Effects of myo-inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells.
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]-GTPgammaS binding to G alpha(q) 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.
Brink
Christiaan B
CB
Division of Pharmacology, Potchefstroom Campus of the North-West University, Potchefstroom, South Africa. fklcbb@puk.ac.za
Viljoen
Susanna L
SL
de Kock
Susanna E
SE
Stein
Dan J
DJ
Harvey
Brian H
BH
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology*; D006801:Humans; D007099:Imipramine / Q000494:pharmacology*; D007294:Inositol / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009447:Neuroblastoma; D010716:Phosphatidylinositols / Q000493:pharmacokinetics; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014316:Tritium; D000077191:Wortmannin
D018759:Adrenergic Uptake Inhibitors; D000730:Androstadienes; D001285:Atropine; D004791:Enzyme Inhibitors; D004963:Estrenes; D005473:Fluoxetine; D007099:Imipramine; D007294:Inositol; D018727:Muscarinic Antagonists; D010716:Phosphatidylinositols; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D044402:Receptor, Serotonin, 5-HT2A; D011976:Receptors, Muscarinic; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium; D000077191:Wortmannin; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione