The effect of chronic administration of desipramine or fluoxetine (10 mg/kg IP once a day for 2 weeks) on extracellular noradrenaline, serotonin and dopamine in the rat prefrontal cortex was studied by transcerebral microdialysis. Chronic desipramine increased extracellular noradrenaline and dopamine by three-fold as compared to saline controls. Acute challenge with 10 mg/kg desipramine increased by more than three-fold extracellular noradrenaline and dopamine in saline controls, but failed further to increase extracellular noradrenaline and dopamine in rats chronically administered desipramine. Chronic fluoxetine more than doubled the extracellular concentrations of serotonin but failed to change the extracellular concentrations of dopamine as compared to saline controls. Challenge with 5 mg/kg fluoxetine while almost doubling extracellular serotonin and dopamine concentrations in saline controls, failed further to increase extracellular serotonin and did not change extracellular dopamine in rats chronically exposed to fluoxetine. In contrast, challenge with 10 mg/kg desipramine normally increased extracellular dopamine in rats chronically exposed to fluoxetine. Therefore, chronic fluoxetine is associated with normal presynaptic dopamine transmission in the prefrontal cortex as a result of tolerance to fluoxetine-induced increase of extracellular dopamine, in contrast, chronic desipramine is associated with an increase of pre-synaptic dopamine transmission in the prefrontal cortex up to a level that cannot be further elevated by acute desipramine challenge. The results suggest that prefrontal cortex dopamine plays a different role in the antidepressant properties of desipramine and fluoxetine.