Amphetamine or cocaine injection causes expression of the immediateearly gene c-fos in the striatum. Previous studies have shown that dopamine D, receptor activation is necessary for this effect, but have not established a consistent role for D, receptors. We have investigated the involvement of D, receptors in indirect dopamine agonist-induced striatal Fos-like immunoreactivity using the selective D, antagonist eticlopride. Eticlopride treatment (0.5 mgkg) caused Fos expression by itself, but also decreased Fos expression in the central striatum due to amphetamine (5.0 mgkg) or cocaine (40 mgkg) by 90% and 85%, respectively. In striatonigral neurons, identified by labeling with the retrograde tracer Fluorogold iontophoresed into the substantia nigra pars reticulata, the blockade of stimulant-induced Fos-like immunofluorescence by eticlopride was nearly complete, with decreases of 98% for amphetamine and 94% for cocaine. In striatonigral neurons, the D, antagonist alone had minimal effect. We conclude that activation of both D, and D2 receptor classes by dopamine agonists is necessary for induction of Fos in the striatonigral cells of normal rats. These results provide an important parallel to behavioral and electrophysiological work that also demonstrates D,/D2 interdependence in the control of normal basal ganglia functions.