The mediation of behavior by nigral and striatal dopamine (DA) D 1 and D 2 receptors was investigated in rats that had sustained extensive unilateral 6-hydroxydopamine-induced injury to ascending DA neurons. Selective D 1 and D 2 agonists and antagonists were injected directly into the DA-denervated substantia nigra pars reticulata or the caudate-putamen via a chronically indwelling cannula. Contralateral rotation resulting from unilateral stimulation of supersensitive DA receptors was quantified over 46 min. Intrastriatal apomorphine (5 μg) or the selective D 2 agonist quinpirole (5 μg), but not the selective D 1 agonist (±)-SKF 38393 (15 μg), induced vigorous rotation. The rotation induced by intrastriatal quinpirole was greatly diminished by systemic administration of the selective D 2 antagonist eticlopride (0.5 mg/kg, i.p.) and could not be enhanced by additional injection of intrastriatal (±)-SKF 38393. Intranigral administration of apomorphine or (±)-SKF 38393, but not quinpirole (same doses as above), elicited vigorous rotation. However, the rotation induced by intranigral (±)-SKF 38393 could not be blocked by systemic administration of the selective D 1 antagonist SCH 23390 (0.5 mg/kg, s.c.), and was mimicked by intranigral (−)-SKF 38393 (15 μg), which exhibits 100-fold less activity than the dextrorotatory enantiomer at the D 1 receptor. In order to circumvent the problem of this drug's apparent non-D 1-mediated action when injected intranigrally, rotation was induced by systemic (±)-SKF 38393 (2.0 mg/kg, i.p.) 10 min after intranigral administration of selective antagonists. Intranigral SCH 23390 (10 μg), but not eticlopride (10 μg), powerfully antagonized the rotation induced by systemic (±)-SKF 38393. Conversely, rotation induced by systemic quinpirole (0.5 mg/kg, i.p.) was potently blocked by intrastriatal eticlopride but not SCH 23390. Rotation induced by systemic apomorphine (0.25 mg/kg, i.p.) was not attenuated by either antagonist alone, regardless of intracerebral injection site. The results indicate that both nigral D 1 and striatal D 2 receptors mediate the behavioral effects of DA agonists. These data may be useful in elucidating the mechanism(s) underlying the D 1/D 2 synergism observed in neurologically intact animals, as well as in understanding the action of drugs used in the treatment of Parkinson's disease.