Rats were administered with lithium carbonate (1 mmole/kg), valproate (300 mg/kg) and their combination for 12 days. Rats in the withdrawal group were treated for 10 days, followed by saline for 2 days. Mid-brain tryptophan levels increased in all the groups except lithium-treated rats. The administration of lithium together with valproate decreased tryptophan hydroxylase activity and 5-hydroxytryptamine levels in certain brain regions compared to either treatment alone. Also, the magnitude of valproate-induced 5-hydroxyindoleacetic acid elevation was decreased after combined treatment. Most of the changes observed after combined exposure persisted even after 2 days of treatment withdrawal. It appears from the data that combined administration of the two drugs produces persistent decrease in 5-hydroxytryptamine synthesis and turnover in the brain.