The purpose of the present study was to examine the effect of subchronic treatment (24 days) with antidepressants displaying differential effects on noradrenaline and serotonin reuptake, on behavior, neurochemistry and hypothalamic-pituitary-adrenal (HPA) axis activity following FST exposure in the rat. Desipramine (7.5 mg/kg, IF) significantly decreased immobility in the FST, whilst paroxetine (7.5 mg/kg IF) and venlafaxine (10 mg/kg, IF) were without effect. Nonetheless, treatment with all three antidepressants significantly attenuated stress-related increases in amygdaloid and cortical serotonin turnover. Of the three antidepressants examined, only desipramine attenuated the stress-associated elevation in serum corticosterone. In conclusion, although FST-induced increases in serotonin turnover in the frontal cortex and amygdala were attenuated following treatment with all three antidepressants, FST-induced behavioral changes and increased HPA axis activity were normalized only following desipramine treatment. In addition, these results suggest that neurochemical mechanisms independent of increased serotonergic activity subserve the normalization of behavior and HPA axis responses in the FST. These data also add to our understanding of the interactions between antidepressants and stress-induced behavioral, neurochemical, and endocrine alterations, and illustrates important differences between classes of antidepressants. (C) 2000 Elsevier Science Inc.