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Lithium is the prototype mood stabilizer but its mechanism is still unresolved. Two hypotheses dominate—the consequences of lithium's inhibition of inositol monophosphatase at therapeutically relevant concentrations (the ‘inositol depletion' hypothesis), and of glycogen-synthase kinase-3. To further elaborate the inositol depletion hypothesis that did not decisively determine whether inositol depletion  per se , or phosphoinositols accumulation induces the beneficial effects, we utilized knockout mice of either of two inositol metabolism-related genes— IMPA1  or  SMIT1 , both mimic several lithium's behavioral and biochemical effects. We assessed  in vivo,  under non-agonist-stimulated conditions,  3 H-inositol incorporation into brain phosphoinositols and phosphoinositides in wild-type, lithium-treated,  IMPA1  and  SMIT1  knockout mice. Lithium treatment increased frontal cortex and hippocampal phosphoinositols labeling by several fold, but decreased phosphoinositides labeling in the frontal cortex of the wild-type mice of the  IMPA1  colony strain by ~50%. Inositol metabolites were differently affected by  IMPA1  and  SMIT1  knockout. Inositoltrisphosphate administered intracerebroventricularly affected bipolar-related behaviors and autophagy markers in a lithium-like manner. Namely, IP 3  but not IP 1  reduced the immobility time of wild-type mice in the forced swim test model of antidepressant action by 30%, an effect that was reversed by an antagonist of all three IP 3  receptors; amphetamine-induced hyperlocomotion of wild-type mice (distance traveled) was 35% reduced by IP 3  administration; IP 3  administration increased hippocampal messenger RNA levels of Beclin-1 (required for autophagy execution) and hippocampal and frontal cortex protein levels ratio of Beclin-1/p62 by about threefold (p62 is degraded by autophagy). To conclude, lithium affects the phosphatidylinositol signaling system in two ways: depleting inositol, consequently decreasing phosphoinositides; elevating inositol monophosphate levels followed by phosphoinositols accumulation. Each or both may mediate lithium-induced behavior.

IP3 accumulation and/or inositol depletion: two downstream lithium’s effects that may mediate its behavioral and cellular changes