Self-administration of D1 receptor agonists by squirrel monkeys

Dopaminergic mechanisms are believed to play a prominent role in the self-administration of cocaine and other abused stimulants. The contribution of D2 receptors is now well established, but less is known about the role of D1 receptors in the reinforcing effects of these drugs. To help clarify the role of D1 mechanisms in stimulant self-administration, agonists differing in D1 receptor selectivity (SKF 81297 > SKF 82958 > SKF 77434) and efficacy (SKF 82958 > SKF 81297 > SKF 77434) were studied for their ability to maintain IV self-administration in squirrel monkeys previously trained to self-administer cocaine. Up to a 100-fold range of doses of each D1 agonist was studied under both a fixed-ratio (FR) and a second-order fixed-interval (FI) schedule of reinforcement. Parallel studies were conducted with the D2 receptor agonists, (+)-PHNO and quinpirole, under the second-order FI schedule. Of the three D1 agonists, only SKF 82958 maintained consistent self-administration under both the FR and second-order FI schedules and had dose-related effects that were qualitatively similar to those of (+)-PHNO and quinpirole under the latter condition. SKF 81297, which has high selectivity at D1 receptors and intermediate agonist efficacy, maintained self-administration in the majority of monkeys under the FR schedule, but did not maintain self-administration under the second-order FI schedule. SKF 77434, which has moderate selectivity at D1 receptors and low agonist efficacy, did not maintain self-administration under either schedule. The results suggest that the ability of D1 agonists to maintain IV self-administration in squirrel monkeys depends both on the type of schedule and on the pharmacological properties (i.e. selectivity and efficacy) of the particular drug. These results are also consistent with the view that D1, in addition to D2, receptor mechanisms play a role in the self-administration of abused stimulants.