Immediate-early genes, such as c-fos, are responsive to dopaminergic stimulation in the brain and can have prolonged effects on the transcription of other genes. Thus, they may mediate some of the long-term consequences of altered dopaminergic transmission on striatal neurons, such as the supersensitivity to dopamine and its agonists that occurs in response to dopamine denervation. The two dopamine receptor families, D1 and D2, interact synergistically under normal conditions but independently after treatments that induce pronounced supersensitivity to dopamine agonists. Using immunocytochemical methods in rats treated with directly acting selective dopamine agonists, we have determined that dopamine-mediated expression of Fos and Fos-like antigens in the striatum normally requires concomitant stimulation of D1 and D2 receptors. Separate administration of a high dose of a selective D1 (SKF 38393; 20 mg/kg) or D2 (quinpirole; 3 mg/kg) agonist induced Fos-like immunoreactivity in few neurons, whereas combined administration of the D1 and D2 agonists produced patches of intensely stained immunoreactive nuclei in the caudate-putamen. Repeated administration of reserpine (1 mg/kg per day for 5 days), which causes supersensitivity to dopamine agonists and a breakdown in D1/D2 synergism behaviorally, also causes a change in control of c-fos, such that independent stimulation of D1 receptors by SKF 38393 (20 mg/kg) elicited pronounced Fos-like immunoreactivity in the striatum; combined treatment with SKF 38393 (20 mg/kg) and quinpirole (3 mg/kg) in reserpine-treated rats elicited Fos-like expression in no more neurons than did D1 agonism alone. These data demonstrate that dopamine-mediated Fos expression in the striatum is indicative of the state of D1/D2 synergism and receptor supersensitivity.