The effect of systemically administered amphetamine, cocaine, phencyclidine and nomifensine on the extracellular concentrations of dopamine in freely moving rats was estimated by microdialysis in the nucleus accumbens and in the dorsal caudate. All the drugs tested stimulated dopamine output in both areas but more effectively in the accumbens as compared to the caudate. Low doses of cocaine (1.0 mg/kg s.c.) stimulated dopamine output only in the nucleus accumbens. Nomifensine (1.25-5.0 mg/kg s.c.) increased by a similar extent peak dopamine output in the two dopaminergic areas but the duration of the effect was longer in the accumbens as compared to the caudate. The effect of cocaine, phencyclidine and nomifensine was prevented by systemic gamma-butyrolactone (700 mg/kg i.p.) and by omitting Ca2+ from the Ringer used for dialysis, the effect of amphetamine was insensitive to these manipulations. Thus, in contrast with amphetamine, cocaine, phencyclidine and nomifensine increase synaptic dopamine concentrations in vivo by a mechanism which depends on intact activity of dopaminergic neurons and by an exocytotic process.