The effects of systematically administered amphetamine (0.25-5.0 mg/kg, sc) on neostriatal neurons recorded in chronically implanted behaving rats were studied. Projection neurons, identified by antidromic activation from the substantia nigra, fired very infrequently during most predrug behaviors (e.g., median rate, 0.02 spikes per second during locomotion; 17 of 18 fired less than 1 spike per second during all rated behaviors). Nonantidromic cells also tended to fire slowly (median rate, 0.02 spikes per second during locomotion; 20 of 24 cells fired less than 1 spike per second). Cells of both type showed up to 10-fold variations in firing rate across behaviors. For most neurons, amphetamine caused a reduction in the firing rate during related pre- and postdrug behaviors. For instance, the firing rate of 28 of 42 neurons was reduced during the initial amphetamine-induced locomotion as compared with the rate during predrug locomotion. Moreover, with the higher doses of amphetamine, there was a further reduction in firing rate corresponding to the transition from locomotion to stereotypies. In contrast to previous studies, which suggest that amphetamine generally increases neostriatal firing rate in behaving animals, these results suggest that amphetamine inhibits the numerous slowly firing neostriatal neurons, many of which were identified as projection neurons. Thus amphetamine alters the magnitude and pattern of neostriatal control of its neural targets.