Dinapsoline is a new potent, full agonist at D1
dopamine receptors with limited selectivity relative to D2 receptors. The efficacy of this compound was assessed in rats with unilateral
6-hydroxydopamine lesions of the medial forebrain bundle, a standard rat model of
Parkinson's disease.
Dinapsoline produced robust contralateral rotation after either subcutaneous or
oral administration. This rotational behavior was attenuated markedly by the D1 receptor antagonist
SCH-23390, but not by the D2 receptor antagonist
raclopride. During a chronic 14-day treatment period in which rats received
dinapsoline 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 D1:D2 selectivity in vitro than other D1 agonists, the contribution of D2 activity to tolerance was assessed. Chronic daily cotreatment with
dinapsoline and
raclopride did not enable the development of tolerance to chronic
dinapsoline treatment. In contrast, when
dinapsoline was administered by osmotic minipump, rapid tolerance was observed. To explore further the contribution of D1 and D2 receptors to tolerance, experiments were performed with the selective D1 agonist
A-77636. Daily dosing with
A-77636 rapidly produced complete tolerance, as previously observed, whereas coadministration of the D2 agonist
quinpirole plus
A-77636 failed to either delay or prevent tolerance. Taken together, these results indicate that the development of tolerance to D1 receptor agonists is influenced by the pattern of
drug exposure but not by the D1:D2 selectivity of the agonist.