Neuroprotective properties of lithium were evaluated by using in vivo NMDA excitotoxicity model. Systemic injection of NMDA to young mice induced neuronal apoptosis mediated by both TNFR-1 and Fas ligand, and long-term lithium treatment showed noticeable neuroprotection against NMDA-induced excitotoxicity: NMDA-damaged neurons expressed several apoptosis-related gene products such as TNFR-1, Fas ligand, and caspase-3, and these gene expressions were not found in the brain of mice chronically treated with lithium. Therefore, it is highly likely that the protection offered by chronic lithium treatment occurred at far upstream of caspase activation, since the chronic lithium treatment increased the expression of Bcl-2, an important antiapoptotic gene known to act upstream of caspase cascade. Timm's histochemistry indicated the complete blockade of the NMDA insults by the treatment. There was no indication of axonal regeneration, which follows synaptic degeneration induced by neuronal damage. Furthermore, this study reports for the first time that TNFR-1 and Fas ligand are involved in neuroprotective effects of lithium in NMDA-induced neuronal apoptosis.