Mood stabilizing drugs decrease central nervous system cyclic AMP signaling. We report here that chronic, but not acute treatment with lithium chloride in human neuroblastoma SH-SY5Y cells, inhibits phosphorylation of cyclic AMP responsive element binding protein and cyclic AMP responsive element DNA binding induced by the adenylyl cyclase activator forskolin, but has no effect on constitutive expression of cyclic AMP responsive element binding protein. These results are consistent with an effect of lithium to blunt the cyclic AMP signal transduction pathway. Such an effect is not shared by the other commonly prescribed mood stabilizer, sodium valproate. Our results suggest that cyclic AMP responsive element binding protein regulated gene expression may be relevant to the long-term prophylactic effect of lithium. Furthermore, sodium valproate, which is also effective in bipolar disorder, would appear to act on other pathways to bring about its therapeutic effects.