Dinapsoline: Characterization of a D-1 dopamine receptor agonist in a rat model of Parkinson's disease

Dinapsoline is a new potent, full agonist at D-1 dopamine receptors with li mited selectivity relative to D-2 receptors. The efficacy of this compound was assessed in rats with unilateral 6-hydroxydopamine lesions of the media l forebrain bundle, a standard rat model of Parkinson's disease. Dinapsolin e produced robust contralateral rotation after either subcutaneous or oral administration. This rotational behavior was attenuated markedly by the D-1 receptor antagonist SCH-23390, but not by the D-2 receptor antagonist racl opride. During a chronic 14-day treatment period in which rats received din apsoline either once or twice a day, dinapsoline did not produce tolerance (in fact, some sensitization of the rotational response was observed in one experiment). Because dinapsoline shows less D-1:D-2 selectivity in vitro t han other D-1 agonists, the contribution of D-2 activity to tolerance was a ssessed. Chronic daily cotreatment with dinapsoline and raclopride did not enable the development of tolerance to chronic dinapsoline treatment. In co ntrast, when dinapsoline was administered by osmotic minipump, rapid tolera nce was observed. To explore further the contribution of D-1 and D-2 recept ors to tolerance, experiments were performed with the selective D-1 agonist A-77636. Daily dosing with A-77636 rapidly produced complete tolerance, as previously observed, whereas coadministration of the D-2 agonist quinpirol e plus A-77636 failed to either delay or prevent tolerance. Taken together, these results indicate that the development of tolerance to D-1 receptor a gonists is influenced by the pattern of drug exposure but not by the D-1:D- 2 selectivity of the agonist.