Chronic lithium treatment inhibits basal and agonist-stimulated responses in rat cerebral cortex and GH3 pituitary cells.
Li+ is used clinically in the management of bipolar-disordered (manic-depressive) illness, but the mechanism of its clinical efficacy remains unclear. Li+ inhibits the metabolism of certain inositol phosphates, leading to a decreased cycling of inositol that may be sufficient to reduce phosphoinositide metabolism. We have tested this hypothesis in slices of rat cerebral cortex and in rat pituitary GH3 cells grown in the presence of low extracellular inositol. We show that basal and stimulated mass levels of inositol-1,4,5-trisphosphate were reduced in rat cerebral cortex and in GH3 cells after chronic, but not acute, treatment with a therapeutic concentration of Li+. In GH3 cells chronic treatment with Li+ also decreased basal levels of intracellular Ca2+ and secretion of prolactin, effects that were prevented by the presence of myo-inositol. Agonist-stimulated mobilization of Ca2+ and prolactin release were also reduced in Li(+)-treated cells. These findings show that chronic perturbation of the phosphoinositide pathway by Li+ is sufficient to reduce basal and agonist-stimulated cellular responses, an action that may underlie its effectiveness in the alleviation of affective disorders.
Varney
M A
MA
University Department of Pharmacology, Oxford.
Godfrey
P P
PP
Drummond
A H
AH
Watson
S P
SP
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects*; D004334:Drug Administration Schedule; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D008094:Lithium / Q000008:administration & dosage*; D009712:Nucleotides, Cyclic / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000187:drug effects* / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems; D012636:Secretory Rate / Q000187:drug effects
D009712:Nucleotides, Cyclic; D015544:Inositol 1,4,5-Trisphosphate; D011388:Prolactin; D008094:Lithium; D002118:Calcium