AGONIST EFFICACY AND THE BEHAVIORAL-EFFECTS OF DOPAMINE D-1 RECEPTOR LIGANDS - DRUG-INTERACTION STUDIES IN SQUIRREL-MONKEYS

Dopamine agonists that reportedly differ in intrinsic activity at dopa mine D-1 receptors were compared for their behavioral effects in squir rel monkeys responding under a fixed-ratio schedule of reinforcement, When administered alone, all drugs produced dose-related decreases in fixed-ratio response rates, Pretreatment with the dopamine D-1 recepto r blocker SCH 39166, but not the dopamine D-2 receptor blocker eticlop ride, produced rightward shifts in the dose-effect functions for the h igh-efficacy dopamine D-1 agonists SKF 82958 7,8-dihydroxy-3-allyl-1-p henyl-2,3,4,5-tetrahydro- 1H-3-benzazepine) SKF 81297 (R,S-6-chloro-7, roxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and dihydrexidine, indicative of surmountable antagonism at dopamine D-1 receptors. Pret reatment with SCH 39166, however, did not antagonize the effects of th e low-efficacy dopamine D-1 agonists SKF 75670 hydroxy-3-methyl-1-phen yl-2,3,4,5-tetrahydro-1H-3- benzazepine), SKF 77434 -dihydroxy-3-allyl -phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) or R-SKF 38393 oxy-1-phe nyl-2,3,4,5-tetrahydro-1H-3-benzazepine); instead, dose-effect functio ns for each of these drugs were shifted downward and to the left, In a dditional experiments, pretreatment with SKF 75670 produced overall ri ghtward shifts in the dose-effect functions for dihydrexidine and SKF 81297; pretreatment with R-SKF 38393 produced an overall rightward shi ft in the dose-effect function for dihydrexidine, but not SKF 81297; a nd pretreatment with SKF 81297 failed to produce a rightward shift in the dose-effect function for dihydrexidine, These findings provide fur ther evidence that the behavioral effects of dopamine D-1 agonists in monkeys are mediated primarily by their actions at dopamine D-1 recept ors. The differing susceptibility of dopamine D-1 agonists to antagoni sm by SCH 39166 and their differing interactions provide functional ev idence for differences in their dopamine D-1 agonist efficacy.