When administered systemically to ambulant animals, amphetamine (AMPH) has both excitatory and inhibitory effects on single-unit activity in the neostriatum and nucleus accumbens. To determine the extent to which these results reflect a direct action of the drug, AMPH was applied iontophoretically to neostriatal and accumbal neurons under naturally occurring behavioral conditions. AMPH dose-dependently (5-40 nA) inhibited the vast majority of spontaneously active units. The inhibition, which was evident at low ejection currents (5-10 nA), had relatively short onset (4-12 s) and offset (6-24 s) latencies, and was positively correlated with basal firing rate. Even stronger dose-dependent inhibitory responses were recorded when neurons having no or a very low rate of spontaneous activity were tonically activated by continuous, low-current applications of glutamate (Glu). Systemic injection of either SCH-23390 (0.1 mg/kg) or haloperidol (0.2 mg/kg), relatively selective D1 and D2 receptor antagonists, respectively, blocked the AMPH-induced inhibition. Prolonged AMPH iontophoresis (2-3 min; 5-30 nA) inhibited both spontaneous impulse activity and Glu-induced excitations, resulting in a complete blockade of the Glu response at relatively high AMPH ejection currents (> or = 20 nA). Taken together, these results suggest that although dopamine is largely responsible for the inhibitory effects of iontophoretic AMPH, dopamine alone cannot account for the complex response of neostriatal and accumbal neurons to systemic AMPH administration.