Lithium and valproate decrease inositol mass and increase expression of the yeast INO1 and INO2 genes for inositol biosynthesis

Bipolar affective disorder (manic-depressive illness) is a chronic, severe, debilitating illness affecting 1-2% of the population. The Food and Drug A dministration-approved drugs lithium and valproate are not completely effec tive in the treatment of this disorder, and the mechanisms underlying their therapeutic effects have not been established, We are employing genetic an d molecular approaches to identify common targets of lithium and valproate in the yeast Saccharomyces cerevisiae, We show that both drugs affect molec ular targets in the inositol metabolic pathway. Lithium and valproate cause a decrease in intracellular myo-inositol mass and an increase in expressio n of both a structural (INO1) and a regulatory ((INO2) gene required for in ositol biosynthesis. The opi1 mutant, which exhibits constitutive expressio n of INO1, is more resistant to inhibition of growth by lithium but not by valproate, suggesting that valproate may inhibit the Ino1p-catalyzed synthe sis of inositol 1-phosphate. Consistent with this possibility, growth in va lproate leads to decreased synthesis of inositol monophosphate, Thus, both lithium and valproate perturb regulation of the inositol biosynthetic pathw ay, albeit via different mechanisms. This is the first demonstration of inc reased expression of genes in the inositol biosynthetic pathway by both lit hium and valproate, Because inositol is a key regulator of many cellular pr ocesses, the effects of lithium and valproate on inositol synthesis have fa r-reaching implications for predicting genetic determinants of responsivene ss and resistance to these agents.