Effects of myo-Inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells

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dc.contributor.authorBrink, C. B.
dc.contributor.authorViljoen, S. L.
dc.contributor.authorDe Kock, S. E.
dc.contributor.authorStein, D. J.
dc.contributor.authorHarvey, B. H.
dc.contributor.authorBrink, C. B.
dc.contributor.authorViljoen, S. L.
dc.contributor.authorDe Kock, S. E.
dc.contributor.authorStein, D. J.
dc.contributor.authorHarvey, B. H.
dc.date.accessioned2011-05-15T15:59:59Z
dc.date.accessioned2011-05-15T15:59:59Z
dc.date.available2011-05-15T15:59:59Z
dc.date.available2011-05-15T15:59:59Z
dc.date.issued2004
dc.date.issued2004
dc.description.abstractmyo-Inositol (mI) is a key metabolic precursor to the phospoinositide (PI) metabolic pathway as a key component of central G-protein coupled receptor signaling systems, including several subtypes of adrenergic, cholinergic, serotonergic and metabotropic glutamatergic receptors. High dose mI has also been shown to be clinically effective in the treatment of obsessive-compulsive disorder, as well as panic and depression, although its mechanism of action remains elusive. The current study aimed to investigate the possible modulatory role of mI versus fluoxetine or imipramine pretreatments on serotonin-2A receptor (5HT2A-R) and muscarinic acetylcholine receptor (mAChR) function and binding in in vitro systems. After pretreating human neuroblastoma cells with different concentrations of mI, fluoxetine, or imipramine, receptor function was measured by second messenger [3H]-IPx accumulation and [35S]-GTPγS binding to Gαq protein. Total [3H]-mI uptake into cells was measured, as well as specific receptor binding to determine receptor binding after the pretreatments. Results suggest that mI reduces 5HT2A-R function at the receptor-G protein level. While fluoxetine also reduced 5HT2A-R function, but to a lesser degree, imipramine increased 5HT2A-R function, which may explain why mI seems to be effective exclusively in selective serotonin reuptake inhibitor-sensitive disorders. In addition mI, and at high concentrations fluoxetine and imipramine, also reduces mAChR function. Furthermore the results suggest that the attenuating effect of mI on mAChRs is partially dependent on the PI metabolic pathway. The data provide novel information on understanding the mechanism of action of mI in depression and related anxiety disorders and added to the evidence suggesting a role for the cholinergic system in the pathophysiology of depression.
dc.description.abstractmyo-Inositol (mI) is a key metabolic precursor to the phospoinositide (PI) metabolic pathway as a key component of central G-protein coupled receptor signaling systems, including several subtypes of adrenergic, cholinergic, serotonergic and metabotropic glutamatergic receptors. High dose mI has also been shown to be clinically effective in the treatment of obsessive-compulsive disorder, as well as panic and depression, although its mechanism of action remains elusive. The current study aimed to investigate the possible modulatory role of mI versus fluoxetine or imipramine pretreatments on serotonin-2A receptor (5HT2A-R) and muscarinic acetylcholine receptor (mAChR) function and binding in in vitro systems. After pretreating human neuroblastoma cells with different concentrations of mI, fluoxetine, or imipramine, receptor function was measured by second messenger [3H]-IPx accumulation and [35S]-GTPγS binding to Gαq protein. Total [3H]-mI uptake into cells was measured, as well as specific receptor binding to determine receptor binding after the pretreatments. Results suggest that mI reduces 5HT2A-R function at the receptor-G protein level. While fluoxetine also reduced 5HT2A-R function, but to a lesser degree, imipramine increased 5HT2A-R function, which may explain why mI seems to be effective exclusively in selective serotonin reuptake inhibitor-sensitive disorders. In addition mI, and at high concentrations fluoxetine and imipramine, also reduces mAChR function. Furthermore the results suggest that the attenuating effect of mI on mAChRs is partially dependent on the PI metabolic pathway. The data provide novel information on understanding the mechanism of action of mI in depression and related anxiety disorders and added to the evidence suggesting a role for the cholinergic system in the pathophysiology of depression.
dc.description.versionConference Paper
dc.description.versionConference Paper
dc.identifier.citationMetabolic Brain Disease
dc.identifier.citation19
dc.identifier.citation02-Jan
dc.identifier.citationMetabolic Brain Disease
dc.identifier.citation19
dc.identifier.citation02-Jan
dc.identifier.issn8857490
dc.identifier.issn8857490
dc.identifier.other10.1023/B:MEBR.0000027417.74156.5f
dc.identifier.other10.1023/B:MEBR.0000027417.74156.5f
dc.identifier.urihttp://hdl.handle.net/10019.1/11468
dc.identifier.urihttp://hdl.handle.net/10019.1/11468
dc.subjectatropine; fluoxetine; guanine nucleotide binding protein; guanosine 5' o (3 thiotriphosphate); imipramine; inositol; muscarinic receptor; muscarinic receptor blocking agent; phosphatidylinositide; phospholipase C inhibitor; serotonin receptor; serotonin uptake inhibitor; tritium; wortmannin; 1 (6 ((3 methoxyestra 1,3,5(10) trien 17 yl)amino)hexyl) 1H pyrrole 2,5 dione; 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; 2 pyrrolidone derivative; adrenergic receptor affecting agent; androstane derivative; diagnostic agent; enzyme inhibitor; estrane derivative; phosphatidylinositol; phosphodiesterase inhibitor; serotonin 2A receptor; anxiety disorder; conference paper; controlled study; depression; human; human cell; neuroblastoma cell; neuromodulation; protein binding; protein function; article; comparative study; drug effect; metabolism; neuroblastoma; tumor cell line; Tritium; Adrenergic Uptake Inhibitors; Androstadienes; Atropine; Cell Line, Tumor; Enzyme Inhibitors; Estrenes; Fluoxetine; Humans; Imipramine; Inositol; Muscarinic Antagonists; Neuroblastoma; Phosphatidylinositols; Phosphodiesterase Inhibitors; Pyrrolidinones; Receptor, Serotonin, 5-HT2A; Receptors, Muscarinic; Serotonin Uptake Inhibitors; Tritium
dc.subjectatropine
dc.subjectfluoxetine
dc.subjectguanine nucleotide binding protein
dc.subjectguanosine 5' o (3 thiotriphosphate)
dc.subjectimipramine
dc.subjectinositol
dc.subjectmuscarinic receptor
dc.subjectmuscarinic receptor blocking agent
dc.subjectphosphatidylinositide
dc.subjectphospholipase C inhibitor
dc.subjectserotonin receptor
dc.subjectserotonin uptake inhibitor
dc.subjecttritium
dc.subjectwortmannin
dc.subject1 (6 ((3 methoxyestra 1,3,5(10) trien 17 yl)amino)hexyl) 1H pyrrole 2,5 dione
dc.subject1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
dc.subject2 pyrrolidone derivative
dc.subjectadrenergic receptor affecting agent
dc.subjectandrostane derivative
dc.subjectdiagnostic agent
dc.subjectenzyme inhibitor
dc.subjectestrane derivative
dc.subjectphosphatidylinositol
dc.subjectphosphodiesterase inhibitor
dc.subjectserotonin 2A receptor
dc.subjectanxiety disorder
dc.subjectconference paper
dc.subjectcontrolled study
dc.subjectdepression
dc.subjecthuman
dc.subjecthuman cell
dc.subjectneuroblastoma cell
dc.subjectneuromodulation
dc.subjectprotein binding
dc.subjectprotein function
dc.subjectarticle
dc.subjectcomparative study
dc.subjectdrug effect
dc.subjectmetabolism
dc.subjectneuroblastoma
dc.subjecttumor cell line
dc.subjectTritium
dc.subjectAdrenergic Uptake Inhibitors
dc.subjectAndrostadienes
dc.subjectAtropine
dc.subjectCell Line, Tumor
dc.subjectEnzyme Inhibitors
dc.subjectEstrenes
dc.subjectFluoxetine
dc.subjectHumans
dc.subjectImipramine
dc.subjectInositol
dc.subjectMuscarinic Antagonists
dc.subjectNeuroblastoma
dc.subjectPhosphatidylinositols
dc.subjectPhosphodiesterase Inhibitors
dc.subjectPyrrolidinones
dc.subjectReceptor, Serotonin, 5-HT2A
dc.subjectReceptors, Muscarinic
dc.subjectSerotonin Uptake Inhibitors
dc.subjectTritium
dc.titleEffects of myo-Inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells
dc.titleEffects of myo-Inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells
dc.typeConference Paper
dc.typeConference Paper
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