The inhibition of cholera toxin-induced 5-HT release by the 5-HT3 receptor antagonist, granisetron, in the rat

PubMed Central

Turvill, J L; Connor, P; Farthing, M J G

2000-01-01

The secretagogue 5-hydroxytryptamine (5-HT) is implicated in the pathophysiology of cholera. 5-HT released from enterochromaffin cells after cholera toxin exposure is thought to activate non-neuronally (5-HT2 dependent) and neuronally (5-HT3 dependent) mediated water and electrolyte secretion. CT-secretion can be reduced by preventing the release of 5-HT. Enterochromaffin cells possess numerous receptors that, under basal conditions, modulate 5-HT release. These include basolateral 5-HT3 receptors, the activation of which is known to enhance 5-HT release. Until now, 5-HT3 receptor antagonists (e.g. granisetron) have been thought to inhibit cholera toxin-induced fluid secretion by blockading 5-HT3 receptors on secretory enteric neurones. Instead we postulated that they act by inhibiting cholera toxin-induced enterochromaffin cell degranulation. Isolated intestinal segments in anaesthetized male Wistar rats, pre-treated with granisetron 75 μg kg−1, lidoocaine 6 mg kg−1 or saline, were instilled with a supramaximal dose of cholera toxin or saline. Net fluid movement was determined by small intestinal perfusion or gravimetry and small intestinal and luminal fluid 5-HT levels were determined by HPLC with fluorimetric detection. Intraluminal 5-HT release was proportional to the reduction in tissue 5-HT levels and to the onset of water and electrolyte secretion, suggesting that luminal 5-HT levels reflect enterochromaffin cell activity. Both lidocaine and granisetron inhibited fluid secretion. However, granisetron alone, and proportionately, reduced 5-HT release. The simultaneous inhibition of 5-HT release and fluid secretion by granisetron suggests that 5-HT release from enterochromaffin cells is potentiated by endogenous 5-HT3 receptors. The accentuated 5-HT release promotes cholera toxin-induced fluid secretion. PMID:10882387

Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors.

PubMed

Smith, R L; Canton, H; Barrett, R J; Sanders-Bush, E

1998-11-01

Extensive behavioral and biochemical evidence suggests an agonist role at the 5-HT2A receptor, and perhaps the 5-HT2C receptor, in the mechanism of action of hallucinogenic drugs. However the published in vitro pharmacological properties of N,N-dimethyltryptamine (DMT), an hallucinogenic tryptamine analog, are not consistent with this hypothesis. We, therefore, undertook an extensive investigation into the properties of DMT at 5-HT2A and 5-HT2C receptors. In fibroblasts transfected with the 5-HT2A receptor or the 5-HT2C receptor, DMT activated the major intracellular signaling pathway (phosphoinositide hydrolysis) to an extent comparable to that produced by serotonin. Because drug efficacy changes with receptor density and cellular microenvironment, we also examined the properties of DMT in native preparations using a behavioral and biochemical approach. Rats were trained to discriminate an antagonist ketanserin from an agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in a two-lever choice paradigm. Pharmacological studies showed that responding on the DOI and ketanserin lever reflected agonist and antagonist activity at 5-HT2A receptors, and hence, was a suitable model for evaluating the in vivo functional properties of DMT. Like other 5-HT2A receptor agonists, DMT substituted fully for DOI. Intact choroid plexus was used to evaluate the agonist properties at endogenous 5-HT2C receptors; DMT was a partial agonist at 5-HT2C receptors in this native preparation. Thus, we conclude that DMT behaves as an agonist at both 5-HT2A and 5-HT2A receptors. One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound desensitization to DMT over time. This difference is interesting in light of the recent report that the hallucinogenic activity of DMT does not tolerate in humans and suggests the 5-HT2C receptor plays a less prominent role in the action of DMT.

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

PubMed

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

2014-01-01

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

Pellet injection research on the HT-6M and HT-7 tokamaks

NASA Astrophysics Data System (ADS)

Yang, Yu; Bao, Yi; Li, Jiangang; Gu, Xuemao; He, Yexi

1999-11-01

A multishot in situ pellet injection system has been constructed in the Institute of Plasma Physics. Single- and multi-pellet injection experiments were performed on the HT-6M and superconducting HT-7 tokamaks. The system proved to be convenient and reliable to operate. Pellets were fired into ohmically and LHCD and ICRF heated plasmas. Single pellet injection in ohmic discharge was found to increase the central density of HT-7 by about one half, while two pellet injection increased the central density in a step-like fashion by one half with each shot. Peaking of the electron density profile and a hollow electron temperature profile were obtained.

Sucrose intake and fasting glucose levels in 5-HT(1A) and 5-HT(1B) receptor mutant mice.

PubMed

Bechtholt, Anita J; Smith, Karen; Gaughan, Stephanie; Lucki, Irwin

2008-03-18

Serotonin (5-HT)(1A) and 5-HT(1B) receptors have been implicated in the incidence and treatment of depression in part through the examination of animals lacking these receptors. Although these receptors have been repeatedly implicated in ingestive behavior there is little information about how 5-HT(1A) and 5-HT(1B) receptor mutant mice react to solutions of varying palatability. In the present experiment male and female 5-HT(1A) and 5-HT(1B) mutant and wild-type mice were presented with increasing concentrations of sucrose using a two-bottle choice procedure. In addition fasting blood glucose levels were assessed. Both male and female 5-HT(1B) mutant mice drank more sucrose than WT mice but also consumed more water. Female, but not male, 5-HT(1A) mutant mice similarly showed increased sucrose consumption, but did not demonstrate increased consumption of water. In addition, the pattern of increased sucrose consumption over genotype and sex was related to fasting blood glucose concentrations such that levels in male 5-HT(1B) mutant mice were reduced relative to wild-type and 5-HT(1A) mutant males, but similar to those of females. The findings in 5-HT(1B) mutant mice emphasize the role of the 5-HT(1B) receptor in regulating ingestive behavior, whereas female sex hormones and 5-HT(1A) receptors may interact to alter sucrose consumption in 5-HT(1A) mutant mice. In addition, these findings may have implications for the role of these receptors in the incidence and treatment of depression since the intake of sucrose has been used as an index of anhedonia in animal models of depression and antidepressant efficacy.

Contribution des avortements et des grossesses extra-utérines dans la mortalité maternelle dans trois hôpitaux universitaires de Yaoundé

PubMed Central

Kamga, Danielle Victoire Tiako; Nana, Philip Njotang; Fouelifack, Florent Ymele; Fouedjio, Jeanne Hortence

2017-01-01

Introduction L'organisation mondiale de santé (OMS) estime que chaque année dans le monde 585 000 femmes meurent de complications liés à la grossesse, à l'accouchement, aux suites de couche et à l'avortement (ce dernier contribuant pour 13% des décès maternels). La GEU est responsable de 10% de mortalité maternelle au premier trimestre de la grossesse. Le taux de mortalité maternelle reste élevé au Cameroun, estimé à 782 pour 100 000 naissances vivantes selon EDS-MICS 2011. La contribution de ces deux entités dans la mortalité maternelle étant peu documentée dans notre pays, nous avons entrepris de réaliser cette étude avec pour objectif d'évaluer la contribution des avortements et des GEU dans la mortalité maternelle au Cameroun. Méthodes il s'agissait d'une étude rétrospective et analytique. Nous avons colligé tous les dossiers des patientes enceintes et décédées avant la 28ème semaine de grossesse, dans trois hôpitaux universitaires: Hôpital Central de Yaoundé (HCY), Hôpital Gynéco-Obstétrique et Pédiatrique de Yaoundé (HGOPY), Centre Hospitalier et Universitaire (CHU), sur la période allant du 1er juin 2011 au 31 mai 2016, soit sur cinq ans. Les données étaient compilées sur une fiche technique préétablie et testée, saisies en utilisant le logiciel CS pro 6.2 et analysées par le logiciel SPSS 20. Les tests statistiques de comparaison utilisés étaient le Khi 2 et le test de Fischer en fonction des effectifs. Le seuil de significativité était retenu pour P < 005. Résultats Tous avons enregistré 524 décès maternels pour 31116 naissances vivantes, soit un taux de mortalité maternelle (TMM) de 1538.9/100 000 naissances vivantes. Sur les 524 décès maternels, 414 dossiers étaient exploitables, parmi lesquels, 100 (soit 24.2%) concernaient les avortements et 24 (soit 5.8%) concernaient les grossesses extra-utérines, ces 2 entités contribuaient ainsi pour 30% de décès maternels (124 dossiers sur 414). L

High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding

PubMed Central

Mc Mahon, Brenda; MacDonald Fisher, Patrick; Jensen, Peter Steen; Svarer, Claus; Moos Knudsen, Gitte

2016-01-01

Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [11C]SB207145 for quantification of brain 5-HT4R binding. The Buss–Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT4R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT4R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5-HT4R binding were associated with high trait aggression in males, but not in females. PMID:26772668

Incubation of cocaine cue reactivity associates with neuroadaptations in the cortical serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system

PubMed Central

Swinford-Jackson, Sarah E.; Anastasio, Noelle C.; Fox, Robert G.; Stutz, Sonja J.; Cunningham, Kathryn A.

2016-01-01

Intensification of craving elicited by drug-associated cues during abstinence occurs over time in human cocaine users while elevation of cue reactivity (“incubation”) is observed in rats exposed to extended forced abstinence from cocaine self-administration. Incubation in rodents has been linked to time-dependent neuronal plasticity in the medial prefrontal cortex (mPFC). We tested the hypothesis that incubation of cue reactivity during abstinence from cocaine self-administration is accompanied by lower potency and/or efficacy of the selective 5-HT2CR agonist WAY163909 to suppress cue reactivity and a shift in the subcellular localization profile of the mPFC 5-HT2CR protein. We observed incubation of cue reactivity (measured as lever presses reinforced by the discrete cue complex) between Day 1 and Day 30 of forced abstinence from cocaine relative to sucrose self-administration. Pharmacological and biochemical analyses revealed that the potency of the selective 5-HT2CR agonist WAY163909 to suppress cue reactivity, the expression of synaptosomal 5-HT2CR protein in the mPFC, and the membrane to cytoplasmic expression of the 5-HT2CR in mPFC were lower on Day 30 vs. Day 1 of forced abstinence from cocaine self-administration. Incubation of cue reactivity assessed during forced abstinence from sucrose self-administration did not associate with 5-HT2CR protein expression in the mPFC. Collectively, these outcomes are the first indication that neuroadaptations in the 5-HT2CR system may contribute to incubation of cocaine cue reactivity. PMID:26926963

Aspects cliniques et thérapeutiques des anomalies de la jonction pyélo-urétérale au CHU du point G

PubMed Central

Tembely, Aly; Kassogué, Amadou; Berthé, Honoré; Ouattara, Zanafon

2016-01-01

Cette étude a été faite pour analyser les aspects cliniques et thérapeutiques des anomalies de la jonction pyélo-urétérale. Etude transversale et descriptive portant sur 35 cas d'anomalies de la jonction pyélo-urétérale (AJPU) colligés au service d'Urologie du CHU du Point G durant une période de 4 ans (Janvier 2010 au Décembre 2014). Les données ont été recueillies sur les fiches d'enquête, les dossiers médicaux et les registres du bloc. Les données sociodémographique, clinique et thérapeutique ont été saisies sur Microsoft Word 2007 et analysées sur Excel 2007 et SPSS 18.0. 35 cas d'AJPU ont été colligés en 4 ans. La moyenne d’âge était de 29,3 ans. La douleur lombaire était le motif de consultation le plus fréquent soit 40%. 20% des patients ont été en consultation pour la première fois 10 ans d’évolution symptomatique. Une destruction rénale avait été observée dans 28,6%. Le couple Echographie + UIV a permis d’établir le diagnostic chez 37,1%. La complication lithiasique était présente chez 17,1% des patients. 51,4% des patients ont reçu une pyéloplastie à ciel ouvert selon Anderson KUSS. L'anomalie de la jonction pyélo-urétérale dans notre étude a été caractérisée par un retard de consultation avec des complications redoutables. La chirurgie à ciel ouvert a été le gold standard avec des résultats satisfaisants. L'endopyéloplastie, la cure de la jonction coelioscopique sont des chirurgies mini invasives non disponible chez nous mais à encourager et à intégrer dans l'arsenal thérapeutique. PMID:27516821

High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding.

PubMed

da Cunha-Bang, Sofi; Mc Mahon, Brenda; Fisher, Patrick MacDonald; Jensen, Peter Steen; Svarer, Claus; Knudsen, Gitte Moos

2016-04-01

Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [(11)C]SB207145 for quantification of brain 5-HT4R binding. The Buss-Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT4R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT4R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5-HT4R binding were associated with high trait aggression in males, but not in females. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT(2A) and 5-HT(2C) receptors.

PubMed

Acuña-Castillo, Claudio; Villalobos, Claudio; Moya, Pablo R; Sáez, Patricio; Cassels, Bruce K; Huidobro-Toro, J Pablo

2002-06-01

The pharmacological profile of a series of (+/-)-2,5-dimethoxy-4-(X)-phenylisopropylamines (X=I, Br, NO(2), CH(3), or H) and corresponding phenylethylamines, was determined in Xenopus laevis oocytes injected with cRNA coding for rat 5-HT(2A) or 5-HT(2C) receptors. The efficacy and relative potency of these drugs were determined and compared to classical 5-HT(2) receptor agonists and antagonists. The rank order of agonist potency at the 5-HT(2A) receptor was: alpha-methyl-5-HT=5-HT>m-CPP>MK-212; at the 5-HT(2C) receptor the order was: 5-HT>alpha-methyl-5-HT>MK-212>m-CPP. All these compounds were full agonists at the 5-HT(2C) receptor, but alpha-methyl-5-HT and m-CPP showed lower efficacy at the 5-HT(2A) receptor. 4-(4-Fluorobenzoyl)-1-(4-phenylbutyl)piperidine (4F 4PP) was 200 times more potent as a 5-HT(2A) antagonist than at 5-HT(2C) receptors. Conversely, RS 102221 was 100 times more potent as a 5-HT(2C) antagonist, confirming their relative receptor selectivities. The phenylisopropylamines were partial agonists at the 5-HT(2A) receptor, with I(max) relative to 5-HT in the 22+/-7 to 58+/-15% range; the corresponding phenylethylamines had lower or undetectable efficacies. All these drugs had higher efficacies at 5-HT(2C) receptors; DOI was a full 5-HT(2C) agonist. 2C-I and the other phenylethylamines examined showed relative efficacies at the 5-HT(2C) receptor ranging from 44+/-10% to 76+/-16%. 2C-N was a 5-HT(2) receptor antagonist; the mechanism was competitive at the 5-HT(2A), but non-competitive at the 5-HT(2C) receptor. The antagonism was time-dependent at the 5-HT(2C) receptor but independent of pre-incubation time at the 5-HT(2A) receptor subtype. The alpha-methyl group determines the efficacy of these phenylalkylamines at the 5-HT(2A) and 5-HT(2C) receptors.

The Experiment of Modulated Toroidal Current on HT-7 and HT-6M Tokamak

NASA Astrophysics Data System (ADS)

Mao, Jian-shan; P, Phillips; Luo, Jia-rong; Xu, Yu-hong; Zhao, Jun-yu; Zhang, Xian-mei; Wan, Bao-nian; Zhang, Shou-yin; Jie, Yin-xian; Wu, Zhen-wei; Hu, Li-qun; Liu, Sheng-xia; Shi, Yue-jiang; Li, Jian-gang; HT-6M; HT-7 Group

2003-02-01

The Experiments of Modulated Toroidal Current were done on the HT-6M tokamak and HT-7 superconducting tokamak. The toroidal current was modulated by programming the Ohmic heating field. Modulation of the plasma current has been used successfully to suppress MHD activity in discharges near the density limit where large MHD m = 2 tearing modes were suppressed by sufficiently large plasma current oscillations. The improved Ohmic confinement phase was observed during modulating toroidal current (MTC) on the Hefei Tokamak-6M (HT-6M) and Hefei superconducting Tokamak-7 (HT-7). A toroidal frequency-modulated current, induced by a modulated loop voltage, was added on the plasma equilibrium current. The ratio of A.C. amplitude of plasma current to the main plasma current ΔIp/Ip is about 12%-30%. The different formats of the frequency-modulated toroidal current were compared.

5-HT2 receptor blockade exhibits 5-HT vasodilator effects via nitric oxide, prostacyclin and ATP-sensitive potassium channels in rat renal vasculature.

PubMed

García-Pedraza, J A; García, M; Martín, M L; Rodríguez-Barbero, A; Morán, A

2016-04-01

The aim of this study was to determine whether orally sarpogrelate (selective 5-HT2 antagonist) treatment (30 mg/kg/day; 14 days) could modify 5-HT renal vasoconstrictor responses, characterizing 5-HT receptors and mediator mechanisms involved in serotonergic responses in the in situ autoperfused rat kidney. Intra-arterial (i.a.) injections of 5-HT (0.00000125 to 0.1 μg/kg) decreased renal perfusion pressure (RPP) but did not affect the mean blood pressure (MBP). i.a. agonists 5-CT (5-HT1/7), CGS-12066B (5-HT1B), L-694,247 (5-HT1D) or AS-19 (5-HT7) mimicked renal 5-HT vasodilator effect. However, neither 8-OH-DPAT (5-HT1A) nor 1-phenylbiguanide (5-HT3) modified RPP. Moreover: (i) GR-55562 (5-HT1B antagonist) and L-NAME (nitric oxide synthase [NOS] inhibitor) blocked CGS-12066B-induced vasodilator response, (ii) LY310762 (5-HT1D antagonist) and indomethacin (non-selective cyclooxygenase inhibitor) blocked L-694,247-induced vasodilator response; (iii) SB-258719 (5-HT7 antagonist) and glibenclamide (ATP-sensitive K+ channel blocker) blocked AS-19-induced vasodilator response; and (iv) 5-HT- or 5-CT-elicited renal vasodilation was significantly blocked by the mixture of GR-55562 + LY310762 + SB-258719. Furthermore, eNOS and iNOS proteins and prostacyclin levels are overexpressed in sarpogrelate-treated rats. Our data suggest that 5-HT exerts renal vasodilator effect in the in situ autoperfused sarpogrelate-treated rat kidney, mediated by 5-HT1D, 5-HT1B and 5-HT7 receptors, involving cyclooxygenase-derived prostacyclin, nitric oxide synthesis/release and ATP-sensitive K+ channels, respectively.

PHP-HT (VitaResc Biotech).

PubMed

Baldwin, A; Wiley, E

2001-04-01

VitaResc (formerly Apex) is developing PHP-HT, pyridoxalated hemoglobin polyoxyethylene conjugate, for the potential treatment of nitric oxide-induced shock (characterized by hypotension), associated with various etiologies, initially in septic shock. A phase I safety study and an initial phase I/II patient trial for NO-induced shock have been completed, and VitaResc has enrolled patients in three of five planned cohorts in a continuation of these trials to include a protocol of continuous infusion and dose escalation [330680,349187,390918]. The results from the dose escalation trials are expected to provide the basis for a randomized, controlled phase II/III pivotal trial of PHP-HT [390918]. VitaResc has licensed PHP-HT exclusively from Ajinomoto for all indications, worldwide, except Japan [275263]. Ajinomoto originally developed the human derived and chemically modified hemoglobin preparation as a blood substitute, but no development has been reported by the company since 1997 [275277,303577]. The other potential indications of PHP-HT include shock associated with burns, pancreatitis, hemodialysis and cytokine therapies [275277]. VitaResc expects the annual market potential of PHP-HT to exceed 1 billion dollars [330680].

Chronic 5-HT2 receptor blockade unmasks the role of 5-HT1F receptors in the inhibition of rat cardioaccelerator sympathetic outflow.

PubMed

García-Pedraza, José Ángel; Hernández-Abreu, Oswaldo; García, Mónica; Morán, Asunción; Villalón, Carlos M

2018-04-01

Serotonin (5-hydroxytryptamine; 5-HT) inhibits the rat cardioaccelerator sympathetic outflow by 5-HT 1B/1D/5 receptors. Because chronic blockade of sympatho-excitatory 5-HT 2 receptors is beneficial in several cardiovascular pathologies, this study investigated whether sarpogrelate (a 5-HT 2 receptor antagonist) alters the pharmacological profile of the above sympatho-inhibition. Rats were pretreated for 2 weeks with sarpogrelate in drinking water (30 mg/kg per day; sarpogrelate-treated group) or equivalent volumes of drinking water (control group). Animals were pithed and prepared for spinal stimulation (C 7 -T 1 ) of the cardioaccelerator sympathetic outflow or for intravenous (i.v.) bolus injections of noradrenaline. Both procedures produced tachycardic responses remaining unaltered after saline. Continuous i.v. infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT receptor agonists 5-carboxamidotryptamine (5-CT; 5-HT 1/5A ), CP 93,129 (5-HT 1B ), or PNU 142633 (5-HT 1D ), but not by indorenate (5-HT 1A ) in both groups; whereas LY344864 (5-HT 1F ) mimicked 5-HT only in sarpogrelate-treated rats. In sarpogrelate-treated animals, i.v. GR 127935 (310 μg/kg; 5-HT 1B/1D/1F receptor antagonist) attenuated 5-CT-induced sympatho-inhibition and abolished LY344864-induced sympatho-inhibition; while GR 127935 plus SB 699551 (1 mg/kg; 5-HT 5A receptor antagonist) abolished 5-CT-induced inhibition. These results confirm the cardiac sympatho-inhibitory role of 5-HT 1B , 5-HT 1D , and 5-HT 5A receptors in both groups; nevertheless, sarpogrelate treatment specifically unmasked a cardiac sympatho-inhibition mediated by 5-HT 1F receptors.

The relaxant 5-HT receptor in the dog coronary artery smooth muscle: pharmacological resemblance to the cloned 5-ht7 receptor subtype.

PubMed Central

Terrón, J. A.

1996-01-01

1. The relaxant effect of 5-hydroxytryptamine (5-HT) in the dog isolated coronary artery deprived of endothelium is mediated by a receptor unrelated to the 5-HT1, 5-HT2, 5-HT3 or 5-HT4 types. Based upon the pharmacological characteristics of this relaxant 5-HT receptor and those reported for the new members of the 5-HT receptor family, the present study explored the possibility that the relaxant 5-HT receptor referred to above, corresponds to the cloned 5-ht7 subtype. Thus, the relaxing and/or blocking effects of several 5-HT receptor drugs as well as some typical and atypical antipsychotic drugs with high affinity for the cloned 5-ht7 receptor in precontracted ring segments were analyzed. 2. 5-HT, 5-carboxamidotryptamine (5-CT) and 5-methoxytryptamine, but not 8-OH-DPAT or sumatriptan, produced concentration-dependent relaxations in endothelium-denuded canine coronary artery rings precontracted with prostaglandin F2a (2 microM). Clozapine (1 microM) produced in some cases a small relaxing effect and antagonized 5-HT- and 5-CT-induced relaxation suggesting a partial agonist effect. In the presence of the 5-HT1D receptor antagonist, GR127935 (100 nM), the rank order of agonist potency was 5-CT > 5-HT > clozapine > or = 5-methoxytryptamine. 8-OH-DPAT and sumatriptan remained inactive as agonists. 3. In GR127935-treated preparations, methiothepin (3 nM) and mianserin (1 microM), as well as the antipsychotics, clozapine (1 microM), pimozide (300 nM), risperidone (3 nM) and spiperone (1 microM), failed to induce a significant relaxation in prostaglandin F2x-precontracted vessels, but produced significant rightward displacements of the concentration-response curves to 5-HT and 5-CT without significantly reducing the Emax. In a final set of experiments with 5-CT, metergoline (100 nM) and mesulergine (300 nM) behaved as competitive antagonists. In contrast, lisuride (3 nM) noncompetitively antagonized 5-CT-induced relaxation. The estimated affinity (apparent pKa values) of

The role of serotonin-2 (5-HT2) and dopamine receptors in the behavioral actions of the 5-HT2A/2C agonist, DOI, and putative 5-HT2C inverse agonist, SR46349B.

PubMed

Scarlota, Laura C; Harvey, John A; Aloyo, Vincent J

2011-02-01

Atypical antipsychotic efficacy is often attributed to actions at serotonin-2 (5-HT(2)) and dopamine receptors, indicating a potential benefit of understanding the interplay between these systems. Currently, it is known that 5-HT(2) receptors modulate dopamine release, although the role of specific dopamine receptors in 5-HT(2)-mediated behavior is not well understood. We examined the role of 5-HT(2A), 5-HT(2C), and dopamine (D1 and D2) receptors in the behavioral response to a 5-HT(2A/2C) agonist (DOI) and 5-HT(2A/2C) antagonist (SR46349B). Effects were assessed by measuring rabbit head bobs (previously characterized as 5-HT(2A) receptor-mediated) and body shakes (5-HT(2C)-mediated). As expected, DOI produced head bobs and body shakes, and these DOI-elicited behaviors were attenuated by the SR46349B pretreatment. Unexpectedly, SR46349B also induced head bobs when administered alone. However, SR46349B-elicited head bobs are distinguishable from those produced by DOI since the 5-HT(2A) antagonist, ketanserin, only attenuated DOI-elicited head bobs. Conversely, 5-HT(2C) ligands (SB242084 and SB206553) inhibited SR46349B but not DOI-induced head bobs. Furthermore, when administered alone, SB206553 (a 5-HT(2C) inverse agonist) produced head bobs, indicating the behavior can be either 5-HT(2A) or 5-HT(2C) mediated. Next, it was revealed that D1 and D2 receptors play a role in DOI-elicited head bobs, but only D1 receptors are required for SR46349B-elicited head bobs. 5-HT(2A) receptor agonism and 5-HT(2C) inverse agonism produce the same behavior, likely due to similar downstream actions at D1 receptors. Consequently, 5-HT(2C) agonism or D1 agonism may be effective therapies for disorders, such as schizophrenia, currently being treated with 5-HT(2A) antagonists.

Serotonin 5-HT3 and 5-HT4 ligands: an update of medicinal chemistry research in the last few years.

PubMed

Modica, M N; Pittalà, V; Romeo, G; Salerno, L; Siracusa, M A

2010-01-01

The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) is one of the most studied neurotransmitters in the central nervous system. It acts through the activation of at least fourteen 5-HT receptor subtypes. Over the last two decades, high attention was devoted to the 5-HT(3) and 5-HT(4) receptors due to their colocalization in the gastrointestinal tract and because their ligands are useful in the treatment of intestinal serotonergic system dysfunctions. The focus of this review is to discuss the literature concerning recent advances on 5-HT(3)R and 5-HT(4)R ligands and their structure-activity relationships from a medicinal chemistry perspective. During the last few years, new and significant progresses have been made in the field of novel potent and selective ligands, mixed ligands, agonists, partial agonists, and antagonists, and a number of patents have been filed. Furthermore several ligands targeting the 5-HT(3)R and 5-HT(4)R have been proposed for novel therapeutic indications such as the treatment of various psychiatric disorders.

Haliotis tuberculata hemocyanin (HtH): analysis of oligomeric stability of HtH1 and HtH2, and comparison with keyhole limpet hemocyanin KLH1 and KLH2.

PubMed

Harris, J R; Scheffler, D; Gebauer, W; Lehnert, R; Markl, J

2000-12-01

The multimeric/higher oligomeric states of the two isoforms of Haliotis tuberculata hemocyanin (HtH1 and HtH2) have been assessed by transmission electron microscopy (TEM) of negatively stained specimens, for comparison with previously published structural data from keyhole limpet hemocyanin (KLH1 and KLH2) [see Harris, J.R., Gebauer, W., Guderian, F.U., Markl, J., 1997a. Keyhole limpet hemocyanin (KLH), I: Reassociation from Immucothel followed by separation of KLH1 and KLH2. Micron, 28, 31-41; Harris, J.R., Gebauer, W., Söhngen, S.M., Nermut, M.V., Markl, J., 1997b. Keyhole limpet hemocyanin (KLH). II: Characteristic reassociation properties of purified KLH1 and KLH2. Micron, 28, 43-56; Harris, J.R., Gebauer, W., Adrian, M., Markl, J., 1998. Keyhole limpet hemocyanin (KLH): Slow in vitro reassociation of KLH1 and KLH2 from Immucothel. Micron, 29, 329-339]. In purified samples of both HtH isoforms, the hollow cylindrical ca 8MDa didecamer predominates together with a small number of decamers, but tri- and longer multidecamers are detectable only in the HtH2. The stability of the two HtH isoforms under varying ionic conditions have been monitored, thereby enabling conditions for the production of stable decamers to be established. The ability of these decamers to reform multimers in the presence of 10 and 100mM concentrations of calcium and magnesium ions in Tris-HCl buffer (pH 7.4), and also of individual HtH1 and HtH2 subunits (produced by pH 9.6 dissociation in glycine-NaOH buffer), to reassociate in the presence of calcium and magnesium ions, has been assessed. For the HtH1 decamers, the predominant multimeric product is the didecamer at 10 and 100mM calcium and magnesium concentrations, whereas for the HtH2 decamers, large numbers of multidecamers are produced, with the reaction proceeding more completely at the higher calcium and magnesium concentration. With the HtH1 subunit, reassociation in the presence of 10 and 100mM calcium and magnesium ions yielded

The antidepressant effects of curcumin in the forced swimming test involve 5-HT1 and 5-HT2 receptors.

PubMed

Wang, Rui; Xu, Ying; Wu, Hong-Li; Li, Ying-Bo; Li, Yu-Hua; Guo, Jia-Bin; Li, Xue-Jun

2008-01-06

Curcuma longa is a main constituent of many traditional Chinese medicines, such as Xiaoyao-san, used to manage mental disorders effectively. Curcumin is a major active component of C. longa and its antidepressant-like effect has been previously demonstrated in the forced swimming test. The purpose of this study was to explore the possible contribution of serotonin (5-HT) receptors in the behavioral effects induced by curcumin in this animal model of depression. 5-HT was depleted by the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA, 100 mg/kg, i.p.) prior to the administration of curcumin, and the consequent results showed that PCPA blocked the anti-immobility effect of curcumin in forced swimming test, suggesting the involvement of the serotonergic system. Moreover, pre-treatment of pindolol (10 mg/kg, i.p., a beta-adrenoceptors blocker/5-HT(1A/1B) receptor antagonist), 4-(2'-methoxy-phenyl)-1-[2'-(n-2''-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (p-MPPI, 1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (isamoltane, 2.5 mg/kg, i.p., a 5-HT(1B) receptor antagonist) was found to prevent the effect of curcumin (10 mg/kg) in forced swimming test. On the other hand, a sub-effective dose of curcumin (2.5 mg/kg, p.o.) produced a synergistic effect when given jointly with (+)-8-hydroxy-2-(di-n-propylamino)tetralin, (8-OH-DPAT, 1 mg/kg, i.p., a 5-HT(1A) receptor agonist), anpirtoline (0.25 mg/kg, i.p., a 5-HT(1B) receptor agonist) or ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), but not with ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist with higher affinity to 5-HT(2A) receptor) or R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg, i.p., a 5-HT(2A) receptor agonist). Taken together, these results indicate that the antidepressant-like effect of curcumin in the forced swimming test is related to serotonergic system and may be mediated by, at least

Spinal 5-HT2 and 5-HT3 receptors mediate low, but not high, frequency TENS-induced antihyperalgesia in rats

PubMed Central

Radhakrishnan, Rajan; King, Ellen W.; Dickman, Janelle K.; Herold, Carli A.; Johnston, Natalie F.; Spurgin, Megan L.; Sluka, Kathleen A.

2009-01-01

Transcutaneous electrical nerve stimulation (TENS) is a form of non-pharmacological treatment for pain. Involvement of descending inhibitory systems is implicated in TENS-induced analgesia. In the present study, the roles of spinal 5-HT and α2-adrenoceptors in TENS analgesia were investigated in rats. Hyperalgesia was induced by inflaming the knee joint with 3% kaolin—carrageenan mixture and assessed by measuring paw withdrawal latency (PWL) to heat before and 4 h after injection. The (1) α2-adrenergic antagonist yohimbine (30 μg), (2) 5-HT antagonist methysergide (5-HT1 and 5-HT2,30 μg), one of the 5-HT receptor subtype antagonists, (3) NAN-190 (5-HT1A, 15 μg), (4) ketanserin (5-HT2A, 30 μg), (5) MDL-72222 (5-HT3, 12 μg), or (6) vehicle was administered intrathecally prior to TENS treatment. Low (4 Hz) or high (100 Hz) frequency TENS at sensory intensity was then applied to the inflamed knee for 20 min and PWL was determined. Selectivity of the antagonists used was confirmed using respective agonists administered intrathecally. Yohimbine had no effect on the antihyperalgesia produced by low or high frequency TENS. Methysergide and MDL-72222 prevented the antihyperalgesia produced by low, but not high, frequency TENS. Ketanserin attenuated the antihyperalgesic effects of low frequency TENS whereas NAN-190 had no effect. The results from the present study show that spinal 5-HT receptors mediate low, but not high, frequency TENS-induced antihyperalgesia through activation of 5-HT2A and 5-HT3 receptors in rats. Furthermore, spinal noradrenergic receptors are not involved in either low or high frequency TENS antihyperalgesia. PMID:14499437

Molecular and pharmacological characterization of serotonin 5-HT2α and 5-HT7 receptors in the salivary glands of the blowfly Calliphora vicina.

PubMed

Röser, Claudia; Jordan, Nadine; Balfanz, Sabine; Baumann, Arnd; Walz, Bernd; Baumann, Otto; Blenau, Wolfgang

2012-01-01

Secretion in blowfly (Calliphora vicina) salivary glands is stimulated by the biogenic amine serotonin (5-hydroxytryptamine, 5-HT), which activates both inositol 1,4,5-trisphosphate (InsP(3))/Ca(2+) and cyclic adenosine 3',5'-monophosphate (cAMP) signalling pathways in the secretory cells. In order to characterize the signal-inducing 5-HT receptors, we cloned two cDNAs (Cv5-ht2α, Cv5-ht7) that share high similarity with mammalian 5-HT(2) and 5-HT(7) receptor genes, respectively. RT-PCR demonstrated that both receptors are expressed in the salivary glands and brain. Stimulation of Cv5-ht2α-transfected mammalian cells with 5-HT elevates cytosolic [Ca(2+)] in a dose-dependent manner (EC(50) = 24 nM). In Cv5-ht7-transfected cells, 5-HT produces a dose-dependent increase in [cAMP](i) (EC(50) = 4 nM). We studied the pharmacological profile for both receptors. Substances that appear to act as specific ligands of either Cv5-HT(2α) or Cv5-HT(7) in the heterologous expression system were also tested in intact blowfly salivary gland preparations. We observed that 5-methoxytryptamine (100 nM) activates only the Cv5-HT(2α) receptor, 5-carboxamidotryptamine (300 nM) activates only the Cv5-HT(7) receptor, and clozapine (1 µM) antagonizes the effects of 5-HT via Cv5-HT(7) in blowfly salivary glands, providing means for the selective activation of each of the two 5-HT receptor subtypes. This study represents the first comprehensive molecular and pharmacological characterization of two 5-HT receptors in the blowfly and permits the analysis of the physiological role of these receptors, even when co-expressed in cells, and of the modes of interaction between the Ca(2+)- and cAMP-signalling cascades.

Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: evidence for direct 5-HT receptor modulation.

PubMed

Jensen, Jesper Bornø; du Jardin, Kristian Gaarn; Song, Dekun; Budac, David; Smagin, Gennady; Sanchez, Connie; Pehrson, Alan Lars

2014-01-01

Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mørk et al., 2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its receptor activities. © 2013 Published by Elsevier B.V. and ECNP.

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

PubMed

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

2012-11-01

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. Copyright © 2012 Elsevier Ltd. All rights reserved.

Molecular and Pharmacological Characterization of Serotonin 5-HT2α and 5-HT7 Receptors in the Salivary Glands of the Blowfly Calliphora vicina

PubMed Central

Röser, Claudia; Jordan, Nadine; Balfanz, Sabine; Baumann, Arnd; Walz, Bernd; Baumann, Otto; Blenau, Wolfgang

2012-01-01

Secretion in blowfly (Calliphora vicina) salivary glands is stimulated by the biogenic amine serotonin (5-hydroxytryptamine, 5-HT), which activates both inositol 1,4,5-trisphosphate (InsP3)/Ca2+ and cyclic adenosine 3′,5′-monophosphate (cAMP) signalling pathways in the secretory cells. In order to characterize the signal-inducing 5-HT receptors, we cloned two cDNAs (Cv5-ht2α, Cv5-ht7) that share high similarity with mammalian 5-HT2 and 5-HT7 receptor genes, respectively. RT-PCR demonstrated that both receptors are expressed in the salivary glands and brain. Stimulation of Cv5-ht2α-transfected mammalian cells with 5-HT elevates cytosolic [Ca2+] in a dose-dependent manner (EC50 = 24 nM). In Cv5-ht7-transfected cells, 5-HT produces a dose-dependent increase in [cAMP]i (EC50 = 4 nM). We studied the pharmacological profile for both receptors. Substances that appear to act as specific ligands of either Cv5-HT2α or Cv5-HT7 in the heterologous expression system were also tested in intact blowfly salivary gland preparations. We observed that 5-methoxytryptamine (100 nM) activates only the Cv5-HT2α receptor, 5-carboxamidotryptamine (300 nM) activates only the Cv5-HT7 receptor, and clozapine (1 µM) antagonizes the effects of 5-HT via Cv5-HT7 in blowfly salivary glands, providing means for the selective activation of each of the two 5-HT receptor subtypes. This study represents the first comprehensive molecular and pharmacological characterization of two 5-HT receptors in the blowfly and permits the analysis of the physiological role of these receptors, even when co-expressed in cells, and of the modes of interaction between the Ca2+- and cAMP-signalling cascades. PMID:23145175

Antibodies specific for HT{sub m4}

DOEpatents

Lim, B.; Adra, C.N.; Lelias, J.M.

1998-01-06

The invention relates to a recombinant DNA molecule which encodes a HT{sub m4} protein, a transformed host cell which has been stably transfected with a DNA molecule which encodes a HT{sub m4} protein and a recombinant HT{sub m4} protein. The invention also relates to a method for detecting the presence of a hereditary atopy. 2 figs.

Antibodies specific for HT.sub.m4

DOEpatents

Lim, Bing; Adra, Chaker N.; Lelias, Jean-Michel

1998-01-01

The invention relates to a recombinant DNA molecule which encodes a HT.sub.m4 protein, a transformed host cell which has been stably transfected with a DNA molecule which encodes a HT.sub.m4 protein and a recombinant HT.sub.m4 protein. The invention also relates to a method for detecting the presence of a hereditary atopy.

3,4-Dihydro-2H-benzoxazinones are 5-HT(1A) receptor antagonists with potent 5-HT reuptake inhibitory activity.

PubMed

Atkinson, Peter J; Bromidge, Steven M; Duxon, Mark S; Gaster, Laramie M; Hadley, Michael S; Hammond, Beverley; Johnson, Christopher N; Middlemiss, Derek N; North, Stephanie E; Price, Gary W; Rami, Harshad K; Riley, Graham J; Scott, Claire M; Shaw, Tracey E; Starr, Kathryn R; Stemp, Geoffrey; Thewlis, Kevin M; Thomas, David R; Thompson, Mervyn; Vong, Antonio K K; Watson, Jeannette M

2005-02-01

Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.

A Novel Aminotetralin-Type Serotonin (5-HT) 2C Receptor-Specific Agonist and 5-HT2A Competitive Antagonist/5-HT2B Inverse Agonist with Preclinical Efficacy for Psychoses

PubMed Central

Morgan, Drake; Felsing, Daniel; Kondabolu, Krishnakanth; Rowland, Neil E.; Robertson, Kimberly L.; Sakhuja, Rajeev; Booth, Raymond G.

2014-01-01

Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (−)-trans-(2S,4R)-4-(3′[meta]-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (−)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (−)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy-4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (−)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (−)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (−)-MBP, the enantiomer (+)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (−)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders. PMID:24563531

Receptor⁻Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment.

PubMed

Borroto-Escuela, Dasiel O; Narváez, Manuel; Ambrogini, Patrizia; Ferraro, Luca; Brito, Ismel; Romero-Fernandez, Wilber; Andrade-Talavera, Yuniesky; Flores-Burgess, Antonio; Millon, Carmelo; Gago, Belen; Narvaez, Jose Angel; Odagaki, Yuji; Palkovits, Miklos; Diaz-Cabiale, Zaida; Fuxe, Kjell

2018-06-03

Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term "heteroreceptor complexes" was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A⁻FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A⁻FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A⁻5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1⁻15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1⁻GalR2⁻5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.

Effects of Constant Flickering Light on Refractive Status, 5-HT and 5-HT2A Receptor in Guinea Pigs.

PubMed

Li, Bing; Luo, Xiumei; Li, Tao; Zheng, Changyue; Ji, Shunmei; Ma, Yuanyuan; Zhang, Shuangshuang; Zhou, Xiaodong

2016-01-01

To investigate the effects of constant flickering light on refractive development, the role of serotonin (i.e.5-hydroxytryptamine, 5-HT)and 5-HT2A receptor in myopia induced by flickering light in guinea pigs. Forty-five guinea pigs were randomly divided into three groups: control, form deprivation myopia (FDM) and flickering light induced myopia (FLM) groups(n = 15 for each group). The right eyes of the FDM group were covered with semitransparent hemispherical plastic shells serving as eye diffusers. Guinea pigs in FLM group were raised with illumination of a duty cycle of 50% at a flash frequency of 0.5Hz. The refractive status, axial length (AL), corneal radius of curvature(CRC) were measured by streak retinoscope, A-scan ultrasonography and keratometer, respectively. Ultramicroscopy images were taken by electron microscopy. The concentrations of 5-HTin the retina, vitreous body and retinal pigment epithelium (RPE) were assessed by high performance liquid chromatography, the retinal 5-HT2A receptor expression was evaluated by immunohistofluorescence and western blot. The refraction of FDM and FLM eyes became myopic from some time point (the 4th week and the 6th week, respectively) in the course of the experiment, which was indicated by significantly decreased refraction and longer AL when compared with the controls (p<0.05). The concentrations of 5-HT in the retina, vitreous body and RPE of FDM and FLM eyes were significantly increased in comparison with those of control eyes (both p<0.05). Similar to FDM eyes, the expression of retinal 5-HT2A receptor in FLM eyes was significantly up-regulated compared to that of control eyes (both p<0.05). Western blot analysis showed that retinal 5-HT2A receptor level elevated less in the FLM eyes than that in the FDM eyes. Moreover, the levels of norepinephrine and epinephrine in FDM and FLM groups generally decreased when compared with control groups (all p<0.05). Constant flickering light could cause progressive myopia in

The 5-HT1-like receptor mediating the increase in canine external carotid blood flow: close resemblance to the 5-HT1D subtype.

PubMed Central

Villalón, C M; Terrón, J A

1994-01-01

1. It has recently been shown that the increase in external carotid blood flow induced by 5-hydroxy-tryptamine (5-HT) in the anaesthetized dog, being mimicked by 5-carboxamidotryptamine (5-CT), inhibited by methiothepin, vagosympathectomy and sympatho-inhibitory drugs, and resistant to blockade by ritanserin and MDL 72222, is mediated by stimulation of prejunctional 5-HT1-like receptors leading to an inhibitory action on carotid sympathetic nerves; these 5-HT1-like receptors are unrelated to either the 5-HT1A, 5-HT1B or 5-HT1C (now 5-HT2C) receptor subtypes. Inasmuch as 5-CT, 5-methoxytryptamine, sumatriptan and metergoline display high affinity, amongst other 5-HT binding sites, for the 5-HT1D subtype, in the present study we have used these drugs in an attempt to determine whether the above inhibitory prejunctional 5-HT1-like receptors correlate with the 5-HT1D subtype. 2. One-minute intracarotid (i.c.) infusions of 5-HT (0.3, 1, 3 and 10 micrograms), 5-CT (0.01, 0.03, 0.1 and 0.3 micrograms), 5-methoxytryptamine (1, 3, 10 and 30 micrograms) and sumatriptan (1, 3, 10, 30 and 100 micrograms) resulted in dose-dependent increases in external carotid blood flow (without changes in mean arterial blood pressure or heart rate) with the following rank order of agonist potency: 5-CT >> 5-HT > 5-methoxytryptamine > or = sumatriptan. Interestingly, sumatriptan-induced vasodilatation was followed by a more pronounced vasoconstriction. 3. The external carotid vasodilator effects of 5-HT, 5-CT, 5-methoxytryptamine and sumatriptan were dose-dependently and specifically antagonized by metergoline (10, 30 and/or 100 micrograms kg-1, i.v.).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7812603

Effects of OPC-14523, a combined sigma and 5-HT1a ligand, on pre- and post-synaptic 5-HT1a receptors.

PubMed

Bermack, Jordanna E; Debonnel, Guy

2007-01-01

OPC-14523 (OPC) is a novel compound with high affinity for sigma and 5-HT1A receptors that shows 'antidepressant-like' effects in animal models of depression. We have previously demonstrated that OPC produces an increase in 5-HT neurotransmission and a decreased response of 5-HT neurons to the acute administration of paroxetine in the DRN, an effect that appears to be mediated by OPC's 5-HT1A receptor affinity. The current study sets out to investigate more specifically the effects of OPC on 5-HT1A pre- and post-synaptic receptors, to assess whether it acts as an agonist or antagonist. Using an electrophysiological model of in vivo extracellular recordings in anaesthetized rats, the effects of OPC was assessed on pre-synaptic DRN 5-HT1A autoreceptors and post-synaptically on hippocampal 5-HT1A receptors of CA3 pyramidal neurons. OPC applied by microiontophoresis, produced a significant decrease in the firing activity of 5-HT neurons of the DRN and of quisqualate-activated CA3 pyramidal neurons of the dorsal hippocampus. The effects of OPC on 5-HT1A receptors were significantly reduced by the co-application of the 5-HT1A antagonist WAY-100635. In addition, the effects of OPC were not blocked by the injection of the sigma antagonists NE-100 or haloperidol. Therefore, OPC is acting as an agonist on both pre- and post-synaptic 5-HT1A receptors. The current findings combined with previous data on OPC suggest a pharmacological profile that warrants further investigation.

MDMA self-administration fails to alter the behavioral response to 5-HT(1A) and 5-HT(1B) agonists.

PubMed

Aronsen, Dane; Schenk, Susan

2016-04-01

Regular use of the street drug, ecstasy, produces a number of cognitive and behavioral deficits. One possible mechanism for these deficits is functional changes in serotonin (5-HT) receptors as a consequence of prolonged 3,4 methylenedioxymethamphetamine (MDMA)-produced 5-HT release. Of particular interest are the 5-HT(1A) and 5-HT(1B) receptor subtypes since they have been implicated in several of the behaviors that have been shown to be impacted in ecstasy users and in animals exposed to MDMA. This study aimed to determine the effect of extensive MDMA self-administration on behavioral responses to the 5-HT(1A) agonist, 8-hydroxy-2-(n-dipropylamino)tetralin (8-OH-DPAT), and the 5-HT(1B/1A) agonist, RU 24969. Male Sprague-Dawley rats self-administered a total of 350 mg/kg MDMA, or vehicle, over 20-58 daily self-administration sessions. Two days after the last self-administration session, the hyperactive response to 8-OH-DPAT (0.03-1.0 mg/kg) or the adipsic response to RU 24969 (0.3-3.0 mg/kg) were assessed. 8-OH-DPAT dose dependently increased horizontal activity, but this response was not altered by MDMA self-administration. The dose-response curve for RU 24969-produced adipsia was also not altered by MDMA self-administration. Cognitive and behavioral deficits produced by repeated exposure to MDMA self-administration are not likely due to alterations in 5-HT(1A) or 5-HT(1B) receptor mechanisms.

Apamin increases 5-HT cell firing in raphe dorsalis and extracellular 5-HT levels in amygdala: a concomitant in vivo study in anesthetized rats.

PubMed

Crespi, F

2009-07-24

The family of calcium-activated slow-potassium (SK) channels comprises 3 members, the SK1, SK2 and SK3 channels, all expressed in neurons, known to mediate the slow-afterhyperpolarization occurring after action potentials. In rats, the SK2 and SK3 channels are expressed in the ascending monoaminergic systems, in particular in the serotonin (5-HT) neurons of the raphe dorsalis nucleus (RDN). In mammals the amygdala, a limbic structure involved in the control of emotion and mood, receives 5-HT-containing projections originating in the RDN. The aim of the present study was to investigate the role of SK channels in mediating the release of 5-HT in the amygdala. Apamin, a polypeptiditic compound with SK2-SK3 channel selectivity, was used to block the channels. A dual probing methodology with Nafion coated carbon-fiber micro-electrode (Nafion-mCFE) was implemented to measure concomitantly the extracellular levels of 5-HT in the amygdala and the firing rate of 5-HT neurons in the RDN of anesthetized rats. Subcutaneous administration of apamin increased both the extracellular 5-HT levels in the amygdala and the firing rate of RDN neurons at doses as low as 12.5 microg. The recorded RDN neurons were of 5-HT phenotype, according to electrophysiologic signature and to the effects observed with peripheral administration of 8-hydroxy-2-(d-n-propyl-amino) tetralin (8-OH-DPAT) a 5-HT(1A) agonist known to selectively reduce the firing of 5-HT neurons in RDN. Increases of extracellular 5-HT levels in the amygdala were also seen when apamin was microinjected into the RDN, suggesting a role for 5-HT neurons of the RDN as target for subcutaneously administered apamin. The confirmation of the involvement of 5-HT neurons projecting from RDN to the amygdala in mediating the effects of apamin was obtained by micro-infusion of tetradotoxine into the bundle of 5-HT ascending fibers located in the region of the posterior amygdala. Attenuation of 5-HT release in the amygdala was observed in

Aptitude visuelle à la conduite automobile: exemple des candidats au permis de conduire à Libreville

PubMed Central

Souhail, Hassane; Assoumou, Prudence; Birinda, Hilda; Mengome, Emmanuel Mve

2015-01-01

L'objectif était d’évaluer l'aptitude visuelle à la conduite automobile des candidats au permis de conduire à Libreville. Il s'agissait d'une étude transversale, descriptive et analytique, qui s'est déroulée à Libreville pendant la période du 4 avril 2012 au 14 juillet 2012 (soit 4 mois et 10 jours). La population d’étude concernait les candidats soumis aux épreuves d'obtention du permis de conduire. Nous avons inclus dans notre travail, les candidats, ayant donné leur consentement par écrit et exclus ceux refusant d'adhérer à l'enquête. Les variables étudiées concernaient l’âge, le sexe, la population d’étude, l'activité professionnelle, l'acuité visuelle de loin et de près, la vision des couleurs, la catégorie du permis de conduire, et l'aptitude visuelle à la conduite automobile. La saisie et l'analyse des données ont été collectées au moyen d'une fiche d'enquête standardisée; après vérification et validation, elles ont été saisies sur le logiciel Excel Windows et analysées sur le logiciel Epi Info version 3.5.1. L’âge moyen des 406 candidats était de 29 ans ± 6,65 ans avec des extrêmes allant de 17 ans à 52 ans. Les hommes représentaient 283 (69,7%) et les femmes 123 (30,3%), soit un ratio de 2,3. Les fonctionnaires étaient retrouvés dans 39,4 % des cas, suivi des élèves-étudiants dans 33,5%. Dans notre population d’étude, 71 sur 406 candidats avaient une baisse de l'acuité visuelle de loin, soit 17,5%. Dans notre série, nous avons retrouvés 34 candidats âgés de 40 ans et plus, et seulement 14 candidats (41,2%) avaient une baisse de l'acuité visuelle de près. La quasi-totalité des patients avaient une vision de couleurs normale (99,5%), cependant 2 candidats avaient une vision de couleurs anormale, soit une prévalence de 0,5%. Dans notre échantillon, 403 (99,3%) sollicitaient un permis de conduire de catégorie léger (perms A, A1, B, F) et 3 (0,7%) sollicitaient un permis de conduire de type

Do dorsal raphe 5-HT neurons encode "beneficialness"?

PubMed

Luo, Minmin; Li, Yi; Zhong, Weixin

2016-11-01

The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) affects numerous behavioral and physiological processes. Drugs that alter 5-HT signaling treat several major psychiatric disorders and may lead to widespread abuse. The dorsal raphe nucleus (DRN) in the midbrain provides a majority of 5-HT for the forebrain. The importance of 5-HT signaling propels the search for a general theoretical framework under which the diverse functions of the DRN 5-HT neurons can be interpreted and additional therapeutic solutions may be developed. However, experimental data so far support several seeming irreconcilable theories, suggesting that 5-HT neurons mediate behavioral inhibition, aversive processing, or reward signaling. Here, we review recent progresses and propose that DRN 5-HT neurons encode "beneficialness" - how beneficial the current environmental context represents for an individual. Specifically, we speculate that the activity of these neurons reflects the possible net benefit of the current context as determined by p·R-C, in which p indicates reward probability, R the reward value, and C the cost. Through the widespread projections of these neurons to the forebrain, the beneficialness signal may reconfigure neural circuits to bias perception, boost positive emotions, and switch behavioral choices. The "beneficialness" hypothesis can explain many conflicting observations, and at the same time raises new questions. We suggest additional experiments that will help elucidate the exact computational functions of the DRN 5-HT neurons. Copyright © 2016 Elsevier Inc. All rights reserved.

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

PubMed

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

2002-11-01

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

Effects of Constant Flickering Light on Refractive Status, 5-HT and 5-HT2A Receptor in Guinea Pigs

PubMed Central

Li, Tao; Zheng, Changyue; Ji, Shunmei; Ma, Yuanyuan; Zhang, Shuangshuang; Zhou, Xiaodong

2016-01-01

Purpose To investigate the effects of constant flickering light on refractive development, the role of serotonin (i.e.5-hydroxytryptamine, 5-HT)and 5-HT2A receptor in myopia induced by flickering light in guinea pigs. Methods Forty-five guinea pigs were randomly divided into three groups: control, form deprivation myopia (FDM) and flickering light induced myopia (FLM) groups(n = 15 for each group). The right eyes of the FDM group were covered with semitransparent hemispherical plastic shells serving as eye diffusers. Guinea pigs in FLM group were raised with illumination of a duty cycle of 50% at a flash frequency of 0.5Hz. The refractive status, axial length (AL), corneal radius of curvature(CRC) were measured by streak retinoscope, A-scan ultrasonography and keratometer, respectively. Ultramicroscopy images were taken by electron microscopy. The concentrations of 5-HTin the retina, vitreous body and retinal pigment epithelium (RPE) were assessed by high performance liquid chromatography, the retinal 5-HT2A receptor expression was evaluated by immunohistofluorescence and western blot. Results The refraction of FDM and FLM eyes became myopic from some time point (the 4th week and the 6th week, respectively) in the course of the experiment, which was indicated by significantly decreased refraction and longer AL when compared with the controls (p<0.05). The concentrations of 5-HT in the retina, vitreous body and RPE of FDM and FLM eyes were significantly increased in comparison with those of control eyes (both p<0.05). Similar to FDM eyes, the expression of retinal 5-HT2A receptor in FLM eyes was significantly up-regulated compared to that of control eyes (both p<0.05). Western blot analysis showed that retinal 5-HT2A receptor level elevated less in the FLM eyes than that in the FDM eyes. Moreover, the levels of norepinephrine and epinephrine in FDM and FLM groups generally decreased when compared with control groups (all p<0.05). Conclusions Constant flickering

5HT(1A) and 5HT(1B) receptors of medial prefrontal cortex modulate anxiogenic-like behaviors in rats.

PubMed

Solati, Jalal; Salari, Ali-Akbar; Bakhtiari, Amir

2011-10-31

Medial prefrontal cortex (MPFC) is one of the brain regions which play an important role in emotional behaviors. The purpose of the present study was to evaluate the role of 5HT(1A) and 5HT(1B) receptors of the MPFC in modulation of anxiety behaviors in rats. The elevated plus maze (EPM) which is a useful test to investigate the effects of anxiogenic or anxiolytic drugs in rodents, was used. Bilateral intra-MPFC administration of 5HT(1A) receptor agonist, 8-OH-DPAT (5, 10, and 50 ng/rat) decreased the percentages of open arm time (OAT%) and open arm entries (OAE%), indicating an anxiogenic response. Moreover, administration of 5HT(1A) receptor antagonist, NAN-190 (0.25, 0.5, and 1 μg/rat) significantly increased OAT% and OAE%. Pre-treatment administration of NAN-190 (0.5 μg/rat), which was injected into the MPFC, reversed the anxiogenic effects of 8-OH-DPAT (5, 10, and 50 ng/rat). Intra-MPFC microinjection of 5HT(1B) receptor agonist, CGS-12066A (0.25, 0.5, and 1 μg/rat) significantly decreased OAT% and OAE%, without any change in locomotor activity, indicating an anxiogenic effect. However, injection of 5HT(1B) receptor antagonist, SB-224289 (0.5, 1, and 2 μg/rat) into the MPFC showed no significant effect. In conclusion, these findings suggest that 5HT(1A) and 5HT(1B) receptors of the MPFC region modulate anxiogenic-like behaviors in rats. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pericic, D.; Mueck-Seler, D.

1990-01-01

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

Hippocampal 5-HT1A Receptor and Spatial Learning and Memory

PubMed Central

Glikmann-Johnston, Yifat; Saling, Michael M.; Reutens, David C.; Stout, Julie C.

2015-01-01

Spatial cognition is fundamental for survival in the topographically complex environments inhabited by humans and other animals. The hippocampus, which has a central role in spatial cognition, is characterized by high concentration of serotonin (5-hydroxytryptamine; 5-HT) receptor binding sites, particularly of the 1A receptor (5-HT1A) subtype. This review highlights converging evidence for the role of hippocampal 5-HT1A receptors in spatial learning and memory. We consider studies showing that activation or blockade of the 5-HT1A receptors using agonists or antagonists, respectively, lead to changes in spatial learning and memory. For example, pharmacological manipulation to induce 5-HT release, or to block 5-HT uptake, have indicated that increased extracellular 5-HT concentrations maintain or improve memory performance. In contrast, reduced levels of 5-HT have been shown to impair spatial memory. Furthermore, the lack of 5-HT1A receptor subtype in single gene knockout mice is specifically associated with spatial memory impairments. These findings, along with evidence from recent cognitive imaging studies using positron emission tomography (PET) with 5-HT1A receptor ligands, and studies of individual genetic variance in 5-HT1A receptor availability, strongly suggests that 5-HT, mediated by the 5-HT1A receptor subtype, plays a key role in spatial learning and memory. PMID:26696889

No contractile effect for 5-HT1D and 5-HT1F receptor agonists in human and bovine cerebral arteries: similarity with human coronary artery

PubMed Central

Bouchelet, Isabelle; Case, Bruce; Olivier, André; Hamel, Edith

2000-01-01

Using subtype-selective 5-HT1 receptor agonists and/or the 5-HT1 receptor antagonist GR127935, we characterized in vitro the 5-HT receptor that mediates the contraction of human and bovine cerebral arteries. Further, we investigated which sumatriptan-sensitive receptors are present in human coronary artery by reverse-transcriptase polymerase chain reaction (RT–PCR). Agonists with affinity at the 5-HT1B receptor, such as sumatriptan, alniditan and/or IS-159, elicited dose-dependent contraction in both human and bovine cerebral arteries. They behaved as full agonists at the sumatriptan-sensitive 5-HT1 receptors in both species. In contrast, PNU-109291 and LY344864, selective agonists at 5-HT1D and 5-HT1F receptors, respectively, were devoid of any significant vasocontractile activity in cerebral arteries, or did not affect the sumatriptan-induced vasocontraction. The rank order of agonist potency was similar in both species and could be summarized as 5-HT=alniditan>sumatriptan=IS-159>>>PNU-109291=LY344864. In bovine cerebral arteries, the 5-HT1 receptor antagonist GR127935 dose-dependently inhibited the vasoconstrictions elicited by both 5-HT and sumatriptan, with respective pA2 values of 8.0 and 8.6. RT–PCR studies in human coronary arteries showed a strong signal for the 5-HT1B receptor while message for the 5-HT1F receptor was weak and less frequently detected. Expression of 5-HT1D receptor mRNA was not detected in any sample. The present results demonstrate that the triptan-induced contraction in brain vessels is mediated exclusively by the 5-HT1B receptor, which is also present in a majority of human coronary arteries. These results suggest that selective 5-HT1D and 5-HT1F receptor agonists might represent new antimigraine drugs devoid of cerebro- and cardiovascular effects. PMID:10711348

In vitro determination of HT oxidation activity and tritium concentration in soil and vegetation during the chronic HT release experiment at Chalk River

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ichimasa, Y.; Ichimasa, M.; Jiang, H.

1995-10-01

The oxidation activity of molecular tritium (HT) in soils and vegetation collected in experimental plots during the 1994 chronic HT release experiment at Chalk River was determined in vitro laboratory experiments after the release. HT oxidation activity was highest in surface soils in the natural plot, about 3-4 times that in soils in the cultivated plots. HT oxidation activity in weeds and Komatsuna leaves was about 2 and 0.4% of that in the cultivated soil, respectively. The number of HT-oxidizing bacteria isolated from soils was highest in the surface soil (0-5 cm) in the natural plot. The viable cell numbersmore » in surface soils in the cultivated and natural plots were almost the same. The total occurrence rates of HT-oxidizing bacteria in the surface soils were 22% in the natural plot, and 7.5% in the cultivated plot. The occurrence rates of HT-oxidizing airborne bacteria during the release on two culture media were 4.2 and 1.9%. 16 refs., 3 figs., 3 tabs.« less

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

PubMed Central

Meneses, Alfredo

2003-01-01

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

The Effect of Serotonin-Targeting Antidepressants on Neurogenesis and Neuronal Maturation of the Hippocampus Mediated via 5-HT1A and 5-HT4 Receptors

PubMed Central

Segi-Nishida, Eri

2017-01-01

Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) specifically increase serotonin (5-HT) levels in the synaptic cleft and are widely used to treat mood and anxiety disorders. There are 14 established subtypes of 5-HT receptors in rodents, each of which has regionally different expression patterns. Many preclinical studies have suggested that the hippocampus, which contains abundant 5-HT1A and 5-HT4 receptor subtypes in the dentate gyrus (DG), is critically involved in the mechanisms of action of antidepressants. This review article will analyze studies demonstrating regulation of hippocampal functions and hippocampus-dependent behaviors by SSRIs and similar serotonergic agents. Multiple studies indicate that 5-HT1A and 5-HT4 receptor signaling in the DG contributes to SSRI-mediated promotion of neurogenesis and increased neurotrophic factors expression. Chronic SSRI treatment causes functions and phenotypes of mature granule cells (GCs) to revert to immature-like phenotypes defined as a “dematured” state in the DG, and to increase monoamine reactivity at the dentate-to-CA3 synapses, via 5-HT4 receptor signaling. Behavioral studies demonstrate that the 5-HT1A receptors on mature GCs are critical for expression of antidepressant effects in the forced swim test and in novelty suppressed feeding; such studies also note that 5-HT4 receptors mediate neurogenesis-dependent antidepressant activity in, for example, novelty-suppressed feeding. Despite their limitations, the collective results of these studies describe a potential new mechanism of action, in which 5-HT1A and 5-HT4 receptor signaling, either independently or cooperatively, modulates the function of the hippocampal DG at multiple levels, any of which could play a critical role in the antidepressant actions of 5-HT-enhancing drugs. PMID:28559799

Adult AMPA GLUA1 receptor subunit loss in 5-HT neurons results in a specific anxiety-phenotype with evidence for dysregulation of 5-HT neuronal activity.

PubMed

Weber, Tillmann; Vogt, Miriam A; Gartside, Sarah E; Berger, Stefan M; Lujan, Rafael; Lau, Thorsten; Herrmann, Elke; Sprengel, Rolf; Bartsch, Dusan; Gass, Peter

2015-05-01

Both the glutamatergic and serotonergic (5-HT) systems are implicated in the modulation of mood and anxiety. Descending cortical glutamatergic neurons regulate 5-HT neuronal activity in the midbrain raphe nuclei through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. To analyze the functional role of GLUA1-containing AMPA receptors in serotonergic neurons, we used the Cre-ERT2/loxP-system for the conditional inactivation of the GLUA1-encoding Gria1 gene selectively in 5-HT neurons of adult mice. These Gria1(5-HT-/-) mice exhibited a distinct anxiety phenotype but showed no alterations in locomotion, depression-like behavior, or learning and memory. Increased anxiety-related behavior was associated with significant decreases in tryptophan hydroxylase 2 (TPH2) expression and activity, and subsequent reductions in tissue levels of 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine in the raphe nuclei. However, TPH2 expression and activity as well as monoamine levels were unchanged in the projection areas of 5-HT neurons. Extracellular electrophysiological recordings of 5-HT neurons revealed that, while α1-adrenoceptor-mediated excitation was unchanged, excitatory responses to AMPA were enhanced and the 5-HT1A autoreceptor-mediated inhibitory response to 5-HT was attenuated in Gria1(5-HT-/-) mice. Our data show that a loss of GLUA1 protein in 5-HT neurons enhances AMPA receptor function and leads to multiple local molecular and neurochemical changes in the raphe nuclei that dysregulate 5-HT neuronal activity and induce anxiety-like behavior.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nonogaki, Katsunori; Nozue, Kana; Oka, Yoshitomo

2006-12-29

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

Etude de la prévalence des infections nosocomiales et des facteurs associes dans les deux hopitaux universitaires de Lubumbashi, République Démocratique du Congo: cas des Cliniques Universitaires de Lubumbashi et l’Hôpital Janson Sendwe

PubMed Central

Kakupa, Danny Kasongo; Muenze, Prosper Kalenga; Byl, Baudouin; Wilmet, Michèle Dramaix

2016-01-01

Introduction Estimer la prévalence « un jour donné » des infections nosocomiales et déterminer leurs facteurs associés, ensuite estimer la prévalence des micro-organismes responsables des infections nosocomiales de Lubumbashi, République Démocratique du Congo. Méthodes Une étude transversale descriptive a été menée dans les deux hôpitaux de Lubumbashi au sein de cinq services d’hospitalisation (Chirurgie, Gynéco-Obstétrique, Médecine interne, Pédiatrie et Réanimation). L’échantillon était constitué de 171 patients hospitalisés et qui ont été interrogés à l’aide d’un questionnaire standardisé. La fiche médicale nous a permit de connaitre le type d’antibiotique administré au patient 48 heures après d’admission. Notre étude s’est déroulée durant le mois de février 2010 dans le cadre de la première enquête locale de prévalence des infections nosocomiales. Résultats Notre étude a permis de recenser 59 patients atteints d’une infection nosocomiale. La prévalence globale est de 34,5% (dont 17,0% pour une infection nosocomiale acquise et 17,5% pour une infection importée). L’infection nosocomiale a été définie selon l’Organisation Mondiale de la Santé comme toute infection acquise pendant un séjour à l’hôpital et qui n’était ni présente ni en incubation au moment de l’admission du patient. Les facteurs de risque suivants ont été associés aux infections nosocomiales acquises: durée d’hospitalisation (les patients admis en long séjour, séjour de plus de sept jours d’hospitalisation avaient un risque plus élevé que ceux admis en séjour court, séjour inférieur ou égal à sept jours d’hospitalisation (Ratio de prévalence: RP =3,6 [IC a 95% 1,4-8,9]). Parmi les infections nosocomiales, les infections du site opératoire étaient les plus fréquentes (27,1%), suivies des infections pulmonaires (22,0%) et des infections urinaires (17,0%). L’examen microbiologique a permis de mettre

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

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

2004-01-01

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

Expression and function of 5-HT4 receptors in the mouse enteric nervous system.

PubMed

Liu, Mintsai; Geddis, Matthew S; Wen, Ying; Setlik, Wanda; Gershon, Michael D

2005-12-01

The aim of the current study was to identify enteric 5-HT(4) splice variants, locate enteric 5-HT(4) receptors, determine the relationship, if any, of the 5-HT(4) receptor to 5-HT(1P) activity, and to ascertain the function of 5-HT(4) receptors in enteric neurophysiology. 5-HT(4a), 5-HT(4b), 5-HT(4e), and 5-HT(4f) isoforms were found in mouse brain and gut. The ratio of 5-HT(4) expression to that of the neural marker, synaptophysin, was higher in gut than in brain but was similar in small and large intestines. Submucosal 5-HT(4) expression was higher than myenteric. Although transcripts encoding 5-HT(4a) and 5-HT(4b) isoforms were more abundant, those encoding 5-HT(4e) and 5-HT(4f) were myenteric plexus specific. In situ hybridization revealed the presence of transcripts encoding 5-HT(4) receptors in subsets of enteric neurons, interstitial cells of Cajal, and smooth muscle cells. IgY antibodies to mouse 5-HT(4) receptors were raised, affinity purified, and characterized. Nerve fibers in the circular muscle and the neuropil in ganglia of both plexuses were highly 5-HT(4) immunoreactive, although only a small subset of neurons contained 5-HT(4) immunoreactivity. No 5-HT(4)-immunoreactive nerves were detected in the mucosa. 5-HT and 5-HT(1P) agonists evoked a G protein-mediated long-lasting inward current that was neither mimicked by 5-HT(4) agonists nor blocked by 5-HT(4) antagonists. In contrast, the 5-HT(4) agonists renzapride and tegaserod increased the amplitudes of nicotinic evoked excitatory postsynaptic currents. Enteric neuronal 5-HT(4) receptors thus are presynaptic and probably exert their prokinetic effects by strengthening excitatory neurotransmission.

Target size analysis of serotonin 5-HT/sub 1/ and 5-HT/sub 2/ receptors in bovine brain membranes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishino, N.; Tanaka, C.

1985-09-23

Freeze-dried crude synaptic membranes prepared from bovine cerebral cortex and striatum were exposed to high energy gamma ray from the source of /sup 60/Co. The size of serotonin 5-HT/sub 1/ receptors labeled by (/sup 3/H)serotonin and that of 5-HT/sub 2/ receptors labeled by (/sup 3/H)spiperone or (/sup 3/H)ketanserin was determined by target size analyses. The values were 57,000 daltons, 145,000 daltons and 152,000 daltons for the cerebral cortex and 56,000 daltons, 141,000 daltons and 150,000 daltons for the striatum, respectively. The estimated sizes were deduced by reference to enzyme standards with known molecular masses and which were irradiated in parallel.more » These results demonstrate that the molecular entities in situ for 5-HT/sub 1/ receptors are distinct from those for 5-HT/sub 2/ receptors, thus supporting data on the existence of two distinct populations of serotonin receptors, hitherto evidenced physiopharmacologically.« less

5-HT6 receptor blockade regulates primary cilia morphology in striatal neurons.

PubMed

Brodsky, Matthew; Lesiak, Adam J; Croicu, Alex; Cohenca, Nathalie; Sullivan, Jane M; Neumaier, John F

2017-04-01

The 5-HT 6 receptor has been implicated in a variety of cognitive processes including habitual behaviors, learning, and memory. It is found almost exclusively in the brain, is expressed abundantly in striatum, and localizes to neuronal primary cilia. Primary cilia are antenna-like, sensory organelles found on most neurons that receive both chemical and mechanical signals from other cells and the surrounding environment; however, the effect of 5-HT 6 receptor function on cellular morphology has not been examined. We confirmed that 5-HT 6 receptors were localized to primary cilia in wild-type (WT) but not 5-HT 6 knockout (5-HT 6 KO) in both native mouse brain tissue and primary cultured striatal neurons then used primary neurons cultured from WT or 5-HT 6 KO mice to study the function of these receptors. Selective 5-HT 6 antagonists reduced cilia length in neurons cultured from wild-type mice in a concentration and time-dependent manner without altering dendrites, but had no effect on cilia length in 5-HT 6 KO cultured neurons. Varying the expression levels of heterologously expressed 5-HT 6 receptors affected the fidelity of ciliary localization in both WT and 5-HT 6 KO neurons; overexpression lead to increasing amounts of 5-HT 6 localization outside of the cilia but did not alter cilia morphology. Introducing discrete mutations into the third cytoplasmic loop of the 5-HT 6 receptor greatly reduced, but did not entirely eliminate, trafficking of the 5-HT 6 receptor to primary cilia. These data suggest that blocking 5-HT 6 receptor activity reduces the length of primary cilia and that mechanisms that regulate trafficking of 5-HT 6 receptors to cilia are more complex than previously thought. Copyright © 2017 Elsevier B.V. All rights reserved.

Recombinant HT{sub m4} gene, protein and assays

DOEpatents

Lim, B.; Adra, C.N.; Lelias, J.M.

1996-09-03

The invention relates to a recombinant DNA molecule which encodes a HT{sub m4} protein, a transformed host cell which has been stably transfected with a DNA molecule which encodes a HT{sub m4} protein and a recombinant HT{sub m4} protein. The invention also relates to a method for detecting the presence of a hereditary atopy. 2 figs.

Recombinant HT.sub.m4 gene, protein and assays

DOEpatents

Lim, Bing; Adra, Chaker N.; Lelias, Jean-Michel

1996-01-01

The invention relates to a recombinant DNA molecule which encodes a HT.sub.m4 protein, a transformed host cell which has been stably transfected with a DNA molecule which encodes a HT.sub.m4 protein and a recombinant HT.sub.m4 protein. The invention also relates to a method for detecting the presence of a hereditary atopy.

P3HT-graphene bilayer electrode for Schottky junction photodetectors

NASA Astrophysics Data System (ADS)

Aydın, H.; Kalkan, S. B.; Varlikli, C.; Çelebi, C.

2018-04-01

We have investigated the effect of a poly (3-hexylthiophene-2.5-diyl)(P3HT)-graphene bilayer electrode on the photoresponsivity characteristics of Si-based Schottky photodetectors. P3HT, which is known to be an electron donor and absorb light in the visible spectrum, was placed on CVD grown graphene by dip-coating method. The results of the UV-vis and Raman spectroscopy measurements have been evaluated to confirm the optical and electronic modification of graphene by the P3HT thin film. Current-voltage measurements of graphene/Si and P3HT-graphene/Si revealed rectification behavior confirming a Schottky junction formation at the graphene/Si interface. Time-resolved photocurrent spectroscopy measurements showed the devices had excellent durability and a fast response speed. We found that the maximum spectral photoresponsivity of the P3HT-graphene/Si photodetector increased more than three orders of magnitude compared to that of the bare graphene/Si photodetector. The observed increment in the photoresponsivity of the P3HT-graphene/Si samples was attributed to the charge transfer doping from P3HT to graphene within the spectral range between near-ultraviolet and near-infrared. Furthermore, the P3HT-graphene electrode was found to improve the specific detectivity and noise equivalent power of graphene/Si photodetectors. The obtained results showed that the P3HT-graphene bilayer electrodes significantly improved the photoresponsivity characteristics of our samples and thus can be used as a functional component in Si-based optoelectronic device applications.

The role of 5-HT(1A) receptors in learning and memory.

PubMed

Ogren, Sven Ove; Eriksson, Therese M; Elvander-Tottie, Elin; D'Addario, Claudio; Ekström, Joanna C; Svenningsson, Per; Meister, Björn; Kehr, Jan; Stiedl, Oliver

2008-12-16

The ascending serotonin (5-HT) neurons innervate the cerebral cortex, hippocampus, septum and amygdala, all representing brain regions associated with various domains of cognition. The 5-HT innervation is diffuse and extensively arborized with few synaptic contacts, which indicates that 5-HT can affect a large number of neurons in a paracrine mode. Serotonin signaling is mediated by 14 receptor subtypes with different functional and transductional properties. The 5-HT(1A) subtype is of particular interest, since it is one of the main mediators of the action of 5-HT. Moreover, the 5-HT(1A) receptor regulates the activity of 5-HT neurons via autoreceptors, and it regulates the function of several neurotransmitter systems via postsynaptic receptors (heteroreceptors). This review assesses the pharmacological and genetic evidence that implicates the 5-HT(1A) receptor in learning and memory. The 5-HT(1A) receptors are in the position to influence the activity of glutamatergic, cholinergic and possibly GABAergic neurons in the cerebral cortex, hippocampus and in the septohippocampal projection, thereby affecting declarative and non-declarative memory functions. Moreover, the 5-HT(1A) receptor regulates several transduction mechanisms such as kinases and immediate early genes implicated in memory formation. Based on studies in rodents the stimulation of 5-HT(1A) receptors generally produces learning impairments by interfering with memory-encoding mechanisms. In contrast, antagonists of 5-HT(1A) receptors facilitate certain types of memory by enhancing hippocampal/cortical cholinergic and/or glutamatergic neurotransmission. Some data also support a potential role for the 5-HT(1A) receptor in memory consolidation. Available results also implicate the 5-HT(1A) receptor in the retrieval of aversive or emotional memories, supporting an involvement in reconsolidation. The contribution of 5-HT(1A) receptors in cognitive impairments in various psychiatric disorders is still

A critical review of 5-HT brain microdialysis and behavior.

PubMed

Rueter, L E; Fornal, C A; Jacobs, B L

1997-01-01

Serotonin (5-HT) has been implicated in many central nervous system-mediated functions including sleep, arousal, feeding, motor activity and the stress response. In order to help establish the precise role of 5-HT in physiology and behavior, in vivo microdialysis studies have sought to identify the conditions under which the release of 5-HT is altered. Extracellular 5-HT levels have been monitored in more than fifteen regions of the brain during a variety of spontaneous behaviors, and in response to several physiological, environmental, and behavioral manipulations. The vast majority of these studies found increases (30-100%) in 5-HT release in almost all brain regions studied. Since electrophysiological studies have shown that behavioral arousal is the primary determinant of brain serotonergic neuronal activity, we suggest that the increase in 5-HT release seen during a wide variety of experimental conditions is largely due to one factor, namely an increase in behavioral arousal/motor activity associated with the manipulation.

5-HT2A receptor activation is necessary for CO2-induced arousal

PubMed Central

Smith, Haleigh R.; MacAskill, Amanda; Richerson, George B.

2015-01-01

Hypercapnia-induced arousal from sleep is an important protective mechanism pertinent to a number of diseases. Most notably among these are the sudden infant death syndrome, obstructive sleep apnea and sudden unexpected death in epilepsy. Serotonin (5-HT) plays a significant role in hypercapnia-induced arousal. The mechanism of 5-HT's role in this protective response is unknown. Here we sought to identify the specific 5-HT receptor subtype(s) involved in this response. Wild-type mice were pretreated with antagonists against 5-HT receptor subtypes, as well as antagonists against adrenergic, cholinergic, histaminergic, dopaminergic, and orexinergic receptors before challenge with inspired CO2 or hypoxia. Antagonists of 5-HT2A receptors dose-dependently blocked CO2-induced arousal. The 5-HT2C receptor antagonist, RS-102221, and the 5-HT1A receptor agonist, 8-OH-DPAT, attenuated but did not completely block CO2-induced arousal. Blockade of non-5-HT receptors did not affect CO2-induced arousal. None of these drugs had any effect on hypoxia-induced arousal. 5-HT2 receptor agonists were given to mice in which 5-HT neurons had been genetically eliminated during embryonic life (Lmx1bf/f/p) and which are known to lack CO2-induced arousal. Application of agonists to 5-HT2A, but not 5-HT2C, receptors, dose-dependently restored CO2-induced arousal in these mice. These data identify the 5-HT2A receptor as an important mediator of CO2-induced arousal and suggest that, while 5-HT neurons can be independently activated to drive CO2-induced arousal, in the absence of 5-HT neurons and endogenous 5-HT, 5-HT receptor activation can act in a permissive fashion to facilitate CO2-induced arousal via another as yet unidentified chemosensor system. PMID:25925320

5-HT receptor probe (/sup 3/H)8-OH-DPAT labels the 5-HT transporter in human platelets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ieni, J.R.; Meyerson, L.R.

1988-01-01

The present study characterizes a serotonin (5-HT) binding site on human platelet membranes, using (/sup 3/H)8-OH-DPAT as the radioligand. (/sup 3/H)8-OH-DPAT binds specifically and saturably to a site on human platelet membranes with an average K/sub D/ of 43 nM and B/sub max/ of 1078 fmol/mg protein. Determinations of IC/sub 50/ values for various serotonergic characterizing agents in platelets for displacement of (/sup 3/H)8-OH-DPAT were performed. The pharmacological inhibitory profile of the platelet 8-OH-DPAT site is not consistent with profiles reported for brain. 8-OH-DPAT does not inhibit (/sup 3/H) imipramine binding, however, it does inhibit (/sup 3/H)5-HT uptake in humanmore » platelets near 5-HT's K/sub m/ value (IC/sub 50/ = 2-4 ..mu..M). These results suggest that the human platelet site labelled by (/sub 3/H)8-OH-DPAT is pharmocologically different from the neuronal site and probably is a component of the 5-HT transporter. 32 references, 1 figure, 4 tables.« less

Orbital period determination in an eclipsing dwarf nova HT Cas

NASA Astrophysics Data System (ADS)

Bąkowska, Karolina; Olech, Arkadiusz

2014-09-01

HT Cassiopeiae was discovered over seventy years ago (Hoffmeister 1943). Unfortunately, for 35 years this object did not receive any attention, until the eclipses of HT Cas were observed by Bond. After a first analysis, Patterson (1981) called HT Cas "a Rosetta stone among dwarf novae". Since then, the literature on this star is still growing, reaching several dozens of publications. We present an orbital period determination of HT Cas during the November 2010 super-outburst, but also during a longer time span, to check its stability.

Methylene blue inhibits function of the 5-HT transporter

PubMed Central

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

2012-01-01

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

Selective verbal and spatial memory impairment after 5-HT1A and 5-HT2A receptor blockade in healthy volunteers pre-treated with an SSRI.

PubMed

Wingen, M; Kuypers, K P C; Ramaekers, J G

2007-07-01

Serotonergic neurotransmission has been implicated in memory impairment. It is unclear however if memory performance is mediated through general 5-HT availability, through specific 5-HT receptors or both. The aim of the present study was to assess the contribution of 5-HT reuptake inhibition and specific blockade of 5-HT(1A) and 5-HT(2A) receptors to memory impairment. The study was conducted according to a randomized, double-blind, placebo-controlled, four-way cross-over design including 16 healthy volunteers. The treatment consisted of oral administration of escitalopram 20 mg + placebo, escitalopram 20 mg + ketanserin 50 mg, escitalopram 20 mg + pindolol 10 mg and placebo on 4 separate days with a washout period of minimum 7 days. Different memory tasks were performed including verbal memory, spatial working memory and reversal learning. Escitalopram showed an impairing effect on immediate verbal recall which nearly reached statistical significance. No effects of escitalopram were found on other types of memory. In combination with pindolol, immediate verbal recall was significantly impaired. Escitalopram in combination with ketanserin impaired spatial working memory significantly. No effects were found on reversal learning. Selective impairment of immediate verbal recall after a 5-HT(1A) partial agonist and selective impairment of spatial working memory performance after 5-HT(2A) receptor antagonist, both in combination with a selective serotonergic reuptake inhibitor (escitalopram), suggests that 5-HT(1A) and 5-HT(2A) receptors are distinctly involved in verbal and spatial memory.

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

PubMed

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

2014-05-01

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

Serotonergic modulation of the rat pup ultrasonic isolation call: studies with 5HT1 and 5HT2 subtype-selective agonists and antagonists.

PubMed

Winslow, J T; Insel, T R

1991-01-01

A modulatory role for serotonin has been described for the development and expression of the ultrasonic call of infant rat pups during brief maternal separations. In previous studies, serotonin reuptake inhibitors selectively reduced the rate of calling following acute administration to 9-11-day-old pups and a serotonin neurotoxin (MDMA) systematically disrupted the development of ultrasonic vocalizations but not other measures of motor development. In the current studies, we extended our investigations to include drugs with purported receptor subtype selectivities. Consistent with previous reports, acute administration of 5HT1A agonists buspirone and 8-OH-DPAT [+/-)-8-hydroxy-2-(di-N-propylamino)tetralin) reduced the rate of calling at doses which did not affect motor activity or core body temperature. The rate reducing effects of buspirone persisted up to 1 but not 2 h after injection. Administration of purported 5HT1B receptor agonists, CGS12066B (7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a] quinoxaline) and TFMPP (1-[3-fluoromethyl)phenyl]-piperazine) increased the rate of calling depending on the specificity of the drug for the 5HT1B receptor. d,l-Propranolol, a 5HT1 receptor antagonist, blocked the effects of both 8-OH-DPAT and TFMPP. m-CPP (1-(3-chlorophenyl)piperazine) and DOI [+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), drugs with putative actions at 5HT1C and 5HT2 receptor sites both decreased calling but differed according to their effects on motor activity. Ritanserin, a 5HT2 and 5HT1C antagonist, produced a dose-related increase in call rate. A dose of ritanserin with no apparent intrinsic effects effectively antagonized DOI rate reducing effects but potentiated the rate reducing effects of m-CPP.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective increases in serotonin 5-HT1B/1D and 5-HT2A/2C binding sites in adult rat basal ganglia following lesions of serotonergic neurons.

PubMed

Compan, V; Segu, L; Buhot, M C; Daszuta, A

1998-05-18

Quantitative autoradiography was used to examine possible adaptive changes in serotonin 5-HT1B/1D and 5-HT2A/2C receptor binding sites in adult rat basal ganglia, after partial or severe lesions of serotonergic neurons produced by intraraphe injections of variable amounts of 5,7-dihydroxytryptamine. In controls, the 5-HT1B/1D sites labeled with S-CM-G[125I]TNH2 were evenly distributed in the core and the shell of the nucleus accumbens. The density of 5-HT1B/1D sites was higher in the ventral than dorsal part of the striatum and no regional differences were detected along the rostrocaudal axis of the structure. The 5-HT2A/2C sites labeled with [125I]DOI were preferentially distributed in the mediodorsal striatum and higher densities were detected in the shell than core of the nucleus accumbens. Following 5,7-dihydroxytryptamine injections, there were no changes in binding of either receptor subtype after partial lesions entailing 80-90% 5-HT depletions. After severe 5-HT depletions (over 95%), large increases in 5-HT1B/1D binding were observed in the substantia nigra (78%), but no changes took place in the globus pallidus. Increases in 5-HT1B/1D binding were also detected in the shell of the nucleus accumbens (27%). Similar sized increases in 5-HT2A/2C binding (22%) were restricted to the medial striatum. The present results suggest a preferential association between 5-HT1B/1D receptors and the striatonigral neurons containing substance P, as indicated by the striatal distribution of these receptors and their selective increases in the substantia nigra after severe 5-HT deprivation. We recently proposed a similar relationship between the 5-HT4 receptors and the striatopallidal neurons containing met-enkephalin. Moreover, the increases in 5-HT1B/1D binding in the substantia nigra and in the shell of the nucleus accumbens reinforce the view of an implication of this receptor subtype in motor functions. In contrast, the prominent increases in 5-HT2A/2C binding after

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

PubMed

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

2010-01-01

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

SHEDS-HT: An Integrated Probabilistic Exposure Model for ...

EPA Pesticide Factsheets

United States Environmental Protection Agency (USEPA) researchers are developing a strategy for highthroughput (HT) exposure-based prioritization of chemicals under the ExpoCast program. These novel modeling approaches for evaluating chemicals based on their potential for biologically relevant human exposures will inform toxicity testing and prioritization for chemical risk assessment. Based on probabilistic methods and algorithms developed for The Stochastic Human Exposure and Dose Simulation Model for Multimedia, Multipathway Chemicals (SHEDS-MM), a new mechanistic modeling approach has been developed to accommodate high-throughput (HT) assessment of exposure potential. In this SHEDS-HT model, the residential and dietary modules of SHEDS-MM have been operationally modified to reduce the user burden, input data demands, and run times of the higher-tier model, while maintaining critical features and inputs that influence exposure. The model has been implemented in R; the modeling framework links chemicals to consumer product categories or food groups (and thus exposure scenarios) to predict HT exposures and intake doses. Initially, SHEDS-HT has been applied to 2507 organic chemicals associated with consumer products and agricultural pesticides. These evaluations employ data from recent USEPA efforts to characterize usage (prevalence, frequency, and magnitude), chemical composition, and exposure scenarios for a wide range of consumer products. In modeling indirec

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

PubMed Central

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

2014-01-01

The serotonergic system plays a key modulatory role in the brain and is the target for many drug treatments for brain disorders either through reuptake blockade or via interactions at the 14 subtypes of 5-HT receptors. This review provides the history and current status of radioligands used for positron emission tomography (PET) and single photon emission computerized tomography (SPECT) imaging of human brain serotonin (5-HT) receptors, the 5-HT transporter (SERT), and 5-HT synthesis rate. Currently available radioligands for in vivo brain imaging of the 5-HT system in humans include antagonists for the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 receptors, and for SERT. Here we describe the evolution of these radioligands, along with the attempts made to develop radioligands for additional serotonergic targets. We describe the properties needed for a radioligand to become successful and the main caveats. The success of a PET or SPECT radioligand can ultimately be assessed by its frequency of use, its utility in humans, and the number of research sites using it relative to its invention date, and so these aspects are also covered. In conclusion, the development of PET and SPECT radioligands to image serotonergic targets is of high interest, and successful evaluation in humans is leading to invaluable insight into normal and abnormal brain function, emphasizing the need for continued development of both SPECT and PET radioligands for human brain imaging. PMID:21674551

Could the 5-HT1B receptor inverse agonism affect learning consolidation?

PubMed

Meneses, A

2001-03-01

Diverse evidence indicates that, the 5-HT system might play a role in learning and memory, since it occurs in brain areas mediating such processes and 5-HT drugs modulate them. Hence in this work, in order to explore further 5-HT involvement on learning and memory 5-HT1B receptors' role is investigated. Evidence indicates that SB-224289 (a 5-HT1B receptor inverse agonist) post-training injection facilitated learning consolidation in an associative autoshaping learning task, this effect was partially reversed by GR 127935 (a 5-HT1B/1D receptor antagonist), but unaffected by MDL 100907 (a 5-HT2A receptor antagonist) or ketanserin (a 5-HT1D/2A/7 receptor antagonist) at low doses. Moreover, SB-224289 antagonized the learning deficit produced by TFMPP (a 5-HT1A/1B/1D/2A/2C receptor agonist), GR 46611 (a 5-HT1A/1B/1D receptor agonist), mCPP (a 5-HT2A/2C/3/7 receptor agonist/antagonist) or GR 127935 (at low dose). SB-224289 did not alter the 8-OH-DPAT (a 5-HT1A/7 receptor agonist) learning facilitatory effect. SB-224289 eliminated the deficit learning produced by the anticholinergic muscarinic scopolamine or the glutamatergic antagonist dizocilpine. Administration of both, GR 127935 (5mg/kg) plus ketanserin (0.01 mg/kg) did not modify learning consolidation; nevertheless, when ketanserin dose was increased (0.1-1.0mg/kg) and SB-224289 dose was maintained constant, a learning facilitation effect was observed. Notably, SB-224289 at 1.0mg/kg potentiated a subeffective dose of the 5-HT1B/1D receptor agonist/antagonist mixed GR 127935, which facilitated learning consolidation and this effect was abolished by ketanserin at a higher dose. Collectively, the data confirm and extend the earlier findings with GR 127935 and the effects of non-selective 5-HT(1B) receptor agonists. Clearly 5-HT1B agonists induced a learning deficit which can be reversed with SB-224289. Perhaps more importantly, SB-224289 enhances learning consolidation when given alone and can reverse the deficits

Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1-yl)ethyl]indoles: potent agonists for the h5-HT1D receptor with high selectivity over the h5-HT1B receptor.

PubMed

Sternfeld, F; Guiblin, A R; Jelley, R A; Matassa, V G; Reeve, A J; Hunt, P A; Beer, M S; Heald, A; Stanton, J A; Sohal, B; Watt, A P; Street, L J

1999-02-25

The design, synthesis, and biological evaluation of a novel series of 3-[2-(pyrrolidin-1-yl)ethyl]indoles with excellent selectivity for h5-HT1D (formerly 5-HT1Dalpha) receptors over h5-HT1B (formerly 5-HT1Dbeta) receptors are described. Clinically effective antimigraine drugs such as Sumatriptan show little selectivity between h5-HT1D and h5-HT1B receptors. The differential expression of h5-HT1D and h5-HT1B receptors in neural and vascular tissue prompted an investigation of whether a compound selective for the h5-HT1D subtype would have the same clinical efficacy but with reduced side effects. The pyrrolidine 3b was initially identified as having 9-fold selectivity for h5-HT1D over h5-HT1B receptors. Substitution of the pyrrolidine ring of 3b with methylbenzylamine groups gave compounds with nanomolar affinity for the h5-HT1D receptor and 100-fold selectivity with respect to h5-HT1B receptors. Modification of the indole 5-substituent led to the oxazolidinones 24a,b with up to 163-fold selectivity for the h5-HT1D subtype and improved selectivity over other serotonin receptors. The compounds were shown to be full agonists by measurement of agonist-induced [35S]GTPgammaS binding in CHO cells expressed with h5-HT receptors. This study suggests that the h5-HT1D and h5-HT1B receptors can be differentiated by appropriate substitution of the ligand in the region which binds to the aspartate residue and reveals a large binding pocket in the h5-HT1D receptor domain which is absent for the h5-HT1B receptor. The compounds described herein will be important tools to delineate the role of h5-HT1D receptors in migraine.

Physiology and pathophysiology of the 5-HT3 receptor.

PubMed

Färber, L; Haus, U; Späth, M; Drechsler, S

2004-01-01

The 5-HT3 receptor is a ligand-gated cation channel located in the central and peripheral nervous system; it has also been detected on a variety of other cells. In the periphery, it is found on autonomic neurons and on neurons of the sensory and enteric nervous system. In the CNS, the 5-HT3 receptor has been localized in the area postrema, nucleus tractus solitarii, nucleus vaudatus, nucleus accumbens, amygdala, hippocampus, entorhinal, frontal, cingulate cortex, and in the dorsal horn ganglia. Further extraneuronal locations include among others lymphocytes, monocytes, and foetal tissue. 5-HT3 receptors modulate the release of neurotransmitters and neuropeptides like dopamine, cholecystokinin, acetylcholine, GABA, substance P, and serotonin itself. They have been demonstrated to be involved in sensory transmission, regulation of autonomic functions, integration of the vomiting reflex, pain processing and control of anxiety. While the physiologic functions of the 5-HT3 receptor are discrete and difficult to detect, it plays a key role in certain pathologic situations related to increased serotonin release. Clinical development of 5-HT3 receptor antagonists revealed a remarkable range of activities. 5-HT3 receptor antagonists do not modify any aspect of normal behaviour in animals or induce pronounced changes of physiological functions in healthy subjects. Clinical efficacy was shown for various forms of emesis like chemotherapy-induced, radiotherapy-induced, and postoperative emesis, diarrhoea-predominant irritable bowel syndrome, anxiety, chronic fatigue syndrome, alcohol abuse, and in pain syndromes such as fibromyalgia and migraine. Most recent data also suggest that 5-HT3 receptor antagonists are effective for the treatment of other rheumatic diseases such as rheumatoid arthritis, tendinopathies, periarthropathies, and myofascial pain. Other possible indications under discussion are chronic heart pain and bulimia. Unfortunately, experimental findings do not yet

5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice.

PubMed

Pogorelov, Vladimir M; Rodriguiz, Ramona M; Cheng, Jianjun; Huang, Mei; Schmerberg, Claire M; Meltzer, Herbert Y; Roth, Bryan L; Kozikowski, Alan P; Wetsel, William C

2017-10-01

All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D 2 or serotonin (5-HT 2A ) receptors, or both; however, these medications are not universally effective, they may produce undesirable side effects, and provide only partial amelioration of negative and cognitive symptoms. The heterogeneity of pharmacological responses in schizophrenic patients suggests that additional drug targets may be effective in improving aspects of this syndrome. Recent evidence suggests that 5-HT 2C receptors may be a promising target for schizophrenia since their activation reduces mesolimbic nigrostriatal dopamine release (which conveys antipsychotic action), they are expressed almost exclusively in CNS, and have weight-loss-promoting capabilities. A difficulty in developing 5-HT 2C agonists is that most ligands also possess 5-HT 2B and/or 5-HT 2A activities. We have developed selective 5-HT 2C ligands and herein describe their preclinical effectiveness for treating schizophrenia-like behaviors. JJ-3-45, JJ-3-42, and JJ-5-34 reduced amphetamine-stimulated hyperlocomotion, restored amphetamine-disrupted prepulse inhibition, improved social behavior, and novel object recognition memory in NMDA receptor hypofunctioning NR1-knockdown mice, and were essentially devoid of catalepsy. However, they decreased motivation in a breakpoint assay and did not promote reversal learning in MK-801-treated mice. Somewhat similar effects were observed with lorcaserin, a 5-HT 2C agonist with potent 5-HT 2B and 5-HT 2A agonist activities, which is approved for treating obesity. Microdialysis studies revealed that both JJ-3-42 and lorcaserin reduced dopamine efflux in the infralimbic cortex, while only JJ-3-42 decreased it in striatum. Collectively, these results provide additional evidence that 5-HT 2C receptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.

Effects of P3HT concentration on the electrical properties of the Au/PEDOT:PSS/P3HT/n-GaN hybrid junction structure

NASA Astrophysics Data System (ADS)

Noh, Ji-yeon; Lee, Ha Young; Lim, Kyung-won; Ahn, Hyung Soo; Yi, Sam Nyung; Jeon, Hunsoo; Shin, Min Jeong; Yu, Young Moon; Ha, Dong Han

2017-09-01

An inorganic-organic hybrid junction has been fabricated by spin coating the p-type poly(3- hexylthiophene-2,5-diyl)(P3HT) and poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT: PSS) on an n-type GaN layer. The GaN layer was formed on Al2O3 by metal organic chemical vapor deposition(MOCVD) method. To investigate the effects of P3HT concentration on the electrical properties, we changed P3HT solution concentration and speed of spin coater. The currentvoltage (I-V ) characteristic of Au/PEDOT:PSS/P3HT/n-GaN shows rectifying behavior. The I-V characteristic was examined in the frame work of the thermionic emission model. The most proper rectifying behavior was obtained for 0.6 wt% and thickness below 65 nm of P3HT used diode. We expect that such hybrid structures, suitably developed, might be enable the fabrication of highquality electronic and optoelectronic devices.

Role of 5-HT5A and 5-HT1B/1D receptors in the antinociception produced by ergotamine and valerenic acid in the rat formalin test.

PubMed

Vidal-Cantú, Guadalupe C; Jiménez-Hernández, Mildred; Rocha-González, Héctor I; Villalón, Carlos M; Granados-Soto, Vinicio; Muñoz-Islas, Enriqueta

2016-06-15

Sumatriptan, dihydroergotamine and methysergide inhibit 1% formalin-induced nociception by activation of peripheral 5-HT1B/1D receptors. This study set out to investigate the pharmacological profile of the antinociception produced by intrathecal and intraplantar administration of ergotamine (a 5-HT1B/1D and 5-HT5A/5B receptor agonist) and valerenic acid (a partial agonist at 5-HT5A receptors). Intraplantar injection of 1% formalin in the right hind paw resulted in spontaneous flinching behavior of the injected hindpaw of female Wistar rats. Intrathecal ergotamine (15nmol) or valerenic acid (1 nmol) blocked in a dose dependent manner formalin-induced nociception. The antinociception by intrathecal ergotamine (15nmol) or valerenic acid (1nmol) was partly or completely blocked by intrathecal administration of the antagonists: (i) methiothepin (non-selective 5-HT5A/5B; 0.01-0.1nmol); (ii) SB-699551 (selective 5-HT5A; up to 10nmol); (iii) anti-5-HT5A antibody; (iv) SB-224289 (selective 5-HT1B; 0.1-1nmol); or (v) BRL-15572 (selective 5-HT1D; 0.1-1nmol). Likewise, antinociception by intraplantar ergotamine (15nmol) and valerenic acid (10nmol) was: (i) partially blocked by methiothepin (1nmol), SB-699551 (10nmol) or SB-224289 (1nmol); and (ii) abolished by BRL-15572 (1nmol). The above doses of antagonists (which did not affect per se the formalin-induced nociception) were high enough to completely block their respective receptors. Our results suggest that ergotamine and valerenic acid produce antinociception via 5-HT5A and 5-HT1B/1D receptors located at both spinal and peripheral sites. This provides new evidence for understanding the modulation of nociceptive pathways in inflammatory pain. Copyright © 2016 Elsevier B.V. All rights reserved.

The role of serotonin 5-HT2A receptors in memory and cognition

PubMed Central

Zhang, Gongliang; Stackman, Robert W.

2015-01-01

Serotonin 5-HT2A receptors (5-HT2ARs) are widely distributed in the central nervous system, especially in brain region essential for learning and cognition. In addition to endogenous 5-HT, several hallucinogens, antipsychotics, and antidepressants function by targeting 5-HT2ARs. Preclinical studies show that 5-HT2AR antagonists have antipsychotic and antidepressant properties, whereas agonist ligands possess cognition-enhancing and hallucinogenic properties. Abnormal 5-HT2AR activity is associated with a number of psychiatric disorders and conditions, including depression, schizophrenia, and drug addiction. In addition to its traditional activity as a G protein-coupled receptor (GPCR), recent studies have defined novel operations of 5-HT2ARs. Here we review progress in the (1) receptor anatomy and biology: distribution, signaling, polymerization and allosteric modulation; and (2) receptor functions: learning and memory, hallucination and spatial cognition, and mental disorders. Based on the recent progress in basic research on the 5-HT2AR, it appears that post-training 5-HT2AR activation enhances non-spatial memory consolidation, while pre-training 5-HT2AR activation facilitates fear extinction. Further, the potential influence that 5-HT2AR-elicited visual hallucinations may have on visual cue (i.e., landmark) guided spatial cognition is discussed. We conclude that the development of selective 5-HT2AR modulators to target distinct signaling pathways and neural circuits represents a new possibility for treating emotional, neuropsychiatric, and neurodegenerative disorders. PMID:26500553

Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes.

PubMed

Borroto-Escuela, Dasiel O; Romero-Fernandez, Wilber; Narvaez, Manuel; Oflijan, Julia; Agnati, Luigi F; Fuxe, Kjell

2014-01-03

Dopamine D2LR-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor-receptor interactions. In the current study the existence of D2L-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist (3)H-raclopride binding sites and significantly reduced the pKiH values of the high affinity D2R agonist binding sites in (3)H-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2LR agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DOI and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists. Copyright © 2013 Elsevier Inc. All rights reserved.

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

ERIC Educational Resources Information Center

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

2014-01-01

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

Déprescription des agonistes des récepteurs des benzodiazépines

PubMed Central

Pottie, Kevin; Thompson, Wade; Davies, Simon; Grenier, Jean; Sadowski, Cheryl A.; Welch, Vivian; Holbrook, Anne; Boyd, Cynthia; Swenson, Robert; Ma, Andy; Farrell, Barbara

2018-01-01

Résumé Objectif Formuler des lignes directrices fondées sur les données probantes visant à aider les cliniciens à décider du moment et de la façon sécuritaire de réduire la dose des agonistes des récepteurs des benzodiazépines (BZRA) pour mettre fin au traitement; se concentrer sur le niveau le plus élevé des données disponibles et obtenir les commentaires des professionnels de première ligne durant le processus de rédaction, de révision et d’adoption des lignes directrices. Méthodes L’équipe comptait 8 cliniciens (1 médecin de famille, 2 psychiatres, 1 psychologue clinique, 1 pharmacologue clinique, 2 pharmaciennes cliniques et 1 gériatre) et une spécialiste de la méthodologie; les membres ont divulgué tout conflit d’intérêts. Nous avons eu recours à un processus systématique, y compris l’approche GRADE (Grading of Recommendations Assessment, Development and Evaluation) pour formuler les lignes directrices. Les données ont été générées par une revue systématique d’études portant sur la déprescription des BZRA contre l’insomnie, de même que par une revue des revues sur les torts liés à la poursuite du traitement par BZRA et des synthèses narratives sur les préférences des patients et les répercussions sur les ressources. Ces données et le score GRADE de qualité des données ont servi à formuler les recommandations. L’équipe a peaufiné le texte sur le contenu et les recommandations des lignes directrices par consensus et a synthétisé les considérations cliniques afin de répondre aux questions des cliniciens de première ligne. Une version préliminaire des lignes directrices a été révisée par les cliniciens et les intervenants. Recommandations Nous recommandons d’offrir la déprescription (réduction lente de la dose) des BZRA à tous les patients âgés (≥ 65 ans) sous un BZRA, sans égard à la durée de l’usage, et suggérons d’offrir la déprescription (réduction lente de la dose) �

5-HT in the enteric nervous system: gut function and neuropharmacology.

PubMed

McLean, Peter G; Borman, Richard A; Lee, Kevin

2007-01-01

In recent times, the perception of functional gastrointestinal disorders such as irritable bowel syndrome (IBS) has shifted fundamentally. Such disorders are now thought of as serious diseases characterized by perturbations in the neuronal regulation of gastrointestinal function. The concept of visceral hypersensitivity, the characterization of neuronal networks in the 'brain-gut axis' and the identification of several novel 5-HT-mediated mechanisms have contributed to this shift. Here, we review how some of the more promising of these new mechanisms (e.g. those involving 5-HT transporters and the 5-HT(2B), 5-HT(7) and putative 5-HT(1p) receptors) might lead to a range of second-generation therapies that could revolutionize the treatment of functional gastrointestinal disorders, particularly IBS.

5-HT2A/5-HT2C Receptor Pharmacology and Intrinsic Clearance of N-Benzylphenethylamines Modified at the Primary Site of Metabolism.

PubMed

Leth-Petersen, Sebastian; Petersen, Ida N; Jensen, Anders A; Bundgaard, Christoffer; Bæk, Mathias; Kehler, Jan; Kristensen, Jesper L

2016-11-16

The toxic hallucinogen 25B-NBOMe is very rapidly degraded by human liver microsomes and has low oral bioavailability. Herein we report on the synthesis, microsomal stability, and 5-HT 2A /5-HT 2C receptor profile of novel analogues of 25B-NBOMe modified at the primary site of metabolism. Although microsomal stability could be increased while maintaining potent 5-HT 2 receptor agonist properties, all analogues had an intrinsic clearance above 1.3 L/kg/h predictive of high first-pass metabolism.

5-HT7 Receptor Antagonists with an Unprecedented Selectivity Profile.

PubMed

Ates, Ali; Burssens, Pierre; Lorthioir, Olivier; Lo Brutto, Patrick; Dehon, Gwenael; Keyaerts, Jean; Coloretti, Francis; Lallemand, Bénédicte; Verbois, Valérie; Gillard, Michel; Vermeiren, Céline

2018-04-23

Selective leads: In this study, we generated a new series of serotonin 5-HT 7 receptor antagonists. Their synthesis, structure-activity relationships, and selectivity profiles are reported. This series includes 5-HT 7 antagonists with unprecedented high selectivity for the 5-HT 7 receptor, setting the stage for lead optimization of drugs acting on a range of neurological targets. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pre-ART nutritional status and its association with mortality in adult patients enrolled on ART at Fiche Hospital in North Shoa, Oromia region, Ethiopia: a retrospective cohort study.

PubMed

Tesfamariam, Kokeb; Baraki, Negga; Kedir, Haji

2016-12-20

Human immunodeficiency virus (HIV) compromises the nutritional status of infected individuals and in turn, malnutrition worsens the effects of the infection itself by weakening the immune system consequently accelerating disease progression and death. However, few studies have examined the association between nutritional status at antiretroviral therapy (ART) initiation and early mortality. Therefore, this study assesses pre-ART nutritional status and other baseline characteristics and mortality among adult patients on ART at Fiche Hospital, Ethiopia. A retrospective cohort study was conducted among 489 ART enrolled adult patients between August 01, 2006 and September 30, 2013 in Fiche Hospital. Study participants were selected by using systematic random sampling method. Actuarial table was used to estimate survival of patients after ART initiation and log rank test was used to compare the survival curves. Cox proportional-hazard regression was used to determine independent predictors of time to death. Most of the study subjects were females 254 (51.9%). A total of 489 patients were included in the analysis, of whom 87 died during a median study follow-up of 22 months. The estimated mortality among malnourished was 21, 28, 33, and 38% at 5, 10, 15, and 25 months respectively with mortality incidence density of 5.63 deaths per 100 person years. The independent predictors of mortality were: BMI <18.5 kg/m 2 (AHR = 5.4 95% CI 3.03-9.58), baseline ambulatory functional status (AHR = 3.84; 95% CI 2.19-6.74), bedridden functional status (AHR = 4.78; 95% CI 2.14-10.65), WHO clinical stage III (AHR 2.21; 95% CI 1.16-4.21), WHO clinical stage IV (AHR 4.05; 95% CI 1.50-10.97) and CD4 count less than 200 cells/μl (AHR = 2.95; 95% CI 1.48-5.88), two and more opportunistic infections (AHR 2.30; 95% CI 1.11-4.75). Undernutrition at the time of ART initiation was associated with increased risk of death, particularly during the first 3 months after ART initiation

[ASSOCIATION BETWEEN FOUR SEROTONIC GENES POLYMORPHISM (5HTTL, 5HT1A, 5HT2A, AND MAOA) AND PERSONALITY TRAITS IN WRESTLERS AND CONTROL GROUP].

PubMed

Butovskaya, P R; Lazebnij, O E; Fekhretdionva, D I; Vasil'ev, V A; Prosikova, E A; Lysenko, V V; Udina, I G; Butovskaya, M L

2015-01-01

This study presents the data on the polymorphisms of the serotonin system genes (5-HTTL, 5-HT1A, 5-HT2A, and MAOA) in male and female wrestlers and in the control group. The population genetics analysis of the 5HTTL gene showed the highest frequency of the SS genotype 5-HTTLPR in sportsmen (p = 0.04), as well as the trend toward higher frequency of united genotypes of the locus of 5-HTTLPR VNTR and SNP rs25531--SASA (p = 0.06) in comparison with the control group. As for the polymorphisms for other genes 5-HT1A (rs6295), 5-HT2A (rs6311), and MAOA (VNTR), we found no significant differences between the groups tested. Using the NEO PI-R questionnaire we analyzed the possible correlations between the genotypes and the psychological traits in our samples. It was demonstrated that the athletic success in elite sportsmen was associated with lower openness to experience and higher conscientiousness. The interaction effect of the gender and 5-HT2A on the self-rating for openness to experience, interaction effect of the level of the sport success and 5-HT2A, and the interaction effect of the gender and 5-HT1A genotype on self-reported conscientiousness were observed as a trend.

Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience.

PubMed

Pokorny, Thomas; Preller, Katrin H; Kraehenmann, Rainer; Vollenweider, Franz X

2016-04-01

The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg p.o.) on psilocybin-induced (170 µg/kg p.o.) psychological effects in two groups (n=19, n=17) of healthy human subjects. Psychological effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (p<0.001), which was mostly driven by a reduction of the VR item cluster scores for elementary and complex visual hallucinations. Further, buspirone also reduced the main scale score for Oceanic Boundlessness (OB) including derealisation and depersonalisation phenomena at a trend level (p=0.062), whereas ergotamine did not show any effects on the psilocybin-induced 5D-ASC main scale scores. The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurological diseases. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

The Role of 5-HT3 Receptors in Signaling from Taste Buds to Nerves.

PubMed

Larson, Eric D; Vandenbeuch, Aurelie; Voigt, Anja; Meyerhof, Wolfgang; Kinnamon, Sue C; Finger, Thomas E

2015-12-02

Activation of taste buds triggers the release of several neurotransmitters, including ATP and serotonin (5-hydroxytryptamine; 5-HT). Type III taste cells release 5-HT directly in response to acidic (sour) stimuli and indirectly in response to bitter and sweet tasting stimuli. Although ATP is necessary for activation of nerve fibers for all taste stimuli, the role of 5-HT is unclear. We investigated whether gustatory afferents express functional 5-HT3 receptors and, if so, whether these receptors play a role in transmission of taste information from taste buds to nerves. In mice expressing GFP under the control of the 5-HT(3A) promoter, a subset of cells in the geniculate ganglion and nerve fibers in taste buds are GFP-positive. RT-PCR and in situ hybridization confirmed the presence of 5-HT(3A) mRNA in the geniculate ganglion. Functional studies show that only those geniculate ganglion cells expressing 5-HT3A-driven GFP respond to 10 μM 5-HT and this response is blocked by 1 μM ondansetron, a 5-HT3 antagonist, and mimicked by application of 10 μM m-chlorophenylbiguanide, a 5-HT3 agonist. Pharmacological blockade of 5-HT3 receptors in vivo or genetic deletion of the 5-HT3 receptors reduces taste nerve responses to acids and other taste stimuli compared with controls, but only when urethane was used as the anesthetic. We find that anesthetic levels of pentobarbital reduce taste nerve responses apparently by blocking the 5-HT3 receptors. Our results suggest that 5-HT released from type III cells activates gustatory nerve fibers via 5-HT3 receptors, accounting for a significant proportion of the neural taste response. Copyright © 2015 the authors 0270-6474/15/3515984-12$15.00/0.

The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT(1A) and 5-HT(2A) receptors.

PubMed

Riga, Maurizio S; Bortolozzi, Analia; Campa, Letizia; Artigas, Francesc; Celada, Pau

2016-02-01

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen, acting as a non-selective serotonin 5-HT(1A)/5-HT(2A)-R agonist. Psychotomimetic agents such as the non-competitive NMDA-R antagonist phencyclidine and serotonergic hallucinogens (DOI and 5-MeO-DMT) disrupt cortical synchrony in the low frequency range (<4 Hz) in rat prefrontal cortex (PFC), an effect reversed by antipsychotic drugs. Here we extend these observations by examining the effect of 5-MeO-DMT on low frequency cortical oscillations (LFCO, <4 Hz) in PFC, visual (V1), somatosensory (S1) and auditory (Au1) cortices, as well as the dependence of these effects on 5-HT(1A)-R and 5-HT(2A)-R, using wild type (WT) and 5-HT(2A)-R knockout (KO2A) anesthetized mice. 5-MeO-DMT reduced LFCO in the PFC of WT and KO2A mice. The effect in KO2A mice was fully prevented by the 5-HT(1A)-R antagonist WAY-100635. Systemic and local 5-MeO-DMT reduced 5-HT release in PFC mainly via 5-HT(1A)-R. Moreover, 5-MeO-DMT reduced LFCO in S1, Au1 and V1 of WT mice and only in V1 of KO2A mice, suggesting the involvement of 5-HT(1A)-R activation in the 5-MeO-DMT-induced disruption of V1 activity. In addition, antipsychotic drugs reversed 5-MeO-DMT effects in WT mice. The present results suggest that the hallucinogen action of 5-MeO-DMT is mediated by simultaneous alterations of the activity of sensory (S1, Au1, V1) and associative (PFC) cortical areas, also supporting a role of 5-HT(1A)-R stimulation in V1 and PFC, in addition to the well-known action on 5-HT(2A)-R. Moreover, the reversal by antipsychotic drugs of 5-MeO-DMT effects adds to previous literature supporting the usefulness of the present model in antipsychotic drug development. Copyright © 2015 Elsevier Ltd. All rights reserved.

HT-LP thermometamorphism modelling : Agly massif, French Pyrenees.

NASA Astrophysics Data System (ADS)

Tournaire Guille, Baptiste; Pascal, Marie-Lola; Lejeune, Anne-Marie; Annen, Catherine

2017-04-01

Owing to the strongly anomalous thermal gradients implied, HT-LP metamorphism is a worldwide type of processes in which magma emplacement and solidification at relatively high levels in the crust must be considered as a potentially major heat source. Thermal modelling (e.g. Annen et al. 2005) is an appropriate tool for constraining the part played by such processes in practical cases of thermometamorphism. We study the Agly massif, an exhumed part of middle crust from the Variscan belt in the French Pyrenees. This massif is a classical example of HT-LP metamorphism (Vielzeuf 1996), composed of a metasedimentary cover, mainly micaschists aged from upper Cambrian to Devonian, unconformably overlying an older basement of para- and orthogneisses. The Variscan metamorphic facies extend from greenschists, in the upper part of the cover, to granulites in the basement (Fonteilles 1976). The apparent geotherm of about 110°/km in the metasedimentary cover (amphibolite and greenschist facies) has given way to contrasting interpretations. Magmatic activity partly synchronous with and probably related to the Variscan thermometamorphism is observed at the outcropping level as at least 4 magmatic bodies of mantle origin (Touil 1994), of Stephanian age, including granodiorites and subordinate diorites and gabbros. Recent U/Pb datations on zircons (Tournaire-Guille et al., in prep) also reveal the presence of lower Cambrian magmatism in the gneisses, therefore confirming their interpretation as a pre-Variscan basement. The location (depth), volume (thickness), temperature (composition) and timing of magma emplacement are the parameters controlling the thermal effect to be modelled with a Matlab® code (Annen et al. 2005). In order to constrain these parameters, we have updated the lithostratigraphy and the PT conditions of the Variscan metamorphism in the Agly area. Mineralogic and petrologic data exploited in thermobarometric analyses compared with thermodynamic PerpleX modelling

TNF-alpha sensitizes HT-29 colonic epithelial cells to intestinal lactobacilli.

PubMed

McCracken, Vance J; Chun, Taehoon; Baldeón, Manuel E; Ahrné, Siv; Molin, Göran; Mackie, Roderick I; Gaskins, H Rex

2002-09-01

The ability of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) to influence epithelial interleukin (IL)-8 responses to the intestinal bacterium Lactobacillus plantarum 299v was analyzed in the human HT-29 colonic epithelial cell line. In the absence of TNF-alpha, IL-8 mRNA expression was not detectable by Northern blot analysis in HT-29 cells alone or in HT-29 cells co-cultured with L. plantarum 299v. However, TNF-alpha induced IL-8 mRNA expression, and co-culture of TNF-alpha-treated HT-29 cells with L. plantarum 299v significantly increased IL-8 mRNA expression above levels induced by TNF-alpha alone in an adhesion-dependent manner. The increase in IL-8 mRNA expression was not observed in TNF-alpha-treated HT-29/L. plantarum 299v co-cultures using heat-killed lactobacilli or when L. plantarum adhesion was prevented using mannoside or a trans-well membrane. Paradoxically, IL-8 secretion was decreased in TNF-alpha-treated HT-29 cells with L. plantarum 299v relative to cells treated with TNF-alpha alone. TNF-alpha-mediated responsiveness to L. plantarum 299v was further investigated by analyzing expression of a coreceptor for bacterial cell wall products CD14. HT-29 cells expressed CD14 mRNA and cell-surface CD14; however, TNF-alpha did not alter CD14 mRNA or cell-surface expression, and blockade of CD14 with monoclonal antibody MY4 did not alter the IL-8 response to L. plantarum 299v in TNF-alpha-treated HT-29 cells. These results indicate that although TNF-alpha sensitizes HT-29 epithelial cells to intestinal lactobacilli, the bacteria exert a protective effect by downregulating IL-8 secretion.

The Role of 5-HT3 Receptors in Signaling from Taste Buds to Nerves

PubMed Central

Vandenbeuch, Aurelie; Voigt, Anja; Meyerhof, Wolfgang; Kinnamon, Sue C.; Finger, Thomas E.

2015-01-01

Activation of taste buds triggers the release of several neurotransmitters, including ATP and serotonin (5-hydroxytryptamine; 5-HT). Type III taste cells release 5-HT directly in response to acidic (sour) stimuli and indirectly in response to bitter and sweet tasting stimuli. Although ATP is necessary for activation of nerve fibers for all taste stimuli, the role of 5-HT is unclear. We investigated whether gustatory afferents express functional 5-HT3 receptors and, if so, whether these receptors play a role in transmission of taste information from taste buds to nerves. In mice expressing GFP under the control of the 5-HT3A promoter, a subset of cells in the geniculate ganglion and nerve fibers in taste buds are GFP-positive. RT-PCR and in situ hybridization confirmed the presence of 5-HT3A mRNA in the geniculate ganglion. Functional studies show that only those geniculate ganglion cells expressing 5-HT3A-driven GFP respond to 10 μm 5-HT and this response is blocked by 1 μm ondansetron, a 5-HT3 antagonist, and mimicked by application of 10 μm m-chlorophenylbiguanide, a 5-HT3 agonist. Pharmacological blockade of 5-HT3 receptors in vivo or genetic deletion of the 5-HT3 receptors reduces taste nerve responses to acids and other taste stimuli compared with controls, but only when urethane was used as the anesthetic. We find that anesthetic levels of pentobarbital reduce taste nerve responses apparently by blocking the 5-HT3 receptors. Our results suggest that 5-HT released from type III cells activates gustatory nerve fibers via 5-HT3 receptors, accounting for a significant proportion of the neural taste response. SIGNIFICANCE STATEMENT Historically, serotonin (5-hydroxytryptamine; 5-HT) has been described as a candidate neurotransmitter in the gustatory system and recent studies show that type III taste receptor cells release 5-HT in response to various taste stimuli. In the present study, we demonstrate that a subset of gustatory sensory neurons express functional

A concise review of Hashimoto thyroiditis (HT) and the importance of iodine, selenium, vitamin D and gluten on the autoimmunity and dietary management of HT patients.Points that need more investigation.

PubMed

Liontiris, Michael I; Mazokopakis, Elias E

2017-01-01

Hashimoto's thyroiditis (HT) is a chronic autoimmune thyroid disease caused by an interaction between genetic factors and environmental conditions, both of which are yet to be fully understood. The management of HT depends on its clinical manifestations, commonly including diffuse or nodular goiter with euthyroidism, subclinical hypothyroidism and permanent hypothyroidism. However, in most cases of patients with HT, lifelong levothyroxine substitution is required. The additional role of diet for the management of HT is usually overlooked. A literature search regarding the importance and the influence of iodine, selenium, vitamin D and gluten on HT was conducted. In HT careful supplementation of possible deficiencies is recommended for the dietary management of these patients. The use of a diet low in gluten among HT patients with or without celiac disease (CD) is discussed.

Role of the serotonin 5-HT(2A) receptor in learning.

PubMed

Harvey, John A

2003-01-01

This study reviews the role of the serotonin 5-HT2A receptor in learning as measured by the acquisition of the rabbit's classically conditioning nictitating membrane response, a component of the eyeblink response. Agonists at the 5-HT2A receptor including LSD (d-lysergic acid diethylamide) enhanced associative learning at doses that produce cognitive effects in humans. Some antagonists such as BOL (d-bromolysergic acid diethylamide), LY53,857, and ketanserin acted as neutral antagonists in that they had no effect on learning, whereas others (MDL11,939, ritanserin, and mianserin) acted as inverse agonists in that they retarded learning through an action at the 5-HT2A receptor. These results were placed in the context of what is known concerning the anatomical distribution and electrophysiological effects of 5-HT2A receptor activation in frontal cortex and hippocampus, as well as the role of cortical 5-HT2A receptors in schizophrenia. It was concluded that the 5-HT2A receptor demonstrates constitutive activity, and that variations in this activity can produce profound alterations in cognitive states.

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

PubMed Central

Hatcher, N. G.; Zhang, X.; Stuart, J. N.; Moroz, L. L.; Sweedler, J. V.; Gillette, R.

2014-01-01

Serotonin (5-HT) is an intrinsic modulator of neural network excitation states in gastropod molluscs. 5-HT and related indole metabolites were measured in single, well-characterized serotonergic neurons of the feeding motor network of the predatory sea-slug Pleurobranchaea californica. Indole amounts were compared between paired hungry and satiated animals. Levels of 5-HT and its metabolite 5-HT-SO4 in the metacerebral giant neurons were observed in amounts approximately four-fold and two-fold, respectively, below unfed partners 24 h after a satiating meal. Intracellular levels of 5-hydroxyindole acetic acid and of free tryptophan did not differ significantly with hunger state. These data demonstrate that neurotransmitter levels and their metabolites can vary in goal-directed neural networks in a manner that follows internal state. PMID:18036151

Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology

PubMed Central

Browning, Kirsteen N.

2015-01-01

Vagal neurocircuits are vitally important in the co-ordination and modulation of GI reflexes and homeostatic functions. 5-hydroxytryptamine (5-HT; serotonin) is critically important in the regulation of several of these autonomic gastrointestinal (GI) functions including motility, secretion and visceral sensitivity. While several 5-HT receptors are involved in these physiological responses, the ligand-gated 5-HT3 receptor appears intimately involved in gut-brain signaling, particularly via the afferent (sensory) vagus nerve. 5-HT is released from enterochromaffin cells in response to mechanical or chemical stimulation of the GI tract which leads to activation of 5-HT3 receptors on the terminals of vagal afferents. 5-HT3 receptors are also present on the soma of vagal afferent neurons, including GI vagal afferent neurons, where they can be activated by circulating 5-HT. The central terminals of vagal afferents also exhibit 5-HT3 receptors that function to increase glutamatergic synaptic transmission to second order neurons of the nucleus tractus solitarius within the brainstem. While activation of central brainstem 5-HT3 receptors modulates visceral functions, it is still unclear whether central vagal neurons, i.e., nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) neurons themselves also display functional 5-HT3 receptors. Thus, activation of 5-HT3 receptors may modulate the excitability and activity of gastrointestinal vagal afferents at multiple sites and may be involved in several physiological and pathophysiological conditions, including distention- and chemical-evoked vagal reflexes, nausea, and vomiting, as well as visceral hypersensitivity. PMID:26578870

Structural basis of ligand recognition in 5-HT3 receptors

PubMed Central

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

2013-01-01

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

Metabolism of HT-2 Toxin and T-2 Toxin in Oats

PubMed Central

Meng-Reiterer, Jacqueline; Bueschl, Christoph; Rechthaler, Justyna; Berthiller, Franz; Lemmens, Marc; Schuhmacher, Rainer

2016-01-01

The Fusarium mycotoxins HT-2 toxin (HT2) and T-2 toxin (T2) are frequent contaminants in oats. These toxins, but also their plant metabolites, may contribute to toxicological effects. This work describes the use of 13C-assisted liquid chromatography–high-resolution mass spectrometry for the first comprehensive study on the biotransformation of HT2 and T2 in oats. Using this approach, 16 HT2 and 17 T2 metabolites were annotated including novel glycosylated and hydroxylated forms of the toxins, hydrolysis products, and conjugates with acetic acid, putative malic acid, malonic acid, and ferulic acid. Further targeted quantitative analysis was performed to study toxin metabolism over time, as well as toxin and conjugate mobility within non-treated plant tissues. As a result, HT2-3-O-β-d-glucoside was identified as the major detoxification product of both parent toxins, which was rapidly formed (to an extent of 74% in HT2-treated and 48% in T2-treated oats within one day after treatment) and further metabolised. Mobility of the parent toxins appeared to be negligible, while HT2-3-O-β-d-glucoside was partly transported (up to approximately 4%) through panicle side branches and stem. Our findings demonstrate that the presented combination of untargeted and targeted analysis is well suited for the comprehensive elucidation of mycotoxin metabolism in plants. PMID:27929394

Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm.

PubMed

Meyer, Jeffrey H; McMain, Shelley; Kennedy, Sidney H; Korman, Lorne; Brown, Gregory M; DaSilva, Jean N; Wilson, Alan A; Blak, Thomas; Eynan-Harvey, Rahel; Goulding, Verdell S; Houle, Sylvain; Links, Paul

2003-01-01

Dysfunctional attitudes are negatively biased assumptions and beliefs regarding oneself, the world, and the future. In healthy subjects, increasing serotonin (5-HT) agonism with a single dose of d-fenfluramine lowered dysfunctional attitudes. To investigate whether the converse, a low level of 5-HT agonism, could account for the higher levels of dysfunctional attitudes observed in patients with major depression or with self-injurious behavior, cortex 5-HT(2) receptor binding potential and dysfunctional attitudes were measured in patients with major depressive disorder, patients with a history of self-injurious behavior, and healthy comparison subjects (5-HT(2) receptor density increases during 5-HT depletion). Twenty-nine healthy subjects were recruited to evaluate the effect of d-fenfluramine or of clonidine (control condition) on dysfunctional attitudes. Dysfunctional attitudes were assessed with the Dysfunctional Attitude Scale 1 hour before and 1 hour after drug administration. In a second experiment, dysfunctional attitudes and 5-HT(2) binding potential were measured in 22 patients with a major depressive episode secondary to major depressive disorder, 18 patients with a history of self-injurious behavior occurring outside of a depressive episode, and another 29 age-matched healthy subjects. Cortex 5-HT(2) binding potential was measured with [(18)F]setoperone positron emission tomography. In the first experiment, dysfunctional attitudes decreased after administration of d-fenfluramine. In the second experiment, in the depressed group, dysfunctional attitudes were positively associated with cortex 5-HT(2) binding potential, especially in Brodmann's area 9 (after adjustment for age). Depressed subjects with extremely dysfunctional attitudes had higher 5-HT(2) binding potential, compared to healthy subjects, particularly in Brodmann's area 9. Low levels of 5-HT agonism in the brain cortex may explain the severely pessimistic, dysfunctional attitudes associated

Therapeutic Potential of 5-HT2C Receptor Agonists for Addictive Disorders.

PubMed

Higgins, Guy A; Fletcher, Paul J

2015-07-15

The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) has long been associated with the control of a variety of motivated behaviors, including feeding. Much of the evidence linking 5-HT and feeding behavior was obtained from studies of the effects of the 5-HT releaser (dex)fenfluramine in laboratory animals and humans. Recently, the selective 5-HT2C receptor agonist lorcaserin received FDA approval for the treatment of obesity. This review examines evidence to support the use of selective 5-HT2C receptor agonists as treatments for conditions beyond obesity, including substance abuse (particularly nicotine, psychostimulant, and alcohol dependence), obsessive compulsive, and excessive gambling disorder. Following a brief survey of the early literature supporting a role for 5-HT in modulating food and drug reinforcement, we propose that intrinsic differences between SSRI and serotonin releasers may have underestimated the value of serotonin-based pharmacotherapeutics to treat clinical forms of addictive behavior beyond obesity. We then highlight the critical involvement of the 5-HT2C receptor in mediating the effect of (dex)fenfluramine on feeding and body weight gain and the evidence that 5-HT2C receptor agonists reduce measures of drug reward and impulsivity. A recent report of lorcaserin efficacy in a smoking cessation trial further strengthens the idea that 5-HT2C receptor agonists may have potential as a treatment for addiction. This review was prepared as a contribution to the proceedings of the 11th International Society for Serotonin Research Meeting held in Hermanus, South Africa, July 9-12, 2014.

h5-HT(1B) receptor-mediated constitutive Galphai3-protein activation in stably transfected Chinese hamster ovary cells: an antibody capture assay reveals protean efficacy of 5-HT.

PubMed

Newman-Tancredi, Adrian; Cussac, Didier; Marini, Laetitia; Touzard, Manuelle; Millan, Mark J

2003-03-01

1. Serotonin 5-HT(1B) receptors couple to G-proteins of the Gi/o family. However, their activation of specific G-protein subtypes is poorly characterised. Using an innovative antibody capture/guanosine-5'-0-(3-[(35)S]thio)-triphosphate ([(35)S]GTPgammaS) binding strategy, we characterised Galpha(i3) subunit activation by h5-HT(1B) receptors stably expressed in Chinese hamster ovary (CHO) cells. 2. The agonists, 5-HT, alniditan and BMS181,101, stimulated Galpha(i3), whereas methiothepin and SB224,289 behaved as inverse agonists. The selective 5-HT(1B) receptor ligand, S18127, modestly stimulated Galpha(i3) and reversed the actions of both 5-HT and methiothepin. S18127 (1 micro M) also produced parallel, dextral shifts of the 5-HT and methiothepin isotherms. 3. Isotopic dilution experiments ([(35)S]GTPgammaS versus GTPgammaS) revealed high-affinity [(35)S]GTPgammaS binding to Galpha(i3) subunits in the absence of receptor ligands indicating constitutive activity. High-affinity [(35)S]GTPgammaS binding was increased 2.8-fold by 5-HT with an increase in the affinity of GTPgammaS for Galpha(i3) subunits. In contrast, methiothepin halved the number of high-affinity binding sites and decreased their affinity. 4. h5-HT(1B) receptor-mediated Galpha(i3) subunit activation was dependent on the concentration of NaCl. At 300 mM, 5-HT stimulated [(35)S]GTPgammaS binding, basal Galpha(i3) activation was low and methiothepin was inactive. In contrast, at 10 mM NaCl, basal activity was enhanced and the inverse agonist activity of methiothepin was accentuated. Under these conditions, 5-HT decreased Galpha(i3) activation. 5. In conclusion, at h5-HT(1B) receptors expressed in CHO cells: (i) inverse agonist induced inhibition of Galpha(i3), and its reversal by S18127, reveals constitutive activation of this Galpha subunit; (ii) constitutive Galpha(i3) activation can be quantified by isotopic dilution [(35)S]GTPgammaS binding and (iii) decreasing NaCl concentrations enhances Galpha(i3

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

PubMed

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

2014-08-05

The development of safe and effective drugs relies on the discovery of selective ligands. Serotonin (5-hydroxytryptamine [5-HT]) G protein-coupled receptors are therapeutic targets for CNS disorders but are also associated with adverse drug effects. The determination of crystal structures for the 5-HT1B and 5-HT2B receptors provided an opportunity to identify subtype selective ligands using structure-based methods. From docking screens of 1.3 million compounds, 22 molecules were predicted to be selective for the 5-HT1B receptor over the 5-HT2B subtype, a requirement for safe serotonergic drugs. Nine compounds were experimentally verified as 5-HT1B-selective ligands, with up to 300-fold higher affinities for this subtype. Three of the ligands were agonists of the G protein pathway. Analysis of state-of-the-art homology models of the two 5-HT receptors revealed that the crystal structures were critical for predicting selective ligands. Our results demonstrate that structure-based screening can guide the discovery of ligands with specific selectivity profiles. Copyright © 2014 Elsevier Ltd. All rights reserved.

Optical properties of different graphene concentration in P3HT

NASA Astrophysics Data System (ADS)

Shariff, N. S. M.; Sarah, M. S. P.; Rusop, M.

2018-05-01

The discovery of Graphene has led to many new findings in material research. P3HT is a polymer that is well used in photovoltaic studies but the main problem is its low photocurrent due to its low electron mobility. Therefore the objective of this research is to increase the mobility in order to achieve higher photocurrent. In this research, P3HT will be mixed with Graphene and used as an active layer. The fabrication method used in this research is spin coating technique. Optical properties such as absorbance, transmittance and photoluminescence is characterized. Each optical properties shows a positive results when compared to P3HT layer. A concentration of 2 wt % shows the optimum absorbance and transmittance while quenching effect can be seen when compared to P3HT layer.

Serotonin (5-HT) augmentation reduces provoked aggression associated with primary psychopathy traits.

PubMed

Fanning, Jennifer R; Berman, Mitchell E; Guillot, Casey R; Marsic, Angelika; McCloskey, Michael S

2014-06-01

Psychopathy has long been associated with aggressive behavior; however, the neurochemical underpinnings of this relationship are poorly understood. Serotonin (5-HT) neurotransmitter system abnormalities have been associated with provoked aggression in general. In addition, 5-HT dysregulation has been linked to empathy, a trait that is lacking in individuals who score high on primary psychopathy. The purpose of this study was to determine if 5-HT modulates the relationship between psychopathic traits and aggression. Participants (N = 47) completed a self-report measure of psychopathy and were then administered either 40 mg paroxetine (acutely augmenting 5-HT) or placebo. Aggression was assessed during a competitive reaction-time game in which electric shocks were exchanged with an increasingly provocative fictitious opponent. Results indicated that primary psychopathy (but not secondary psychopathy) was related to aggressive responding to provocation. Moreover, 5-HT augmentation attenuated this effect, supporting the notion that aggressive responding associated with primary psychopathic traits may be due in part to 5-HT dysregulation.

Design of fluorinated 5-HT(4)R antagonists: influence of the basicity and lipophilicity toward the 5-HT(4)R binding affinities.

PubMed

Fontenelle, Clement Q; Wang, Zhong; Fossey, Christine; Cailly, Thomas; Linclau, Bruno; Fabis, Frederic

2013-12-01

Analogues of potent 5-HT(4)R antagonists possessing a fluorinated N-alkyl chain have been synthesized in order to investigate the effect of the resulting change in basicity and lipophilicity on the affinity and selectivity profile. We demonstrate that for this series, the affinity is decreased with decreased basicity of the piperidine's nitrogen atom. In contrast, the resulting increase in lipophilicity has minimal impact on binding affinity and selectivity. 3,3,3-Trifluoropropyl and 4,4,4-trifluorobutyl derivatives 6d and 6e have shown to bind to the 5-HT(4)R while maintaining their pharmacological profile and selectivity toward other 5-HT receptors. Copyright © 2013 Elsevier Ltd. All rights reserved.

Quantitative Analysis of the Molecular Dynamics of P3HT:PCBM Bulk Heterojunction.

PubMed

Guilbert, Anne A Y; Zbiri, Mohamed; Dunbar, Alan D F; Nelson, Jenny

2017-09-28

The optoelectronic properties of blends of conjugated polymers and small molecules are likely to be affected by the molecular dynamics of the active layer components. We study the dynamics of regioregular poly(3-hexylthiophene) (P3HT):phenyl-C61-butyric acid methyl ester (PCBM) blends using molecular dynamics (MD) simulation on time scales up to 50 ns and in a temperature range of 250-360 K. First, we compare the MD results with quasi-elastic neutron-scattering (QENS) measurements. Experiment and simulation give evidence of the vitrification of P3HT upon blending and the plasticization of PCBM by P3HT. Second, we reconstruct the QENS signal based on the independent simulations of the three phases constituting the complex microstructure of such blends. Finally, we found that P3HT chains tend to wrap around PCBM molecules in the amorphous mixture of P3HT and PCBM; this molecular interaction between P3HT and PCBM is likely to be responsible for the observed frustration of P3HT, the plasticization of PCBM, and the partial miscibility of P3HT and PCBM.

Development of the 5-HT2CR-Tango System Combined with an EGFP Reporter Gene.

PubMed

Watanabe, Yoshihisa; Tsujimura, Atsushi; Aoki, Miku; Taguchi, Katsutoshi; Tanaka, Masaki

2016-02-01

The serotonin 2C receptor (5-HT2CR) is a G-protein-coupled receptor implicated in emotion, feeding, reward, and cognition. 5-HT2CRs are pharmacological targets for mental disorders and metabolic and reward system abnormalities, as alterations in 5-HT2CR expression, RNA editing, and SNPs are involved in these disturbances. To date, 5-HT2CR activity has mainly been measured by quantifying inositol phosphate production and intracellular Ca(2+) release, but these assays are not suitable for in vivo analysis. Here, we developed a 5-HT2CR-Tango assay system, a novel analysis tool of 5-HT2CR activity based on the G-protein-coupled receptor (GPCR)-arrestin interaction. With desensitization of activated 5-HT2CR by arrestin, this system converts the 5-HT2CR-arrestin interaction into EGFP reporter gene signal via the LexA transcriptional activation system. For validation of our system, we measured activity of two 5-HT2CR RNA-editing isoforms (INI and VGV) in HEK293 cells transfected with EGFP reporter gene. The INI isoform displayed both higher basal- and 5-HT-stimulated activities than the VGV isoform. Moreover, an inhibitory effect of 5-HT2CR antagonist SB242084 was also detected by 5-HT2CR-Tango system. This novel tool is useful for in vitro high-throughput targeted 5-HT2CR drug screening and can be applied to future in vivo brain function studies associated with 5-HT2CRs in transgenic animal models.

Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders.

PubMed

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

2012-04-01

The nonselective 5-HT(4) receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT(4) agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT(4) agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT(4) agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT(1) receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT(4) agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT(4) agonists with no hERG or 5-HT(1) affinity (renzapride, clebopride, mosapride). 5-HT(4) agonists for GI disorders differ in chemical structure and selectivity for 5-HT(4) receptors. Selectivity for 5-HT(4) over non-5-HT(4) receptors may influence the agent's safety and overall risk-benefit profile. Based on available evidence, highly selective 5-HT(4) agonists may offer improved safety to treat patients with impaired GI motility. © 2012 Blackwell Publishing Ltd.

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

PubMed Central

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

2012-01-01

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

Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation.

PubMed

Valencia-Torres, Lourdes; Olarte-Sánchez, Cristian M; Lyons, David J; Georgescu, Teodora; Greenwald-Yarnell, Megan; Myers, Martin G; Bradshaw, Christopher M; Heisler, Lora K

2017-06-01

Obesity is primarily due to food intake in excess of the body's energetic requirements, intake that is not only associated with hunger but also the incentive value of food. The 5-hydroxytryptamine 2C receptor (5-HT 2C R) is a target for the treatment of human obesity. Mechanistically, 5-HT 2C Rs are positioned to influence both homeostatic feeding circuits within the hypothalamus and reward circuits within the ventral tegmental area (VTA). Here we investigated the role of 5-HT 2C Rs in incentive motivation using a mathematical model of progressive ratio (PR) responding in mice. We found that the 5-HT 2C R agonist lorcaserin significantly reduced both ad libitum chow intake and PR responding for chocolate pellets and increased c-fos expression in VTA 5-HT 2C R expressing γ-aminobutyric acid (GABA) neurons, but not 5-HT 2C R expressing dopamine (DA) neurons. We next adopted a chemogenetic approach using a 5-HT 2C R CRE line to clarify the function of subset of 5-HT 2C receptor expressing VTA neurons in the modulation of appetite and food-motivated behavior. Activation of VTA 5-HT 2C receptor expressing neurons significantly reduced ad libitum chow intake, operant responding for chocolate pellets, and the incentive value of food. In contrast, chemogenetic inhibition of VTA 5-HT 2C receptor expressing neurons had no effect on the feeding behavior. These results indicate that activation of the subpopulation of 5-HT 2C R neurons within the VTA is sufficient to significantly reduce homeostatic feeding and effort-based intake of palatable food, and that this subset has an inhibitory role in motivational processes. These findings are relevant to the treatment of obesity.

Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation

PubMed Central

Valencia-Torres, Lourdes; Olarte-Sánchez, Cristian M; Lyons, David J; Georgescu, Teodora; Greenwald-Yarnell, Megan; Myers, Martin G; Bradshaw, Christopher M; Heisler, Lora K

2017-01-01

Obesity is primarily due to food intake in excess of the body's energetic requirements, intake that is not only associated with hunger but also the incentive value of food. The 5-hydroxytryptamine 2C receptor (5-HT2CR) is a target for the treatment of human obesity. Mechanistically, 5-HT2CRs are positioned to influence both homeostatic feeding circuits within the hypothalamus and reward circuits within the ventral tegmental area (VTA). Here we investigated the role of 5-HT2CRs in incentive motivation using a mathematical model of progressive ratio (PR) responding in mice. We found that the 5-HT2CR agonist lorcaserin significantly reduced both ad libitum chow intake and PR responding for chocolate pellets and increased c-fos expression in VTA 5-HT2CR expressing γ-aminobutyric acid (GABA) neurons, but not 5-HT2CR expressing dopamine (DA) neurons. We next adopted a chemogenetic approach using a 5-HT2CRCRE line to clarify the function of subset of 5-HT2C receptor expressing VTA neurons in the modulation of appetite and food-motivated behavior. Activation of VTA 5-HT2C receptor expressing neurons significantly reduced ad libitum chow intake, operant responding for chocolate pellets, and the incentive value of food. In contrast, chemogenetic inhibition of VTA 5-HT2C receptor expressing neurons had no effect on the feeding behavior. These results indicate that activation of the subpopulation of 5-HT2CR neurons within the VTA is sufficient to significantly reduce homeostatic feeding and effort-based intake of palatable food, and that this subset has an inhibitory role in motivational processes. These findings are relevant to the treatment of obesity. PMID:27882999

Novel pyridylmethylamines as highly selective 5-HT(1A) superagonists.

PubMed

Bollinger, Stefan; Hübner, Harald; Heinemann, Frank W; Meyer, Karsten; Gmeiner, Peter

2010-10-14

To further improve the maximal serotonergic efficacy and better understand the configurational requirements for 5-HT(1A) binding and activation, we generated and biologically investigated structural variants of the lead structure befiradol. For a bioisosteric replacement of the 3-chloro-4-fluoro moiety, a focused library of 63 compounds by solution phase parallel synthesis was developed. Target binding of our compound collection was investigated, and their affinities for 5-HT(2), α(1), and α(2)-adrenergic as well as D(1)-D(4) dopamine receptors were compared. For particularly interesting test compounds, intrinsic activities at 5-HT(1A) were examined in vitro employing a GTPγS assay. The investigation guided us to highly selective 5HT(1A) superagonists. The benzothiophene-3-carboxamide 8bt revealed almost exclusive 5HT(1A) recognition with a K(i) value of 2.7 nM and a maximal efficacy of 124%. To get insights into the bioactive conformation of our compound collection, we synthesized conformationally constrained bicyclic scaffolds when SAR data indicated a chair-type geometry and an equatorially dispositioned aminomethyl substituent for the 4,4-disubstituted piperidine moiety.

Modification of smoothing in 4253H[T

NASA Astrophysics Data System (ADS)

Azmi, Nurul Nisa'Khairol; Adam, Mohd Bakri; Shitan, Mahendran; Ali, Norhaslinda Mohd

2017-05-01

Some modified non-linear smoothers particularly 4253H[T] are explained in this paper. The modifications are focused on estimating the middle point of running median for even span by applying the following types of means; geometric, harmonic, quadratic and contraharmonic. The performance of the techniques is assessed by applying it to daily price index of a bank in Malaysia that issues sukuk for funding in Islamic banking and financial business. The results show that 4253H[T] with geometric mean modification is better than others in preserving variation and curve fitting.

h5-HT1B receptor-mediated constitutive Gαi3-protein activation in stably transfected Chinese hamster ovary cells: an antibody capture assay reveals protean efficacy of 5-HT

PubMed Central

Newman-Tancredi, Adrian; Cussac, Didier; Marini, Laetitia; Touzard, Manuelle; Millan, Mark J

2003-01-01

Serotonin 5-HT1B receptors couple to G-proteins of the Gi/o family. However, their activation of specific G-protein subtypes is poorly characterised. Using an innovative antibody capture/guanosine-5′-0-(3-[35S]thio)-triphosphate ([35S]GTPγS) binding strategy, we characterised Gαi3 subunit activation by h5-HT1B receptors stably expressed in Chinese hamster ovary (CHO) cells. The agonists, 5-HT, alniditan and BMS181,101, stimulated Gαi3, whereas methiothepin and SB224,289 behaved as inverse agonists. The selective 5-HT1B receptor ligand, S18127, modestly stimulated Gαi3 and reversed the actions of both 5-HT and methiothepin. S18127 (1 μM) also produced parallel, dextral shifts of the 5-HT and methiothepin isotherms. Isotopic dilution experiments ([35S]GTPγS versus GTPγS) revealed high-affinity [35S]GTPγS binding to Gαi3 subunits in the absence of receptor ligands indicating constitutive activity. High-affinity [35S]GTPγS binding was increased 2.8-fold by 5-HT with an increase in the affinity of GTPγS for Gαi3 subunits. In contrast, methiothepin halved the number of high-affinity binding sites and decreased their affinity. h5-HT1B receptor-mediated Gαi3 subunit activation was dependent on the concentration of NaCl. At 300 mM, 5-HT stimulated [35S]GTPγS binding, basal Gαi3 activation was low and methiothepin was inactive. In contrast, at 10 mM NaCl, basal activity was enhanced and the inverse agonist activity of methiothepin was accentuated. Under these conditions, 5-HT decreased Gαi3 activation. In conclusion, at h5-HT1B receptors expressed in CHO cells: (i) inverse agonist induced inhibition of Gαi3, and its reversal by S18127, reveals constitutive activation of this Gα subunit; (ii) constitutive Gαi3 activation can be quantified by isotopic dilution [35S]GTPγS binding and (iii) decreasing NaCl concentrations enhances Gαi3 activation and leads to protean agonist properties of 5-HT: that is a switch to inhibition of Gαi3. PMID:12684263

Functional antagonistic properties of clozapine at the 5-HT3 receptor.

PubMed

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

1996-08-23

The atypical neuroleptic clozapine is thought to exert its psychopharmacological actions through a variety of neurotransmitter receptors. It binds preferentially to D4 and 5-HT2 receptors; however, little is known on it's interaction with the 5-HT3 receptor. Using a cell line stably expressing the 5-HT3 receptor, whole-cell voltage-clamp analysis revealed functional antagonistic properties of clozapine at low nanomolar concentrations in view of a binding affinity in the upper nanomolar range. Because the concentration of clozapine required for an interaction with the 5-HT3 receptor can be achieved with therapeutical doses, functional antagonistic properties at this ligand-gated ion channel may contribute to its unique psychopharmacological profile.

Characterization, solubilization and partial purification of serotonin 5-HT1C receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yagaloff, K.A.

1986-01-01

/sup 125/I-Lysergic acid diethylamide (/sup 125/I-LSD) binds with high affinity to a unique serotonergic site on rat choroid plexus. These sites were localized to choroid plexus epithelial cells using a novel high resolution autoradiographic technique. In membrane preparations, the serotonergic site density was 3100 fmol/mg protein, which is 10 fold higher than the density of any other serotonergic site in brain homogenates. The pharmacology of this site, termed the 5-HT1c site, does not match that of 5-Ht1a, 5-HT1b or 5HT2 serotonergic sites. 5-Ht1c sites were solubilized from pig choroid plexus using the zwitterionic detergent, CHAPS. High affinity labelling of themore » solubilized site was obtained using the serotonergic radioligand, N1-methyl-2-(/sup 125/I)lysergic acid diethylamide (/sup 125/I-MIL). Choroid plexus tumors obtained from transgenic mice were examined for the presence of serotonin 5-HT1c receptors. /sup 125/I-LSD binding to choroid plexus tumors displays a pharmacological profile that matches the properties of 5-HT1c receptors in normal choroid plexus. The tumor exhibits the highest site density of serotonin receptors (6600 fmol/mg protein) found in any tissue. /sup 125/I-LSD autoradiography of brain sections from transgenic mice shows high levels of specific labelling over the tumor. The affinities of various indolealkyl, phenlakyl and beta-carboline derivatives for the serotonin 5-HT1c receptor were measured in pig choroid plexus using /sup 125/I-MIL. Serotonin precursors and metabolites were all very weak inhibitors of specific /sup 125/I-MIL binding. Structure-affinity relationships were determined for a number of indolealkylamine analogues. Only serotonin is present in cerebrospinal fluid at concentrations near its 5-HT1c inhibition constant, suggesting that serotonin is the natural 5-HT1c agonist.« less

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

PubMed Central

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

2000-01-01

The pharmacological characterization of a 5-HT receptor-mediated contractile response in the mouse isolated ileum is described. In the presence of methysergide (1 μM), 5-hydroxytryptamine (5-HT, 0.3–100 μM) produced phasic concentration-dependent contractions of segments of the mouse isolated ileum with a pEC50 value of 5.47±0.09. The 5-HT3 receptor selective agonists m-chlorophenylbiguanide (0.3–100 μM, pEC50 5.81±0.04), 1-phenylbiguanide (3–100 μM, pEC50 5.05±0.06) and 2-methyl-5-HT (3–100 μM, pEC50 5.00±0.07) acted as full agonists to induce contractile responses. 5-methoxytryptamine (0.1–100 μM), RS 67506 (0.1–100 μM) and α-methyl-5-HT (0.1–100 μM) failed to mimic the 5-HT responses. The contractile response to 5-HT was not antagonized by either 5-HT2 receptor antagonists ritanserin (0.1 μM) or ketanserin (1 μM) nor the 5-HT4 receptor antagonist SB 204070 (0.1 μM). The 5-HT3 receptor selective antagonists granisetron (0.3–1 nM), tropisetron (1–10 nM), ondansetron (10 nM–1 μM) and MDL 72222 (10 nM–1 μM) caused rightward displacement of the concentration-response curves to 5-HT. The lower concentrations of the antagonists caused approximate parallel rightward shifts of the concentration-response curves to 5-HT with apparent pKB values for granisetron (9.70±0.39), tropisetron (9.18±0.20), ondansetron (8.84±0.24) and MDL 72222 (8.65±0.35). But higher concentrations of antagonists resulted in a progressive reduction in the maximum responses. The contractile response to 5-HT was abolished by tetrodotoxin (0.3 μM); atropine (0.1 and 1 μM) decreased the maximum response of the 5-HT concentration-response curve by approximately 65%. It is concluded that a neuronally located 5-HT3 receptor mediates a contractile response to 5-HT in the mouse ileum. The 5-HT3 receptor in the mouse ileum has a different pharmacological profile to that reported for the guinea-pig ileum. PMID:11139451

Effect of Peripheral 5-HT on Glucose and Lipid Metabolism in Wether Sheep

PubMed Central

Watanabe, Hitoshi; Saito, Ryo; Nakano, Tatsuya; Takahashi, Hideyuki; Takahashi, Yu; Sumiyoshi, Keisuke; Sato, Katsuyoshi; Chen, Xiangning; Okada, Natsumi; Iwasaki, Shunsuke; Harjanti, Dian W.; Sekiguchi, Natsumi; Sano, Hiroaki; Kitazawa, Haruki; Rose, Michael T.; Ohwada, Shyuichi; Watanabe, Kouichi; Aso, Hisashi

2014-01-01

In mice, peripheral 5-HT induces an increase in the plasma concentrations of glucose, insulin and bile acids, and a decrease in plasma triglyceride, NEFA and cholesterol concentrations. However, given the unique characteristics of the metabolism of ruminants relative to monogastric animals, the physiological role of peripheral 5-HT on glucose and lipid metabolism in sheep remains to be established. Therefore, in this study, we investigated the effect of 5-HT on the circulating concentrations of metabolites and insulin using five 5-HT receptor (5HTR) antagonists in sheep. After fasting for 24 h, sheep were intravenously injected with 5-HT, following which-, plasma glucose, insulin, triglyceride and NEFA concentrations were significantly elevated. In contrast, 5-HT did not affect the plasma cholesterol concentration, and it induced a decrease in bile acid concentrations. Increases in plasma glucose and insulin concentrations induced by 5-HT were attenuated by pre-treatment with Methysergide, a 5HTR 1, 2 and 7 antagonist. Additionally, decreased plasma bile acid concentrations induced by 5-HT were blocked by pre-treatment with Ketanserin, a 5HTR 2A antagonist. However, none of the 5HTR antagonists inhibited the increase in plasma triglyceride and NEFA levels induced by 5-HT. On the other hand, mRNA expressions of 5HTR1D and 1E were observed in the liver, pancreas and skeletal muscle. These results suggest that there are a number of differences in the physiological functions of peripheral 5-HT with respect to lipid metabolism between mice and sheep, though its effect on glucose metabolism appears to be similar between these species. PMID:24505376

Chronic Sarpogrelate Treatment Reveals 5-HT7 Receptor in the Serotonergic Inhibition of the Rat Vagal Bradycardia.

PubMed

García-Pedraza, José Ángel; García, Mónica; Martín, María Luisa; Eleno, Nélida; Morán, Asunción

2017-01-01

5-Hydroxytryptamine (5-HT) modulates the cardiac parasympathetic neurotransmission, inhibiting the bradyarrhythmia by 5-HT2 receptor activation. We aimed to determine whether the chronic selective 5-HT2 blockade (sarpogrelate) could modify the serotonergic modulation on vagal cardiac outflow in pithed rat. Bradycardic responses in rats treated with sarpogrelate (30 mg·kg·d; orally) were obtained by electrical stimulation of the vagal fibers (3, 6, and 9 Hz) or intravenous (IV) injections of acetylcholine (1, 5, and 10 μg/kg). 5-HT7 receptor expression was quantified by Western blot in vagus nerve and right atrium. The IV administration of 5-HT (10-200 μg/kg) dose dependently decreased the vagally induced bradycardia, and agonists 5-CT (5-HT1/7), 8-OH-DPAT (5-HT1A), or AS-19 (5-HT7) (50 μg/kg each) mimicked the 5-HT-induced inhibitory effect. Neither agonists CGS-12066B (5-HT1B), L-694,247 (5-HT1D), nor 1-phenylbiguanide (5-HT3) modified the electrically-induced bradycardic responses. Moreover, SB-258719 (5-HT7 antagonist) abolished the 5-HT-, 5-CT-, 8-OH-DPAT-, and AS-19-induced bradycardia inhibition; 5-HT or AS-19 did not modify the bradycardia induced by IV acetylcholine; and 5-HT7 receptor was expressed in both the vagus nerve and the right atrium. Our outcomes suggest that blocking chronically 5-HT2 receptors modifies the serotonergic influence on cardiac vagal neurotransmission exhibiting 5-HT as an exclusively inhibitory agent via prejunctional 5-HT7 receptor.

Vecteurs Singuliers des Theories des Champs Conformes Minimales

NASA Astrophysics Data System (ADS)

Benoit, Louis

En 1984 Belavin, Polyakov et Zamolodchikov revolutionnent la theorie des champs en explicitant une nouvelle gamme de theories, les theories quantiques des champs bidimensionnelles invariantes sous les transformations conformes. L'algebre des transformations conformes de l'espace-temps presente une caracteristique remarquable: en deux dimensions elle possede un nombre infini de generateurs. Cette propriete impose de telles conditions aux fonctions de correlations qu'il est possible de les evaluer sans aucune approximation. Les champs des theories conformes appartiennent a des representations de plus haut poids de l'algebre de Virasoro, une extension centrale de l'algebre conforme du plan. Ces representations sont etiquetees par h, le poids conforme de leur vecteur de plus haut poids, et par la charge centrale c, le facteur de l'extension centrale, commune a toutes les representations d'une meme theorie. Les theories conformes minimales sont constituees d'un nombre fini de representations. Parmi celles-ci se trouvent des theories unitaires dont les representation forment la serie discrete de l'algebre de Virasoro; leur poids h a la forme h_{p,q}(m)=[ (p(m+1) -qm)^2-1] (4m(m+1)), ou p,q et m sont des entiers positifs et p+q<= m+1. L'entier m parametrise la charge centrale: c(m)=1 -{6over m(m+1)} avec n>= 2. Ces representations possedent un sous-espace invariant engendre par deux sous-representations avec h_1=h_{p,q} + pq et h_2=h_{p,q} + (m-p)(m+1-q) dont chacun des vecteurs de plus haut poids portent le nom de vecteur singulier et sont notes respectivement |Psi _{p,q}> et |Psi_{m-p,m+1-q}>. . Les theories super-conformes sont une version super-symetrique des theories conformes. Leurs champs appartiennent a des representation de plus haut poids de l'algebre de Neveu-Schwarz, une des deux extensions super -symetriques de l'algebre de Virasoro. Les theories super -conformes minimales possedent la meme structure que les theories conformes minimales. Les representations

5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver

USDA-ARS?s Scientific Manuscript database

Mice lacking 5-HT 2C receptors displayed hepatic insulin resistance, a phenotype normalized by re-expression of 5-HT2CRs only in pro-opiomelanocortin (POMC) neurons. 5-HT2CR deficiency also abolished the anti-diabetic effects of meta-chlorophenylpiperazine (a 5-HT2CR agonist); these effects were re...

Effects of combined administration of 5-HT1A and/or 5-HT1B receptor antagonists and paroxetine or fluoxetine in the forced swimming test in rats.

PubMed

Tatarczyńska, Ewa; Kłodzińska, Aleksandra; Chojnacka-Wójcik, Ewa

2002-01-01

Clinical data suggest that coadministration of pindolol, a 5-HT1A/5-HT1B/beta-adrenoceptor antagonist, and selective serotonin reuptake inhibitors (SSRIs) may shorten the time of onset of a clinical action and may increase beneficial effects of the therapy of drug-resistant depression. Effects of combined administration of SSRIs and 5-HT receptor ligands are currently evaluated in animal models for the detection of an antidepressant-like activity; however, the obtained results turned out to be inconsistent. The aim of the present study was to investigate effects of a 5-HT1A antagonist (WAY 100635), 5-HT1B antagonists (SB 216641 and GR 127935) or pindolol, given in combination with paroxetine or fluoxetine (SSRIs), in the forced swimming test in rats (Porsolt test). When given alone, paroxetine (10 and 20 mg/kg), fluoxetine (10 and 20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), SB 216641 (2 mg/kg), GR 127935 (10 and 20 mg/kg) and pindolol (4 and 8 mg/kg) did not shorten the immobility time of rats in that test. Interestingly, SB 216641 administered alone at a dose of 4 mg/kg produced a significant reduction of the immobility time in that test. A combination of paroxetine (20 mg/kg) and WAY 100635 or pindolol failed to reveal a significant interaction; on the other hand, when paroxetine was given jointly with SB 216641 (2 mg/kg) or GR 127935 (10 and 20 mg/kg), that combination showed a significant antiimmobility action in the forced swimming test in rats. The active behaviors in that test did not reflect increased general activity because combined administration of both the 5-HT1B antagonists and paroxetine failed to alter the locomotor activity of rats, measured in the open field test. Coadministration of fluoxetine and all the antagonists used did not affect the behavior of rats in the forced swimming test. The obtained results seem to indicate that blockade of 5-HT1B receptors, but not 5-HT1A ones, can facilitate the antidepressant-like effect of paroxetine in the

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

PubMed Central

Villalón, C. M.; Ramírez-San Juan, E.; Castillo, C.; Castillo, E.; López-Muñoz, F. J.; Terrón, J. A.

1995-01-01

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

Ebselen has lithium-like effects on central 5-HT2A receptor function.

PubMed

Antoniadou, I; Kouskou, M; Arsiwala, T; Singh, N; Vasudevan, S R; Fowler, T; Cadirci, E; Churchill, G C; Sharp, T

2018-02-27

Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in G q protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here we investigated both ebselen and lithium in models of the 5-HT 2A receptor, a G q protein coupled receptor implicated in lithium's actions. 5-HT 2A receptor function was modelled in mice by measuring the behavioural (head-twitches) and cortical immediate early gene (IEG; Arc, c-fos and Erg2 mRNA) responses to 5-HT 2A receptor agonist administration. Ebselen and lithium were administered either acutely or chronically prior to assessment of 5-HT 2A receptor function. Given the SSRI augmenting action of lithium and 5-HT 2A antagonists, ebselen was also tested for this action by co-administration with the SSRI citalopram in microdialysis (extracellular 5-HT) experiments. Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT 2A receptor agonist DOI. Repeated lithium also inhibited DOI-evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L-690,330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR-A014418) did not. Finally, ebselen increased regional brain 5-HT synthesis and enhanced the increase in extracellular 5-HT induced by citalopram. The current data demonstrate lithium-mimetic effects of ebselen in different experimental models of 5-HT 2A receptor function, likely mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorder, including as an antidepressant augmenting agent. This article is protected by copyright. All rights reserved.

A Subpopulation of Serotonergic Neurons That Do Not Express the 5-HT1A Autoreceptor

PubMed Central

2012-01-01

5-HT neurons are topographically organized in the hindbrain, and have been implicated in the etiology and treatment of psychiatric diseases such as depression and anxiety. Early studies suggested that the raphe 5-HT neurons were a homogeneous population showing similar electrical properties, and feedback inhibition mediated by 5-HT1A autoreceptors. We utilized histochemistry techniques in ePet1-eGFP and 5-HT1A-iCre/R26R mice to show that a subpopulation of 5-HT neurons do not express the somatodendritic 5-HT1A autoreceptor mRNA. In addition, we performed patch-clamp recordings followed by single-cell PCR in ePet1-eGFP mice. From 134 recorded 5-HT neurons located in the dorsal, lateral, and median raphe, we found lack of 5-HT1A mRNA expression in 22 cells, evenly distributed across raphe subfields. We compared the cellular characteristics of these neuronal types and found no difference in passive membrane properties and general excitability. However, when injected with large depolarizing current, 5-HT1A-negative neurons fired more action potentials, suggesting a lack of autoinhibitory action of local 5-HT release. Our results support the hypothesis that the 5-HT system is composed of subpopulations of serotonergic neurons with different capacity for adaptation. PMID:23336048

Distinct circuits underlie the effects of 5-HT1B receptors on aggression and impulsivity

PubMed Central

Nautiyal, Katherine M.; Tanaka, Kenji F.; Barr, Mary M.; Tritschler, Laurent; Le Dantec, Yannick; David, Denis J.; Gardier, Alain M.; Blanco, Carlos; Hen, René; Ahmari, Susanne E.

2015-01-01

Summary Impulsive and aggressive behaviors are both modulated by serotonergic signaling, specifically through the serotonin 1B receptor (5-HT1BR). 5-HT1BR knockout mice show increased aggression and impulsivity, and 5-HT1BR polymorphisms are associated with aggression and drug addiction in humans. To dissect the mechanisms by which the 5-HT1BR affects these phenotypes, we developed a mouse model to spatially and temporally regulate 5-HT1BR expression. Our results demonstrate that forebrain 5-HT1B heteroreceptors expressed during an early postnatal period contribute to the development of the neural systems underlying adult aggression. However, distinct heteroreceptors acting during adulthood are involved in mediating impulsivity. Correlating with the impulsivity, dopamine in the nucleus accumbens is elevated in the absence of 5-HT1BRs, and normalized following adult rescue of the receptor. Overall, these data show that while adolescent expression of 5-HT1BRs influences aggressive behavior, a distinct set of 5-HT1B receptors modulate impulsive behavior during adulthood. PMID:25892302

Hippocampal 5-HT Input Regulates Memory Formation and Schaffer Collateral Excitation.

PubMed

Teixeira, Catia M; Rosen, Zev B; Suri, Deepika; Sun, Qian; Hersh, Marc; Sargin, Derya; Dincheva, Iva; Morgan, Ashlea A; Spivack, Stephen; Krok, Anne C; Hirschfeld-Stoler, Tessa; Lambe, Evelyn K; Siegelbaum, Steven A; Ansorge, Mark S

2018-06-06

The efficacy and duration of memory storage is regulated by neuromodulatory transmitter actions. While the modulatory transmitter serotonin (5-HT) plays an important role in implicit forms of memory in the invertebrate Aplysia, its function in explicit memory mediated by the mammalian hippocampus is less clear. Specifically, the consequences elicited by the spatio-temporal gradient of endogenous 5-HT release are not known. Here we applied optogenetic techniques in mice to gain insight into this fundamental biological process. We find that activation of serotonergic terminals in the hippocampal CA1 region both potentiates excitatory transmission at CA3-to-CA1 synapses and enhances spatial memory. Conversely, optogenetic silencing of CA1 5-HT terminals inhibits spatial memory. We furthermore find that synaptic potentiation is mediated by 5-HT4 receptors and that systemic modulation of 5-HT4 receptor function can bidirectionally impact memory formation. Collectively, these data reveal powerful modulatory influence of serotonergic synaptic input on hippocampal function and memory formation. Copyright © 2018 Elsevier Inc. All rights reserved.

HT.sub.m4 methods of treatment and assays, agonists and antagonists

DOEpatents

Lim, Bing; Adra, Chaker N.; Lelias, Jean-Michel

1999-01-01

The invention relates to a recombinant DNA molecule which encodes a HT.sub.m4 protein, a transformed host cell which has been stably transfected with a DNA molecule which encodes a HT.sub.m4 protein and a recombinant HT.sub.m4 protein. The invention also relates to a method for detecting the presence of a hereditary atopy.

H-Mode Behavior Induced by Modulated Toroidal Current on HT-7 and HT-6M Tokamak

NASA Astrophysics Data System (ADS)

Mao, J. S.; Luo, J. R.; Xu, Y. H.; Zhao, J. Y.; Zhang, X. M.; Li, J. G.; Zhang, X. M.; Gao, X.; Li, Y. D.; Jie, Y. X.; Wu, Z. W.; Hu, L. Q.; Liu, S. X.; Zhang, X. D.; Bao, Y.; Yang, K.; Wang, G. X.; Chen, L.; Shi, Y. J.; Qin, P. J.; Gu, X. M.; Cui, N. Z.; Fan, H. Y.; Chen, Y. F.; Xia, C. Y.; Ruan, H. L.; Tong, X. D.; Phillips, P. E.

2001-10-01

An improved Ohmic confinement phase (similar to H-mode) has been observed during Modulating Toroidal Current on the Hefei Tokamak-6M (HT-6M) and Hefei super-conducting Tokamak-7 (HT-7). This improved plasma confinement phase is characterized by: (a) an increase in ne and T_e(0); (b) reduced H_α radiation from the edge; (c) steeper density and temperature profiles at the edge; (d) a more negative radial electric field inside the limiter; (e) a deeper electrostatic potential well at the edge; (f) reduced magnetic fluctuations at the edge; (g) MHD suppressing; (h) and by an increase in global energy confinement time, τ _e, by 27%-45%. The well-like structure of the radial electric field E_r, appears at an L-H like transition.

Serotonergic 5-HT6 Receptor Antagonists: Heterocyclic Chemistry and Potential Therapeutic Significance.

PubMed

Bali, Alka; Singh, Shalu

2015-01-01

The serotonin 5-HT(6) receptor (5- HT(6)R) is amongst the recently discovered serotonergic receptors with almost exclusive localization in the brain. Hence, this receptor is fast emerging as a promising target for cognition enhancement in central nervous system (CNS) diseases such as Alzheimer's disease (cognitive function), obesity, schizophrenia and anxiety. The last decade has seen a surge of literature reports on the functional role of this receptor in learning and memory processes and investigations related to the chemistry and pharmacology of 5-HT(6) receptor ligands, especially 5- HT(6) receptor antagonists. Studies show the involvement of multiple neurotransmitter systems in cognitive enhancement by 5-HT(6)R antagonists including cholinergic, glutamatergic, and GABAergic systems. Several of the 5-HT(6)R ligands are indole based agents bearing structural similarity to the endogenous neurotransmitter serotonin. Based on the pharmacophoric models proposed for these agents, drug designing has been carried out incorporating various heterocyclic replacements for the indole nucleus. In this review, we have broadly summarized the medicinal chemistry and current status of this fairly recent class of drugs along with their potential therapeutic applications.

Contributions of 5-HT neurons to respiratory control: neuromodulatory and trophic effects.

PubMed

Hodges, Matthew R; Richerson, George B

2008-12-10

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.

G-LiHT: Goddard's LiDAR, Hyperspectral and Thermal Airborne Imager

NASA Technical Reports Server (NTRS)

Cook, Bruce; Corp, Lawrence; Nelson, Ross; Morton, Douglas; Ranson, Kenneth J.; Masek, Jeffrey; Middleton, Elizabeth

2012-01-01

Scientists at NASA's Goddard Space Flight Center have developed an ultra-portable, low-cost, multi-sensor remote sensing system for studying the form and function of terrestrial ecosystems. G-LiHT integrates two LIDARs, a 905 nanometer single beam profiler and 1550 nm scanner, with a narrowband (1.5 nanometers) VNIR imaging spectrometer and a broadband (8-14 micrometers) thermal imager. The small footprint (approximately 12 centimeters) LIDAR data and approximately 1 meter ground resolution imagery are advantageous for high resolution applications such as the delineation of canopy crowns, characterization of canopy gaps, and the identification of sparse, low-stature vegetation, which is difficult to detect from space-based instruments and large-footprint LiDAR. The hyperspectral and thermal imagery can be used to characterize species composition, variations in biophysical variables (e.g., photosynthetic pigments), surface temperature, and responses to environmental stressors (e.g., heat, moisture loss). Additionally, the combination of LIDAR optical, and thermal data from G-LiHT is being used to assess forest health by sensing differences in foliage density, photosynthetic pigments, and transpiration. Low operating costs (approximately $1 ha) have allowed us to evaluate seasonal differences in LiDAR, passive optical and thermal data, which provides insight into year-round observations from space. Canopy characteristics and tree allometry (e.g., crown height:width, canopy:ground reflectance) derived from G-LiHT data are being used to generate realistic scenes for radiative transfer models, which in turn are being used to improve instrument design and ensure continuity between LiDAR instruments. G-LiHT has been installed and tested in aircraft with fuselage viewports and in a custom wing-mounted pod that allows G-LiHT to be flown on any Cessna 206, a common aircraft in use throughout the world. G-LiHT is currently being used for forest biomass and growth estimation

Photoaffinity labelling and solubilization on the central 5-HT1A receptor binding site.

PubMed

Gozlan, H; Emerit, M B; el Mestikawy, S; Cossery, J M; Marquet, A; Besselievre, R; Hamon, M

1987-01-01

Two complementary approaches, covalent labelling and solubilization, have been used to study the biochemical properties of the central 5-HT1A receptor binding site. We have first designed a photoaffinity ligand containing the structure of 8-OH-DPAT, a potent and specific agonist of 5-HT1A sites. Thus, 8-methoxy-2[N-n-propyl,N-3-(2-nitro-4-azido-phenyl)- aminopropyl]aminotetralin or 8-methoxy-3'-NAP-amino-PAT, was found to displace, in the dark, [3H]8-OH-DPAT from 5-HT1A sites in rat hippocampal membranes with an IC50 of 6.6 nM. Under two cumulative UV irradiations (366 nm, for 20 min at 4 degrees C), 8-methoxy-3-'-NAP-amino-PAT (30 nM) blocked irreversibly 55-60% of 5-HT1A binding sites. This blockade was specific of 5-HT1A sites since the other serotoninergic sites, 5-HT1B, 5-HT2 and also the presynaptic 5-HT3 sites were not affected by the treatment. In addition, the binding of [3H]Spiperone and [3H]7-OH-DPAT to striatal dopamine sites remained unchanged under similar photolysis conditions. The tritiated derivative of the photoaffinity ligand (92 Ci/mmol) was then synthesized for the identification of the covalently bound protein(s). SDS-PAGE of solubilized membranes irradiated in the presence of 20 nM 3H-8-methoxy-3'-NAP-amino-PAT allowed the detection of a 63 kD protein whose labelling appeared specific. Thus, 3H-incorporation into the 63 kD band could be prevented by microM concentrations of 5-HT, 8-OH-DPAT and other selective 5-HT1A ligands such as isapirone. In contrast, the 5-HT2 antagonist ketanserin, norepinephrine and dopamine-related ligands (including 7-OH-DPAT) were ineffective. Direct solubilization of 5-HT1A receptor binding sites was also attempted from rat hippocampal membranes. The best results were obtained using CHAPS (10 mM) plus NaCl (0.2 M), which led to 50% recovery of 5-HT1A sites in the 100,000 g supernatant. The pharmacological properties and sensitivity to N-ethyl-maleimide and GppNHp of soluble sites appeared near identical to those of

Differential inhibition of N and P/Q Ca2+ currents by 5-HT1A and 5-HT1D receptors in spinal neurons of Xenopus larvae

PubMed Central

Sun, Qian-Quan; Dale, Nicholas

1998-01-01

In whole-cell patch clamp recordings made from non-sensory neurons acutely isolated from the spinal cord of Xenopus (stage 40–42) larvae, two forms of inhibition of the high voltage-activated (HVA) Ca2+ currents were produced by 5-HT. One was voltage dependent and associated with both slowing of the activation kinetics and shifting of the voltage dependence of the HVA currents. This inhibition was relieved by strong depolarizing prepulses. A second form of inhibition was neither associated with slowing of the activation kinetics nor relieved by depolarizing prepulses and was thus voltage independent. In all neurons examined, 5-HT (1 μM) reversibly reduced 34 ± 1.6 % (n = 102) of the HVA Ca2+ currents. In about 40 % of neurons, the inhibition was totally voltage independent. In another 5 %, the inhibition was totally voltage dependent. In the remaining neurons, inhibition was only partially (by around 40 %) relieved by a large depolarizing prepulse, suggesting that in these, the inhibition consisted of both voltage-dependent and -independent components. By using selective channel blockers, we found that 5-HT acted on both N- and P/Q-type channels. However, whereas the inhibition of P/Q-type currents was only voltage independent, the inhibition of N-type currents had both voltage-dependent and -independent components. The effects of 5-HT on HVA Ca2+ currents were mediated by 5-HT1A and 5-HT1D receptors. The 5-HT1A receptors not only preferentially caused voltage-independent inhibition, but did so by acting mainly on the ω-agatoxin-IVA-sensitive Ca2+ channels. In contrast, the 5-HT1D receptor produced both voltage-dependent and -independent inhibition and was preferentially coupled to ω-conotoxin-GVIA sensitive channels. This complexity of modulation may allow fine tuning of transmitter release and calcium signalling in the spinal circuitry of Xenopus larvae. PMID:9625870

Paroxetine-induced reduction of sexual incentive motivation in female rats is not modified by 5-HT1B or 5-HT2C antagonists.

PubMed

Kaspersen, Helge; Agmo, Anders

2012-03-01

Clinical data show that paroxetine causes sexual dysfunction in a substantial proportion of women taking this compound. This work was conducted to determine whether chronic paroxetine reduces sexual incentive motivation in female rats and whether this compound can modify any aspect of paced mating. The role of the 5-HT(1B) and 5-HT(2C) receptors in any potential effects was also evaluated. Ovariectomized female rats were implanted with osmotic minipumps releasing 10 mg/kg per day of paroxetine or vehicle for 28 days. Tests for sexual incentive motivation and paced mating were performed just before implantation and at regular intervals thereafter. The females were primed with estradiol benzoate (25 μg/rat) and progesterone (1 mg/rat) before each of these tests. On days 25-27 of treatment, the females were injected with the 5-HT(1B) antagonist GR125,743 (5 mg/kg), the 5-HT(2C) antagonist SB206,553 (5 mg/kg) and vehicle in counterbalanced order. Preinjection time was 30 min. Paroxetine reduced sexual incentive motivation on day 20 of treatment without affecting any aspect of paced mating. None of the antagonists modified the inhibitory effect of paroxetine on sexual incentive motivation. In the group chronically treated with vehicle, SB206,553 reduced proceptive behaviors in the paced mating test. No other effect was obtained. The effects of paroxetine seen in female rats are similar to those observed in women, suggesting that disturbances of sexual incentive motivation in rats are predictive of sexual dysfunction in women. The 5-HT(1B) and 5-HT(2C) receptors do not seem to be of any importance for paroxetine's inhibitory effect.

Epithelioma Spinocellulaire sur Cicatrice de Brulure (a Propos de Cinq Cas)

PubMed Central

Tourabi, K.; Mejjati, H.; Ribqg, Y.; Achbouk, A.; Arrob, A.; Moussaoui, A.; Ihrai, H.

2009-01-01

Summary Pour étudier l'ulcère de Marjolin, tous les dossiers des patients qui se sont présentés pendant une période quinquennale à un Service de Chirurgie Plastique et des Brûlés au Maroc ayant un cancer sur cicatrice de brûlure, objectivé par un examen histopathologique, ont été inclus dans une fiche de recueil de données comprenant des paramètres liés à l'identité du malade, à l'inventaire préthérapeutique, au traitement et à l'évolution du cas. Les Auteurs, après avoir présenté les données des cinq patients inclus dans l'étude, considèrent les problèmes posés par les épithéliomas spinocellulaires sur cicatrice de brûlure, qui sont des affections graves et rares. La dégénérescence des cicatrices de brûlures est une évolution dramatique, causée par la négligence. Le traitement préventif par exérèse systématique de toute lésion suspecte doit être fortement souligné puisqu'il garantit la guérison quasi certaine. PMID:21991185

Serotonin homeostasis and serotonin receptors as actors of cortical construction: special attention to the 5-HT3A and 5-HT6 receptor subtypes

PubMed Central

Vitalis, Tania; Ansorge, Mark S.; Dayer, Alexandre G.

2013-01-01

Cortical circuits control higher-order cognitive processes and their function is highly dependent on their structure that emerges during development. The construction of cortical circuits involves the coordinated interplay between different types of cellular processes such as proliferation, migration, and differentiation of neural and glial cell subtypes. Among the multiple factors that regulate the assembly of cortical circuits, 5-HT is an important developmental signal that impacts on a broad diversity of cellular processes. 5-HT is detected at the onset of embryonic telencephalic formation and a variety of serotonergic receptors are dynamically expressed in the embryonic developing cortex in a region and cell-type specific manner. Among these receptors, the ionotropic 5-HT3A receptor and the metabotropic 5-HT6 receptor have recently been identified as novel serotonergic targets regulating different aspects of cortical construction including neuronal migration and dendritic differentiation. In this review, we focus on the developmental impact of serotonergic systems on the construction of cortical circuits and discuss their potential role in programming risk for human psychiatric disorders. PMID:23801939

Thermal Decomposition Behavior of Hydroxytyrosol (HT) in Nitrogen Atmosphere Based on TG-FTIR Methods.

PubMed

Tu, Jun-Ling; Yuan, Jiao-Jiao

2018-02-13

The thermal decomposition behavior of olive hydroxytyrosol (HT) was first studied using thermogravimetry (TG). Cracked chemical bond and evolved gas analysis during the thermal decomposition process of HT were also investigated using thermogravimetry coupled with infrared spectroscopy (TG-FTIR). Thermogravimetry-Differential thermogravimetry (TG-DTG) curves revealed that the thermal decomposition of HT began at 262.8 °C and ended at 409.7 °C with a main mass loss. It was demonstrated that a high heating rate (over 20 K·min -1 ) restrained the thermal decomposition of HT, resulting in an obvious thermal hysteresis. Furthermore, a thermal decomposition kinetics investigation of HT indicated that the non-isothermal decomposition mechanism was one-dimensional diffusion (D1), integral form g ( x ) = x ², and differential form f ( x ) = 1/(2 x ). The four combined approaches were employed to calculate the activation energy ( E = 128.50 kJ·mol -1 ) and Arrhenius preexponential factor (ln A = 24.39 min -1 ). In addition, a tentative mechanism of HT thermal decomposition was further developed. The results provide a theoretical reference for the potential thermal stability of HT.

5-HT1D receptor inhibits renal sympathetic neurotransmission by nitric oxide pathway in anesthetized rats.

PubMed

García-Pedraza, José-Ángel; García, Mónica; Martín, María-Luisa; Morán, Asunción

2015-09-01

Although serotonin has been shown to inhibit peripheral sympathetic outflow, serotonin regulation on renal sympathetic outflow has not yet been elucidated. This study investigated which 5-HT receptor subtypes are involved. Wistar rats were anesthetized (sodium pentobarbital; 60mg/kg, i.p.), and prepared for in situ autoperfused rat kidney, which allows continuous measurement of systemic blood pressure (SBP), heart rate (HR) and renal perfusion pressure (PP). Electrical stimulation of renal sympathetic nerves resulted in frequency-dependent increases in PP (18.3±1.0, 43.7±2.7 and 66.7±4.0 for 2, 4 and 6Hz, respectively), without altering SBP or HR. 5-HT, 5-carboxamidotryptamine (5-HT1/7 agonist) (0.00000125-0.1μg/kg each) or l-694,247 (5-HT1D agonist; 0.0125μg/kg) i.a. bolus inhibited vasopressor responses by renal nerve electrical stimulation, unlike i.a. bolus of agonists α-methyl-5-HT (5-HT2), 1-PBG (5-HT3), cisapride (5-HT4), AS-19 (5-HT7), CGS-12066B (5-HT1B) or 8-OH-DPAT (5-HT1A) (0.0125μg/kg each). The effect of l-694,247 did not affect the exogenous norepinephrine-induced vasoconstrictions, whereas was abolished by antagonist LY310762 (5-HT1D; 1mg/kg) or l-NAME (nitric oxide; 10mg/kg), but not by indomethacin (COX1/2; 2mg/kg) or glibenclamide (ATP-dependent K(+) channel; 20mg/kg). These results suggest that 5-HT mechanism-induced inhibition of rat vasopressor renal sympathetic outflow is mainly mediated by prejunctional 5-HT1D receptors via nitric oxide release. Copyright © 2015 Elsevier Inc. All rights reserved.

Optical and electrical properties of P3HT:graphene composite based devices

NASA Astrophysics Data System (ADS)

Yadav, Anjali; Verma, Ajay Singh; Gupta, Saral Kumar; Negi, Chandra Mohan Singh

2018-04-01

The polymer-carbon derivate composites are well known for their uses and performances in the photovoltaic and optoelectronic industries. In this paper, we synthesis P3HT:graphene composites and discuss their optical and electrical properties. The composites have been prepared by using spin-coating technique onto the glass substrates. It has been found that the incorporation of graphene reduces absorption intensity. However, absorption peak remain unchanged with addition of graphene. The surface morphology studies display homogeneous distribution of graphene with P3HT. Raman studies suggest that chemical structure was not affected by graphene doping. Devices having the structure of glass/ITO/P3HT/ Al and glass ITO/P3HT:graphene/Al were then fabricated. I-V behavior of the fabricated devices was found to be similar to the Schottky diode. ITO/P3HT:graphene/Al structure shows tremendous increase in current values as compared to the ITO/P3HT/Al. Furthermore, charge transport mechanism were studied by analyzing the double logarithmic J-V characteristics curve, which indicates that the current at low voltage follows Ohmic behavior, trap-charge limited conduction (TCLC) mechanism at an intermediate voltage and space charge limited conduction (SCLC) mechanism at sufficiently high voltages.

The absence of 5-HT4 receptors modulates depression- and anxiety-like responses and influences the response of fluoxetine in olfactory bulbectomised mice: Adaptive changes in hippocampal neuroplasticity markers and 5-HT1A autoreceptor.

PubMed

Amigó, J; Díaz, A; Pilar-Cuéllar, F; Vidal, R; Martín, A; Compan, V; Pazos, A; Castro, E

2016-12-01

Preclinical studies support a critical role of 5-HT 4 receptors (5-HT 4 Rs) in depression and anxiety, but their influence in depression- and anxiety-like behaviours and the effects of antidepressants remain partly unknown. We evaluated 5-HT 4 R knockout (KO) mice in different anxiety and depression paradigms and mRNA expression of some neuroplasticity markers (BDNF, trkB and Arc) and the functionality of 5-HT 1A R. Moreover, the implication of 5-HT 4 Rs in the behavioural and molecular effects of chronically administered fluoxetine was assessed in naïve and olfactory bulbectomized mice (OBX) of both genotypes. 5-HT 4 R KO mice displayed few specific behavioural impairments including reduced central activity in the open-field (anxiety), and decreased sucrose consumption and nesting behaviour (anhedonia). In these mice, we measured increased levels of BDNF and Arc mRNA and reduced levels of trkB mRNA in the hippocampus, and a desensitization of 5-HT 1A autoreceptors. Chronic administration of fluoxetine elicited similar behavioural effects in WT and 5-HT 4 R KO mice on anxiety-and depression-related tests. Following OBX, locomotor hyperactivity and anxiety were similar in both genotypes. Interestingly, chronic fluoxetine failed to reverse this OBX-induced syndrome in 5-HT 4 R KO mice, a response associated with differential effects in hippocampal neuroplasticity biomarkers. Fluoxetine reduced hippocampal Arc and BDNF mRNA expressions in WT but not 5-HT 4 R KO mice subjected to OBX. These results demonstrate that the absence of 5-HT 4 Rs triggers adaptive changes that could maintain emotional states, and that the behavioural and molecular effects of fluoxetine under pathological depression appear to be critically dependent on 5-HT 4 Rs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Function and distribution of 5-HT2 receptors in the honeybee (Apis mellifera).

PubMed

Thamm, Markus; Rolke, Daniel; Jordan, Nadine; Balfanz, Sabine; Schiffer, Christian; Baumann, Arnd; Blenau, Wolfgang

2013-01-01

Serotonin plays a pivotal role in regulating and modulating physiological and behavioral processes in both vertebrates and invertebrates. In the honeybee (Apis mellifera), serotonin has been implicated in division of labor, visual processing, and learning processes. Here, we present the cloning, heterologous expression, and detailed functional and pharmacological characterization of two honeybee 5-HT2 receptors. Honeybee 5-HT2 receptor cDNAs were amplified from brain cDNA. Recombinant cell lines were established constitutively expressing receptor variants. Pharmacological properties of the receptors were investigated by Ca(2+) imaging experiments. Quantitative PCR was applied to explore the expression patterns of receptor mRNAs. The honeybee 5-HT2 receptor class consists of two subtypes, Am5-HT2α and Am5-HT2β. Each receptor gene also gives rise to alternatively spliced mRNAs that possibly code for truncated receptors. Only activation of the full-length receptors with serotonin caused an increase in the intracellular Ca(2+) concentration. The effect was mimicked by the agonists 5-methoxytryptamine and 8-OH-DPAT at low micromolar concentrations. Receptor activities were blocked by established 5-HT receptor antagonists such as clozapine, methiothepin, or mianserin. High transcript numbers were detected in exocrine glands suggesting that 5-HT2 receptors participate in secretory processes in the honeybee. This study marks the first molecular and pharmacological characterization of two 5-HT2 receptor subtypes in the same insect species. The results presented should facilitate further attempts to unravel central and peripheral effects of serotonin mediated by these receptors.

Function and Distribution of 5-HT2 Receptors in the Honeybee (Apis mellifera)

PubMed Central

Thamm, Markus; Rolke, Daniel; Jordan, Nadine; Balfanz, Sabine; Schiffer, Christian; Baumann, Arnd; Blenau, Wolfgang

2013-01-01

Background Serotonin plays a pivotal role in regulating and modulating physiological and behavioral processes in both vertebrates and invertebrates. In the honeybee (Apis mellifera), serotonin has been implicated in division of labor, visual processing, and learning processes. Here, we present the cloning, heterologous expression, and detailed functional and pharmacological characterization of two honeybee 5-HT2 receptors. Methods Honeybee 5-HT2 receptor cDNAs were amplified from brain cDNA. Recombinant cell lines were established constitutively expressing receptor variants. Pharmacological properties of the receptors were investigated by Ca2+ imaging experiments. Quantitative PCR was applied to explore the expression patterns of receptor mRNAs. Results The honeybee 5-HT2 receptor class consists of two subtypes, Am5-HT2α and Am5-HT2β. Each receptor gene also gives rise to alternatively spliced mRNAs that possibly code for truncated receptors. Only activation of the full-length receptors with serotonin caused an increase in the intracellular Ca2+ concentration. The effect was mimicked by the agonists 5-methoxytryptamine and 8-OH-DPAT at low micromolar concentrations. Receptor activities were blocked by established 5-HT receptor antagonists such as clozapine, methiothepin, or mianserin. High transcript numbers were detected in exocrine glands suggesting that 5-HT2 receptors participate in secretory processes in the honeybee. Conclusions This study marks the first molecular and pharmacological characterization of two 5-HT2 receptor subtypes in the same insect species. The results presented should facilitate further attempts to unravel central and peripheral effects of serotonin mediated by these receptors. PMID:24324783

Study of P3HT/ PCBM morphology using Raman spectroscopy

NASA Astrophysics Data System (ADS)

Kumar, Sunil; Kumar, Manoj; Rathi, Sonika; Yadav, Anjali; Upadhyaya, Aditi; Gupta, Saral K.; Singh, Amarjeet

2018-05-01

In the present work we have deposited PEDOT: PSS (poly3,4-ethylene dioxythiophene -poly (styrenesulfonate)) then Pristine P3HT (Poly-3 hexylthiophene-2,5-diyl), PCBM (6,6- PhenylC61 butyric acid methyl ester) and its blend composite (P3HT:PCBM) thin films on ITO substrate via spin coating technique. Pristine P3HT, pristine PCBM and blend thin film samples were annealed at different temperatures (50°C, 80°C and 110°C) for 1 hr. Raman spectra was measured for each thin film samples as prepared (at room temperature or 25°C) and annealed at different temperatures (50°C, 80°C, 110°C). Then we calculated area under Raman peaks which is representation of Raman Intensity and observed that area under Raman peak varies with annealing temperatures. The increase in peak intensity appears due to increased crystallinity in annealed thin films. The mixing of PCBM hinders the crystallization of P3HT in blend. Mixed amorphous phase plays major role in charge transportation in electronic devices.

Effects of acute MDMA intoxication on mood and impulsivity: role of the 5-HT2 and 5-HT1 receptors.

PubMed

van Wel, Janelle H P; Kuypers, Kim P C; Theunissen, Eef L; Bosker, Wendy M; Bakker, Katja; Ramaekers, Johannes G

2012-01-01

MDMA induces positive mood and increases impulse control during intoxication, but only a few studies on the neuropharmacological mechanisms underlying these processes have been conducted. It was hypothesized that pretreatment with 5-HT(1) and 5-HT(2) receptor blockers would prevent MDMA effects on mood and impulsivity. Subjects (N = 17) participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. T1-T2 combinations were: placebo-placebo, 20 mg pindolol-placebo, 50 mg ketanserin-placebo, placebo-75 mg MDMA, 20 mg pindolol-75 mg MDMA and 50 mg ketanserin-75 g MDMA. Subjects completed a Profile of Mood States (POMS) questionnaire and several impulsivity tasks (Stop signal task, Matching familiar figures task, Cue dependent reversal learning task) at 1.5 hrs post-treatment. MDMA alone increased both positive (vigor, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. MDMA also increased stop reaction time in the Stop signal task and reaction time in the Matching familiar figures task. Pretreatment with ketanserin blocked MDMA effects on positive affect, but not negative affect. Ketanserin did not influence the effects of MDMA on impulsivity. Pindolol did not interact with MDMA on any of the measures. In conclusion, 5-HT(2) receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. 5-HT(1) receptors do not appear to be involved in MDMA effects on mood and impulse control. Nederlands Trial Register NTR2352.

Serotonin inputs to the dorsal BNST modulate anxiety in a 5-HT1A receptor dependent manner

PubMed Central

Garcia-Garcia, Alvaro L.; Canetta, Sarah; Stujenske, Joseph M.; Burghardt, Nesha S.; Ansorge, Mark S.; Dranovsky, Alex; Leonardo, E. David

2017-01-01

Serotonin (5-HT) neurons project from the raphe nuclei throughout the brain where they act to maintain homeostasis. Here, we study 5-HT inputs into the bed nucleus of the stria terminalis (BNST), a major subdivision of the extended amygdala that has been proposed to regulate responses to anxiogenic environments in humans and rodents. While the dorsal part of the BNST (dBNST) receives dense 5-HT innervation, whether and how 5-HT in the dBNST normally modulates anxiety remains unclear. Using optogenetics, we demonstrate that activation of 5-HT terminals in the dBNST reduces anxiety in a highly anxiogenic environment. Further analysis revealed that optogenetic inhibition of 5-HT inputs into the dBNST increases anxiety in a less anxiogenic environment. We found that 5-HT predominantly hyperpolarizes dBNST neurons, reducing their activity in a manner that can be blocked by a 5-HT1A antagonist. Finally, we demonstrate that activation of 5-HT1A receptors in the dBNST is necessary for the anxiolytic effect observed following optogenetic stimulation of 5-HT inputs into the dBNST. These data reveal that 5-HT release in the dBNST modulates anxiety-like behavior via 5-HT1A receptors under naturalistic conditions. PMID:28761080

Study of dielectric phenomenon for P3HT: PCBM blend

NASA Astrophysics Data System (ADS)

Kumar, Sunil; Kumar, Manoj; Rathi, Sonika; Singh, Amarjeet

2017-05-01

In this present work we prepared the film sample of blend (P3HT (poly (3-hexylthiophene-2, 5-diyl)): PCBM ([6,6]-phenyl C61-butyric acid methyl ester)), P3HT and PCBM solution on ITO substrate by drop cast method. Capacitance and tangent loss (tan δ) were measured and dielectric constants έ and dielectric loss ɛ″ were deduced from them as function frequency at room temperature. Blend samples show strong frequency dependence as compared to pristine P3HT and pristine PCBM sample. The high dielectric constant in blend films at low frequency was attributed to characteristic slow relaxation process in polymers along with polarization of isolated grains in the blend sample.

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

PubMed Central

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

2012-01-01

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. PMID:22845622

Pharmacology of the hypothermic response to 5-HT1A receptor activation in humans.

PubMed

Lesch, K P; Poten, B; Söhnle, K; Schulte, H M

1990-01-01

The selective 5-HT1A receptor ligand ipsapirone (IPS) caused dose-related hypothermia in humans. The response was attenuated by the nonselective 5-HT1/2 receptor antagonist metergoline and was completely antagonized by the nonselective beta-adrenoceptor antagonist pindolol, which interacts stereoselectively with the 5-HT1A receptor. The selective beta 1-adrenergic antagonist betaxolol had no effect. The findings indicate that IPS-induced hypothermia specifically involves activation of (presynaptic) 5-HT1A receptors. Therefore, the hypothermic response to IPS may provide a convenient in vivo paradigma to assess the function of the presynaptic 5-HT receptor in affective disorders and its involvement in the effects of psychotropic drugs.

Peripheral 5-HT3 Receptors Are Involved in the Antinociceptive Effect of Bunodosine 391.

PubMed

Ferreira Junior, Wilson Alves; Zaharenko, Andre Junqueira; Kazuma, Kohei; Picolo, Gisele; Gutierrez, Vanessa Pacciari; de Freitas, Jose Carlos; Konno, Katsuhiro; Cury, Yara

2017-12-27

Bunodosine 391 (BDS 391), a low molecular weight compound isolated from the sea anemone Bunodosoma cangicum , increases the nociceptive threshold and inhibits inflammatory hyperalgesia. Serotonin receptors are involved in those effects. In this study, we have expanded the characterization of the antinociceptive effect of BDS 391 demonstrating that, in rats: (a) the compound inhibits (1.2-12 ng/paw) overt pain, in the formalin test, and mechanical hyperalgesia (0.6-6.0 ng/paw) detected in a model of neuropathic pain; (b) intraplantar administration of ondansetron, a selective 5-HT3 receptor antagonist, blocks the effect of BDS 391, whereas ketanserin, a 5-HT2 receptor antagonist, partially reversed this effect, indicating the involvement of peripheral 5-HT2 and 5-HT3 receptors in BDS 391 antinociception; and (c) in binding assay studies, BDS 391 was not able to displace the selective 5-HT receptor antagonists, suggesting that this compound does not directly bind to these receptors. The effect of biguanide, a selective 5-HT3 receptor agonist, was also evaluated. The agonist inhibited the formalin's nociceptive response, supporting an antinociceptive role for 5-HT3 receptors. Our study is the first one to show that a non-peptidic low molecular weight compound obtained from a sea anemone is able to induce antinociception and that activation of peripheral 5-HT3 receptors contributes to this effect.

Radiosensitization of HT-29 cells and xenografts by the nitric oxide donor DETANONOate.

PubMed

Gao, Xiaohuan; Saha, Debabrata; Kapur, Payal; Anthony, Thomas; Livingston, Edward H; Huerta, Sergio

2009-08-01

Mechanisms of radioresistance in rectal cancer remain unclear. To determine mechanisms of radioresistance in rectal cancer cells and to assess the role of the nitric oxide donor DETANONOate as a radiosensitizing agent. Survival was determined by clonogenic assays, apoptosis by PARP-1 cleavage, and phenotypic differences by Western blot analysis. SCID mice bearing HT-29 xenografts were treated with ionizing radiation (IR) [2.0 Gy x 5], DETANONOate [0.4 mg/kg i.p.], or combination treatment. Colorectal cancer HT-29-p53-null cells were resistant and HCT-116-p53 wild-type cells sensitive to IR, which correlated with cleaved PARP-1. Increased levels of p21 occurred in HCT-116 cells, while Bcl-2 and survivin were elevated in HT-29 cells. Radiosensitization was achieved with a substantial elevation of cleaved PARP-1 in DETANONOate-HT-29-treated versus control cells, which was accompanied by elevation of p21, p27, and BAX, and a concomitant decrease in Bcl-2. SCID mice bearing HT-29 xenografts demonstrated a 37.6%, 51.1%, and 70.1% inhibition in tumor growth in mice receiving IR, DETANONOate, and combination treatment versus control, respectively. Radioresistant HT-29 cells are p53-null and have substantially decreased levels of p21. DETANONOate radiosensitized HT-29 cells in vitro and in vivo by an additive effect in apoptosis.

Vortioxetine restores reversal learning impaired by 5-HT depletion or chronic intermittent cold stress in rats.

PubMed

Wallace, Ashley; Pehrson, Alan L; Sánchez, Connie; Morilak, David A

2014-10-01

Current treatments for depression, including serotonin-specific reuptake inhibitors (SSRIs), are only partially effective, with a high incidence of residual symptoms, relapse, and treatment resistance. Loss of cognitive flexibility, a component of depression, is associated with dysregulation of the prefrontal cortex. Reversal learning, a form of cognitive flexibility, is impaired by chronic stress, a risk factor for depression, and the stress-induced impairment in reversal learning is sensitive to chronic SSRI treatment, and is mimicked by serotonin (5-HT) depletion. Vortioxetine, a novel, multimodal-acting antidepressant, is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and inhibits the 5-HT transporter. Using adult male rats, we first investigated the direct effects of vortioxetine, acting at post-synaptic 5-HT receptors, on reversal learning that was compromised by 5-HT depletion using 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), effectively eliminating any contribution of 5-HT reuptake blockade. PCPA induced a reversal learning impairment that was alleviated by acute or sub-chronic vortioxetine administration, suggesting that post-synaptic 5-HT receptor activation contributes to the effects of vortioxetine. We then investigated the effects of chronic dietary administration of vortioxetine on reversal learning that had been compromised in intact animals exposed to chronic intermittent cold (CIC) stress, to assess vortioxetine's total pharmacological effect. CIC stress impaired reversal learning, and chronic vortioxetine administration prevented the reversal-learning deficit. Together, these results suggest that the direct effect of vortioxetine at 5-HT receptors may contribute to positive effects on cognitive flexibility deficits, and may enhance the effect of 5-HT reuptake blockade.

Effets tardifs d'une irradiation corporelle totale sur le métabolisme intraneuronal de la dopamine et de la sérotonine

NASA Astrophysics Data System (ADS)

Joubert, C.; Jacquet, N.; Lambert, F.; Martin, S.; Martin, C.

1998-04-01

Whole-body irradiation leads to delayed cognitive dysfunction which could result from perturbations of neurotransmission, specially the dopaminergic and the serotoninergic one. The aim of this study was to determine the concentrations of dopamine (DA), serotonin (5-HT) and their metabolites in three cerebral areas of rats, one month after (neutron-gamma) irradiation at 3.38Gy. An increase of DA, 5-HT, and their catabolites was observed. These effects are weak but observed in older rats. Au cours des mois suivant une irradiation corporell totale peuvent se manifester des troubles comportementaux qui pourraient être la conséquence d'altérations de la neuraotransmission, plus particulièrement de la transmission dopaminergique ou sérotoninergique. Nous avons recherché les variations des taux de dopamine (DA), de sérotonine (5-HT) et de leurs métabolites dans 3structures cérébrales 1 mois après une irradiation (neutron-gamma) à la dose de 3,38Gy. Les résultats préliminaires mettent en évidence une augmentation des taux de DA, de 5-HT et de leurs catabolites ; ces effets sont plus discrets mais similaires à ceux observés chez des animaux plus âgés.

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

PubMed

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

2010-04-01

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-HT(1) receptor of an insect model for neurobiology, physiology and pharmacology. A cDNA encoding for the Periplaneta americana 5-HT(1) 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. The P. americana 5-HT(1) receptor (Pea5-HT(1)) shares pronounced sequence and functional similarity with mammalian 5-HT(1) receptors. Activation with 5-HT reduced adenylyl cyclase activity in a dose-dependent manner. Pea5-HT(1) 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. This study marks the first pharmacological identification of an inverse agonist and a neutral antagonist at an insect 5-HT(1) receptor. The results presented here should facilitate further analyses of 5-HT(1) receptors in mediating central and peripheral effects of 5-HT in insects.

The current status of knowledge of herbal medicine and medicinal plants in Fiche, Ethiopia

PubMed Central

2014-01-01

Background A majority of Ethiopians rely on traditional medicine as their primary form of health care, yet they are in danger of losing both their knowledge and the plants they have used as medicines for millennia. This study, conducted in the rural town of Fiche in Ethiopia, was undertaken with the support of Southern Cross University (SCU) Australia, Addis Ababa University (AAU) Ethiopia, and the Ethiopian Institute of Biodiversity (EIB), Ethiopia. The aim of this study, which included an ethnobotanical survey, was to explore the maintenance of tradition in the passing on of knowledge, the current level of knowledge about medicinal herbs and whether there is awareness and concern about the potential loss of both herbal knowledge and access to traditional medicinal plants. Methods This study was conducted using an oral history framework with focus groups, unstructured and semi-structured interviews, field-walk/discussion sessions, and a market survey. Fifteen people were selected via purposeful and snowball sampling. Analysis was undertaken using a grounded theory methodology. Results Fourteen lay community members and one professional herbalist provided information about 73 medicinal plants used locally. An ethnobotanical survey was performed and voucher specimens of 53 of the plants, representing 33 families, were collected and deposited at the EIB Herbarium. The community members are knowledgeable about recognition of medicinal plants and their usage to treat common ailments, and they continue to use herbs to treat sickness as they have in the past. A willingness to share knowledge was demonstrated by both the professional herbalist and lay informants. Participants are aware of the threat to the continued existence of the plants and the knowledge about their use, and showed willingness to take steps to address the situation. Conclusion There is urgent need to document the valuable knowledge of medicinal herbs in Ethiopia. Ethnobotanical studies are imperative

Rational Design, Pharmacomodulation, and Synthesis of Dual 5-Hydroxytryptamine 7 (5-HT7)/5-Hydroxytryptamine 2A (5-HT2A) Receptor Antagonists and Evaluation by [(18)F]-PET Imaging in a Primate Brain.

PubMed

Deau, Emmanuel; Robin, Elodie; Voinea, Raluca; Percina, Nathalie; Satała, Grzegorz; Finaru, Adriana-Luminita; Chartier, Agnès; Tamagnan, Gilles; Alagille, David; Bojarski, Andrzej J; Morisset-Lopez, Séverine; Suzenet, Franck; Guillaumet, Gérald

2015-10-22

We report the synthesis of 46 tertiary amine-bearing N-alkylated benzo[d]imidazol-2(3H)-ones, imidazo[4,5-b]pyridin-2(3H)-ones, imidazo[4,5-c]pyridin-2(3H)-ones, benzo[d]oxazol-2(3H)-ones, oxazolo[4,5-b]pyridin-2(3H)-ones and N,N'-dialkylated benzo[d]imidazol-2(3H)-ones. These compounds were evaluated against 5-HT7R, 5-HT2AR, 5-HT1AR, and 5-HT6R as potent dual 5-HT7/5-HT2A serotonin receptors ligands. A thorough study of the structure-activity relationship of the aromatic rings and their substituents, the alkyl chain length and the tertiary amine was conducted. 1-(4-(4-(4-Fluorobenzoyl)piperidin-1-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one (79) and 1-(6-(4-(4-fluorobenzoyl)piperidin-1-yl)hexyl)-1H-benzo[d]imidazol-2(3H)-one (81) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, KB = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, KB = 0.6 and 16 nM, respectively) signaling pathways of 5-HT7R and 5-HT2AR. Both antagonists crossed the blood-brain barrier as evaluated with [(18)F] radiolabeled compounds [(18)F]79 and [(18)F]81 in a primate's central nervous system using positron emission tomography. Both radioligands showed standard uptake values ranging from 0.8 to 1.1, a good plasmatic stability, and a distribution consistent with 5-HT7R and 5-HT2AR in the CNS.

Serotonin inputs to the dorsal BNST modulate anxiety in a 5-HT1A receptor-dependent manner.

PubMed

Garcia-Garcia, A L; Canetta, S; Stujenske, J M; Burghardt, N S; Ansorge, M S; Dranovsky, A; Leonardo, E D

2017-08-01

Serotonin (5-HT) neurons project from the raphe nuclei throughout the brain where they act to maintain homeostasis. Here, we study 5-HT inputs into the bed nucleus of the stria terminalis (BNST), a major subdivision of the extended amygdala that has been proposed to regulate responses to anxiogenic environments in humans and rodents. While the dorsal part of the BNST (dBNST) receives dense 5-HT innervation, whether and how 5-HT in the dBNST normally modulates anxiety remains unclear. Using optogenetics, we demonstrate that activation of 5-HT terminals in the dBNST reduces anxiety in a highly anxiogenic environment. Further analysis revealed that optogenetic inhibition of 5-HT inputs into the dBNST increases anxiety in a less anxiogenic environment. We found that 5-HT predominantly hyperpolarizes dBNST neurons, reducing their activity in a manner that can be blocked by a 5-HT 1A antagonist. Finally, we demonstrate that activation of 5-HT 1A receptors in the dBNST is necessary for the anxiolytic effect observed following optogenetic stimulation of 5-HT inputs into the dBNST. These data reveal that 5-HT release in the dBNST modulates anxiety-like behavior via 5-HT 1A receptors under naturalistic conditions.Molecular Psychiatry advance online publication, 1 August 2017; doi:10.1038/mp.2017.165.

Tuning of the Morphology and Optoelectronic Properties of ZnO/P3HT/P3HT- b-PEO Hybrid Films via Spray Deposition Method.

PubMed

Wang, Kun; Bießmann, Lorenz; Schwartzkopf, Matthias; Roth, Stephan V; Müller-Buschbaum, Peter

2018-06-20

The self-assembly of amphiphilic diblock copolymers yields the possibility of using them as a template for tailoring the film morphologies of sol-gel chemistry-derived inorganic electron transport materials, such as mesoporous ZnO and TiO 2 . However, additional steps including etching and backfilling are required for the common bulk heterojunction fabrication process when using insulating diblock copolymers. Here, we use the conducting diblock copolymer poly(3-hexylthiophene)- block-poly(ethylene oxide) (P3HT- b-PEO) in which P3HT acts as charge carrier transport material and light absorber, whereas PEO serves as a template for ZnO synthesis. The initial solution is subsequently spray-coated to obtain the hybrid film. Scanning electron microscopy and grazing-incidence small-angle X-ray scattering measurements reveal a significant change in the morphology of the hybrid films during deposition. Optoelectronic properties illustrate the improved charge separation and charge transfer process. Both the amount of the diblock copolymer and the annealing temperature play an important role in tuning the morphology and the optoelectronic properties. Hybrid films being sprayed from a solution with the ratio of ω ZnO , ω P3HT , and ω P3HT- b-PEO of 2:1:1 and subsequent annealing at 80 °C show the most promising morphology combined with an optimal photoluminescence quenching. Thus, the presented simple, reagent- and energy-saving fabrication method provides a promising approach for a large-scale preparation of bulk heterojunction P3HT/ZnO films on flexible substrates.

Stress-induced alterations in 5-HT1A receptor transcriptional modulators NUDR and Freud-1.

PubMed

Szewczyk, Bernadeta; Kotarska, Katarzyna; Daigle, Mireille; Misztak, Paulina; Sowa-Kucma, Magdalena; Rafalo, Anna; Curzytek, Katarzyna; Kubera, Marta; Basta-Kaim, Agnieszka; Nowak, Gabriel; Albert, Paul R

2014-11-01

The effect of stress on the mRNA and protein level of the 5-HT1A receptor and two of its key transcriptional modulators, NUDR and Freud-1, was examined in the prefrontal cortex (PFC) and hippocampus (Hp) using rodent models: olfactory bulbectomy (OB) and prenatal stress (PS) in male and female rats; chronic mild stress in male rats (CMS) and pregnancy stress. In PFC, CMS induced the most widespread changes, with significant reduction in both mRNA and protein levels of NUDR, 5-HT1A receptor and in Freud-1 mRNA; while in Hp 5-HT1A receptor and Freud-1 protein levels were also decreased. In male, but not female OB rats PFC Freud-1 and 5-HT1A receptor protein levels were reduced, while in Hp 5-HT1A receptor, Freud-1 and NUDR mRNA's but not protein were reduced. In PS rats PFC 5-HT1A receptor protein was reduced more in females than males; while in Hp Freud-1 protein was increased in females. In pregnancy stress, PFC NUDR, Freud-1 and 5-HT1A protein receptor levels were reduced, and in HP 5-HT1A receptor protein levels were also reduced; in HP only NUDR and Freud-1 mRNA levels were reduced. Overall, CMS and stress during pregnancy produced the most salient changes in 5-HT1A receptor and transcription factor expression, suggesting a primary role for altered transcription factor expression in chronic regulation of 5-HT1A receptor expression. By contrast, OB (in males) and PS (in females) produced gender-specific reductions in PFC 5-HT1A receptor protein levels, suggesting a role for post-transcriptional regulation. These and previous data suggest that chronic stress might be a key regulator of NUDR/Freud-1 gene expression.

Stress-induced alterations in 5-HT1A receptor transcriptional modulators NUDR and Freud-1

PubMed Central

Szewczyk, Bernadeta; Kotarska, Katarzyna; Daigle, Mireille; Misztak, Paulina; Sowa-Kucma, Magdalena; Rafalo, Anna; Curzytek, Katarzyna; Kubera, Marta; Basta-Kaim, Agnieszka; Nowak, Gabriel; Albert, Paul R

2015-01-01

The effect of stress on the mRNA and protein level of the 5-HT1A receptor and two of its key transcriptional modulators, NUDR and Freud-1, was examined in the prefrontal cortex (PFC) and hippocampus (Hp) using rodent models: olfactory bulbectomy (OB) and prenatal stress (PS) in male and female rats; chronic mild stress in male rats (CMS) and pregnancy stress. In PFC, CMS induced the most widespread changes, with significant reduction in both mRNA and protein levels of NUDR, 5-HT1A receptor and in Freud-1 mRNA; while in Hp 5-HT1A receptor and Freud-1 protein levels were also decreased. In male, but not female OB rats PFC Freud-1 and 5-HT1A receptor protein levels were reduced, while in Hp 5-HT1A receptor, Freud-1 and NUDR mRNA’s but not protein were reduced. In PS rats PFC 5-HT1A receptor protein was reduced more in females than males; while in Hp Freud-1 protein was increased in females. In pregnancy stress, PFC NUDR, Freud-1 and 5-HT1A protein receptor levels were reduced, and in HP 5-HT1A receptor protein levels were also reduced; in HP only NUDR and Freud-1 mRNA levels were reduced. Overall, CMS and stress during pregnancy produced the most salient changes in 5-HT1A receptor and transcription factor expression, suggesting a primary role for altered transcription factor expression in chronic regulation of 5-HT1A receptor expression. By contrast, OB (in males) and PS (in females) produced gender-specific reductions in PFC 5-HT1A receptor protein levels, suggesting a role for post-transcriptional regulation. These and previous data suggest that chronic stress might be a key regulator of NUDR/Freud-1 gene expression. PMID:24946016

Effects of chronic sumatriptan and zolmitriptan treatment on 5-HT receptor expression and function in rats.

PubMed

Reuter, U; Salomone, S; Ickenstein, G W; Waeber, C

2004-05-01

Triptans are commonly used anti-migraine drugs and show agonist action mainly at serotonin 5-HT(1B/1D/1F) receptors. It is not known whether frequent or long-term treatment with these drugs would alter 5-HT receptor function. We investigated the effects of protracted (14-18 days) sumatriptan and zolmitriptan treatment in rats on 5-HT(1) receptor mRNA expression and function in tissues related to migraine pathophysiology. RT-PCR analysis revealed that 5-HT(1B/1D/1F) receptor mRNA was reduced in the trigeminal ganglion after treatment with either triptan (reduction by: sumatriptan 39% and zolmitriptan 61% for 5-HT(1B); 60%vs 41% for 5-HT(1D); 32%vs 68% for 5-HT(1F)). Sumatriptan attenuated 5-HT(1D) receptor mRNA by 49% in the basilar artery, whereas zolmitriptan reduced 5-HT(1B) mRNA in this tissue by 70%. No change in 5-HT(1) receptor mRNA expression was observed in coronary artery and dura mater. Chronic triptan treatment had no effect in two functional assays [sumatriptan mediated inhibition (50 mg/kg, i.p.) of electrically induced plasma protein extravasation in dura mater and 5-nonyloxytryptamine-stimulated [(35)S]guanosine-5'-O-(3-thio)triphosphate binding in substantia nigra]. Furthermore, vasoconstriction to 5-HT in isolated basilar artery was not affected by chronic triptan treatment, while it was slightly reduced in coronary artery. We conclude that, although our treatment protocol altered mRNA receptor expression in several tissues relevant to migraine pathophysiology, it did not attenuate 5-HT(1) receptor-dependent functions in rats.

Novel antipsychotic agents with 5-HT(1A) agonist properties: role of 5-HT(1A) receptor activation in attenuation of catalepsy induction in rats.

PubMed

Kleven, Mark S; Barret-Grévoz, Catherine; Bruins Slot, Liesbeth; Newman-Tancredi, Adrian

2005-08-01

Compounds possessing 5-HT(1A) agonist properties attenuate catalepsy induced by D(2) receptor blockade. Here we examined the role of 5-HT(1A) receptor agonism in the reduced cataleptogenic potential of several novel antipsychotic agents in the crossed leg position (CLP) and the bar catalepsy tests in rats. When administered alone, ziprasidone produced marked catalepsy, whereas aripiprazole, bifeprunox, SLV313, SSR181507 and sarizotan did not. However, when 5-HT(1A) receptors were blocked with the selective antagonist, WAY100635 (0.63 mg/kg, SC), robust cataleptogenic properties of SLV313, bifeprunox and sarizotan were unmasked and the catalepsy induced by ziprasidone was accentuated. In contrast, only modest catalepsy was induced by aripiprazole and SSR181507, even following a higher dose of WAY100635 (2.5 mg/kg). This suggests that these compounds possess other anti-cataleptic properties, such as partial agonism at dopamine D(2) receptors. The capacity to reverse neuroleptic-induced catalepsy was investigated in interaction studies with haloperidol (2.5 mg/kg, SC). Whereas ziprasidone and aripiprazole did not markedly reduce the effects of haloperidol, SLV313 and sarizotan attenuated CLP catalepsy. In contrast, SSR181507 and bifeprunox potently inhibited both CLP and bar catalepsy. Taken together, these data show that 5-HT(1A) receptor activation reduces the cataleptogenic potential of novel antipsychotic agents but indicate marked diversity in the contribution of 5-HT(1A) and/or other mechanisms to the profiles of the drugs.

5HT-1A receptors and anxiety-like behaviours: studies in rats with constitutionally upregulated/downregulated serotonin transporter.

PubMed

Bordukalo-Niksic, Tatjana; Mokrovic, Gordana; Stefulj, Jasminka; Zivin, Marko; Jernej, Branimir; Cicin-Sain, Lipa

2010-12-01

Altered activity of brain serotonergic (5HT) system has been implicated in a wide range of behaviours and behavioural disorders, including anxiety. Functioning of 5HT-1A receptor has been suggested as a modulator of emotional balance in both, normal and pathological forms of anxiety. Here, we studied serotonergic modulation of anxiety-like behaviour using a genetic rat model with constitutional differences in 5HT homeostasis, named Wistar-Zagreb 5HT (WZ-5HT) rats. The model, consisting of high-5HT and low-5HT sublines, was developed by selective breeding of animals for extreme activities of peripheral (platelet) 5HT transporter, but selection process had affected also central 5HT homeostasis, as evidenced from neurochemical and behavioural studies. Anxiety-like behaviour in WZ-5HT rats was evaluated by two commonly used paradigms: open field and elevated-plus maze. The involvement of 5HT-1A receptors in behavioural response was assessed by measuring mRNA expression in cell bodies (raphe nuclei) and projection regions (frontal cortex, hippocampus) by use of RT-PCR and in situ hybridization, and by measuring functionality of cortical 5HT-1A receptors by use of [(3)H]8-OH-DPAT radioligand binding. Animals from the high-5HT subline exhibit increased anxiety-like behaviour and decreased exploratory activity when exposed to novel environment. No measurable differences in constitutional (baseline) functionality or expression of 5HT-1A receptors between sublines were found. The results support contribution of increased serotonergic functioning to the anxiety-like behaviour. They also validate the high-5HT subline of WZ-5HT rats as a potential model to study mechanisms of anxiety, especially of its nonpathological form, while the low-5HT subline may be useful to model sensation seeking phenotype. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Analysis of the 5-HT1A receptor involvement in passive avoidance in the rat

PubMed Central

Misane, Ilga; Johansson, Christina; Ove Ögren, Sven

1998-01-01

The effects of the 5-HT2A/2C agonist DOB, the selective 5-HT1A agonist NDO 008 (3-dipropylamino-5-hydroxychroman), and the two enantiomers of the selective 5-HT1A agonist 8-OH-DPAT (R(+)-8-OH-DPAT and S(−)-8-OH-DPAT) were studied in a step-through passive avoidance (PA) test in the male rat.The 5-HT1A agonists injected prior to training (conditioning) produced a dose-dependent impairment of PA retention when examined 24 h later. R(+)-8-OH-DPAT was four times more effective than S(−)-8-OH-DPAT to cause an impairment of PA retention. Both NDO 008 and the two enantiomers of 8-OH-DPAT induced the serotonin syndrome at the dose range that produced inhibition of the PA response, thus, indicating activation of postsynaptic 5-HT1A receptors.Neither NDO 008 nor R(+)-8-OH-DPAT induced head-twitches, a behavioural response attributed to stimulation of postsynaptic 5-HT2A receptors. In contrast, DOB induced head-twitches at the 0.01 mg kg−1 dose while a 200 times higher dose was required to produce a significant impairment of PA retention.The impairment of PA retention induced by both NDO 008 and R(+)-8-OH-DPAT was fully blocked by the active S(+)- enantiomer of the selective 5-HT1A antagonist WAY 100135 and the mixed 5-HT1A/β-adrenoceptor antagonist L(−)-alprenolol. In contrast, the mixed 5-HT2A/2C antagonists ketanserin and pirenperone were found to be ineffective. Moreover, the β2-adrenoceptor antagonist ICI 118551, the β1-antagonist metoprolol as well as the mixed β-adrenoceptor blocker D(+)-alprenolol all failed to modify the deficit of PA retention by NDO 008 and R(+)-8-OH-DPAT. None of the 5-HT1A or 5-HT2A/2C receptor antagonists tested or the β-blockers altered PA retention by themselves.A 3 day pretreatment procedure (200+100+100 mg kg−1) with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) did not alter PA retention and did not prevent the inhibitory action of the 5-HT1A agonists, indicating that their effects on PA do not

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

PubMed

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

2013-02-01

The presence of distinct class of 5-HT receptors in the melanophores of tilapia (Oreochromis mossambicus) is reported. The cellular responses to 5-HT (5-hydroxytryptamine), 5-HT(1), and 5-HT(2), agonists on isolated scale melanophores were observed with regard to pigment translocation within the cells. It was found that 5-HT exerted rapid and strong concentration dependent pigment granule dispersion within the melanophores. The threshold pharmacological dose of 5-HT that could elicit a measurable response was as low as 4.7×10(-12) M/L. Selective 5-HT(1) and 5-HT(2) agonists, sumatriptan and myristicin were investigated and resulted in dose-dependent pigment dispersion. The dispersing effects were effectively antagonized by receptor specific antagonists. It is suggested that 5-HT-induced physiological effects are mediated via distinct classes of receptors that possibly participate in modulation of pigmentary responses of the fish. Copyright © 2012 Elsevier Inc. All rights reserved.

From Chemotherapy-Induced Emesis to Neuroprotection: Therapeutic Opportunities for 5-HT3 Receptor Antagonists.

PubMed

Fakhfouri, Gohar; Mousavizadeh, Kazem; Mehr, Sharam Ejtemaei; Dehpour, Ahmad Reza; Zirak, Mohammad Reza; Ghia, Jean-Eric; Rahimian, Reza

2015-12-01

5-HT3 receptor antagonists are extensively used as efficacious agents in counteracting chemotherapy-induced emesis. Recent investigations have shed light on other potential effects (analgesic, anxiolytic, and anti-psychotic). Some studies have reported neuroprotective properties for the 5-HT3 receptor antagonists in vitro and in vivo. When administered to Aβ-challenged rat cortical neurons, 5-HT3 receptor antagonists substantially abated apoptosis, elevation of cytosolic Ca(2), glutamate release, reactive oxygen species (ROS) generation, and caspase-3 activity. In addition, in vivo studies show that 5-HT3 receptor antagonists possess, alongside their anti-emetic effects, notable immunomodulatory properties in CNS. We found that pretreatment with tropisetron significantly improved neurological deficits and diminished leukocyte transmigration into the brain, TNF-α level, and brain infarction in a murine model of embolic stroke. Our recent investigation revealed that tropisetron protects against Aβ-induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and -independent pathways. Tropisetron, in vitro, was found to be an efficacious inhibitor of the signaling pathway leading to the activation of pro-inflammatory NF-κB, a transcription factor pivotal to the upregulation of several neuroinflammatory mediators in brain. This mini review summarizes novel evidence concerning effects of 5-HT3 antagonists and their possible mechanisms of action in ameliorating neurodegenerative diseases including Alzheimer, multiple sclerosis, and stroke. Further, we discuss some newly synthesized 5-HT3 receptor antagonists with dual properties of 5-HT3 receptor blockade/alpha-7 nicotinic receptor activator and their potential in management of memory impairment. Since 5-HT3 receptor antagonists possess a large therapeutic window, they can constitute a scaffold for design and synthesis of new neuroprotective medications.

Characterization of prejunctional 5-HT receptors mediating inhibition of sympathetic vasopressor responses in the pithed rat.

PubMed Central

Villalón, C. M.; Contreras, J.; Ramírez-San Juan, E.; Castillo, C.; Perusquía, M.; Terrón, J. A.

1995-01-01

1. It has recently been shown that continuous infusions of 5-hydroxytryptamine (5-HT) are able to inhibit, in a dose-dependent manner, the pressor responses induced by preganglionic (T7-T9) sympathetic stimulation in pithed rats pretreated with desipramine (50 micrograms kg-1, i.v.). This inhibitory effect, besides being significantly more pronounced at lower frequencies of stimulation (0.03-I Hz) and devoid of tachyphylaxis, is reversible after interrupting the infusions of 5-HT (up to 5.6 micrograms kg-1 min-1). In the present study we have characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5-HT. 2. The inhibition induced by 5.6 micrograms kg-1 min-1 of 5-HT on sympathetically-induced pressor responses was not blocked after i.v. treatment with physiological saline (1 ml kg-1), ritanserin (0.1 mg kg-1), MDL 72222 (0.15 mg kg-1) or tropisetron (3 mg kg-1), which did not modify the sympathetically-induced pressor responses per se, but was significantly antagonized by the 5-HT1-like and 5-HT2 receptor antagonist, methysergide (0.3 mg kg-1), which also produced a slight attenuation of the pressor responses to 0.03 and 0.1 Hz per se. 3. Unexpectedly and contrasting with methysergide, the 5-HT1-like and 5-HT2 receptor antagonists, methiothepin (0.01, 0.03 and 0.1 mg kg-1) and metergoline (1 and 3 mg kg-1), apparently failed to block the above 5-HT-induced inhibition. Nevertheless, it is noteworthy that these antagonists also blocked the electrically-induced pressor responses per se, presumably by blockade of vascular alpha 1-adrenoceptors and, indeed, this property might have masked their potential antagonism at the inhibitory 5-HT1-like receptors. 4. Consistent with the above findings, 5-carboxamidotryptamine (5-CT, a potent 5-HT1-like receptor agonist), metergoline and methysergide mimicked the inhibitory action of 5-HT with the following rank order of agonist potency: 5CT > > 5-HT > metergoline > or = methysergide. 5

5-HT7 receptor activation: procognitive and antiamnesic effects.

PubMed

Meneses, A; Perez-Garcia, G; Liy-Salmeron, G; Ponce-López, T; Lacivita, E; Leopoldo, M

2015-02-01

The serotonin (5-hydroxytryptamine (5-HT)) 5-HT7 receptor is localized in brain areas mediating memory; however, the role of this receptor on memory remains little explored. First, demonstrating the associative nature of Pavlovian/instrumental autoshaping (P/I-A) task, rats were exposed (three sessions) to CS-US (Pavlovian autoshaping), truly random control, free operant, and presentations of US or CS, and they were compared with rats trained-tested for one session to the P/I-A procedure. Also, effects of the 5-HT7 receptor agonist LP-211 administered intraperitoneally after training was determined on short- (1.5 h) and long-term memory 24 and 48 h) and on scopolamine-induced memory impairment and cAMP production. Autoshaping and its behavioral controls were studied. Other animals were subjected to an autoshaping training session and immediately afterwards were given (intraperitoneal) vehicle or LP-211 (0.1-10 mg/kg) and/or scopolamine (0.2 mg/kg) and tested for short-term memory (STM) and long-term memory (LTM); their brains were extracted for the cAMP ELISA immunoassay. P/I-A group produced the higher %CR. LP-211 did not affect STM; nonetheless, at 0.5 and 1.0 mg/kg, it improved LTM. The 5-HT7 receptor antagonist SB-269970 (SB; 10.0 mg/kg) alone had no effect; nevertheless, the LP-211 (1.0 mg/kg) LTM facilitation was reversed by SB. The scopolamine (0.2 mg/kg) induced-decrement in CR was accompanied by significant increased cAMP production. The scopolamine-induced decrement in CR and increments in cAMP were significantly attenuated by LP-211. Autoshaping is a reliable associative learning task whose consolidation is facilitated by the 5-HT7 receptor agonist LP-211.

Peripheral 5-HT3 Receptors Are Involved in the Antinociceptive Effect of Bunodosine 391

PubMed Central

Ferreira Junior, Wilson Alves; Zaharenko, Andre Junqueira; Kazuma, Kohei; Picolo, Gisele; Gutierrez, Vanessa Pacciari; de Freitas, Jose Carlos; Konno, Katsuhiro

2017-01-01

Bunodosine 391 (BDS 391), a low molecular weight compound isolated from the sea anemone Bunodosoma cangicum, increases the nociceptive threshold and inhibits inflammatory hyperalgesia. Serotonin receptors are involved in those effects. In this study, we have expanded the characterization of the antinociceptive effect of BDS 391 demonstrating that, in rats: (a) the compound inhibits (1.2–12 ng/paw) overt pain, in the formalin test, and mechanical hyperalgesia (0.6–6.0 ng/paw) detected in a model of neuropathic pain; (b) intraplantar administration of ondansetron, a selective 5-HT3 receptor antagonist, blocks the effect of BDS 391, whereas ketanserin, a 5-HT2 receptor antagonist, partially reversed this effect, indicating the involvement of peripheral 5-HT2 and 5-HT3 receptors in BDS 391 antinociception; and (c) in binding assay studies, BDS 391 was not able to displace the selective 5-HT receptor antagonists, suggesting that this compound does not directly bind to these receptors. The effect of biguanide, a selective 5-HT3 receptor agonist, was also evaluated. The agonist inhibited the formalin’s nociceptive response, supporting an antinociceptive role for 5-HT3 receptors. Our study is the first one to show that a non-peptidic low molecular weight compound obtained from a sea anemone is able to induce antinociception and that activation of peripheral 5-HT3 receptors contributes to this effect. PMID:29280949

Effects of Acute MDMA Intoxication on Mood and Impulsivity: Role of the 5-HT2 and 5-HT1 Receptors

PubMed Central

van Wel, Janelle H. P.; Kuypers, Kim P. C.; Theunissen, Eef L.; Bosker, Wendy M.; Bakker, Katja; Ramaekers, Johannes G.

2012-01-01

MDMA induces positive mood and increases impulse control during intoxication, but only a few studies on the neuropharmacological mechanisms underlying these processes have been conducted. It was hypothesized that pretreatment with 5-HT1 and 5-HT2 receptor blockers would prevent MDMA effects on mood and impulsivity. Subjects (N = 17) participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. T1–T2 combinations were: placebo-placebo, 20 mg pindolol-placebo, 50 mg ketanserin-placebo, placebo-75 mg MDMA, 20 mg pindolol-75 mg MDMA and 50 mg ketanserin-75 g MDMA. Subjects completed a Profile of Mood States (POMS) questionnaire and several impulsivity tasks (Stop signal task, Matching familiar figures task, Cue dependent reversal learning task) at 1.5 hrs post-treatment. MDMA alone increased both positive (vigor, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. MDMA also increased stop reaction time in the Stop signal task and reaction time in the Matching familiar figures task. Pretreatment with ketanserin blocked MDMA effects on positive affect, but not negative affect. Ketanserin did not influence the effects of MDMA on impulsivity. Pindolol did not interact with MDMA on any of the measures. In conclusion, 5-HT2 receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. 5-HT1 receptors do not appear to be involved in MDMA effects on mood and impulse control. Trial Registration Nederlands Trial Register NTR2352 PMID:22808116

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

PubMed Central

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

2010-01-01

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. PMID:20233210

Potentiation of 5-methoxy-N,N-dimethyltryptamine-induced hyperthermia by harmaline and the involvement of activation of 5-HT1A and 5-HT2A receptors.

PubMed

Jiang, Xi-Ling; Shen, Hong-Wu; Yu, Ai-Ming

2015-02-01

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are serotonin (5-HT) analogs often abused together, which alters thermoregulation that may indicate the severity of serotonin toxicity. Our recent studies have revealed that co-administration of monoamine oxidase inhibitor harmaline leads to greater and prolonged exposure to 5-HT agonist 5-MeO-DMT that might be influenced by cytochrome P450 2D6 (CYP2D6) status. This study was to define the effects of harmaline and 5-MeO-DMT on thermoregulation in wild-type and CYP2D6-humanized (Tg-CYP2D6) mice, as well as the involvement of 5-HT receptors. Animal core body temperatures were monitored noninvasively in the home cages after implantation of telemetry transmitters and administration of drugs. Harmaline (5 and 15 mg/kg, i.p.) alone was shown to induce hypothermia that was significantly affected by CYP2D6 status. In contrast, higher doses of 5-MeO-DMT (10 and 20 mg/kg) alone caused hyperthermia. Co-administration of harmaline (2, 5 or 15 mg/kg) remarkably potentiated the hyperthermia elicited by 5-MeO-DMT (2 or 10 mg/kg), which might be influenced by CYP2D6 status at certain dose combination. Interestingly, harmaline-induced hypothermia was only attenuated by 5-HT1A receptor antagonist WAY-100635, whereas 5-MeO-DMT- and harmaline-5-MeO-DMT-induced hyperthermia could be suppressed by either WAY-100635 or 5-HT2A receptor antagonists (MDL-100907 and ketanserin). Moreover, stress-induced hyperthermia under home cage conditions was not affected by WAY-100635 but surprisingly attenuated by MDL-100907 and ketanserin. Our results indicate that co-administration of monoamine oxidase inhibitor largely potentiates 5-MeO-DMT-induced hyperthermia that involves the activation of both 5-HT1A and 5-HT2A receptors. These findings shall provide insights into development of anxiolytic drugs and new strategies to relieve the lethal hyperthermia in serotonin toxicity.

Potentiation of 5-methoxy-N,N-dimethyltryptamine-induced hyperthermia by harmaline and the involvement of activation of 5-HT1A and 5-HT2A receptors

PubMed Central

Jiang, Xi-Ling; Shen, Hong-Wu; Yu, Ai-Ming

2014-01-01

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are serotonin (5-HT) analogs often abused together, which alters thermoregulation that may indicate the severity of serotonin toxicity. Our recent studies have revealed that co-administration of monoamine oxidase inhibitor harmaline leads to greater and prolonged exposure to 5-HT agonist 5-MeO-DMT that might be influenced by cytochrome P450 2D6 (CYP2D6) status. This study was to define the effects of harmaline and 5-MeO-DMT on thermoregulation in wild-type and CYP2D6-humanized (Tg-CYP2D6) mice, as well as the involvement of 5-HT receptors. Animal core body temperatures were monitored noninvasively in the home cages after implantation of telemetry transmitters and administration of drugs. Harmaline (5 and 15 mg/kg, i.p.) alone was shown to induce hypothermia that was significantly affected by CYP2D6 status. In contrast, higher doses of 5-MeO-DMT (10 and 20 mg/kg) alone caused hyperthermia. Co-administration of harmaline (2, 5 or 15 mg/kg) remarkably potentiated the hyperthermia elicited by 5-MeO-DMT (2 or 10 mg/kg), which might be influenced by CYP2D6 status at certain dose combination. Interestingly, harmaline-induced hypothermia was only attenuated by 5-HT1A receptor antagonist WAY-100635, whereas 5-MeO-DMT- and harmaline-5-MeO-DMT-induced hyperthermia could be suppressed by either WAY-100635 or 5-HT2A receptor antagonists (MDL-100907 and ketanserin). Moreover, stress-induced hyperthermia under home cage conditions was not affected by WAY-100635 but surprisingly attenuated by MDL-100907 and ketanserin. Our results indicate that co-administration of monoamine oxidase inhibitor largely potentiates 5-MeO-DMT-induced hyperthermia that involves the activation of both 5-HT1A and 5-HT2A receptors. These findings shall provide insights into development of anxiolytic drugs and new strategies to relieve the lethal hyperthermia in serotonin toxicity. PMID:25446678

Dm5-HT2B: Pharmacological Characterization of the Fifth Serotonin Receptor Subtype of Drosophila melanogaster.

PubMed

Blenau, Wolfgang; Daniel, Stöppler; Balfanz, Sabine; Thamm, Markus; Baumann, Arnd

2017-01-01

Serotonin (5-hydroxytryptamine, 5-HT) is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects) and deuterostomes (e.g., mammals). In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster , a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT 1A , Dm5-HT 1B , and Dm5-HT 7 couple to cAMP signaling cascades, the Dm5-HT 2A receptor leads to Ca 2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT 2B receptor. Knowledge about this receptor's pharmacological properties is very limited. This is quite surprising because Dm5-HT 2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT 2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT 2B 's pharmacology, we evaluated the receptor's response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT 2B signaling in vitro and in vivo .

Dm5-HT2B: Pharmacological Characterization of the Fifth Serotonin Receptor Subtype of Drosophila melanogaster

PubMed Central

Blenau, Wolfgang; Daniel, Stöppler; Balfanz, Sabine; Thamm, Markus; Baumann, Arnd

2017-01-01

Serotonin (5-hydroxytryptamine, 5-HT) is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects) and deuterostomes (e.g., mammals). In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster, a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT1A, Dm5-HT1B, and Dm5-HT7 couple to cAMP signaling cascades, the Dm5-HT2A receptor leads to Ca2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT2B receptor. Knowledge about this receptor’s pharmacological properties is very limited. This is quite surprising because Dm5-HT2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT2B’s pharmacology, we evaluated the receptor’s response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT2B signaling in vitro and in vivo. PMID:28553207

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

NASA Astrophysics Data System (ADS)

Ivachtchenko, A. V.

2014-05-01

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

Investigations into the binding affinities of different human 5-HT4 receptor splice variants.

PubMed

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

2010-01-01

This study examined whether the drug-receptor-binding sites of 5 selected human 5-HT(4) receptor splice variants [h5-HT4(a), h5-HT4(b), h5-HT4(c), h5-HT4(d) and h5-HT4(g)] display preferential affinities towards agonists. The agonists selected on the basis of chemical diversity and clinical relevance were: 5-HT4 benzamides, renzapride, zacopride and prucalopride; the benzimidazolones, DAU 6236 and BIMU 1; the aromatic ketone, RS67333, and the indole carbazimidamide tegaserod. The rank order of affinities ranging across the splice variants was: tegaserod (pKi: 7.38-7.91) > or = Y-36912 (pKi: 7.03-7.85) = BIMU 1 (pKi: 6.92-7.78) > or = DAU 6236 (pKi: 6.79-7.99) > or = 5-HT (pKi: 5.82-7.29) > or = 5-MeOT (pKi: 5.64-6.83) > or = renzapride (pKi: 4.85-5.56). We obtained affinity values for the 5-HT4(b), (d) and (g) variants for RS67333 (pKi: 7:48-8.29), prucalopride (pKi: 6.86-7.37) and zacopride (pKi: 5.88-7.0). These results indicate that the ligands interact with the same conserved site in each splice variant. Some splice variants have a higher affinity for certain agonists and the direction of selectivity followed a common trend of lowest affinity at the (d) variant. However, this trend was not evident in functional experiments. Our findings suggest that it may be possible to design splice variant selective ligands, which may be of relevance for experimental drugs but may be difficult to develop clinically. 2010 S. Karger AG, Basel.

Hallucinogen-like effects of N,N-dipropyltryptamine (DPT): possible mediation by serotonin 5-HT1A and 5-HT2A receptors in rodents

PubMed Central

Fantegrossi, William E.; Reissig, Chad J.; Katz, Elyse B.; Yarosh, Haley L.; Rice, Kenner C.; Winter, Jerrold C.

2008-01-01

N,N-dipropyltryptamine (DPT) is a synthetic tryptamine hallucinogen which has been used psychotherapeutically in humans, but has been studied preclinically only rarely. In the present studies, DPT was tested in a drug-elicited head twitch assay in mice, and in rats trained to discriminate lysergic acid diethylamide (LSD), N,N-dimethyl-4-phosphoryloxytryptamine (psilocybin), or 3,4-methylenedioxymethamphetamine (MDMA). A separate group of rats was also trained to recognize DPT itself as a discriminative stimulus, and in all cases, the behavioral effects of DPT were challenged with the selective serotonin (5-HT)2A antagonist M100907, the 5-HT1A selective antagonist WAY-100635, or their combination. In the head twitch assay, DPT elicited dose-dependent effects, producing a biphasic dose-effect curve. WAY-100635 produced a parallel rightward shift in the dose-effect curve for head twitches, indicative of surmountable antagonism, but the antagonist effects of M100907 were functionally insurmountable. DPT produced partial to full substitution when tested in rats trained to discriminate LSD, psilocybin or MDMA, and served as a discriminative stimulus. In all cases, the antagonist effects of M100907 were more profound than were those of WAY-100635. DPT is thus active in two rodent models relevant to 5-HT2 agonist activity. The effectiveness with which M100907 antagonizes the behavioral actions of this compound strongly suggests that the 5-HT2A receptor is an important site of action for DPT, but the modulatory actions of WAY-100635 also imply a 5-HT1A-mediated component to the actions of this compound. PMID:17905422

Preclinical and clinical characterization of the selective 5-HT(1A) receptor antagonist DU-125530 for antidepressant treatment.

PubMed

Scorza, M C; Lladó-Pelfort, L; Oller, S; Cortés, R; Puigdemont, D; Portella, M J; Pérez-Egea, R; Alvarez, E; Celada, P; Pérez, V; Artigas, F

2012-11-01

The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective. We characterized the pharmacological properties of the 5-HT(1A) receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430). DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function. © 2011 The Authors. British Journal of

5-HT2C Receptor Desensitization Moderates Anxiety in 5-HTT Deficient Mice: From Behavioral to Cellular Evidence

PubMed Central

Martin, Cédric BP; Martin, Vincent S.; Trigo, José M.; Chevarin, Caroline; Maldonado, Rafael; Fink, Latham H.; Cunningham, Kathryn A.; Hamon, Michel; Lanfumey, Laurence

2015-01-01

Background: Desensitization and blockade of 5-HT2C receptors (5-HT2CR) have long been thought to be central in the therapeutic action of antidepressant drugs. However, besides behavioral pharmacology studies, there is little in vivo data documenting antidepressant-induced 5-HT2CR desensitization in specific brain areas. Methods: Mice lacking the 5-HT reuptake carrier (5-HTT-/-) were used to model the consequences of chronic 5-HT reuptake inhibition with antidepressant drugs. The effect of this mutation on 5-HT2CR was evaluated at the behavioral (social interaction, novelty-suppressed feeding, and 5-HT2CR–induced hypolocomotion tests), the neurochemical, and the cellular (RT-qPCR, mRNA editing, and c-fos–induced expression) levels. Results: Although 5-HTT-/- mice had an anxiogenic profile in the novelty-suppressed feeding test, they displayed less 5-HT2CR–mediated anxiety in response to the agonist m-chlorophenylpiperazine in the social interaction test. In addition, 5-HT2CR–mediated inhibition of a stress-induced increase in 5-HT turnover, measured in various brain areas, was markedly reduced in 5-HTT-/- mutants. These indices of tolerance to 5-HT2CR stimulation were associated neither with altered levels of 5-HT2CR protein and mRNA nor with changes in pre-mRNA editing in the frontal cortex. However, basal c-fos mRNA production in cells expressing 5-HT2CR was higher in 5-HTT-/- mutants, suggesting an altered basal activity of these cells following sustained 5-HT reuptake carrier inactivation. Furthermore, the increased c-fos mRNA expression in 5-HT2CR–like immune-positive cortical cells observed in wild-type mice treated acutely with the 5-HT2CR agonist RO-60,0175 was absent in 5-HTT-/- mutants. Conclusions: Such blunted responsiveness of the 5-HT2CR system, observed at the cell signaling level, probably contributes to the moderation of the anxiety phenotype in 5-HTT-/- mice. PMID:25522398

The role of 5 HT6-receptor antagonists in Alzheimer's disease: an update.

PubMed

Khoury, Rita; Grysman, Noam; Gold, Jake; Patel, Kush; Grossberg, George T

2018-06-01

Despite recent advances in Alzheimer's disease (AD) research, no breakthrough treatments have been discovered. Cholinesterase inhibitors and the NMDA-receptor antagonist memantine are currently the two approved symptomatic treatments for AD. 5-HT6 receptor antagonism has recently emerged as a promising treatment strategy to improve cognition in AD, with a modest side-effect profile. Areas covered: 5-HT6 receptors, exclusively found in the central nervous system, modulate primarily GABA and glutamate levels, facilitating the secondary release of other neurotransmitters including dopamine, noradrenaline, and acetylcholine, all of which are compromised in AD. This review discusses findings of preclinical and phase I-III clinical trials conducted with three major 5-HT6 receptor antagonists: idalopirdine, intepirdine, and SUVN-502, in the field of AD. Expert opinion: Despite early positive findings, larger phase-III trials have failed to demonstrate any statistically significant impact on cognition for both idalopirdine and intepirdine, as adjunct to cholinesterase inhibitors. Paradoxically, 5-HT6 receptor agonists have also been shown to have cognitive enhancing properties. Thus, a better understanding of the mechanism of action of the 5-HT6 receptor and its ligands is warranted. Investigating 5-HT6 receptor partial or inverse agonists may be promising in future AD trials.

Fabrication of a P3HT-ZnO Nanowires Gas Sensor Detecting Ammonia Gas

PubMed Central

Kuo, Chin-Guo; Chen, Jung-Hsuan; Chao, Yi-Chieh; Chen, Po-Lin

2017-01-01

In this study, an organic-inorganic semiconductor gas sensor was fabricated to detect ammonia gas. An inorganic semiconductor was a zinc oxide (ZnO) nanowire array produced by atomic layer deposition (ALD) while an organic material was a p-type semiconductor, poly(3-hexylthiophene) (P3HT). P3HT was suitable for the gas sensing application due to its high hole mobility, good stability, and good electrical conductivity. In this work, P3HT was coated on the zinc oxide nanowires by the spin coating to form an organic-inorganic heterogeneous interface of the gas sensor for detecting ammonia gas. The thicknesses of the P3HT were around 462 nm, 397 nm, and 277 nm when the speeds of the spin coating were 4000 rpm, 5000 rpm, and 6000 rpm, respectively. The electrical properties and sensing characteristics of the gas sensing device at room temperature were evaluated by Hall effect measurement and the sensitivity of detecting ammonia gas. The results of Hall effect measurement for the P3HT-ZnO nanowires semiconductor with 462 nm P3HT film showed that the carrier concentration and the mobility were 2.7 × 1019 cm−3 and 24.7 cm2∙V−1∙s−1 respectively. The gas sensing device prepared by the P3HT-ZnO nanowires semiconductor had better sensitivity than the device composed of the ZnO film and P3HT film. Additionally, this gas sensing device could reach a maximum sensitivity around 11.58 per ppm. PMID:29295573

Fabrication of a P3HT-ZnO Nanowires Gas Sensor Detecting Ammonia Gas.

PubMed

Kuo, Chin-Guo; Chen, Jung-Hsuan; Chao, Yi-Chieh; Chen, Po-Lin

2017-12-25

In this study, an organic-inorganic semiconductor gas sensor was fabricated to detect ammonia gas. An inorganic semiconductor was a zinc oxide (ZnO) nanowire array produced by atomic layer deposition (ALD) while an organic material was a p-type semiconductor, poly(3-hexylthiophene) (P3HT). P3HT was suitable for the gas sensing application due to its high hole mobility, good stability, and good electrical conductivity. In this work, P3HT was coated on the zinc oxide nanowires by the spin coating to form an organic-inorganic heterogeneous interface of the gas sensor for detecting ammonia gas. The thicknesses of the P3HT were around 462 nm, 397 nm, and 277 nm when the speeds of the spin coating were 4000 rpm, 5000 rpm, and 6000 rpm, respectively. The electrical properties and sensing characteristics of the gas sensing device at room temperature were evaluated by Hall effect measurement and the sensitivity of detecting ammonia gas. The results of Hall effect measurement for the P3HT-ZnO nanowires semiconductor with 462 nm P3HT film showed that the carrier concentration and the mobility were 2.7 × 10 19 cm -3 and 24.7 cm²∙V -1 ∙s -1 respectively. The gas sensing device prepared by the P3HT-ZnO nanowires semiconductor had better sensitivity than the device composed of the ZnO film and P3HT film. Additionally, this gas sensing device could reach a maximum sensitivity around 11.58 per ppm.

Novel selective and potent 5-HT reuptake inhibitors with 5-HT1D antagonist activity: chemistry and pharmacological evaluation of a series of thienopyran derivatives.

PubMed

Torrado, Alicia; Lamas, Carlos; Agejas, Javier; Jiménez, Alma; Diaz, Nuria; Gilmore, Jeremy; Boot, John; Findlay, Jeremy; Hayhurst, Lorna; Wallace, Louise; Broadmore, Richard; Tomlinson, Rosemarie

2004-10-15

A series of compounds combining the naphthylpiperazine and thienopyran scaffolds has been prepared and evaluated for 5-HT reuptake inhibition with 5-HT1D antagonist activity. The design of these compounds has been based on the 'overlapping type' strategy where two pharmacophores are linked in a single molecule. The resultant dual pharmacological profile has the potential to deliver a more efficient treatment for depression.

The serotonin hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT1A and 5-HT2A receptors.

PubMed

Riga, Maurizio S; Lladó-Pelfort, Laia; Artigas, Francesc; Celada, Pau

2017-12-06

5-MeO-DMT is a natural hallucinogen acting as serotonin 5-HT 1A /5-HT 2A receptor agonist. Its ability to evoke hallucinations could be used to study the neurobiology of psychotic symptoms and to identify new treatment targets. Moreover, recent studies revealed the therapeutic potential of serotonin hallucinogens in treating mood and anxiety disorders. Our previous results in anesthetized animals show that 5-MeO-DMT alters cortical activity via 5-HT 1A and 5-HT 2A receptors. Here, we examined 5-MeO-DMT effects on oscillatory activity in prefrontal (PFC) and visual (V1) cortices, and in mediodorsal thalamus (MD) of freely-moving wild-type (WT) and 5-HT 2A -R knockout (KO2A) mice. We performed local field potential multi-recordings evaluating the power at different frequency bands and coherence between areas. We also examined the prevention of 5-MeO-DMT effects by the 5-HT 1A -R antagonist WAY-100635. 5-MeO-DMT affected oscillatory activity more in cortical than in thalamic areas. More marked effects were observed in delta power in V1 of KO2A mice. 5-MeO-DMT increased beta band coherence between all examined areas. In KO2A mice, WAY100635 prevented most of 5-MeO-DMT effects on oscillatory activity. The present results indicate that hallucinatory activity of 5-MeO-DMT is likely mediated by simultaneous alteration of prefrontal and visual activities. The prevention of these effects by WAY-100635 in KO2A mice supports the potential usefulness of 5-HT 1A receptor antagonists to treat visual hallucinations. 5-MeO-DMT effects on PFC theta activity and cortico-thalamic coherence may be related to its antidepressant activity. Copyright © 2017. Published by Elsevier Ltd.

Impact de la preparation des anodes crues et des conditions de cuisson sur la fissuration dans des anodes denses

NASA Astrophysics Data System (ADS)

Amrani, Salah

La fabrication de l'aluminium est realisee dans une cellule d'electrolyse, et cette operation utilise des anodes en carbone. L'evaluation de la qualite de ces anodes reste indispensable avant leur utilisation. La presence des fissures dans les anodes provoque une perturbation du procede l'electrolyse et une diminution de sa performance. Ce projet a ete entrepris pour determiner l'impact des differents parametres de procedes de fabrication des anodes sur la fissuration des anodes denses. Ces parametres incluent ceux de la fabrication des anodes crues, des proprietes des matieres premieres et de la cuisson. Une recherche bibliographique a ete effectuee sur tous les aspects de la fissuration des anodes en carbone pour compiler les travaux anterieurs. Une methodologie detaillee a ete mise au point pour faciliter le deroulement des travaux et atteindre les objectifs vises. La majorite de ce document est reservee pour la discussion des resultats obtenus au laboratoire de l'UQAC et au niveau industriel. Concernant les etudes realisees a l'UQAC, une partie des travaux experimentaux est reservee a la recherche des differents mecanismes de fissuration dans les anodes denses utilisees dans l'industrie d'aluminium. L'approche etait d'abord basee sur la caracterisation qualitative du mecanisme de la fissuration en surface et en profondeur. Puis, une caracterisation quantitative a ete realisee pour la determination de la distribution de la largeur de la fissure sur toute sa longueur, ainsi que le pourcentage de sa surface par rapport a la surface totale de l'echantillon. Cette etude a ete realisee par le biais de la technique d'analyse d'image utilisee pour caracteriser la fissuration d'un echantillon d'anode cuite. L'analyse surfacique et en profondeur de cet echantillon a permis de voir clairement la formation des fissures sur une grande partie de la surface analysee. L'autre partie des travaux est basee sur la caracterisation des defauts dans des echantillons d'anodes crues

Time-course of 5-HT(6) receptor mRNA expression during memory consolidation and amnesia.

PubMed

Huerta-Rivas, A; Pérez-García, G; González-Espinosa, C; Meneses, A

2010-01-01

Growing evidence indicates that antagonists of the 5-hydroxytryptamine (serotonin) receptor(6) (5-HT(6)) improve memory and reverse amnesia although the mechanisms involved are poorly understood. Hence, in this paper RT-PCR was used to evaluate changes in mRNA expression of 5-HT(6) receptor in trained and untrained rats treated with the 5-HT(6) receptor antagonist SB-399885 and amnesic drugs scopolamine or dizocilpine. Changes in mRNA expression of 5-HT(6) receptor were investigated at different times in prefrontal cortex, hippocampus and striatum. Data indicated that memory in the Pavlovian/instrumental autoshaping task was a progressive process associated to reduced mRNA expression of 5-HT(6) receptor in the three structures examined. SB-399885 improved long-term memory at 48h, while the muscarinic receptor antagonist scopolamine or the non-competitive NMDA receptor antagonist dizocilpine impaired it at 24h. Autoshaping training and treatment with SB-399885 increased 5-HT(6) receptor mRNA expression in (maximum increase) prefrontal cortex and striatum, 24 or 48h. The scopolamine-induced amnesia suppressed 5-HT(6) receptor mRNA expression while the dizocilpine-induced amnesia did not modify 5-HT(6) receptor mRNA expression. SB-399885 and scopolamine or dizocilpine were able to reestablish memory and 5-HT(6) receptor mRNA expression. These data confirmed previous memory evidence and of more interest is the observation that training, SB-399885 and amnesic drugs modulated 5-HT(6) receptor mRNA expression in prefrontal cortex, hippocampus and striatum. Further investigation in different memory tasks, times and amnesia models together with more complex control groups might provide further clues. Copyright 2009 Elsevier Inc. All rights reserved.

Human-derived gut microbiota modulates colonic secretion in mice by regulating 5-HT3 receptor expression via acetate production.

PubMed

Bhattarai, Yogesh; Schmidt, Bradley A; Linden, David R; Larson, Eric D; Grover, Madhusudan; Beyder, Arthur; Farrugia, Gianrico; Kashyap, Purna C

2017-07-01

Serotonin [5-hydroxytryptamine (5-HT)], an important neurotransmitter and a paracrine messenger in the gastrointestinal tract, regulates intestinal secretion by its action primarily on 5-HT 3 and 5-HT 4 receptors. Recent studies highlight the role of gut microbiota in 5-HT biosynthesis. In this study, we determine whether human-derived gut microbiota affects host secretory response to 5-HT and 5-HT receptor expression. We used proximal colonic mucosa-submucosa preparation from age-matched Swiss Webster germ-free (GF) and humanized (HM; ex-GF colonized with human gut microbiota) mice. 5-HT evoked a significantly greater increase in short-circuit current (Δ I sc ) in GF compared with HM mice. Additionally, 5-HT 3 receptor mRNA and protein expression was significantly higher in GF compared with HM mice. Ondansetron, a 5-HT 3 receptor antagonist, inhibited 5-HT-evoked Δ I sc in GF mice but not in HM mice. Furthermore, a 5-HT 3 receptor-selective agonist, 2-methyl-5-hydroxytryptamine hydrochloride, evoked a significantly higher Δ I sc in GF compared with HM mice. Immunohistochemistry in 5-HT 3A -green fluorescent protein mice localized 5-HT 3 receptor expression to enterochromaffin cells in addition to nerve fibers. The significant difference in 5-HT-evoked Δ I sc between GF and HM mice persisted in the presence of tetrodotoxin (TTX) but was lost after ondansetron application in the presence of TTX. Application of acetate (10 mM) significantly lowered 5-HT 3 receptor mRNA in GF mouse colonoids. We conclude that host secretory response to 5-HT may be modulated by gut microbiota regulation of 5-HT 3 receptor expression via acetate production. Epithelial 5-HT 3 receptor may function as a mediator of gut microbiota-driven change in intestinal secretion. NEW & NOTEWORTHY We found that gut microbiota alters serotonin (5-HT)-evoked intestinal secretion in a 5-HT 3 receptor-dependent mechanism and gut microbiota metabolite acetate alters 5-HT 3 receptor expression in

The 5-HT7 receptor in learning and memory. Importance of the hippocampus

PubMed Central

Roberts, Amanda J.; Hedlund, Peter B.

2011-01-01

The 5-HT7 receptor is a more recently discovered G-protein-coupled receptor for serotonin. The functions and possible clinical relevance of this receptor are not yet fully understood. The present paper reviews to what extent the use of animal models of learning and memory and other techniques have implicated the 5-HT7 receptor in such processes. The studies have used a combination of pharmacological and genetic tools targeting the receptor to evaluate effects on behavior and cellular mechanisms. In tests such as the Barnes maze, contextual fear conditioning and novel location recognition that involve spatial learning and memory there is a considerable amount of evidence supporting an involvement of the 5-HT7 receptor. Supporting evidence has also been obtained in studies of mRNA expression and cellular signaling as well as in electrophysiological experiments. Especially interesting are the subtle but distinct effects observed in hippocampus-dependent models of place learning where impairments have been described in mice lacking the 5-HT7 receptor or after administration of a selective antagonist. While more work is required, it appears that 5-HT7 receptors are particularly important in allocentric representation processes. In instrumental learning tasks both procognitive effects and impairments in memory have been observed using pharmacological tools targeting the 5-HT7 receptor. In conclusion, the use of pharmacological and genetic tools in animal studies of learning and memory suggest a potentially important role for the 5-HT7 receptor in cognitive processes. PMID:21484935

Effects of the potential 5-HT7 receptor agonist AS 19 in an autoshaping learning task.

PubMed

Perez-García, Georgina S; Meneses, A

2005-08-30

This work aimed to evaluate further the role of 5-HT7 receptors during memory formation in an autoshaping Pavlovian/instrumental learning task. Post-training administration of the potential 5-HT7 receptor agonist AS 19 or antagonist SB-269970 enhanced memory formation or had no effect, respectively. The AS 19 facilitatory effect was reversed by SB-269970, but not by the selective 5-HT1A antagonist WAY100635. Amnesia induced by scopolamine (cholinergic antagonist) or dizocilpine (NMDA antagonist) was also reversed by AS 19. Certainly, reservations regarding the selectivity of AS 19 for 5-HT7 and other 5-HT receptors in vivo are noteworthy and, therefore, its validity for use in animal models as a pharmacological tool. Having mentioned that, it should be noticed that together these data are providing further support to the notion of the 5-HT7 receptors role in memory formation. Importantly, this 5-HT7 receptor agonist AS 19 appears to represent a step forward respect to the notion that potent and selective 5-HT7 receptor agonists can be useful in the treatment of dysfunctional memory in aged-related decline and Alzheimer's disease.

New-generation 5-HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders.

PubMed

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

2010-06-01

Gastrointestinal (GI) dysmotility is an important mechanism in functional GI disorders (FGIDs) including constipation, irritable bowel syndrome, functional dyspepsia, and gastroparesis. 5-hydroxytryptamine(4) (5-HT(4)) receptors are targets for the treatment of GI motility disorders. However, older 5-HT(4) receptor agonists had limited clinical success because they were associated with changes in the function of the cardiac HERG potassium channel. We conducted a PubMed search using the following key words alone or in combination: 5-HT(4), safety, toxicity, pharmacokinetics, pharmacodynamics, clinical trial, cardiac, hERG, arrhythmia, potassium current, elderly, prucalopride, ATI-7505, and velusetrag (TD-5108), to review mechanisms of action, clinical efficacy, safety and tolerability of three new-generation 5-HT(4) receptor agonists. Prucalopride, ATI-7505, and velusetrag (TD-5108) are highly selective, high-affinity 5-HT(4) receptor agonists that are devoid of action on other receptors within their therapeutic range. Their efficacy has been demonstrated in pharmacodynamic studies which demonstrate acceleration of colonic transit and, to a variable degree, in clinical trials that significantly relieve chronic constipation. Currently available evidence shows that the new 5-HT(4) receptor agonists have safe cardiac profiles. New-generation 5-HT(4) receptor agonists and future drugs targeting organ-specific splice variants are promising approaches to treat GI dysmotility, particularly colonic diseases.

Effects of 5-HT and insulin on learning and memory formation in food-deprived snails.

PubMed

Aonuma, Hitoshi; Totani, Yuki; Kaneda, Mugiho; Nakamura, Ryota; Watanabe, Takayuki; Hatakeyama, Dai; Dyakonova, Varvara E; Lukowiak, Ken; Ito, Etsuro

2018-02-01

The pond snail Lymnaea stagnalis learns conditioned taste aversion (CTA) and consolidates it into long-term memory (LTM). How well they learn and form memory depends on the degree of food deprivation. Serotonin (5-HT) plays an important role in mediating feeding, and insulin enhances the memory consolidation process following CTA training. However, the relationship between these two signaling pathways has not been addressed. We measured the 5-HT content in the central nervous system (CNS) of snails subjected to different durations of food deprivation. One-day food-deprived snails, which exhibit the best learning and memory, had the lowest 5-HT content in the CNS, whereas 5-day food-deprived snails, which do not learn, had a high 5-HT content. Immersing 1-day food-deprived snails in 5-HT impaired learning and memory by causing an increase in 5-HT content, and that the injection of insulin into these snails reversed this impairment. We conclude that insulin rescues the CTA deficit and this may be due to a decrease in the 5-HT content in the CNS of Lymnaea. Copyright © 2018 Elsevier Inc. All rights reserved.

Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT1A and 5-HT7 Antagonists in Animal Models

PubMed Central

Pytka, Karolina; Partyka, Anna; Jastrzębska-Więsek, Magdalena; Siwek, Agata; Głuch-Lutwin, Monika; Mordyl, Barbara; Kazek, Grzegorz; Rapacz, Anna; Olczyk, Adrian; Gałuszka, Adam; Błachuta, Marian; Waszkielewicz, Anna; Marona, Henryk; Sapa, Jacek; Filipek, Barbara; Wesołowska, Anna

2015-01-01

The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14—FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15—FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds. PMID:26554929

Morphologic differentiation of colon carcinoma cell lines HT-29 and HT-29KM in rotating-wall vessels

NASA Technical Reports Server (NTRS)

Goodwin, T. J.; Jessup, J. M.; Wolf, D. A.

1992-01-01

A new low shear stress microcarrier culture system has been developed at NASA's Johnson Space Center that permits three-dimensional tissue culture. Two established human colon adenocarcinoma cell lines, HT-29, an undifferentiated, and HT-29KM, a stable, moderately differentiated subline of HT-29, were grown in new tissue culture bioreactors called Rotating-Wall Vessels (RWVs). RWVs are used in conjunction with multicellular cocultivation to develop a unique in vitro tissue modeling system. Cells were cultivated on Cytodex-3 microcarrier beads, with and without mixed normal human colonic fibroblasts, which served as the mesenchymal layer. Culture of the tumor lines in the absence of fibroblasts produced spheroidlike growth and minimal differentiation. In contrast, when tumor lines were co-cultivated with normal colonic fibroblasts, initial growth was confined to the fibroblast population until the microcarriers were covered. The tumor cells then commenced proliferation at an accelerated rate, organizing themselves into three-dimensional tissue masses that achieved 1.0- to 1.5-cm diameters. The masses displayed glandular structures, apical and internal glandular microvilli, tight intercellular junctions, desmosomes, cellular polarity, sinusoid development, internalized mucin, and structural organization akin to normal colon crypt development. Differentiated samples were subjected to transmission and scanning electron microscopy and histologic analysis, revealing embryoniclike mesenchymal cells lining the areas around the growth matrices. Necrosis was minimal throughout the tissue masses. These data suggest that the RWV affords a new model for investigation and isolation of growth, regulatory, and structural processes within neoplastic and normal tissue.

Enhanced Fluorescent Siderophore Biosynthesis and Loss of Phenazine-1-Carboxamide in Phenotypic Variant of Pseudomonas chlororaphis HT66.

PubMed

Liu, Yang; Wang, Zheng; Bilal, Muhammad; Hu, Hongbo; Wang, Wei; Huang, Xianqing; Peng, Huasong; Zhang, Xuehong

2018-01-01

Pseudomonas chlororaphis HT66 is a plant-beneficial bacterium that exhibits wider antagonistic spectrum against a variety of plant pathogenic fungi due to its main secondary metabolite, i.e., phenazine-1-carboxamide (PCN). In the present study, a spontaneous phenotypic variant designated as HT66-FLUO was isolated from the fermentation process of wild-type HT66 strain. The newly isolated phenotypic variant was morphologically distinct from the wild-type strain such as larger cell size, semi-transparent, non-production of PCN (Green or yellow crystals) and enhanced fluorescence under UV light. The whole-genome, RNA-sequencing, and phenotypic assays were performed to identify the reason of phenotypic variation in HT66-FLUO as compared to the HT66. Transcriptomic analysis revealed that 1,418 genes, representing approximately 22% of the 6393 open reading frames (ORFs) had undergone substantial reprogramming of gene expression in the HT66-FLUO. The whole-genome sequence indicated no gene alteration in HT66-FLUO as compared to HT66 according to the known reference sequence. The levels of global regulatory factor gacA and gacS expression were not significantly different between HT66 and HT66-FLUO. It was observed that overexpressing gacS rather than gacA in HT66-FLUO can recover switching of the variant to HT66. The β-galactosidase ( LacZ ) activity and qRT-PCR results indicate the downregulated expression of rsmX, rsmY , and rsmZ in HT66-FLUO as compared to HT66. Overexpressing three small RNAs in HT66-FLUO can revert switching of colony phenotype toward wild-type HT66 up to a certain degree, restore partial PCN production and reduces the fluorescent siderophores yield. However, the origin of the spontaneous phenotypic variant was difficult to be determined. In conclusion, this study helps to understand the gene regulatory effect in the spontaneous phenotypic variant.

Enhanced Fluorescent Siderophore Biosynthesis and Loss of Phenazine-1-Carboxamide in Phenotypic Variant of Pseudomonas chlororaphis HT66

PubMed Central

Liu, Yang; Wang, Zheng; Bilal, Muhammad; Hu, Hongbo; Wang, Wei; Huang, Xianqing; Peng, Huasong; Zhang, Xuehong

2018-01-01

Pseudomonas chlororaphis HT66 is a plant-beneficial bacterium that exhibits wider antagonistic spectrum against a variety of plant pathogenic fungi due to its main secondary metabolite, i.e., phenazine-1-carboxamide (PCN). In the present study, a spontaneous phenotypic variant designated as HT66-FLUO was isolated from the fermentation process of wild-type HT66 strain. The newly isolated phenotypic variant was morphologically distinct from the wild-type strain such as larger cell size, semi-transparent, non-production of PCN (Green or yellow crystals) and enhanced fluorescence under UV light. The whole-genome, RNA-sequencing, and phenotypic assays were performed to identify the reason of phenotypic variation in HT66-FLUO as compared to the HT66. Transcriptomic analysis revealed that 1,418 genes, representing approximately 22% of the 6393 open reading frames (ORFs) had undergone substantial reprogramming of gene expression in the HT66-FLUO. The whole-genome sequence indicated no gene alteration in HT66-FLUO as compared to HT66 according to the known reference sequence. The levels of global regulatory factor gacA and gacS expression were not significantly different between HT66 and HT66-FLUO. It was observed that overexpressing gacS rather than gacA in HT66-FLUO can recover switching of the variant to HT66. The β-galactosidase (LacZ) activity and qRT-PCR results indicate the downregulated expression of rsmX, rsmY, and rsmZ in HT66-FLUO as compared to HT66. Overexpressing three small RNAs in HT66-FLUO can revert switching of colony phenotype toward wild-type HT66 up to a certain degree, restore partial PCN production and reduces the fluorescent siderophores yield. However, the origin of the spontaneous phenotypic variant was difficult to be determined. In conclusion, this study helps to understand the gene regulatory effect in the spontaneous phenotypic variant. PMID:29740409

Fiabilité des structures mécaniques adaptatives: effet de la panne des actionneurs ou des capteurs sur la stabilité

NASA Astrophysics Data System (ADS)

Fall, H.; Charon, W.; Kouta, R.

2002-12-01

Ces dernières décennies, des activités significatives dans le monde étaient dirigées autour du contrôle actif. Le but de ces recherches était essentiellement d'améliorer les performances, la fiabilité et la sécurité des systèmes. Notamment dans le cas des structures soumises à des vibrations aléatoires. D'importants travaux ont été consacré à l'utilisation des “matériaux intelligents” comme capteurs et actionneurs. Cette article propose l'analyse de la fiabilité des systèmes mécaniques en étudiant les pannes des actionneurs ou des capteurs. L'effet de ces pannes sur la stabilité et la performance du système y est démontré. Les méthodologies de conception y sont rappelées. Des exemples numériques sont fournis à travers le contrôle d'un panneau sous chargement dynamique pour illustrer la méthode proposée.

Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists.

PubMed

Cheng, Jianjun; McCorvy, John D; Giguere, Patrick M; Zhu, Hu; Kenakin, Terry; Roth, Bryan L; Kozikowski, Alan P

2016-11-10

On the basis of the structural similarity of our previous 5-HT 2C agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT 2C agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT 2C agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.

Human colon cancer HT-29 cell death responses to doxorubicin and Morus Alba leaves flavonoid extract.

PubMed

Fallah, S; Karimi, A; Panahi, G; Gerayesh Nejad, S; Fadaei, R; Seifi, M

2016-03-31

The mechanistic basis for the biological properties of Morus alba flavonoid extract (MFE) and chemotherapy drug of doxorubicin on human colon cancer HT-29 cell line death are unknown. The effect of doxorubicin and flavonoid extract on colon cancer HT-29 cell line death and identification of APC gene expression and PARP concentration of HT-29 cell line were investigated. The results showed that flavonoid extract and doxorubicin induce a dose dependent cell death in HT-29 cell line. MFE and doxorubicin exert a cytotoxic effect on human colon cancer HT-29 cell line by probably promoting or induction of apoptosis.

Corrosion Properties of Dissimilar Friction Stir Welded 6061 Aluminum and HT590 Steel

NASA Astrophysics Data System (ADS)

Seo, Bosung; Song, Kuk Hyun; Park, Kwangsuk

2018-05-01

Corrosion properties of dissimilar friction stir welded 6061 aluminum and HT590 steel were investigated to understand effects of galvanic corrosion. As cathode when coupled, HT590 was cathodically protected. However, the passivation of AA6061 made the aluminum alloy cathode temporarily, which leaded to corrosion of HT590. From the EIS analysis showing Warburg diffusion plot in Nyquist plots, it can be inferred that the stable passivation layer was formed on AA6061. However, the weld as well as HT590 did not show Warburg diffusion plot in Nyquist plots, suggesting that there was no barrier for corrosion or even if it exists, the barrier had no function for preventing and/or retarding charge transport through the passivation layer. The open circuit potential measurements showed that the potential of the weld was similar to that of HT590, which lied in the pitting region for AA6061, making the aluminum alloy part of the weld keep corrosion state. That resulted in the cracked oxide film on AA6061 of the weld, which could not play a role of corrosion barrier.

Serotonin receptor 5-HT5A in rat hippocampus decrease by leptin treatment.

PubMed

García-Alcocer, Guadalupe; Rodríguez, Angelina; Moreno-Layseca, Paulina; Berumen, Laura C; Escobar, Jesica; Miledi, Ricardo

2010-12-17

5-Hydroxytryptamine (5-HT) is involved in a variety of different physiological processes and behaviors through the activation of equally diverse receptors subtypes. In this work we studied the changes on the expression of 5-HT(5A) receptors in rat hippocampus induced by leptin, an adipocyte-derived hormone that has been reported to participate in the modulation of food intake and in adult hippocampal neurogenesis. To study the effect of leptin on the 5-HT(5A) receptor gene expression a qRT-PCR was used and the distribution of those receptors in the hippocampus was visualized by immunohistochemistry. Rats were separated in four groups: control (untreated rats), leptin-treated, serotonin-treated and leptin+serotonin treated. The results showed that even though the 5-HT(5A) gene expression did not change in the hippocampus of any of the treated groups, in the rats treated with leptin and serotonin, the specific immunostaining for the 5-HT(5A) serotonin receptor decreased significantly in the dentate gyrus. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

High-voltage electroencephalogram spindles in rats, aging and 5-HT2 antagonism.

PubMed

Moyanova, S; Kortenska, L; Kirov, R

1998-03-09

We examined the effects of serotonin-2 (5-hydroxytryptamine-2, 5-HT2) receptor antagonists on the so-called high-voltage spindles (HVS, electroencephalographic patterns, characterized by large amplitude rhythmic waves mainly in the alpha band), recorded from the frontal cortex of young, middle-aged and old freely-moving rats during waking immobility. The study was based on the assumption that the effects of 5-HT2 receptor antagonists on the HVS activity depend on the age of rats, because there is evidence for an age-related decrease in the 5-HT2 binding sites density. Four parameters of the electroencephalogram (EEG) were used to characterize the HVS activity: the square root-transformed EEG peak power in the alpha band, the frequency corresponding to this peak (both measured from the EEG power spectra using the fast Fourier transform), the HVS mean duration, and the HVS incidence (both measured from the EEG records). The EEG parameters were analyzed after i.p. administration of three 5-HT2 receptor antagonists: ketanserin, ritanserin and cyproheptadine. In young rats, the three drugs increased the alpha power, but did not change the alpha peak-corresponding frequency. Ketanserin and ritanserin did not change the HVS mean duration and HVS incidence, while cyproheptadine increased both these parameters in young rats. In middle-aged and old untreated rats, the HVS activity was significantly increased. The three 5-HT2 antagonists did not change the HVS activity in aged rats, which could be due to age-related suppression of the 5-HT2 receptor functions. Copyright 1998 Elsevier Science B.V.

Identification and expression analyses of a novel serotonin receptor gene, 5-HT2β, in the field cricket, Gryllus bimaculatus.

PubMed

Watanabe, T; Aonuma, H

2012-01-01

Biogenic amine serotonin (5-HT) modulates various aspects of behaviors such as aggressive behavior and circadian behavior in the cricket. In our previous report, in order to elucidate the molecular basis of the cricket 5-HT system, we identified three genes involved in 5-HT biosynthesis, as well as four 5-HT receptor genes (5-HT1A, 5-HT1B, 5-HT2α, and 5-HT7) expressed in the brain of the field cricket Gryllus bimaculatus DeGeer [7]. In the present study, we identified Gryllus 5-HT2β gene, an additional 5-HT receptor gene expressed in the cricket brain, and examined its tissue-specific distribution and embryonic stage-dependent expression. Gryllus 5-HT2β gene was ubiquitously expressed in the all examined adult tissues, and was expressed during early embryonic development, as well as during later stages. This study suggests functional differences between two 5-HT2 receptors in the cricket.

The Role of 5-HT2A, 5-HT2C and mGlu2 Receptors in the Behavioral Effects of Tryptamine Hallucinogens N,N-Dimethyltryptamine and N,N-Diisopropyltryptamine in Rats and Mice

PubMed Central

Carbonaro, Theresa M.; Eshleman, Amy J.; Forster, Michael J.; Cheng, Kejun; Rice, Kenner C.; Gatch, Michael B.

2014-01-01

Rationale: Serotonin 5-HT2A and 5-HT2C receptors are thought to be the primary pharmacological mechanisms for serotonin-mediated hallucinogenic drugs, but recently there has been interest in metabotropic glutamate (mGluR2) receptors as contributors to the mechanism of hallucinogens. Objective: The present study assesses the role of these 5-HT and glutamate receptors as molecular targets for two tryptamine hallucinogens, N,N-dimethyltryptamine (DMT) and N,N-diisopropyltryptamine (DiPT). Methods: Drug discrimination, head twitch and radioligand binding assays were used. A 5-HT2AR inverse agonist (MDL100907), 5-HT2CR antagonist (SB242084) and mGluR2/3 agonist (LY379268) were tested for their ability to attenuate the discriminative stimulus effects of DMT and DiPT; an mGluR2/3 antagonist (LY341495) was tested for potentiation. MDL100907 was used to attenuate head twitches induced by DMT and DiPT. Radioligand binding studies and inosital-1-phosphate (IP-1) accumulation were performed at the 5-HT2CR for DiPT. Results: MDL100907 fully blocked the discriminative stimulus effects of DMT, but only partially blocked DiPT. SB242084 partially attenuated the discriminative stimulus effects of DiPT, but produced minimal attenuation of DMT’s effects. LY379268 produced potent, but only partial blockade of the discriminative stimulus effects of DMT. LY341495 facilitated DMT- and DiPT-like effects. Both compounds elicited head twitches (DiPT>DMT) which were blocked by MDL1000907. DiPT was a low potency full agonist at 5-HT2CR in vitro. Conclusions: The 5-HT2AR likely plays a major role in mediating the effects of both compounds. 5-HT2C and mGluR2 receptors likely modulate the discriminative stimulus effects of both compounds to some degree. PMID:24985890

The role of 5-HT2A, 5-HT 2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N,N-dimethyltryptamine and N,N-diisopropyltryptamine in rats and mice.

PubMed

Carbonaro, Theresa M; Eshleman, Amy J; Forster, Michael J; Cheng, Kejun; Rice, Kenner C; Gatch, Michael B

2015-01-01

Serotonin 5-HT2A and 5-HT2C receptors are thought to be the primary pharmacological mechanisms for serotonin-mediated hallucinogenic drugs, but recently there has been interest in metabotropic glutamate (mGluR2) receptors as contributors to the mechanism of hallucinogens. The present study assesses the role of these 5-HT and glutamate receptors as molecular targets for two tryptamine hallucinogens, N,N-dimethyltryptamine (DMT) and N,N-diisopropyltryptamine (DiPT). Drug discrimination, head twitch, and radioligand binding assays were used. A 5-HT2AR inverse agonist (MDL100907), 5-HT2CR antagonist (SB242084), and mGluR2/3 agonist (LY379268) were tested for their ability to attenuate the discriminative stimulus effects of DMT and DiPT; an mGluR2/3 antagonist (LY341495) was tested for potentiation. MDL100907 was used to attenuate head twitches induced by DMT and DiPT. Radioligand binding studies and inosital-1-phosphate (IP-1) accumulation were performed at the 5-HT2CR for DiPT. MDL100907 fully blocked the discriminative stimulus effects of DMT, but only partially blocked DiPT. SB242084 partially attenuated the discriminative stimulus effects of DiPT, but produced minimal attenuation of DMT's effects. LY379268 produced potent, but only partial blockade of the discriminative stimulus effects of DMT. LY341495 facilitated DMT- and DiPT-like effects. Both compounds elicited head twitches (DiPT>DMT) which were blocked by MDL1000907. DiPT was a low-potency full agonist at 5-HT2CR in vitro. The 5-HT2AR likely plays a major role in mediating the effects of both compounds. 5-HT2C and mGluR2 receptors likely modulate the discriminative stimulus effects of both compounds to some degree.

Role of 5-HT5A receptors in the consolidation of memory.

PubMed

Gonzalez, Roberto; Chávez-Pascacio, Karla; Meneses, Alfredo

2013-09-01

5-HT5 receptor occurs in brain areas implicated in learning and memory. Hence, the effects (0.01-3.0 mg/kg) of SB-6995516 (a 5-HT5A receptor antagonist) in the associative learning task of autoshaping were studied. The results showed that post-training injection of SB-699551 decreased conditioned responses (CR) during short-term (STM; 1.5h; at 0.1mg/kg) and long-term memory (LTM; 24 h; at 3.0 mg/kg) relative to the vehicle animals. Moreover, considering that there are no selective 5-HT5A receptor agonists, next, diverse doses of the serotonin precursor l-tryptophan were studied during STM and LTM, showing that l-tryptophan (5-100mg/kg) facilitated performance, particularly at 50mg/kg. In interactions experiments, l-tryptophan (50 mg/kg) attenuated the impairment effect induced by SB-699551 (either 0.3 or 3.0 mg/kg). All together this evidence suggests that the blockade of 5-HT5A receptor appear to be able to impair STM and LTM (24 h), while its stimulation might facilitate it. Of course further investigation is necessary, meanly with selective 5-HT5A compounds are necessary. Copyright © 2013 Elsevier B.V. All rights reserved.

Evidence that the atypical 5-HT3 receptor ligand, [3H]-BRL46470, labels additional 5-HT3 binding sites compared to [3H]-granisetron.

PubMed Central

Steward, L. J.; Ge, J.; Bentley, K. R.; Barber, P. C.; Hope, A. G.; Lambert, J. J.; Peters, J. A.; Blackburn, T. P.; Barnes, N. M.

1995-01-01

1. The radioligand binding characteristics of the 3H-derivative of the novel 5-HT3 receptor antagonist BRL46470 were investigated and directly compared to the well characterized 5-HT3 receptor radioligand [3H]-granisetron, in tissue homogenates prepared from rat cerebral cortex/hippocampus, rat ileum, NG108-15 cells, HEK-5-HT3As cells and human putamen. 2. In rat cerebral cortex/hippocampus, rat ileum, NG108-15 cell and HEK-5-HT3As cell homogenates, [3H]-BRL46470 bound with high affinity (Kd (nM): 1.57 +/- 0.18, 2.49 +/- 0.30, 1.84 +/- 0.27, 3.46 +/- 0.36, respectively; mean +/- s.e. mean, n = 3-4) to an apparently homogeneous saturable population of sites (Bmax (fmol mg-1 protein): 102 +/- 16, 44 +/- 4, 968 +/- 32 and 2055 +/- 105, respectively; mean +/- s.e. mean, n = 3-4) but failed to display specific binding in human putamen homogenates. 3. In the same homogenates of rat cerebral cortex/hippocampus, rat ileum, NG108-15 cells, HEK-5-HT3As cells and human putamen as used for the [3H]-BRL46470 studies, [3H]-granisetron also bound with high affinity (Kd (nM): 1.55 +/- 0.61, 2.31 +/- 0.44, 1.89 +/- 0.36, 2.03 +/- 0.42 and 6.46 +/- 2.58 respectively; mean +/- s.e. mean, n = 3-4) to an apparently homogeneous saturable population of sites (Bmax (fmol mg-1 protein): 39 +/- 4, 20 +/- 2, 521 +/- 47, 870 +/- 69 and 18 +/- 2, respectively; mean +/- s.e. mean, n = 3-4).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8528560

AVN-492, A Novel Highly Selective 5-HT6R Antagonist: Preclinical Evaluation.

PubMed

Ivachtchenko, Alexandre V; Okun, Ilya; Aladinskiy, Vladimir; Ivanenkov, Yan; Koryakova, Angela; Karapetyan, Ruben; Mitkin, Oleg; Salimov, Ramiz; Ivashchenko, Andrey

2017-01-01

Discovery of 5-HT6 receptor subtype and its exclusive localization within the central nervous system led to extensive investigations of its role in Alzheimer's disease, schizophrenia, and obesity. In the present study, we present preclinical evaluation of a novel highly-potent and highly-selective 5-HT6R antagonist, AVN-492. The affinity of AVN-492 to bind to 5-HT6R (Ki = 91 pM) was more than three orders of magnitude higher than that to bind to the only other target, 5-HT2BR, (Ki = 170 nM). Thus, the compound displayed great 5-HT6R selectivity against all other serotonin receptor subtypes, and is extremely specific against any other receptors such as adrenergic, GABAergic, dopaminergic, histaminergic, etc. AVN-492 demonstrates good in vitro and in vivo ADME profile with high oral bioavailability and good brain permeability in rodents. In behavioral tests, AVN-492 shows anxiolytic effect in elevated plus-maze model, prevents an apomorphine-induced disruption of startle pre-pulse inhibition (the PPI model) and reverses a scopolamine- and MK-801-induced memory deficit in passive avoidance model. No anti-obesity effect of AVN-492 was found in a murine model. The data presented here strongly indicate that due to its high oral bioavailability, extremely high selectivity, and potency to block the 5-HT6 receptor, AVN-492 is a very promising tool for evaluating the role the 5-HT6 receptor might play in cognitive and neurodegenerative impairments. AVN-492 is an excellent drug candidate to be tested for treatment of such diseases, and is currently being tested in Phase I trials.

The 5-HT1A Receptor and the Stimulus Effects of LSD in the Rat

PubMed Central

Reissig, C.J.; Eckler, J.R.; Rabin, R.A.; Winter, J.C.

2005-01-01

Rationale It has been suggested that the 5-HT1A receptor plays a significant modulatory role in the stimulus effects of the indoleamine hallucinogen lysergic acid diethylamide (LSD). Objectives The present study sought to characterize the effects of several compounds with known affinity for the 5-HT1A receptor on the discriminative stimulus effects of LSD. Methods 12 Male F-344 rats were trained in a two-lever, fixed ratio10, food reinforced task with LSD (0.1 mg/kg; IP; 15 min pretreatment) as a discriminative stimulus. Combination and substitution tests with the 5-HT1A agonists, 8-OH-DPAT, buspirone, gepirone, and ipsapirone, with LSD-induced stimulus control were then performed. The effects of these 5-HT1A ligands were also tested in the presence of the selective 5-HT1A receptor antagonist, WAY-100,635 (0.3 mg/kg; SC; 30 min. pretreatment). Results In combination tests stimulus control by LSD was increased by all 5-HT1A receptor ligands with agonist properties. Similarly, in tests of antagonism, the increase in drug-appropriate responding caused by stimulation of the 5-HT1A receptor was abolished by administration of WAY-100,635. Conclusions These data, obtained using a drug discrimination model of the hallucinogenic effects of LSD, provide support for the hypothesis that the 5-HT1A receptor has a significant modulatory role in the stimulus effects of LSD. PMID:16025319

Developpement des betons semi autoplacants a rheologie adaptee pour des infrastructures

NASA Astrophysics Data System (ADS)

Sotomayor Cruz, Cristian Daniel

Au cours des dernières décennies, les infrastructures canadiennes et québécoises comportent plusieurs structures en béton armé présentant des problèmes de durabilité dus aux conditions climatiques sévères, à la mauvaise conception des structures, à la qualité des matériaux, aux types des bétons choisis, aux systèmes de construction ou à l'existence d'événements incontrôlables. En ce qui concerne le choix du béton pour la construction des infrastructures, une vaste gamme de béton divisée en deux principaux types peut être utilisée: le béton conventionnel vibré (BCV) et le béton autoplaçant (BAP). Dans le cas d'un BCV, la consolidation inadéquate par vibration a été un problème récurrent, occasionnant des dommages structuraux. Ceci a conduit à une réduction de la durabilité et à une augmentation du coût d'entretien et de réparation des infrastructures. Rien que l'utilisation d'un BAP a des avantages tels que l'élimination de la vibration, la réduction des coûts de main d'oeuvre et l'amélioration de la qualité des structures, néanmoins, le coût initial d'un BAP par rapport à un BCV ne permet pas encore de généraliser son utilisation dans l'industrie de la construction. Ce mémoire présente la conception d'une nouvelle gamme de béton semi-autoplaçant pour la construction des infrastructures (BSAP-I) exigeant une vibration minimale. Il s'agit de trouver un équilibre optimal entre la rhéologie et le coût initial du nouveau béton pour conférer une bonne performance structurale et économique aux structures. Le programme expérimental établi a premièrement permis d'évaluer la faisabilité d'utilisation des BSAP-I pour la mise en place des piliers d'une infrastructure de pont à Sherbrooke. En plus, l'utilisation d'un plan d'expériences a permis l'évaluation de trois paramètres de formulation sur les propriétés des mélanges de BSAP-I à l'état frais et durci. Finalement, l'évaluation de la performance des

Paternité des articles et intérêts concurrents : une analyse des recommandations aux auteurs des journaux traitant de pratique pharmaceutique

PubMed Central

Courbon, Ève; Tanguay, Cynthia; Lebel, Denis; Bussières, Jean-François

2014-01-01

RÉSUMÉ Contexte : La présence d’auteurs honorifiques et fantômes ainsi que les intérêts concurrents représentent des difficultés bien documentées, liées à la publication d’articles scientifiques. Il existe des lignes directrices encadrant la rédaction et la publication de manuscrits scientifiques, notamment celles de l’International Committee of Medical Journal Editors (ICMJE). Objectifs : L’objectif principal de cette étude descriptive et transversale visait à recenser les instructions portant sur la paternité des articles et les intérêts concurrents provenant des recommandations aux auteurs des journaux traitant de pratique pharmaceutique. L’objectif secondaire visait à déterminer des mesures correctrices pour une paternité des articles plus transparente. Méthode : La recherche a débuté par l’identification des journaux traitant de pratique pharmaceutique. La consultation des instructions aux auteurs des journaux a permis ensuite de recenser les recommandations destinées à éviter les problèmes de paternité des articles et d’intérêts concurrents. Finalement, les membres de l’équipe de recherche se sont consultés afin de définir des mesures correctrices possibles à l’intention des chercheurs. Résultats : Des 232 journaux traitant de pharmacie, 33 ont été définis comme traitant de pratique pharmaceutique. Un total de 24 (73 %) journaux mentionnaient suivre la politique de l’ICMJE, 14 (42 %) demandaient aux auteurs de remplir un formulaire de déclaration d’intérêts concurrents au moment de la soumission de l’article, 17 (52 %) présentaient une définition de la qualité d’auteur et 5 (15 %) demandaient de détailler les contributions de chaque auteur. Une grille de 40 critères a été élaborée pour définir l’attribution du statut d’auteur. Conclusion : Moins de la moitié des journaux demandait aux auteurs de transmettre un formulaire de déclaration des intérêts concurrents au moment de la

The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens.

PubMed

Canal, Clinton E; Murnane, Kevin S

2017-01-01

Classic hallucinogens share pharmacology as serotonin 5-HT 2A , 5-HT 2B , and 5-HT 2C receptor agonists. Unique among most other Schedule 1 drugs, they are generally non-addictive and can be effective tools in the treatment of addiction. Mechanisms underlying these attributes are largely unknown. However, many preclinical studies show that 5-HT 2C agonists counteract the addictive effects of drugs from several classes, suggesting this pharmacological property of classic hallucinogens may be significant. Drawing from a comprehensive analysis of preclinical behavior, neuroanatomy, and neurochemistry studies, this review builds rationale for this hypothesis, and also proposes a testable, neurobiological framework. 5-HT 2C agonists work, in part, by modulating dopamine neuron activity in the ventral tegmental area-nucleus accumbens (NAc) reward pathway. We argue that activation of 5-HT 2C receptors on NAc shell, GABAergic, medium spiny neurons inhibits potassium Kv1.x channels, thereby enhancing inhibitory activity via intrinsic mechanisms. Together with experiments that show that addictive drugs, such as cocaine, potentiate Kv1.x channels, thereby suppressing NAc shell GABAergic activity, this hypothesis provides a mechanism by which classic hallucinogen-mediated stimulation of 5-HT 2C receptors could thwart addiction. It also provides a potential reason for the non-addictive nature of classic hallucinogens.

Involvement of 5-HT3 receptors in the action of vortioxetine in rat brain: Focus on glutamatergic and GABAergic neurotransmission.

PubMed

Riga, Maurizio S; Sánchez, Connie; Celada, Pau; Artigas, Francesc

2016-09-01

The antidepressant vortioxetine is a 5-HT3-R, 5-HT7-R and 5-HT1D-R antagonist, 5-HT1B-R partial agonist, 5-HT1A-R agonist, and serotonin (5-HT) transporter (SERT) inhibitor. Vortioxetine occupies all targets at high therapeutic doses and only SERT and 5-HT3-R at low doses. Vortioxetine increases extracellular monoamine concentrations in rat forebrain more than selective serotonin reuptake inhibitors (SSRI) and shows pro-cognitive activity in preclinical models. Given its high affinity for 5-HT3-R (Ki = 3.7 nM), selectively expressed in GABA interneurons, we hypothesized that vortioxetine may disinhibit glutamatergic and monoaminergic neurotransmission following 5-HT3-R blockade. Here we assessed vortioxetine effect on pyramidal neuron activity and extracellular 5-HT concentration using in vivo extracellular recordings of rat medial prefrontal cortex (mPFC) pyramidal neurons and microdialysis in mPFC and ventral hippocampus (vHPC). Vortioxetine, but not escitalopram, increased pyramidal neuron discharge in mPFC. This effect was prevented by SR57227A (5-HT3-R agonist) and was mimicked by ondansetron (5-HT3-R antagonist) and by escitalopram/ondansetron combinations. In microdialysis experiments, ondansetron augmented the 5-HT-enhancing effect of escitalopram in mPFC and vHPC. Local ondansetron in vHPC augmented escitalopram effect, indicating the participation of intrinsic mechanisms. Since 5-HT neurons express GABAB receptors, we examined their putative involvement in controlling 5-HT release after 5-HT3-R blockade. Co-perfusion of baclofen (but not muscimol) reversed the increased 5-HT levels produced by vortioxetine and escitalopram/ondansetron combinations in vHPC. The present results suggest that vortioxetine increases glutamatergic and serotonergic neurotransmission in rat forebrain by blocking 5-HT3 receptors in GABA interneurons. Copyright © 2016. Published by Elsevier Ltd.

Pindolol antagonises G-protein activation at both pre- and postsynaptic serotonin 5-HT1A receptors: a.

PubMed

Newman-Tancredi, A; Chaput, C; Touzard, M; Millan, M J

2001-04-01

The arylalkylamine, pindolol, may potentiate the clinical actions of antidepressant agents. Although it is thought to act via blockade of 5-HT1A autoreceptors, its efficacy at these sites remains controversial. Herein, we evaluated the actions of pindolol at 5-HT1A autoreceptors and specific populations of postsynaptic 5-HT1A receptors employing [35S]GTPgammaS autoradiography, a measure of receptor-mediated G-protein activation. Both 8-OH-DPAT (1 microM) and 5-HT (10 microM) elicited a pronounced increase in [35S]GTPyS binding in the dorsal raphe nucleus, which contains serotonergic cell bodies bearing 5-HT1A autoreceptors. Pindolol abolished their actions. In the dentate gyrus, lateral septum and entorhinal cortex, structures enriched in postsynaptic 5-HT1A receptors, 8-OH-DPAT (1 microM) and 5-HT (10 microM) also elicited a marked increase in [35S]GTPgammaS binding which was likewise blocked by pindolol. The antagonism of 5-HT-induced [35S]GTPgammaS labelling in the dentate gyrus was shown to be concentration-dependent, yielding a pIC50 of 5.82. Pindolol did not, itself, affect [35S]GTPgammaS binding in any brain region examined. In conclusion, these data suggest that, as characterised by [35S]GTPgammaS autoradiography, and compared with 5-HT and 8-OH-DPAT, pindolol possesses low efficacy at both pre- and postsynaptic 5-HT1A receptors.

Sensitization of restraint-induced corticosterone secretion after chronic restraint in rats: Involvement of 5-HT7 receptors

PubMed Central

García-Iglesias, Brenda B.; Mendoza-Garrido, María E.; Gutiérrez-Ospina, Gabriel; Rangel-Barajas, Claudia; Noyola-Díaz, Martha; Terrón, José A.

2013-01-01

Serotonin (5-HT) modulates the hypothalamic-pituitary-adrenal (HPA) axis response to stress. We examined the effect of chronic restraint stress (CRS; 20 min/day) as compared to control (CTRL) conditions for 14 days, on: 1) restraint-induced ACTH and corticosterone (CORT) secretion in rats pretreated with vehicle or SB-656104 (a 5-HT7 receptor antagonist); 2) 5-HT7 receptor-like immunoreactivity (5-HT7-LI) and protein in the hypothalamic paraventricular nucleus (PVN) and adrenal glands (AG); 3) baseline levels of 5-HT and 5-hydroxyindolacetic acid (5-HIAA), and 5-HIAA/5-HT ratio in PVN and AG; and 4) 5-HT-like immunoreactivity (5-HT-LI) in AG and tryptophan hydroxylase (TPH) protein in PVN and AG. On day 15, animals were subdivided into Treatment and No treatment groups. Treatment animals received an i.p. injection of vehicle or SB-656104; No Treatment animals received no injection. Sixty min later, Treatment animals were either decapitated with no further stress (0 min) or submitted to acute restraint (10, 30, 60 or 120 min); hormone serum levels were measured. No Treatment animals were employed for the rest of measurements. CRS decreased body weight gain and increased adrenal weight. In CTRL animals, acute restraint increased ACTH and CORT secretion in a time of restraint-dependent manner; both responses were inhibited by SB-656104. Exposure to CRS abolished ACTH but magnified CORT responses to restraint as compared to CTRL conditions; SB-656104 had no effect on ACTH levels but significantly inhibited sensitized CORT responses. In CTRL animals, 5-HT7-LI was detected in magnocellular and parvocellular subdivisions of PVN and sparsely in adrenal cortex. Exposure to CRS decreased 5-HT7-LI and protein in the PVN, but increased 5-HT7-LI in the adrenal cortex and protein in whole AG. Higher 5-HT and 5-HIAA levels were detected in PVN and AG from CRS animals but 5-HIAA/5-HT ratio increased in AG only. Finally, whereas 5-HT-LI was sparsely observed in the adrenal cortex

Functional expression of 5-HT{sub 2A} receptor in osteoblastic MC3T3-E1 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hirai, Takao; Kaneshige, Kota; Kurosaki, Teruko

2010-05-28

In the previous study, we reported the gene expression for proteins related to the function of 5-hydroxytryptamine (5-HT, serotonin) and elucidated the expression patterns of 5-HT{sub 2} receptor subtypes in mouse osteoblasts. In the present study, we evaluated the possible involvement of 5-HT receptor subtypes and its inactivation system in MC3T3-E1 cells, an osteoblast cell line. DOI, a 5-HT{sub 2A} and 5-HT{sub 2C} receptor selective agonist, as well as 5-HT concentration-dependently increased proliferative activities of MC3T3-E1 cells in their premature period. This effect of 5-HT on cell proliferation were inhibited by ketanserin, a 5-HT{sub 2A} receptor specific antagonist. Moreover, bothmore » DOI-induced cell proliferation and phosphorylation of ERK1 and 2 proteins were inhibited by PD98059 and U0126, selective inhibitors of MEK in a concentration-dependent manner. Furthermore, treatment with fluoxetine, a 5-HT specific re-uptake inhibitor which inactivate the function of extracellular 5-HT, significantly increased the proliferative activities of MC3T3-E1 cells in a concentration-dependent manner. Our data indicate that 5-HT fill the role for proliferation of osteoblast cells in their premature period. Notably, 5-HT{sub 2A} receptor may be functionally expressed to regulate mechanisms underlying osteoblast cell proliferation, at least in part, through activation of ERK/MAPK pathways in MC3T3-E1 cells.« less

Dual effects of 5-HT(1a) receptor activation on breathing in neonatal mice.

PubMed

Corcoran, Andrea E; Commons, Kathryn G; Wu, Yuanming; Smith, Jeffrey C; Harris, Michael B; Richerson, George B

2014-01-01

Inhibitory 5-HT(1a) receptors are located on serotonin (5-HT) neurons (autoreceptors) as well as neurons of the respiratory network (heteroreceptors). Thus, effects on breathing of 5-HT(1a) agonists, such as (R)-(+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), could either be due to decreased firing of 5-HT neurons or direct effects on the respiratory network. Mice in which the transcription factor LMX1B is genetically deleted selectively in Pet1-1-expressing cells (Lmx1b(f/f/p)) essentially have complete absence of central 5-HT neurons, providing a unique opportunity to separate the effect of activation of downstream 5-HT(1a) heteroreceptors from that of autoreceptors. We used rhythmically active medullary slices from wild-type (WT) and Lmx1b(f/f/p) neonatal mice to differentiate autoreceptor versus heteroreceptor effects of 8-OH-DPAT on hypoglossal nerve respiratory output. 8-OH-DPAT transiently increased respiratory burst frequency in Lmx1b(f/f/p) preparations, but not in WT slices. This excitation was abolished when synaptic inhibition was blocked by GABAergic/glycinergic receptor antagonists. Conversely, after 10 min of application, frequency in Lmx1b(f/f/p) slices was not different from baseline, whereas it was significantly depressed in WT slices. In WT mice in vivo, subcutaneous injection of 8-OH-DPAT produced similar biphasic respiratory effects as in Lmx1b(f/f/p) mice. We conclude that 5-HT1a receptor agonists have two competing effects: rapid stimulation of breathing due to excitation of the respiratory network, and delayed inhibition of breathing due to autoreceptor inhibition of 5-HT neurons. The former effect is presumably due to inhibition of inhibitory interneurons embedded in the respiratory network.

Dual Effects of 5-HT1a Receptor Activation on Breathing in Neonatal Mice

PubMed Central

Commons, Kathryn G.; Wu, Yuanming; Smith, Jeffrey C.; Harris, Michael B.; Richerson, George B.

2014-01-01

Inhibitory 5-HT1a receptors are located on serotonin (5-HT) neurons (autoreceptors) as well as neurons of the respiratory network (heteroreceptors). Thus, effects on breathing of 5-HT1a agonists, such as (R)-(+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), could either be due to decreased firing of 5-HT neurons or direct effects on the respiratory network. Mice in which the transcription factor LMX1B is genetically deleted selectively in Pet1-1-expressing cells (Lmx1bf/f/p) essentially have complete absence of central 5-HT neurons, providing a unique opportunity to separate the effect of activation of downstream 5-HT1a heteroreceptors from that of autoreceptors. We used rhythmically active medullary slices from wild-type (WT) and Lmx1bf/f/p neonatal mice to differentiate autoreceptor versus heteroreceptor effects of 8-OH-DPAT on hypoglossal nerve respiratory output. 8-OH-DPAT transiently increased respiratory burst frequency in Lmx1bf/f/p preparations, but not in WT slices. This excitation was abolished when synaptic inhibition was blocked by GABAergic/glycinergic receptor antagonists. Conversely, after 10 min of application, frequency in Lmx1bf/f/p slices was not different from baseline, whereas it was significantly depressed in WT slices. In WT mice in vivo, subcutaneous injection of 8-OH-DPAT produced similar biphasic respiratory effects as in Lmx1bf/f/p mice. We conclude that 5-HT1a receptor agonists have two competing effects: rapid stimulation of breathing due to excitation of the respiratory network, and delayed inhibition of breathing due to autoreceptor inhibition of 5-HT neurons. The former effect is presumably due to inhibition of inhibitory interneurons embedded in the respiratory network. PMID:24381267

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

PubMed Central

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

1996-01-01

1. NIE-115 mouse neuroblastoma cells were studied under voltage clamp in the whole-cell patch-clamp configuration. Peak currents induced by bath application of 5-hydroxytryptamine (5-HT) were inwardly rectifying, reversed at 0.4 +/- 0.2 mV (mean +/- s.e.mean), and were approximately half-inhibited (at 1 microM 5-HT) by 2 nM of the 5-HT3 selective antagonist MDL-72222 (3-tropanyl-3,5-dichlorobenzoate). 2. Peak inward currents activated by a low concentration of 5-HT at a holding potential of -50 mV were potentiated by volatile general anaesthetics. At their human minimum alveolar concentrations (MACs), the degree of potentiation increased in the order isoflurane < halothane < enflurane < methoxyflurane. Potentiation by methoxyflurane was independent of membrane potential in the range -70 mV to +40 mV. The reversal potential was the same in the presence and absence of methoxyflurane. 3. Methoxyflurane shifted the 5-HT dose-response curve to lower 5-HT concentrations, without significantly changing the Hill coefficient or maximum response. The EC50 concentration for 5-HT decreased from 1.86 +/- 0.02 microM to 1.07 +/- 0.11 microM (means +/- s.e.mean) due to the presence of 1 MAC (270 microM) methoxyflurane. 4. In contrast to the volatile anaesthetics, the barbiturate anaesthetic, thiopentone, inhibited the 5-HT3 receptor. Hill analysis of thiopentone dose-response data gave an average IC50 = 117 +/- 8 microM thiopentone and Hill coefficient = 1.6 +/- 0.2 (means +/- s.e.mean). These parameters were not significantly different for data obtained at 5-HT concentrations above and below the control EC50 concentration for 5-HT, consistent with non-competitive inhibition. 5. The n-alcohols occupied an intermediate position between the volatile and barbiturate anaesthetics. The lower alcohols (butanol and hexanol) potentiated 5-HT responses at low alcohol concentrations but inhibited them at high concentrations. In contrast, the higher alcohols (octanol, decanol, dodecanol

Attention switching after dietary brain 5-HT challenge in high impulsive subjects.

PubMed

Markus, C Rob; Jonkman, Lisa M

2007-09-01

High levels of impulsivity have adverse effects on performance in cognitive tasks, particularLy in those tasks that require high attention investment. Furthermore, both animal and human research has indicated that reduced brain serotonin (5-HT) function is associated with increases in impulsive behaviour or decreased inhibition ability, but the effects of 5-HT challenge have not yet been investigated in subjects vulnerable to impulsivity. The present study aimed to investigate whether subjects with high trait impulsivity perform worse than low impulsive subjects in a task switching paradigm in which they have to rapidly shift their attention between two response rules, and to investigate the influence of a 5-HT enhancing diet. Healthy subjects with high ( n = 19) and low (n = 18) trait impulsivity scores participated in a double-blind placebo-controlled study. All subjects performed the attention switch task in the morning following breakfast containing either tryptophan-rich alpha-lactalbumin (4.8 g/100 g TRP) or placebo protein (1.4 g/100 g TRP). Whereas there were no baseline differences between high and low impulsive subjects in task switching abilities, high impulsive subjects made significantly more switch errors and responded slower after dietary 5-HT stimulation, whereas no dietary effects were found on task switching performance in low-impulsive subjects. The deterioration in task switching performance induced by the 5-HT enhancing diet in high impulsive subjects was suggested to be established by general arousal/attention-reducing effects of 5-HT, which might have a larger impact in high impulsive subjects due to either different brain circuitry involved in task switching in this group or lower baseline arousal levels.

A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying agents

PubMed Central

Heal, D J; Cheetham, S C; Prow, M R; Martin, K F; Buckett, W R

1998-01-01

Effects on 5-HT function of sibutramine and its active metabolites, BTS 54 354 and BTS 54 505, were compared with fluoxetine, (+)-fenfluramine and (+)-amphetamine.In vitro sibutramine weakly inhibited [3H]-5-HT uptake into brain synaptosomes. BTS 54 354, BTS 54 505 and fluoxetine were powerful [3H]-5-HT uptake inhibitors, whereas (+)-fenfluramine and (+)-amphetamine were very much weaker. Conversely, whilst sibutramine, its metabolites and fluoxetine did not release [3H]-5-HT from brain slices at ⩽10−5M, (+)-fenfluramine and (+)-amphetamine concentration-dependently increased [3H]-5-HT release.Sibutramine and fluoxetine had no effect on 5-hydroxytryptophan (5-HTP) accumulation in either frontal cortex or hypothalamus at doses <10 mg kg−1. In contrast, (+)-amphetamine (⩾3 mg kg−1) reduced 5-HTP in hypothalamus, whilst (+)-fenfluramine (⩾1 mg kg−1) decreased 5-HTP in both regions.Sibutramine (10 mg kg−1 i.p.) and fluoxetine (10 mg kg−1 i.p.) produced slow, prolonged increases of extracellular 5-HT in the anterior hypothalamus. In contrast, (+)-fenfluramine (3 mg kg−1 i.p.) and (+)-amphetamine (4 mg kg−1 i.p.) induced rapid, short-lasting increases in extracellular 5-HT.Only (+)-fenfluramine (10 mg kg−1) altered 5-HT2A receptors in rat frontal cortex when given for 14 days, producing a 61% reduction in receptor number and a 18% decrease in radioligand affinity.These results show that sibutramine powerfully enhances central 5-HT function via its secondary and primary amine metabolites; this effect, like that of fluoxetine, is almost certainly mediated through 5-HT uptake inhibition. By contrast, (+)-fenfluramine enhances 5-HT function predominantly by increasing 5-HT release. (+)-Amphetamine, though weaker than (+)-fenfluramine, also enhances 5-HT function by release. PMID:9786502

Caracterisation des melanges developpes pour le moulage basse pression des poudres metalliques (LPIM) =

NASA Astrophysics Data System (ADS)

Fareh, Fouad

Le moulage par injection basse pression des poudres metalliques est une technique de fabrication qui permet de fabriquer des pieces possedant la complexite des pieces coulees mais avec les proprietes mecaniques des pieces corroyees. Cependant, l'optimisation des etapes de deliantage et de frittage a ete jusqu'a maintenant effectuee a l'aide de melange pour lesquels la moulabilite optimale n'a pas encore ete demontree. Ainsi, la comprehension des proprietes rheologiques et de la segregation des melanges est tres limitee et cela presente le point faible du processus de LPIM. L'objectif de ce projet de recherche etait de caracteriser l'influence des liants sur le comportement rheologique des melanges en mesurant la viscosite et la segregation des melanges faible viscosite utilises dans le procede LPIM. Afin d'atteindre cet objectif, des essais rheologiques et thermogravimetriques ont ete conduits sur 12 melanges. Ces melanges ont ete prepares a base de poudre d'Inconel 718 de forme spherique (chargement solide constant a 60%) et de cires, d'agents surfactants ou epaississants. Les essais rheologiques ont ete utilises entre autre pour calculer l'indice d'injectabilite ?STV des melanges, tandis que les essais thermogravimetriques ont permis d'evaluer precisement la segregation des poudres dans les melanges. Il a ete demontre que les trois (3) melanges contenant de la cire de paraffine et de l'acide stearique presentent des indices alpha STV plus eleves qui sont avantageux pour le moulage par injection des poudres metalliques (MIM), mais segregent beaucoup trop pour que la piece fabriquee produise de bonnes caracteristiques mecaniques. A l'oppose, le melange contenant de la cire de paraffine et de l'ethylene-vinyle acetate ainsi que le melange contenant seulement de la cire de carnauba segregent peu voire pas du tout, mais possedent de tres faibles indices alphaSTV : ils sont donc difficilement injectables. Le meilleur compromis semble donc etre les melanges contenant de

Regulatory role of a neurotransmitter (5-HT) on glial Na+/K(+)-ATPase in the rat brain.

PubMed

Mercado, R; Hernández, J

1992-07-01

In the present work we studied the effect of serotonin (5-HT) on the kinetics of Na+/K(+)-ATPase in subcellular preparations of the cerebral cortex from male Wistar rats using various concentrations of ATP and K+ with and without added 5-HT. Also we studied the effect of 5-HT on the enzyme in glial or neuronal preparations. The results indicated that there was a significant increase (P < 0.05) of the Vmax in the presence of 5-HT in the whole tissue preparation (homogenate) but not in the subcellular fractions, suggesting that the interaction could be preferentially with the glial pump. Further results supported that this was the case since activation by 5-HT was mainly in the glial preparations. Kinetic data and the binding of [3H]ouabain supported that the enzyme is activated by 5-HT through the exposure of more enzymatic active sites.

La participation des enfants et des adolescents à la boxe

PubMed Central

Purcell, Laura K; LeBlanc, Claire MA

2012-01-01

RÉSUMÉ Des milliers de garçons et de filles de moins de 19 ans font de la boxe en Amérique du Nord. Même si la boxe comporte des avantages pour ceux qui y participent, y compris l’exercice, l’autodiscipline et la confiance en soi, le sport lui-même favorise et récompense des coups délibérés à la tête et au visage. Les personnes qui font de la boxe risquent de subir des blessures à la tête, au visage et au cou, y compris des traumatismes neurologiques chroniques et même fatals. Les commotions cérébrales sont l’une des principales blessures causées par la boxe. En raison du risque de blessures crâniennes et faciales, la Société canadienne de pédiatrie et l’American Academy of Pediatrics s’opposent vigoureusement à la boxe comme activité sportive pour les enfants et les adolescents. Ces organismes recommandent que les médecins s’élèvent contre la boxe auprès des jeunes et les encouragent à participer à d’autres activités dans lesquelles les coups intentionnels à la tête ne constituent pas un élément essentiel du sport.

ENHANCED 5-HT1A RECEPTOR-DEPENDENT FEEDBACK CONTROL OVER DORSAL RAPHE SEROTONIN NEURONS IN THE SERT KNOCKOUT MOUSE

PubMed Central

Soiza-Reilly, Mariano; Goodfellow, Nathalie M.; Lambe, Evelyn K.; Commons, Kathryn G.

2014-01-01

5-HT1A receptors are widely expressed in the brain and play a critical role in feedback inhibition of serotonin (5-HT) neurons through multiple mechanisms. Yet, it remains poorly understood how these feedback mechanisms, particularly those involving long-range projections, adapt in mood disorders. Here, we examined several aspects of 5-HT1A receptor function in the 5-HT transporter knockout mouse (SERT-KO), a model of vulnerability to stress and mood disorders. We found that in comparison to wild-type (WT) mice, SERT-KO mice had more passive coping in response to acute swim stress and this was accompanied by hypo-activation of medial prefrontal cortex (mPFC) Fos expression. Both of these effects were reversed by systemically blocking 5-HT1A receptors. Ex-vivo electrophysiological experiments showed that 5-HT exerted greater 5-HT1A-mediated inhibitory effects in the mPFC of SERT-KO mice compared to WT. Since 5-HT1A receptors in the mPFC provide a key feedback regulation of the dorsal raphe nucleus (DRN), we used a disinhibition strategy to examined endogenous feedback control of 5-HT neurons. Blocking 5-HT1A receptors disinhibited several fold more 5-HT neurons in the DRN of SERT-KO than in WT mice, revealing the presence of enhanced feedback inhibition of 5-HT neurons in the SERT-KO. Taken together our results indicate that increased stress sensitivity in the SERT-KO is associated with the enhanced capacity of 5-HT1A receptors to inhibit neurons in the mPFC as well as to exert feedback inhibition of DRN 5-HT neurons. PMID:25261781

Selective Modulation of K+ Channel Kv7.4 Significantly Affects the Excitability of DRN 5-HT Neurons.

PubMed

Zhao, Chen; Su, Min; Wang, Yingzi; Li, Xinmeng; Zhang, Yongxue; Du, Xiaona; Zhang, Hailin

2017-01-01

The serotonin (5-HT) system originating in the dorsal raphe nucleus (DRN) is implicated in various mood- and emotion-related disorders, such as anxiety, fear and stress. Abnormal activity of DRN 5-HT neurons is the key factor in the development of these disorders. Here, we describe a crucial role for the Kv7.4 potassium channel in modulating DRN 5-HT neuronal excitability. We demonstrate that Kv7.4 is selectively expressed in 5-HT neurons of the DRN. Using selective Kv7.4 opener fasudil and Kv7.4 knock-out mice, we demonstrate that Kv7.4 is a potent modulator of DRN 5-HT neuronal excitability. Furthermore, we demonstrate that the cellular redox signaling mechanism is involved in this 5-HT activation of Kv7.4. The current study suggests a new strategy for treating psychiatric disorders related to altered activity of DRN 5-HT neurons using K + channel modulators.

Selective Modulation of K+ Channel Kv7.4 Significantly Affects the Excitability of DRN 5-HT Neurons

PubMed Central

Zhao, Chen; Su, Min; Wang, Yingzi; Li, Xinmeng; Zhang, Yongxue; Du, Xiaona; Zhang, Hailin

2017-01-01

The serotonin (5-HT) system originating in the dorsal raphe nucleus (DRN) is implicated in various mood- and emotion-related disorders, such as anxiety, fear and stress. Abnormal activity of DRN 5-HT neurons is the key factor in the development of these disorders. Here, we describe a crucial role for the Kv7.4 potassium channel in modulating DRN 5-HT neuronal excitability. We demonstrate that Kv7.4 is selectively expressed in 5-HT neurons of the DRN. Using selective Kv7.4 opener fasudil and Kv7.4 knock-out mice, we demonstrate that Kv7.4 is a potent modulator of DRN 5-HT neuronal excitability. Furthermore, we demonstrate that the cellular redox signaling mechanism is involved in this 5-HT activation of Kv7.4. The current study suggests a new strategy for treating psychiatric disorders related to altered activity of DRN 5-HT neurons using K+ channel modulators. PMID:29311835

5-HT1 receptor augmentation strategies as enhanced efficacy: therapeutics for psychiatric disorders.

PubMed

Dawson, Lee A; Bromidge, Steve M

2008-01-01

Since the initial observations linking 5-HT to psychiatric illness, evidence for a role of 5-HT and, in particular, a decreased brain serotonergic function in the pathology of a plethora of related disorders, has grown. However, it is the role of 5-HT in the pathogenesis of anxiety disorders and depression and the mechanism of action of antidepressants which has received the most attention. Thus enhanced serotonergic neurotransmission has become one of the unifying mechanisms of action of modern day antidepressants/anxiolytics such as monoamine oxidase inhibitors, tricyclic antidepressants, and serotonin reuptake inhibitors. Interestingly all of these treatments are associated with a delay to therapeutic efficacy and in some cases treatment resistance, despite immediate enhancements in serotonergic neurotransmission. The postulated reason for this is the need for temporal neuroplastic changes in the control of serotonergic neurotransmission, and more specifically changes in 5-HT(1) autoreceptor function. Thus significant research has gone into pharmacologically targeting these 5-HT(1) autoreceptors as a means of augmenting the efficacy of current therapeutic mechanisms. Here we will review the rationale behind the various augmentation strategies adopted and the progress made in identifying novel therapeutics for conditions such as depression and anxiety disorders.

Quinoxalin-2-carboxamides: synthesis and pharmacological evaluation as serotonin type-3 (5-HT3) receptor antagonists.

PubMed

Mahesh, Radhakrishnan; Devadoss, Thangaraj; Pandey, Dilip Kumar; Yadav, Shushil Kumar

2011-10-01

A series of quinoxalin-2-carboxamides were designed as per the pharmacophoric requirements of 5-HT(3) receptor antagonists and synthesized by condensing the carboxylic group of quinoxalin-2-carboxylic acid with various amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole. The structures of the synthesized compounds were confirmed by physical and spectroscopic data. The carboxamides were evaluated for their 5-HT(3) receptor antagonisms in longitudinal muscle-myenteric plexus preparation from guinea pig ileum against 5-HT(3) agonist, 2-methy-5-HT. All the synthesized compounds showed 5-HT(3) receptor antagonism, (4-benzylpiperazin-1-yl)(quinoxalin-2-yl)methanone was the most potent compound among this series.

Serotonin 5-HT2 Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

PubMed Central

Cunningham, Kathryn A.

2015-01-01

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

Atypical sympathomimetic drug lerimazoline mediates contractile effects in rat aorta predominantly by 5-HT2A receptors.

PubMed

Rizvić, Eldina; Janković, Goran; Kostić-Rajačić, Slađana; Savić, Miroslav M

2017-08-20

Lerimazoline is a sympathomimetic drug that belongs to the imidazoline class of compounds, and is used as a nasal decongestant. Studies on lerimazoline are rare, and its pharmacological profile is not completely understood. Here, we analyzed the affinity of lerimazoline for dopamine receptor D2, serotonin 5-HT1A and 5-HT2A receptors and α1-adrenoceptor, and investigated lerimazoline contractile effects in isolated rat thoracic aorta. We also determined the effect of several antagonists on the contractile response to lerimazoline, including prazosin (α1-adrenoceptor antagonist), RX 821002 and rauwolscine (α2-adrenoceptor antagonists), JP 1302 (α2C-adrenoceptor antagonist), methiothepin (non-selective 5-HT receptor antagonist), SB 224289 (5-HT1B receptor antagonist), BRL 15572 (5-HT1D receptor antagonist), and ketanserin (5-HT2A receptor antagonist). Lerimazoline displayed high affinity for the 5-HT1A receptor (Ki = 162.5 nM), similar to the previously reported affinity for the 5-HT1D receptor. Binding affinity estimates (Ki) for α1, 5-HT2A, and D2 receptors were 6656, 4202 and 3437.5 nM, respectively (the literature reported Ki for 5-HT1B receptor is 3480 nM). Lerimazoline caused concentration-dependent contractions in 70% of preparations, varying in the range between 40% and 55% of the maximal contraction elicited by phenylephrine. While prazosin reduced the maximum contractile response to lerimazoline, rauwolscine showed a non-significant trend in reduction of the response. Both ketanserin (10 nM and 1 µM) and methiothepin strongly suppressed the maximum response to lerimazoline. Overall, our results suggest that 5-HT2A and, less distinctly, α1-adrenergic receptors are involved in the lerimazoline-induced contractions, which makes lerimazoline an "atypical" decongestant.

The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens

PubMed Central

Canal, Clinton E; Murnane, Kevin S

2017-01-01

Classic hallucinogens share pharmacology as serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonists. Unique among most other Schedule 1 drugs, they are generally non-addictive and can be effective tools in the treatment of addiction. Mechanisms underlying these attributes are largely unknown. However, many preclinical studies show that 5-HT2C agonists counteract the addictive effects of drugs from several classes, suggesting this pharmacological property of classic hallucinogens may be significant. Drawing from a comprehensive analysis of preclinical behavior, neuroanatomy, and neurochemistry studies, this review builds rationale for this hypothesis, and also proposes a testable, neurobiological framework. 5-HT2C agonists work, in part, by modulating dopamine neuron activity in the ventral tegmental area—nucleus accumbens (NAc) reward pathway. We argue that activation of 5-HT2C receptors on NAc shell, GABAergic, medium spiny neurons inhibits potassium Kv1.x channels, thereby enhancing inhibitory activity via intrinsic mechanisms. Together with experiments that show that addictive drugs, such as cocaine, potentiate Kv1.x channels, thereby suppressing NAc shell GABAergic activity, this hypothesis provides a mechanism by which classic hallucinogen-mediated stimulation of 5-HT2C receptors could thwart addiction. It also provides a potential reason for the non-addictive nature of classic hallucinogens. PMID:27903793

Membrane fluidization by alcohols inhibits DesK-DesR signalling in Bacillus subtilis.

PubMed

Vaňousová, Kateřina; Beranová, Jana; Fišer, Radovan; Jemioła-Rzemińska, Malgorzata; Matyska Lišková, Petra; Cybulski, Larisa; Strzałka, Kazimierz; Konopásek, Ivo

2018-03-01

After cold shock, the Bacillus subtilis desaturase Des introduces double bonds into the fatty acids of existing membrane phospholipids. The synthesis of Des is regulated exclusively by the two-component system DesK/DesR; DesK serves as a sensor of the state of the membrane and triggers Des synthesis after a decrease in membrane fluidity. The aim of our work is to investigate the biophysical changes in the membrane that are able to affect the DesK signalling state. Using linear alcohols (ethanol, propanol, butanol, hexanol, octanol) and benzyl alcohol, we were able to suppress Des synthesis after a temperature downshift. The changes in the biophysical properties of the membrane caused by alcohol addition were followed using membrane fluorescent probes and differential scanning calorimetry. We found that the membrane fluidization induced by alcohols was reflected in an increased hydration at the lipid-water interface. This is associated with a decrease in DesK activity. The addition of alcohol mimics a temperature increase, which can be measured isothermically by fluorescence anisotropy. The effect of alcohols on the membrane periphery is in line with the concept of the mechanism by which two hydrophilic motifs located at opposite ends of the transmembrane region of DesK, which work as a molecular caliper, sense temperature-dependent variations in membrane properties. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed Central

2015-01-01

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

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

PubMed Central

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

1995-01-01

1. The pharmacological properties of 5-hydroxytryptamine (5-HT), the 5-HT4 receptor agonists, DAU 6236 and SC 53116 and the 5-HT4 receptor antagonist, GR 1130808, were studied in the rat oesophagus, rat ileum and human colon. 2. 5-HT relaxed the longitudinal muscle of the rat oesophagus and rat ileum and the circular muscle of the human colon. Absolute values of relaxation were measured and showed the order of the maximum responses, rat oesophagus >> human colon > rat ileum with EC50 values of 189 +/- 15 nM, 157 +/- 4 nM, 306 +/- 72 nM, respectively. 5-HT also inhibited the spontaneous contractions of the human colon with an EC50 value of 119 +/- 1 nM. The effect of 5-HT on the human colon was not affected by methysergide (10 microM) or ondansetron (1 microM). 3. The use of the uptake and metabolism inhibitors, cocaine (30 microM) and pargyline (100 microM), did not increase the potency of 5-HT in the rat oesophagus or human colon. In the rat oesophagus, cocaine (30 microM) produced a reduction in carbachol-induced tone of 22.2 +/- 0.6% and reduced the 5-HT maximum effect by 52.0 +/- 0.4%. 4. The compounds, DAU 6236 and SC 53116, showed a different pattern of potencies and efficacies in the rat oesophagus, rat ileum and human colon compared to 5-HT. DAU 6236 relaxed the human colonic circular muscle with an EC50 value of 129 +/- 16 nM but its efficacy was less than that of 5-HT. DAU 6236 (1 microM) also antagonized the 5-HT-induced relaxation of the human colon with a dose-ratio of 9.9. In the rat oesophagus and rat ileum, DAU 6236 was inactive in the majority of tissues. In the minority of oesophagus tissues that did respond the EC50 value was 1.2 +/- 0.7 microM. DAU 6236 also antagonized the effect of 5-HT in the rat oesophagus in a non-surmountable fashion. SC 53116 relaxed the rat oesophagus with an EC50 value of 91 +/- 4 nM, with an efficacy less than that observed to 5-HT; however, at 200 nM it did not antagonize the 5-HT-induced relaxation of the rat

The roles of 5-HT1A and 5-HT2 receptors in the effects of 5-MeO-DMT on locomotor activity and prepulse inhibition in rats.

PubMed

Krebs-Thomson, Kirsten; Ruiz, Erbert M; Masten, Virginia; Buell, Mahalah; Geyer, Mark A

2006-12-01

The hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is structurally similar to other indoleamine hallucinogens such as LSD. The present study examined the effects of 5-MeO-DMT in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration, and the prepulse inhibition of startle (PPI) paradigm. A series of interaction studies using the serotonin (5-HT)(1A) antagonist WAY-100635 (1.0 mg/kg), the 5-HT(2A) antagonist M100907 (1.0 mg/kg), and the 5-HT(2C) antagonist SER-082 (0.5 mg/kg) were performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) in the BPM and PPI paradigms. 5-MeO-DMT decreased locomotor activity, investigatory behavior, the time spent in the center of the BPM chamber, and disrupted PPI. All of these effects were antagonized by WAY-100635 pretreatment. M100907 pretreatment failed to attenuate any of these effects, while SER-082 pretreatment only antagonized the PPI disruption produced by 5-MeO-DMT. While the prevailing view was that the activation of 5-HT(2) receptors is solely responsible for hallucinogenic drug effects, these results support a role for 5-HT(1A) receptors in the effects of the indoleamine hallucinogen 5-MeO-DMT on locomotor activity and PPI in rats.

Role of 5-HT1-7 receptors in short- and long-term memory for an autoshaping task: intrahippocampal manipulations.

PubMed

Liy-Salmeron, Gustavo; Meneses, Alfredo

2007-05-25

It was previously reported that brain areas containing serotonin (5-hydroxytryptamine, 5-HT) receptors mediate memory consolidation as well as short (STM)- and long-term memory (LTM). Here the effects of systemic and intrahippocampal administration of 5-HT agonists and antagonists on an autoshaping learning task were explored, which requires hippocampal translation and transduction as well as 5-HT receptors expression. As previously reported ketamine (glutamatergic antagonist) and two well-known amnesic drugs, scopolamine (cholinergic antagonist) and dizocilpine (NMDA antagonist) impaired STM but not LTM; dizocilpine even improved the latter. Since ketamine produces hallucinations and impairs memory in humans, we address the question if well-known antipsychotic haloperidol and clozapine might affect STM deficit. Indeed, systemic administration of clozapineHT(1A/2A/6/7) receptors, systemic and intrahippocampal administration of 5-HT drugs were further explored. The ketamine STM-induced deficit was blocked by 8-OHDPAT (5-HT(1A/7) agonist) and SB-399885 (a 5-HT(6) antagonist) but not by 5-HT(1B), 5-HT(2) and 5-HT(7) antagonists, thus implicating 5-HT(1A/7) and 5-HT(6) receptors. These data also suggest that ketamine (at 10 mg/kg) represents a reliable pharmacological tool to explore memory deficits related to hippocampus and schizophrenia.

Etude du processus de changement vecu par des familles ayant decide d'adopter volontairement des comportements d'attenuation des changements climatiques

NASA Astrophysics Data System (ADS)

Leger, Michel T.

Les activites humaines energivores telles l'utilisation intensive de l'automobile, la surconsommation de biens et l'usage excessif d'electricite contribuent aux changements climatiques et autres problemes environnementaux. Bien que plusieurs recherches rapportent que l'etre humain est de plus en plus conscient de ses impacts sur le climat de la planete, ces memes recherches indiquent qu'en general, les gens continuent a se comporter de facon non ecologique. Que ce soit a l'ecole ou dans la communaute, plusieurs chercheurs en education relative a l'environnement estiment qu'une personne bien intentionnee est capable d'adopter des comportements plus respectueux de l'environnement. Le but de cette these etait de comprendre le processus d'integration de comportements d'attenuation des changements climatiques dans des familles. A cette fin, nous nous sommes fixe deux objectifs : 1) decrire les competences et les procedes qui favorisent l'adoption de comportements d'attenuation des changements climatiques dans des familles et 2) decrire les facteurs et les dynamiques familiales qui facilitent et limitent l'adoption de comportements d'attenuation des changements climatiques dans des familles. Des familles ont ete invitees a essayer des comportements personnels et collectifs d'attenuation des changements climatiques de sorte a integrer des modes de vie plus ecologiques. Sur une periode de huit mois, nous avons suivi leur experience de changement afin de mieux comprendre comment se produit le processus de changement dans des familles qui decident volontairement d'adopter des comportements d'attenuation des changements climatiques. Apres leur avoir fourni quelques connaissances de base sur les changements climatiques, nous avons observe le vecu de changement des familles durant huit mois d'essais a l'aide de journaux reflexifs, d'entretiens d'explicitation et du journal du chercheur. La these comporte trois articles scientifiques. Dans le premier article, nous presentons une

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

PubMed

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

1995-05-01

1. The pharmacological properties of 5-hydroxytryptamine (5-HT), the 5-HT4 receptor agonists, DAU 6236 and SC 53116 and the 5-HT4 receptor antagonist, GR 1130808, were studied in the rat oesophagus, rat ileum and human colon. 2. 5-HT relaxed the longitudinal muscle of the rat oesophagus and rat ileum and the circular muscle of the human colon. Absolute values of relaxation were measured and showed the order of the maximum responses, rat oesophagus > human colon > rat ileum with EC50 values of 189 +/- 15 nM, 157 +/- 4 nM, 306 +/- 72 nM, respectively. 5-HT also inhibited the spontaneous contractions of the human colon with an EC50 value of 119 +/- 1 nM. The effect of 5-HT on the human colon was not affected by methysergide (10 microM) or ondansetron (1 microM). 3. The use of the uptake and metabolism inhibitors, cocaine (30 microM) and pargyline (100 microM), did not increase the potency of 5-HT in the rat oesophagus or human colon. In the rat oesophagus, cocaine (30 microM) produced a reduction in carbachol-induced tone of 22.2 +/- 0.6% and reduced the 5-HT maximum effect by 52.0 +/- 0.4%. 4. The compounds, DAU 6236 and SC 53116, showed a different pattern of potencies and efficacies in the rat oesophagus, rat ileum and human colon compared to 5-HT. DAU 6236 relaxed the human colonic circular muscle with an EC50 value of 129 +/- 16 nM but its efficacy was less than that of 5-HT. DAU 6236 (1 microM) also antagonized the 5-HT-induced relaxation of the human colon with a dose-ratio of 9.9. In the rat oesophagus and rat ileum, DAU 6236 was inactive in the majority of tissues. In the minority of oesophagus tissues that did respond the EC50 value was 1.2 +/- 0.7 microM. DAU 6236 also antagonized the effect of 5-HT in the rat oesophagus in a non-surmountable fashion. SC 53116 relaxed the rat oesophagus with an EC50 value of 91 +/- 4 nM, with an efficacy less than that observed to 5-HT; however, at 200 nM it did not antagonize the 5-HT-induced relaxation of the rat

Design of the Cryostat for HT-7U Superconducting Tokamak

NASA Astrophysics Data System (ADS)

Yu, Jie; Wu, Song-tao; Song, Yun-tao; Weng, Pei-de

2002-06-01

The cryostat of HT-7U tokamak is a large vacuum vessel surrounding the entire basic machine with a cylindrical shell, a dished top and a flat bottom. The main function of HT-7U cryostat is to provide a thermal barrier between an ambient temperature test hall and a liquid helium-cooled superconducting magnet. The loads applied to the cryostat are from sources of vacuum pressure, dead weight, seismic events and electromagnetic forces originated by eddy currents. It also provides feed-through penetrations for all the connecting elements inside and outside the cryostat. The main material selected for the cryostat is stainless steel 304L. The structural analyses including buckling for the cryostat vessel under the plasma operation condition have been carried out by using a finite element code. Stress analysis results show that the maximum stress intensity was below the allowable value. In this paper, the structural analyses and design of HT-7U cryostat are emphasized.

Characteristics of 5-HT-containing chemoreceptor cells of the chicken aortic body

PubMed Central

Ito, Shigeo; Ohta, Toshio; Nakazato, Yoshikazu

1999-01-01

Voltage-dependent and oxygen-sensitive currents in 5-HT-containing epithelioid cells isolated from chicken thoracic aorta were examined using the whole-cell patch clamp technique. 5-HT immunoreactive cells were identified with Neutral Red. The release of 5-HT from chicken thoracic aorta in the presence of excess KCl and veratridine was also examined using HPLC. At a holding potential of −70 mV with CsCl pipette solution, depolarizing steps between −30 and +60 mV produced inward currents that were blocked by tetrodotoxin (0.2 μm). In the presence of tetrodotoxin and BaCl2 (5 mm), depolarizing steps evoked slow inward currents that were sensitive to CoCl2 (2 mm). Nifedipine (1 μm) decreased the currents to 79.4 ± 1.7%, and ω-conotoxin GVIA (1 μm) to 20.2 ± 3.8%. When KCl pipette solution was used, depolarizing potentials positive to −40 mV caused outward currents that were inhibited by tetraethylammonium chloride. The K+ currents evoked by depolarizing steps to +20 mV were reduced to 90.3 ± 0.8% by hypoxia in five out of seven cells. Two cells failed to respond to hypoxia. The K+ current response was partly decreased by Neutral Red (20 μm). Excess KCl (60 mm) and veratridine (30 μm) both caused the release of 5-HT from aortic strips. 5-HT outputs induced by both stimuli were partly inhibited by nifedipine (1 μm) and by ω-conotoxin GVIA (1 μm), and were abolished by these drugs in combination and by extracellular Ca2+ removal. These results suggest that epithelioid cells containing 5-HT act as chemoreceptor cells in the chicken aortic body, having voltage-dependent Na+, K+, and L- and N-type Ca2+ channels, and oxygen-sensitive K+ channels. PMID:9925877

NK1R/5-HT1AR interaction is related to the regulation of melanogenesis.

PubMed

Wu, Huali; Zhao, Yucheng; Huang, Qiaoling; Cai, Minxuan; Pan, Qi; Fu, Mengsi; An, Xiaohong; Xia, Zhenjiang; Liu, Meng; Jin, Yu; He, Ling; Shang, Jing

2018-06-01

Substance P (SP) is a candidate mediator along the brain-skin axis and can mimic the effects of stress to regulate melanogenesis. Previously, we and others have found that the regulation of SP for pigmentary function was mediated by neurokinin 1 receptor (NK1R). Emerging evidence has accumulated that psychologic stress can induce dysfunction in the cutaneous serotonin 5-hydroxytryptamine (5-HT)-5-HT1A/1B receptor system, thereby resulting in skin hypopigmentation. Moreover, NK1R and 5-HTR (except 5-HT3) belong to GPCR. The present study aimed at assessing the possible existence of NK1R-5-HTR interactions and related melanogenic functions. Western blot and PCR detection revealed that SP reduced expression of 5-HT1A receptor via the NK1 receptor. Biochemical analyses showed that NK1R and 5-HT1AR could colocalize and interact in a cell and in the skin. When the N terminus of the NK1R protein was removed NK1R surface targeting was prevented, the interaction between NK1R-5-HT1AR decreased, and the depigmentation caused by SP and WAY100635 could be rescued. Importantly, pharmaceutical coadministration of NK1R agonist (SP) and 5-HT1A antagonist (WAY100635) enhanced the NK1-5-HT1A receptor coimmunoprecipitation along with the depigmentary response. SP and WAY100635 cooperation elicited activation of a signaling cascade (the extracellular, regulated protein kinase p-JNK signaling pathway) and inhibition of p70S6K1 phosphorylation and greatly reduced melanin production in vitro and in vivo in mice and zebrafish. Moreover, the SP-induced depigmentation response did not be occur in 5-htr1aa +/- zebrafish embryos. Taken together, the results of our systemic study increases our knowledge of the roles of NK1R and 5-HT1AR in melanogenesis and provides possible, novel therapeutic strategies for treatment of skin hypo/hyperpigmentation.-Wu, H., Zhao, Y., Huang, Q., Cai, M., Pan, Q., Fu, M., An, X., Xia, Z., Liu, M., Jin, Y., He, L., Shang, J. NK1R/5-HT1AR interaction is related to

Antidepressant-like responses to the combined sigma and 5-HT1A receptor agonist OPC-14523.

PubMed

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

2001-12-01

The antidepressant-like activity of a novel compound, OPC-14523, was investigated in comparison with the conventional antidepressants, fluoxetine and imipramine. OPC-14523 bound with nanomolar affinities to sigma receptors (IC(50)=47-56 nM), the 5-HT(1A) receptor (IC(50)=2.3 nM), and the 5-HT transporter (IC(50)=80 nM). OPC-14523 inhibited the in vitro reuptake of 3H-5-HT (IC(50)=27 nM), but it showed very weak inhibitory activity on 3H-NE and 3H-DA reuptake. OPC-14523 did not inhibit MAO A or B activities or muscarinic receptors. A single oral administration of OPC-14523 produced a marked antidepressant-like effect in the forced swimming test (FST) with rats (ED(50)=27 mg/kg) and mice (ED(50)=20mg/kg) without affecting the general locomotor activity. In contrast, fluoxetine and imipramine each required at least four days of repeated dosing to show this activity. The acute activity of OPC-14523 was blocked by pretreatment with the sigma receptor antagonist NE-100 or the selective 5-HT(1A) receptor antagonist WAY-100635. The induction of flat body posture by OPC-14523 was blocked by the selective 5-HT(1A) receptor antagonist NAN-190, and forebrain 5-HT biosynthesis was attenuated by OPC-14523 at behaviorally effective doses. In contrast, OPC-14523, unlike fluoxetine, failed to inhibit 5-HT reuptake at oral doses below 100mg/kg. Thus, the acute antidepressant-like action of OPC-14523 is achieved by the combined stimulation of sigma and 5-HT(1A) receptors without inhibition of 5-HT reuptake in vivo.

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

PubMed Central

Green, A R

2008-01-01

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

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

PubMed

Green, A R

2008-08-01

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

Effects of the 5-HT7 receptor antagonists SB-269970 and DR 4004 in autoshaping Pavlovian/instrumental learning task.

PubMed

Meneses, Alfredo

2004-12-06

There is an important debate regarding the functional role of the 5-HT(1A) and 5-HT(7) receptor in memory systems. Hence, the objective of this paper is to investigate the function of serotonin (5-hydroxytryptamine, 5-HT) in memory consolidation, utilising an autoshaping Pavlovian/instrumental learning test. Specific antagonists at 5-HT(1A) (WAY 100635) and 5-HT(7) (SB-269970 or DR 4004) receptors administered i.p. or s.c.) after training, significantly decreased the improvement of performance produced by the 5-HT(1A/7) agonist 8-OH-DPAT to levels lower than controls'. These same antagonists attenuated the decreased level of performance produced by mCPP, although they decrease the performance levels after p-chloroamphetamine (PCA) lesion of the 5-HT system, which has no effect on its own on the conditioned response. Moreover, SB-269970 or DR 4004 reversed amnesia induced by scopolamine and dizocilpine. These data confirm a role for 5-HT(1A) and 5-HT(7) receptors in memory formation and support the hypothesis that serotonergic, cholinergic, and glutamatergic systems interact in cognitively impaired animals. These findings support a potential role for both 5-HT(1A) and 5-HT(7) receptors in the pathophysiology and/or treatment of schizophrenia, cognitive deficits and the mechanism of action of atypical antipsychotic drugs.

Potentiation of transient receptor potential V1 functions by the activation of metabotropic 5-HT receptors in rat primary sensory neurons

PubMed Central

Ohta, Toshio; Ikemi, Yuki; Murakami, Matsuka; Imagawa, Toshiaki; Otsuguro, Ken-ichi; Ito, Shigeo

2006-01-01

5-Hydroxytryptamine (5-HT) is one of the major chemical mediators released in injured and inflamed tissue and is capable of inducing hyperalgesia in vivo. However, the cellular mechanisms of 5-HT-induced hyperalgesia remain unclear. Transient receptor potential V1 (TRPV1) plays a pivotal role in nociceptive receptors. In the present study, we determined whether 5-HT changes TRPV1 functions in cultured dorsal root ganglion (DRG) neurons isolated from neonatal rats, using Ca2+ imaging and whole-cell patch-clamp techniques. In more than 70% of DRG neurons, 5-HT potentiated the increases of [Ca2+]i induced by capsaicin, protons and noxious heat. Capsaicin-induced current and depolarizing responses, and proton-induced currents were also augmented by 5-HT. RT-PCR analysis revealed the expression of 5-HT2A and 5-HT7 receptors in rat DRG neurons. Agonists for 5-HT2A and 5-HT7 receptors mimicked the potentiating effect of 5-HT, and their antagonists decreased it. In DRG ipsilateral to the complete Freund's adjuvant-injected inflammation side, expression levels of 5-HT2A and 5-HT7 mRNAs increased, and the potentiating effect of 5-HT was more prominent than in the contralateral control side. These results suggest that the PKC- and PKA-mediated signalling pathways are involved in the potentiating effect of 5-HT on TRPV1 functions through the activation of 5-HT2A and 5-HT7 receptors, respectively. Under inflammatory conditions, the increases of the biosynthesis of these 5-HT receptors may lead to further potentiation of TRPV1 functions, resulting in the generation of inflammatory hyperalgesia in vivo. PMID:16901936

Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist

PubMed Central

Newman-Tancredi, A; Martel, J-C; Assié, M-B; Buritova, J; Lauressergues, E; Cosi, C; Heusler, P; Slot, L Bruins; Colpaert, FC; Vacher, B; Cussac, D

2009-01-01

Background and purpose: Activation of post-synaptic 5-HT1A receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT1A receptor agonist. Experimental approach: F15599 was compared with a chemical congener, F13714, and with (+)8-OH-DPAT in models of signal transduction in vitro and ex vivo. Key results: F15599 was highly selective for 5-HT1A receptors in binding experiments and in [35S]-GTPγS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5-HT1A receptors. In cell lines expressing h5-HT1A receptors, F15599 more potently stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, compared with G-protein activation, internalization of h5-HT1A receptors or inhibition of cAMP accumulation. F13714, (+)8-OH-DPAT and 5-HT displayed a different rank order of potency for these responses. F15599 stimulated [35S]-GTPγS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated Gαi than Gαo activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT1A receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT1A receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT1A receptors in vivo almost as potently as F13714. Conclusions and implications: F15599 showed a distinctive activation profiles for 5-HT1A receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT1A receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition. PMID:19154445

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment.

PubMed

Palacios, Jose M; Pazos, Angel; Hoyer, Daniel

2017-05-01

This paper is a personal account on the discovery and characterization of the 5-HT 2C receptor (first known as the 5-HT 1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT 2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT 1C R, the 5-HT 2C R was discovered while studying the pharmacological features and the distribution of [ 3 H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [ 3 H]mesulergine-labelling to the rat choroid plexus. [ 3 H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT 2 binding, the new binding site was called 5-HT 1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT 1C R (later named 5-HT 2C ) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT 2C R is a GPCR, with a very complex gene structure. It constitutes a rarity in the GPCR family: many 5-HT 2C R variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT 2C R splice variants. Intense research led to therapeutically active 5-HT 2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5-HT 2C R antagonists/inverse agonists. Agomelatine, a 5-HT 2C R antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction

Acute effects of moclobemide and deprenyl on 5-HT synthesis rates in the rat brain: An autoradiographic study.

PubMed

Nishi, Kyoko; Mück-Seler, Dorotea; Hasegawa, Shu; Watanabe, Arata; Diksic, Mirko

2006-10-16

Serotonin (5-HT), norepinephrine (NE) and dopamine (DA) released from nerve terminals in the brain are primarily removed from the synaptic cleft by a reuptake mechanism. In part, the homeostasis is maintained by monoamine oxidase (MAO) deamination achieved primarily intracellularly. The present study's aim was to examine the effect of the acute administration of the MAO inhibitors, moclobemide (a MAO-A inhibitor) and deprenyl (a MAO-B inhibitor), on 5-HT synthesis rates, measured in discrete regions of the rat brain by an autoradiographic method, using alpha-[14C]methyl-l-tryptophan as a tracer. MAO inhibitors have different effects on 5-HT synthesis rates in the cell bodies and areas of the nerve terminals. Moclobemide (10 mg/kg, i.p. 30 min before the tracer injection) and deprenyl (3 mg/kg, i.p. 2 h before the tracer injection) decreased the 5-HT synthesis rates in the dorsal (-18% and -22%) and median (-22% and -33%) raphe, respectively. Moclobemide also significantly decreased 5-HT synthesis in the entire nerve terminal areas investigated. The reductions were between 23% (cingulate cortex) and 50% (locus coeruleus). Deprenyl did not significantly affect 5-HT synthesis in the nerve terminals. The present results suggest that MAO-A, and to a lesser extent, MAO-B, are involved in the regulation of 5-HT synthesis in the rat brain. The mechanism(s) of MAO inhibitors' action on 5-HT synthesis in the raphe nuclei are probably related to an increase in the extraneuronal 5-HT concentration and also to the interaction between the serotonergic and catecholaminergic neurons. The reduction of 5-HT synthesis in the raphe nuclei likely occurs by an action of extracellular 5-HT via the dendritic autoreceptors with a possible contribution from the action of extracellular DA and NE. In the terminal regions, the most likely mechanism is via the presynaptic autoreceptors through which elevated extraneuronal 5-HT acts on synthesis control. However, there is also a possibility that

The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT3 receptors.

PubMed

Lochner, Martin; Thompson, Andrew J

2016-09-01

Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [(3)H]granisetron (Ki = 6.76 μM) and G-FL (Ki = 4.90 μM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 μM, and competed with G-FL with a Ki of 7.94 μM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 μM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Robust presynaptic serotonin 5-HT1B receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment

PubMed Central

Ding, Shengyuan; Li, Li

2015-01-01

The striatonigral projection is a striatal output pathway critical to motor control, cognition, and emotion regulation. Its axon terminals in the substantia nigra pars reticulata (SNr) express a high level of serotonin (5-HT) type 1B receptors (5-HT1BRs), whereas the SNr also receives an intense 5-HT innervation that expresses 5-HT transporters, providing an anatomic substrate for 5-HT and selective 5-HT reuptake inhibitor (SSRI)-based antidepressant treatment to regulate the striatonigral output. In this article we show that 5-HT, by activating presynaptic 5-HT1BRs on the striatonigral axon terminals, potently inhibited the striatonigral GABA output, as reflected in the reduction of the striatonigral inhibitory postsynaptic currents in SNr GABA neurons. Functionally, 5-HT1BR agonism reduced the striatonigral GABA output-induced pause of the spontaneous high-frequency firing in SNr GABA neurons. Equally important, chronic SSRI treatment with fluoxetine enhanced this presynaptic 5-HT1BR-mediated pause reduction in SNr GABA neurons. Taken together, these results indicate that activation of the 5-HT1BRs on the striatonigral axon terminals can limit the motor-promoting GABA output. Furthermore, in contrast to the desensitization of 5-HT1 autoreceptors, chronic SSRI-based antidepressant treatment sensitizes this presynaptic 5-HT1BR-mediated effect in the SNr, a novel cellular mechanism that alters the striatonigral information transfer, potentially contributing to the behavioral effects of chronic SSRI treatment. PMID:25787955

Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Sojin; Jin, Zhenhua; Lee, Goeun

2015-01-02

Highlights: • Prostaglandin E2 (PGE{sub 2}) effect was tested on visceral afferent neurons. • PGE{sub 2} did not evoke response but potentiated serotonin (5-HT) currents up to 167%. • PGE{sub 2}-induced potentiation was blocked by E-prostanoid type 4 receptors antagonist. • PGE{sub 2} effect on 5-HT response was also blocked by protein kinase A inhibitor KT5720. • Thus, PGE{sub 2} modulate visceral afferent neurons via synergistic signaling with 5-HT. - Abstract: Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E{sub 2} (PGE{sub 2}) level increase was oftenmore » reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE{sub 2} induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE{sub 2} effect on visceral afferent sensory neurons of the rat. Interestingly, PGE{sub 2} itself did not evoked any response but enhanced serotonin (5-HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE{sub 2}-induced potentiation were blocked by a selective E-prostanoid type4 (EP{sub 4}) receptors antagonist, L-161,982, but type1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE{sub 2} effects. PGE{sub 2} induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE{sub 2} potentiation of 5-HT currents. Our findings may open a possibility for screen a new type drugs with lower side effects than currently using steroidal

The postnatal 5-HT1A receptor regulates adult anxiety and depression differently via multiple molecules.

PubMed

Ishikawa, Chihiro; Shiga, Takashi

2017-08-01

Serotonin (5-HT) and the 5-HT 1A receptor during development are known to modulate anxiety and depression in later life. However, the brain mechanisms linking the postnatal 5-HT system and adult behavior remain unknown. Here, we examined the effects of pharmacological 5-HT 1A receptor activation during the postnatal period on anxiety and depression-like behavior in adult BALB/c male mice. To elucidate the underlying mechanisms, we measured mRNA expression of the 5-HT 1A receptor, brain-derived neurotrophic factor (BDNF), GABA A receptor subunits, and AMPA receptor subunits in the medial prefrontal cortex (mPFC), amygdala, and hippocampus. Treatment with the selective 5-HT reuptake inhibitor (fluoxetine) and 5-HT 1A receptor agonist (8-OH-DPAT) during the postnatal period decreased anxiety-like behavior in adulthood, whereas only 8-OH-DPAT treatment increased depression-like behavior. Concomitantly with the behavioral effects, postnatal treatment with fluoxetine and 8-OH-DPAT decreased the mRNA expression of the GABA A receptor α3 subunit in the mPFC and ventral hippocampus in adulthood, while 8-OH-DPAT, but not fluoxetine, decreased the mRNA expression of the 5-HT 1A receptor and BDNF in the mPFC and the GABA A receptor α2 subunit in the mPFC and ventral hippocampus. On the basis of the correlative changes between behavior and mRNA expression, these results suggest that the GABA A receptor α3 subunit in the mPFC and ventral hippocampus may regulate anxiety-like behavior. In contrast, depression-like behavior may be regulated by the 5-HT 1A receptor and BDNF in the mPFC and by the GABA A receptor α2 subunit in the mPFC and ventral hippocampus. In summary, activation of the 5-HT 1A receptor during the postnatal period may reduce anxiety levels, but increase depression levels during adulthood via different multiple molecules in the mPFC and ventral hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

Des ballons pour demain

NASA Astrophysics Data System (ADS)

Régipa, R.

A partir d'une théorie sur la détermination des formes et des contraintes globales d'un ballon de révolution, ou s'en rapprochant, une nouvelle famille de ballons a été définie. Les ballons actuels, dits de ``forme naturelle'', sont calculés en général pour une tension circonférencielle nulle. Ainsi, pour une mission donnée, la tension longitudinale et la forme de l'enveloppe sont strictement imposées. Les ballons de la nouvelle génération sont globalement cylindriques et leurs pôles sont réunis par un câble axial, chargé de transmettre une partie des efforts depuis le crochet (pôle inférieur), directement au pôle supérieur. De plus, la zone latérale cylindrique est soumise à un faible champ de tensions circonférencielles. Ainsi, deux paramètres permettent de faire évoluer la distribution des tensions et la forme de l'enveloppe: - la tension du câble de liaison entre pôles (ou la longueur de ce câble) - la tension circonférencielle moyenne désirée (ou le rayon du ballon). On peut donc calculer et réaliser: - soit des ballons de forme adaptée, comme les ballons à fond plat pour le bon fonctionnement des montgolfières infrarouge (projet MIR); - soit des ballons optimisés pour une bonne répartition des contraintes et une meilleure utilisation des matériaux d'enveloppe, pour l'ensemble des programmes stratosphériques. Il s'ensuit une économie sensible des coûts de fabrication, une fiabilité accrue du fonctionnement de ces ballons et une rendement opérationnel bien supérieur, permettant entre autres, d'envisager des vols à très haute altitude en matériaux très légers.

(+)Lysergic acid diethylamide, but not its nonhallucinogenic congeners, is a potent serotonin 5HT1C receptor agonist

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burris, K.D.; Breeding, M.; Sanders-Bush, E.

Activation of central serotonin 5HT2 receptors is believed to be the primary mechanism whereby lysergic acid diethylamide (LSD) and other hallucinogens induce psychoactive effects. This hypothesis is based on extensive radioligand binding and electrophysiological and behavioral studies in laboratory animals. However, the pharmacological profiles of 5HT2 and 5HT1C receptors are similar, making it difficult to distinguish between effects due to activation of one or the other receptor. For this reason, it was of interest to investigate the interaction of LSD with 5HT1C receptors. Agonist-stimulated phosphoinositide hydrolysis in rat choroid plexus was used as a direct measure of 5HT1C receptor activation.more » (+)LSD potently stimulated phosphoinositide hydrolysis in intact choroid plexus and in cultures of choroid plexus epithelial cells, with EC50 values of 9 and 26 nM, respectively. The effect of (+)LSD in both systems was blocked by 5HT receptor antagonists with an order of activity consistent with interaction at 5HT1C receptors. Neither (+)-2-bromo-LSD nor lisuride, two nonhallucinogenic congeners of LSD, were able to stimulate 5HT1C receptors in cultured cells or intact choroid plexus. In contrast, lisuride, like (+)LSD, is a partial agonist at 5HT2 receptors in cerebral cortex slices and in NIH 3T3 cells transfected with 5HT2 receptor cDNA. The present finding that (+)LSD, but not its nonhallucinogenic congeners, is a 5HT1C receptor agonist suggests a possible role for these receptors in mediating the psychoactive effects of LSD.« less

Diethylstilbestrol (DES) and Cancer

MedlinePlus

... Genetics Services Directory Cancer Prevention Overview Research Diethylstilbestrol (DES) and Cancer On This Page What is DES? ... outlined in the table below. Fertility Problems in DES Daughters ( 7 ) Fertility Complication Hazard Ratio Percent Cumulative ...

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barrett, R.J.; Appell, K.C.; Kilpatrick, B.F.

1991-01-01

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

Neuroprotective effect of Aronia melanocarpa extract against glutamate-induced oxidative stress in HT22 cells.

PubMed

Lee, Hyeon Yong; Weon, Jin Bae; Ryu, Gahee; Yang, Woo Seung; Kim, Nam Young; Kim, Myong Ki; Ma, Choong Je

2017-04-11

Glutamate (an endogenous excitatory neurotransmitter) at high concentrations contributes to the development of neurodegenerative diseases. Aronia melanocarpa (A. melanocarpa) berries contain anthocyanins and have high antioxidant activities. In this study, we evaluated whether A. melanocarpa berries could protect neuronal cells against glutamate-induced oxidative stress. A. melanocarpa berries exerted a protective effect against cytotoxicity in HT22 mouse hippocampal cells by MTT assay. We evaluated oxidative stress parameters including ROS level, intracellular Ca 2+ level, glutathione level and antioxidant enzyme activity in HT22 cells to elucidate the mechanism of its neuroprotective effect. A. melanocarpa berries decreased glutamate-induced death of HT22 cells. In addition, A. melanocarpa berries reduced ROS and intracellular Ca 2+ levels. Glutathione level, antioxidant enzymes, glutathione reductase and glutathione peroxide activities and mitochondrial membrane potential were also increased in HT22 cells. These results suggested that A. melanocarpa berries protected HT22 cells by exerting an antioxidant effect.

Maladie des vibrations

PubMed Central

Shen, Shixin (Cindy); House, Ronald A.

2017-01-01

Résumé Objectif Permettre aux médecins de famille de comprendre l’épidémiologie, la pathogenèse, les symptômes, le diagnostic et la prise en charge de la maladie des vibrations, une maladie professionnelle importante et courante au Canada. Sources d’information Une recherche a été effectuée sur MEDLINE afin de relever les recherches et comptes rendus portant sur la maladie des vibrations. Une recherche a été effectuée sur Google dans le but d’obtenir la littérature grise qui convient au contexte canadien. D’autres références ont été tirées des articles relevés. Message principal La maladie des vibrations est une maladie professionnelle répandue touchant les travailleurs de diverses industries qui utilisent des outils vibrants. La maladie est cependant sous-diagnostiquée au Canada. Elle compte 3 éléments : vasculaire, sous la forme d’un phénomène de Raynaud secondaire; neurosensoriel; et musculosquelettique. Aux stades les plus avancés, la maladie des vibrations entraîne une invalidité importante et une piètre qualité de vie. Son diagnostic exige une anamnèse minutieuse, en particulier des antécédents professionnels, un examen physique, des analyses de laboratoire afin d’éliminer les autres diagnostics, et la recommandation en médecine du travail aux fins d’investigations plus poussées. La prise en charge consiste à réduire l’exposition aux vibrations, éviter les températures froides, abandonner le tabac et administrer des médicaments. Conclusion Pour assurer un diagnostic rapide de la maladie des vibrations et améliorer le pronostic et la qualité de vie, les médecins de famille devraient connaître cette maladie professionnelle courante, et pouvoir obtenir les détails pertinents durant l’anamnèse, recommander les patients aux cliniques de médecine du travail et débuter les demandes d’indemnisation de manière appropriée. PMID:28292812

Clozapine Reverses Phencyclidine-Induced Desynchronization of Prefrontal Cortex through a 5-HT1A Receptor-Dependent Mechanism

PubMed Central

Kargieman, Lucila; Riga, Maurizio S; Artigas, Francesc; Celada, Pau

2012-01-01

The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP)—used as a pharmacological model of schizophrenia—disrupts prefrontal cortex (PFC) activity. PCP markedly increased the discharge rate of pyramidal neurons and reduced slow cortical oscillations (SCO; 0.15–4 Hz) in rat PFC. Both effects were reversed by classical (haloperidol) and atypical (clozapine) antipsychotic drugs. Here we extended these observations to mice brain and examined the potential involvement of 5-HT2A and 5-HT1A receptors (5-HT2AR and 5-HT1AR, respectively) in the reversal by clozapine of PCP actions. Clozapine shows high in vitro affinity for 5-HT2AR and behaves as partial agonist in vivo at 5-HT1AR. We used wild-type (WT) mice and 5-HT1AR and 5-HT2AR knockout mice of the same background (C57BL/6) (KO-1A and KO-2A, respectively). Local field potentials (LFPs) were recorded in the PFC of WT, KO-1A, and KO-2A mice. PCP (10 mg/kg, intraperitoneally) reduced SCO equally in WT, KO-2A, and KO-1A mice (58±4%, 42±7%, and 63±7% of pre-drug values, n=23, 13, 11, respectively; p<0.0003). Clozapine (0.5 mg/kg, intraperitoneally) significantly reversed PCP effect in WT and KO-2A mice, but not in KO-1A mice nor in WT mice pretreated with the selective 5-HT1AR antagonist WAY-100635.The PCP-induced disorganization of PFC activity does not appear to depend on serotonergic function. However, the lack of effect of clozapine in KO-1A mice and the prevention by WAY-100635 indicates that its therapeutic action involves 5-HT1AR activation without the need to block 5-HT2AR, as observed with clozapine-induced cortical dopamine release. PMID:22012474

Characterization of SB-271046: A potent, selective and orally active 5-HT6 receptor antagonist

PubMed Central

Routledge, Carol; Bromidge, Steven M; Moss, Stephen F; Price, Gary W; Hirst, Warren; Newman, Helen; Riley, Graham; Gager, Tracey; Stean, Tania; Upton, Neil; Clarke, Stephen E; Brown, Anthony M; Middlemiss, Derek N

2000-01-01

SB-271046, potently displaced [3H]-LSD and [125I]-SB-258585 from human 5-HT6 receptors recombinantly expressed in HeLa cells in vitro (pKi 8.92 and 9.09 respectively). SB-271046 also displaced [125I]-SB-258585 from human caudate putamen and rat and pig striatum membranes (pKi 8.81, 9.02 and 8.55 respectively). SB-271046 was over 200 fold selective for the 5-HT6 receptor vs 55 other receptors, binding sites and ion channels. In functional studies on human 5-HT6 receptors SB-271046 competitively antagonized 5-HT-induced stimulation of adenylyl cyclase activity with a pA2 of 8.71. SB-271046 produced an increase in seizure threshold over a wide-dose range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum effective dose of ⩽0.1 mg kg−1 p.o. and maximum effect at 4 h post-dose. The level of anticonvulsant activity achieved correlated well with the blood concentrations of SB-271046 (EC50 of 0.16 μM) and brain concentrations of 0.01–0.04 μM at Cmax. These data, together with the observed anticonvulsant activity of other selective 5-HT6 receptor antagonists, SB-258510 (10 mg kg−1, 2–6 h pre-test) and Ro 04-6790 (1–30 mg kg−1, 1 h pre-test), in the rat MEST test, suggest that the anticonvulsant properties of SB-271046 are likely to be mediated by 5-HT6 receptors. Overall, these studies demonstrate that SB-271046 is a potent and selective 5-HT6 receptor antagonist and is orally active in the rat MEST test. SB-271046 represents a valuable tool for evaluating the in vivo central function of 5-HT6 receptors. PMID:10928964

Effects of serotonin (5-HT)1B receptor ligands on amphetamine-seeking behavior in rats.

PubMed

Miszkiel, Joanna; Przegaliński, Edmund

2013-01-01

Numerous studies have indicated that serotonin (5-HT)1B receptor ligands affect the behavioral effects of psychostimulants (cocaine, amphetamine), including the reinforcing activities of these drugs. To substantiate a role for those receptors in incentive motivation for amphetamine, we used the extinction/reinstatement model to examine the effects of the 5-HT1B receptor ligands on the reinstatement of extinguished amphetamine-seeking behavior. Rats trained to self-administer amphetamine (0.06 mg/kg/infusion) subsequently underwent the extinction procedure. These rats were then tested for the amphetamine-primed or amphetamine-associated cue-induced reinstatement of extinguished amphetamine-seeking behavior. The 5-HT1B receptor antagonist SB 216641 (5-7.5 mg/kg) attenuated the amphetamine (1.5 mg/kg)- and the amphetamine-associated cue combined with the threshold dose of amphetamine (0.5 mg/kg)-induced reinstatement of amphetamine-seeking behavior. The 5-HT1B receptor agonist CP 94253 (1.25-5 mg/kg) also inhibited the amphetamine-seeking behavior induced by amphetamine (1.5 mg/kg) but not by the cue combined with the threshold dose of amphetamine. The inhibitory effect of CP94253 on amphetamine-seeking behavior remained unaffected by the 5-HT1B receptor antagonist. Our results indicate that tonic activation of 5-HT1B receptors is involved in amphetamine- and cue-induced reinstatement of amphetamine-seeking behavior and that the inhibitory effects of 5-HT1B receptor antagonists on these phenomena are directly related to the motivational aspects of amphetamine abuse. The inhibitory effect of CP 94253 on amphetamine-seeking behavior seems to be unrelated to 5-HT1B receptor activation and may result from a general reduction of motivation.

Ontogeny of brain and blood serotonin levels in 5-HT receptor knockout mice: potential relevance to the neurobiology of autism.

PubMed

Janusonis, Skirmantas; Anderson, George M; Shifrovich, Ilya; Rakic, Pasko

2006-11-01

The most consistent neurochemical finding in autism has been elevated group mean levels of blood platelet 5-hydroxytryptamine (5-HT, serotonin). The origin and significance of this platelet hyperserotonemia remain poorly understood. The 5-HT(1A) receptor plays important roles in the developing brain and is also expressed in the gut, the main source of platelet 5-HT. Post-natal tissue levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan were examined in the brain, duodenum and blood of 5-HT(1A) receptor-knockout and wild-type mice. At 3 days after birth, the knockout mice had lower mean brain 5-HT levels and normal mean platelet 5-HT levels. Also, at 3 days after birth, the mean tryptophan levels in the brain, duodenum and blood of the knockout mice were around 30% lower than those of the wild-type mice. By 2 weeks after birth, the mean brain 5-HT levels of the knockout mice normalized, but their mean platelet 5-HT levels became 24% higher than normal. The possible causes of these dynamic shifts were explored by examining correlations between central and peripheral levels of 5-HT, 5-HIAA and tryptophan. The results are discussed in relation to the possible role of 5-HT in the ontogeny of autism.

Etat des lieux des soins de premier recours des malades mentaux à Antananarivo : étude rétrospective

PubMed Central

Bakohariliva, Hasina Andrianarivony; Rafehivola, Imisanavalona Hanitrinihaja; Raobelle, Evah Norotiana; Raharivelo, Adeline; Rajaonarison, Bertille Hortense

2018-01-01

Résumé Religion et guérisseurs traditionnels occupent encore une place prépondérante dans la prise en charge des maladies mentales à Madagascar. Ainsi, nous nous sommes fixés comme objectif d'établir un état des lieux sur les soins de premier recours des malades mentaux. Nous avons mené une étude rétrospective descriptive s'étalant sur une période de 16 mois allant de janvier 2014 en avril 2015 au sein du service de psychiatrie du CHU de Befelatanana à Antananarivo. La prévalence des psychoses était de 25%. Le genre féminin (53%), l'ethnie merina (77%), les étudiants (45%), le niveau d'étude secondaire (40%), les célibataires (72%), la religion protestante (45%), ainsi que le niveau socio-économique moyen (57,5%) étaient prédominants. Dans les paramètres cliniques, le mode de début brutal (52%), le premier recours à la religion (40%), la présence d'antécédents des cas similaire (90%), étaient majoritaires. La schizophrénie était la pathologie la plus rencontrée dans la moitié des cas. Le délai d'amélioration en cas de traitement religieux et traditionnels était dans la moitié des cas de plus de 10 jours d'hospitalisation. Les patients ayant reçu une prise en charge psychiatrique en premier recours, étaient améliorés dans 75 % cas en moins de 10jours. Le retard du recours aux soins psychiatriques est une réalité à Madagascar qui aggrave le pronostic des psychoses. PMID:29632623

Adaptive Control of Dorsal Raphe by 5-HT4 in the Prefrontal Cortex Prevents Persistent Hypophagia following Stress.

PubMed

Jean, Alexandra; Laurent, Laetitia; Delaunay, Sabira; Doly, Stéphane; Dusticier, Nicole; Linden, David; Neve, Rachael; Maroteaux, Luc; Nieoullon, André; Compan, Valérie

2017-10-24

Transient reduced food intake (hypophagia) following high stress could have beneficial effects on longevity, but paradoxically, hypophagia can persist and become anorexia-like behavior. The neural underpinnings of stress-induced hypophagia and the mechanisms by which the brain prevents the transition from transient to persistent hypophagia remain undetermined. In this study, we report the involvement of a network governing goal-directed behavior (decision). This network consists of the ascending serotonergic inputs from the dorsal raphe nucleus (DR) to the medial prefrontal cortex (mPFC). Specifically, adult restoration of serotonin 4 receptor (5-HT 4 R) expression in the mPFC rescues hypophagia and specific molecular changes related to depression resistance in the DR (5-HT release elevation, 5-HT 1A receptor, and 5-HT transporter reductions) of stressed 5-HT 4 R knockout mice. The adult mPFC-5-HT 4 R knockdown mimics the null phenotypes. When mPFC-5-HT 4 Rs are overexpressed and DR-5-HT1ARs are blocked in the DR, hypophagia following stress persists, suggesting an antidepressant action of early anorexia. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Alterations in melatonin and 5-HT signalling in the colonic mucosa of mice with dextran-sodium sulfate-induced colitis.

PubMed

MacEachern, Sarah J; Keenan, Catherine M; Papakonstantinou, Evangelia; Sharkey, Keith A; Patel, Bhavik Anil

2018-05-01

Inflammatory bowel disease (IBD) is characterized by pain, bleeding, cramping and altered gastrointestinal (GI) function. Changes in mucosal 5-HT (serotonin) signalling occur in animal models of colitis and in humans suffering from IBD. Melatonin is co-released with 5-HT from the mucosa and has a wide variety of actions in the GI tract. Here, we examined how melatonin signalling is affected by colitis and determined how this relates to 5-HT signalling. Using electroanalytical approaches, we investigated how 5-HT release, reuptake and availability as well as melatonin availability are altered in dextran sodium sulfate (DSS)-induced colitis in mice. Studies were conducted to explore if melatonin treatment during active colitis could reduce the severity of colitis. We observed an increase in 5-HT and a decrease in melatonin availability in DSS-induced colitis. A significant reduction in 5-HT reuptake was observed in DSS-induced colitis animals. A reduction in the content of 5-HT was observed, but no difference in tryptophan levels were observed. A reduction in deoxycholic acid-stimulated 5-HT availability and a significant reduction in mechanically-stimulated 5-HT and melatonin availability were observed in DSS-induced colitis. Orally or rectally administered melatonin once colitis was established did not significantly suppress inflammation. Our data suggest that DSS-induced colitis results in a reduction in melatonin availability and an increase in 5-HT availability, due to a reduction/loss of tryptophan hydroxylase 1 enzyme, 5-HT content and 5-HT transporters. Mechanosensory release was more susceptible to inflammation when compared with chemosensory release. © 2018 The British Pharmacological Society.

5-HT receptors as novel targets for optimizing pigmentary responses in dorsal skin melanophores of frog, Hoplobatrachus tigerinus

PubMed Central

Ali, Sharique A; Salim, Saima; Sahni, Tarandeep; Peter, Jaya; Ali, Ayesha S

2012-01-01

BACKGROUND AND PURPOSE Biochemical identification of 5-HT has revealed similar projection patterns across vertebrates. In CNS, 5-HT regulates major physiological functions but its peripheral functions are still emerging. The pharmacology of 5-HT is mediated by a diverse range of receptors that trigger different responses. Interestingly, 5-HT receptors have been detected in pigment cells indicating their role in skin pigmentation. Hence, we investigated the role of this monoaminergic system in amphibian pigment cells, melanophores, to further our understanding of its role in pigmentation biology together with its evolutionary significance. EXPERIMENTAL APPROACH Pharmacological profiling of 5-HT receptors was achieved using potent/selective agonists and antagonists. In vitro responses of melanophores were examined by Mean Melanophores Size Index assay. The melanophores of lower vertebrates are highly sensitive to external stimuli. The immediate cellular responses to drugs were defined in terms of pigment translocation within the cells. KEY RESULTS 5-HT exerted strong concentration-dependent pigment dispersion at threshold dose of 1 × 10−6 g·mL−1. Specific 5-HT1 and 5-HT2 receptor agonists, sumatriptan and myristicin. also induced dose-dependent dispersion. Yohimbine and metergoline synergistically antagonized sumatriptan-mediated dispersion, whereas trazodone partially blocked myristicin-induced dispersion. Conversely, 5-HT3 and 5-HT4 receptor agonists, 1 (3 chlorophenyl) biguanide (1,3 CPB) and 5-methoxytryptamine (5-MT), caused a dose-dependent pigment aggregation. The aggregatory effect of 1,3 CPB was completely blocked by ondansetron, whereas L-lysine partially blocked the effect of 5-MT. CONCLUSIONS AND IMPLICATIONS The results suggest that 5-HT-induced physiological effects are mediated via distinct classes of receptors, which possibly participate in the modulation of pigmentary responses in amphibian. PMID:21880033

Hyperthyroidism enhances 5-HT-induced contraction of the rat pulmonary artery: role of calcium-activated chloride channel activation.

PubMed

Oriowo, Mabayoje A; Oommen, Elsie; Khan, Islam

2011-11-01

Experimentally-induced hyperthyroidism in rodents is associated with signs and symptoms of pulmonary hypertension. The main objective of the present study was to investigate the effect of thyroxine-induced pulmonary hypertension on the contractile response of the pulmonary artery to 5-HT and the possible underlying signaling pathway. 5-HT concentration-dependently contracted artery segments from control and thyroxine-treated rats with pD(2) values of 5.04 ± 0.19 and 5.34 ± 0.14, respectively. The maximum response was significantly greater in artery segments from thyroxine-treated rats. Neither BW 723C86 (5-HT(2B)-receptor agonist) nor CP 93129 (5-HT(1B)-receptor agonist) contracted ring segments of the pulmonary artery from control and thyroxine-treated rats at concentrations up to 10(-4)M. There was no significant difference in the level of expression of 5-HT(2A)-receptor protein between the two groups. Ketanserin (3 × 10(-8)M) produced a rightward shift of the concentration-response curve to 5-HT in both groups with equal potency (-logK(B) values were 8.1 ± 0.2 and 7.9 ± 0.1 in control and thyroxine-treated rats, respectively). Nifedipine (10(-6)M) inhibited 5-HT-induced contractions in artery segments from control and thyroxine-treated rats and was more effective against 5-HT-induced contraction in artery segments for thyroxine-treated rats. The calcium-activated chloride channel blocker, niflumic acid (10(-4)M) also inhibited 5-HT-induced contractions in artery segments from control and thyroxine-treated rats and was more effective against 5-HT-induced contraction in artery segments for thyroxine-treated rats. It was concluded that hyperthyroidism enhanced 5-HT-induced contractions of the rat pulmonary artery by a mechanism involving increased activity of calcium-activated chloride channels. Copyright © 2011 Elsevier B.V. All rights reserved.

Evaluation of polyherbal formulation (SJT-HT-03) for antihypertensive activity in albino rats.

PubMed

Ghelani, Hardik S; Patel, Bipin M; Gokani, Rina H; Rachchh, Manish A

2014-01-01

Hypertension is an incurable pathological condition and lifelong therapy is required. Long term use of conventional synthetic anti-hypertensive drugs is associated with a spectrum of toxic effects. However, therapeutic interventions using herbal drugs for hypertension have gained considerable attention worldwide. To evaluate the anti-hypertensive activity of polyherbal formulation (SJT-HT-03). The polyherbal formulation (SJT-HT-03) comprises of leaves of Aegle marmelos L., fruits of Benincasa hispida Thunb., Garcinia indica Thouars, and flowers of Musa paradiasica L., Rosa indica L., Hibiscus rosa sinensis L. Selected plants as mentioned above were collected, dried and extracted with different solvents. Formulation SJT-HT-03 (250 mg/kg, p.o.), was evaluated using two kidney one clip (2K1C) model and deoxycorticosterone acetate (DOCA)-salt-induced hypertension model using the enalapril (10 mg/kg, p.o.) and hydrochlorothiazide (5 mg/kg, p.o.) as a reference standard drug in respective models. SJT-HT-03 significantly reduced (P < 0.001, one-way analysis of variance followed by Turkey's multiple comparison tests) systolic as well as diastolic blood pressure (BP) in 2K1C and DOCA-salt model. Further, SJT-HT-03 has shown a significant reduction (P < 0.01) in angiotensin converting enzyme (ACE) activity in serum, clipped kidney as well as in lungs in 2K1C model, whereas significant reduction (P < 0.05) in serum Na(+) and increase in serum K(+) level in DOCA model. Polyherbal formulation SJT-HT-03 possess significant anti-hypertensive activity by producing direct depressant effect on heart, inhibition of ACE, aldosterone antagonistic as well as diuretic effect and thereby act on multiple targets to achieve optimal effect.

The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors

PubMed Central

Thompson, A J; Lochner, M; Lummis, S C R

2007-01-01

Background and Purpose: The antimalarial compounds quinine, chloroquine and mefloquine affect the electrophysiological properties of Cys-loop receptors and have structural similarities to 5-HT3 receptor antagonists. They may therefore act at 5-HT3 receptors. Experimental Approach: The effects of quinine, chloroquine and mefloquine on electrophysiological and ligand binding properties of 5-HT3A receptors expressed in HEK 293 cells and Xenopus oocytes were examined. The compounds were also docked into models of the binding site. Key Results: 5-HT3 responses were blocked with IC 50 values of 13.4 μM, 11.8 μM and 9.36 μM for quinine, chloroquine and mefloquine. Schild plots indicated quinine and chloroquine behaved competitively with pA 2 values of 4.92 (K B=12.0 μM) and 4.97 (K B=16.4 μM). Mefloquine displayed weakly voltage-dependent, non-competitive inhibition consistent with channel block. On and off rates for quinine and chloroquine indicated a simple bimolecular reaction scheme. Quinine, chloroquine and mefloquine displaced [3H]granisetron with K i values of 15.0, 24.2 and 35.7 μ M. Docking of quinine into a homology model of the 5-HT3 receptor binding site located the tertiary ammonium between W183 and Y234, and the quinoline ring towards the membrane, stabilised by a hydrogen bond with E129. For chloroquine, the quinoline ring was positioned between W183 and Y234 and the tertiary ammonium stabilised by interactions with F226. Conclusions and Implications: This study shows that quinine and chloroquine competitively inhibit 5-HT3 receptors, while mefloquine inhibits predominantly non-competitively. Both quinine and chloroquine can be docked into a receptor binding site model, consistent with their structural homology to 5-HT3 receptor antagonists. PMID:17502851

Neonatal citalopram treatment inhibits the 5-HT depleting effects of MDMA exposure in rats.

PubMed

Schaefer, Tori L; Grace, Curtis E; Skelton, Matthew R; Graham, Devon L; Gudelsky, Gary A; Vorhees, Charles V; Williams, Michael T

2012-01-18

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

5-HT2C Receptor Knockdown in the Amygdala Inhibits Neuropathic-Pain-Related Plasticity and Behaviors.

PubMed

Ji, Guangchen; Zhang, Wei; Mahimainathan, Lenin; Narasimhan, Madhusudhanan; Kiritoshi, Takaki; Fan, Xiuzhen; Wang, Jigong; Green, Thomas A; Neugebauer, Volker

2017-02-08

Neuroplasticity in the amygdala drives pain-related behaviors. The central nucleus (CeA) serves major amygdala output functions and can generate emotional-affective behaviors and modulate nocifensive responses. The CeA receives excitatory and inhibitory inputs from the basolateral nucleus (BLA) and serotonin receptor subtype 5-HT 2C R in the BLA, but not CeA, has been implicated anxiogenic behaviors and anxiety disorders. Here, we tested the hypothesis that 5-HT 2C R in the BLA plays a critical role in CeA plasticity and neuropathic pain behaviors in the rat spinal nerve ligation (SNL) model. Local 5-HT 2C R knockdown in the BLA with stereotaxic injection of 5-HT 2C R shRNA AAV vector decreased vocalizations and anxiety- and depression-like behaviors and increased sensory thresholds of SNL rats, but had no effect in sham controls. Extracellular single-unit recordings of CeA neurons in anesthetized rats showed that 5-HT 2C R knockdown blocked the increase in neuronal activity (increased responsiveness, irregular spike firing, and increased burst activity) in SNL rats. At the synaptic level, 5-HT 2C R knockdown blocked the increase in excitatory transmission from BLA to CeA recorded in brain slices from SNL rats using whole-cell patch-clamp conditions. Inhibitory transmission was decreased by 5-HT 2C R knockdown in control and SNL conditions to a similar degree. The findings can be explained by immunohistochemical data showing increased expression of 5-HT 2C R in non-GABAergic BLA cells in SNL rats. The results suggest that increased 5-HT 2C R in the BLA contributes to neuropathic-pain-related amygdala plasticity by driving synaptic excitation of CeA neurons. As a rescue strategy, 5-HT 2C R knockdown in the BLA inhibits neuropathic-pain-related behaviors. SIGNIFICANCE STATEMENT Neuroplasticity in the amygdala has emerged as an important pain mechanism. This study identifies a novel target and rescue strategy to control abnormally enhanced amygdala activity in an

Enhanced 5-hydroxytryptamine (5-HT) release from vascular adrenergic nerves in spontaneously hypertensive rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kawasaki, H.; Urabe, M.; Takasaki, K.

1986-03-01

The release of 5-HT from vascular adrenergic nerves was compared between normotensive Wistar Kyoto rats (WKY) and SHR. The mesenteric vascular bed isolated from WKY and SHR was perfused with Krebs solution at a constant flow rate of 5 ml/min. Periarterial nerve stimulation (PNS) was delivered at 4 to 16 Hz for 30 sec. In the SHR preparation, the pressor response to PNS, previously decreased by prazonsin (50 nM), was greatly potentiated after treatment with 5-HT(1 ..mu..M) for 15 min and a frequency-dependent pressor response to PNS reappeared, whereas the 5-HT treatment did not alter the pressor response to exogenousmore » norepinephrine (1 nmol) previously reduced by prazonsin. The potentiation of pressor response to PNS after 5-HT treatment was small in the WKY preparation. This potentiation in both WKY and SHR did not occur in the presence of ketanserin (10 nM). In the preparation labeled with (/sup 3/H)-5-HT, PNS (4-16 Hz) evoked a frequency-dependent increase of (/sup 3/H)-efflux, which was abolished by treatment with tetrodotoxin (100 nM) or 6-hydroxydopamine (50 mg/kg i.p. x 2) and in calcium-free Krebs solution. The PNS evoked-(/sup 3/H)-efflux was much greater in SHR than WKY. These results suggest that the release of 5-HT from vascular adrenergic nerves by PNS is enhanced in the SHR preparation.« less

Interplay of Nanoscale, Hybrid P3HT/ZTO Interface on Optoelectronics and Photovoltaic Cells.

PubMed

Lai, Jian-Jhong; Li, Yu-Hsun; Feng, Bo-Rui; Tang, Shiow-Jing; Jian, Wen-Bin; Fu, Chuan-Min; Chen, Jiun-Tai; Wang, Xu; Lee, Pooi See

2017-09-27

Photovoltaic effects in poly(3-hexylthiophene-2,5-diyl) (P3HT) have attracted much attention recently. Here, natively p-type doped P3HT nanofibers and n-type doped zinc tin oxide (ZTO) nanowires are used for making not only field-effect transistors (FETs) but also p-n nanoscale diodes. The hybrid P3HT/ZTO p-n heterojunction shows applications in many directions, and it also facilitates the investigation of photoelectrons and photovoltaic effects on the nanoscale. As for applications, the heterojunction device shows a simultaneously high on/off ratio of n- and p-type FETs, gatable p-n junction diodes, tristate buffer devices, gatable photodetectors, and gatable solar cells. On the other hand, P3HT nanofibers are taken as a photoactive layer and the role played by the p-n heterojunction in the photoelectric and photovoltaic effects is investigated. It is found that the hybrid P3HT/ZTO p-n heterojunction assists in increasing photocurrents and enhancing photovoltaic effects. Through the controllable gating of the heterojunction, we can discuss the background mechanisms of photocurrent generation and photovoltaic energy harvesting.

Serotonin controls initiation of locomotion and afferent modulation of coordination via 5-HT7 receptors in adult rats.

PubMed

Cabaj, Anna M; Majczyński, Henryk; Couto, Erika; Gardiner, Phillip F; Stecina, Katinka; Sławińska, Urszula; Jordan, Larry M

2017-01-01

Experiments on neonatal rodent spinal cord showed that serotonin (5-HT), acting via 5-HT 7 receptors, is required for initiation of locomotion and for controlling the action of interneurons responsible for inter- and intralimb coordination, but the importance of the 5-HT system in adult locomotion is not clear. Blockade of spinal 5-HT 7 receptors interfered with voluntary locomotion in adult rats and fictive locomotion in paralysed decerebrate rats with no afferent feedback, consistent with a requirement for activation of descending 5-HT neurons for production of locomotion. The direct control of coordinating interneurons by 5-HT 7 receptors observed in neonatal animals was not found during fictive locomotion, revealing a developmental shift from direct control of locomotor interneurons in neonates to control of afferent input from the moving limb in adults. An understanding of the afferents controlled by 5-HT during locomotion is required for optimal use of rehabilitation therapies involving the use of serotonergic drugs. Serotonergic pathways to the spinal cord are implicated in the control of locomotion based on studies using serotonin type 7 (5-HT 7 ) receptor agonists and antagonists and 5-HT 7 receptor knockout mice. Blockade of these receptors is thought to interfere with the activity of coordinating interneurons, a conclusion derived primarily from in vitro studies on isolated spinal cord of neonatal rats and mice. Developmental changes in the effects of serotonin (5-HT) on spinal neurons have recently been described, and there is increasing data on control of sensory input by 5-HT 7 receptors on dorsal root ganglion cells and/or dorsal horn neurons, leading us to determine the effects of 5-HT 7 receptor blockade on voluntary overground locomotion and on locomotion without afferent input from the moving limb (fictive locomotion) in adult animals. Intrathecal injections of the selective 5-HT 7 antagonist SB269970 in adult intact rats suppressed locomotion by

5-HT2A receptor gene polymorphisms in Croatian subjects with autistic disorder.

PubMed

Hranilovic, Dubravka; Blazevic, Sofia; Babic, Marina; Smurinic, Maja; Bujas-Petkovic, Zorana; Jernej, Branimir

2010-08-15

Disturbances in the expression/function of the 5-HT2A receptor are implicated in autism. The association of the 5-HT2A receptor gene with autism was studied in the Croatian population. Distribution frequencies for alleles, genotypes and haplotypes of -1438 A/G and His452Tyr polymorphisms were compared in samples of 103 autistic and 214 control subjects. Significant overrepresentation of the G allele and the GG genotype of the -1438 A/G polymorphism was observed in group of autistic subjects, supporting the possible involvement of the 5-HT2A receptor in the development of autism. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Study of charge transport in composite blend of P3HT and PCBM

NASA Astrophysics Data System (ADS)

Kumar, Manoj; Kumar, Sunil; Upadhyaya, Aditi; Yadav, Anjali; Gupta, Saral K.; Singh, Amarjeet

2018-05-01

Poly (3-hexylthiophene-2,5diyl) (P3HT) as donor and [6,6]-phenyl C61 butyric acid methyl ester (PCBM) as acceptor are mostly used as active medium in polymeric electronic device. In this paper we have prepare the P3HT - PCBM based bulk hetero junction thin films by spin coating technique. The charge transport properties of P3HT:PCBM blends are investigated by the current-voltage measurements using Ag as an electron injecting electrode and ITO as a hole injecting contact. The current density v/s voltage relationships are analyzed in the backdrop of Schottky and Space charge limited current model.

An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells.

PubMed

Brindley, Rebecca L; Bauer, Mary Beth; Blakely, Randy D; Currie, Kevin P M

2016-11-01

Adrenal chromaffin cells (ACCs), the neuroendocrine arm of the sympathetic nervous system, secrete catecholamines to mediate the physiological response to stress. Although ACCs do not synthesize 5-HT, they express the serotonin transporter (SERT). Genetic variations in SERT are linked to several CNS disorders but the role(s) of SERT/5-HT in ACCs has remained unclear. Adrenal glands from wild-type mice contained 5-HT at ≈ 750 fold lower abundance than adrenaline, and in SERT(-/-) mice this was reduced by ≈80% with no change in catecholamines. Carbon fibre amperometry showed that SERT modulated the ability of 5-HT1A receptors to inhibit exocytosis. 5-HT reduced the number of amperometric spikes (vesicular fusion events) evoked by KCl in SERT(-/-) cells and wild-type cells treated with escitalopram, a SERT antagonist. The 5-HT1A receptor antagonist WAY100635 blocked the inhibition by 5-HT which was mimicked by the 5-HT1A agonist 8-OH-DPAT but not the 5-HT1B agonist CP93129. There was no effect on voltage-gated Ca(2+) channels, K(+) channels, or intracellular [Ca(2+)] handling, showing the 5-HT receptors recruit an atypical inhibitory mechanism. Spike charge and kinetics were not altered by 5-HT receptors but were reduced in SERT(-/-) cells compared to wild-type cells. Our data reveal a novel role for SERT and suggest that adrenal chromaffin cells might be a previously unrecognized hub for serotonergic control of the sympathetic stress response. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of serotonin 5-HT1A agonist in advanced Parkinson's disease.

PubMed

Bara-Jimenez, William; Bibbiani, Francesco; Morris, Michael J; Dimitrova, Tzvetelina; Sherzai, Abdullah; Mouradian, Maral M; Chase, Thomas N

2005-08-01

Intermittent stimulation of striatal dopaminergic receptors seems to contribute to motor dysfunction in advanced Parkinson's disease (PD). With severe dopaminergic denervation, exogenous levodopa is largely decarboxylated to dopamine in serotonergic terminals. If 5-HT1A autoreceptors regulate dopamine as well as serotonin release, in parkinsonian patients inhibition of striatal serotonergic neuron firing might help maintain more physiological intrasynaptic dopamine concentrations and thus ameliorate motor fluctuations and dyskinesias. To evaluate this hypothesis, effects of a selective 5-HT1A agonist, sarizotan, given orally at 2 and 5 mg twice daily to 18 relatively advanced parkinsonian patients, were compared with baseline placebo function during a 3-week, double-blind, placebo-controlled, proof-of-concept study. Sarizotan alone or with intravenous levodopa had no effect on parkinsonian severity. But at safe and tolerable doses, sarizotan coadministration reduced levodopa-induced dyskinesias and prolonged its antiparkinsonian response (P < or = 0.05). Under the conditions of this study, our findings suggest that 5-HT1A receptor stimulation in levodopa-treated parkinsonian patients can modulate striatal dopaminergic function and that 5-HT1A agonists may be useful as levodopa adjuvants in the treatment of PD. Copyright 2005 Movement Disorder Society

Functional Characterization of 5-HT1B Receptor Drugs in Nonhuman Primates Using Simultaneous PET-MR.

PubMed

Hansen, Hanne D; Mandeville, Joseph B; Sander, Christin Y; Hooker, Jacob M; Catana, Ciprian; Rosen, Bruce R; Knudsen, Gitte M

2017-11-01

In the present study, we used a simultaneous PET-MR experimental design to investigate the effects of functionally different compounds (agonist, partial agonist, and antagonist) on 5-HT 1B receptor (5-HT 1B R) occupancy and the associated hemodynamic responses. In anesthetized male nonhuman primates ( n = 3), we used positron emission tomography (PET) imaging with the radioligand [ 11 C]AZ10419369 administered as a bolus followed by constant infusion to measure changes in 5-HT 1B R occupancy. Simultaneously, we measured changes in cerebral blood volume (CBV) as a proxy of drug effects on neuronal activity. The 5-HT 1B R partial agonist AZ10419369 elicited a dose-dependent biphasic hemodynamic response that was related to the 5-HT 1B R occupancy. The magnitude of the response was spatially overlapping with high cerebral 5-HT 1B R densities. High doses of AZ10419369 exerted an extracranial tissue vasoconstriction that was comparable to the less blood-brain barrier-permeable 5-HT 1B R agonist sumatriptan. By contrast, injection of the antagonist GR127935 did not elicit significant hemodynamic responses, even at a 5-HT 1B R cerebral occupancy similar to the one obtained with a high dose of AZ10419369. Given the knowledge we have of the 5-HT 1B R and its function and distribution in the brain, the hemodynamic response informs us about the functionality of the given drug: changes in CBV are only produced when the receptor is stimulated by the partial agonist AZ10419369 and not by the antagonist GR127935, consistent with low basal occupancy by endogenous serotonin. SIGNIFICANCE STATEMENT We here show that combined simultaneous positron emission tomography and magnetic resonance imaging uniquely enables the assessment of CNS active compounds. We conducted a series of pharmacological interventions to interrogate 5-HT 1B receptor binding and function and determined blood-brain barrier passage of drugs and demonstrate target involvement. Importantly, we show how the spatial

Predominant mucosal expression of 5-HT4(+h) receptor splice variants in pig stomach and colon

PubMed Central

Priem, Evelien KV; De Maeyer, Joris H; Vandewoestyne, Mado; Deforce, Dieter; Lefebvre, Romain A

2013-01-01

AIM: To investigate cellular 5-HT4(-h/+h) receptor distribution, particularly in the epithelial layer, by laser microdissection and polymerase chain reaction (PCR) in porcine gastrointestinal (GI) tissues. METHODS: A stepwise approach was used to evaluate RNA quality and to study cell-specific 5-HT4 receptor mRNA expression in the porcine gastric fundus and colon descendens. After freezing, staining and laser microdissection and pressure catapulting (LMPC), RNA quality was evaluated by the Experion automated electrophoresis system. 5-HT4 receptor and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expressions were examined by endpoint reverse transcription (RT)-PCR in mucosal and muscle-myenteric plexus (MMP) tissue fractions, in mucosal and MMP parts of hematoxylin and eosin (HE) stained tissue sections and in microdissected patches of the epithelial and circular smooth muscle cell layer in these sections. Pig gastric fundus tissue sections were also stained immunohistochemically (IHC) for enterochromaffin cells (EC cells; MAB352); these cells were isolated by LMPC and examined by endpoint RT-PCR. RESULTS: After HE staining, the epithelial and circular smooth muscle cell layer of pig colon descendens and the epithelial cell layer of gastric fundus were identified morphologically and isolated by LMPC. EC cells of pig gastric fundus were successfully stained by IHC and isolated by LMPC. Freezing, HE and IHC staining, and LMPC had no influence on RNA quality. 5-HT4 receptor and GAPDH mRNA expressions were detected in mucosa and MMP tissue fractions, and in mucosal and MMP parts of HE stained tissue sections of pig colon descendens and gastric fundus. In the mucosa tissue fractions of both GI regions, the expression of h-exon containing receptor [5-HT4(+h) receptor] mRNA was significantly higher (P < 0.01) compared to 5-HT4(-h) receptor expression, and a similar trend was obtained in the mucosal part of HE stained tissue sections. Large microdissected patches of the

Litigation involving DES.

PubMed

Rheingold, P D

1976-01-01

Focus is on the diethylstilbestrol (DES) litigation which has resulted from the 1971 discovery that this synthetic estrogen can cause cancer in the daughters of women who used the drug during pregnancy in an effort to prevent threatened abortion. Possibly 100 suits are pending at this time in which DES daughters claim injuries. In most of these vaginal or cervical cancer has appeared -- with or without a hysterectomy having been performed. Several women died from cancer. The fact that the use of DES occurred many years ago is the legal hurdle most troublesome to lawyers. The average women coming to a lawyer's office today has a mother who used some form of DES, perhaps in 1955. Few drugstores have records today of the prescriptions which they filled 20 years ago. It has been estimated that over the 1950-1970 period more than 200 different companies manufactured or "tabletized" under their own name DES plus a variety of similar synthetic estrogens promoted for the prevention of threatened abortion. A further hurdle caused by the passage of time is that even the records of the physicians are frequently lost. A final problem created by the age of the cases is statute of limitations. If the actual manufacturer of the DES cannot be identified, this is generally the end of the lawyer's interest in the case. The chance of the plaintiff winning may be increased if the action against all the manufacturers is a class action. Most of the pending DES suits are against the manufacturer and not against the doctor. Thus far no DES case has been tried to completion. Several have been settled by the manufacturers on the eve of the trial, generally for less than the full sum that a cancer victim would expect to receive.

Médecine des voyages

PubMed Central

Aw, Brian; Boraston, Suni; Botten, David; Cherniwchan, Darin; Fazal, Hyder; Kelton, Timothy; Libman, Michael; Saldanha, Colin; Scappatura, Philip; Stowe, Brian

2014-01-01

Résumé Objectif Définir la pratique de la médecine des voyages, présenter les éléments fondamentaux d’une consultation complète préalable aux voyages à des voyageurs internationaux et aider à identifier les patients qu’il vaudrait mieux envoyer en consultation auprès de professionnels de la médecine des voyages. Sources des données Les lignes directrices et les recommandations sur la médecine des voyages et les maladies liées aux voyages publiées par les autorités sanitaires nationales et internationales ont fait l’objet d’un examen. Une recension des ouvrages connexes dans MEDLINE et EMBASE a aussi été effectuée. Message principal La médecine des voyages est une spécialité très dynamique qui se concentre sur les soins préventifs avant un voyage. Une évaluation exhaustive du risque pour chaque voyageur est essentielle pour mesurer avec exactitude les risques particuliers au voyageur, à son itinéraire et à sa destination et pour offrir des conseils sur les interventions les plus appropriées en gestion du risque afin de promouvoir la santé et prévenir les problèmes médicaux indésirables durant le voyage. Des vaccins peuvent aussi être nécessaires et doivent être personnalisés en fonction des antécédents d’immunisation du voyageur, de son itinéraire et du temps qu’il reste avant son départ. Conclusion La santé et la sécurité d’un voyageur dépendent du degré d’expertise du médecin qui offre le counseling préalable à son voyage et les vaccins, au besoin. On recommande à ceux qui donnent des conseils aux voyageurs d’être conscients de l’ampleur de cette responsabilité et de demander si possible une consultation auprès de professionnels de la médecine des voyages pour tous les voyageurs à risque élevé.

Educational Technology Program. Quarterly Technical Summary, 1 December 1970 through 28 February 1971.

ERIC Educational Resources Information Center

Frick, Frederick C.

The decision to employ direct rather than diffraction recording in the Lincoln Training System (LTS) is reported. This resulted from the findings that direct recording was practical at higher densities than previously thought possible and that rapid access to a number of fiche would compensate for the limited number of frames per fiche realized…

Identification of spinal 5-HT sub 3 receptors and their role in the modulation of nociceptive responses in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Glaum, S.R.

1988-01-01

The project consisted of two related studies: (1) the characterization of serotonin binding sites in crude and purified synaptic membranes prepared from the rat spinal cord, and (2) the association of serotonin binding sites with functional 5-HT receptor responses in the modulation of nociceptive information at the level of the spinal cord. The first series of experiments involved the preparation of membranes from the dorsal and ventral halves of the rat spinal cord and the demonstration of specific ({sup 3}H)serotonin binding to these membranes. High affinity binding sites which conformed to the 5-HT{sub 3} subtype were identified in dorsal, butmore » not ventral spinal cord synaptic membranes. These experiments also confirmed the presence of high affinity ({sup 3}H)5-HT binding sites in dorsal spinal cord synaptic membranes of the 5-HT{sub 1} subtype. The second group of studies demonstrated the ability of selective 5-HT{sub 3} antagonists to inhibit the antinociceptive response to intrathecally administered 5-HT, as measured by a change in tail flick and hot plate latencies. Intrathecal pretreatment with the selective 5-HT{sub 3} antagonists ICS 205-930 or MDL 72222 abolished the antinociceptive effects of 5-HT. Furthermore, the selective 5-HT{sub 3} agonist 2-methyl-5-HT mimicked the antinociceptive effects of 5-HT.« less

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

NASA Technical Reports Server (NTRS)

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

2000-01-01

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

NASA Goddards LiDAR, Hyperspectral and Thermal (G-LiHT) Airborne Imager

NASA Technical Reports Server (NTRS)

Cook, Bruce D.; Corp, Lawrence A.; Nelson, Ross F.; Middleton, Elizabeth M.; Morton, Douglas C.; McCorkel, Joel T.; Masek, Jeffrey G.; Ranson, Kenneth J.; Ly, Vuong; Montesano, Paul M.

2013-01-01

The combination of LiDAR and optical remotely sensed data provides unique information about ecosystem structure and function. Here, we describe the development, validation and application of a new airborne system that integrates commercial off the shelf LiDAR hyperspectral and thermal components in a compact, lightweight and portable system. Goddard's LiDAR, Hyperspectral and Thermal (G-LiHT) airborne imager is a unique system that permits simultaneous measurements of vegetation structure, foliar spectra and surface temperatures at very high spatial resolution (approximately 1 m) on a wide range of airborne platforms. The complementary nature of LiDAR, optical and thermal data provide an analytical framework for the development of new algorithms to map plant species composition, plant functional types, biodiversity, biomass and carbon stocks, and plant growth. In addition, G-LiHT data enhance our ability to validate data from existing satellite missions and support NASA Earth Science research. G-LiHT's data processing and distribution system is designed to give scientists open access to both low- and high-level data products (http://gliht.gsfc.nasa.gov), which will stimulate the community development of synergistic data fusion algorithms. G-LiHT has been used to collect more than 6,500 km2 of data for NASA-sponsored studies across a broad range of ecoregions in the USA and Mexico. In this paper, we document G-LiHT design considerations, physical specifications, instrument performance and calibration and acquisition parameters. In addition, we describe the data processing system and higher-level data products that are freely distributed under NASA's Data and Information policy.

Review article: the many potential roles of intestinal serotonin (5-hydroxytryptamine, 5-HT) signalling in inflammatory bowel disease.

PubMed

Coates, M D; Tekin, I; Vrana, K E; Mawe, G M

2017-09-01

Serotonin (5-hydroxytryptamine, 5-HT) is an important mediator of every major gut-related function. Recent investigations also suggest that 5-HT can influence the development and severity of inflammation within the gut, particularly in the setting of inflammatory bowel disease (IBD). To review the roles that the intestinal serotonin signalling system plays in gut function, with a specific focus on IBD. We reviewed manuscripts from 1952 to 2017 that investigated and discussed roles for 5-HT signalling in gastrointestinal function and IBD, as well as the influence of inflammation on 5-HT signalling elements within the gut. Inflammation appears to affect every major element of intestinal 5-HT signalling, including 5-HT synthesis, release, receptor expression and reuptake capacity. Importantly, many studies (most utilising animal models) also demonstrate that modulation of selective serotonergic receptors (via agonism of 5-HT 4 R and antagonism of 5-HT 3 R) or 5-HT signal termination (via serotonin reuptake inhibitors) can alter the likelihood and severity of intestinal inflammation and/or its complicating symptoms. However, there are few human studies that have studied these relationships in a targeted manner. Insights discussed in this review have strong potential to lead to new diagnostic and therapeutic tools to improve the management of IBD and other related disorders. Specifically, strategies that focus on modifying the activity of selective serotonin receptors and reuptake transporters in the gut could be effective for controlling disease activity and/or its associated symptoms. Further studies in humans are required, however, to more completely understand the pathophysiological mechanisms underlying the roles of 5-HT in this setting. © 2017 John Wiley & Sons Ltd.

Antidepressant-like activity of VN2222, a serotonin reuptake inhibitor with high affinity at 5-HT1A receptors.

PubMed

Tordera, Rosa M; Monge, Antonio; Del Río, Joaquín; Lasheras, Berta

2002-05-03

It has been suggested that drugs combining serotonin (5-hydroxytryptamine, 5-HT) transporter blockade and 5-HT1A autoreceptor antagonism could be a novel strategy for a shorter onset of action and higher therapeutic efficacy of antidepressants. The present study was aimed at characterizing the pharmacology of 1-(3-benzo[b]tiophenyl)-3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-propanol (VN2222) a new synthetic compound with high affinity at both the 5-HT transporter and 5-HT1A receptors and devoid of high affinity at other receptors studied, with the only exception of alpha1-adrenoceptors. In keeping with the binding affinity at the 5-HT transporter, VN2222 inhibited 5-HT uptake in vitro both in rat cortical synaptosomes and in mesencephalic cultures and also in vivo when administered locally into the rat ventral hippocampus. After systemic administration, VN2222 exhibited an inverted U-shape effect so the inhibition of [3H]5-HT uptake ex vivo and the increase in 5-HT extracellular levels in microdialysis experiments was observed at low doses of 0.01-0.1 mg/kg whereas higher doses were ineffective. In studies related to 5-HT1A receptor function, 0.01-0.1 microM VN2222 produced a partial inhibition of forskolin-stimulated cAMP formation behaving as a weak agonist of 5-HT1A receptors. In body temperature studies, 5 mg/kg VN2222 produced a mild hypothermic effect in mice, suggesting a weak agonist activity at presynaptic 5-HT1A receptors; much lower doses (0.01-0.5 mg/kg) partially antagonized the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) possibly through 5-HT transporter blockade. In the learned helplessness test in rats, an animal model for antidepressants, 1-5 mg/kg VN2222 reduced significantly the number of escape failures. Consequently, VN2222 is a new compound with a dual effect on the serotonergic system, as 5-HT uptake blocker and 5-HT1A receptor partial agonist, and with a remarkable activity in an animal model of depression with

The relationship between reward and punishment processing and the 5-HT1A receptor as shown by PET.

PubMed

Faulkner, Paul; Selvaraj, Sudhakar; Pine, Alex; Howes, Oliver D; Roiser, Jonathan P

2014-07-01

The serotonin (5-HT) system has been reported to be involved in decision-making. A key component of this neurotransmitter system is the 5-HT1A receptor, and research is beginning to show how this receptor can influence decision-making. However, this relationship has rarely been studied in humans. This study assessed whether individual variability in 5-HT1A availability correlates with decision-making in healthy volunteers. We measured regional availability of the 5-HT1A receptor in the hippocampal complex and striatum using positron emission tomography and correlated this with performance on two decision-making tasks measuring sensitivity to probability, rewards and punishments and temporal discounting, respectively. No relationship between decision-making behaviour and 5-HT1A availability in the striatum was found. However, a positive correlation was detected between participants' 5-HT1A availability in the hippocampal complex and their sensitivity to the probability of winning. Furthermore, there was a negative correlation between the degree to which participants discounted future rewards and 5-HT1A availability in the hippocampal complex. These data support a role for the 5-HT1A receptor in the aberrant decision-making that can occur in neuropsychiatric disorders such as depression.

Enhancement in light harvesting ability of photoactive layer P3HT: PCBM using CuO nanoparticles

NASA Astrophysics Data System (ADS)

Tiwari, D. C.; Dwivedi, Shailendra Kumar; Dipak, Pukhrambam; Chandel, Tarun

2018-05-01

In this paper, we have synthesized CuO nanoparticles via precipitation method and incorporated CuO nanoparticles in the P3HT-poly (3-hexyl) thiophene: PCBM-[6, 6]-phenyl-C61-butyric acid methyl ester heterogeneous blend. The ratio of P3HT to CuO in the blend was varied, while maintaining the fixed ratio of PCBM. The UV-visible absorption spectra of P3HT: PCBM photoactive layer containing different weight percentages of CuO nanoparticles showed a clear enhancement in the photo absorption of the active layer. The absorption band starts from 310 nm to 750 nm for P3HT: CuO (NPs):PCBM (0.5:0.5:1). This shows that incorporation of CuO nanoparticles leads to larger absorption band. In addition, the X-ray diffraction (XRD) shows improvement in P3HT crystallinity and the better formation of CuO nanostructures.

Shifting Topographic Activation and 5-HT1A-Receptor Mediated Inhibition of Dorsal Raphe Serotonin Neurons Produced by Nicotine Exposure and Withdrawal

PubMed Central

Sperling, Robin; Commons, Kathryn G.

2011-01-01

Nicotine activates serotonin (5-HT) neurons innervating the forebrain and this is thought to reduce anxiety. Nicotine withdrawal has also been associated with an activation of 5-HT neurotransmission, although withdrawal increases anxiety. In each case, 5-HT1A receptors have been implicated in the response. To determine if there are different subgroups of 5-HT cells activated during nicotine administration and withdrawal, we mapped the appearance of Fos, a marker of neuronal activation, in 5-HT cells of the dorsal and median raphe nuclei (DR and MR). To understand the role 5-HT1A receptor feedback inhibitory pathways on 5-HT cell activity during these conditions, we administered a selective 5-HT1A-receptor antagonist and measured novel disinhibited Fos expression within 5-HT cells. Using these approaches, we found evidence that acute nicotine activates 5-HT neurons rostrally and in the lateral wings of the DR while there is 5-HT1A dependent inhibition of cells located ventrally both at rostral and mid levels. Previous chronic nicotine exposure did not modify the pattern of Fos activation produced by acute nicotine, but increased 5-HT1A-dependent inhibition of 5-HT cells in the caudal DR. This pattern was nearly reversed during nicotine withdrawal when there was evidence for caudal activation and mid- and rostral-5-HT1A-dependent inhibition. These results suggest that the distinct behavioral states produced by nicotine exposure and withdrawal correlate with reciprocal rostral-caudal patterns of activation and 5-HT1A-mediated inhibition of DR 5-HT neurons. The complimentary patterns of activation and inhibition suggest that 5-HT1A receptors may help shape distinct topographic patterns of activation within the DR. PMID:21501256

Determination des Parametres Atmospheriques des Etoiles Naines Blanches de Type DB

NASA Astrophysics Data System (ADS)

Beauchamp, Alain

1995-01-01

Les etoiles naines blanches dont les spectres visibles sont domines par des raies fortes d'helium neutre sont subdivisees en trois classes, DB (raies d'helium neutre seulement), DBA (raies d'helium neutre et d'hydrogene) et DBZ (raies d'helium neutre et d'elements lourds). Nous analysons trois echantillons de spectres observes de ces types de naines blanches. Les echantillons consistent, respectivement, de 48 spectres dans le domaine du visible (3700-5100 A). 24 dans l'ultraviolet (1200-3100 A) et quatre dans la partie rouge du visible (5100-6900) A). Parmi les objets de l'echantillon visible, nous identifions quatre nouvelles DBA, ainsi que deux nouvelles DBZ, auparavant classees DB. L'analyse nous permet de determiner spectroscopiquement les parametres atmospheriques, soit la temperature effective, la gravite de surface, ainsi que l'abondance relative de l'hydrogene, N(H)/N(He), dans le cas des DBA. Pour les objets plus chauds que ~15,000 K, la gravite de surface determinee est fiable, et nous obtenons les masses stellaires avec une relation masse -rayon theorique. Les exigences propres a l'analyse de ces objets ont requis d'importantes ameliorations dans la modelisation de leurs atmospheres et distributions de flux de radiation emis par ces derniers. Nous avons inclus dans les modeles d'atmospheres, pour la premiere fois a notre connaissance, les effets dus a la molecule He_sp{2 }{+}, ainsi que l'equation d'etat de Hummer et Mihalas (1988), qui tient compte des perturbations entre particules dans le calcul des populations des differents niveaux atomiques. Nous traitons la convection dans le cadre de la theorie de la longueur de melange. Trois grilles de modeles d'atmospheres a l'ETL (equilibre thermodynamique local) ont ete produites, pour un ensemble de temperatures effectives, gravites de surface et abondances d'hydrogene couvrant les proprietes des etoiles de nos echantillons; elles sont caracterisees par differentes parametrisations appelees, respectivement

Experimental and theoretical investigation of HT-S/PMR-PI composites for application to advanced aircraft engines

NASA Technical Reports Server (NTRS)

Hanson, M. P.; Chamis, C. C.

1973-01-01

Investigations were performed in order to: (1) demonstrate that high quality angleplied laminates can be made from HT-S/PMR-PI (PMR in situ polymerization of monomeric reactants), (2) characterize the PMR-PI material and to determine the HT-S unidirectional composite properties required for composite micro and macromechanics and laminate analyses, and (3) select HT-S/PMR laminate configurations to meet the general design requirements for high-tip-speed compressor blades. The results of the investigation show that HT-S/PMR laminate configurations can be fabricated which satisfy the high-tip-speed compressor blade design requirements when operating within the temperature capability of the polyimide matrix.

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

PubMed Central

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

1974-01-01

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

Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists.

PubMed

Hansen, Martin; Phonekeo, Karina; Paine, James S; Leth-Petersen, Sebastian; Begtrup, Mikael; Bräuner-Osborne, Hans; Kristensen, Jesper L

2014-03-19

N-Benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor.

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

PubMed Central

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

2015-01-01

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

5-HT(1A) receptor antagonism reverses and prevents fluoxetine-induced sexual dysfunction in rats.

PubMed

Sukoff Rizzo, Stacey J; Pulicicchio, Claudine; Malberg, Jessica E; Andree, Terrance H; Stack, Gary P; Hughes, Zoë A; Schechter, Lee E; Rosenzweig-Lipson, Sharon

2009-09-01

Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapies. 5-HT(1A) antagonists have been suggested as beneficial adjunctive treatment in respect of antidepressant efficacy; however, the effects of 5-HT(1A) antagonism on antidepressant-induced side-effects has not been fully examined. The present study was conducted to evaluate the ability of acute or chronic treatment with 5-HT(1A) antagonists to alter chronic fluoxetine-induced impairments in sexual function. Chronic 14-d treatment with fluoxetine resulted in a marked reduction in the number of non-contact penile erections in sexually experienced male rats, relative to vehicle-treated controls. Acute administration of the 5-HT(1A) antagonist WAY-101405 resulted in a complete reversal of chronic fluoxetine-induced deficits on non-contact penile erections at doses that did not significantly alter baselines. Chronic co-administration of the 5-HT(1A) antagonists WAY-100635 or WAY-101405 with fluoxetine prevented fluoxetine-induced deficits in non-contact penile erections in sexually experienced male rats. Moreover, withdrawal of WAY-100635 from co-treatment with chonic fluoxetine, resulted in a time-dependent reinstatement of chronic fluoxetine-induced deficits in non-contact penile erections. Additionally, chronic administration of SSA-426, a molecule with dual activity as both a SSRI and 5-HT(1A) antagonist, did not produce deficits in non-contact penile erections at doses demonstrated to have antidepressant-like activity in the olfactory bulbectomy model. Taken together, these data suggest that 5-HT(1A) antagonist treatment may have utility for the management of SSRI-induced sexual dysfunction.

Lithium prevents acrolein-induced neurotoxicity in HT22 mouse hippocampal cells.

PubMed

Huang, Yingjuan; Qin, Jian; Chen, Meihui; Chao, Xiaojuan; Chen, Ziwei; Ramassamy, Charles; Pi, Rongbiao; Jin, Minghua

2014-04-01

Acrolein is a highly electrophilic alpha, beta-unsaturated aldehyde to which humans are exposed in many situations and has been implicated in neurodegenerative diseases, such as Alzheimer's disease. Lithium is demonstrated to have neuroprotective and neurotrophic effects in brain ischemia, trauma, neurodegenerative disorders, and psychiatric disorders. Previously we have found that acrolein induced neuronal death in HT22 mouse hippocampal cells. In this study, the effects of lithium on the acrolein-induced neurotoxicity in HT22 cells as well as its mechanism(s) were investigated. We found that lithium protected HT22 cells against acrolein-induced damage by the attenuation of reactive oxygen species and the enhancement of the glutathione level. Lithium also attenuated the mitochondrial dysfunction caused by acrolein. Furthermore, lithium significantly increased the level of phospho-glycogen synthase kinase-3 beta (GSK-3β), the non-activated GSK-3β. Taken together, our findings suggest that lithium is a protective agent for acrolein-related neurotoxicity.

Induction of apoptosis in HT-29 colon cancer cells by phloretin.

PubMed

Park, So Young; Kim, Eun Ji; Shin, Hyun-Kyung; Kwon, Dae Young; Kim, Myung Sunny; Surh, Young-Joon; Park, Jung Han Yoon

2007-12-01

Phloretin, which is present in apples and pears, has been found to inhibit the growth of several cancer cells and induce apoptosis of B16 melanoma and HL60 human leukemia cells. The present study examined whether and how phloretin induces apoptosis of HT-29 human colon cancer cells. Phloretin (0-100 micromol/L) substantially decreased viable cell number and induced apoptosis of HT-29 cells in a dose-dependent manner. Western blot analysis of total cell lysates revealed that phloretin increased the protein levels of Bax but had no effect on Bcl-2. In addition, phloretin induced cleavage of caspase-8, -9, -7, and -3 and poly(ADP-ribose) polymerase. Furthermore, phloretin increased the levels of cytochrome c and Smac/Diablo in the cytosol. The present results indicate that phloretin inhibits HT-29 cell growth by inducing apoptosis, which may be mediated through changes in mitochondrial membrane permeability and activation of the caspase pathways.

5-HT1A receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function

PubMed Central

Garcia-Garcia, Alvaro; Tancredi, Adrian Newman-; Leonardo, E. David

2014-01-01

Rationale Serotonin (5-HT) neurotransmission is intimately linked to anxiety and depression and a diverse body of evidence supports the involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in both disorders. Objectives In this review, we examine the function of 5-HT1A receptor sub-populations and re-interpret our understanding of their role in mental illness in light of new data, separating both spatial (autoreceptor vs heteroreceptor) and the temporal (developmental vs adult) roles of the endogenous 5-HT1A receptors, emphasizing their distinct actions in mediating anxiety and depression-like behaviors. Results It is difficult to unambiguously distinguish the effects of different populations of the 5-HT1A receptors with traditional genetic animal models and pharmacological approaches. However, with the advent of novel genetic systems and subpopulation-selective pharmacological agents, direct evidence for distinct roles of these populations in governing emotion related behavior are emerging. Conclusions There is strong and growing evidence for a functional dissociation between auto and heteroreceptor populations in mediating anxiety and depressive-like behaviors respectively. Furthermore, while it is well established that 5-HT1A receptors act developmentally to establish normal anxiety-like behaviors, the developmental role of 5-HT1A heteroreceptors is less clear, and the specific mechanisms underlying the developmental role of each subpopulation are likely to be key elements determining mood control in adult subjects. PMID:24337875

Charge Exchange Recombination Spectroscopy Based on Diagnostic Neutral Beam in HT-7 Tokamak

NASA Astrophysics Data System (ADS)

Shi, Yuejiang; Fu, Jia; Li, Yingying; William, Rowan; Huang, He; Wang, Fudi; Gao, Huixian; Huang, Juann; Zhou, Qian; Liu, Sheng; Zhang, Jian; Li, Jun; Xie, Yuanlai; Liu, Zhimin; Huang, Yiyun; Hu, Chundong; Wan, Baonian

2010-02-01

Charge exchange recombination spectroscopy (CXRS) based on a diagnostic neutral beam (DNB) installed in the HT-7 tokamak is introduced. DNB can provide a 6 A extracted current at 50 kV for 0.1 s in hydrogen. It can penetrate into the core plasma in HT-7. The CXRS system is designed to observe charge exchange (CX) transitions in the visible spectrum. CX light from the beam is focused onto 10 optical fibers, which view the plasma from -5 cm to 20 cm. The CXRS system can measure the ion temperature as low as 0.1 keV. With CXRS, the local ion temperature profile in HT-7 was obtained for the first time.

Role of the 5-HT2A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice

PubMed Central

Halberstadt, Adam L.; Powell, Susan B.; Geyer, Mark A.

2014-01-01

The 5-HT2A receptor mediates the effects of serotonergic hallucinogens and may play a role in the pathophysiology of certain psychiatric disorders, including schizophrenia. Given these findings, there is a need for animal models to assess the behavioral effects of 5-HT2A receptor activation. Our previous studies demonstrated that the phenylalkylamine hallucinogen and 5-HT2A/2C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces dose-dependent effects on locomotor activity in C57BL/6J mice, increasing activity at low to moderate doses and reducing activity at high doses. DOI did not increase locomotor activity in 5-HT2A knockout mice, indicating the effect is a consequence of 5-HT2A receptor activation. Here, we tested a series of phenylalkylamine hallucinogens in C57BL/6J mice using the Behavioral Pattern Monitor (BPM) to determine whether these compounds increase locomotor activity by activating the 5-HT2A receptor. Low doses of mescaline, 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-propylamphetamine (DOPR), 2,4,5-trimethoxyamphetamine (TMA-2), and the conformationally restricted phenethylamine (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2) increased locomotor activity. By contrast, the non-hallucinogenic phenylalkylamine 2,5-dimethoxy-4-tert-butylamphetamine (DOTB) did not alter locomotor activity at any dose tested (0.1-10 mg/kg i.p.). The selective 5-HT2A antagonist M100907 blocked the locomotor hyperactivity induced by mescaline and TCB-2. Similarly, mescaline and TCB-2 did not increase locomotor activity in 5-HT2A knockout mice. These results confirm that phenylalkylamine hallucinogens increase locomotor activity in mice and demonstrate that this effect is mediated by 5-HT2A receptor activation. Thus, locomotor hyperactivity in mice can be used to assess phenylalkylamines for 5-HT2A agonist activity and hallucinogen-like behavioral effects. These studies provide additional support for the link between 5-HT2A activation and

Involvement of CAT in the detoxification of HT-induced ROS burst in rice anther and its relation to pollen fertility.

PubMed

Zhao, Qian; Zhou, Lujian; Liu, Jianchao; Cao, Zhenzhen; Du, Xiaoxia; Huang, Fudeng; Pan, Gang; Cheng, Fangmin

2018-05-01

HT-induced ROS burst in developing anther is closely related to the lowered CAT activity as the result of the markedly suppressed OsCATB transcript, thereby causing severe fertility injury for rice plants exposed to HT at meiosis stage. The reproductive stage of rice plants is highly sensitive to heat stress. In this paper, different rice cultivars were used to investigate the relationship of HT-induced floret sterility with reactive oxygen species (ROS) detoxification in rice anthers under well-controlled climatic conditions. Results showed that high temperature (HT) exposure significantly enhanced the ROS level and malondialdehyde (MDA) content in developing anther, and the increase in ROS amount in rice anther under HT exposure was closely associated with HT-induced decline in the activities of several antioxidant enzymes. For various antioxidant enzymes, SOD and CAT were more susceptible to the ROS burst in rice anther induced by HT exposure than APX and POD, in which SOD and CAT activity in developing anther decreased significantly by HT exposure, whereas APX activity was relatively stable among different temperature regimes. HT-induced decrease in CAT activity was attributable to the suppressed transcript of OsCATB. This occurrence was strongly responsible for HT-induced increase in ROS level and oxidative-damage in rice anther, thereby it finally caused significant reduction in pollen viability and floret fertility for the rice plants exposed to HT during meiosis. Exogenous application of 1000 µM salicylic acid (SA) may alleviate HT-induced reduction in pollen viability and floret fertility, concomitantly with the increased CAT activity and reduced ROS level in rice anther.

5-HT2A receptor antagonists improve motor impairments in the MPTP mouse model of Parkinson's disease.

PubMed

Ferguson, Marcus C; Nayyar, Tultul; Deutch, Ariel Y; Ansah, Twum A

2010-01-01

Clinical observations have suggested that ritanserin, a 5-HT(2A/C) receptor antagonist may reduce motor deficits in persons with Parkinson's Disease (PD). To better understand the potential antiparkinsonian actions of ritanserin, we compared the effects of ritanserin with the selective 5-HT(2A) receptor antagonist M100907 and the selective 5-HT(2C) receptor antagonist SB 206553 on motor impairments in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated mice exhibited decreased performance on the beam-walking apparatus. These motor deficits were reversed by acute treatment with L-3,4-dihydroxyphenylalanine (levodopa). Both the mixed 5-HT(2A/C) antagonist ritanserin and the selective 5-HT(2A) antagonist M100907 improved motor performance on the beam-walking apparatus. In contrast, SB 206553 was ineffective in improving the motor deficits in MPTP-treated mice. These data suggest that 5-HT(2A) receptor antagonists may represent a novel approach to ameliorate motor symptoms of Parkinson's disease. Published by Elsevier Ltd.

5-HT2A receptor antagonists improve motor impairments in the MPTP mouse model of Parkinson's disease

PubMed Central

Ferguson, Marcus C.; Nayyar, Tultul; Deutch, Ariel Y.; Ansah, Twum A.

2010-01-01

Clinical observations have suggested that ritanserin, a 5-HT2A/C receptor antagonist may reduce motor deficits in persons with Parkinson's Disease (PD). To better understand the potential antiparkinsonian actions of ritanserin, we compared the effects of ritanserin with the selective 5-HT2A receptor antagonist M100907 and the selective 5-HT2C receptor antagonist SB 206553 on motor impairments in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated mice exhibited decreased performance on the beam-walking apparatus. These motor deficits were reversed by acute treatment with L-3,4-dihydroxyphenylalanine (levodopa). Both the mixed 5-HT2A/C antagonist ritanserin and the selective 5-HT2A antagonist M100907 improved motor performance on the beam-walking apparatus. In contrast, SB 206553 was ineffective in improving the motor deficits in MPTP-treated mice. These data suggest that 5-HT2A receptor antagonists may represent a novel approach to ameliorate motor symptoms of Parkinson's disease. PMID:20361986

Herbal Formula HT048 Attenuates Diet-Induced Obesity by Improving Hepatic Lipid Metabolism and Insulin Resistance in Obese Rats.

PubMed

Lee, Yoon Hee; Jin, Bora; Lee, Sung Hyun; Song, MiKyung; Bae, HyeonHui; Min, Byung Jae; Park, Juyeon; Lee, Donghun; Kim, Hocheol

2016-10-25

It is well established that obesity causes a variety of chronic diseases such as cardiovascular diseases and diabetes. Despite the diligent scientific efforts to find effective ways to lower the level of obesity, the size of obese population grows continuously around the world. Here we present the results that show feeding diet containing HT048, a mixture of the extracts of Crataegus pinnatifida leaves and Citrus unshiu peel, two of the well-known traditional herbal medicines in Eastern Asia, decreases obesity in rats. We fed rats with five different diets for 10 weeks: chow diet (STD), high-fat diet (HFD), high-fat diet with 0.04% orlistat, a drug to treat obesity (HFD + Orlistat), high-fat diet with 0.2% HT048 ( w / w ; HFD + 0.2% HT048), and high-fat diet with 0.6% HT048 ( w / w ; HFD + 0.6% HT048). It was found that both body and total white adipose tissue weight of HT048 groups significantly decreased compared to those of the HFD group. Moreover, HT048 decreased serum insulin levels in HFD-fed obese rats. At the molecular level, HT048 supplementation downregulated genes involved in lipogenesis, gluconeogenesis, and adipogenesis, while the expression level of β-oxidation genes was increased. Supplementation-drug interactions are not likely as HFD and HT048-containing diet did not significantly induce genes encoding CYPs. Collectively, this study suggests that HT048 taken as dietary supplement helps to decrease obesity and insulin resistance in HFD-fed obese rats.

Am5-HT7: molecular and pharmacological characterization of the first serotonin receptor of the honeybee (Apis mellifera).

PubMed

Schlenstedt, Jana; Balfanz, Sabine; Baumann, Arnd; Blenau, Wolfgang

2006-09-01

The biogenic amine serotonin (5-HT) plays a key role in the regulation and modulation of many physiological and behavioural processes in both vertebrates and invertebrates. These functions are mediated through the binding of serotonin to its receptors, of which 13 subtypes have been characterized in vertebrates. We have isolated a cDNA from the honeybee Apis mellifera (Am5-ht7) sharing high similarity to members of the 5-HT(7) receptor family. Expression of the Am5-HT(7) receptor in HEK293 cells results in an increase in basal cAMP levels, suggesting that Am5-HT(7) is expressed as a constitutively active receptor. Serotonin application to Am5-ht7-transfected cells elevates cyclic adenosine 3',5'-monophosphate (cAMP) levels in a dose-dependent manner (EC(50) = 1.1-1.8 nm). The Am5-HT(7) receptor is also activated by 5-carboxamidotryptamine, whereas methiothepin acts as an inverse agonist. Receptor expression has been investigated by RT-PCR, in situ hybridization, and western blotting experiments. Receptor mRNA is expressed in the perikarya of various brain neuropils, including intrinsic mushroom body neurons, and in peripheral organs. This study marks the first comprehensive characterization of a serotonin receptor in the honeybee and should facilitate further analysis of the role(s) of the receptor in mediating the various central and peripheral effects of 5-HT.

Activation of 5-HT7 receptors reverses NMDA-R-dependent LTD by activating PKA in medial vestibular neurons.

PubMed

Li, Yan-Hai; Han, Lei; Wu, Kenneth Lap Kei; Chan, Ying-Shing

2017-09-01

The medial vestibular nucleus (MVN) is a major output station for neurons that project to the vestibulo-spinal pathway. MVN neurons show capacity for long-term depression (LTD) during the juvenile period. We investigated LTD of MVN neurons using whole-cell patch-clamp recordings. High frequency stimulation (HFS) robustly induced LTD in 90% of type B neurons in the MVN, while only 10% of type A neurons were responsive, indicating that type B neurons are the major contributors to LTD in the MVN. The neuromodulator serotonin (5-HT) is known to modulate LTD in neural circuits of the cerebral cortex and the hippocampus. We therefore aim to determine the action of 5-HT on the LTD of type B MVN neurons and elucidate the relevant 5-HT receptor subtypes responsible for its action. Using specific agonists and antagonists of 5-HT receptors, we found that selective activation of 5-HT 7 receptor in type B neurons in the MVN of juvenile (P13-16) rats completely abolished NMDA-receptor-mediated LTD in a protein kinase A (PKA)-dependent manner. Our finding that 5-HT restricts plasticity of type B MVN neurons via 5-HT 7 receptors offers a mechanism whereby vestibular tuning contributes to the maturation of the vestibulo-spinal circuit and highlights the role of 5-HT in postural control. Copyright © 2017 Elsevier Ltd. All rights reserved.

The platelet-poor plasma 5-HT response to carbohydrate rich meal administration in adult autistic patients compared with normal controls.

PubMed

Vered, Yaffa; Golubchik, Pavel; Mozes, Tamar; Strous, Rael; Nechmad, Allon; Mester, Roberto; Weizman, Abraham; Spivak, Baruch

2003-07-01

There are cumulative data indicating involvement of the 5-HT system in autistic disorder. Most studies examining 5-HT function have focused on whole blood 5-HT content. The carbohydrate-rich meal test (CRMT) is a dietary manipulation that could significantly influence platelet-poor plasma (PPP) 5-HT levels and reflect the responsiveness of the serotonergic system in 'free' plasma. In this study, CRMT was used as an indicator of 5-HT responsivity in drug-free adults with autistic disorder (n = 7), compared with normal controls (n = 10). The PPP 5-HT levels were measured at baseline and during 3 h after administration of the CRMT. A significant elevation in PPP 5-HT levels in adult autistic patients was reached 60 min after meal administration (p < 0.03 vs control and p = 0.05 vs baseline) and a significant decrease was noted after 120 min (p < 0.01 vs baseline). In contrast to the biphasic response of the autistic patients, normal controls exhibited a gradual linear increase of PPP 5-HT levels. Our results indicate that in adult autistic patients, the pattern of PPP 5-HT responsivity to a dietary challenge of CRMT is dysregulated compared with normal controls and provide further support for the role of 5-HT in autism. Copyright 2003 John Wiley & Sons, Ltd.

Junctional adhesion molecule-C promotes metastatic potential of HT1080 human fibrosarcoma.

PubMed

Fuse, Chiaki; Ishida, Yuuki; Hikita, Tomoya; Asai, Tomohiro; Oku, Naoto

2007-03-16

The junctional adhesion molecule (JAM) family is a key molecule in a process called transendothelial migration or diapedesis. Here, we report implications of JAM-C in cancer metastasis. We first determined the mRNA expression of JAMs in 19 kinds of cancer cell lines. JAM-C was expressed in most of tumors having potent metastatic properties. Especially in murine K-1735 melanoma cell lines, the highly metastatic sublines (M2 and X21) strongly expressed JAM-C when compared with the poorly metastatic ones (C-10 and C23). Next, we investigated the role of JAM-C in cancer metastasis by using human JAM-C (hJAM-C) gene-transfected HT1080 fibrosarcoma cells. In comparison with mock-transfected HT1080 cells, these cells showed a significant increase in the adhesion to various extracellular substrates and the invasion across a Matrigel-coated membrane. The knockdown of hJAM-C using small interfering RNA resulted in the suppression of both the adhesion and the invasion of HT1080 cells, suggesting that endogenous hJAM-C might be involved in tumor metastasis. Finally, we studied the role of hJAM-C in an in vivo experimental metastatic model. The results showed that the overexpression of hJAM-C in HT1080 cells significantly decreased the life spans of the tumorbearing mice. In contrast, the knockdown of hJAM-C in HT1080 cells suppressed the weight gain of the lungs with metastatic colonies. We conclude that the expression of JAM-C promotes metastasis by enhancing both the adhesion of cancer cells to extracellular matrices and the subsequent invasion.

Charge carrier transport and photogeneration in P3HT:PCBM photovoltaic blends.

PubMed

Laquai, Frédéric; Andrienko, Denis; Mauer, Ralf; Blom, Paul W M

2015-06-01

This article reviews the charge transport and photogeneration in bulk-heterojunction solar cells made from blend films of regioregular poly(3-hexylthiophene) (RR-P3HT) and methano-fullerene (PCBM). The charge transport, specifically the hole mobility in the RR-P3HT phase of the polymer:fullerene photovoltaic blend, is dramatically affected by thermal annealing. The hole mobility increases more than three orders of magnitude and reaches a value of up to 2 × 10(-4) cm(2) V(-1) s(-1) after the thermal annealing process as a result of an improved semi-crystallinity of the film. This significant increase of the hole mobility balances the electron and hole mobilities in a photovoltaic blend in turn reducing space-charge formation, and this is the most important factor for the strong enhancement of the photovoltaic efficiency compared to an as cast, that is, non-annealed device. In fact, the balanced charge carrier mobility in RR-P3HT:PCBM blends in combination with a field- and temperature-independent charge carrier generation and greatly reduced non-geminate recombination explains the large quantum efficiencies mea-sured in P3HT:PCBM photovoltaic devices. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

PubMed

Van den Hooff, P; Galvan, M

1992-08-01

1. The actions of 5-hydroxytryptamine (5-HT) and some 5-HT1A receptor ligands on neurones in the rat dorso-lateral septal nucleus were recorded in vitro by intracellular recording techniques. 2. In the presence of tetrodotoxin (1 microM) to block any indirect effects, bath application of 5-HT (0.3-30 microM) hyperpolarized the neurones in a concentration-dependent manner and reduced membrane resistance. The hyperpolarization did not exhibit desensitization and was sometimes followed by a small depolarization. 3. The 5-HT1A receptor ligands, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) and buspirone but not the non-selective 5-HT1 receptor agonist, 1-m-trifluoromethylphenylpiperazine (TFMPP), also hyperpolarized the neurones. 4. 5-HT, 8-OH-DPAT and DP-5-CT appeared to act as full agonists whereas buspirone behaved as a partial agonist. The estimated EC50S were: DP-5-CT 15 nM, 8-OH-DPAT 110 nM, 5-HT 3 microM and buspirone 110 nM. 5. At a concentration of 3 microM, the putative 5-HT1A receptor antagonists, spiperone, methiothepin, NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl]piperazine) and MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8- azaspiro[4,5]decane-7,9-dione methyl sulphonate), produced a parallel rightward shift in the concentration-response curve to 5-HT with no significant reduction in the maximum response. The estimated pA2 values were: NAN-190 6.79, MDL 73005EF 6.59, spiperone 6.54 and methiothepin 6.17.6. The 5-HT2/5-HTlc receptor antagonist, ketanserin (3 microM) and the 5HT3 receptor antagonist, tropisetron (3 microM) did not antagonize the 5-HT-induced hyperpolarizations; however, ketanserin blocked the depolarization which sometimes followed the hyperpolarization.7. It is concluded that the 5-HT-induced membrane hyperpolarization of rat dorso-lateral septal neurones is mediated by 5-HTA receptors.

Serotonin controls initiation of locomotion and afferent modulation of coordination via 5‐HT7 receptors in adult rats

PubMed Central

Majczyński, Henryk; Couto, Erika; Gardiner, Phillip F.; Stecina, Katinka; Sławińska, Urszula

2016-01-01

Key points Experiments on neonatal rodent spinal cord showed that serotonin (5‐HT), acting via 5‐HT7 receptors, is required for initiation of locomotion and for controlling the action of interneurons responsible for inter‐ and intralimb coordination, but the importance of the 5‐HT system in adult locomotion is not clear.Blockade of spinal 5‐HT7 receptors interfered with voluntary locomotion in adult rats and fictive locomotion in paralysed decerebrate rats with no afferent feedback, consistent with a requirement for activation of descending 5‐HT neurons for production of locomotion.The direct control of coordinating interneurons by 5‐HT7 receptors observed in neonatal animals was not found during fictive locomotion, revealing a developmental shift from direct control of locomotor interneurons in neonates to control of afferent input from the moving limb in adults.An understanding of the afferents controlled by 5‐HT during locomotion is required for optimal use of rehabilitation therapies involving the use of serotonergic drugs. Abstract Serotonergic pathways to the spinal cord are implicated in the control of locomotion based on studies using serotonin type 7 (5‐HT7) receptor agonists and antagonists and 5‐HT7 receptor knockout mice. Blockade of these receptors is thought to interfere with the activity of coordinating interneurons, a conclusion derived primarily from in vitro studies on isolated spinal cord of neonatal rats and mice. Developmental changes in the effects of serotonin (5‐HT) on spinal neurons have recently been described, and there is increasing data on control of sensory input by 5‐HT7 receptors on dorsal root ganglion cells and/or dorsal horn neurons, leading us to determine the effects of 5‐HT7 receptor blockade on voluntary overground locomotion and on locomotion without afferent input from the moving limb (fictive locomotion) in adult animals. Intrathecal injections of the selective 5‐HT7 antagonist SB269970 in adult

NASA Rotor 37 CFD Code Validation: Glenn-HT Code

NASA Technical Reports Server (NTRS)

Ameri, Ali A.

2010-01-01

In order to advance the goals of NASA aeronautics programs, it is necessary to continuously evaluate and improve the computational tools used for research and design at NASA. One such code is the Glenn-HT code which is used at NASA Glenn Research Center (GRC) for turbomachinery computations. Although the code has been thoroughly validated for turbine heat transfer computations, it has not been utilized for compressors. In this work, Glenn-HT was used to compute the flow in a transonic compressor and comparisons were made to experimental data. The results presented here are in good agreement with this data. Most of the measures of performance are well within the measurement uncertainties and the exit profiles of interest agree with the experimental measurements.

Etude numerique et experimentale de la reponse vibro-acoustique des structures raidies a des excitations aeriennes et solidiennes

NASA Astrophysics Data System (ADS)

Mejdi, Abderrazak

Les fuselages des avions sont generalement en aluminium ou en composite renforces par des raidisseurs longitudinaux (lisses) et transversaux (cadres). Les raidisseurs peuvent etre metalliques ou en composite. Durant leurs differentes phases de vol, les structures d'avions sont soumises a des excitations aeriennes (couche limite turbulente : TBL, champs diffus : DAF) sur la peau exterieure dont l'energie acoustique produite se transmet a l'interieur de la cabine. Les moteurs, montes sur la structure, produisent une excitation solidienne significative. Ce projet a pour objectifs de developper et de mettre en place des strategies de modelisations des fuselages d'avions soumises a des excitations aeriennes et solidiennes. Tous d'abord, une mise a jour des modeles existants de la TBL apparait dans le deuxieme chapitre afin de mieux les classer. Les proprietes de la reponse vibro-acoustique des structures planes finies et infinies sont analysees. Dans le troisieme chapitre, les hypotheses sur lesquelles sont bases les modeles existants concernant les structures metalliques orthogonalement raidies soumises a des excitations mecaniques, DAF et TBL sont reexamines en premier lieu. Ensuite, une modelisation fine et fiable de ces structures est developpee. Le modele est valide numeriquement a l'aide des methodes des elements finis (FEM) et de frontiere (BEM). Des tests de validations experimentales sont realises sur des panneaux d'avions fournis par des societes aeronautiques. Au quatrieme chapitre, une extension vers les structures composites renforcees par des raidisseurs aussi en composites et de formes complexes est etablie. Un modele analytique simple est egalement implemente et valide numeriquement. Au cinquieme chapitre, la modelisation des structures raidies periodiques en composites est beaucoup plus raffinee par la prise en compte des effets de couplage des deplacements planes et transversaux. L'effet de taille des structures finies periodiques est egalement pris en

Synthesis and Structure–Activity Relationships of N-Benzyl Phenethylamines as 5-HT2A/2C Agonists

PubMed Central

2014-01-01

N-Benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor. PMID:24397362

5HT2A receptor blockade in dorsomedial striatum reduces repetitive behaviors in BTBR mice.

PubMed

Amodeo, D A; Rivera, E; Cook, E H; Sweeney, J A; Ragozzino, M E

2017-03-01

Restricted and repetitive behaviors are a defining feature of autism, which can be expressed as a cognitive flexibility deficit or stereotyped, motor behaviors. There is limited knowledge about the underlying neuropathophysiology contributing to these behaviors. Previous findings suggest that central 5HT 2A receptor activity is altered in autism, while recent work indicates that systemic 5HT 2A receptor antagonist treatment reduces repetitive behaviors in an idiopathic model of autism. 5HT 2A receptors are expressed in the orbitofrontal cortex and striatum. These two regions have been shown to be altered in autism. The present study investigated whether 5HT 2A receptor blockade in the dorsomedial striatum or orbitofrontal cortex in the BTBR mouse strain, an idiopathic model of autism, affects the phenotype related to restricted and repetitive behaviors. Microinfusion of the 5HT 2A receptor antagonist, M100907 into the dorsomedial striatum alleviated a reversal learning impairment and attenuated grooming behavior. M100907 infusion into the orbitofrontal cortex increased perseveration during reversal learning and potentiated grooming. These findings suggest that increased 5HT 2A receptor activity in the dorsomedial striatum may contribute to behavioral inflexibility and stereotyped behaviors in the BTBR mouse. 5HT 2A receptor signaling in the orbitofrontal cortex may be critical for inhibiting a previously learned response during reversal learning and expression of stereotyped behavior. The present results suggest which brain areas exhibit abnormalities underlying repetitive behaviors in an idiopathic mouse model of autism, as well as which brain areas systemic treatment with M100907 may principally act on in BTBR mice to attenuate repetitive behaviors. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Etude de l'amelioration de la qualite des anodes par la modification des proprietes du brai

NASA Astrophysics Data System (ADS)

Bureau, Julie

La qualite des anodes produites se doit d'etre bonne afin d'obtenir de l'aluminium primaire tout en reduisant le cout de production du metal, la consommation d'energie et les emissions environnementales. Or, l'obtention des proprietes finales de l'anode necessite une liaison satisfaisante entre le coke et le brai. Toutefois, la matiere premiere actuelle n'assure pas forcement la compatibilite entre le coke et le brai. Une des solutions les plus prometteuses, pour ameliorer la cohesion entre ces deux materiaux, est la modification des proprietes du brai. L'objectif de ce travail consiste a modifier les proprietes du brai par l'ajout d'additifs chimiques afin d'ameliorer la mouillabilite du coke par le brai modifie pour produire des anodes de meilleure qualite. La composition chimique du brai est modifiee en utilisant des tensioactifs ou agents de modification de surface choisis dans le but d'enrichir les groupements fonctionnels susceptibles d'ameliorer la mouillabilite. L'aspect economique, l'empreinte environnementale et l'impact sur la production sont consideres dans la selection des additifs chimiques. Afin de realiser ce travail, la methodologie consiste a d'abord caracteriser les brais non modifies, les additifs chimiques et les cokes par la spectroscopie infrarouge a transformee de Fourier (FTIR) afin d'identifier les groupements chimiques presents. Puis, les brais sont modifies en ajoutant un additif chimique afin de possiblement modifier ses proprietes. Differentes quantites d'additif sont ajoutees afin d'examiner l'effet de la variation de la concentration sur les proprietes du brai modifie. La methode FTIR permet d'evaluer la composition chimique des brais modifies afin de constater si l'augmentation de la concentration d'additif enrichit les groupements fonctionnels favorisant l'adhesion coke/brai. Ensuite, la mouillabilite du coke par le brai est observee par la methode goutte- sessile. Une amelioration de la mouillabilite par la modification a l'aide d

Occurrence of Fusarium langsethiae and T-2 and HT-2 Toxins in Italian Malting Barley

PubMed Central

Morcia, Caterina; Tumino, Giorgio; Ghizzoni, Roberta; Badeck, Franz W.; Lattanzio, Veronica M.T.; Pascale, Michelangelo; Terzi, Valeria

2016-01-01

T-2 and HT-2 toxins are two of the most toxic members of type-A trichothecenes, produced by a number of Fusarium species. The occurrence of these mycotoxins was studied in barley samples during a survey carried out in the 2011–2014 growing seasons in climatically different regions in Italy. The percentage of samples found positive ranges from 22% to 53%, with values included between 26 and 787 μg/kg. The percentage of samples with a T-2 and HT-2 content above the EU indicative levels for barley of 200 μg/kg ranges from 2% to 19.6% in the 2011–2014 period. The fungal species responsible for the production of these toxins in 100% of positive samples has been identified as Fusarium langsethiae, a well-known producer of T-2 and HT-2 toxins. A positive correlation between the amount of F. langsethiae DNA and of the sum of T-2 and HT-2 toxins was found. This is the first report on the occurrence of F. langsethiae—and of its toxic metabolites T-2 and HT-2—in malting barley grown in Italy. PMID:27556490

Occurrence of Fusarium langsethiae and T-2 and HT-2 Toxins in Italian Malting Barley.

PubMed

Morcia, Caterina; Tumino, Giorgio; Ghizzoni, Roberta; Badeck, Franz W; Lattanzio, Veronica M T; Pascale, Michelangelo; Terzi, Valeria

2016-08-20

T-2 and HT-2 toxins are two of the most toxic members of type-A trichothecenes, produced by a number of Fusarium species. The occurrence of these mycotoxins was studied in barley samples during a survey carried out in the 2011-2014 growing seasons in climatically different regions in Italy. The percentage of samples found positive ranges from 22% to 53%, with values included between 26 and 787 μg/kg. The percentage of samples with a T-2 and HT-2 content above the EU indicative levels for barley of 200 μg/kg ranges from 2% to 19.6% in the 2011-2014 period. The fungal species responsible for the production of these toxins in 100% of positive samples has been identified as Fusarium langsethiae, a well-known producer of T-2 and HT-2 toxins. A positive correlation between the amount of F. langsethiae DNA and of the sum of T-2 and HT-2 toxins was found. This is the first report on the occurrence of F. langsethiae-and of its toxic metabolites T-2 and HT-2-in malting barley grown in Italy.

Knockdown of peroxiredoxin V increases glutamate‑induced apoptosis in HT22 hippocampal neuron cells.

PubMed

Shen, Gui-Nan; Liu, Lei; Feng, Li; Jin, Yu; Jin, Mei-Hua; Han, Ying-Hao; Jin, Cheng-Hao; Jin, Yong-Zhe; Lee, Dong-Soek; Kwon, Tae Ho; Cui, Yu-Dong; Sun, Hu-Nan

2018-06-01

High concentrations of glutamate may mediate neuronal cell apoptosis by increasing intracellular reactive oxygen species (ROS) levels. Peroxiredoxin V (Prx V), a member of the Prx family, serves crucial roles in protecting cells from oxidative stress. The present study investigated the regulatory effect of Prx V on glutamate‑induced effects on viability and apoptosis in HT22 cells. Western blotting was used for protein expression analysis and Annexin V/PI staining and flow cytometry for determination of apoptosis. The results demonstrated that glutamate may ROS‑dependently increase HT22 cell apoptosis and upregulate Prx V protein levels. Furthermore, knockdown of Prx V protein expression with a lentivirus significantly enhanced HT22 cell apoptosis mediated by glutamate, which was reversed by inhibition of ROS with N‑acetyl‑L‑cysteine. Inhibiting the extracellular signal‑regulated kinase (ERK) signaling pathway with PD98059, a specific inhibitor for ERK phosphorylation, markedly decreased glutamate‑induced HT22 cell apoptosis in Prx V knockdown cells, indicating the potential involvement of ERK signaling in glutamate‑induced HT22 cell apoptosis. In addition, an increase in nuclear apoptosis‑inducing factor was observed in Prx V knockdown HT22 cells following glutamate treatment, compared with mock cells, whereas no differences in B‑cell lymphoma‑2 and cleaved‑caspase‑3 protein expression levels were observed between mock and Prx V knockdown cells. The results of the present study indicated that Prx V may have potential as a therapeutic molecular target for glutamate‑induced neuronal cell death and provide novel insight into the role of Prx V in oxidative‑stress induced neuronal cell death.

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol.

PubMed

Hogendorf, Adam S; Hogendorf, Agata; Kurczab, Rafał; Satała, Grzegorz; Lenda, Tomasz; Walczak, Maria; Latacz, Gniewomir; Handzlik, Jadwiga; Kieć-Kononowicz, Katarzyna; Wierońska, Joanna M; Woźniak, Monika; Cieślik, Paulina; Bugno, Ryszard; Staroń, Jakub; Bojarski, Andrzej J

2017-05-04

A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT 7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-1H-indole (AGH-107, 1o, K i 5-HT7  = 6 nM, EC 50  = 19 nM, 176-fold selectivity over 5-HT 1A R) and 1e (5-methoxy analogue, K i 5-HT7  = 30 nM, EC 50  = 60 nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (C max  = 2723 ng/g) were found for 1o after i.p. (5 mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5 mg/kg. Docking to 5-HT 7 R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT 1A R selectivity.

Repeated 7-Day Treatment with the 5-HT2C Agonist Lorcaserin or the 5-HT2A Antagonist Pimavanserin Alone or in Combination Fails to Reduce Cocaine vs Food Choice in Male Rhesus Monkeys

PubMed Central

Banks, Matthew L; Negus, S Stevens

2017-01-01

Cocaine use disorder is a global public health problem for which there are no Food and Drug Administration-approved pharmacotherapies. Emerging preclinical evidence has implicated both serotonin (5-HT) 2C and 2A receptors as potential mechanisms for mediating serotonergic attenuation of cocaine abuse-related neurochemical and behavioral effects. Therefore, the present study aim was to determine whether repeated 7-day treatment with the 5-HT2C agonist lorcaserin (0.1–1.0 mg/kg per day, intramuscular; 0.032–0.1 mg/kg/h, intravenous) or the 5-HT2A inverse agonist/antagonist pimavanserin (0.32–10 mg/kg per day, intramuscular) attenuated cocaine reinforcement under a concurrent ‘choice’ schedule of cocaine and food availability in rhesus monkeys. During saline treatment, cocaine maintained a dose-dependent increase in cocaine vs food choice. Repeated pimavanserin (3.2 mg/kg per day) treatments significantly increased small unit cocaine dose choice. Larger lorcaserin (1.0 mg/kg per day and 0.1 mg/kg/h) and pimavanserin (10 mg/kg per day) doses primarily decreased rates of operant behavior. Coadministration of ineffective lorcaserin (0.1 mg/kg per day) and pimavanserin (0.32 mg/kg per day) doses also failed to significantly alter cocaine choice. These results suggest that neither 5-HT2C receptor activation nor 5-HT2A receptor blockade are sufficient to produce a therapeutic-like decrease in cocaine choice and a complementary increase in food choice. Overall, these results do not support the clinical utility of 5-HT2C agonists and 5-HT2A inverse agonists/antagonists alone or in combination as candidate anti-cocaine use disorder pharmacotherapies. PMID:27857126

Repeated 7-Day Treatment with the 5-HT2C Agonist Lorcaserin or the 5-HT2A Antagonist Pimavanserin Alone or in Combination Fails to Reduce Cocaine vs Food Choice in Male Rhesus Monkeys.

PubMed

Banks, Matthew L; Negus, S Stevens

2017-04-01

Cocaine use disorder is a global public health problem for which there are no Food and Drug Administration-approved pharmacotherapies. Emerging preclinical evidence has implicated both serotonin (5-HT) 2C and 2A receptors as potential mechanisms for mediating serotonergic attenuation of cocaine abuse-related neurochemical and behavioral effects. Therefore, the present study aim was to determine whether repeated 7-day treatment with the 5-HT 2C agonist lorcaserin (0.1-1.0 mg/kg per day, intramuscular; 0.032-0.1 mg/kg/h, intravenous) or the 5-HT 2A inverse agonist/antagonist pimavanserin (0.32-10 mg/kg per day, intramuscular) attenuated cocaine reinforcement under a concurrent 'choice' schedule of cocaine and food availability in rhesus monkeys. During saline treatment, cocaine maintained a dose-dependent increase in cocaine vs food choice. Repeated pimavanserin (3.2 mg/kg per day) treatments significantly increased small unit cocaine dose choice. Larger lorcaserin (1.0 mg/kg per day and 0.1 mg/kg/h) and pimavanserin (10 mg/kg per day) doses primarily decreased rates of operant behavior. Coadministration of ineffective lorcaserin (0.1 mg/kg per day) and pimavanserin (0.32 mg/kg per day) doses also failed to significantly alter cocaine choice. These results suggest that neither 5-HT 2C receptor activation nor 5-HT 2A receptor blockade are sufficient to produce a therapeutic-like decrease in cocaine choice and a complementary increase in food choice. Overall, these results do not support the clinical utility of 5-HT 2C agonists and 5-HT 2A inverse agonists/antagonists alone or in combination as candidate anti-cocaine use disorder pharmacotherapies.

Highly Sensitive Ammonia Gas Sensor Based on Single-Crystal Poly(3-hexylthiophene) (P3HT) Organic Field Effect Transistor.

PubMed

Mun, Seohyun; Park, Yoonkyung; Lee, Yong-Eun Koo; Sung, Myung Mo

2017-11-28

A highly sensitive organic field-effect transistor (OFET)-based sensor for ammonia in the range of 0.01 to 25 ppm was developed. The sensor was fabricated by employing an array of single-crystal poly(3-hexylthiophene) (P3HT) nanowires as the organic semiconductor (OSC) layer of an OFET with a top-contact geometry. The electrical characteristics (field-effect mobility, on/off current ratio) of the single-crystal P3HT nanowire OFET were about 2 orders of magnitude larger than those of the P3HT thin film OFET with the same geometry. The P3HT nanowire OFET showed excellent sensitivity to ammonia, about 3 times higher than that of the P3HT thin film OFET at 25 ppm ammonia. The ammonia response of the OFET was reversible and was not affected by changes in relative humidity from 45 to 100%. The high ammonia sensitivity of the P3HT nanowire OFET is believed to result from the single crystal nature and high surface/volume ratio of the P3HT nanowire used in the OSC layer.

Investigation of 5-HT3 receptor-triggered serotonin release from guinea-pig isolated colonic mucosa: a role of PYY-containing endocrine cell.

PubMed

Kojima, Shu-Ichi; Kojima, Ken; Fujita, Tomoe

2017-03-15

The effect of a 5-HT 3 receptor-selective agonist SR57227A was investigated on the outflow of 5-hydroxytryptamine (5-HT) from isolated muscle layer-free mucosal preparations of guinea-pig colon. The mucosal preparations were incubated in vitro and the outflow of 5-HT from these preparations was determined by high-performance liquid chromatography with electrochemical detection. SR57227A (100μM) produced a tetrodotoxin-resistant and sustained increase in the outflow of 5-HT from the mucosal preparations. The SR57227A-evoked sustained 5-HT outflow was completely inhibited by the 5-HT 3 receptor antagonist ramosetron (1μM). The neuropeptide Y 1 receptor antagonist BIBO3304 (100nM) partially inhibited the SR57227A-evoked sustained 5-HT outflow, but the Y 2 receptor antagonist BIIE0246 (1μM) or the glucagon-like peptide-1 (GLP-1) receptor antagonist exendin-(9-39) (1μM), showed a minimal effect on the SR57227A-evoked sustained 5-HT outflow. In the presence of BIBO3304 (100nM) and exendin-(9-39) (1μM), SR57227A (100μM) failed to produce a sustained increase in the outflow of 5-HT. The Y 1 receptor agonist [Leu 31 , Pro 34 ]-neuropeptide Y (10nM), but not GLP-1-(7-36) amide (100nM), produced a sustained increase in the outflow of 5-HT. We found that 5-HT 3 receptor-triggered 5-HT release from guinea-pig colonic mucosa is mediated by the activation of 5-HT 3 receptors located at endocrine cells (enterochromaffin cells and peptide YY (PYY)-containing endocrine cells). The activation of both Y 1 and GLP-1 receptors appears to be required for the maintenance of 5-HT 3 receptor-triggered 5-HT release. It is therefore considered that 5-HT 3 receptors located at colonic mucosa play a crucial role in paracrine signaling between enterochromaffin cells and PYY-containing endocrine cells. Copyright © 2017 Elsevier B.V. All rights reserved.

5-HT modulation of pain perception in humans.

PubMed

Martin, Sarah L; Power, Andrea; Boyle, Yvonne; Anderson, Ian M; Silverdale, Monty A; Jones, Anthony K P

2017-10-01

Although there is clear evidence for the serotonergic regulation of descending control of pain in animals, little direct evidence exists in humans. The majority of our knowledge comes from the use of serotonin (5-HT)-modulating antidepressants as analgesics in the clinical management of chronic pain. Here, we have used an acute tryptophan depletion (ATD) to manipulate 5-HT function and examine its effects of ATD on heat pain threshold and tolerance, attentional manipulation of nociceptive processing and mood in human volunteers. Fifteen healthy participants received both ATD and balanced amino acid (BAL) drinks on two separate sessions in a double-blind cross-over design. Pain threshold and tolerance were determined 4 h post-drink via a heat thermode. Additional attention, distraction and temperature discrimination paradigms were completed using a laser-induced heat pain stimulus. Mood was assessed prior and throughout each session. Our investigation reported that the ATD lowered plasma TRP levels by 65.05 ± 7.29% and significantly reduced pain threshold and tolerance in response to the heat thermode. There was a direct correlation between the reduction in total plasma TRP levels and reduction in thermode temperature. In contrast, ATD showed no effect on laser-induced pain nor significant impact of the distraction-induced analgesia on pain perception but did reduce performance of the painful temperature discrimination task. Importantly, all findings were independent of any effects of ATD on mood. As far as we are aware, it is the first demonstration of 5-HT effects on pain perception which are not confounded by mood changes.

Hydrogen sulfide activates TRPA1 and releases 5-HT from epithelioid cells of the chicken thoracic aorta.

PubMed

Delgermurun, Dugar; Yamaguchi, Soichiro; Ichii, Osamu; Kon, Yasuhiro; Ito, Shigeo; Otsuguro, Ken-Ichi

2016-09-01

Epithelioid cells in the chicken thoracic aorta are chemoreceptor cells that release 5-HT in response to hypoxia. It is likely that these cells play a role in chemoreception similar to that of glomus cells in the carotid bodies of mammals. Recently, H2S was reported to be a key mediator of carotid glomus cell responses to hypoxia. The aim of the present study was to reveal the mechanism of action of H2S on 5-HT outflow from chemoreceptor cells in the chicken thoracic aorta. The 5-HT outflow induced by NaHS, an H2S donor, and Na2S3, a polysulfide, was measured by using a HPLC equipped with an electrochemical detector. NaHS (0.3-3mM) caused a concentration-dependent increase in 5-HT outflow, which was significantly inhibited by the removal of extracellular Ca(2+). 5-HT outflow induced by NaHS (0.3mM) was also significantly inhibited by voltage-dependent L- and N-type Ca(2+) channel blockers and a selective TRPA1 channel blocker. Cinnamaldehyde, a TRPA1 agonist, mimicked the secretory response to H2S. 5-HT outflow induced by Na2S3 (10μM) was also inhibited by the TRPA1 channel blocker. Furthermore, the expression of TRPA1 was localized to 5-HT-containing chemoreceptor cells in the aortic wall. These findings suggest that the activation of TRPA1 and voltage-dependent Ca(2+) channels is involved in H2S-evoked 5-HT release from chemoreceptor cells in the chicken aorta. Copyright © 2016 Elsevier Inc. All rights reserved.

Differences in 5-HT1A receptor-mediated hypothermia in rats with low or high exploratory activity.

PubMed

Kõiv, Kadri; Harro, Jaanus

2010-12-01

Alterations in the serotonin (5-HT) system and the 5-HT1A receptor function have a significant role in anxiety-related and depression-related states. This study investigated the stress-induced hyperthermia (SIH) response and sensitivity to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetraline in rats with persistently low or high levels of exploratory activity (LE and HE, respectively), of which the LE rats show more anxiety-like and depressive-like phenotypes. No differences in the SIH in response to novel cage or injection stress were found using rectal temperature measurements. However, the LE rats had significantly less pronounced decreases in SIH in response to the 0.3 mg/kg dose of 8-hydroxy-2-(di-n-propylamino)-tetraline. Exploratory behaviour correlated significantly and positively with the magnitude of change in body temperature in response to the 5-HT1A receptor agonist. This finding suggests a less effective 5-HT1A function in the LE rats and implicates the 5-HT1A receptor in the anxiety component of passive behaviour in novel surroundings.

Gq/5-HT2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice.

PubMed

Spoida, Katharina; Masseck, Olivia A; Deneris, Evan S; Herlitze, Stefan

2014-04-29

Serotonin 2c receptors (5-HT2c-Rs) are drug targets for certain mental disorders, including schizophrenia, depression, and anxiety. 5-HT2c-Rs are expressed throughout the brain, making it difficult to link behavioral changes to circuit specific receptor expression. Various 5-HT-Rs, including 5-HT2c-Rs, are found in the dorsal raphe nucleus (DRN); however, the function of 5-HT2c-Rs and their influence on the serotonergic signals mediating mood disorders remain unclear. To investigate the role of 5-HT2c-Rs in the DRN in mice, we developed a melanopsin-based optogenetic probe for activation of Gq signals in cellular domains, where 5-HT2c-Rs are localized. Our results demonstrate that precise temporal control of Gq signals in 5-HT2c-R domains in GABAergic neurons upstream of 5-HT neurons provides negative feedback regulation of serotonergic firing to modulate anxiety-like behavior in mice.

Gq/5-HT2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice

PubMed Central

Spoida, Katharina; Masseck, Olivia A.; Deneris, Evan S.; Herlitze, Stefan

2014-01-01

Serotonin 2c receptors (5-HT2c-Rs) are drug targets for certain mental disorders, including schizophrenia, depression, and anxiety. 5-HT2c-Rs are expressed throughout the brain, making it difficult to link behavioral changes to circuit specific receptor expression. Various 5-HT-Rs, including 5-HT2c-Rs, are found in the dorsal raphe nucleus (DRN); however, the function of 5-HT2c-Rs and their influence on the serotonergic signals mediating mood disorders remain unclear. To investigate the role of 5-HT2c-Rs in the DRN in mice, we developed a melanopsin-based optogenetic probe for activation of Gq signals in cellular domains, where 5-HT2c-Rs are localized. Our results demonstrate that precise temporal control of Gq signals in 5-HT2c-R domains in GABAergic neurons upstream of 5-HT neurons provides negative feedback regulation of serotonergic firing to modulate anxiety-like behavior in mice. PMID:24733892

Large scale analysis of the mutational landscape in HT-SELEX improves aptamer discovery

PubMed Central

Hoinka, Jan; Berezhnoy, Alexey; Dao, Phuong; Sauna, Zuben E.; Gilboa, Eli; Przytycka, Teresa M.

2015-01-01

High-Throughput (HT) SELEX combines SELEX (Systematic Evolution of Ligands by EXponential Enrichment), a method for aptamer discovery, with massively parallel sequencing technologies. This emerging technology provides data for a global analysis of the selection process and for simultaneous discovery of a large number of candidates but currently lacks dedicated computational approaches for their analysis. To close this gap, we developed novel in-silico methods to analyze HT-SELEX data and utilized them to study the emergence of polymerase errors during HT-SELEX. Rather than considering these errors as a nuisance, we demonstrated their utility for guiding aptamer discovery. Our approach builds on two main advancements in aptamer analysis: AptaMut—a novel technique allowing for the identification of polymerase errors conferring an improved binding affinity relative to the ‘parent’ sequence and AptaCluster—an aptamer clustering algorithm which is to our best knowledge, the only currently available tool capable of efficiently clustering entire aptamer pools. We applied these methods to an HT-SELEX experiment developing aptamers against Interleukin 10 receptor alpha chain (IL-10RA) and experimentally confirmed our predictions thus validating our computational methods. PMID:25870409

5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders

PubMed Central

Ciranna, Lucia; Catania, Maria Vincenza

2014-01-01

Serotonin type 7 receptors (5-HT7) are expressed in several brain areas, regulate brain development, synaptic transmission and plasticity, and therefore are involved in various brain functions such as learning and memory. A number of studies suggest that 5-HT7 receptors could be potential pharmacotherapeutic target for cognitive disorders. Several abnormalities of serotonergic system have been described in patients with autism spectrum disorder (ASD), including abnormal activity of 5-HT transporter, altered blood and brain 5-HT levels, reduced 5-HT synthesis and altered expression of 5-HT receptors in the brain. A specific role for 5-HT7 receptors in ASD has not yet been demonstrated but some evidence implicates their possible involvement. We have recently shown that 5-HT7 receptor activation rescues hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome, a monogenic cause of autism. Several other studies have shown that 5-HT7 receptors modulate behavioral flexibility, exploratory behavior, mood disorders and epilepsy, which include core and co-morbid symptoms of ASD. These findings further suggest an involvement of 5-HT7 receptors in ASD. Here, we review the physiological roles of 5-HT7 receptors and their implications in Fragile X Syndrome and other ASD. PMID:25221471

Differences in 5-HT2A and mGlu2 Receptor Expression Levels and Repressive Epigenetic Modifications at the 5-HT2A Promoter Region in the Roman Low- (RLA-I) and High- (RHA-I) Avoidance Rat Strains.

PubMed

Fomsgaard, Luna; Moreno, Jose L; de la Fuente Revenga, Mario; Brudek, Tomasz; Adamsen, Dea; Rio-Alamos, Cristobal; Saunders, Justin; Klein, Anders Bue; Oliveras, Ignasi; Cañete, Toni; Blazquez, Gloria; Tobeña, Adolf; Fernandez-Teruel, Albert; Gonzalez-Maeso, Javier; Aznar, Susana

2018-03-01

The serotonin 2A (5-HT 2A ) and metabotropic glutamate 2 (mGlu2) receptors regulate each other and are associated with schizophrenia. The Roman high- (RHA-I) and the Roman low- (RLA-I) avoidance rat strains present well-differentiated behavioral profiles, with the RHA-I strain emerging as a putative genetic rat model of schizophrenia-related features. The RHA-I strain shows increased 5-HT 2A and decreased mGlu2 receptor binding levels in prefrontal cortex (PFC). Here, we looked for differences in gene expression and transcriptional regulation of these receptors. The striatum (STR) was included in the analysis. 5-HT 2A , 5-HT 1A , and mGlu2 mRNA and [ 3 H]ketanserin binding levels were measured in brain homogenates. As expected, 5-HT 2A binding was significantly increased in PFC in the RHA-I rats, while no difference in binding was observed in STR. Surprisingly, 5-HT 2A gene expression was unchanged in PFC but significantly decreased in STR. mGlu2 receptor gene expression was significantly decreased in both PFC and STR. No differences were observed for the 5-HT 1A receptor. Chromatin immunoprecipitation assay revealed increased trimethylation of histone 3 at lysine 27 (H3K27me3) at the promoter region of the HTR2A gene in the STR. We further looked at the Akt/GSK3 signaling pathway, a downstream point of convergence of the serotonin and glutamate system, and found increased phosphorylation levels of GSK3β at tyrosine 216 and increased β-catenin levels in the PFC of the RHA-I rats. These results reveal region-specific regulation of the 5-HT 2A receptor in the RHA-I rats probably due to absence of mGlu2 receptor that may result in differential regulation of downstream pathways.

Serotonin 5-HT7 receptor agents: structure-activity relationships and potential therapeutic applications in central nervous system disorders

PubMed Central

Leopoldo, Marcello; Lacivita, Enza; Berardi, Francesco; Perrone, Roberto; Hedlund, Peter B.

2010-01-01

Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT7 receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT7 receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT7 receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT7 receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT7 receptor agonists and antagonists in central nervous system disorders is presented. PMID:20923682

Rikkunshito and isoliquiritigenin counteract 5-HT-induced 2C receptor-mediated activation of pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus.

PubMed

Arai, Takeshi; Maejima, Yuko; Muroya, Shinji; Yada, Toshihiko

2013-08-01

Anorexia deteriorates the quality of life in patients with anorexia nervosa, stress disorders, gastrointestinal disorders, and cancer. Pro-opiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC), serotonin (5-HT) and its 2C receptor (5-HT2CR) are implicated in anorexia. Rikkunshito, a traditional Japanese medicine, has been used to treat anorexia and gastrointestinal disorders. The present study aimed to clarify whether rikkunshito influences the 5-HT action on ARC POMC neurons. We isolated single neurons from the ARC of adult rats and measured cytosolic Ca²⁺ concentration ([Ca²⁺](i)) by fura-2 microfluorometry combined with immunocytochemical identification of POMC neurons. Administration of 5-HT increased [Ca²⁺](i) in ARC neurons, and 80% of the 5-HT-responsive neurons were immunoreactive to POMC. Rikkunshito concentration-dependently and 5-HT2CR antagonist SB242084 significantly suppressed 5-HT-induced [Ca²⁺](i) increases. The rikkunshito-suppressed neurons highly overlapped SB242084-suppressed neurons. Isoliquiritigenin, an ingredient of rikkunshito, suppressed 5-HT-induced [Ca²⁺](i) increases to a lesser extent than rikkunshito. These results demonstrate that rikkunshito counteracts 5-HT-induced 5-HT2CR-mediated Ca²⁺ signaling in ARC POMC neurons, and that isoliquiritigenin may serve as an active component of rikkunshito. The ability of rikkunshito to antagonize 5-HT action in ARC POMC neurons could underlie the rikkunshito's action to attenuate anorexia induced by excessive 5-HT release and/or action associated with psychiatric diseases, gastrointestinal disorders, cancer, and anti-cancer medicines. Copyright © 2013 Elsevier Ltd. All rights reserved.

Facilitation by 8-OH-DPAT of passive avoidance performance in rats after inactivation of 5-HT1A receptors

PubMed Central

Otano, Ana; García-Osta, Ana; Ballaz, Santiago; Frechilla, Diana; Del Río, Joaquín

1999-01-01

Pretraining administration of 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT 0.1 mg kg−1), a 5-HT1A receptor agonist, or buspirone (1 mg kg−1), a 5-HT1A receptor partial agonist, markedly impaired passive avoidance retention in rats 24 h later. The effect of 8-OH-DPAT was prevented by the 5-HT1A receptor antagonists, NAN-190 and WAY-100635, at doses without any intrinsic effect.N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ 10 mg kg−1), an alkylating agent that inactivates different G-protein coupled receptors, impaired retention performance when given 48 h pretraining. The disruptive effect of EEDQ was reversed by 8-OH-DPAT or buspirone, given 30 min before training.Non-specific actions did not account for 8-OH-DPAT-induced reversal of the EEDQ effect since no significant difference in locomotor activity or in pain threshold was found between rats receiving EEDQ or EEDQ+8-OH-DPAT.When NAN-190 (1 mg kg−1) or WAY-100635 (0.5 mg kg−1) were given before 8-OH-DPAT to EEDQ-pretreated animals, the reversal by 8-OH-DPAT of EEDQ-induced retention impairment was still more pronounced. However, no EEDQ reversal by 8-OH-DPAT was found when 5-HT1A receptors were protected by WAY-100635 (10 mg kg−1) 30 min before EEDQ.In the hippocampus of EEDQ-treated rats, 5-HT7 receptors were less inactivated than 5-HT1A receptors and significant increases were found in 5-HT1A but not in 5-HT7 receptor mRNA levels. Ritanserin and methiothepin (10 mg kg−1 each), antagonists with higher affinity at 5-HT7 than at 5-HT1A receptors, prevented the retention impairment induced by EEDQ but did not significantly protect against 5-HT7 receptor inactivation.The results indicate that the facilitatory effect of 8-OH-DPAT is not mediated through 5-HT1A receptors and suggest that other 8-OH-DPAT-sensitive receptors could be involved in the dual effect of 8-OH-DPAT on passive avoidance performance in rats. PMID:10588924

Pharmacological profile of DA-6886, a novel 5-HT4 receptor agonist to accelerate colonic motor activity in mice.

PubMed

Lee, Min Jung; Cho, Kang Hun; Park, Hyun Min; Sung, Hyun Jung; Choi, Sunghak; Im, Weonbin

2014-07-15

DA-6886, the gastrointestinal prokinetic benzamide derivative is a novel 5-HT4 receptor agonist being developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C). The purpose of this study was to characterize in vitro and in vivo pharmacological profile of DA-6886. We used various receptor binding assay, cAMP accumulation assay, organ bath experiment and colonic transit assay in normal and chemically constipated mice. DA-6886 exhibited high affinity and selectivity to human 5-HT4 receptor splice variants, with mean pKi of 7.1, 7.5, 7.9 for the human 5-HT4a, 5-HT4b and 5-HT4d, respectively. By contrast, DA-6886 did not show significant affinity for several receptors including dopamine D2 receptor, other 5-HT receptors except for 5-HT2B receptor (pKi value of 6.2). The affinity for 5-HT4 receptor was translated into functional agonist activity in Cos-7 cells expressing 5-HT4 receptor splice variants. Furthermore, DA-6886 induced relaxation of the rat oesophagus preparation (pEC50 value of 7.4) in a 5-HT4 receptor antagonist-sensitive manner. The evaluation of DA-6886 in CHO cells expressing hERG channels revealed that it inhibited hERG channel current with an pIC50 value of 4.3, indicating that the compound was 1000-fold more selective for the 5-HT4 receptor over hERG channels. In the normal ICR mice, oral administration of DA-6886 (0.4 and 2mg/kg) resulted in marked stimulation of colonic transit. Furthermore, in the loperamide-induced constipation mouse model, 2mg/kg of DA-6886 significantly improved the delay of colonic transit, similar to 10mg/kg of tegaserod. Taken together, DA-6886 is a highly potent and selective 5-HT4 receptor agonist to accelerate colonic transit in mice, which might be therapeutic agent having a favorable safety profile in the treatment of gastrointestinal motor disorders such as IBS-C and chronic constipation. Copyright © 2014 Elsevier B.V. All rights reserved.

Quantification des besoins en intrants antipaludiques: contribution à l'actualisation des hypothèses pour la quantification des intrants de prise en charge des cas de paludisme grave en République Démocratique du Congo

PubMed Central

Likwela, Joris Losimba; Otokoye, John Otshudiema

2015-01-01

Les formes graves de paludisme à Plasmodium falciparum sont une cause majeure de décès des enfants de moins de 5 ans en Afrique Sub-saharienne. Un traitement rapide dépend de la disponibilité de médicaments appropriés au niveau des points de prestation de service. La fréquence des ruptures de stock des commodités antipaludiques, en particuliers celles utilisées pour le paludisme grave, avait nécessité une mise à jour des hypothèses de quantification. Les données issues de la collecte de routine du PNLP de 2007 à 2012 ont été comparées à celles rapportés par d'autres pays africains et utilisées pour orienter les discussions au cours d'un atelier organisé par le PNLP et ses partenaires techniques et financiers afin de dégager un consensus national. La proportion des cas de paludisme rapportés comme grave en RDC est resté autour d'une médiane de 7% avec un domaine de variation de 6 à 9%. Hormis la proportion rapportée au Kenya (2%), les pays africains ont rapporté une proportion de cas grave variant entre 5 et 7%. Il apparaît que la proportion de 1% précédemment utilisée pour la quantification en RDC a été sous-estimée dans le contexte de la gestion des cas graves sur terrain. Un consensus s'est dégagé autour de la proportion de 5% étant entendu que des efforts de renforcement des capacités seraient déployés afin d'améliorer le diagnostic au niveau des points de prestation des services. PMID:26213595

Effects of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and para-methoxyamphetamine on striatal 5-HT when co-administered with moclobemide.

PubMed

Freezer, Alexander; Salem, Abdallah; Irvine, Rodney J

2005-04-11

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") and para-methoxyamphetamine (PMA) are commonly used recreational drugs. PMA, often mistaken for MDMA, is reported to be more toxic in human use than MDMA. Both of these drugs have been shown to facilitate the release and prevent the reuptake of 5-hydroxytryptamine (5-HT, serotonin). PMA is also a potent inhibitor of monoamine oxidase type A (MAO-A), an enzyme responsible for the catabolism of 5-HT, and this characteristic may contribute to its increased toxicity. In humans, co-administration of MDMA with the reversible MAO-A inhibitor moclobemide has led to increased apparent toxicity with ensuing fatalities. In the present study, using microdialysis, we examined the effects of co-administration of MDMA and PMA with moclobemide on extracellular concentrations of 5-HT and 5-hydroxy indol acetic acid (5-HIAA) in the striatum of the rat. 5-HT-mediated effects on body temperature and behavior were also recorded. Rats were pretreated with saline or 20 mg/kg (i.p.) moclobemide and 60 min later injected with 10 mg/kg MDMA, PMA, or saline. Dialysate samples were collected every 30 min for 5 h and analyzed by HPLC-ED. Both MDMA and PMA produced significant increases in extracellular 5-HT concentrations (590% and 360%, respectively, P < 0.05). Rats treated with PMA and MDMA displayed significantly increased 5-HT-related behaviors (P < 0.05). Furthermore, only MDMA was capable of producing additional significant increases in 5-HT concentrations (980%, P < 0.05) when co-administered with moclobemide. These data suggest that co-administration of MDMA with moclobemide increases extracellular 5-HT and 5-HT-mediated behaviors and may cause increased 5-HT related toxicity similar to that reported with PMA.

Effects of autoshaping procedures on 3H-8-OH-DPAT-labeled 5-HT1a binding and 125I-LSD-labeled 5-HT2a binding in rat brain.

PubMed

Tomie, Arthur; Di Poce, Jason; Aguado, Allison; Janes, Amy; Benjamin, Daniel; Pohorecky, Larissa

2003-06-13

Effects of experience with Pavlovian autoshaping procedures on lever-press autoshaping conditioned response (CR) performance and 3H-8-OH-DPAT-labeled binding of 5-HT(1a) receptors as well as 125I-LSD-labeled binding of 5-HT(2a) receptors were evaluated in four groups of male Long-Evans hooded rats. Two groups of rats (Group Paired High CR and Group Paired Low CR) received Pavlovian autoshaping procedures wherein the presentation of a lever (conditioned stimulus, CS) was followed by the response-independent presentation of food (unconditioned stimulus, US). Rats in Group Paired High CR (n=12) showed more rapid CR acquisition and higher asymptotic levels of lever-press autoshaping CR performance relative to rats in Group Low CR (n=12). Group Omission (n=9) received autoshaping with an omission contingency, such that performing the lever-press autoshaping CR resulted in the cancellation the food US, while Group Random (n=9) received presentations of lever CS and food US randomly with respect to one another. Though Groups Omission and Random did not differ in lever-press autoshaping CR performance, Group Omission showed significantly lower levels of 3H-8-OH-DPAT-labeled 5-HT(1a) binding in post-synaptic areas (frontal cortex, septum, caudate putamen), as well as significantly higher plasma corticosterone levels than Group Random. In addition, Group Random showed higher levels of 3H-8-OH-DPAT-labeled 5-HT(1a) binding in pre-synaptic somatodendritic autoreceptors on dorsal raphe nucleus relative to each of the other three groups. Autoradiographic analysis of 125I-LSD-labeled 5-HT(2a) receptor binding revealed no significant differences between Groups Paired High CR and Paired Low CR or between Groups Omission and Random in any brain regions.

PKM2 Subcellular Localization Is Involved in Oxaliplatin Resistance Acquisition in HT29 Human Colorectal Cancer Cell Lines

PubMed Central

Ginés, Alba; Bystrup, Sara; Ruiz de Porras, Vicenç; Guardia, Cristina; Musulén, Eva; Martínez-Cardús, Anna; Manzano, José Luis; Layos, Laura; Abad, Albert; Martínez-Balibrea, Eva

2015-01-01

Chemoresistance is the main cause of treatment failure in advanced colorectal cancer (CRC). However, molecular mechanisms underlying this phenomenon remain to be elucidated. In a previous work we identified low levels of PKM2 as a putative oxaliplatin-resistance marker in HT29 CRC cell lines and also in patients. In order to assess how PKM2 influences oxaliplatin response in CRC cells, we silenced PKM2 using specific siRNAs in HT29, SW480 and HCT116 cells. MTT test demonstrated that PKM2 silencing induced resistance in HT29 and SW480 cells and sensitivity in HCT116 cells. Same experiments in isogenic HCT116 p53 null cells and double silencing of p53 and PKM2 in HT29 cells failed to show an influence of p53. By using trypan blue stain and FITC-Annexin V/PI tests we detected that PKM2 knockdown was associated with an increase in cell viability but not with a decrease in apoptosis activation in HT29 cells. Fluorescence microscopy revealed PKM2 nuclear translocation in response to oxaliplatin in HCT116 and HT29 cells but not in OXA-resistant HTOXAR3 cells. Finally, by using a qPCR Array we demonstrated that oxaliplatin and PKM2 silencing altered cell death gene expression patterns including those of BMF, which was significantly increased in HT29 cells in response to oxaliplatin, in a dose and time-dependent manner, but not in siPKM2-HT29 and HTOXAR3 cells. BMF gene silencing in HT29 cells lead to a decrease in oxaliplatin-induced cell death. In conclusion, our data report new non-glycolytic roles of PKM2 in response to genotoxic damage and proposes BMF as a possible target gene of PKM2 to be involved in oxaliplatin response and resistance in CRC cells. PMID:25955657

Fabrication of organic solar cells with design blend P3HT: PCBM variation of mass ratio

NASA Astrophysics Data System (ADS)

Supriyanto, Agus; Mustaqim, Amrina; Agustin, Maya; Ramelan, Ari H.; Suyitno; Septa Rosa, Erlyta; Yofentina; Nurosyid, Fahru

2016-02-01

Organic solar cells of FTO/PEDOT: PSS/P3HT: PCBM/Al has been fabricated, and its performance has been tested in dark and under various illumination of light intensity 1000 W/m2. The active materials used in this study are poly (3- hexylthiophene) (P3HT) and [6, 6]-phenyl-C61-butyric acid methyl ester (PCBM). P3HT is the donor while PCBM acts as an acceptor. Variation of PCBM and P3HT are 1:1, 1:2, 1:3, 1:4 and 1:5. P3HT: PCBM was mixed by chlorobenzene solvents. The mixing was done by using the ultrasonic cleaner. The absorbance characterization using by UV-Visible Spectrometer Lambda 25 instrument and I-V characterization has been tested using a set of 2602A Keithley instrument. Absorbance characterization shows that two peaks are formed. The first peak in the range of 300 to 350 nm which is a range of PCBM and the second peak range from 450 to 600 nm which is a range of P3HT. As the mass ratio increases, the second peak of P3HT increases while the first peak does not change. The gap energy estimated by the Tauc method is 2.0 eV. I-V characterization of the efficiency was obtained. The efficiency of sample 1, 2, 3, 4, and 5 are 5.80x10-2%; 6.46x10-2%; 7.72x10-2%; 8.25x10-2% and 9.81x10-2%, respectively. The highest value of efficiency was obtained at mass ratio 1:5.

Enhanced Stress Response in 5-HT1AR Overexpressing Mice: Altered HPA Function and Hippocampal Long-Term Potentiation.

PubMed

Pilar-Cuéllar, Fuencisla; Vidal, Rebeca; Díaz, Álvaro; Garro-Martínez, Emilio; Linge, Raquel; Castro, Elena; Haberzettl, Robert; Fink, Heidrun; Bert, Bettina; Brosda, Jan; Romero, Beatriz; Crespo-Facorro, Benedicto; Pazos, Ángel

2017-11-15

Postsynaptic 5-HT 1A receptors (5-HT 1A R) play an important role in anxiety and stress, although their contribution is still controversial. Previous studies report that mice overexpressing postsynaptic 5-HT 1A Rs show no changes in basal anxiety, though the influence of stress conditions has not been addressed yet. In this study, we used this animal model to evaluate the role of 5-HT 1A Rs in anxiety response after pre-exposure to an acute stressor. Under basal conditions, 5-HT 1A R overexpressing animals presented high corticosterone levels and a lower mineralocorticoid/glucocorticoid receptor ratio. After pre-exposure to a single stressor, they showed a high anxiety-like response, associated with a blunted increase in corticosterone levels and higher c-Fos activation in the prefrontal cortex. Moreover, these mice also presented a lack of downregulation of hippocampal long-term potentiation after stress exposure. Therefore, higher postsynaptic 5-HT 1A R activation might predispose to a high anxious phenotype and an impaired stress coping behavior.

The 5-HT7 receptor as a potential target for treating drug and alcohol abuse

PubMed Central

Hauser, Sheketha R.; Hedlund, Peter B.; Roberts, Amanda J.; Sari, Youssef; Bell, Richard L.; Engleman, Eric A.

2015-01-01

Alcohol and drug abuse take a large toll on society and affected individuals. However, very few effective treatments are currently available to treat alcohol and drug addiction. Basic and clinical research has begun to provide some insights into the underlying neurobiological systems involved in the addiction process. Several neurotransmitter pathways have been implicated and distinct reward neurocircuitry have been proposed—including the mesocorticolimbic dopamine (MCL-DA) system and the extended amygdala. The serotonin (5-HT) neurotransmitter system is of particular interest and multiple 5-HT receptors are thought to play significant roles in alcohol and drug self-administration and the development of drug dependence. Among the 5-HT receptors, the 5-HT7 receptor is currently undergoing characterization as a potential target for the treatment of several psychiatric disorders. Although this receptor has received only limited research regarding addictive behaviors, aspects of its neuroanatomical, biochemical, physiological, pharmacological, and behavioral profiles suggest that it could play a key role in the addiction process. For instance, genomic studies in humans have suggested a link between variants in the gene encoding the 5-HT7 receptor and alcoholism. Recent behavioral testing using high-affinity antagonists in mice and preliminary tests with alcohol-preferring rats suggest that this receptor could mediate alcohol consumption and/or reinforcement and play a role in seeking/craving behavior. Interest in the development of new and more selective pharmacological agents for this receptor will aid in examining the 5-HT7 receptor as a novel target for treating addiction. PMID:25628528

Serotonin 5-HT2C receptor-mediated inhibition of the M-current in hypothalamic POMC neurons.

PubMed

Roepke, T A; Smith, A W; Rønnekleiv, O K; Kelly, M J

2012-06-01

Hypothalamic proopiomelanocortin (POMC) neurons are controlled by many central signals, including serotonin. Serotonin increases POMC activity and reduces feeding behavior via serotonion [5-hydroxytryptamine (5-HT)] receptors by modulating K(+) currents. A potential K(+) current is the M-current, a noninactivating, subthreshold outward K(+) current. Previously, we found that M-current activity was highly reduced in fasted vs. fed states in neuropeptide Y neurons. Because POMC neurons also respond to energy states, we hypothesized that fasting may alter the M-current and/or its modulation by serotonergic input to POMC neurons. Using visualized-patch recording in neurons from fed male enhanced green fluorescent protein-POMC transgenic mice, we established that POMC neurons expressed a robust M-current (102.1 ± 6.7 pA) that was antagonized by the selective KCNQ channel blocker XE-991 (40 μM). However, the XE-991-sensitive current in POMC neurons did not differ between fed and fasted states. To determine if serotonin suppresses the M-current via the 5-HT(2C) receptor, we examined the effects of the 5-HT(2A)/5-HT(2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) on the M-current. Indeed, DOI attenuated the M-current by 34.5 ± 6.9% and 42.0 ± 5.3% in POMC neurons from fed and fasted male mice, respectively. In addition, the 5-HT(1B)/5-HT(2C) receptor agonist m-chlorophenylpiperazine attenuated the M-current by 42.4 ± 5.4% in POMC neurons from fed male mice. Moreover, the selective 5-HT(2C) receptor antagonist RS-102221 abrogated the actions of DOI in suppressing the M-current. Collectively, these data suggest that although M-current expression does not differ between fed and fasted states in POMC neurons, serotonin inhibits the M-current via activation of 5-HT(2C) receptors to increase POMC neuronal excitability and, subsequently, reduce food intake.

5-HT2C receptor involvement in the control of persistence in the reinforced spatial alternation animal model of obsessive-compulsive disorder.

PubMed

Papakosta, Vassiliki-Maria; Kalogerakou, Stamatina; Kontis, Dimitris; Anyfandi, Eleni; Theochari, Eirini; Boulougouris, Vasileios; Papadopoulos, Sokrates; Panagis, George; Tsaltas, Eleftheria

2013-04-15

The serotonergic system is implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD. Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence. Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence. These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD. Copyright © 2013 Elsevier B.V. All rights reserved.