- Background: Lithium has numerous biochemical effects but it is difficult to dissect which of these is responsible for its therapeutic action in bipolar disorder. In the current study we aimed to address one of the major hypotheses, the inositol depletion hypothesis. This hypothesis postulates that lithium's mood-stabilizing effect is mediated by the depletion of brain inositol levels and the subsequent effect on cellular signaling. Methods: We studied whether acute intracerebroventricular (ICV) administration of myo-inositol could reverse the antidepressant-like effect of chronic lithium treatment in the forced swim test (FST). Results: In contrast with our prediction, acute myo-inositol administration did not reverse the effect of chronic lithium to decrease immobility in the FST. Conclusions: The results of the present study are limited due to the following: (1) inositol was given acutely while possible events downstream of inositol depletion might require a longer period and (2) ICV inositol may not have reached those areas of the brain involved in the FST.