Venlafaxine is recognised as an effective treatment for depression and is known to inhibit the reuptake of serotonin (5-HT) and noradrenaline (NA). Another antidepressant, bupropion, acts to inhibit dopamine (DA) and NA reuptake and is commonly co-administered with other antidepressants to improve the efficacy of the antidepressant effect. The present study was designed to investigate the acute effect of combining the 2 drugs on extracellular levels of 5-HT, DA, and NA in rat frontal cortex using brain microdialysis, with the drugs being administered by intraperitoneal injection (i.p). Bupropion (10 mg/kg body mass, i.p.) alone had no effect on extracellular 5-HT levels, whereas venlafaxine (10 mg/kg, i.p.) alone significantly elevated extracellular 5-HT over basal values. As expected, bupropion alone elevated extracellular dopamine above basal values at 40 min post-drug administration, and this effect lasted for a further 2 h. Venlafaxine alone did not statistically elevate extracellular dopamine. The co-administration of venlafaxine with bupropion resulted in a dramatic increase in extracellular dopamine, and this effect was significantly greater than that seen with bupropion alone. In the frontal cortex, NA was elevated by bupropion alone and venlafaxine alone, relative to the control animals. The combination of bupropion and venlafaxine resulted in a marked elevation of NA.