- Two leading hypotheses to explain lithium action in bipolar disorder propose either inositol depletion or inhibition of GSK-3 as mechanisms of action. Behavioral effects of lithium are mimicked in Gsk-3β +/− mice, but the contribution of inositol depletion to these behaviors has not been tested. According to the inositol depletion hypothesis, lithium-sensitive behavior is secondary to impaired phosphatidylinositol synthesis caused by inositol deficiency. By disrupting the sodium myo-inositol transporter1 gene, SMIT1 , we show that depletion of brain myo-inositol in SMIT1 +/− mice has no effect on lithium-sensitive behavior. These findings, taken together with our previous work showing that SMIT −/− mice have an even greater depletion of inositol in brain with no reduction in phosphatidylinositol levels, are difficult to reconcile with the current formulation of the inositol depletion hypothesis.