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5-HT5A Receptor

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David R. Thomas – One of the best experts on this subject based on the ideXlab platform.

  • SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4′-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), a novel 5-HT5A Receptor-selective antagonist, enhances 5-HT neuronal function: Evidence for an autoReceptor
    Neuropharmacology, 2006
    Co-Authors: David R. Thomas, Sara A. Coggon, Ellen M. Soffin, Claire Roberts, James N.c. Kew, Raúl De La Flor, Lee A. Dawson, Victoria Anne Honey Fry, Stefania Faedo, Philip David Hayes
    Abstract:

    Abstract This study utilised the selective 5-ht 5A Receptor antagonist, SB-699551-A (3-cyclopentyl- N -[2-(dimethylamino)ethyl]- N -[(4′-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), to investigate 5-ht 5A Receptor function in guinea pig brain. SB-699551-A competitively antagonised 5-HT-stimulated [ 35 S]GTPγS binding to membranes from human embryonic kidney (HEK293) cells transiently expressing the guinea pig 5-ht 5A Receptor (p A 2 8.1 ± 0.1) and displayed 100-fold selectivity versus the serotonin transporter and those 5-HT Receptor subtypes (5-HT 1A/B/D , 5-HT 2A/C and 5-HT 7 ) reported to modulate central 5-HT neurotransmission in the guinea pig. In guinea pig dorsal raphe slices, SB-699551-A (1 μM) did not alter neuronal firing per se but attenuated the 5-CT-induced depression in serotonergic neuronal firing in a subpopulation of cells insensitive to the 5-HT 1A Receptor-selective antagonist WAY-100635 (100 nM). In contrast, SB-699551-A (100 or 300 nM) failed to affect both electrically-evoked 5-HT release and 5-CT-induced inhibition of evoked release measured using fast cyclic voltvoltammetry in vitro . SB-699551-A (0.3, 1 and 3 mg/kg s.c.) did not modulate extracellular levels of 5-HT in the guinea pig frontal cortex in vivo . However, when administered in combination with WAY-100635 (0.3 mg/kg s.c.), SB-699551-A (0.3, 1 or 3 mg/kg s.c.) produced a significant increase in extracellular 5-HT levels. These studies provide evidence for an autoReceptor role for the 5-ht 5A Receptor in guinea pig brain.

  • 5-HT5A Receptors as a therapeutic target.
    Pharmacology & therapeutics, 2006
    Co-Authors: David R. Thomas
    Abstract:

    Abstract The 5-HT5A Receptor is enigmatic among 5-HT Receptors since, although the human Receptor was cloned in 1994, until recently, very little has been learnt about the function of the Receptor in native tissues. Findings from 5-HT5A Receptor mRNA localisation and immunolabelling studies have revealed widespread expression in the CNS, and have provided pointers to the potential functional role(s) of the Receptor. The expression of the 5-HT5A Receptor in raphe nuclei and in higher brain areas, such as the cerebral cortex and hippocampus, suggests a potential autoReceptor function whilst localisation in the suprachiasmatic nucleus (SCN) suggests a role in circadian rhythm control. Additionally, 5-HT5A Receptor knockout mousmouse phenotyping studies support a role in the control of exploratory behaviour. The lack of understanding of the role of the Receptor has been, in part, due to the lack of available selective 5-HT5A Receptor ligands. However, a selective 5-HT5A Receptor antagonist, 3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4′-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride (SB-699551-A), has recently been identified which appears to be a useful tool with which to elucidate the physiological function of the Receptor. Brain localisation and functional studies to date potentially implicate the Receptor in the control of circadian rhythms, mood and cognitive function, whilst gene association studies implicate the Receptor in the aetiology of schizophrenia. Although much is still to be learnt about the function of the 5-HT5A Receptor, on the basis of these findings, it can be speculated that 5-HT5A Receptor-selective ligands might show utility in psychiatric disorders such as schizophrenia and unipolar depression in which cognitive or mood disturbances are a feature.

  • Discovery of a potent and selective 5-HT5A Receptor antagonist by high-throughput chemistry.
    Bioorganic & medicinal chemistry letters, 2005
    Co-Authors: David F. Corbett, Tom D. Heightman, Stephen Moss, Steven Mark Bromidge, Sara A. Coggon, Mark J. Longley, Ana Maria Roa, Jennifer A. Williams, David R. Thomas
    Abstract:

    Abstract High-throughput screening of an array of biphenylmethylamines synthesised by high-throughput solid-phase chemistry resulted in the identification of compounds with high-affinity for the 5-HT5A Receptor. The structure–activity relationship within this series and further array synthesis led to the identification of the biphenylmethylamine derivative 11, a potent and selective 5-HT5A Receptor antagonist.

Ricardo Miledi – One of the best experts on this subject based on the ideXlab platform.

  • Expression of hippocampal serotonin Receptors 5-HT2C and 5-HT5A in a rat model of diet-induced obesity supplemented with tryptophan.
    International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 2015
    Co-Authors: Sarahi Lopez‐esparza, Laura C Berumen, Ricardo Miledi, Karla Padilla, Guadalupe García-alcocer
    Abstract:

    Food intake regulation is a complex mechanism that involves endogenous substances and central nervous system structures like hypothalamus or even hippocampus. The neurotransmitter serotonin is distinguished as food intake mediator; within its multiples Receptors, the 5-HT2C type is characterized by its inhibitory appetite action but there is no information about 5-HT5A Receptors involvement in obesity disease. It is also unknown if there are any changes in the Receptors expression in rats hippocampus with induced obesity during development through a high energy diet (HED) supplemented with tryptophan (W). To appreciate the Receptors expression pattern in the hippocampus, obesity was induced to young Sprague Dawley rats through a HED and supplemented with W. Immunocytochemical and western blot techniques were used to study the Receptor distribution and quantify the protein expression. The rats with HED diet developed obesity until week 13 of treatment. The 5-HT2C Receptor expression decreased in CA1, CA2, CA3 and DG of HED group; and also in CA2, CA3 and DG for HEDW group. The 5-HT5A Receptor expression only decreased in DG for HED group. Variations of the two serotonin Receptors subtypes support their potential role in obesity.

  • Serotonin Receptor 5-HT5A in rat hippocampus decrease by leptin treatment.
    Neuroscience letters, 2010
    Co-Authors: Guadalupe García-alcocer, Laura C Berumen, Angelina Rodríguez, Paulina Moreno-layseca, Jesica Escobar, Ricardo Miledi
    Abstract:

    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-HT5A Receptors in rat hippocampus induced by leptin, an adipocyte-derived hor- mone 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-HT5A 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 lep- tin + serotonin treated. The results showed that even though the 5-HT5A 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-HT5A serotonin Receptor decreased significantly in the dentate gyrus. © 2010 Elsevier Ireland Ltd. All rights reserved.

  • Developmental expression of 5-HT5A Receptor mRNA in the rat brain
    Neuroscience letters, 2005
    Co-Authors: Guadalupe García-alcocer, Gabriela Sarabia-altamirano, Ataúlfo Martínez-torres, Ricardo Miledi
    Abstract:

    Abstract In the central nervous system, serotonin (5-HT) may function as a mitogen as well as a neurotransmitter; and its early appearance suggests a potential role in development. The present experiments were done to determine the localization of the mRNA coding for the 5-HT 5A Receptor during development of the rat brain. 5-HT 5A gene transcription was assessed by in situ hybridization, from E18 and during postnatal (PN) development. An intense signal of 5-HT 5A mRNA was found in the cerebral cortex and olfactory nucleus at E18, PN0 and PN5. A sharp decrease at PN11 was followed by an increase until reaching the adult level in the cerebral cortex; whereas in the olfactory nucleus, transcription remained weak. In contrast, in the hippocampal formation the signal was weak in the CA1, CA2 and CA3 regions at E18 and PO; increased at P5 and then decreased at P11 before attaining the adult level. We conclude that the gene coding for the 5-HT 5A Receptor is already active in the embryonic rat brain and is differentially expressed during development.

René Hen – One of the best experts on this subject based on the ideXlab platform.

  • Human 5-HT5 Receptors: the 5-HT5A Receptor is functional but the 5-HT5B Receptor was lost during mammalian evolution
    European journal of pharmacology, 2001
    Co-Authors: Régis Grailhe, Gregg W. Grabtree, René Hen
    Abstract:

    Abstract We have isolated from a human genomic library the human 5-hydroxytryptamine 5-HT 5A and 5-HT 5B genes. The human 5-HT 5A gene encodes a protein with similar characteristics to its mouse homologue. When expressed in monkey COS-7 cells, the human 5-HT 5A Receptor displayed a high affinity for tritiated 5-carbamidotryptamine ([ 3 H]5-CT; K D =2.8 nM) and iodinated lysergic acid diethylamide ([ 125 I]LSD; K D =187 pM). These binding sites displayed the following displacement profile: Ergotamine>Methiothepin>5-CT, Ritanserin>5-HT. Reverse trantranscriptase polymerase chain reaction (RT-PCR) experiments revealed the presence of human 5-HT 5A mRNA in the central nervous system but not in peripheral organs. When expressed in Xenopus oocytes, the 5-HT 5A Receptor was able to couple to the inwardly rectifying K + channel, GIRK 1 . In contrast to the human 5-HT 5A gene and the mouse 5-HT 5B gene, the human 5-HT 5B gene does not encode a functional protein because its coding sequence is interrupted by stop codons. Our results suggest, therefore, that the 5-HT 5B Receptor has been lost during evolution after the divergence between rodents and primates. The 5-HT 5B Receptor is the first example of a brain-specific protein that is absent in human.

  • Increased Exploratory Activity and Altered Response to LSD in Mice Lacking the 5-HT5A Receptor
    Neuron, 1999
    Co-Authors: Régis Grailhe, Christian Waeber, Stephanie C. Dulawa, Jean P Hornung, Xiaoxi Zhuang, Dani Brunner, Mark A. Geyer, René Hen
    Abstract:

    In order to determine the distribution and function of the 5-HT5A serotonin Receptor subtype, we generated knockout mice lacking the 5-HT5A gene. Comparative autoradiography studies of brains of wild-type (wt) and 5-HT5A knockout (5A-KO) mice revealed the existence of binding sites with high affinity for [125I]LSD that correspond to 5-HT5A Receptors and that are concentrated in the olfactory bulb, neocortex, and medial habenula. When exposed to novel environments, the 5A-KO mice displayed increased exploratory activity but no change in anxiety-related behaviors. In addition, the stimulatory effect of LSD on exploratory activity was attenuated in 5A-KO mice. These results suggest that 5-HT5A Receptors modulate the activity of neural circuits involved specifically in exploratory behavior and suggest that some of the psychotropic effects of LSD may be mediated by 5-HT5A Receptors.

  • Putative 5-ht5 Receptors: localization in the mouse CNS and lack of effect in the inhibition of dural protein extravasation.
    Annals of the New York Academy of Sciences, 1998
    Co-Authors: Christian Waeber, René Hen, Régis Grailhe, Michael A. Moskowitz
    Abstract:

    Putative 5-ht5 Receptor binding sites were visualized by in vitro autoradiography using [125I]LSD (in the presence of clozapine and spiperone) or [3H]5-carboxamidotryptamine (in the presence 8-OH-DPAT, GR127935 and spiperone). Under these conditions, no [3H]5-carboxamidotryptamine labeling was detected in the brain of mice lacking the gene encoding the putative 5-HT5A Receptor (knockout mice), whereas intermediate densities of binding sites were seen in the olfactory bulb and neocortex of wild-type mice. [125I]LSD labeled the same areas as [3H]5-carboxamidotryptamine in wild-type mice. High densities of [125I]LSD binding sites were observed in the medial habenula of wild type and knockout mice. 5-CT competed for [125I]LSD binding sites with an affinity of 2 nM in the olfactory bulb and neocortex of wild-type mice and an affinity of 30 nM in the habenula of knockout mice, suggesting that habenular labeling might be accounted for by putative 5-ht5b Receptors. In the presence of 5′-guanylylimidodiphosphate, 5-CT displaced [125I]LSD from putative 5-HT5A and 5-ht5b sites with a 6-times and 3-times lower affinity, respectively, suggesting that both Receptor subtypes are coupled to G protproteins in brain. We also studied the inhibitory effect of 5-CT on dural neurogenic inflammation in knockout mice. In wild type mice, 3 ng/kg 5-CT inhibited dural protein extravasation by 60%. A similar effect was observed in knockout mice, even in the presence of the 5-HT1B Receptor antagonist GR127935. These results suggest that the inhibitory effects of 5-CT are not mediated by a site with the characteristics of the putative 5-ht5 Receptor.

Beatriz Godínez-chaparro – One of the best experts on this subject based on the ideXlab platform.

Guadalupe García-alcocer – One of the best experts on this subject based on the ideXlab platform.

  • Expression of hippocampal serotonin Receptors 5-HT2C and 5-HT5A in a rat model of diet-induced obesity supplemented with tryptophan.
    International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 2015
    Co-Authors: Sarahi Lopez‐esparza, Laura C Berumen, Ricardo Miledi, Karla Padilla, Guadalupe García-alcocer
    Abstract:

    Food intake regulation is a complex mechanism that involves endogenous substances and central nervous system structures like hypothalamus or even hippocampus. The neurotransmitter serotonin is distinguished as food intake mediator; within its multiples Receptors, the 5-HT2C type is characterized by its inhibitory appetite action but there is no information about 5-HT5A Receptors involvement in obesity disease. It is also unknown if there are any changes in the Receptors expression in rats hippocampus with induced obesity during development through a high energy diet (HED) supplemented with tryptophan (W). To appreciate the Receptors expression pattern in the hippocampus, obesity was induced to young Sprague Dawley rats through a HED and supplemented with W. Immunocytochemical and western blot techniques were used to study the Receptor distribution and quantify the protein expression. The rats with HED diet developed obesity until week 13 of treatment. The 5-HT2C Receptor expression decreased in CA1, CA2, CA3 and DG of HED group; and also in CA2, CA3 and DG for HEDW group. The 5-HT5A Receptor expression only decreased in DG for HED group. Variations of the two serotonin Receptors subtypes support their potential role in obesity.

  • Serotonin Receptor 5-HT5A in rat hippocampus decrease by leptin treatment.
    Neuroscience letters, 2010
    Co-Authors: Guadalupe García-alcocer, Laura C Berumen, Angelina Rodríguez, Paulina Moreno-layseca, Jesica Escobar, Ricardo Miledi
    Abstract:

    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-HT5A Receptors in rat hippocampus induced by leptin, an adipocyte-derived hor- mone 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-HT5A 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 lep- tin + serotonin treated. The results showed that even though the 5-HT5A 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-HT5A serotonin Receptor decreased significantly in the dentate gyrus. © 2010 Elsevier Ireland Ltd. All rights reserved.

  • Developmental expression of 5-HT5A Receptor mRNA in the rat brain
    Neuroscience letters, 2005
    Co-Authors: Guadalupe García-alcocer, Gabriela Sarabia-altamirano, Ataúlfo Martínez-torres, Ricardo Miledi
    Abstract:

    Abstract In the central nervous system, serotonin (5-HT) may function as a mitogen as well as a neurotransmitter; and its early appearance suggests a potential role in development. The present experiments were done to determine the localization of the mRNA coding for the 5-HT 5A Receptor during development of the rat brain. 5-HT 5A gene transcription was assessed by in situ hybridization, from E18 and during postnatal (PN) development. An intense signal of 5-HT 5A mRNA was found in the cerebral cortex and olfactory nucleus at E18, PN0 and PN5. A sharp decrease at PN11 was followed by an increase until reaching the adult level in the cerebral cortex; whereas in the olfactory nucleus, transcription remained weak. In contrast, in the hippocampal formation the signal was weak in the CA1, CA2 and CA3 regions at E18 and PO; increased at P5 and then decreased at P11 before attaining the adult level. We conclude that the gene coding for the 5-HT 5A Receptor is already active in the embryonic rat brain and is differentially expressed during development.