Effects of myo-Inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells
Date
2004, 2004
Authors
Brink, C. B.
Viljoen, S. L.
De Kock, S. E.
Stein, D. J.
Harvey, B. H.
Brink, C. B.
Viljoen, S. L.
De Kock, S. E.
Stein, D. J.
Harvey, B. H.
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
myo-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.
myo-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.
myo-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.
Description
Keywords
atropine; 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, atropine, 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
Citation
Metabolic Brain Disease
19
02-Jan
Metabolic Brain Disease
19
02-Jan
19
02-Jan
Metabolic Brain Disease
19
02-Jan