In the rabbit isolated aorta, ketanserin and spiperone were potent, specific, competitively-acting antagonists of the contractile effects of 5-HT. In contrast, in the dog isolated saphenous vein neither ketanserin nor spiperone caused any rightward displacement of concentration-response curves to 5-HT although the maximum response was reduced by about 10%. In the rabbit aorta 5-carboxamidotryptamine (5-CONH2-T) was a weak agonist whilst the 5-N,N-dimethyl and 5-N-ethyl derivatives were even weaker or inactive. The contractile effect of 5-CONH2-T in the rabbit aorta was potently and competitively antagonized by ketanserin. In contrast, in the dog saphenous vein 5-CONH2-T and its 5-N,N-dimethyl and 5-N-ethyl derivatives were all potent agonists. The contractile effect of 5-CONH2-T was not markedly affected by ketanserin. The profile of action of ketanserin and spiperone in the rabbit aorta is consistent with the view that 5-HT2 receptors mediate contraction in this preparation. However, the 5-HT receptor mediating contraction in the dog saphenous vein appears to be '5-HT1-like', sharing a number of characteristics with the 5-HT1 recognition site identified from [3H]-5-HT ligand binding studies in brain tissue.

Feniuk, W.; Humphrey, P. P.; Perren, M. J.; Watts, A. D.



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

PubMed Central

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

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



Studies on the role of dopamine in the degeneration of 5-HT nerve endings in the brain of Dark Agouti rats following 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') administration.  


1. We investigated whether dopamine plays a role in the neurodegeneration of 5-hydroxytryptamine (5-HT) nerve endings occurring in Dark Agouti rat brain after 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') administration. 2. Haloperidol (2 mg kg(-1) i.p.) injected 5 min prior and 55 min post MDMA (15 mg kg(-1) i.p.) abolished the acute MDMA-induced hyperthermia and attenuated the neurotoxic loss of 5-HT 7 days later. When the rectal temperature of MDMA + haloperidol treated rats was kept elevated, this protective effect was marginal. 3. MDMA (15 mg kg(-1)) increased the dopamine concentration in the dialysate from a striatal microdialysis probe by 800%. L-DOPA (25 mg kg(-1) i.p., plus benserazide, 6.25 mg kg(-1) i.p.) injected 2 h after MDMA (15 mg kg(-1)) enhanced the increase in dopamine in the dialysate, but subsequent neurodegeneration was unaltered. L-DOPA (25 mg kg(-1)) injected before a sub-toxic dose of MDMA (5 mg kg(-1)) failed to induce neurodegeneration. 4. The MDMA-induced increase in free radical formation in the hippocampus (indicated by increased 2,3- and 2,5-dihydroxybenzoic acid in a microdialysis probe perfused with salicylic acid) was unaltered by L-DOPA. 5. The neuroprotective drug clomethiazole (50 mg kg(-1) i.p.) did not influence the MDMA-induced increase in extracellular dopamine. 6. These data suggest that previous observations on the protective effect of haloperidol and potentiating effect of L-DOPA on MDMA-induced neurodegeneration may have resulted from effects on MDMA-induced hyperthermia. 7. The increased extracellular dopamine concentration following MDMA may result from effects of MDMA on dopamine re-uptake, monoamine oxidase and 5-HT release rather than an 'amphetamine-like' action on dopamine release, thus explaining why the drug does not induce degeneration of dopamine nerve endings. PMID:10193771

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



5Hydroxytryptamine induces endothelium-independent relaxations of sheep pulmonary vein: role of cyclic nucleotide  

Microsoft Academic Search

5-Hydroxytryptamine produced concentration-dependent relaxations in isolated sheep pulmonary vein, which were insensitive to removal of the endothelium. 5-Hydroxytryptamine stimulated concentration-dependent increases of cyclic AMP levels in the pulmonary vein, and there was a significant linear correlation between relaxations elicited by 5-hydroxytryptamine and tissue cyclic AMP formations. The soluble guanylate cyclase inhibitor methylene blue (10 ?M) failed to block 5-hydroxytryptamine-induced relaxations.

Lubo Zhang; Donald C. Dyer; Ronald R. Fiscus; Zoran Grujic; Xian Wang



Byssinosis: Release of prostaglandins, thromboxane, and 5-hydroxytryptamine in bronchopulmonary lavage fluid after inhalation of cotton dust extracts.  

PubMed Central

New Zealand White rabbits were exposed intratracheally to aerosolized cotton dust extract (CDE) for 5 minutes of tidal breathing and lavaged 15 minutes 1, 4, and 6 hours after exposure. Bronchoalveolar lavage cells were counted, and the number of macrophages and polymorphonuclear leukocytes (PMNs) was determined. Cell recruitment, which began 1 hour after exposure to CDE and plateaued at 6 hours, consisted of both mononuclear cells and PMNs. Lavage fluid was analyzed for concentrations of prostaglandin F2 alpha (PGF2 alpha), prostaglandin E1 and E2 (PGE), thromboxane B2 (TxB2), and 5-hydroxytryptamine (5-HT). PGF2 alpha, PGE, TxB2, and 5-HT were maximally increased in the lavage 4 hours after exposure to CDE. This is the first study to demonstrate the in vivo release of arachidonic acid metabolites and 5-HT in the lung in response to CDE inhalation. This study also demonstrates that maximum mediator release occurs at 4 hours after exposure to aerosolized CDE. These findings strongly suggest that arachidonic acid metabolites are available to mediate either totally or partially the pathogenic mechanism(s) of bronchoconstriction seen in the acute byssinotic reaction of man.

Mundie, T. G.; Whitener, C.; Ainsworth, S. K.



Differential involvement of 5-HT(1A) and 5-HT(1B/1D) receptors in human interferon-alpha-induced immobility in the mouse forced swimming test.  


Although Interferon-alpha (IFN-alpha, CAS 9008-11-1) is a powerful drug in treating several viral infections and certain tumors, a considerable amount of neuropsychiatric side-effects such as depression and anxiety are an unavoidable consequence. Combination with the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine (CAS 56296-78-7) significantly improved the situation. However, the potential 5-HT(1A) receptor- and 5-HT(1B) receptor-signals involved in the antidepressant effects are still unclear. The effects of 5-HT(1A) receptor- and 5-HT(1B) receptor signals were analyzed by using the mouse forced swimming test (FST), a predictive test of antidepressant-like action. The present results indicated that (1) fluoxetine (administrated intragastrically, 30 mg/kg; not subactive dose: 15 mg/kg) significantly reduced IFN-alpha-induced increase of the immobility time in the forced swimming test; (2) 5-HT(1A) receptor- and 5-HT(1B) receptor ligands alone or in combination had no effects on IFN-alpha-induced increase of the immobility time in the FST; (3) surprisingly, WAY 100635 (5-HT(1A) receptor antagonist, 634908-75-1) and 8-OH-DPAT(5-HT(1A) receptor agonist, CAS 78950-78-4) markedly enhanced the antidepressant effect of fluoxetine at the subactive dose (15 mg/kg, i. g.) on the IFN-alpha-treated mice in the FST. Further investigations showed that fluoxetine combined with WAY 100635 and 8-OH-DPAT failed to produce antidepressant effects in the FST. (4) Co-application of CGS 12066A (5-HT(1B) receptor agonist, CAS 109028-09-3) or GR 127935 (5-HT(1B/1D) receptor antagonist, CAS 148642-42-6) with fluoxetine had no synergistic effects on the IFN-alpha-induced increase of immobility time in FST. (5) Interestingly, co-administration of GR 127935, WAY 100635 and fluoxetine significantly reduced the IFN-alpha-induced increase in immobility time of FST, being more effective than co-administration of WAY 100635 and fluoxetine. All results suggest that (1) compared to the 5-HT(1B) receptor, the 5-HT(1A) receptor signal plays the dominant role in improving the anti-immobility effect of fluoxetine in the IFN-alpha-induced depression; (2) combination of the 5-HT(1A) antagonist with subactive fluoxetine can be helpful in IFN-alpha-induced depression treatment. PMID:20422941

Zhang, Hongmei; Wang, Wei; Jiang, Zhenzhou; Shang, Jing; Zhang, Luyong



Towards metabolically stable 5-HT7 receptor ligands: a study on 1-arylpiperazine derivatives and related isosters.  


Serotonin 7 (5-hydroxytryptamine7 or 5-HT7) is the most recently identified serotonin receptor. It is involved in mood disorders and is studied as a target for antidepressants. Here, we report on the structural manipulation of the 5-HT7 receptor ligand 4-[2-(3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)piperazine (1a) aimed at obtaining 5-HT7 receptor ligands endowed with good in vitro metabolic stability. A set of N-[3-methoxyphenyl)ethyl-substituted] 1-arylpiperazine, 4-arylpiperidine and 1-aryl-4-aminopiperidine was synthesized and tested in radioligand binding assays at human cloned 5-HT7 and 5-HT1A receptors. In vitro metabolic stability of the target compounds was assessed after incubation with rat hepatic S9 microsomal fraction. Among the new compounds, 1-(2-biphenyl)-4-[2-(3-methoxyphenyl)ethyl]piperazine (1d) and 4-(2-biphenyl)-1-[2-(3-methoxyphenyl)ethyl]piperidine (2d) showed a good compromise between affinity at 5-HT7 receptor (K i = 7.5 nM and 13 nM, respectively) and in vitro metabolic stability (26 and 65 % recovery of parent compound, respectively) but were poorly selective over 5-HT1A receptor. PMID:23571499

Lacivita, Enza; De Giorgio, Paola; Patarnello, Daniela; Niso, Mauro; Colabufo, Nicola A; Berardi, Francesco; Perrone, Roberto; Satala, Grzegorz; Duszynska, Beata; Bojarski, Andrzej J; Leopoldo, Marcello



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

PubMed Central

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

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



Morphine desensitization, internalization, and down-regulation of the mu opioid receptor is facilitated by serotonin 5-hydroxytryptamine2A receptor coactivation.  


Analysis of the distribution of mRNA encoding the serotonin (5-hydroxytryptamine) 5-HT(2A) receptor and the mu opioid peptide receptor in rat brain demonstrated their coexpression in neurons in several distinct regions. These regions included the periaqueductal gray, an area that plays an important role in morphine-induced analgesia but also in the development of tolerance to morphine. To explore potential cross-regulation between these G protein-coupled receptors, the human mu opioid peptide receptor was expressed stably and constitutively in Flp-In T-REx human embryonic kidney 293 cells that harbored the human 5-HT(2A) receptor at the inducible Flp-In locus. In the absence of the 5-HT(2A) receptor, pretreatment with the enkephalin agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin but not with the alkaloid agonist morphine produced desensitization, internalization, and down-regulation of the mu opioid peptide receptor. Induction of 5-HT(2A) receptor expression in these cells resulted in up-regulation of mu opioid peptide receptor levels that was blocked by both a 5-HT(2A) receptor inverse agonist and selective inhibition of signaling via Galpha(q)/Galpha(11) G proteins. After induction of the 5-HT(2A) receptor, coaddition of 5-HT with morphine now also resulted in desensitization, receptor internalization, and down-regulation of the mu opioid peptide receptor. It has been argued that enhancement of mu opioid peptide receptor internalization in response to morphine would limit the development of tolerance without limiting analgesia. These data suggest that selective activation of the 5-HT(2A) receptor in concert with treatment with morphine might achieve this aim. PMID:18703670

Lopez-Gimenez, Juan F; Vilaró, M Teresa; Milligan, Graeme



5-Hydroxytryptamine and pain modulation in man: a clinical pharmacological approach with tryptophan and parachlorophenylalanine.  


Monoamines are involved in the central nervous assimilation and modulation of the pain flow. According to a personal hypothesis, a disorder of this biochemical control (in particular a precariousness of brain 5-hydroxytryptamine turnover), is the basic mechanism of some painful conditions, such as migraine and other essential headaches. Acute (infusion) and chronic (ingestion) administration of tryptophan to migraine-headache sufferers improved the clinical course significantly in respect to placebo. Few patients with untractable pain from disseminated cancer received daily infusion of tryptophan and ingested a few gr of this amnioacid: improvement of pain and reduction of morphine necessity was observed. Parachlorophenylalanine chronic administration in migraine-headache sufferers lowered the pain threshold so far as to provoke (in 20% of cases) spontaneous pains in the trunk, legs and arms. This systemic pain syndrome was promptly reversible by discontinuing the treatment. Spontaneous pain syndrome was not reported by others in the healthy subject; this suggests an apparent vulnerability of 5HT turnover in essential headaches. PMID:146417

Sicuteri, F; Anselmi, B; Del Bene, E; Galli, P



Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior.  


Serotonin (5-hydroxytryptamine; 5-HT) signaling through the 5-HT(2C) receptor (5-HT(2C)R) is essential in normal physiology, whereas aberrant 5-HT(2C)R function is thought to contribute to the pathogenesis of multiple neural disorders. The 5-HT(2C)R interacts with specific protein partners, but the impact of such interactions on 5-HT(2C)R function is poorly understood. Here, we report convergent cellular and behavioral data that the interaction between the 5-HT(2C)R and protein phosphatase and tensin homolog (PTEN) serves as a regulatory mechanism to control 5-HT(2C)R-mediated biology but not that of the closely homologous 5-HT(2A)R. A peptide derived from the third intracellular loop of the human 5-HT(2C)R [3L4F (third loop, fourth fragment)] disrupted the association, allosterically augmented 5-HT(2C)R-mediated signaling in live cells, and acted as a positive allosteric modulator in rats in vivo. We identified the critical residues within an 8 aa fragment of the 3L4F peptide that maintained efficacy (within the picomolar range) in live cells similar to that of the 3L4F peptide. Last, molecular modeling identified key structural features and potential interaction sites of the active 3L4F peptides against PTEN. These compelling data demonstrate the specificity and importance of this protein assembly in cellular events and behaviors mediated by 5-HT(2C)R signaling and provide a chemical guidepost to the future development of drug-like peptide or small-molecule inhibitors as neuroprobes to study 5-HT(2C)R allostery and therapeutics for 5-HT(2C)R-mediated disorders. PMID:23345234

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



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


1. The vasodilator effects of 5-hydroxytryptamine (5-HT) in the external carotid bed of anaesthetized dogs with intact sympathetic tone are mediated by prejunctional sympatho-inhibitory 5-HT1B/1D receptors and postjunctional 5-HT receptors. The prejunctional vasodilator mechanism is abolished after vagosympathectomy which results in the reversal of the vasodilator effect to vasoconstriction. The blockade of this vasoconstrictor effect of 5-HT with the 5-HT1B/1D receptor antagonist, GR 127935, unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this postjunctional vasodilator 5-HT receptor in the external carotid bed of vagosympathectomized dogs pretreated with GR 127935 (20 micrograms kg-1, i.v.). 2. One-minute intracarotid (i.c.) infusions of 5-HT (0.3-30 micrograms min-1), 5-carboxamidotryptamine (5-CT; 0.01-0.3 microgram min-1), 5-methoxytryptamine (1-100 micrograms min-1) and lisuride (3-1000 micrograms min-1) resulted in dose-dependent increases in external carotid blood flow (without changes in blood pressure or heart rate) with a rank order of agonist potency of 5-CT > > 5-HT > or = 5-methoxytryptamine > lisuride, whereas cisapride (100-1000 micrograms min-1, i.c.) was practically inactive. Interestingly, lisuride (mean dose of 85 +/- 7 micrograms kg-1, i.c.), but not cisapride (mean dose of 67 +/- 7 micrograms kg-1, i.c.), specifically abolished the responses induced by 5-HT, 5-CT and 5-methoxytryptamine, suggesting that a common site of action may be involved. In contrast, 1 min i.c. infusions of 8-OH-DPAT (3-3000 micrograms min-1) produced dose-dependent decreases, not increases, in external carotid blood flow and failed to antagonize (mean dose of 200 +/- 33 micrograms kg-1, i.c.) the agonist-induced vasodilator responses. 3. The external carotid vasodilator responses to 5-HT, 5-CT and 5-methoxytryptamine were not modified by intravenous (i.v.) pretreatment with either saline, (+/-)-pindolol (4 mg kg-1) or ritanserin (100 micrograms kg-1) plus granisetron (300 micrograms kg-1), but were dose-dependently blocked by i.v. administration of methiothepin (10 and 30 micrograms kg-1, given after ritanserin plus granisetron), mesulergine (10 and 30 micrograms kg-1), metergoline (1 and 3 mg kg-1), methysergide (1 and 3 mg kg-1) or clozapine (0.3 and 1 mg kg-1). Nevertheless, the blockade of the above responses, not significant after treatment with the lower of the two doses of metergoline and mesulergine, was nonspecific after administration of the higher of the two doses of methysergide and clozapine. 4. Based upon the above rank order of agonist potencies and the antagonism produced by a series of drugs showing high affinity for the cloned 5-ht7 receptor, our results indicate that the 5-HT receptor mediating external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs is operationally similar to the putative 5-HT7 receptor mediating relaxation of vascular and non-vascular smooth muscles (e.g. rabbit femoral vein, canine coronary artery, rat systemic vasculature and guinea-pig ileum) as well as tachycardia in the cat. PMID:9105708

Villalón, C M; Centurión, D; Luján-Estrada, M; Terrón, J A; Sánchez-López, A



Synthesis and structure-activity relationship of novel conformationally restricted analogues of serotonin as 5-HT6 receptor ligands.  


5-Hydroxytryptamine 6 receptors (5-HT(6)R) are being perceived as the possible target for treatment of cognitive disorders as well as obesity. The present article deals with the design, synthesis, in vitro binding and structure-activity relationship of a novel series of tetracyclic tryptamines with the rigidized N-arylsulphonyl, N-arylcarbonyl and N-benzyl substituents as 5-HT(6) receptor ligands. The chiral sulphonyl derivatives 15a and 17a showed high affinity at 5-HT(6)R with the K(i) of 23.4 and 20.5?nM, respectively. The lead compound from the series 15a has acceptable ADME properties, adequate brain penetration and is active in animal models of cognition like Novel Object Recognition Task (NORT) and water maze. PMID:21774748

Nirogi, Ramakrishna V S; Kambhampati, Ramasastri; Kothmirkar, Prabhakar; Konda, Jagadishbabu; Bandyala, Thrinath Reddy; Gudla, Parandhama; Arepalli, Sobhanadri; Gangadasari, Narasimhareddy P; Shinde, Anil K; Deshpande, Amol D; Dwarampudi, Adireddy; Chindhe, Anil K; Dubey, Pramod Kumar



The nature of the binding between LSD and a 5-HT receptor: a possible explanation for hallucinogenic activity.  


1 (+)-Lysergic acid diethylamide (LSD) mimicked 5-hydroxytryptamine (5-HT) in its ability to stimulate fluid secretion, to change transepithelial and intracellular potentials as well as to increase the cyclic 3',5'-adenosine monophosphate (cyclic AMP) concentrations of isolated salivary glands of Calliphora.2 Unlike 5-HT, LSD disengages slowly from the receptor and fluid secretion continues despite repeated washing.3 Both 5-HT and tryptamine prevented LSD from acting on the glands.4 LSD bound to the receptor was slowly displaced when glands were treated with agonists (tryptamine) or antagonists (gramine).5 The property of LSD which permits it to function as an agonist despite remaining tightly bound to the receptor is discussed as a possible basis for its profound effects within the central nervous system. PMID:4375525

Berridge, M J; Prince, W T



The Peptides Mimicking the Third Intracellular Loop of 5Hydroxytryptamine Receptors of the Types 1B and 6 Selectively Activate G Proteins and Receptor-Specifically Inhibit Serotonin Signaling via the Adenylyl Cyclase System  

Microsoft Academic Search

The third intracellular loop (ICL3) of G protein-coupled receptors has, as a rule, a key role in their interaction with heterotrimeric\\u000a G proteins. We synthesized peptides corresponding to the C-terminal region of the ICL3 (C-ICL3) of 5-hydroxytryptamine receptors\\u000a of the type 1B (5-HT1BR) and 6 (5-HT6R) and studied their influence on the functional activity of adenylyl cyclase signaling system (ACSS)

Alexander O. ShpakovElena; Elena A. Shpakova; Irina I. Tarasenko; Kira V. Derkach; Gennady P. Vlasov



In vivo labeling of 5-hydroxytryptamine uptake sites in mouse brain with ( sup 3 H)-6-nitroquipazine  

SciTech Connect

6-Nitroquipazine (DU 24565; 6-nitro 2-piperazinylquinoline) is a very potent 5-hydroxytryptamine (5-HT; serotonin) uptake inhibitor. It has been demonstrated very recently that (3H)-6-nitroquipazine is a suitable radioligand for studying 5-HT uptake sites. The present study evaluates (3H)6-nitroquipazine as a radioligand for in vivo labeling of 5-HT uptake sites in mouse brain. Very high uptake of radioactivity in the brain after i.v. administration of (3H)-6-nitroquipazine was shown. Regional distribution of the radioactivity in mouse brain 3 hr after injection of (3H)-6-nitroquipazine was in the order (highest to lowest) hypothalamus greater than midbrain greater than striatum greater than hippocampus greater than cerebral cortex greater than medulla oblongata greater than cerebellum. The regional distribution of in vivo (3H)-6-nitroquipazine binding in mouse brain was highly correlated with that in rat brain obtained from previous in vitro binding studies. Coadministration of carrier 6-nitroquipazine (5 mg/kg) significantly decreased the radioactivity in the hypothalamus, whereas that in the cerebellum and cerebral cortex was increased. Because the cerebellum has very low density of (3H)-6-nitroquipazine binding sites, the radioactivity in the cerebellum could, therefore, reflect the amount on nonspecific binding and free ligand. Kinetic studies showed highest in vivo specific binding 1 hr after injection of (3H)-6-nitroquipazine and slow clearance of specific binding. Specific binding in the hypothalamus was inhibited in a stereoselective manner by the stereoisomers of norzimelidine. Furthermore, specific binding in the hypothalamus was reduced by several 5-HT uptake inhibitors, in a dose-dependent manner.

Hashimoto, K.; Goromaru, T. (Univ. of Fukuyama (Japan))



Inhibition of 5-hydroxytryptamine and noradrenaline uptake in platelets and synaptosomes incubated in plasma from human subjects treated with amitriptyline or nortriptyline: Utilization of the principle for a bioassay method  

Microsoft Academic Search

To estimate the inhibition of amine uptake caused in vivo by tricyclic drugs used at a clinical dose, normal human blood platelets or rat hypothalamic or cortical synaptosomes were incubated with 3H-5-hydroxytryptamine (3H-5-HT) or 3H-noradrenaline (3H-NA) in platelet-free plasma of healthy volunteers receiving a single dose of 50 mg amitriptyline (AT) or nortriptyline (NT) orally. Venous blood samples were taken

Jouko Tuomisto; Erkki Tukiainen; Raija Voutilainen; Päivi Tuomainen



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

PubMed Central

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.

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



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

PubMed Central

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.

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



Role of serotonin in angiogenesis: induction of angiogenesis by sarpogrelate via endothelial 5-HT1B/Akt/eNOS pathway in diabetic mice.  


Serotonin (5-hydroxytryptamine, 5-HT) plays a crucial role in peripheral artery disease (PAD) and diabetes mellitus (DM). In these conditions, the balance between the 5-HT2A receptor in smooth muscle cells and the 5-HT1B receptor in endothelial cells (ECs) regulates vascular tonus. In the present study, we focused on the role of 5-HT in endothelial dysfunction using a selective 5-HT2A receptor blocker, sarpogrelate. In human EC, 5-HT markedly stimulated eNOS expression and the phosphorylation of eNOS, Akt and ERK1/2. In addition, a dose-dependent increase in tubule-formation on Matrigel was observed after 5-HT treatment. In contrast, high glucose significantly inhibited tubule formation and eNOS expression through inactivation of Akt, while 5-HT significantly attenuated these actions of high glucose (P<0.01). These results indicate that 5-HT stimulated angiogenesis through activation of Akt in ECs. However, in clinical situations, 5-HT seems to act as the "devil". To examine the role of 5-HT in diabetic PAD, a hindlimb ischemia model was created in diabetic mice. The blood flow ratio of the ischemic to non-ischemic limb was significantly lower in DM mice than in normal mice, while sarpogrelate significantly attenuated the decrease in the blood flow ratio compared to control (P<0.01). Consistently, the decrease in eNOS expression and Akt activity in DM mice was significantly attenuated by sarpogrelate. Overall, the present study demonstrated that selective inhibition of 5-HT2A by sarpogrelate significantly restored ischemic limb blood perfusion in a severe diabetic mouse model through stimulation of the eNOS/Akt pathway via the endothelial 5-HT1B receptor. Enhancement of vasodilation and angiogenesis by sarpogrelate might provide a unique treatment for PAD and DM patients. PMID:22172591

Iwabayashi, Masaaki; Taniyama, Yoshiaki; Sanada, Fumihiro; Azuma, Junya; Iekushi, Kazuma; Kusunoki, Hiroshi; Chatterjee, Amarnath; Okayama, Keita; Rakugi, Hiromi; Morishita, Ryuichi



Corticosteroids alter the 5-HT(1A) receptor-mediated response in CA1 hippocampal pyramidal cells.  


The hippocampus, prolonged excessive corticosterone secretion, and the 5-hydroxytryptamine (5-HT) neurotransmitter system are implicated in the etiology and treatment of psychiatric disorders. Corticosterone regulates CA1 hippocampal physiology and the 5-HT(1A) receptor-effector pathway; however the effect of chronic stress levels of corticosterone is unknown. Bilateral adrenalectomy (ADX), adrenalectomy with high dose corticosterone replacement (HCT), or surgical sham (SHAM) treatments were for 2 weeks. Standard intracellular recording techniques were used in hippocampal slices to measure active and passive cellular properties and 5-HT(1A) receptor-mediated responses in CA1 pyramidal cells. The magnitude and half-decay time of the slow after-hyperpolarization (sAHP) were decreased and the membrane time constant (tau) was increased by HCT treatment. The E(max) and EC(50), but not the slope, of the concentration-response curve for 5-HT activation of the 5-HT(1A) receptor were reduced in cells recorded from HCT versus SHAM treated rats. The net effect of treatment with stress levels of corticosterone was to increase the excitability of the CA1 hippocampal pyramidal cell through changes in membrane properties and 5-HT(1A) receptor-mediated response. PMID:10989269

Mueller, N K; Beck, S G



5-HT causes an increase in cAMP that stimulates, rather than inhibits, oocyte maturation in marine nemertean worms.  


In the nemertean worms Cerebratulus lacteus and Micrura alaskensis, 5-HT (=5-hydroxytryptamine, or serotonin) causes prophase-arrested oocytes to mature and complete germinal vesicle breakdown (GVBD). To identify the intracellular pathway that mediates 5-HT stimulation, follicle-free oocytes of nemerteans were assessed for GVBD rates in the presence or absence of 5-HT after being treated with various modulators of cAMP, a well known transducer of 5-HT signaling and an important regulator of hormone-induced maturation in general. Unlike in many animals where high levels of intra-oocytic cAMP block maturation, treatment of follicle-free nemertean oocytes with agents that elevate cAMP (8-bromo-cAMP, forskolin or inhibitors of phosphodiesterases) triggered GVBD in the absence of added 5-HT. Similarly, 5-HT caused a substantial cAMP increase prior to GVBD in nemertean oocytes that had been pre-injected with a cAMP fluorosensor. Such a rise in cAMP seemed to involve G-protein-mediated signaling and protein kinase A (PKA) stimulation, based on the inhibition of 5-HT-induced GVBD by specific antagonists of these transduction steps. Although the downstream targets of activated PKA remain unknown, neither the synthesis of new proteins nor the activation of MAPKs (mitogen-activated protein kinases) appeared to be required for GVBD after 5-HT stimulation. Alternatively, pre-incubation in roscovitine, an inhibitor of maturation-promoting factor (MPF), prevented GVBD, indicating that maturing oocytes eventually need to elevate their MPF levels, as has been documented for other animals. Collectively, this study demonstrates for the first time that 5-HT can cause immature oocytes to undergo an increase in cAMP that stimulates, rather than inhibits, meiotic maturation. The possible relationship between such a form of oocyte maturation and that observed in other animals is discussed. PMID:11262241

Stricker, S A; Smythe, T L



Acidic biphenyl derivatives: Synthesis and biological activity of a new series of potent 5-HT4 receptor antagonists.  


Serotonin (5-hydroxytryptamine, 5-HT) is an important signaling molecule in the central nervous system (CNS) and in non-neuronal tissues and organs. Serotonin mediates a positive chronotropic and inotropic response through 5-HT4 receptors in the atrium and ventricle of the heart. Recent investigations have revealed increased expression of the 5-HT4(b) isoform in cardiomyocytes of chronic arrhythmic and failing hearts, and that the use of 5-HT4 receptor antagonists may be beneficial for treating these conditions. The 5-HT4 receptor possesses a transmembrane (TM) binding site important for ligand affinity and recognition, as well as a capacity to accommodate bulky ligands. A new series of peripherally-acting 5-HT4 receptor antagonists were prepared by combining the acidic biphenyl group from the class of angiotensin II receptor blockers (ARBs) with the SB207266 (piboserod) scaffold. The new compounds were pharmacologically evaluated and carboxylic acid 21 was identified as a potent and promising 5-HT4 receptor antagonist with moderate affinity for the AT1 receptor. The permeability of carboxylic acid 21 in a Caco-2 assay was low and the corresponding prodrug esters 23a-f were therefore prepared. The pharmacokinetics of methyl ester 20 and n-butyl ester 23c were evaluated in a rat model, revealing incomplete metabolism to carboxylic acid 21. However, methyl ester 20 is a potent 5-HT4 receptor antagonist with binding affinities in the low picomolar range. Methyl ester 20 has promising oral bioavailability and pharmacokinetics and may target 5-HT4 receptors in both CNS and peripheral organs. PMID:24113240

Brudeli, Bjarne; Andressen, Kjetil Wessel; Moltzau, Lise Román; Nilsen, Nils Olav; Levy, Finn Olav; Klaveness, Jo



The properties of 5-HT3 receptors in clonal cell lines studied by patch-clamp techniques.  

PubMed Central

1 The characteristics of transmembrane currents evoked by 5-hydroxytryptamine (5-HT) in the neuroblastoma x Chinese hamster brain cell line NCB-20 and neuroblastoma clonal cell line N1E-115 have been studied under voltage-clamp conditions by the whole-cell recording and outside-out membrane patch modes of the patch-clamp technique. 2 In 73% of NCB-20 cells examined (n = 221), and all N1E-115 cells studied (n = 80), 5-HT (10 microM) elicited a transient inward current at negative holding potentials, this being associated with an increase in membrane conductance. In both cell lines responses to 5-HT reversed in sign at a potential of approximately -2 mV and demonstrated inward rectification. 3 The reversal potential of 5-HT-induced currents (E5-HT) recorded from either NCB-20 or N1E-115 cells was unaffected by total replacement of internal K+ by Cs+. In N1E-115 cells, reducing internal K+ concentration from 140 to 20 mM produced a positive shift in E5-HT of approximately 28 mV, whereas reducing external Na+ from 143 to 20 mM was associated with a negative shift in E5-HT of about 37 mV. A large reduction in internal Cl- concentration (from 144 to 6 mM) had little effect on E5-HT. 4 5-HT-induced currents of NCB-20 cells were unaffected by methysergide (1 microM) or ketanserin (1 microM), but were reversibly antagonized by GR38032F (0.1-1.0 nM) with an IC50 of 0.25 nM. GR 38032F (0.3 nM) reduced 5-HT-induced currents in N1E-115 cells to approximately 26% of their control value. 5 On outside-out membrane patches excised from both NCB-20 and N1E-115 cells, 5-HT induced small inward currents which could not be clearly resolved into discrete single channel events. Such responses were: (i) reversibly antagonized by GR 38032F (1 nM) (ii) reversed in sign at 0 mV, and (iii) subject to desensitization. 6 Fluctuation analysis of inward currents evoked by 5-HT (1 microM) in N1E-115 cells suggests that 5-HT gates a channel with a conductance of approximately 310fS. Such a relatively small conductance could readily explain why the response of outside-out membrane patches to 5-HT cannot at present be resolved into clear single channel events.

Lambert, J. J.; Peters, J. A.; Hales, T. G.; Dempster, J.



Increased gut cholinergic activity and antagonism of 5-hydroxytryptamine M-receptors by BRL 24924: potential clinical importance of BRL 24924.  

PubMed Central

The mechanisms by which BRL 24924 ([(+/-)- (endo)])-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo-[3.3.1]-non- 4-yl) benzamide hydrochloride stimulates gut motility and the relationships between BRL 24924 and 5-hydroxytryptamine (5-HT) receptors have been studied. In guinea-pig isolated ileum, BRL 24924 (10(-14)-10(-6) M) increased electrically-evoked, cholinergically-mediated contractions, probably by increasing acetylcholine (ACh) release. This action of BRL 24924 was prevented by the presence of high concentrations of 5-HT, but not by hexamethonium, phentolamine and propranolol, methysergide or ICS 205-930. The mechanism by which BRL 24924 can increase gut ACh release is not certain, but most likely involves activation of an enteric 5-HT receptor which differs from those 5-HT M-receptors antagonized by ICS 205-930 or by higher concentrations of BRL 24924 in other test systems. BRL 24924 antagonized 5-HT-evoked, cholinergically-mediated contractions of guinea-pig isolated ileum (pA2 = 7.56 +/- 0.12). Similar and higher concentrations of BRL 24924 did not antagonize contractions evoked by nicotinic receptor stimulation. In rabbit isolated heart, BRL 24924 1-10 nM reduced the tachycardia evoked by 5-HT. In anaesthetized rats, BRL 24924 0.3-83 nmol kg-1 i.v. antagonized the Bezold-Jarisch reflex evoked by 5-HT; the ID50 for BRL 24924 was 10.2 +/- 3.0 nmol kg-1 (3.7 +/- 1.1 microgram kg-1). A direct action of BRL 24924 on nerve function was excluded. In rat cortex, BRL 24924 10(-6) M did not displace [3H]-5-HT or [3H]-ketanserin binding to 5-HT1 and 5-HT2 receptors. The actions of BRL 24924 are discussed in terms of its potential clinical use as a stimulant of gastric motility and as a 5-HT M-receptor antagonist.

Sanger, G. J.



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

PubMed Central

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)

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



5-HT6 receptors and Alzheimer's disease  

PubMed Central

During the past 20 years, the 5-HT6 receptor has received increasing attention and become a promising target for improving cognition. Several studies with structurally different compounds have shown that not only antagonists but also 5-HT6 receptor agonists improve learning and memory in animal models. A large number of publications describing the development of ligands for this receptor have come to light, and it is now quite evident that 5-HT6 receptors have great pharmaceutical potential in terms of related patents. However, 5-HT6 receptor functionality is much more complex than initially defined. According to the existing data, different cellular pathways may be activated, depending on the drug being used. This article reviews preclinical and clinical evidence of the effects that 5-HT6 receptor compounds have on cognition. In addition, the biochemical and neurochemical mechanisms of action through which 5-HT6 receptor compounds can influence cognition will be described. Overall, several 5-HT6-targeted compounds can reasonably be regarded as powerful drug candidates for the treatment of Alzheimer's disease.



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

Microsoft Academic Search

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

O. Spigset; Tom Mjörndal



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

Microsoft Academic Search

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

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



Calcineurin-dependent cofilin activation and increased retrograde actin flow drive 5-HT-dependent neurite outgrowth in Aplysia bag cell neurons.  


Neurite outgrowth in response to soluble growth factors often involves changes in intracellular Ca(2+); however, mechanistic roles for Ca(2+) in controlling the underlying dynamic cytoskeletal processes have remained enigmatic. Bag cell neurons exposed to serotonin (5-hydroxytryptamine [5-HT]) respond with a threefold increase in neurite outgrowth rates. Outgrowth depends on phospholipase C (PLC) ? inositol trisphosphate ? Ca(2+) ? calcineurin signaling and is accompanied by increased rates of retrograde actin network flow in the growth cone P domain. Calcineurin inhibitors had no effect on Ca(2+) release or basal levels of retrograde actin flow; however, they completely suppressed 5-HT-dependent outgrowth and F-actin flow acceleration. 5-HT treatments were accompanied by calcineurin-dependent increases in cofilin activity in the growth cone P domain. 5-HT effects were mimicked by direct activation of PLC, suggesting that increased actin network treadmilling may be a widespread mechanism for promoting neurite outgrowth in response to neurotrophic factors. PMID:23097492

Zhang, Xiao-Feng; Hyland, Callen; Van Goor, David; Forscher, Paul



Lysergic Acid Diethylamide: Role in Conversion of Plasma Tryptophan to Brain Serotonin (5Hydroxytryptamine)  

Microsoft Academic Search

Injections of D-lysergic acid diethylamide decrease the turnover rate of 5-hydroxytryptamine of rat brain, as measured from the conversion of 14C-tryptophan into 14C-5-hydroxytryptamine. The 2-bromolysergic acid diethylamide given in doses fivefold greater than those of lysergic acid diethylamide fails to change the rate of 14C-tryptophan conversion into 14C-5-hydroxytryptamine. The effect of D-lysergic acid diethylamide is discussed with regard to its

Robert C. Lin; S. H. Ngai; E. Costa



Design, synthesis and preliminary screening of novel 3-(2-N,N-dimethylaminoethylthio) indole derivatives as potential 5-HT(6) receptor ligands.  


The synthesis and potential 5-hydroxytryptamine(6) receptor (5-HT6R) antagonist activity of a novel series of N-arylsulfonyl-3-(2-N,N-dimethylaminoethylthio) indoles has been reported. The molecular modeling, synthesis and in-vitro radioligand binding data of this series are discussed. The present article describes 37 derivatives of the title series. It was observed that the increased side-chain length with the insertion of a sulfur atom did not lead to the loss of binding affinity of these compounds, although the affinities were reduced. The compounds exhibited moderate affinity and selectivity to human 5-HT6 receptors. PMID:18569332

Kambhampati, Ramasastri; Konda, Jagadishbabu; Reballi, Veena; Shinde, Anil K; Dubey, Pramod K; Nirogi, Ramakrishna V S



Comparison of 50- and 100-g l -tryptophan depletion and loading formulations for altering 5HT synthesis: pharmacokinetics, side effects, and mood states  

Microsoft Academic Search

Rationale  Differences in 5-hydroxytryptamine (5-HT) function have been the subject of extensive research in psychiatric studies. Many\\u000a studies have manipulated l-tryptophan (Trp) levels to temporarily decrease (depletion) or increase (loading) 5-HT synthesis. While most researchers\\u000a have used a 100-g formulation, there has been ongoing interest in using smaller-sized formulations.\\u000a \\u000a \\u000a \\u000a Objectives  This study examined the time course of multiple plasma indicators of brain

Donald M. Dougherty; Dawn M. Marsh-Richard; Charles W. Mathias; Ashley J. Hood; Merideth A. Addicott; F. Gerard Moeller; Christopher J. Morgan; Abdulla A.-B. Badawy



Efficacy of the 5HT1A Agonist Tandospirone Citrate in Improving Symptoms of Patients With Functional Dyspepsia: A Randomized Controlled Trial  

Microsoft Academic Search

OBJECTIVES:Functional dyspepsia (FD) is a common condition in the general population; however, its treatment remains a challenge. The aim of this study was to examine the efficacy of tandospirone citrate, a new partial agonist of the 5-hydroxytryptamine 1A (5-HT1A) receptor, in improving the symptoms of patients with FD.METHODS:In this double-blind, placebo-controlled, multicenter study, FD patients were randomized to treatment with

Hiroto Miwa; A Nagahara; K Tominaga; T Yokoyama; Y Sawada; K Inoue; Kiyoshi Ashida; T Fukuchi; M Hojo; H Yamashita; T Tomita; K Hori; T Oshima



Effect of GBR 12909 and fluoxetine on the acute and long term changes induced by MDMA (‘ecstasy’) on the 5HT and dopamine concentrations in mouse brain  

Microsoft Academic Search

We examined the long term effect of 3,4 methylenedioxymethamphetamine (MDMA, 10, 20 and 30 mg\\/kg, i.p.) on the cerebral 5-hydroxytryptamine (5-HT) and dopamine content in Swiss Webster mice. Three injections of MDMA (20 or 30 mg\\/kg, i.p.) given 3 h apart produced a marked depletion in the striatal content of dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid

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



Molecular Actions of Propofol on Human 5HT3A Receptors: Enhancement as Well as Inhibition by Closely Related Phenol Derivatives  

Microsoft Academic Search

BACKGROUND: 5-Hydroxytryptamine type 3 (5-HT3) receptors are excitatory ligand- gated ion channels which are involved in postoperative nausea and vomiting. They are depressed by the anesthetic propofol, which, in contrast, enhances the activity of inhibitory ligand-gated ion channels such as -aminobutyric acid type A receptors and glycine receptors. To investigate the molecular mechanisms respon- sible for these contrasting actions, we

Martin Barann; Isabelle Linden; Stefan Witten; Bernd W. Urban



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

PubMed Central

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

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



R 50 595, a selective non-competitive antagonist of cisapride, BRL 24924 and 5-hydroxytryptamine on the guinea-pig ileum.  


5-Hydroxytryptamine and substituted benzamides such as cisapride and BRL 24924 enhance the twitch responses of the electrically stimulated longitudinal muscle-myenteric plexus preparation of the guinea-pig. The effects of these benzamides and 5-HT could possibly be mediated via similar receptor-effector systems. The aim of our study was therefore to determine whether R 50 595, an analogue of cisapride devoid of intrinsic activity, could specifically interfere with the effects of cisapride and BRL 24924 and if so, whether it would also affect the responses to serotonin. R 50 595 had no effect on the twitch responses of the electrically stimulated preparation up to a concentration of 3 X 10(-7) M. Cisapride and BRL 24924 both enhanced the contractile response to electrical stimulation by a maximum of 37 +/- 7% at 3 X 10(-7) M for cisapride and 36 +/- 6% for BRL 24924, also at 3 X 10(-7) M. R 50 595 (10(-7)(-3) X 10(-7) M) antagonized the effects of cisapride and BRL 24924 in a non-competitive way. 5-HT enhanced the contractile responses by a maximum of 24 +/- 3.2% at 3 X 10(-8) M. The effects of 5-HT were completely abolished at a concentration of 3 X 10(-7) M R 50 595. R 50 595 also antagonized the effects of 5-HT in a non-competitive way.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2387319

Van den Brink, H W; Schuurkes, J A; Van Nueten, J M; Van Rossum, J M



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

PubMed Central

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

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



Voltage dependence of 5-hydroxytryptamine release at a synapse between identified leech neurones in culture.  

PubMed Central

The release of 5-hydroxytryptamine (5-HT) from presynaptic terminals has been studied by the voltage-clamp technique at synapses made by isolated Retzius and pressure (P) sensory neurones dissected from the leech C.N.S. and maintained in tissue culture. At these synapses facilitation, depression and modulation of release occur with action potentials and with voltage-clamp pulses. Depolarization of Retzius cells from a constant holding potential by steps of varying amplitude (5 ms in duration) caused graded release of 5-HT. The steep transfer function for release using these short test pulses resembled that seen at the giant synapse of the squid: synaptic potentials increased markedly with presynaptic depolarizations beyond -25 mV and decreased with large depolarizing pulses beyond +40 mV. When the steady holding potential of voltage-clamped Retzius cells was suddenly displaced to a new value within the range of -40 mV to -85 mV, there followed a slow but smaller change of the post-synaptic P-cell membrane potential in the same direction. After an initial delay of about 40 ms, the post-synaptic potential reached its new level with an exponential time course and a time constant of 0.7 s. Since Retzius and P cells are not electrically coupled, these effects can be accounted for by alterations in tonic release of transmitter. Changes of presynaptic holding potential to a more depolarized level resulted in an increase in voltage noise recorded in the P cell. Conversely, hyperpolarization from a depolarized level reduced noise. Noise analysis showed that these changes could be accounted for by quantal events with a mean amplitude of about 0.15 mV. This value is similar to that for spontaneous miniature potentials and quantal fluctuations observed at synapses between Retzius and P cells. Changes in steady holding potential also had marked effects upon the transfer function observed with brief depolarizing pulses of the Retzius cell. The post-synaptic responses evoked by depolarizations to 0 mV with pulses of 5 ms duration were reduced in amplitude as the holding potential of the Retzius cell was increased from the resting value of -45 to -75 mV. For example, depolarization to 0 mV starting from -45 mV evoked synaptic potentials as much as ten times larger than those evoked by depolarizations to 0 mV starting from -75 mV.(ABSTRACT TRUNCATED AT 400 WORDS) Images Plate 1

Dietzel, I D; Drapeau, P; Nicholls, J G



Carbamylcholine- and 5-hydroxytryptamine-induced contraction in rat isolated airways: inhibition by calcitonin gene-related peptide.  

PubMed Central

1. The effects of rat and human alpha-calcitonin gene-related peptide (alpha-CGRP) were investigated in isolated smooth muscle preparations obtained from three levels of the rat respiratory tract. 2. Neither peptide (10(-10)-10(-6) M) had any effect on resting tension or on carbamylcholine (10(-6) M)-induced tone of trachea or main bronchus. In contrast, CGRP sometimes reduced spontaneous or carbamylcholine-induced tone of lung parenchymal strips. 3. CGRP produced a significant rightward shift of the log concentration-response curves to carbamylcholine and 5-hydroxytryptamine (5-HT) in the main bronchus. A rightward shift was also seen in trachea and parenchymal strips but this did not achieve the level of significance. The maximal response to 5-HT was reduced in the main bronchus and lung parenchyma whereas the maximal contraction to carbamylcholine was decreased in parenchymal strip only. 4. In all three airway preparations, CGRP caused concentration-dependent inhibition of responses elicited by challenges with 10(-7) M carbamylcholine or 5 x 10(-7) M 5-HT. The inhibitory effect of the peptide was inversely related to the size of the airways: the smaller the calibre, the greater the inhibition. 5. The inhibitory action of CGRP was not modified by pretreatment with tetrodotoxin (10(-6) M), propranolol (10(-6) M) or indomethacin (10(-6) M). 6. The results strongly suggest that (a) CGRP has a nonspecific inhibitory action on airway smooth muscle cells, (b) CGRP may act as a potent inhibitor of responses elicited by bronchoconstrictor substances and (c) its inhibitory activity may be most powerfully expressed in peripheral regions of the respiratory tract.

Cadieux, A.; Lanoue, C.; Sirois, P.; Barabe, J.



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


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

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



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


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

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



5-HT1B but not 5-HT6 or 5-HT7 receptors mediate depression of spinal nociceptive reflexes in vitro  

PubMed Central

The identity of the serotonin (5-HT) receptors modulating the transmission of segmental C-fibre mediated signals was studied using an in vitro preparation of the hemisected spinal cord from rat pups. Responses to trains of stimuli delivered to a lumbar dorsal root were recorded from the corresponding ventral root. The resulting cumulative depolarization (CD) mediated by unmyelinated fibres was quantified in terms of integrated area. The amplitude of the mono-synaptic reflex was also measured. Serotonergic agents were superfused at known concentrations and their effects on the reflexes evaluated. 5-HT had depressant effects on the CD (EC50 34??M). The rank order of potency of agonists for the depression of the CD was 5-carboxamidotryptamine (5-CT)>?-methylserotonin (?-met-5-HT) ?5-HT>42-methylserotonin (2-met-5-HT)?8-OH-DPAT. All the agonists including 2-met-5-HT and 8-OH-DPAT had strong depressant effects on the mono-synaptic reflex with the following order of potency: 5-CT>48-OH-DPAT>4?-met-5-HT ?5-HT?2-met-5-HT. The inhibitory effects of 5-HT, ?-met-5-HT and 5-CT were attenuated by the non-specific 5-HT antagonist methiothepin (1??M) and by the 5-HT1A/1B antagonist SDZ 21009 (100?nM) but not by the selective 5-HT1A antagonist WAY 100135 (1??M). Other antagonists known to block 5-HT2, 5-HT6 and/or 5-HT7 receptors (ketanserin, RO 04-6790, ritanserin and clozapine) did not change the effect of the agonists. The data suggest an important contribution of 5-HT1B receptors to the inhibition of spinal C-fibre mediated nociceptive reflexes but no experimental support was found for the intervention of 5-HT2, 5-HT6 or 5-HT7 receptors in this in vitro model.

Hedo, G; Lopez-Garcia, J A



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


Recently, we discovered that transient receptor potential ankyrin1 channel (TRPA1) is highly expressed in human and rat enterochromaffin (EC) cells, and those TRPA1 agonists such as allyl isothiocyanates (AITC) and cinnamaldehyde (CA) enhance the release of serotonin (5-hydroxytryptamine; 5-HT) from EC cells in vitro. In this study, QGP-1 cells, a human pancreatic endocrine cell line, were found to highly express TRPA1 and EC cell marker genes, such as tryptophan hydroxylase 1 (TPH1), chromogranin A (CgA), synaptophysin, ATP-dependent vesicular monoamine transporter 1 (VMAT1), metabotropic glutamate receptor 4 (mGluR4), beta1-adrenergic receptor (ADB1), muscarinic 4 acetylcholine receptor (ACM4), substance P, serotonin transporter (SERT), and guanylin. Furthermore, the TRPA1 agonists AITC, CA, and acrolein concentration dependently evoked a