A local infusion of d-amphetamine (d-AMPH) into the dorsal raphe nucleus (DRN) inhibited neuronal activity in this site and produced a mirror-image excitation in the ventrolateral, but not dorsomedial, neostriatum. This effect, which was mimicked by &methoxy-N,N-dimethyltryptamine, a serotonin autoreceptor agonist, was not altered by pretreatment with cu-methyl-p-tyrosine. Similar regional differences in neostriatal activity were obtained following an electrolytic lesion of the DRN or an intraperitoneal injection of d-AMPH. In fact, whereas 1.0 mg/kg of d-AMPH accelerated ventrolateral activity and inhibited dorsomedial neurons, 7.5 mg/kg produced the opposite effect. At both doses, however, DRN activity was inversely related to firing rate in the ventrolateral, but not dorsomedial, neostriatum. These results indicate that only certain regions of the neostriatum are responsive to changes in DRN activity and that these regions respond differently to systemic injections of d-AMPH than other neostriatal sites.