Lithium cloride (10 meq/kg/day) administered to rats for 3 days before pharmacological challenge with cocaine hydrochloride (100 mg/kg) antagonized the effects of the stimulant drug on complementary constituents of serotonin synthesis. This neurobiological antagonism, as well as lithium's antagonism of the behavioral effects of other drugs that can produce extreme moods in man, suggests that lithium may work against mania and depression by "buffering" the serotonergic system--that is, by pushing two adaptive processes respectively to their upper and lower limits, which returns the net synthesis of transmitter to a "normal" range and keeps it there.