- Lithium (Li) pre-treatment of rats or mice given low dose pilocarpine induces a unique limbic seizure syndrome. This syndrome is stereospecifically reversed by myo -inositol, which suggests that it is a behavioral model for Li depletion of brain inositol. However, this syndrome has little face validity because seizures are not a component of bipolar disorder. Moreover, other animal species that maintain higher brain inositol levels than mice or rats do not show Li–pilocarpine seizures and a study in humans suggests that humans do not show this syndrome as well. It could be suggested that Li–pilocarpine seizures are an in vivo bioassay for inositol depletion. Recent studies of knockout mice lacking inositol monophosphatase-1 or the sodium myo -inositol transporter-1 found that both these knockout mice given pilocarpine develop limbic seizures as if they had been pre-treated with Li. These mice in addition to such pilocarpine sensitivity have other behaviors such as decreased immobility in the Porsolt forced swim test that suggests that their inositol depletion has Li-like effects. Thus, the Li–pilocarpine seizure model may, despite its lack of face validity, be a biochemical marker for a model of mania treatment in animals.