Agonist efficacy and the behavioral effects of dopamine D1 receptor ligands: drug interaction studies in squirrel monkeys

Dopamine agonists that reportedly differ in intrinsic activity at dopamine D1 receptors were compared for their behavioral effects in squirrel monkeys responding under a fixed-ration schedule of reinforcement. When administered alone, all drugs produced dose-related decreases in fixed-ratio response rates. Pretreatment with the dopamine D1 receptor blocker SCH 39166, but not the dopamine D2 receptor blocker eticlopride, produced rightward shifts in the dose-effect functions for the high-efficacy dopamine D1 agonists SKF 82958 (R,S-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine) SKF 81297 (R,S-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine ) and dihydrexidine, indicative of surmountable antagonism at dopamine D1 receptors. Pretreatment with SCH 39166, however, did not antagonize the effects of the low-efficacy dopamine D1 agonists SKF 75670 (R,S-7,8-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine ), SKF 77434 (R,S-7,8-dihydroxy-3-allyl-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) or R-SKF 38393 (R-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine); instead, dose-effect functions for each of these drugs were shifted downward and to the left. In additional experiments, pretreatment with SKF 75670 produced overall rightward shifts in the dose-effect functions for dihydrexidine and SKF 81297; pretreatment with R-SKF 38393 produced an overall rightward shift in the dose-effect function for dihydrexidine, but not SKF 81297; and pretreatment with SKF 81297 failed to produce a rightward shift in the dose-effect function for dihydrexidine. These findings provide further evidence that the behavioral effects of dopamine D1 agonists in monkeys are mediated primarily by their actions at dopamine D1 receptors. The differing susceptibility of dopamine D1 agonists to antagonism by SCH 39166 and their differing interactions provide functional evidence for differences in their dopamine D1 agonist efficacy.