Inhibition of the high affinity myo-inositol transport system: a common mechanism of action of antibipolar drugs?
The mechanism of action of antibipolar drugs like lithium, carbamazepine, and valproate that are used in the treatment of manic-depressive illness, is unknown. Lithium is believed to act through uncompetitive inhibition of inositolmonophosphatase, which results in a depletion of neural cells of inositol and a concomitant modulation of phosphoinositol signaling. Here, we show that lithium ions, carbamazepine, and valproate, but not the tricyclic antidepressant amitriptyline, inhibit at therapeutically relevant concentrations and with a time course similar to their clinical actions the high affinity myo-inositol transport in astrocyte-like cells and downregulate the level of the respective mRNA. Inhibition of inositol uptake could thus represent an additional pathway for inositol depletion, which might be relevant in the mechanism of action of all three antibipolar drugs.
Lubrich
B
B
Department of Psychiatry, University of Freiburg, Germany.
van Calker
D
D
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects; D002220:Carbamazepine / Q000494:pharmacology; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007294:Inositol / Q000378:metabolism*; D008094:Lithium / Q000494:pharmacology; D008565:Membrane Proteins; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D018692:Antimanic Agents; D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D027981:Symporters; C073884:SLC5A3 protein, human; D000639:Amitriptyline; D002220:Carbamazepine; D007294:Inositol; D014635:Valproic Acid; D008094:Lithium