It has been half a century since lithium salts were introduced into modern pharmacotherapy to control the symptoms of manic-depressive illness. However, the mechanism of action of this cation remains elusive. We recently reported that cysteine string proteins (csps) are up-regulated in vivo in rat brain at therapeutically relevant concentrations of lithium (SFN Abstract 25,1066). Here, we extend these observations to an in vitro system, the adrenal pheochromocytoma cell line, PC12. These cells are a useful model for studying excitable cell function because they exhibit neuron-like properties when differentiated by nerve growth factor (NGF) and display regulated secretion of catecholamines. Our results revealed that lithium at 1 mM up-regulated csp gene expression in NGF-differentiated PC12 cells, whereas the same lithium treatment of undifferentiated cells did not alter csp gene expression. As with the in vivo findings, the expression of SY and SNAP-25 was not altered by this lithium treatment. Concentrati...