Lithium modulation of second messenger signal amplification in man: inhibition of phosphatidylinositol-specific phospholipase C and adenylate cyclase activity.

The activity of phosphatidylinositol-specific phospholipase C was significantly reduced in platelets obtained from 20 euthymic manic-depressive patients on therapeutic lithium doses (mean blood level 0.85 mEq/l) compared to an age- and sex-matched group of 36 control subjects. The activities of prostaglandin E1-, aluminum/NaF-, and forskolin-stimulated platelet adenylate cyclase activity were also measured in a similar group of 16 lithium-treated and 22 control subjects. A marked reduction in both postreceptor (aluminum/NaF and forskolin) and receptor-stimulated (prostaglandin E1) platelet adenylate cyclase activity was observed in the lithium-treated group (mean blood level 0.81 mEq/l). These findings support the hypothesis that lithium's therapeutic mode of action in manic-depressive psychosis is mediated by the combined down-regulation of both principal second messenger systems, inositol phosphates and cyclic adenosine monophosphate, by reducing the activity of phosphatidylinositol-specific phospholipase C and adenylate cyclase.