Nigral D1 and striatal D2 receptors mediate the behavioral effects of dopamine agonists

The mediation of behavior by nigral and striatal dopamine (DA) D1 and D2 receptors was investigated in rats that had sustained extensive unilateral 6-hydroxydopamine-induced injury to ascending DA neurons. Selective D1 and D2 agonists and antagonists were injected directly into the DA-denervated substantia nigra pars reticula 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 micrograms) or the selective D2 agonist quinpirole (5 micrograms), but not the selective D1 agonist (+/-)-SKF 38393 (15 micrograms), induced vigorous rotation. The rotation induced by intrastriatal quinpirole was greatly diminished by systemic administration of the selective D2 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 D1 antagonist SCH 23390 (0.5 mg/kg, s.c.), and was mimicked by intranigral (-)-SKF 38393 (15 micrograms), which exhibits 100-fold less activity than the dextrorotatory enantiomer at the D1 receptor. In order to circumvent the problem of this drug's apparent non-D1-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 micrograms), but not eticlopride (10 micrograms), 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 D1 and striatal D2 receptors mediate the behavioral effects of DA agonists. These data may be useful in elucidating the mechanism(s) underlying the D1/D2 synergism observed in neurologically intact animals, as well as in understanding the action of drugs used in the treatment of Parkinson's disease.