serotonin 5-HT2B receptors


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(Updated 8/9/04)

Kantor S, Jakus R, Balogh B, Benko A, Bagdy G.
Increased wakefulness, motor activity and decreased theta activity after blockade of the 5-HT2B receptor by the subtype-selective antagonist SB-215505.
Br J Pharmacol. 2004 Jul 20 [Epub ahead of print]
"Serotonin-2 receptor antagonists, like ritanserin, greatly enhance deep slow wave sleep (SWS-2) and low-frequency EEG power in humans and rodents. 5-HT2A and 5-HT2C receptors may be involved in these effects, but the role of the 5-HT2B receptor is still unclear. To investigate the role of the 5-HT2B receptor in regulation of the sleep-wake cycle, the subtype-selective antagonist SB-215505 (0.1, 0.3 and 1.0 mg kg(-1) i.p.) was administered to Sprague-Dawley rats at light onset (beginning of passive phase). EEG, EMG and motor activity were recorded during the subsequent 8 h. SB-215505 dose-dependently increased wakefulness (W) at the expense of the intermediate stage of sleep, paradoxical sleep (PS) and SWS-2 in the first hour. Parallel to increased W, significantly increased motor activity was found. Spectral analysis of the EEG in W showed a dose-dependent decrease in power density in the 3-8 Hz frequency range (maximum effect at 6 Hz). In light slow wave sleep and SWS-2, the drug reduced low-frequency (<8 Hz) EEG power, suggesting decreased sleep intensity after SB-215505 treatment. In PS, the drug dose-dependently decreased EEG power solely in the theta (6-9 Hz) band, primarily affecting the peak power value (7 Hz). The well-known SWS-2 enhancing effect of 5-HT2 receptor antagonists is mediated by 5-HT2A and/or 5-HT2C receptors. In contrast, blockade of 5-HT2B receptors increases motor activity and W along with decreased theta activity during W and PS. Activation of 5-HT2B receptors may contribute to initiation of sleep and to theta generation during W and PS under physiological conditions." [Abstract]

Poissonnet G, Parmentier JG, Boutin JA, Goldstein S.
The emergence of selective 5-HT 2B antagonists structures, activities and potential therapeutic applications.
Mini Rev Med Chem. 2004 Mar;4(3):325-30.
"5-HT(2) receptors mediate a large array of physiological and behavioral functions in humans via three distinct subtypes: 5-HT(2A), 5-HT(2B)and 5-HT(2C). While selective 5-HT(2A)antagonists have been known for some time, knowledge of the precise role played by the 5-HT(2B)receptor was hampered by the existence of solely 5-HT(2B)5-HT(2C) mixed antagonists. However, selective 5-HT(2B)antagonists began recently to emerge in the literature. Indeed, four structural classes belonging to the piperazine, indole, naphthylpyrimidine and tetrahydro-beta-carboline scaffolds were reported. In this paper, we will briefly review the structural and pharmacological features of selective 5-HT(2B) antagonists, including patent literature of the last five years." [Abstract]

Sanden N, Thorlin T, Blomstrand F, Persson PA, Hansson E.
5-Hydroxytryptamine2B receptors stimulate Ca2+ increases in cultured astrocytes from three different brain regions.
Neurochem Int 2000 Apr;36(4-5):427-34
"The expression of 5-hydroxytryptamine-2B (5-HT2B) receptor mRNA has recently been shown in cultured astrocytes. Here the expression of functional 5-HT2B receptors has been studied in cultured astrocytes from rat cerebral cortex, hippocampus, and brain stem. Fluo-3- and fura-2-based microspectrofluorometry was used for measuring changes in intracellular free calcium concentrations ([Ca2+]i). The 5-HT2B agonist alpha-methyl 5-HT (40 nM) produced rapid transient increases in [Ca2+]i in astrocytes from all three brain regions studied, and these responses were blocked by the selective 5-HT2B antagonist rauwolscine (1 microM). The specificity of the responses to alpha-methyl 5-HT was further demonstrated by the failure of 4-(4-fluorobenzoyl)-1-(4-phenylbutyl)-piperidine oxalate (1 microM), a specific 5-HT2A/5-HT2C antagonist, to block these responses. The 5-HT2B-induced increases in [Ca2+]i persisted in Ca2+-free buffer, indicating that the increase in [Ca2+]i results from mobilization of intracellular Ca2+ stores. The expression of 5-HT2B receptors on astroglial cells was further verified immunohistochemically and by Western blot analysis. These results provide evidence of the existence of 5-HT2B receptors on astrocytes in primary culture." [Abstract]

Helton LA, Thor KB, Baez M.
5-hydroxytryptamine2A, 5-hydroxytryptamine2B, and 5-hydroxytryptamine2C receptor mRNA expression in the spinal cord of rat, cat, monkey and human.
Neuroreport 1994 Dec 20;5(18):2617-20
"Spinal cord tissue from all four species contained 5-HT2B message. Brain tissue from cat and monkey contained 5-HT2B mRNA, but this was not detected in rat brain." [Abstract]

Hamel E.
The biology of serotonin receptors: focus on migraine pathophysiology and treatment.
Can J Neurol Sci 1999 Nov;26 Suppl 3:S2-6
"Serotonin receptors are highly heterogeneous and they have been regrouped within seven different families (5-HT1-5-HT7). With the exception of the 5-HT3 which is a ligand-gated ion channel, all others are G-protein coupled receptors with each family sharing structural, pharmacological and transductional characteristics. 5-HT receptors have been implicated in the regulation of several psychiatric and neurological disorders related to serotonergic neurotransmission, and specific receptor subtypes have recently been associated with either the pathogenesis or the treatment of migraine headache. In this respect, activation of vascular 5-HT2B and/or 5-HT7 receptors, possibly as a consequence of the sudden rise in 5-HT levels reported at the onset of a migraine attack, would hypothetically result in dilation of cerebral blood vessels and concomitant activation of sensory trigeminovascular afferents, hence initiating the manifestation of head pain. At this stage in the migraine process, activation of specific subtypes of 5-HT1 receptors has proven clinically effective in relieving migraine pain. Neural 5-HT1D and/or 5-HT1F receptors localized pre-junctionally on trigeminovascular afferents appear to mediate the triptan-induced inhibition of the neurogenic inflammatory response, with possible additional sites of action for brain penetrant 5-HT1 receptor agonists in inhibiting the transmission of pain centrally. In contrast, activation of vascular 5-HT1B receptors would constrict meningeal vessels hence recovering their pre-migraine diameter. The recent availability of subtype selective 5-HT1D and 5-HT1F receptor agonists should allow a further test of the neural/vascular hypothesis and could possibly lead to antimigraine drugs with a safer cardiovascular profile." [Abstract]

Schmuck K, Ullmer C, Kalkman HO, Probst A, Lubbert H.
Activation of meningeal 5-HT2B receptors: an early step in the generation of migraine headache?
Eur J Neurosci 1996 May;8(5):959-67
"Several pharmaceuticals are frequently dispensed to prevent or reduce the occurrence of migraine attacks. The prophylactic effect of these drugs has been suggested to be caused through blockade of serotonin (5-HT) receptors of type 5-HT2B or 5-HT2C. To elucidate which of these receptors is involved, we first used radioligand binding assays to determine the pharmacological profile of the human and rat-5-HT2B receptor. Furthermore, the potency of drugs used in migraine prophylaxis to stimulate or inhibit 5-HT2B or 5-HT2C receptor-mediated potency of drugs used in migraine prophylaxis to stimulate or inhibit 5-HT2B or 5-HT2C receptor-mediated phosphatidyl inositol hydrolysis was measured. All these drugs were found to block both human receptors. Correlation of the receptor affinities with the potencies used in migraine prophylaxis showed significant correlations, which were better for the 5-HT2B (P = 0.001) than for the 5-HT2C receptor (P = 0.005). Migraine headache is thought to be transmitted by the trigeminal nerve from the meninges and their blood vessels. Using the reverse transcription-polymerase chain reaction, the expression patterns of all cloned G-protein-coupled serotonin receptors were analysed in various human meningeal tissues. All tissues expressed 5-HT1Dbeta, 5-HT2A, 5-HT2B, 5-HT4 and 5-HT7 mRNAs. Only trace amounts of 5-HT2C receptor mRNA were found. With organ bath experiments we showed that the 5-HT2B receptor stimulated the relaxation of the pig cerebral artery via the release of nitric oxide. Our data support the hypothesis that 5-HT2B receptors located on endothelial cells of meningeal blood vessels trigger migraine headache through the formation of nitric oxide." [Abstract]

Johnson KW, Nelson DL, Dieckman DK, Wainscott DB, Lucaites VL, Audia JE, Owton WM, Phebus LA.
Neurogenic dural protein extravasation induced by meta-chlorophenylpiperazine (mCPP) involves nitric oxide and 5-HT2B receptor activation.
Cephalalgia. 2003 Mar;23(2):117-23.
"The compound m-chlorophenylpiperazine (mCPP), which is known to trigger migraine-like head pain in some subjects, was evaluated for its ability to induce dural plasma protein extravasation (PPE) in guinea pigs. Intravenous mCPP dose-dependently increased PPE. This effect was inhibited by non-selective 5-HT2 receptor antagonists (methysergide, LY53857, LY215840), by a peripherally restricted 5-HT2 receptor antagonist (xylamidine) and by a 5-HT2B selective receptor antagonist (LY202146). These data suggests that peripheral 5-HT2B receptors mediate mCPP-induced PPE. The nitric oxide synthase inhibitor L-NAME and 5-HT1 agonist sumatriptan also blocked mCPP-induced PPE, suggesting a role for nitric oxide (NO) and the trigeminal system, respectively. NO release has been linked to activation of the 5-HT2B receptor on the vascular endothelium. However, LY202146 did not block PPE induced by electrical stimulation of the trigeminal ganglion. These data are consistent with activation of peripheral 5-HT2B receptors initiating PPE and the theory that selective 5-HT2B antagonists might be effective prophylactic therapies for migraine." [Abstract]

Fitzgerald, Lawrence W., Burn, Timothy C., Brown, Barry S., Patterson, John P., Corjay, Martha H., Valentine, Patricia A., Sun, Jung-Hui, Link, John R., Abbaszade, Ilgar, Hollis, Jeannine M., Largent, Brian L., Hartig, Paul R., Hollis, Gregory F., Meunier, Paul C., Robichaud, Albert J., Robertson, David W.
ACCELERATED COMMUNICATION: Possible Role of Valvular Serotonin 5-HT2B Receptors in the Cardiopathy Associated with Fenfluramine
Mol Pharmacol 2000 57: 75-81 [Full Text]

Richard B. Rothman, Michael H. Baumann, Jason E. Savage, Laura Rauser, Ace McBride, Sandra J. Hufeisen, and Bryan L. Roth
Evidence for Possible Involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications
Circulation 102: 2836-2841, 2000. [Full Text]

Philippe Manivet, Sophie Mouillet-Richard, Jacques Callebert, Canan G. Nebigil, Luc Maroteaux, Syun Hosoda, Odile Kellermann, and Jean-Marie Launay
PDZ-dependent Activation of Nitric-oxide Synthases by the Serotonin 2B Receptor
J. Biol. Chem. 275: 9324-9331, 2000.
"Taking advantage of three cellular systems, we established that 5-HT(2B) receptors are coupled with NO signaling pathways. In the 1C11 serotonergic cell line and Mastomys natalensis carcinoid cells, which naturally express the 5-HT(2B) receptor, as well as in transfected LMTK(-) fibroblasts, stimulation of the 5-HT(2B) receptor triggers intracellular cGMP production through dual activation of constitutive nitric-oxide synthase (cNOS) and inducible NOS (iNOS). The group I PDZ motif at the C terminus of the 5-HT(2B) receptor is required for recruitment of the cNOS and iNOS transduction pathways. Indeed, the 5-HT(2B) receptor-mediated NO coupling is abolished not only upon introduction of a competitor C-terminal 5-HT(2B) peptide in the three cell types but also in LMTK(-) fibroblasts expressing a receptor C-terminally truncated or harboring a point mutation within the PDZ domain. The occurrence of a direct functional coupling between the receptor and cNOS activity is supported by highly significant correlations between the binding constants of drugs on the receptor and their effects on cNOS activity. The 5-HT(2B)/iNOS coupling mechanisms appear more complex because neutralization of endogenous Galpha(13) by specific antibodies cancels the cellular iNOS response while not interfering with cNOS activities. These findings may shed light on physiological links between the 5-HT(2B) receptor and NO and constitute the first demonstration that PDZ interactions participate in downstream transductional pathways of a G protein-coupled receptor." [Full Text]

Gavarini S, Becamel C, Chanrion B, Bockaert J, Marin P.
Molecular and functional characterization of proteins interacting with the C-terminal domains of 5-ht2 receptors: emergence of 5-ht2 "receptosomes".
Biol Cell. 2004 Jun;96(5):373-81.
"Many cellular functions are carried out by multiprotein complexes. The last five years of research have revealed that many G-protein coupled receptor (GPCR) functions that are not mediated by G proteins involve protein networks, which interact with their intracellular domains. This review focuses on one family of GPCRs activated by serotonin, the 5-HT(2) receptor family, which comprises three closely related subtypes, the 5-HT(2A), the 5-HT(2B) and the 5-HT(2c) receptors. These receptors still raise particular interest, because a large number of psychoactive drugs including hallucinogens, anti-psychotics, anxiolytics and anti-depressants, mediate their action, at least in part, through activation of 5-HT(2) receptors. Recent studies based on two-hybrid screens, proteomic, biochemical and cell biology approaches, have shown that the C-terminal domains of 5-HT(2) receptors interact with intracellular proteins. To date, the protein network associated with the C-terminus of the 5-HT(2C) receptor has been the most extensively characterized, using a proteomic approach combining affinity chromatography, mass spectrometry and immunoblotting. It includes scaffolding proteins containing one or several PDZ domains, signalling proteins and proteins of the cytoskeleton. Data indicating that the protein complexes interacting with 5-HT(2) receptor C-termini tightly control receptor trafficking and receptor-mediated signalling will also be reviewed." [Abstract]

Canan G. Nebigil, Jean-Marie Launay, Pierre Hickel, Claire Tournois, and Luc Maroteaux
5-Hydroxytryptamine 2B receptor regulates cell-cycle progression: Cross-talk with tyrosine kinase pathways
PNAS 97: 2591-2596; published online before print as 10.1073/pnas.050282397, 2000.
"In this paper, we present evidence that activation of 5-hydroxytryptamine 2B (5-HT2B) receptors by serotonin (5-HT) leads to cell-cycle progression through retinoblastoma protein hyperphosphorylation and through activation of both cyclin D1/cdk4 and cyclin E/cdk2 kinases by a mechanism that depends on induction of cyclin D1 and cyclin E protein levels. The induction of cyclin D1 expression, but not that of cyclin E, is under mitogen-activated protein kinase (MAPK) control, indicating an independent regulation of these two cyclins in the 5-HT2B receptor mitogenesis. Moreover, by using the specific platelet-derived growth factor receptor (PDGFR) inhibitor AG 1296 or by overexpressing a kinase-mutant PDGFR, we show that PDGFR kinase activity is essential for 5-HT2B-triggered MAPK/cyclin D1, but not cyclin E, signaling pathways. 5-HT2B receptor activation also increases activity of the Src family kinase, c-Src, Fyn, and c-Yes. Strikingly, c-Src, but not Fyn or c-Yes, is the crucial molecule between the Gq protein-coupled 5-HT2B receptor and the cell-cycle regulators. Inhibition of c-Src activity by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) or depletion of c-Src is sufficient to abolish the 5-HT-induced (i) PDGFR tyrosine kinase phosphorylation and MAPK activation, (ii) cyclin D1 and cyclin E expression levels, and (iii) thymidine incorporation. This paper elucidates a model of 5-HT2B receptor mitogenesis in which c-Src acts alone to control cyclin E induction and in concert with the receptor tyrosine kinase PDGFR to induce cyclin D1 expression via the MAPK/ERK pathway." [Full Text]

Kennett GA, Ainsworth K, Trail B, Blackburn TP.
BW 723C86, a 5-HT2B receptor agonist, causes hyperphagia and reduced grooming in rats.
Neuropharmacology 1997 Feb;36(2):233-9
"The 5-HT2B receptor agonist, BW 723C86 (10 and 20 mg/kg s.c.), increased the time spent in feeding behaviour of freely-fed rats in observation cages over 15 min. BW 723C86 (20 and 50 mg/kg s.c. 30 min pre-test) also modestly increased food consumption of freely-fed rats over 1 and 2 hr, but not 4 hr, in their home cages. This action was at least partly mediated centrally, as it was reproduced by i.c.v. infusion of 1 and 10 micrograms in freely-fed rats. The effect is also likely to be 5-HT2B receptor-mediated, as no hyperphagic response to BW 723C86 (20 mg/kg s.c. 30 min pre-test) was observed in freely-fed rats pretreated with the 5-HT2C/2B receptor antagonist SB 206553 (1, 3, 20 or 40 mg/kg p.o. 1 hr pre-test) while the selective 5-HT1A receptor antagonist, WAY 100635 (0.1 or 0.3 mg/kg s.c. 30 min pre-test), had no effect. Systemic (1, 10 and 20 mg/kg s.c. 30 min pre-test) but not i.c.v. (1-30 micrograms) BW 723C86 also reduced the frequency of grooming bouts of rats in observation cages. BW 723C86 given either s.c. (1-20 mg/kg 30 min pre-test) or i.c.v. (1-30 micrograms) did not cause hypolocomotion, penile erection, oral dyskinesias or hyperthermia, behaviours associated with administration of the 5-HT2C/2B receptor agonist m-chlorophenylpiperazine (mCPP), and are thus likely to involve-5-HT2C receptor activation." [Abstract]

Kennett GA, Trail B, Bright F.
Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated.
Neuropharmacology 1998 Dec;37(12):1603-10
"The 5-HT2B receptor agonist, BW 723C86 (10, 30(mg/kg i.p. 30 min pre-test), increased the number of punishments accepted in a rat Vogel drinking conflict paradigm over 3 min, as did the benzodiazepine anxiolytics, chlordiazepoxide (2.5-10 mg/kg p.o. 1 h pre-test) and alprazolam (0.2-5 mg/kg p.o. 1 h pre-test), but not the 5-HT2C/2B receptor agonist, m-chlorophenylpiperazine (mCPP, 0.3-3 mg/kg i.p) or the 5-HT1A receptor agonist, buspirone (5-20 mg/kg p.o. 1 h pre-test). The effect of BW 723C86 was unlikely to be secondary to enhanced thirst, as BW 723C86 did not increase the time that rats with free access to water spent drinking, nor did it reduce sensitivity to shock in the apparatus. The anti-punishment effect of BW 723C86 was opposed by prior treatment with the 5-HT2/2B receptor antagonist, SB-206553 (10 and 20 mg/kg p.o. 1 h pre-test), and the selective 5-HT2B receptor antagonist, SB-215505 (1 and 3 mg/kg p.o. 1 h pre-test), but not by the selective 5-HT2C receptor antagonist, SB-242084 (5 mg/kg p.o.), or the 5-HT1A receptor antagonist, WAY 100635 (0.1 or 0.3 mg/kg s.c. 30 min pre-test). Thus, the anti-punishment action of BW 723C86 is likely to be 5-HT2B receptor mediated. This is consistent with previous reports that BW 723C86 exhibited anxiolytic-like properties in both the social interaction and Geller-Seifter conflict tests." [Abstract]

Kennett, GA, Bright, F, Trail, B, Baxter, GS, Blackburn, TP
Effects of the 5-HT2B receptor agonist, BW 723C86, on three rat models of anxiety
Br. J. Pharmacol. 1996 117: 1443-1448
"1. BW 723C86 (3 and 10 mg kg-1, s.c. 30 min pretest), a 5-HT2B receptor agonist, increased total interaction, but not locomotion in a rat social interaction test, a profile consistent with anxiolysis. 2. The effect of BW 723C86 in the social interaction test is likely to be 5- HT2B receptor-mediated as it was prevented by pretreatment with the 5- HT2C/2B receptor antagonist, SB 200646A, (1 and 2 mg kg-1, p.o., 1 h pretest) which did not affect basal levels of social interaction at the doses used. 3. An anxiolytic-like action was also observed in the rat Geller-Seifter conflict test, where BW 723C86 (0.5-50 mg kg-1, s.c. 30 min pretest) modestly, but significantly increased punished, but not unpublished responding. 4. In a rat 5 min elevated x-maze test, BW 723C86 (1-10 mg kg-1, s.c.) had no significant effect. 5. The maximal anxiolytic-like effect of BW 723C86 approached that of the benzodiazepine anxiolytic, chloradiazepoxide (5 mg kg-1, s.c. 30 min pretest) in the social interaction test, but was markedly less in the Geller-Siefter test. The effect of BW 723C86 was also clearly less than chlordiazepoxide in the elevated x-maze procedure where it had no significant effect. 6. In conclusion, BW 723C86 exerted an appreciable anxiolytic-like profile in a rat social interaction test, but had a weaker effect in the Geller-Siefter and was ineffective in the elevated x-maze test used. These effects are likely to be 5-HT2B receptor- mediated." [Abstract]

Kong EK, Peng L, Chen Y, Yu AC, Hertz L.
Up-regulation of 5-HT2B receptor density and receptor-mediated glycogenolysis in mouse astrocytes by long-term fluoxetine administration.
Neurochem Res 2002 Feb;27(1-2):113-20
"The effects were studied of short-term (1 week) versus long-term (2-3 weeks) fluoxetine treatment of primary cultures of mouse astrocytes, differentiated by treatment with dibutyryl cyclic AMP. From previous experiments it is known that acute treatment with fluoxetine stimulates glycogenolysis and increases free cytosolic Ca2+ concentration ([Ca2+]i]) in these cultures, whereas short-term (one week) treatment with 10 microM down-regulates the effects on glycogen and [Ca2+]i, when fluoxetine administration is renewed (or when serotonin is administered). Moreover, antagonist studies have shown that these responses are evoked by activation of a 5-HT2, receptor that is different from the 5-HT2A receptor and therefore at that time tentatively were interpreted as being exerted on 5-HT2C receptors. In the present study the cultures were found by RT-PCR to express mRNA for 5-HT2A and 5-HT2B receptors, but not for the 5-HT2C receptor, identifying the 5-HT2 receptor activated by fluoxetine as the 5-HT2B receptor, the most recently cloned 5-Ht2 receptor and a 5-HT receptor known to be more abundant in human, than in rodent, brain. Both short-term and long-term treatment with fluoxetine increased the specific binding of [3H]mesulergine, a ligand for alL three 5-HT2 receptors. Long-term treatment with fluoxetine caused an agonist-induced up-regulation of the glycogenolytic response to renewed administration of fluoxetine, whereas short-term treatment abolished the fluoxetine-induced hydrolysis of glycogen. Thus, during a treatment period similar to that required for fluoxetine's clinical response to occur, 5-HT2B-mediated effects are initially down-regulated and subsequently up- regulated." [Abstract]

Kursar, JD, Nelson, DL, Wainscott, DB, Baez, M
Molecular cloning, functional expression, and mRNA tissue distribution of the human 5-hydroxytryptamine2B receptor
Mol Pharmacol 1994 46: 227-234
"Clones encoding a portion of the human 5-hydroxytryptamine (5-HT)2B receptor gene were isolated from a human placental genomic library. Based on distribution studies of 5-HT2B receptor mRNA, human uterus cDNA libraries were constructed and screened, resulting in the isolation of several full-length cDNA clones. These clones harbored a common single open reading frame encoding a protein of 481 amino acids. The deduced amino acid sequence of the human 5-HT2B receptor displayed 91.5% identity within the transmembrane domains and 82% identity overall with the rat 5-HT2B receptor. The human 5-HT2B receptor stably expressed in AV12-664 cells demonstrated high affinity (Kd = 10.18 +/- 1.60 nM), saturable [3H]serotonin binding, similar to that previously described for the rat 5-HT2B receptor. The pharmacological profile of the human 5-HT2B receptor was virtually identical to that of the rat 5- HT2B receptor, with the exceptions of the 5-HT2A receptor antagonists ketanserin and spiperone. Both compounds exhibited higher affinity at the human 5-HT2B receptor (ketanserin, Ki = 376 +/- 58 nM; spiperone, Ki = 697 +/- 54 nM) than at the rat 5-HT2B receptor (ketanserin, Ki = 3559 +/- 175 nM; spiperone, Ki = 3278 +/- 92 nM). Functional coupling of the human 5-HT2B receptor was also demonstrated in AV12-664 cells, where 5-HT produced a dose-dependent increase in phosphatidylinositol hydrolysis (EC50 = 27 +/- 12 nM) analogous to that seen with the rat 5- HT2B receptor. Reverse transcription-polymerase chain reaction studies revealed human 5-HT2B receptor mRNA to be expressed in many tissues, including the central nervous system. The presence of 5-HT2B receptor mRNA in human brain and not in rat brain raises the possibility that the 5-HT2B receptor may be of significance in higher brain function."

Wainscott, DB, Lucaites, VL, Kursar, JD, Baez, M, Nelson, DL
Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences
J Pharmacol Exp Ther 1996 276: 720-727
"The 5-Hydroxytryptamine2B (5-HT2B) receptor was cloned originally from rat stomach fundus and its pharmacology was determined to be consistent with that of the receptor responsible for contraction of rat fundal tissue in response to 5-HT. Recently, the cloning of the human homolog of the 5-HT2B receptor has been reported and, in this study, we report a detailed pharmacological characterization of this human receptor. The cloned human 5-HT2B receptor has high affinity for [3H]5-HT (Kd = 10.6 +/- 1.5 nM), and the pharmacology of this receptor matches closely the rat 5-HT2B receptor, consistent with the structural relatedness of these two proteins. Most compounds tested show no difference in affinity for the human or rat receptors. There were, however, groups of compounds that discriminated between the human and rat 5-HT2B receptors. Examples include certain ergolines such as methysergide and mesulergine, which have higher affinity for the human than for the rat receptor. Similarly, certain benzoylpiperidines, e.g., ketanserin, pirenperone and pipamperone, and the antipsychotics clozapine and olanzapine have higher affinity for the human 5-HT2B receptor. These pharmacological findings reinforce the desirability of having the human forms of receptors when considering drug actions."

Schmuck K, Ullmer C, Engels P, Lubbert H.
Cloning and functional characterization of the human 5-HT2B serotonin receptor.
FEBS Lett 1994 Mar 28;342(1):85-90
"Recently, we have reported the cloning of the rat 5-HT2B receptor cDNA. This receptor is particularly interesting since it may be involved in diseases such as migraine. Here, we describe the isolation of a human 5-HT2B receptor clone from a cDNA library derived from SH-SY5Y cells. Although the receptor sequence was only 80% homologous to the rat sequence, the exon-intron distribution was conserved between the two species. In the human body, the receptor mRNA was detected in most peripheral organs. Only low expression levels were found in the brain. After expression in HEK 293 cells, activation of the receptor stimulated the production of phosphatidylinositol. The pharmacology of this functional response correlated well with that of the rodent receptor." [Abstract]

Choi DS, Maroteaux L.
Immunohistochemical localisation of the serotonin 5-HT2B receptor in mouse gut, cardiovascular system, and brain.
FEBS Lett 1996 Aug 5;391(1-2):45-51
"We recently reported the cloning of a new member of the serotonin 5-HT2 family, the 5-HT2B receptor. We now report the production and characterisation of a specific antiserum directed against the C-terminal portion of the mouse 5-HT2B receptor. After affinity purification, this polyclonal antibody recognises specifically the mouse 5-HT2B receptor. Immunohistochemical analysis of cryosections from various adult mouse tissues reveals a major 5-HT2B receptor expression in stomach, intestine and pulmonary smooth muscles as well as in myocardium. Furthermore, the antiserum recognises specific areas of the mouse brain, including cerebellar Purkinje cells and their projection areas." [Abstract]

Claire Tournois, Vincent Mutel, Philippe Manivet, Jean-Marie Launay, and Odile Kellermann
Cross-talk between 5-Hydroxytryptamine Receptors in a Serotonergic Cell Line. INVOLVEMENT OF ARACHIDONIC ACID METABOLISM
J. Biol. Chem. 273: 17498-17503, 1998.
"The study of signaling cascades and of functional interactions between 5-hydroxytryptamine (5-HT) receptor pathways with heterogenous brain cell populations remains an arduous task. We took advantage of a serotonergic cell line to elucidate cross-talks between 5-HT receptors and to demonstrate the involvement of two 5-HT2 receptor subtypes in the regulation of 5-HT1B/1D function. The inducible 1C11 cell line has the unique property of acquiring within 4 days a complete serotonergic phenotype (1C11* cells), including three 5-HT receptors. 5-HT1B/1D and 5-HT2B receptors are expressed since day 2 of the serotonergic differentiation while 5-HT2A receptors are induced at day 4. We first established that 5-HT2B receptors are coupled with the phospholipase A2 (PLA2)-mediated release of arachidonic acid (AA) and that the activation of 5-HT2B receptors in 1C11*d2 cells inhibits the 5-HT1B/1D receptor function via a cyclooxygenase-dependent AA metabolite. At day 4, this 5-HT2B-mediated inhibition of the 5-HT1B/1D function can be blocked upon concomitant 5-HT2A activation although a 5-HT2A/PLA2 positive coupling was evidenced. This suggests the existence in 1C11*d4 cells of pathway(s) for 5-HT2A receptors, distinct from PLC and PLA2. Finally, this study reveals the antagonistic roles of 5-HT2A and 5-HT2B receptors in regulating the function of 5-HT1B/1D, a receptor involved in neuropsychiatric disorders and migraine pathogenesis." [Full Text]

Philippe Manivet, Benoît Schneider, Jeremy Christopher Smith, Doo-Sup Choi, Luc Maroteaux, Odile Kellermann, and Jean-Marie Launay
The Serotonin Binding Site of Human and Murine 5-HT2B Receptors. MOLECULAR MODELING AND SITE-DIRECTED MUTAGENESIS
J. Biol. Chem. 277: 17170-17178, February 2002.
"Bacteriorhodopsin and rhodopsin crystal structures were used as templates to build structural models of the mouse and human serotonin (5-HT)-2B receptors (5-HT(2B)Rs). Serotonin was docked to the receptors, and the amino acids predicted to participate to its binding were subjected to mutagenesis. 5-HT binding affinity and 5-HT-induced inositol triphosphate production were measured in LMTK(-) cells transfected with either wild-type or mutated receptor genes. According to these measurements, the bacteriorhodopsin-based models of the 5-HT(2B)Rs appear more confident than the rhodopsin-based ones. Residues belonging to the transmembrane domains 3 and 6, i.e. Asp(3.32), Ser(3.36), Phe(6.52), and Asn(6.55), make direct contacts with 5-HT. In addition, Trp(3.28), Phe(3.35), Phe(6.52), and Phe(7.38) form an aromatic box surrounding 5-HT. The specificity of human and mouse 5-HT(2B)Rs may be reflected by different rearrangements of the aromatic network upon 5-HT binding. Two amino acids close to Pro(5.50) in the human transmembrane domain 5 sequence were permuted to introduce a "mouse-like" sequence. This change was enough to confer the human 5-HT(2B)R properties similar to those of the mouse. Taken together, the computed models and the site-directed mutagenesis experiments give a structural explanation to (i) the different 5-HT pK(D) values measured with the human and mouse 5-HT(2B)Rs (7.9 and 5.8, respectively) and (ii) the specificity of 5-HT binding to 5-HT(2B)Rs as compared with other serotonergic G-protein coupled receptors." [Abstract]

Jean-Marie Launay, Guillaume Birraux, Dominique Bondoux, Jacques Callebert, Doo-Sup Choi, Sylvain Loric, and Luc Maroteaux
Ras Involvement in Signal Transduction by the Serotonin 5-HT2B Receptor
J. Biol. Chem. 271: 3141-3147, 1996.
"The family of serotonin 5-HT2 receptors stimulates the phospholipase C second messenger pathway via the alpha subunit of the Gq GTP-binding protein. Here, we show that agonist stimulation of the 5-HT2B receptor subtype stably expressed in the mouse fibroblast LMTK- cell line causes a rapid and transient activation of the proto-oncogene product p21ras as measured by an increase in GTP-bound Ras in response to serotonin. Furthermore, 5-HT2B receptor stimulation activates p42mapk/p44mapk (ERK2/ERK1) mitogen-activated protein kinases as assayed by phosphorylation of myelin basic protein. Antibodies against p21ras, Galphaq, -beta, or -gamma2 subunits of the GTP-binding protein inhibit MAP kinase-dependent phosphorylation. The MAP kinase activation is correlated with a stimulation of cell division by serotonin. In addition to this mitogenic action, transforming activity of serotonin is mediated by the 5-HT2B receptor since its expression in LMTK- cells is absolutely required for foci formation and for these foci to form tumors in nude mice. Finally, we detected expression of the 5-HT2B receptor in spontaneous human and Mastomys natalensis carcinoid tumors and, similar to the 5-HT2B receptor transfected cells, the Mastomys tumor cells are also responsive to serotonin with similar coupling to p21ras activation." [Full Text]

Borman, R.A., Tilford, N.S., Harmer, D.W., Day, N., Ellis, E.S., Sheldrick, R.L.G., Carey, J., Coleman, R.A., Baxter, G.S.
5-HT2B receptors play a key role in mediating the excitatory effects of 5-HT in human colon in vitro
Br. J. Pharmacol. 2002 135: 1144-1151
"1. 5-Hydroxytryptamine (5-HT) is known to produce a number of different effects in the gastrointestinal tract of various species, and has been proposed to play a key role in a number of intestinal disorders in man, including irritable bowel syndrome (IBS), although the receptors involved have yet to be established. The aim of the present study was to investigate the distribution and function of 5-HT(2B) receptors in human colon, and to establish their possible role in the aetiology of IBS. 2. The distribution of 5-HT(2B) receptor mRNA and protein were investigated by quantitative RT - PCR, Western analysis and immunocytochemistry. High levels of both mRNA and protein for 5-HT(2B) receptors were found throughout the human gastrointestinal tract, and in particular in colon, where 5-HT(2B) receptors were found predominantly in the longitudinal and circular smooth muscle layers within the muscularis externa, and in the myenteric nerve plexus lying between these two layers. 3. Electrical field stimulation of longitudinal muscle preparations of human colon mounted in organ baths resulted in neuronally-mediated contractile responses, that were significantly potentiated by application of 5-HT (up to 10(-7) M), with a pEC(50) of 8.2 +/- 0.1 (n=49 donors). The response to 5-HT was inhibited by a number of selective 5-HT(2B) receptor antagonists. 4. This study has shown for the first time that, in contrast to animal studies, the excitatory effects of 5-HT in human colon are mediated by 5-HT(2B) receptors. It is proposed that these receptors contribute to the putative 5-HT-induced colonic smooth muscle hypersensitivity associated with IBS." [Abstract]

Porter, R. H.P., Benwell, K. R., Lamb, H., Malcolm, C. S., Allen, N. H., Revell, D. F., Adams, D. R., Sheardown, M. J.
Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells
Br. J. Pharmacol. 1999 128: 13-20
"1. The goal of this study was to characterize the agonist pharmacology of human 5-HT2A, 5-HT2B and 5-HT2C (VSV) receptors expressed in CHO-K1 (Chinese hamster ovary) cells. 2. We used a fluorometric imaging plate reader (FLIPR) which allows rapid detection of rises in intracellular calcium levels upon the addition of agonists. 3. Stimulation of all three receptors by 5-HT caused a robust concentration dependent increase in intracellular calcium levels. No such effect was observed from non-transfected control CHO-K1 cells. 4. The rank order of potency of agonists at the different receptor subtypes varied. Tryptamines, BW-723C86, d-norfenfluramine, Ro 60-0175 and LSD exhibited the following rank order of potency; 5-HT2B>5-HT2C>5-HT2A. Piperazines such as m-Chlorophenylpiperazine (mCPP), ORG-12962, MK-212 and also ORG-37684 exhibited a rank order of potency of 5-HT2C>5-HT2B>5-HT2A. The phenylisopropylamines DOI and DOB had a rank order of 5-HT2A>5-HT2B>5-HT2C. 5. Many agonists tested had partial agonist actions when compared to 5-HT, and a wide range of relative efficacies were exhibited, which was cell line dependent. For example, mCPP had a relative efficacy of 65% at 5-HT2C receptors but <25% at either 5-HT2A or 5-HT2B receptors. 6. Interpretation of literature values of functional assays using different cell lines, different receptor expression levels and different receptor isoforms, is complex. Species differences and the previous use of antagonist radioligands to characterize agonist potency in binding assays emphasizes the importance of studying agonists in the same experiment using the same assay conditions and parental cell lines." [Full Text]

Nebigil CG, Etienne N, Messaddeq N, Maroteaux L.
Serotonin is a novel survival factor of cardiomyocytes: mitochondria as a target of 5-HT2B receptor signaling.
FASEB J. 2003 Jul;17(10):1373-5. Epub 2003 May 08.
"Identification of factors regulating cardiomyocyte survival and growth is important to understand the pathogenesis of congenital heart diseases. Little is known about the molecular mechanism of cardiac functions triggered by serotonin. The link between signaling circuitry of external stimuli and the mitochondrial apoptotic machinery is of wide interest in cardiac diseases. Using cultured cardiomyocytes and 5-hydroxytryptamine (5-HT)2B-receptor knockout mice as an animal model of dilated cardiomyopathy, for the first time we show that serotonin via the Gq-coupled 5-HT2B-receptor protect cardiomyocytes against serum deprivation-induced apoptosis as manifested by DNA fragmentation, nuclear chromatin condensation, and TUNEL labeling. Serotonin prevents cytochrome c release and caspase-9 and -3 activation after serum deprivation via cross-talks between phosphatidylinositol-3 kinase/Akt and extracellular signal-regulated kinase (ERK) 1/2 signaling pathways. Serotonin binding to 5-HT2B-receptor activates ERK kinases to inhibit Bax expression induced by serum deprivation. Serotonin via phosphatidylinositol-3 kinase/Akt can activate NF-kappaB that is required for the regulation of the mitochondrial adenine nucleotide translocator (ANT-1). Parallel to these observations, ultrastructural analysis in the 5-HT2B-receptor knockout mice heart revealed pronounced mitochondrial defects in addition to altered mitochondrial enzyme activities (cytochrome oxidase and succinate dehydrogenase) and ANT-1 and Bax expressions. These findings identify 5-HT as a novel survival factor targeting mitochondria in cardiomyocytes." [Abstract]

Nebigil CG, Jaffre F, Messaddeq N, Hickel P, Monassier L, Launay JM, Maroteaux L.
Overexpression of the serotonin 5-HT2B receptor in heart leads to abnormal mitochondrial function and cardiac hypertrophy.
Circulation. 2003 Jul 1;107(25):3223-9. Epub 2003 Jun 16.
"BACKGROUND: Identification of factors regulating myocardial structure and function is important to understand the pathogenesis of heart disease. We previously reported that 5-HT2B receptor ablation in mice leads to dilated cardiomyopathy. In this study, we investigated the pathological consequence of overexpressing 5-HT2B receptors in heart in vivo. METHODS AND RESULTS: We have generated transgenic mice overexpressing the Gq-coupled 5-HT2B receptor specifically in heart. We found that overexpression of 5-HT2B receptor in heart leads to ventricular hypertrophy as the result of increased cell number and size. Increased atrial natriuretic peptide and myosin heavy chain expression demonstrated activation of the molecular program for cardiac hypertrophy. Echocardiographic analysis indicated the presence of thickened ventricular free wall without alteration of the systolic function, showing that transgenic mice have compensated hypertrophy. Electron microscopic analysis revealed structural abnormalities including mitochondrial proliferation, as also manifested by histological staining. Transgenic mouse heart displayed a specific reduction in the expression levels of the adenine nucleotide translocator associated to increase in the succinate dehydrogenase and cytochrome C oxidase mitochondrial activities. CONCLUSIONS: Our results constitute the first genetic evidence that overexpression of the 5-HT2B receptor in the heart leads to compensated hypertrophic cardiomyopathy associated with proliferation of the mitochondria. This observation suggests a role for mitochondria in the hypertrophic signaling that is regulated by serotonin. These transgenic mice provide a new genetic model for hypertrophic heart disease." [Abstract]

Canan G. Nebigil, Doo-Sup Choi, Andrée Dierich, Pierre Hickel, Marianne Le Meur, Nadia Messaddeq, Jean-Marie Launay, and Luc Maroteaux
Serotonin 2B receptor is required for heart development
PNAS 97: 9508-9513, August 2000.
"Several lines of evidence suggest that the serotonin (5-hydroxytryptamine, 5-HT) regulates cardiovascular functions during embryogenesis and adulthood. 5-HT binds to numerous cognate receptors to initiate its biological effects. However, none of the 5-HT receptor disruptions in mice have yet resulted in embryonic defects. Here we show that 5-HT2B receptor is an important regulator of cardiac development. We found that inactivation of 5-HT2B gene leads to embryonic and neonatal death caused by heart defects. 5-HT2B mutant embryos exhibit a lack of trabeculae in the heart and a specific reduction in the expression levels of a tyrosine kinase receptor, ErbB-2, leading to midgestation lethality. These in vivo data suggest that the Gq-coupled receptor 5-HT2B uses the signaling pathway of tyrosine kinase receptor ErbB-2 for cardiac differentiation. All surviving newborn mice display a severe ventricular hypoplasia caused by impaired proliferative capacity of myocytes. In adult mutant mice, cardiac histopathological changes including myocyte disarray and ventricular dilation were consistently observed. Our results constitute genetic evidence that 5-HT via 5-HT2B receptor regulates differentiation and proliferation of developing and adult heart. This mutation provides a genetic model for cardiopathy and should facilitate studies of both the pathogenesis and therapy of cardiac disorders in humans." [Full Text]

Irene Westbroek, Arie van der Plas, Karien E. de Rooij, Jenneke Klein-Nulend, and Peter J. Nijweide
Expression of Serotonin Receptors in Bone
J. Biol. Chem. 276: 28961-28968, 2001.
"Here we report the presence of 5-HT2B receptor in fetal chicken bone cells. 5-HT2B receptor mRNA expression was demonstrated in osteocytes, osteoblasts, and periosteal fibroblasts, a population containing osteoblast precursor cells. Pharmacological studies using several agonists and antagonists showed that occupancy of the 5-HT2B receptor stimulates the proliferation of periosteal fibroblasts. Activity of the 5-HT2A receptor could however not be excluded. mRNA for both receptors was shown to be equally present in adult mouse osteoblasts. Osteocytes, which showed the highest expression of 5-HT2B receptor mRNA in chicken, and to a lesser extent osteoblasts, are considered to be mechanosensor cells involved in the adaptation of bone to its mechanical usage. Nitric oxide is one of the signaling molecules that is released upon mechanical stimulation of osteocytes and osteoblasts. The serotonin analog alpha-methyl-5-HT, which preferentially binds to 5-HT2 receptors, decreased nitric oxide release by mechanically stimulated mouse osteoblasts. These results demonstrate that serotonin is involved in bone metabolism and its mechanoregulation." [Full Text]

Ullmer, C, Boddeke, HG, Schmuck, K, Lubbert, H
5-HT2B receptor-mediated calcium release from ryanodine-sensitive intracellular stores in human pulmonary artery endothelial cells
Br. J. Pharmacol. 1996 117: 1081-1088
"1. We have characterized the 5-hydroxytryptamine (5-HT)-induced calcium signalling in endothelial cells from the human pulmonary artery. Using RT-PCR we show, that of all cloned G-protein coupled 5-HT receptors, these cells express only 5-HT1D beta, 5-HT2B and little 5-HT4 receptor mRNA. 2. In endothelial cells 5-HT inhibits the formation of adenosine 3':5'-cyclic monophosphate (cyclic AMP) via 5-HT1D beta receptors but fails to activate phosphoinositide (PI) turnover. However, the latter pathway is strongly activated by histamine. 3. Despite the lack of detectable inositol phosphate (IP) formation in human pulmonary artery endothelial cells, 5-HT (pD2 = 5.82 +/- 0.06, n = 6) or the selective 5- HT2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (pD2 = 5.66 +/- 0.03, n = 7) elicited transient calcium signals comparable to those evoked by histamine (pD2 = 6.44 +/- 0.01, n = 7). Since 5-HT2A and 5-HT2C receptor mRNAs are not detectable in pulmonary artery endothelial cells, activation of 5-HT2B receptors is responsible for the transient calcium release. The calcium transients are independent of the inhibition of adenylate cyclase, since DOI does not stimulate 5- HT1D beta receptors. 4. Both, the 5-HT- and histamine-stimulated calcium signals were also observed when the cells were placed in calcium-free medium. This indicates that 5-HT triggers calcium release from intracellular stores. 5. Heparin is an inhibitor of the IP3- activated calcium release channels on the endoplasmic reticulum. Intracellular infusion of heparin through patch pipettes in voltage clamp experiments failed to block 5-HT-induced calcium signals, whereas it abolished the histamine response. This supports the conclusion that the 5-HT-induced calcium release is independent of IP3 formation. 6. Unlike the histamine response, the 5-HT response was sensitive to micromolar concentrations of ryanodine and, to a lesser extent, ruthenium red. This implies that 5-HT2B receptors trigger calcium release from a ryanodine-sensitive calcium pool. 7. It has been postulated that cyclic ADP-ribose (cADPR) is a soluble second messenger which activates ryanodine receptors. However, calcium signals similar to the 5-HT response could not be elicited by intracellular infusion with cADPR. Furthermore, the subsequent application of 5-HT or DOI elicited a calcium signal that was not affected by the above pretreatment. 8. We conclude that human 5-HT2B receptors stimulate calcium release from intracellular stores through a novel pathway, which involves activation of ryanodine receptors, and is independent of PI-hydrolysis and cADPR." [Abstract]

Knowles, Ian D., Ramage, Andrew G.
Evidence that activation of central 5-HT2B receptors causes renal sympathoexcitation in anaesthetized rats
Br. J. Pharmacol. 2000 129: 177-183 [Abstract]

Choi DS, Kellermann O, Richard S, Colas JF, Bolanos-Jimenez F, Tournois C, Launay JM, Maroteaux L.
Mouse 5-HT2B receptor-mediated serotonin trophic functions.
Ann N Y Acad Sci 1998 Dec 15;861:67-73
"5-HT2B receptors, in addition to phospholipase C stimulation, are able to trigger activation of the proto-oncogene product p21ras. During mouse embryogenesis, a peak of 5-HT2B receptor expression is detected at the neurulation stage; we localized the 5-HT2B expression in neural crest cells, heart myocardium, and somites. The requirement for functional 5-HT2B receptors shortly after gastrulation, is supported by culture of embryos exposed to 5-HT2B-high affinity antagonist such as ritanserin, which induces morphological defects in the cephalic region, heart and neural tube. Functional 5-HT2B receptors are also expressed during the serotonergic differentiation of the mouse F9 teratocarcinoma-derived clonal cell line 1C11. Upon 2 days of induction by cAMP, 5-HT2B receptors become functional, and on day 4, the appearance of 5-HT2A receptors coincides with the onset of active serotonin transporter by these cells. Active serotonin uptake is modulated by serotonin suggesting autoreceptor functions for 5-HT2B receptors." [Abstract]

Amy K.L. Banes, and Stephanie W. Watts
Upregulation of Arterial Serotonin 1B and 2B Receptors in Deoxycorticosterone Acetate-Salt Hypertension
Hypertension 39: 394-398, doi:10.1161/hy02t2.102793, 2002. [Abstract]

Russell, Amber, Banes, Amy, Berlin, Hilary, Fink, Gregory D., Watts, Stephanie W.
5-Hydroxytryptamine2B Receptor Function Is Enhanced in the Nomega -Nitro-L-arginine Hypertensive Rat
J Pharmacol Exp Ther 2002 303: 179-187 [Abstract]

Stephanie W. Watts, and Gregory D. Fink
5-HT2B-receptor antagonist LY-272015 is antihypertensive in DOCA-salt-hypertensive rats
Am J Physiol Heart Circ Physiol 276: H944-H952, 1999. [Full Text]

Fiorica-Howells, Elena, Maroteaux, Luc, Gershon, Michael D.
Serotonin and the 5-HT2B Receptor in the Development of Enteric Neurons
J. Neurosci. 2000 20: 294-305
"mRNA encoding 5-HT2A and 5-HT2B receptors was detected in the fetal bowel (stomach and small and large intestine), but that encoding the 5-HT2C receptor was not. mRNA encoding the 5-HT2B receptor and 5-HT2B immunoreactivity were found to be abundant in primordial [embryonic day 15 (E15)-E16] but not in mature myenteric ganglia. 5-HT2B-immunoreactive cells were found to be a subset of cells that expressed the neuronal marker PGP9.5. These data demonstrate for the first time that the 5-HT2B receptor is expressed in the small intestine as well as the stomach and that it is expressed by enteric neurons as well as by muscle. It is possible that by stimulating 5-HT2B receptors, 5-HT affects the fate of the large subset of enteric neurons that arises after the development of endogenous sources of 5-HT." [Full Text]

Cox, DA, Cohen, ML
5-Hydroxytryptamine2B receptor signaling in rat stomach fundus: role of voltage-dependent calcium channels, intracellular calcium release and protein kinase C
J Pharmacol Exp Ther 1995 272: 143-150 [Abstract]

Kovacs A, Gacsalyi I, Wellmann J, Schmidt E, Szucs Z, Dubreuil V, Nicolas JP, Boutin J, Bozsing D, Egyed A, Tihanyi K, Spedding M, Szenasi G.
Effects of EGIS-7625, a selective and competitive 5-HT2B receptor antagonist.
Cardiovasc Drugs Ther. 2003 Sep-Nov;17(5-6):427-34.
"Our aim was to specify the 5-HT(2) subtype selectivity of EGIS-7625 (1-benzyl-4-[(2-nitro-4-methyl-5-amino)-phenyl]-piperazine), a new 5-HT(2B) ligand, in receptor binding studies and characterize its pharmacology at 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors in in vivo experiments and in isolated organs, in vitro. EGIS-7625 had high affinity for recombinant human 5-HT(2B) receptors (pK(i) = 9.0) but much weaker affinity for 5-HT(2A) and 5-HT(2C) receptors (pK(i) = 6.2 and 7.7, respectively). In the classic 5-HT(2B) test, EGIS-7625 produced a concentration-related parallel rightward shift in the concentration-response relationship for the 5-HT-induced smooth muscle constriction in rat stomach fundus strips with a pA(2) of 9.4. On the other hand, EGIS-7625 was a weak competitive antagonist at 5-HT(2A) receptors as it shifted 5-HT-induced concentration-response curves to the right at high concentrations (pA(2) = 6.7) in rabbit pulmonary artery strips. The m-chlorophenylpiperazine-induced hypomotility and hypophagia was only partially attenuated by EGIS-7625 even at a dose of 30 mg/kg i.p. while mianserin, a non-selective 5-HT antagonist was almost fully effective in these tests at 3 mg/kg i.p., suggesting weak antagonistic effect of EGIS-7625 at neuronal 5-HT(2C) receptors, in vivo. In conclusion, EGIS-7625 is a potent, selective and competitive 5-HT(2B) antagonist that seems to be a good research tool for the separation of the functional roles of vascular 5-HT(2A) and 5-HT(2B) receptors." [Abstract]

Canan G. Nebigil, Pierre Hickel, Nadia Messaddeq, Jean-Luc Vonesch, Marie P. Douchet, Laurent Monassier, Katalin György, Rachel Matz, Ramaroson Andriantsitohaina, Philippe Manivet, Jean-Marie Launay, and Luc Maroteaux
Ablation of Serotonin 5-HT2B Receptors in Mice Leads to Abnormal Cardiac Structure and Function
Circulation 103: 2973-2979, 2001.
"Mutation of 5-HT2B receptor leads to a cardiomyopathy without hypertrophy and a disruption of intercalated disks. 5-HT2B receptor is required for cytoskeleton assembly to membrane structures by its regulation of N-cadherin expression. These results constitute, for the first time, strong genetic evidence that serotonin, via the 5-HT2B receptor, regulates cardiac structure and function." [Full Text]

Choi, DS, Ward, SJ, Messaddeq, N, Launay, JM, Maroteaux, L
5-HT2B receptor-mediated serotonin morphogenetic functions in mouse cranial neural crest and myocardiac cells
Development 1997 124: 1745-1755 [Abstract/Full Text]

Ellis, ES, Byrne, C, Murphy, OE, Tilford, NS, Baxter, GS
Mediation by 5-hydroxytryptamine2B receptors of endothelium-dependent relaxation in rat jugular vein
Br. J. Pharmacol. 1995 114: 400-404
"1. An 'atypical' 5-HT2 receptor which is located on the endothelium of rat jugular vein has been described. In the present study we have further defined the nature of the 5-HT2 receptor subtype present in this preparation. 2. In experiments conducted in the presence of ketanserin to preclude involvement of 5-HT2 receptors, the mixed 5- HT2B/2C antagonist, SB 200646, acted as an antagonist of 5-HT at the endothelial 5-HT receptor (pA2 = 7.2). Yohimbine, which exhibits negligible affinity for rat 5-HT2C receptors but has high 5-HT2B receptor affinity, acted as a potent but non-surmountable antagonist (pA2 > or = 7.3) in rat jugular vein. Neither yohimbine nor SB 200646 affected endothelium-dependent relaxations induced by carbachol. 3. Mianserin also acted as a surmountable antagonist (pA2 = 7.3) and the 5- HT2B agonist, BW 723C86, acted as a potent partial agonist (pEC50 [95% C L], intrinsic activity +/- s.e. mean = 7.9 [7.6-8.3], 0.84 +/- 0.04). Responses to BW 723C86 were antagonized by SB 200646 (0.3 microM) yielding an 'apparent' pA2 [95% CL] of 7.03 [6.76-7.32]. 4. These data are consistent with the presence of 5-HT2B receptors mediating endothelium-dependent relaxation of rat jugular vein." [Abstract]

Loric, S, Maroteaux, L, Kellermann, O, Launay, JM
Functional serotonin-2B receptors are expressed by a teratocarcinoma- derived cell line during serotoninergic differentiation
Mol Pharmacol 1995 47: 458-466
"Among immortalized teratocarcinoma-derived cells, the clone 1C11 is a committed precursor of the neuronal lineage. On day 2 of its serotoninergic differentiation, this clone expresses only one subtype of serotonin [5-hydroxytryptamine (5-HT)] receptor, which is functionally coupled to phosphatidylinositol hydrolysis. The identity of these receptors was established by comparing their properties with those of 5-HT2B receptors expressed by LMTK- fibroblasts stably transfected with the recently cloned murine cDNA NP75 (LM5 cells). In both cell types, the analysis of (+/-)-1-(2,5-dimethoxy-4- [125I]iodophenyl)- 2-aminopropane HCl ([125I]DOI) binding revealed the presence of a single class of sites, the affinity of which was 1 order of magnitude lower than that reported for 5-HT2A receptors. In 1C11 cells differentiated for 2 days, as well as in LM5 cells, DOI binding was decreased by nonhydrolyzable analogs of GTP, indicating that the 5- HT2B receptor is functionally coupled to a G protein. The DOI-induced increase of phosphoinositide hydrolysis, which was correlated with both GTPase activity and binding data, is mediated by a Gq protein. This work demonstrates that the 5-HT2B receptor is functionally expressed before complete serotoninergic differentiation of 1C11 cells. The inducible 1C11 clone thus provides an in vitro model to investigate the possible role of the 5-HT2B receptor in the expression of the serotoninergic phenotype."


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Recent 5-HT2B Receptor Research

1) Fujitsuka N, Asakawa A, Amitani H, Hattori T, Inui A
Efficacy of ghrelin in cancer cachexia: clinical trials and a novel treatment by rikkunshito.
Crit Rev Oncog. 2012;17(3):277-84.
Cachexia is characterized by decreased food intake, increased energy expenditure, and muscle wasting. It is observed in 80% of patients with advanced-stage cancer and is a major source of decreased quality of life and increased morbidity and mortality in cancer patients. Ghrelin plays an important role in stimulating hunger and maintaining energy homeostasis and is the first-line treatment option for cancer cachexia. Several studies in rodent models and clinical trials have demonstrated that ghrelin or ghrelin receptor (GHS-R) agonists are effective in the treatment of cancer cachexia; however, further large-scale long-term clinical trials are needed to confirm sustained effects. Recently, the traditional Japanese medicine rikkunshito has been shown to increase food intake in rats with cancer or administered chemotherapeutics. The orexigenic effect of rikkunshito is involved in the stimulation of endogenous ghrelin secretion by blocking the serotonin (5-HT) 2b/2c receptor pathway and the enhancement of GHS-R activity. A potentiator of ghrelin signaling such as rikkunshito may represent a novel approach for the treatment of cancer cachexia. [PubMed Citation] [Order full text from Infotrieve]

2) Baptista D, Nunes-de-Souza RL, Canto-de-Souza A
Activation of 5-HT(2C) receptors in the dorsal periaqueductal gray increases antinociception in mice exposed to the elevated plus-maze.
Behav Brain Res. 2012 Jul 16;
Several findings have pointed to the role of the dorsal periaqueductal gray (dPAG) serotonin 5-HT(1A) and 5-HT(2A-C) receptor subtypes in the modulation of defensive behavior in animals exposed to the elevated plus-maze (EPM). Besides displaying anxiety-like behavior, rodents also exhibit antinociception in the EPM. This study investigated the effects of intra-dPAG injections of 5-HT(1A) and 5-HT(2B/2C) receptor ligands on EPM-induced antinociception in mice. Male Swiss mice received 0.1?l intra-dPAG injections of vehicle, 5.6 and 10nmol of 8-OHDPAT, a 5-HT(1A) receptor agonist (Experiment 1), or 0.01, 0.03 and 0.1nmol of mCPP, a 5-HT(2B/2C) receptor agonist (Experiment 2). Five minutes later, each mouse received an intraperitoneal injection of 0.6% acetic acid (0.1ml/10g body weight; nociceptive stimulus) and was individually confined in the open (OA) or enclosed (EA) arms of the EPM for 5min, during which the number of abdominal writhes induced by the acetic acid was recorded. While intra-dPAG injection of 8-OHDPAT did not change open-arm antinociception (OAA), mCPP (0.01nmol) enhanced it. Combined injections of ketanserin (10nmol/0.1?l), a 5-HT(2A/2C) receptor antagonist, and 0.01nmol of mCPP (Experiment 3), selectively and completely blocked the OAA enhancement induced by mCPP. Although intra-dPAG injection of mCPP (0.01nmol) also produced antinociception in EA-confined mice (Experiment 2), this effect was not confirmed in Experiment 3. Moreover, no other compound changed the nociceptive response in EA-confined animals. These results suggest that the 5-HT(2C) receptors located within the PAG play a role in this type of environmentally induced pain inhibition in mice. [PubMed Citation] [Order full text from Infotrieve]

3) Chen G, Cho SJ, Huang XP, Jensen NH, Svennebring A, Sassano MF, Roth BL, Kozikowski AP
Rational Drug Design Leading to the Identification of a Potent 5-HT(2C) Agonist Lacking 5-HT(2B) Activity.
ACS Med Chem Lett. 2011 Dec 8;2(12):929-932.
The 5-HT(2C) receptor is an attractive drug target in the quest for new therapeutics to treat a variety of human disorders. We have previously undertaken a structural optimization campaign that has led to some potent and moderately selective 5-HT(2C) receptor agonists. After expanding our structure-function library, we were able to combine our datasets so as to allow the design of compounds of improved selectivity and potency. We disclose herein the structural optimization of our previously reported 5-HT(2B)/5-HT(2C) agonists, which has led to the identification of a highly selective 5-HT(2C) agonist, (+)-trans-[2-(2-cyclopropylmethoxyphenyl)cyclopropyl]methylamine hydrochloride, with an EC(50) of 55 nM and no detectable agonism at the 5-HT(2B) receptor. [PubMed Citation] [Order full text from Infotrieve]

4) Martins LC, Rocha NP, Torres KC, Dos Santos RR, França GS, de Moraes EN, Mukhamedyarov MA, Zefirov AL, Rizvanov AA, Kiyasov AP, Vieira LB, Guimarães MM, Yalvaç ME, Teixeira AL, Bicalho MA, Janka Z, Romano-Silva MA, Palotás A, Reis HJ
Disease-specific expression of the serotonin-receptor 5-HT(2C) in natural killer cells in Alzheimer's dementia.
J Neuroimmunol. 2012 Jul 3;
Alzheimer's dementia (AD) is a degenerative brain disorder characterized mainly by cholinergic failure, but other neuro-transmitters are also deficient especially at late stages of the disease. Misfolded ?-amyloid peptide has been identified as a causative agent, however inflammatory changes also play a pivotal role. Even though the most prominent pathology is seen in the cognitive functions, specific abnormalities of the central nervous system (CNS) are also reflected in the periphery, particularly in the immune responses of the body. The aim of this study was to characterize the dopaminergic and serotonergic systems in AD, which are also markedly disrupted along with the hallmark acetyl-choline dysfunction. Peripheral blood mono-nuclear cells (PBMCs) from demented patients were judged against comparison groups including individuals with late-onset depression (LOD), as well as non-demented and non-depressed subjects. Cellular sub-populations were evaluated by mono-clonal antibodies against various cell surface receptors: CD4/CD8 (T-lymphocytes), CD19 (B-lymphocytes), CD14 (monocytes), and CD56 (natural-killer (NK)-cells). The expressions of dopamine D(3) and D(4), as well as serotonin 5-HT(1A), 5-HT(2A), 5-HT(2B) and 5-HT(2C) were also assessed. There were no significant differences among the study groups with respect to the frequency of the cellular sub-types, however a unique profound increase in 5-HT(2C) receptor exclusively in NK-cells was observed in AD. The disease-specific expression of 5-HT(2C), as well as the NK-cell cyto-toxicity, has been linked with cognitive derangement in dementia. These changes not only corroborate the existence of bi-directional communication between the immune system and the CNS, but also elucidate the role of inflammatory activity in AD pathology, and may serve as potential biomarkers for less invasive and early diagnostic purposes as well. [PubMed Citation] [Order full text from Infotrieve]

5) Li B, Dong L, Wang B, Cai L, Jiang N, Peng L
Cell Type-Specific Gene Expression and Editing Responses to Chronic Fluoxetine Treatment in the In Vivo Mouse Brain and Their Relevance for Stress-Induced Anhedonia.
Neurochem Res. 2012 Jun 19;
Recently developed methods for fluorescence-activated cell sorting (FACS) of freshly-isolated brain cells from transgenic mice combining fluorescent signals with cell type-specific markers allow cell-type separation. Based upon previous observations in primary cultures of mouse astrocytes we treated transgenic mice tagged with a neuron-specific or an astrocyte-specific marker with fluoxetine, either acute (10 mg/kg for 2 h) or chronic (10 mg/kg daily for 2 weeks). Acute treatment upregulated cfos and fosB mRNA expression in astrocytes and neurons. Chronic effects on astrocytes replicated those demonstrated in cultures, i.e., upregulation of mRNA and/or protein expression of 5-HT(2B) receptors (5-HT(2B)R), and GluK2 receptors, and of cPLA(2a) and ADAR2, together with increased GluK2 and 5-HT(2B)R editing. Neurons showed increased GluK4 and 5-HT(2C) receptor expression. To further correlate these findings with major depression we compared the changes in gene expression with those in a mouse model of anhedonia. Three out of 4 genes up-regulated in astrocytes by fluoxetine were down-regulated, whereas the neuronally upregulated 5-HT(2C) receptor gene showed no change. References are made to recent review papers discussing potential relations between observed fluoxetine effects and clinical effects of SSRIs, emphasizing that all 5 clinically used SSRIs have identical and virtually equipotent effects on cultured astrocytes. [PubMed Citation] [Order full text from Infotrieve]

6) Lin X, Huang XP, Chen G, Whaley R, Peng S, Wang Y, Zhang G, Wang SX, Wang S, Roth BL, Huang N
Life Beyond Kinases: Structure-Based Discovery of Sorafenib as Nanomolar Antagonist of 5-HT Receptors.
J Med Chem. 2012 Jun 28;55(12):5749-59.
Of great interest in recent years has been computationally predicting the novel polypharmacology of drug molecules. Here, we applied an "induced-fit" protocol to improve the homology models of 5-HT(2A) receptor, and we assessed the quality of these models in retrospective virtual screening. Subsequently, we computationally screened the FDA approved drug molecules against the best induced-fit 5-HT(2A) models and chose six top scoring hits for experimental assays. Surprisingly, one well-known kinase inhibitor, sorafenib, has shown unexpected promiscuous 5-HTRs binding affinities, K(i) = 1959, 56, and 417 nM against 5-HT(2A), 5-HT(2B), and 5-HT(2C), respectively. Our preliminary SAR exploration supports the predicted binding mode and further suggests sorafenib to be a novel lead compound for 5HTR ligand discovery. Although it has been well-known that sorafenib produces anticancer effects through targeting multiple kinases, carefully designed experimental studies are desirable to fully understand whether its "off-target" 5-HTR binding activities contribute to its therapeutic efficacy or otherwise undesirable side effects. [PubMed Citation] [Order full text from Infotrieve]

7) Ivachtchenko AV, Golovina ES, Kadieva MG, Kysil VM, Mitkin OD, Vorobiev AA, Okun I
Antagonists of 5-HT(6) receptors. Substituted 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines-Synthesis and 'structure-activity' relationship.
Bioorg Med Chem Lett. 2012 Jul 1;22(13):4273-80.
Synthesis and biological evaluation of a new series of structurally unrestricted and intramolecular hydrogen bond restricted derivatives of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines (angular tricyclics) and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines (linear tricyclics) are described. Structurally restricted derivatives are highly potent and selective blockers of 5-HT(6) receptors with little difference between angular or linear shape of the tricyclic core, the angular species being only slightly more potent. The angular representative of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines, 5, can be considered as more favorable candidate for further development as it shows only weak 5-HT(2B) blocking activity (IC(50)=6.16?M as compared with IC(50)=1.8nM for 5-HT(6) receptors) and very low hERG potassium channel blocking potency (IC(50)=54.2?M). The linear analog, 11, is less favorable as while showing no binding to the 5-HT(2B) receptor at concentrations of up to 10?M, it exhibits quite a high potency to block the hERG channel (IC(50)=0.5?M). [PubMed Citation] [Order full text from Infotrieve]

8) Bharti S, Singh R, Kumar R, Malik S, Hussain T, Al-Attas OS, Arya DS
Hsp70 overexpression coordinately regulates myocardial hypertrophy, fibrosis and contractile function in 5-HT(2B) blockade mediated anti-hypertrophic effect.
Biochim Biophys Acta. 2012 May 29;
Of all the serotonin receptor subtypes, 5-HT(2B) receptor blockade (5-HT(2B)RB) has emerged as the strongest candidate in ameliorating cardiac hypertrophy; however the concerned mechanism driving this activity is largely unknown. Since heat shock protein70 (Hsp70) has been shown to prevent myocardial damage through regulation of oxidative stress, cell survival and demise of cardiomyocytes; there might exist a cross-talk between 5-HT(2B)R and Hsp70. To test this hypothesis, we administered a 5-HT(2B)R blocker, SB-204741 (1mg/kg/day, i.p.) and SB-204741 plus Hsp70 inhibitor, KNK437 (25mg/kg/day, i.p.) in isoproterenol (3mg/kg/day, s.c.) or angiotensin-II (100ng/kg/min, s.c.) induced rat model of cardiac hypertrophy for 28days. Intriguingly, 5-HT(2B)RB significantly (P<0.01) ameliorated myocardial dysfunction, myocyte area, interstitial and perivascular fibrosis, mitochondrial swelling and myocardial architecture in isoproterenol and angiotensin-II insulted myocardium. Moreover, this improvement in functional and morphological changes was associated with suppression of hypertrophic, inflammatory (IKK-?/NF-?B/TNF-? and CRP), and apoptotic markers along with amplified expressions of Hsp70 and MnSOD. Enzyme mobility shift assay (EMSA) further confirmed the binding of NF-?B to the promoter region of Hsp70 and 5-HT(2B). Surprisingly, KNK437 significantly (P<0.05) abrogated the preventive action of 5-HT(2B)RB and exacerbated the myocardial injury as evidenced by decreased expression of Hsp70 and augmented levels of hypertrophic, inflammatory, and apoptotic markers, thereby substantiating the role of Hsp70 in 5-HT(2B)RB mediated anti-hypertrophic effect. In conclusion, for the first time, present findings signify that induction of Hsp70 is at least in part is accountable for the anti-hypertrophic effect of 5-HT(2B)RB, and abrogation of Hsp70 induction significantly attenuates the anti-hypertrophic effect of 5-HT(2B)RB. [PubMed Citation] [Order full text from Infotrieve]

9) Kadiri N, Lagière M, Le Moine C, Millan MJ, De Deurwaerdère P, Navailles S
Diverse effects of 5-HT(2C) receptor blocking agents on c-Fos expression in the rat basal ganglia.
Eur J Pharmacol. 2012 Aug 15;689(1-3):8-16.
Serotonin(2C) receptors (5-HT(2)C) exert continuous control on the activity of specific populations of neurons in the basal ganglia. While antagonists block the effect of endogenous 5-HT at 5-HT(2C) receptors, the actions of inverse agonists may also involve interruption of activity at constitutively active populations of 5-HT(2C) receptors. We have evaluated the regional impact of these controls by studying, in rats, the expression of the product of the proto-oncogene c-Fos in rat basal ganglia after peripheral doses of the 5-HT(2C) antagonist SB 243213 (5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline) and the 5-HT(2B/2C) inverse agonists SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole.hydrochloride) and S32006 (N-pyridin-3-yl-1,2-dihydro-3H-benzo[e]indole-3-carboxamide). The results show that 1 and 10mg/kg SB 243213 enhanced equally c-Fos expression in the subthalamic nucleus (STN) and dose-dependently in the striatum and nucleus accumbens core (NAcc). SB 206553 (1-10mg/kg), at 10mg/kg only, enhanced c-Fos expression in STN, striatum (except the dorsomedial part), NAcc, entopeduncular nucleus, substantia nigra pars reticulata (SNr) and compacta (SNc) and ventral tegmental area. S32006 induced a similar increase in c-Fos expression in the medial parts of the striatum and NAcc at doses of 1-10mg/kg while it dose-dependently enhanced c-Fos expression in medial parts of the STN and SNr. None of these drugs induced c-Fos expression in the globus pallidus. The distinct pattern of c-Fos expression elicited by the 5-HT(2C) antagonist and inverse agonists suggests the existence of cellular and functional heterogeneity in the response of the basal ganglia to drugs inhibiting 5-HT(2C) receptors. [PubMed Citation] [Order full text from Infotrieve]

10) Yarman S, Kurtulmus N, Bilge A
Optimal effective doses of cabergoline and bromocriptine and valvular leasions in men with prolactinomas.
Neuro Endocrinol Lett. 2012;33(3):340-6.
[PubMed Citation] [Order full text from Infotrieve]

11) Uezono Y, Miyano K, Suzuki M, Sudo Y, Shiraishi S, Terawaki K
A review of traditional Japanese medicines and their potential mechanism of action.
Curr Pharm Des. 2012 May 23;
Traditional Japanese herbal, or Kampo medicine was developed and modified from Chinese herbal medicine. After the Japanese government approved Kampo for clinical use, much attention has been paid to establishing scientific evidence for the effectiveness of these medicines. Recent progress has been made in elucidating the mechanisms of action of some types of Kampo medicine, including rikkunshito (RKT), daikenchuto, and yokukansan. In this review, we focused on identifying the target molecules and the active ingredients of RKT. Thus far, many target molecules have been implicated in the mechanism of action of Kampo medicines, such as ion channels, enzymes, and receptors. In particular, G protein-coupled receptors are attractive candidates for explaining herbal medicine activity. This is particularly true of RKT, which is composed of 8 independent, crude drug extracts. Recent reports have shown that RKT elicits its effects through dual action to the G protein-coupled receptors: inhibition of serotonergic 5-HT2C and 5-HT2B receptors and activation of ghrelin receptors via specific ingredients of RKT. In addition, we suggest that the identification of the effective ingredients from Kampo medicines could contribute to the discovery and development of new drugs by means of modern high-throughput drug screening technology. [PubMed Citation] [Order full text from Infotrieve]

12) Zhang Y, Zhang RX, Zhang M, Shen XY, Li A, Xin J, Ren K, Berman BM, Tan M, Lao L
Electroacupuncture inhibition of hyperalgesia in an inflammatory pain rat model: involvement of distinct spinal serotonin and norepinephrine receptor subtypes.
Br J Anaesth. 2012 Aug;109(2):245-52.
[PubMed Citation] [Order full text from Infotrieve]

13) Dawson P, Moffatt JD
Cardiovascular toxicity of novel psychoactive drugs: Lessons from the past.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 May 10;
The long use of ephedrine, amphetamines, cocaine, LSD and more recently 3,4-methylenedioxy-N-methylamphetamine (MDMA; "Ecstasy") allows us to predict with some confidence what cardiovascular risks are likely to be associated with novel psychoactive substances (NPS). Once the probably multiple biological activities of a compound are known it is possible to define the likely risks of cardiovascular toxicity. Agonists of 5-HT(2A) receptors or alpha-adrenoceptors may cause vasoconstriction and tissue ischemia. Drugs which have agonist affinity for 5-HT(2B) receptors will probably promote heart valve fibrosis leading to heart failure. Compounds that interfere with uptake of dopamine or 5-hydroxytryptamine (5-HT) are likely to also have effects on noradrenergic neurotransmission and lead to sympathomimetic effects on the heart and vasculature. Drugs that cause dopamine release, or inhibit uptake are likely to be addictive and lead to chronic use. Other drugs (particularly the so-called empathogens) are associated with weekly usage in social settings; over time such use can lead to cardiovascular harm. Defining which of these effects NPS have is an important element of predicting the harm they may cause and informing those appointed to introduce regulations to control them. [PubMed Citation] [Order full text from Infotrieve]

14) Evrard HC, Forro T, Logothetis NK
Von Economo neurons in the anterior insula of the macaque monkey.
Neuron. 2012 May 10;74(3):482-9.
The anterior insular cortex (AIC) and its unique spindle-shaped von Economo neuron (VEN) emerged within the last decade as having a potentially major role in self-awareness and social cognition in humans. Invasive examination of the VEN has been precluded so far by the assumption that this neuron occurs among primates exclusively in humans and great apes. Here, we demonstrate the presence of the VEN in the agranular anterior insula of the macaque monkey. The morphology, size, laminar distribution, and proportional distribution of the monkey VEN suggest that it is at least a primal anatomical homolog of the human VEN. This finding sheds new light on the phylogeny of the VEN and AIC. Most importantly, it offers new and much-needed opportunities to investigate the primal connections and physiology of a neuron that could be crucial for human self-awareness, social cognition, and related neuropsychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

15) Davis RP, Pattison J, Thompson JM, Tiniakov R, Scrogin KE, Watts SW
5-hydroxytryptamine (5-HT) reduces total peripheral resistance during chronic infusion: direct arterial mesenteric relaxation is not involved.
BMC Pharmacol. 2012 May 6;12(1):4.
ABSTRACT: Serotonin (5-hydroxytryptamine; 5-HT) delivered over 1 week results in a sustained fall in blood pressure in the sham and deoxycorticosterone acetate (DOCA)-salt rat. We hypothesized 5-HT lowers blood pressure through direct receptor-mediated vascular relaxation. In vivo, 5-HT reduced mean arterial pressure (MAP), increased heart rate, stroke volume, cardiac index, and reduced total peripheral resistance during a 1 week infusion of 5-HT (25 micrograms/kg/min) in the normotensive Sprague Dawley rat. The mesenteric vasculature was chosen as an ideal candidate for the site of 5-HT receptor mediated vascular relaxation given the high percentage of cardiac output the site receives. Real-time RT-PCR demonstrated that mRNA transcripts for the 5-HT2B, 5-HT1B, and 5-HT7 receptors are present in sham and DOCA-salt superior mesenteric arteries. Immunohistochemistry and Western blot validated the presence of the 5-HT2B, 5-HT1B and 5-HT7 receptor protein in sham and DOCA-salt superior mesenteric artery. Isometric contractile force was measured in endothelium-intact superior mesenteric artery and mesenteric resistance arteries in which the contractile 5-HT2A receptor was antagonized. Maximum concentrations of BW-723C86 (5-HT2B agonist), CP 93129 (5-HT1B agonist) or LP-44 (5-HT7 agonist) did not relax the superior mesenteric artery from DOCA-salt rats vs. vehicle. Additionally, 5-HT (1 nM to 10 uM) did not cause relaxation in either contracted mesenteric resistance arteries or superior mesenteric arteries from normotensive Sprague-Dawley rats. Thus, although 5-HT receptors known to mediate vascular relaxation are present in the superior mesenteric artery, they are not functional, and are therefore not likely involved in a 5-HT-induced fall in total peripheral resistance and MAP. [PubMed Citation] [Order full text from Infotrieve]

16) Urtikova N, Berson N, Van Steenwinckel J, Doly S, Truchetto J, Maroteaux L, Pohl M, Conrath M
Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain.
Pain. 2012 Jun;153(6):1320-31.
Serotonin is critically involved in neuropathic pain. However, its role is far from being understood owing to the number of cellular targets and receptor subtypes involved. In a rat model of neuropathic pain evoked by chronic constriction injury (CCI) of the sciatic nerve, we studied the role of 5-HT(2B) receptor in dorsal root ganglia (DRG) and the sciatic nerve. We showed that 5-HT(2B) receptor activation both prevents and reduces CCI-induced allodynia. Intrathecal administration of 5-HT(2B) receptor agonist BW723C86 significantly attenuated established mechanical and cold allodynia; this effect was prevented by co-injection of RS127445, a selective 5-HT(2B) receptor antagonist. A single application of BW723C86 on the sciatic nerve concomitantly to CCI dose-dependently prevented mechanical allodynia and significantly reduced cold allodynia 17 days after CCI. This behavioral effect was accompanied with a marked decrease in macrophage infiltration into the sciatic nerve and, in the DRG, with an attenuated abnormal expression of several markers associated with local neuroinflammation and neuropathic pain. CCI resulted in a marked upregulation of 5-HT(2B) receptor expression in sciatic nerve and DRG. In the latter structure, it was biphasic, consisting of a transient early increase (23-fold), 2 days after the surgery and before the neuropathic pain emergence, followed by a steady (5-fold) increase, that remained constant until pain disappeared. In DRG and sciatic nerve, 5-HT(2B) receptors were immunolocalized on sensory neurons and infiltrating macrophages. Our data reveal a relationship between serotonin, immunocytes, and neuropathic pain development, and demonstrate a critical role of 5-HT(2B) receptors in blood-derived macrophages. [PubMed Citation] [Order full text from Infotrieve]

17) Aira Z, Buesa I, García Del Caño G, Salgueiro M, Mendiable N, Mingo J, Aguilera L, Bilbao J, Azkue JJ
Selective impairment of spinal mu-opioid receptor mechanism by plasticity of serotonergic facilitation mediated by 5-HT2A and 5-HT2B receptors.
Pain. 2012 Jul;153(7):1418-25.
Opioid analgesia is compromised by intracellular mediators such as protein kinase C (PKC). The phosphatidylinositol hydrolysis-coupled serotonin receptor 5-HT2 is ideally suited to promote PKC activation. We test the hypothesis that 5-HT2A and 5-HT2B receptors, which have been previously shown to become pro-excitatory after spinal nerve ligation (SNL), can negatively influence the ability of opioids to depress spinal excitation evoked by noxious input. Spinal superfusion with (100nM) mu-opioid receptor (MOR)-agonist DAMGO significantly depressed C fiber-evoked spinal field potentials. Simultaneous administration of subclinical 5-HT2AR antagonist 4F 4PP (100nM) or 5-HT2BR antagonist SB 204741 (100nM) significantly reduced the IC50 value for DAMGO in nerve-ligated rats (97.56nM±1.51 and 1.20nM±1.28 respectively, relative to 104nM±1.08 at the baseline condition), but not in sham-operated rats. Both antagonists failed to alter depression induced by delta-opioid receptor (DOR)-agonist D-ala2-deltorphin II after SNL as well as in the sham condition. Western blot analysis of dorsal horn homogenates revealed bilateral upregulation of 5-HT2AR and 5-HT2BR protein band densities after SNL. As assessed from double immunofluorescence labeling for confocal laser scanning microscopy, scarce dorsal horn cell processes showed co-localization color overlay for 5-HT2AR/MOR, 5-HT2BR/MOR, 5-HT2AR/DOR, or 5-HT2BR/DOR in sham-operated rats. Intensity correlation-based analyses showed significant increases in 5-HT2AR/MOR and 5-HT2BR/MOR co-localizations after SNL. These results indicate that plasticity of spinal serotonergic neurotransmission can selectively reduce spinal MOR mechanisms via 5-HT2A and 5-HT2B receptors, including upregulation of the latter and increased expression in dorsal horn neurons containing MOR. [PubMed Citation] [Order full text from Infotrieve]

18) Henriksen R, Dizeyi N, Abrahamsson PA
Expression of serotonin receptors 5-HT1A, 5-HT1B, 5-HT2B and 5-HT4 in ovary and in ovarian tumours.
Anticancer Res. 2012 Apr;32(4):1361-6.
[PubMed Citation] [Order full text from Infotrieve]

19) Cervantes-Durán C, Vidal-Cantú GC, Barragán-Iglesias P, Pineda-Farias JB, Bravo-Hernández M, Murbartián J, Granados-Soto V
Role of peripheral and spinal 5-HT2B receptors in formalin-induced nociception.
Pharmacol Biochem Behav. 2012 Jul;102(1):30-5.
In this study we assessed the role of local peripheral and spinal serotonin 2B (5-HT(2B)) receptors in rats submitted to the formalin test. For this, local peripheral ipsilateral, but not contralateral, administration of the highly selective 5-HT(2B) receptor antagonist 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyridine (RS-127445, 0.01-1 nmol/paw) significantly prevented 1% formalin-induced flinching behavior. Moreover, local peripheral ipsilateral, but not contralateral, of the selective 5-HT(2) receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI, 1-10 nmol/paw) augmented 0.5% formalin-induced nociceptive behavior. The local pronociceptive effect of the 5-HT(2) receptor agonist DOI (10 nmol/paw) was significantly prevented by the local injection of RS-127445 (0.01 nmol/paw). Moreover, intrathecal injection of the selective 5-HT(2B) receptor antagonist RS-127445 (0.1-10 nmol/rat) also prevented 1% formalin-induced nociceptive behavior. In contrast, spinal injection of the 5-HT(2) receptor agonist DOI (1-10 nmol/rat) significantly increased flinching behavior induced by 0.5% formalin. The spinal pronociceptive effect of the 5-HT(2) receptor agonist DOI (10 nmol/rat) was prevented by the intrathecal injection of the 5-HT(2B) receptor antagonist RS-127445 (0.1 nmol/rat). Our results suggest that the 5-HT(2B) receptors play a pronociceptive role in peripheral as well as spinal sites in the rat formalin test. 5-HT(2B) receptors could be a target to develop analgesic drugs. [PubMed Citation] [Order full text from Infotrieve]

20) Lapi F, Nicotra F, Scotti L, Vannacci A, Thompson M, Pieri F, Mugelli N, Zambon A, Corrao G, Mugelli A, Rubino A
Br J Clin Pharmacol. 2012 Feb 22;
Aim: To quantify the risk of Cardiac Valvulopathy (CV) associated with the use of antidepressant Serotoninergic Medications (SMs) that activate 5-HT(2B) receptors. Methods: We conducted a case-control study nested in a cohort of antidepressant SMs users selected from The Health Improvement Network database. Patients who experienced a CV (index date) event during follow-up were cases. Cases were ascertained in a random sample of them. Up to 10 controls were matched to each case by sex, age, month and year of the study entry. Antidepressant SMs use during follow-up was defined as current (the last antidepressant SMs prescription occurred in the 2 months before the index date), recent (in the 2-12 months before the index date) and past (? 12 months before the index date). We fitted a conditional regression model to estimate the association between antidepressant SMs use and the risk of CV by means of Odds Ratios (OR) and corresponding 95% Confidence Intervals (CI). Sensitivity analyses were conducted to test the robustness of our results. Results: The study cohort included 752,945 subjects aged 18-89 years. Throughout follow-up 1663 (3.4 per 10,000 person-years) cases of CV were detected and were matched to 16566 controls. The adjusted OR (95% CI) for current and recent users compared to past users of antidepressant SMs were 1.16 (0.96-1.40) and 1.06 (0.93-1.22), respectively. Consistent effect estimates were obtained when considering cumulative exposure to antidepressant SMs during follow-up. Conclusions: These results would suggest that antidepressant SMs exposure is not associated with an increased risk of CV. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society. [PubMed Citation] [Order full text from Infotrieve]