The ability of subtype-preferring alpha(2)-adrenoceptor antagonists to enhance the neurochemical effects of the antidepressant, fluoxetine, was evaluated by in vivo microdialysis. Combining the selective alpha(2A)-adrenoceptor antagonist, BRL-44408 (10 mg/kg, s.c.), with fluoxetine (30 mg/kg, s.c.) elevated the extracellular levels of serotonin (5-HT) and noradrenaline in the rat frontal cortex, an effect not observed following antidepressant treatment alone. In contrast, combining fluoxetine with the alpha(2B)- or alpha(2C)-adrenoceptor antagonists, imiloxan (10 mg/kg, s.c.) or rauwolscine (10 mg/kg, s.c.), respectively, did not similarly alter biogenic amine levels. Collectively, these results reveal a specific role for the alpha(2A)-adrenoceptor subtype in augmenting the neurochemical effects of antidepressants.