This investigation tested if lithium, the primary therapeutic agent for bipolar mood disorder, modulated activation of the AP-1 transcription factor in PC12 cells treated with nerve growth factor (NGF), which induces robust responses in these cells. NGF induced large, time-dependent increases in AP-1 DNA binding activity. Pretreatment with 5 mmol/L lithium for 24 h reduced AP-1 induction by NGF by 42%; shorter treatments and lower concentrations of lithium had smaller inhibitory effects on AP-1. This effect of lithium was not limited to AP-1, as it also inhibited NGF-induced cyclic AMP responsive element (CRE) DNA binding activity. In contrast, activation of AP-1 and CRE by forskolin was unaffected by lithium. AP-1 constituent proteins were differentially susceptible to lithium, as cJun was reduced by 55%, cFos was unaffected by lithium, and an intermediate effect was observed with Jun B. These results reveal that lithium modulates the activation of transcription factors in a neuronal cell model, indicating that selective regulation of gene expression may contribute to the long term in vivo effect of lithium.