Systemic fencamfamine (0.5-16 mg/kg, i.v.) significantly but incompletely inhibited spontaneous activity of nigrostriatal and mesolimbic/mesocortical dopamine (DA) neurons. Inhibition was reversed by haloperidol (0.1 mg/kg, i.v.) and prevented by pretreatment with alpha-methyltyrosine (50 mg/kg, i.v.) plus reserpine (5 mg/kg, i.p.). Pretreatment with alpha-methyltyrosine alone attenuated inhibition at high but not low doses of fencamfamine. Microiontophoresed fencamfamine had little direct effect on DA neurons and did not consistently modulate the effects of co-microiontophoresed DA. In contrast, systemic fencamfamine blocked the inhibitory effects of low doses of apomorphine (10-40 micrograms/kg, i.v.). Fencamfamine appears to be an indirect DA agonist which interacts with both vesicular and newly synthesized DA storage pools. Fencamfamine may also cause a rapid desensitization to the effects of DA autoreceptor stimulation.