The adaptive neuronal changes that follow chronic administration of antidepressant drugs are thought to underlie clinical improvement in patient populations. Recent evidence suggests that alterations specific to N-methyl-D-aspartate (NMDA) receptors may be a final common pathway to antidepressant action. To investigate this possibility, we sought to establish the effects of chronic fluoxetine or imipramine treatment on the monoamine stimulating effect of the non-competitive NMDA antagonist phencyclidine. Male, Sprague-Dawley rats (n=9/group) were treated with saline (1 ml/kg, i.p.), imipramine (10 mg/kg, i.p.) or fluoxetine (10 mg/kg, i.p.) once daily for 14 consecutive days. After a 7-day drug-free period, animals given an acute challenge of either saline or phencyclidine (5 mg/kg, i.p.). One hour later, animals were killed, brains were removed, and the prefrontal cortex, striatum, and nucleus accumbens were dissected. Samples were assayed for the monoamines and their primary metabolites by HPLC. Repeated treatment with fluoxetine or imipramine did not alter baseline dopamine or serotonin turnover. Acute phencyclidine treatment increased prefrontal cortex and nucleus accumbens dopamine turnover in saline-treated animals (P<0.01); however, the effect in the nucleus accumbens was prevented in animals pretreated with imipramine or fluoxetine. Acute phencyclidine challenge also increased serotonin turnover in prefrontal cortex of saline- or imipramine-pretreated rats (P<0.01), though this effect was attenuated in animals pretreated with fluoxetine. Overall, the data suggest that repeated antidepressant treatment alters monoamine turnover in specific brain regions in response to blockade of NMDA receptors. The data highlight the importance of adaptive responses to NMDA receptors resulting from chronic antidepressant treatment.