Valproic acid (VPA), a simple branched fatty acid anticonvulsant, has been demonstrated to have clinical efficacy in the treatment of manic-depressive illness (Bowden et al., 1994), but the mechanism(s) by which VPA produces its therapeutic effects remain to be elucidated. VPA's clinical antimanic action require a lag period for onset and are not immediately reversed upon discontinuation of treatment, effects that suggest alterations at the genomic level; we therefore investigated the effects of VPA on the modulation of the DNA binding activity of key transcription factors. DNA binding activities of activator protein 1 (AP-1) and cAMP responsive element binding protein (CREB) were studied in acute (hours) and chronic (days) VPA-treated rat C6 glioma cells. VPA did not affect CREB DNA binding activity, but concentration- and time-dependently increased AP-1 DNA binding activity. The activity was raised at 2 hours (the shortest time examined) and remained high after 6 days (the longest time used) of continuing VPA treatment. VPA also enhanced AP-1 DNA binding activity in human neuroblastoma (SH-SY5Y) cells. Because the effects of VPA were markedly inhibited by cycloheximide, they appear to require new protein synthesis. Taken together, the data suggest that antimanic agents may affect gene expression by modulation of the activity of major transcription factors; in view of the key roles of these nuclear transcription regulatory factors in long-term neuronal plasticity and cellular responsiveness, these effects may play a major role in VPA's therapeutic efficacy and are worthy of further study.