The inositol monophosphatase inhibitor L-690,330 affects pilocarpine-behavior and the forced swim test

Rationale: Lithium has been a standard pharmacological treatment for bipolar disorder over the last 60 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. Attenuation of the phosphatidylinositol signal transduction pathway as a consequence of inhibition of inositol monophosphatase (IMPase) has been proposed as one of the possible mechanisms for lithium-induced mood stabilization. Objectives: The objective was to study the behavioral effect of the specific competitive IMPase inhibitor L-690,330 in mice in the lithium-sensitive pilocarpine-induced seizures paradigm and the forced swim test (FST). Methods: The inhibitor was administered intracerebroventricularly in liposomes. Results: L-690,330 increased the sensitivity to subconvulsive doses of pilocarpine and decreased immobility time in the FST. Conclusions: It is possible that the behavioral effects of lithium in the pilocarpine-induced seizures and in the FST are mediated through the inhibition of IMPase, but reversal of the inhibitor's effect with intracerebroventricular inositol would be an important further step in proof.